1
Acknowledgements
This nine month lasting project is the result of the work, dedication and support of many people at the Inorganic Chemistry Institute at the Ruprecht-Karls-University of Heidelberg and at the Department of Chemistry at the University of Pisa.
First of all I would like to express my sincere gratitude to Prof. Dr. Lutz H. Gade and Prof. Dr. Fabio Marchetti, for their precious and generous dedication to all stages of my work. I am also thankful to Mrs. Beate Termin (NMR spectroscopy), Prof. Dr. Markus Enders (NMR spectroscopy instructor, kind host and advisor in my new experience in Germany), Mrs. Heidrun Haungs and Prof. Dr. Hubert Wadepohl (single crystal X-ray diffraction analysis). Still, my work would not have had the same productivity without the contribution of the Microanalysis Laboratory of the Faculty of Chemistry and Earth Sciences for elemental analysis and the University of Heidelberg Mass Spectrometry Facility for mass spectrometry. I am also grateful to Mrs. Marion Apermann for her support in the international bureaucratic procedures for my traineeship in Germany.
I would like to show my gratitude to Torsten Roth, highly inspirational with his energic and creative approach to our work together, and always able to give the right suggestions in critical stages of my work. Furthermore, I would like to express my sincere thanks to Alexander Kochan for his generous help and the countless practical tips and advices he gave me. I am also grateful to Jan Wenz, Marko Damjanovic, Vladislav Vasilenko, Tim Bleith and all coworkers in the Prof. Dr. Lutz H. Gade research group for their helpful attitude, and for the nice environment in our laboratories.
I would like to thank Elena for our new life together in Heidelberg, and for our precious music on Sundays. My family has been unique in supporting me during the whole cycle of my studies and so I am extremely grateful to my father Umberto, my mother Raffaella, my brother Alex and my grandfather Angelo. My friends Alessio, Riccarlo e Giangarlo from the group of Niffaldone have been the strongest supporters and companions in our long lasting hard work together in Pisa.
2
Abstract
The object of the present work has been a -alkoxy isocyanide-based Passerini-like multicomponent reaction promoted by Ti(OiPr)4 and leading to functionalized
morpholines. In the presence of a stoichiometric amount of Ti(OiPr)4 and a strong
base such as tBuLi, the reaction of a 2-oxazoline, an aromatic Grignard reagent and
an aromatic nitrile yields a functionalized morpholine as the main product after hydrolysis. The optimization of this multicomponent reaction, with the aim to increase the yield of the reaction itself and to develop a general procedure for the synthesis of differently functionalized morpholines, has been carried out. Moreover, a preliminary study of the reaction mechanism has been realized and a hypothetical key reaction intermediate has been proposed. Following the optimized standard procedure, additional reagents expected to react in a predictable way with the intermediate have been used, with the aim of trapping the supposed intermediate into products that fit the mechanistic hypothesis. Most of the reactions presented in the present work are expected to share the same intermediate type, and as a whole represent an interesting synthetic cluster of related multicomponent reactions.
3
Content
List of Abbreviations
... 5List of Figures
... 7List of Schemes
... 8List of Tables
... 101. Introduction
... 111.1. The Isocyanide Function
... 111.2. Coordination Chemistry of Isocyanides: a Brief Summary
... 141.2.1. Nucleophilic and Electrophilic Addition to Metal-Activated Isocyanides ... 16
1.2.2. Isocyanide Insertion into Metal-Carbon Bonds ... 19
1.3. A Ti-Mediated Passerini-Like Multicomponent Reaction:
Synthesis of Functionalized Morpholines
... 242. Results and Discussion
... 252.1. Optimization of the Reaction
... 252.2. Synthesis of Functionalized Morpholines
... 282.3. Mechanistic Study
... 333. Conclusions and Outlook
... 424. Experimental Section
... 434.1. Commercial Chemicals
... 434.2. General Remarks
... 444.3. Synthetic Procedures and Analytical Data
... 464.3.1. Synthesis of Morpholines ... 46
4.3.2. Synthesis of (S)-4-Phenyl-2-oxazoline ... 59
4.3.3. Synthesis of Amino Alcohols ... 60
4 4.3.5. Synthesis of a 2,2-Diaryl-1,3-oxazolidine ... 67
4.3.6. Synthesis of an Amino Diol ... 68
5
List of Abbreviations
(CN) isocyanide stretching frequency (CO) carbonyl stretching frequency
chemical shift Ar aromatic br broad bpy bipyridyl Cp cyclopentadienyl d doublet D°298 bond enthalpy at 298K FPh fluorophenyl
HOMO highest occupied molecular orbital
J coupling constant
L ligand
LDA lithium diisopropylamide
LUMO lowest unoccupied molecular orbital
IR infrared spectroscopy m multiplet M metal Me methyl MO molecular orbital MS mass spectroscopy
DART direct analysis in real time NMR nuclear magnetic resonance
Nu nucleophile
OiPr isopropoxide
Ph phenyl
6 ppm parts per million
q quartet quin quintet RT room temperature sept septet s singlet t triplet tBu tert-butyl Th thienyl THF tetrahydrofurane Xi xilyl
7
List of Figures
1.1 General electronic framework for the coordination of isocyanides to
transition metal centers ... 14
1.2 Molecular orbital diagrams for carbon monoxide and alkyl isocyanides .. 15
2.1 1H NMR spectrum of 1f ... 28
2.2 Single crystal X-ray diffraction structure of 1d ... 30
2.3 Single crystal X-ray diffraction structure of 1g ... 30
2.4 Single crystal X-ray diffraction structure of 1h ... 32
2.5 1H NMR spectra of 3 and 3-d 1 ... 34
2.6 Hypothetical reaction intermediate H0 ... 35
2.7 Kinetic study of the morpholine synthesis reaction ... 36
2.8 1H NMR spectrum of 4a ... 38
2.9 Single crystal X-ray diffraction structure of 4a ... 39
2.10 1H NMR spectrum of 5 ... 40
8
List of Schemes
1.1a Passerini reaction ... 12
1.1b A suitable ionic mechanism for Passerini reaction ... 12
1.2 Ugi reaction ... 13
1.3 Reaction of fac-[Mn(CNR)(CO)3(bpy)]+ with MeNH2 ... 17
1.4 Reaction of [CpFe(CO)(PNC)]+ with amines ... 17
1.5 Reaction of cis-[PdCl2(CNR)2] with amines ... 17
1.6 Reaction of [CpFe(CO)(PNC)]+ with alkoxides ... 17
1.7 Intramolecular cyclization of ReI-bound functionalized isocyanides ... 18
1.8 Formation of a rhenium monocarbonyl complex by CN cleavage at a isocyanide ligand ... 18
1.9 Bis-insertion and multiple insertion of isocyanides into M-X bonds ... 20
1.10 Resonance structures for M-2-iminoacyl systems ... 22
1.11 Isocyanide insertion into Ti-C bonds and related reactions ... 23
1.12 Double alkyl migration to a Ti-bound isocyanide carbon ... 23
1.13 Imine release from a 2-imine titanium complex by exchange with a suitable bidentate ligand ... 23
1.14 A Ti-mediated Passerini-like multicomponent reaction for the synthesis of functionalized morpholines ... 24
1.15 Ring opening reaction for C2-lithiated 4,4-dialkyl-2-oxazolines ... 24
2.1 A Ti-mediated Passerini-like multicomponent reaction for the synthesis of functionalized morpholines ... 25
2.2a Reaction protocol resulting in a 24% reaction yield ... 26
2.2b Reaction protocol resulting in a 30% reaction yield ... 26
2.2c Reaction protocol resulting in a 40% reaction yield ... 26
2.2d Reaction protocol resulting in a 45% reaction yield ... 26
2.3 General Procedure 1 (GP-1) for the synthesis of 1a-g ... 28
2.4 Procedure 1’ (P-1’) for the synthesis of 1h ... 31
2.5 Possible anomeric exchange reaction for 1h ... 32
2.6 Procedures P-3 and P-3’ for the synthesis of 3, 3-d1 ... 33
2.7 A six-membered alkoxy isocyanide-based metallacyclic ring (H0) as a feasible reaction intermediate ... 35
2.8 General Procedure 4 (GP-4) for the synthesis of 4a-d ... 37
2.9 Procedure 5 (P-5) for the synthesis of 5 ... 39
9 3 Summary of the explored Ti-mediated reactivity ... 42
4.1 General Procedure 1 (GP-1) for the synthesis of 1a-g ... 46
10
List of Tables
2.1 Synthesis of functionalized morpholines ... 29
11
1. Introduction
1.1. The Isocyanide Function
Isocyanides are unique in their flexibility as building blocks and in the enhanced convergence of their synthetic chemistry. They had been erroneously identified as nitriles until 1867, when Gautier1 and Hofmann2 first showed their real chemical
nature and proposed two feasible routes for their synthesis: the reaction of silver cyanide with alkyl iodides, and the reaction of aniline with chloroform in the presence of potassium hydroxide (also known as the “carbylamine reaction”). Very little improvement in the synthetic accessibility of isocyanides was made in the successive one hundred years, and consequently the wide-spreading potential of this functional group was ignored for a long time. In the 1960s a new way for the synthesis of isocyanides was proposed by Ugi3, who developed an effective route
to isocyanides based on the dehydration of the corresponding formamide. In the next decades the importance of isocyanides as building blocks received a substantial boost up, mainly due to their ability to react both as electrophiles and nucleophiles. Today isocyanides are generally used in oligo- and polymerizations, in the synthesis of highly functionalized heterocycles and in advanced multicomponent reactions. Many of these processes involve transition metal complexes as reagents or catalysts.
When the isocyanide group is located next to -CH bonds, strong organometallic bases are usually able to deprotonate and metallate the -carbon position. Schöllkopf and Gerhart4 first proposed the use of -metalated isocyanides for the
olefination of carbonyls in 1968. Since then the chemistry of -metalated isocyanides has given rise to many novel cocyclization reactions, aimed at the synthesis of functionalized nitrogen-containing heterocycles5. The cocyclization of
imines or ketones with -metalated isocyanides leads to 2-imidazolines or
1 A. Gautier, Ann. Chem. Pharm. 1868, 146, 119-124. 2 A. W. Hofmann, Ann. Chem. Pharm. 1867, 144, 114-120.
3 I. Ugi, U. Fetzer, U. Eholzer, H. Knupfer, K. Offermann, Angew. Chem. Int. Ed. Engl., 1965, 4, 472. 4 a) U. Schöllkopf, F. Gerhart, Angew. Chem. 1968, 80, 842-843; b) Angew. Chem. Int. Ed. Engl.
1968, 7, 805-806.
12 2-oxazolines6, respectively. Nitroalkenes can react with -metalated isocyanides
leading to 1,2-disubstituted pyrroles, in the so-called Barton-Zard pyrrole synthesis7.
The base-induced deprotonation of the ,-unsaturated isocyanides at the allylic position leads to allyl anions, capable of reacting with ,-unsatured aldehydes and analogous compounds giving indoles, benzimidazoles and benzoxazoles8. A Cu2
O-catalyzed cocyclization of different isocyanides leading to 1,4-disubstituted imidazoles was proposed by Yamamoto9, and a similar dimerization was observed
under Au(I) and Ag(I) catalysis10. Multicomponent reactions involving an isocyanide,
a carboxylic acid and an aldehyde (or a ketone) to give an -acyloxy amide (so-called Passerini reaction11) were proposed in the 1920s as the first of their kind
(Scheme 1.1a; a suitable ionic mechanism for the reaction is showed in Scheme 1.1b).
6 a) R. S. Bon, C. Hong, M. J. Bouma, R. F. Schmitz, F. J. J. de Kanter, M. Lutz, A. L. Spek, R. V. A.
Orru, Org. Lett. 2003, 5, 3759–3762; b) R. S. Bon, C. Hong, B. van Vliet, N. E. Sprenkels, R. F. Schmitz, F. J. J. de Kanter, C. V. Stevens, M. Swart, F. M. Bickelhaupt, M. Groen, R. V. A. Orru, J.
Org. Chem. 2005, 70, 3542–3553; c) R. S. Bon, C. Hong, M. J. Bouma, R. F. Schmitz, F. J. J. de Kanter, M. Lutz, A. L. Spek, R. V. A. Orru, Org. Lett. 2006, 5, 3759–3762; d) N. Elders, R. F. Schmitz, F. J. J. de Kanter, E. Ruijter, M. B. Groen, R. V. A. Orru, J. Org. Chem. 2007, 72, 6135–6142; e) R. S. Bon, F. J. J. de Kanter, M. Lutz, A. L. Spek, M. C. Jahnke, F. E. Hahn, M. B. Groen, R. V. A. Orru,
Organometallics 2007, 26, 3639–3650.
7 a) D. H. R. Barton, S. Z. Zard, J. Chem. Soc. Chem. Commun. 1985, 1098–1100; b) D. H. R. Barton,
J. Kervagoret, S. Z. Zard, Tetrahedron 1990, 46, 7587–7598; c) J. L. Sessler, A. Mozattari, M. Johnson, Org. Synth. 1992, 70, 68–77.
8 a) J. Moskal, R. van Stralen, D. Postma, A. M. van Leusen, Tetrahedron Lett. 1986, 27, 2173–2176;
b) J. Moskal, A. M. van Leusen, J. Org. Chem. 1986, 51, 4131–4139.
9 C. Kanazawa, S. Kamijo, Y. Yamamoto, J. Am. Chem. Soc. 2006, 128, 10662–10663.
10 a) O. V. Larionov, A. de Meijere, Angew. Chem. 2005, 117, 5809–5813; Angew. Chem. Int. Ed.
2005, 44, 5664–5667; b) A. V. Lygin, O. V. Larionov, V. S. Korotkov, A. de Meijere, Chem. Eur. J.
2009, 15, 227–236; c) R. Grigg, M. I. Lansdell, M. Thornton-Pett, Tetrahedron 1999, 55, 2025–2044.
11 M. Passerini, L. Simone, Gazz. Chim. Ital. 1921, 51, 126–29.
Scheme 1.1a Passerini reaction.
13
Scheme 1.2 Ugi reaction.
A development of the Passerini reaction, starting from the same reagents but in the presence of an amine and leading to a bis-amide, was proposed by Ugi12 in 1959
(Scheme 1.2).
Subsequently asymmetric versions of the Passerini and Ugi reactions were developed13.
12 I. Ugi, C. Steinbrückner, Angew. Chem. 1960, 72, 267–268.
14
Figure 1.1 General electronic framework for the coordination of isocyanides to transition metal centers.
1.2. Coordination Chemistry of Isocyanides: a Brief
Summary
In 1915 L. A. Chugaev described a Pt(II)-mediated carbene synthesis via the addition of hydrazine to the isocyanide ligand14, first carrying out a relevant
isocyanide reaction involving transition metal centers. However the carbene ligand was not identified as such. A real boost in the coordination chemistry of isocyanides took place only in the last decades of the 20th century, mainly driven by the increased interest in the development of transition metal-based catalysts. The isocyanide group is isoelectronic with carbon monoxide and exhibits similar properties in its binding to transition metal centers (Figure 1.1).
The bonding between the metal and the ligand can be envisioned as the combination of two contributions: a -bond arises from the isocyanide *-HOMO-MO lone pair donation to the metal, and a -bond involves the back-donation of electron density from a metal d-orbital to the isocyanide *-LUMO-MO. The magnitude of the two contributions depends on many parameters, but it is mainly dependent on the electron density at the metal center: low valent electron rich metals accept weak -donation from the ligand, and offer strong -back donation to the RNC system; high valent electron deficient metal centers receive a strong -contribution from the isocyanide whereas the -back donation to the ligand is weak. The -back donation is responsible for an increase in electron density in the
15 isocyanide *-antibonding orbital: the stronger the back donation, the weaker the C-N bonding. Infrared spectroscopy allows for an easy characterization of this feature, as the C-N bond stretching vibrational band shifts to lower frequencies for metal isocyanide complexes in low oxidation states, and to higher frequencies for high valent species. Many homoleptic isocyanides of group 4 to 11 transition metal carbonyls are known today. In spite of the strong similarity between the two functions, the isocyanide group is more reactive towards nucleophiles and electrophiles, and it is able to bond to higher valent and electropositive metal centers. Compared to carbon monoxide, the isocyanide function acts a stronger -donor and a weaker -acceptor in its complexes, which is consistent with the higher energy of both its 5’- and 2’-MOs (Figure 1.2).
The wide-ranging isocyanide-based synthetic chemistry currently includes a large number of nucleophilic and electrophilic additions to metal-activated isocyanides, together with countless isocyanide insertion reactions into metal-ligand bonds15.
15
V. P. Boyarskiy, N. A. Bokach, K. V. Luzyanin, V. Yu. Kukushkin, Chem. Rev. 2015, 115, 2698– 2779.
16
1.2.1. Nucleophilic and Electrophilic Addition to Metal-Activated
Isocyanides
Isocyanides become generally activated towards nucleophilic addition at the RNC carbon upon coordination at a suitable transition metal center. This phenomenon is comparable to the metal-mediated carbon monoxide activation, although some distinctions have been reported15. For example the reaction of mixed ligand
carbonyl/isocyanide transition metal complexes with nucleophiles shows a general selectivity for nucleophilic addition at the isocyanide ligand, giving the corresponding aminocarbene species still bound to the metal16. The carbonyl ligand is generally
not reacting in any significant extent, as the resulting expected carbamoyl ligand is not detected17. The observed chemoselectivity can be rationalized taking account
of the higher stability of the appropriate aminocarbene derivative in comparison with the carbamoyl product and the assumption that the relevant transition state is product-like17.
The carbon monoxide and isocyanide triple bond IR stretching frequency is indicative of the extent of bond activation. The threshold value of the susceptibility to nucleophilic attack was found to be (CN) = (CN)coordinated – (CN)free > 40cm-1
for the isocyanide ligand; (CO) frequencies above 2000 cm−1 were similarly
assumed to be highly indicative for the carbon monoxide activation18, 17. Many
chemoselective nucleophilic additions involving nitrogen donors have been reported15, 17, 19, 20, involving mainly mid-to-late transition metals (Schemes 1.3,
1.4, 1.5).
16 J. Ruiz, B. F. Perandones, Organometallics 2009, 28, 830.
17 J. Ruiz, L. García, C. Mejuto, B. F. Perandones, M. Vivanco, Organometallics 2012, 31, 6420. 18 R. A. Michelin, A. J. L. Pombeiro, M. F. C. Guedes da Silva, Coord. Chem. Rev. 2001, 218, 75. 19 I. Yu, C. J. Wallis, B. O. Patrick, P. L. Diaconescu, P. Mehrkhodavandi, Organometallics 2010,
29, 6065.
17
Scheme 1.4 Reaction of [CpFe(CO)(PNC)]+ with amines19.
Scheme 1.5 Reaction of cis-[PdCl2(CNR)2] with amines20.
Scheme 1.6 Reaction of [CpFe(CO)(PNC)]+ with alkoxides19.
Oxygen nucleophiles are effective as well, and several transition metal-mediated nucleophilic additions were described such as the example represented in Scheme 1.6 15, 19.
18
Scheme 1.7 Intramolecular cyclization of ReI-bound functionalized isocyanides21.
Scheme 1.8 Formation of a rhenium monocarbonyl complex by CN cleavage at a isocyanide ligand23.
The nucleophilic attack can occur in an intramolecular fashion if the isocyanide ligand brings the nucleophile as its functionalization. This kind of reaction leads to heterocylic products through an intramolecular cyclization step (Scheme 1.7)21.
Furthermore the isocyanide group can be activated toward electrophilic attack upon coordination at the appropriate metal center15, 22. The -electrophilic addition occurs
at the N atom of the RNC ligand and yields the corresponding aminocarbyne species still coordinated to the metal15, 22. A very strong -back donation from the metal
center to the isocyanide ligand is generally responsible for this kind of activation, that is indeed observed at low-valent electron-rich metal centers of the Groups 6, 715, 22. The conversion of rhenium isocyanide complexes into carbonyl complexes
by a prolonged acidic hydrolytic treatment was reported23. The authors proposed,
as a feasible mechanistic pathway for this reaction, the multiple electrophilic attack of H+ to the isocyanide nitrogen, followed by nucleophilic attack of H2O to the
isocyanide carbon and by the subsequent H+ release23 (Scheme 1.8).
21 F. E. Hahn, M. C. Jahnke, Angew. Chem. Int. Ed. 2008, 47, 3122–3172.
22 A. J. L. Pombeiro, M. F. C. Guedes da Silva, R. A. Michelin, Coord. Chem. Rev. 2001, 218, 43. 23 H. Spies, M. Glaser, H. J. Pietzsch, F. E. Hahn, T. Lügger, Inorg. Chim. Acta 1995, 240, 465.
19
1.2.2. Isocyanide Insertion into Metal-Carbon Bonds
Isocyanides are widely known to undergo migratory insertion into M-H, M-N, M-O and M-C bonds15. The insertion into the M-C bond is the most common and easy to
carry out for early-to-mid transition metals. It was suggested that, among all of the available bonds in the complex, the insertion usually occurs at the weakest: for early-to-mid transition metals the M-C bond is usually weaker than many other M-element bonds, therefore the observed chemoselectivity seems to be thermodynamically controlled24, 25, 26. Thus, for example, mixed ligand alkyl/amide
titanium complexes react with isocyanides initially at the Ti-C bonds and only subsequently at the Ti-N bonds (D°298(Ti-C) = 423 kJ/mol; D°298(Ti-N) = 476
kJ/mol)26. On the other hand, for the less oxophilic late transition metals a
completely different reactivity was reported: in mixed ligand alkyl/alkoxy platinum complexes the insertion usually takes place at the M-O bond rather than at the M-C bond (D°298(Pt-O) = 392 kJ/mol; D°298(Pt-C) = 598 kJ/mol)27, although several
exceptions from this general trend have been observed15.
A gain in the bulkiness of the isocyanide ligand usually slows down the insertion, eventually leading to its total inhibition15. The insertion seems to be effective only for
M-(primary alkyl) bonds, even though insertions into M-(secondary alkyl) bonds have been reported15. The latter case has been observed mainly for transition metal
complexes of the second and third transition series.
Isocyanides and carbon monoxide show a similar behavior towards the insertion reaction into M-C bonds; these reactions yield metal-iminoacyl and metal-acyl complexes, respectively, through a rapid C-C coupling process15. Experimental
evidence suggests a different insertion mechanism for isocyanides and carbon monoxide into the M-C bond for early and late transition metal complexes: the isocyanide insertion can be envisioned as the true insertion of the isocyanide carbon atom into a M-C bond, whereas the CO insertion is better depicted as an anionic ligand migration towards the carbon monoxide C atom (“migratory insertion)15. The
24 A. M. Martins, J. R. Ascenso, C. G. de Azevedo, A. R. Dias, M. T. Duarte, J. F. da Silva, L. F.
Veiros, S. S. Rodrigues, Organometallics 2003, 22, 4218.
25 J. Cano, M. Sudupe, P. J. Royo, J. Organomet. Chem. 2007, 692, 4448.
26 D. R. Lide, CRC Handbook of Chemistry and Physics, 81st ed., CRC Press, 2000. 27 J. Wu, P. R. Sharp, Organometallics 2008, 27, 4810.
20
Scheme 1.9 Bis-insertion and multiple insertion of isocyanides into M-X bonds.
coordinated iminoacyl system is usually more stable than its acyl counterpart with respect to de-insertion15, 28. Thus LnM-C(R’)NR species are generally easier to be
isolated and characterized than LnM-C(R’)O compounds. Several complexes
containing two iminoacyl functions at the same metal center have been characterized as products of “bis-insertion” reactions. At early transition metal centers the two iminoacyl ligands easily undergo intramolecular coupling to produce ene-diolate, enamidolate or ene-diamide ligands15, 28. Furthermore “multiple
insertion” reactions of two or more isocyanides can give rise to oligomers and polymers M-(CNR)n-C15. On the other hand the acyl ligand chemistry does not
include analogous bis-insertion or multiple insertion reactions (Scheme 1.9)15.
The metal-iminoacyl or metal-acyl systems resulting from the insertion can be usually described by a 1-binding model for late electron-rich metal centers15. The
hapticity of these ligands increases towards a 2-binding fashion15, 29 for high valent
early transition metal complexes: for these systems a relatively strong metal-nitrogen or metal-oxygen bond is generally observed15. The coordination of the
ligand through both the carbon and the heteroatom leads to a characteristic modulation of the acyl or iminoacyl reactivity. This can be attributed to an oxy-carbenoid character for the 2-acyl group, and to the corresponding amido-carbene
character for the 2-iminoacyl group30. The characteristic reactivity of the 2-bound
acyl group was related to the low-lying *-LUMO of the R-CO system, lowered in
28 M. G. Thorn, P. E. Fanwick, I. P. Rothwell, Organometallics 1999, 18, 4442-4447. 29 L. R. Chamberlain, J. C. Huffman, J. Am. Chem. Soc. 1987, 109, 390-402. 30 L. D. Durfee, I. P. Rothwell, Organometallics 1990, 9, 75-80.
21 energy by symmetry-matching empty d-orbitals on the metal31.
Group 10 transition metal complexes are most versatile as far as the isocyanide insertion reaction into M-C bonds is concerned. Palladium complexes are known to mediate single and multiple isocyanide insertions, carbon/nitrogen coupling reactions of coordinated 2-iminoacyl species as well as isocyanide insertions into
M-allyl systems15. Furthermore, group 10 transition metal complexes were reported
to promote catalytic isocyanide insertions and related reactions15, 32.
Nickel-catalyzed living arylisocyanide polymerization and multiple isocyanide insertion were recently reported33, and chiral arylisocyanides have been employed for the
catalytic synthesis of predominantly one-handed helical poly-isocyanides, with narrow polydispersity33. The use of isocyanides and palladium catalysts for the
synthesis of 4-aminoquinolines34 and 2-arylindoles35, and for the carbonylative
Sonogashira coupling of aryl bromides36 was also reported.
Many notable isocyanide insertion reactions have been reported for Group 6, 5, 4 transition metal alkyl/isocyanide complexes15. Many high valent Group 4 transition
metal complexes effectively support the isocyanide insertion into M-C bonds, and stabilize the insertion product in their coordination sphere in a 2-bonding fashion.
In particular, d0 and d1 titanium complexes were reported to quantitatively undergo
this kind of transformation15, 37.
Structural data for zirconocene 2-iminoacyl derivatives show short C-N distances
(compatible with a “slightly elonged” double bond model) as well as short Zr-N distances (shorter than the Zr-N distance for a pyridyl ligand, but too long for an amido ligand model) and Zr-C distances which were found to be slightly shorter than for alkyl ligands29. Furthermore, zirconium(IV) aryloxide derivatives show Zr-C
distances which are longer than for zirconocene derivatives29. The ancillary ligands
play an important role in the electron density rearrangement within the
31 R. Chamberlain, R. Wang, J. Am. Chem. Soc. 1987, 109, 390-402.
32 A. F. G. Ribeiro, P. T. Gomes, A. R. Dias, J. L. Ferreira da Silva, M. T. Duarte, R. T. Henriques,
C. Freire, Polyhedron 2004, 23, 2715.
33 S. Asaoka, A. Joza, S. Minagawa, L. Song, Y. Suzuki, T. Iyoda, ACS Macro Lett. 2013, 2, 906. 34 Z. Y. Gu, T. H. Zhu, J. J. Cao, X. P. Xu, S. Y. Wang, S. J. Ji, ACS Catal. 2014, 4, 49.
35 T. Nanjo, S. Yamamoto, C. Tsukano, T. Takemoto, Org. Lett. 2013, 15, 3754.
36 T. Tang, X. D. Fei, Z. Y. Ge, Z. Chen, Y. M. Zhu, S. J. Ji, J. Org. Chem. 2013, 78, 3170. 37 E. F. Trunkely, A. Epshteyn, P. Y. Zavalij, L. R. Sita, Organometallics 2010, 29, 6587.
22 M-2-iminoacyl system. For more electron rich systems the M-2-iminoacyl fragment
becomes more similar to an amido-carbene metallaaziridine-like cycle: the order of all of the three bonds involved approaches those of single bonds30. This
azametallacycle model was found to be appropriate for the aryloxide titanium derivative Ti(OAr-2,6-iPr2)2(2-tBuNCCH2Ph)(CH2Ph), in which the carbon and the
nitrogen atoms are bound to the metal mimicking alkyl- and dialkylamido-ligands, respectively30. In conclusion, depending on the electron density at the metal center,
the real nature of the organic framework in the M-2-iminoacyl system lies between
an imine and an amido-carbene structures (Scheme 1.10)29.
The insertion of isocyanide ligands into Ti-C bonds leading to Ti-2-iminoacyl
systems was reported to be much faster than the preceding isocyanide coordination to the Ti(IV) center: therefore the rate determining step for the reaction is usually the coordination of the RNC ligand to the electron-deficient metal fragment38. The
dimethyl Ti(IV) compound [Ti(OAr)2Me2] can react with 2 equivalents of XyNC giving
a bis2-iminoacyl) compound, that slowly and spontaneously undergoes
intramolecular coupling of the two 2-iminoacyl ligands, yielding the corresponding
enediamide ligand28 (Scheme 1.11). A second alkyl migration to the 2-iminoacyl
group gives a 2-imine complex, and is competitive with the second isocyanide
insertion28 (Scheme 1.11). The 2-imine complex is susceptible of alkyne and alkene
insertion, yielding the corresponding 5-membered metallacyclic product28
(Scheme 1.11).
38 F. De Angelis, S. Fantacci, A. Sgamellotti, Theor. Chem. Acc. 2003, 110, 196.
23
Scheme 1.11 Isocyanide insertion into Ti-C bonds and related reactions.
For alkyl groups different from methyl, the second alkyl migration to the mono-inserted system seems to require further coordination of an incoming ligand, for example pyridine30 (Scheme 1.12).
Finally, the 2-imine complex can actually release a free imine via the exchange with
a suitable bidentate incoming ligand30 (Scheme 1.13).
Scheme 1.12 Double alkyl migration to a Ti-bound isocyanide carbon.
Scheme 1.13 Imine release from a 2-imine titanium complex by exchange
24
Scheme 1.14A Ti-mediated Passerini-like multicomponent reaction for the synthesis
of functionalized morpholines.
1.3. A Ti-Mediated Passerini-Like Multicomponent
Reaction: Synthesis of Functionalized Morpholines
It has been observed in a preliminar previous study that in the presence of a stoichiometric amount of Ti(OiPr)4 and a strong base such as tBuLi, the reaction of
a 2-oxazoline, an aromatic Grignard reagent and an aromatic nitrile yields after hydrolysis a functionalized morpholine as the main product (Scheme 1.14). In the present work we will present a first study of this Passerini-like multicomponent reaction mediated by a titanium complex.
Oxazolines, oxazoles and related compounds are known to react with strong organometallic bases leading to deprotonation at the C2 position39. The resulting C2
-metalated species undergo ring-opening reactions giving the corresponding -alkoxy isocyanides (Scheme 1.15)39.
The isocyanide group is then supposed to be the key functionality in the present Ti-mediated Passerini-like multicomponent reaction. The whole process can be viewed as a ring-expansion reaction, that leads to a functionalized six-membered morpholine ring starting from a five-membered oxazoline ring.
39 S. E. Whitney, B. Rickborn, J. Org. Chem. 1991, 56, 3058-3063.
25
Scheme 2.1A Ti-mediated Passerini-like multicomponent reaction for the synthesis of
functionalized morpholines.
2. Results and Discussion
In the present work the optimization of the Ti-mediated Passerini-like multicomponent reaction presented in Section 1.3 will be discussed together with a preliminary study of the reaction mechanism. A general procedure for the synthesis of differently functionalized morpholines will be presented.
2.1. Optimization of the Reaction
In a first stage of our work, the optimization of the present Passerini-like multicomponent reaction procedure was carried out. The reaction is conceived as a one-pot process: all of the reagents were consecutively added in the same reaction flask under argon atmosphere. With the aim of maximizing the reaction yield several parameters in the synthetic procedure have been varied (temperature, order of addition of the reagents, time interval between the addition of consecutive reagents, stoichiometric coefficients for the reaction equation). In this process benzonitrile and 4-fluorophenylmagnesium bromide were used as aromatic nitrile and aromatic Grignard reagent, respectively. In all reactions 4,4-dimethyl-2-oxazoline was used as the starting oxazoline. Four selected examples of the variation of the reaction protocol are given below with their reaction conversions to the desired product (Schemes 2.2a, 2.2b. 2.2c, 2.2d).
26
Scheme 2.2a Reaction protocol resulting in a 24% reaction yield.
Scheme 2.2b Reaction protocol resulting in a 30% reaction yield.
Scheme 2.2c Reaction protocol resulting in a 40% reaction yield.
27 All procedures start from the same deprotonation / ring-opening step at the oxazoline substrate (addition of tBuLi at −78°C). The key for the optimization of the
reaction procedure has been found in keeping the reaction mixture cooled (Schemes 2.2c, 2.2d) during the addition of all of the reagents, along with the addition of the metal complex at an early stage and the use of an excess of the Grignard reagent (Schemes 2.2b, 2.2c, 2.2d).
28
Scheme 2.3 General Procedure 1 (GP-1) for the synthesis of 1a-g.
Figure 2.1 1H NMR spectrum of 1f. The integral area of the peaks (referred to the number of the
corresponding protons) has been reported.
1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 ppm 3 .0 5 3 .0 4 1 .0 2 1 .0 1 2 .0 3 2 .0 4 9 .0 5
2.2. Synthesis of Functionalized Morpholines
Following the principles stated in the previous section (Schemes 2.2a, 2.2b. 2.2c, 2.2d), a general optimized procedure (General Procedure 1, GP-1, Scheme 2.3) was developed for the synthesis of morpholines with different functionalizations. According to the GP-1 procedure, seven different morpholines (compounds 1a-g) were synthesized starting from 4,4-dimethyl-2-oxazoline and using different aromatic nitriles and aromatic Grignard reagents, with yields resulting in between 35% and 55% (Table 2.1).
Ar = 4-Fluorophenyl, 3-Fluorophenyl
29 (1a) (1b) (1c) (1d) (1e) (1f) (1g) Table 2.1 Synthesis of functionalized morpholines.
Nitrile Grignard Morpholine Conversion Yield
58% 55% 55% 48% 53% 48% 51% 35% 46% 40% 38% 32% 51% 43%
30
Figure 2.2 Molecular structure of 1d. Hydrogen atoms (except for the hydrogens of the amine groups) have been omitted for clarity.
Figure 2.3 Molecular structure of 1g. Hydrogen atoms (except for the hydrogens of the amine groups) have been omitted for clarity.
Crystals of 1d and 1g suitable for single crystal X-ray diffraction analysis were obtained (Figures 2.2, 2.3).
The use of 2-methoxyphenylmagnesium bromide, 2-thienylmagnesium bromide and phenyllithium as organometallic reagents within the GP-1 procedure did not lead to the isolation of morpholines. On the other hand, the GP-1 procedure showed a good tolerance towards different aromatic nitrile reagents (Table 2.1).
31
Scheme 2.4 Procedure 1’ (P-1’) for the synthesis of 1h.
A slightly different procedure (P-1’, Scheme 2.4) was developed for a chiral morpholine synthesis (product 1h) starting from (S)-4-phenyl-2-oxazoline. The presence of a relatively acidic -proton at the oxazoline C4 represents a sensitive
element under the conditions of this multicomponent synthesis, as strong bases such as tBuLi are known to be able to deprotonate oxazolines40 and oxazoles41 even
at the C4 position. Furthermore an additional gain in the acidity of the -proton could
be expected as a consequence of its benzylic nature. According to the P-1’ procedure, LDA was then used instead of tBuLi for the starting material and just a
stoichiometric amount (instead of an excess) of the Grignard reagent was used. Despite systematic variation of the reaction conditions, yields not greater than 20% were achievable for this transformation.
The new stereocenter generated in the product 1h lies on an anomeric carbon, and this could lead to a loss of steric information about any original reaction stereoselectivity: an eventually established anomeric exchange equilibrium could lead to a thermodynamic mixture of the two possible diastereoisomers (Scheme 2.5). Only the (2R, 5S) diastereoisomer was isolated as reaction product, but as a consequence of the plausible anomeric exchange it is not possible to say whether the stereoselectivity is also kinetically controlled or not (the only observed diastereoisomer is actually the most thermodynamically stable one).
40 U. Schollkopf et al., Liebigs Ann. Chem. 1976, 183-202.
32
Figure 2.4 Molecular structure of 1h. Hydrogen atoms (except for the hydrogens of the amine groups and of the chiral C3 carbon) have been omitted for clarity.
33
Scheme 2.6 Procedures P-3 (quenching with water, giving 3) and P-3’ (quenching with deuterium oxide, giving 3-d1).
2.3. Mechanistic Study
In a first attempt to shed some light onto the reaction mechanism, modified versions of the basic morpholine synthesis were studied in which one or more of the reagents was missing. Remarkable results came from a reaction procedure in the absence of nitrile, but otherwise fully analogous to the general procedure GP-1: the amino alcohol 3 was isolated with a reaction yield of 60% (P-3, Scheme 2.6). The same procedure was carried out adding deuterium oxide instead of water in the last reaction stage, and the corresponding deuterated amino alcohol 3-d1 was isolated
34
Figure 2.5 1H NMR spectra of 3 and 3-d
1. The integral area of the peaks (referred to the number
of the corresponding protons) has been reported.
1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 ppm 6 .0 2 2 .0 1 1 .0 0 4 .0 0 4 .0 0 (3-d1) (3) >95% deuteration
35
Scheme 2.7 A six-membered alkoxy isocyanide-based
metallacyclic ring (H0) as a feasible reaction intermediate.
Figure 2.6 Hypothetical reaction intermediate H0.
Given the starting deprotonation / ring opening oxazoline reaction39, the ability of
-alkoxy isocyanides to bind to transition metal centers42, and the ease of the
isocyanide insertion into Ti-C bonds43, a first mechanistic hypothesis was
developed. The six-membered alkoxy isocyanide-based metallacyclic ring H0 was proposed as a key reaction intermediate (Scheme 2.7, Figure 2.6).
According to our hypothesis, the amino alcohol 3 derives from the supposed reaction intermediate H0 as its direct hydrolysis product (Scheme 2.7). A kinetic study of the morpholine synthesis reaction was then carried out (Figure 2.7), and the reaction conversion in terms of the morpholine 1f and of the amino alcohol 3 were determined spectroscopically (19F{1H} NMR). The measurements were carried
out on small fractions of the main reaction mixture, treated with an excess of water
42 a) W. P. Fehlhammer, K. Bartel, B. Weinberger, U. Plaia, Chem. Ber 1985, 118, 2220-2234; b)
W. P. Fehlhammer, K. Bartel, U. Plaia, A. Völkl und A. T. Liu, Chem. Ber 1985, 118, 2235-2254.
43 a) M. G. Thorn, P. E. Fanwick, I. P. Rothwell, Organometallics 1999, 18, 4442-4447; b) J. Wu, P.
R. Sharp, Organometallics 2008, 27, 4810; c) F. De Angelis, S. Fantacci, A. Sgamellotti, Theor.
36
*
Figure 2.7 Kinetic study of the morpholine synthesis reaction.
to hydrolyze the expected intermediate H0 or complete the morpholine formation (Scheme 2.7).
The zero point on the time axis corresponds to the time of addition of the Grignard reagent to the reaction mixture, and therefore all provided reagents are present from this stage on. It is remarkable that only the amino alcohol 3 is isolated after hydrolysis of the reaction mixture as long as the system is cooled to −78°C; moreover, after warming to room temperature (t = 30min) the morpholine 1f appears in the reaction mixture, and its concentration rapidly increases while the concentration of the amino alcohol 3 decreases at the same rate. According to the proposed model, the migration of two 4-fluorophenyl residues to the original C2
oxazoline carbon seems to be facile even at low temperature, as the amino alcohol
3 is rapidly yielded at −78°C; on the other hand, the formation of the morpholine 1f
is observable only at higher temperature, and this reaction seems to correlate with
37
Scheme 2.8 General Procedure 4 (GP-4) for the synthesis of 4a-d.
the formation of the amino alcohol 3. These results are compatible with the hypothesis of a H0-type intermediate.
With the aim to provide further evidence for the hypothetical intermediate H0, several modified versions of the P-3 procedure were designed: additional reagents expected to react in a predictable way with intermediate H0 and leading to products that would fit the hypothesis were used. All experiments share a common root scheme, starting from an oxazoline deprotonation / ring opening stage followed by the addition of Ti(OiPr)4 and of an aromatic Grignard reagent. Following the general procedure
GP-4 (Scheme 2.8), allylic alkoxides were added as trapping reagents to the
reaction mixture, with the aim of obtaining homoallylic amines44 as final products.
The synthesis of three different homoallylic amines (Table 2.2, compounds 4a-d) with yields between 39% and 65% was carried out.
44 D. Yang, G. C. Micalizio, J. Am. Chem. Soc 2009, 131, 17548–17549.
Ar = 4-Fluorophenyl, p-Tolyl R1, R2 = H, Methyl, Pentyl
38
(4a)
(4b)
(4c, d)
Figure 2.8 1H NMR spectrum of 4a. The integral area of the peaks (referred to the number of
the corresponding protons) has been reported.
1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 ppm 6 .0 1 3 .0 1 3 .0 3 2 .0 0 2 .0 3 1 .0 0 4 .0 2 4 .0 0
Table 2.2 Synthesis of homo-allylic amines.
Allylic
Alkoxide Grignard Homoallylic Amine Yield
39%
57%
65%
(cis-trans mixture)
39
Figure 2.9 Molecular structure of 4a. Hydrogen atoms (except for the hydrogens of the amine and the hydroxyl groups) have been omitted for clarity.
Scheme 2.9 Procedure 5 (P-5) for the synthesis of 5.
Following the Procedure 5 (P-5, Scheme 2.9), Br2 was added as a trapping reagent
to the reaction mixture, looking for a possible bromolytic cleavage of the M-C bond45
within the metallacyclic intermediate H0. The expected 2,2-diaryl-2-oxazolidine (compound 5) was isolated in 30% yield.
45 a) G. M. Whitesides, D. J. Boschetto, J. Amer. Chem. Soc. 1971, 93, 1529; b) R. G. Pearson and
40
Figure 2.10 1H NMR spectrum of 5. The integral area of the peaks (referred to the number of
the corresponding protons) has been reported.
Figure 2.11 Molecular structure of 5. Hydrogen atoms (except for the hydrogen of the amine group) have been omitted for clarity.
1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 ppm 6 .0 0 2 .0 1 4 .0 6 4 .0 0
41
Scheme 2.10 Procedure 6 (P-6) for the synthesis of 6.
Finally, following the Procedure 6 (P-6, Scheme 2.10), 4-chlorobenzaldehyde was added as trapping reagent to the reaction mixture. This Passerini-like multicomponent reaction is highly comparable to the morpholine synthesis previously described (GP-1), except that an aromatic aldehyde being added instead of an aromatic nitrile. The expected amino diole (compound 6) was isolated in 55% yield.
42
Scheme 3 Summary of the explored Ti-mediated reactivity.
3. Conclusions and Outlook
As part of a study into a Ti-mediated Passerini-like multicomponent reaction for the synthesis of functionalized morpholines, the optimization of the reaction procedure has been carried out (Section 2.1). Morpholines with different functionalities were synthesized following a general optimized procedure (Section 2.2). A key reaction intermediate has been proposed (Section 2.3) for which further confirmation was sought by way of a series of trapping reactions chosen to give rise to predictable structures. A first kinetic study has been carried out, which provides indirect support for the reaction intermediate hypothesis (Section 2.3). A summary of the products obtained in the present work is reported in Scheme 3.
A more detailed study of the hypothetical reaction intermediate, together with a deeper kinetic characterization of the explored reactivity and with the optimization of the reactions for a larger variety of synthetic building blocks could lead to a further development of our knowledge about this interesting cluster of reactions.
43
4. Experimental Section
Unless otherwise stated, all reactions were carried out in oven-dried flasks (150°C) under dry inert gas atmosphere, according to Schlenk standard techniques. As inert gas Argon 5.0 purchased from Messer Group GmbH was used after drying over Granusic© phosphorus pentoxide granulate. All chemicals were purchased from commercial suppliers (Sigma Aldrich®, ACROS ORGANICS, abcr GmbH).
4.1. Commercial Chemicals
C5H9NO (4,4-dimethyl-2-oxazoline): colorless liquid, MW = 99.13 g/mol,
d = 0.94 g/mL.
C7H5N (Benzonitrile): colorless liquid, MW = 103.04 g/mol, d = 1.0 g/mL.
C7H4FN (4-Fluorobenzonitrile): white solid, MW = 121.11 g/mol.
C8H7NO (4-Methoxybenzonitrile): white solid, MW = 133.15 g/mol.
C13H9N (4-Phenylbenzonitrile): white solid, MW = 179.22 g/mol.
C5H3NS (2-Thiophenecarbonitrile): clear yellow brown liquid, MW = 109.15 g/mol,
d = 1.172 g/mL.
C12H28O4Ti (Titanium(IV) isopropoxide): clear brown liquid, MW = 284.22 g/mol,
d = 0.96 g/mL.
C4H9Li (tert-Butyllithium): pentane solution, 1.9 M.
C6H4BrFMg (3-Fluorophenylmagnesium bromide): THF solution, 1.0 M.
C6H4BrFMg (4-Fluorophenylmagnesium bromide): THF solution, 1.0 M.
C7H7BrMg (p-Tolylmagnesium bromide): THF solution, 1.0 M.
C8H11NO ((S)-(+)-2-Phenylglycinol): white solid, MW = 137.18 g/mol.
C7H16O3 (Triethyl orthoformate): colorless liquid, MW = 148.20 g/mol,
d = 0.891 g/mL.
C2HF3O2 (Trifluoroacetic acid): colorless liquid, MW = 114.02 g/mol, d = 1.489 g/mL.
C5H10O (2-Methyl-3-buten-2-ol): colorless liquid, MW = 86.13 g/mol, d = 0.824 g/mL.
C8H16O (1-Octen-3-ol): colorless liquid, MW = 128.22 g/mol, d = 0.83 g/mL.
C2H4Cl2 (Dichloroethane): colorless liquid, MW = 98.96 g/mol, d = 1.256 g/mL.
D2O (Deuterium oxide): colorless liquid, MW = 20.03 g/mol, d = 1.107 g/mL.
Br2 (Bromine): red liquid, MW = 159.81 g/mol, d = 3.119 g/mL.
44
Solvents: THF, diethyl ether, toluene and hexane were dried over activated alumina
columns using a M. Braun SPS 800 solvent purification system, and stored under argon atmosphere in glass ampules. Column chromatography solvents (pentane, ethyl acetate, dichloromethane, methanol) were used without any preliminar treatment.
4.2. General remarks
All novel compounds were characterized by multinuclear magnetic resonance spectroscopy (NMR), high resolution mass spectroscopy (HR-MS), and in selected cases elemental analysis and single-crystal X-ray diffraction. Reaction conversions for fluorinated compounds were estimated by 19F{1H} NMR measurement, on the
crude product added of 1,4-bis(trifluoromethyl)benzene as an internal standard.
1H-NMR spectroscopy: NMR spectra were recorded in deuterated chloroform-d1
at room temperature on a Bruker Avance II (400MHz) or a Bruker Avance III (600MHz) spectrometer. Chemical shifts are reported in parts per million (ppm) and referenced internally to the choloroform-d1 residual proton signal ( = 7,26 ppm).
NMR resonances are reported as chemical shift, multiplicity, coupling constant J and integration. The multiplicity is reported by the labels s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), sept (septet), m (multiplet), br (broad signal). In addition, signals are assigned to their respective protons, or labelled as HFPh (fluorophenyl
proton), HPh (non-fluorinated-phenyl proton), HTh (thienyl proton), HAr (aromatic
proton).
13C-NMR spectroscopy: NMR spectra were recorded as described for 1H-NMR
spectra. Chemical shifts are reported in parts per million (ppm) and referenced internally to the choloroform-d1 carbon ( = 77,16 ppm). NMR resonances are
reported as chemical shift, multiplicity, coupling constant J. The multiplicity is reported by the labels s (singlet), d (doublet) t (triplet). In addition, signals are assigned to their respective carbons, or labelled as CFPh (fluorophenyl carbon), CPh
45
19F-NMR Spectroscopy: NMR spectra were recorded in deuterated chloroform-d1
or non deuterated solvents at room temperature on a Bruker Avance II (400MHz). Chemical shifts are reported in parts per million (ppm) and referenced to an external standard (CFCl3).
All spectra were processed by Bruker NMR software TopSpin 3.0.
Mass Spectrometry: mass spectra and high-resolution mass spectra were
measured by the University of Heidelberg Mass Spectrometry Facility. High- resolution mass spectra were acquired on Brucker ApexQe Hybrid 9.4 T FT-ICR and JEOL JMS-700 magnetic sector (EI, LIFDI) spectrometers.
Elemental Analysis: measurements were performed at the Heidelberg University
Microanalysis Laboratory of the Faculty of Chemistry and Earth Sciences, with an Elementar vario MICRO cube machine.
Single Crystal X-Ray Diffraction: measurements were performed on a Bruker AXS
Smart 1000 or an Agilent SuperNova diffractometer with molybdenum K ( =
0.71073 Å) or copper K ( = 1.5418 Å) radiation at low temperature. Structures
46
4.3. Synthetic Procedures and Analytical Data
4.3.1. Synthesis of Morpholines
Morpholines 1a-g were synthesized following a general procedure (General Procedure 1, GP-1).
General Procedure 1 (GP-1)
To a solution of 4,4-dimethyl-2-oxazoline (0.50 mL, 4.7 mmol, 1.0 eq) in THF (10 mL) a solution of tBuLi (1.9 M in pentane, 2.6 mL, 1.0 eq) was added dropwise at −78°C.
Keeping the mixture cooled at −78°C, Ti(OiPr)4 (1.5 mL, 4.7 mmol, 1.0 eq), the
aromatic nitrile and the aromatic Grignard reagent were subsequently added with a time interval of 20-30 min between the addition of each consecutive reagent (Scheme 4.1). The reaction mixture remained colorless until the addition of the Grignard reagent, thus it turned readily black. The cooling bath was then removed, the mixture was stirred at room temperature for 18 h and distilled water (1.5 mL) was finally added dropwise. Purification by column chromatography (SiO2,
pentane : ethyl acetate = 50 : 1) followed by recrystallization in pentane / ethyl acetate gave colorless crystals of 1a-g.
Scheme 4.1 General Procedure 1 (GP-1) for the synthesis of 1a-g.
Ar = 4-Fluorophenyl, 3-Fluorophenyl
47
Compound 1a
Compound 1a GP-1
Nitrile: benzonitrile (0.48 mL, 4.7 mmol, 1.0 eq);
Grignard reagent: 3-fluorophenylmagnesium bromide (1.0 M THF solution, 14 mL, 14 mmol, 3.0 eq).
Conversion: 58%
Yield: 1.0 g, colorless solid (2.6 mmol, 55%).
1H NMR (CDCl3, 399.89 MHz, 297.6 K): = 7.46 - 7.31 (m, 3 H, HPh); 7.26 - 7.10 (m, 6 H, H-7/13, 9/15, 11/17, HPh); 7.08 - 6.87 (m, 3 H, H-9/13, 9/15, 10/16); 6.82 - 6.74 (m, 1 H, H-10/16); 4.23 (d, 2JHH = 11.75 Hz, 1 H, H-1a/1b); 3.62 (d, 2JHH = 11.75 Hz, 1 H, H-1a/1b); 2.58 (br, 2 H, NH2); 1.66 (br, 1 H, NH); 1.18 (s, 3 H, H-3/4); 0.61 (s, 3 H, H-3/4) ppm. 13C{1H} NMR (CDCl3, 100.55 MHz, 295.0 K): = 161.86 (d, 1JCF = 243.8 Hz, C-8/14); 161.60 (d, 1JCF = 243.4 Hz, C-8/14); 151.14 (d, 3JCF = 6.0 Hz, C-6/12); 149.18 (d, 3JCF = 6.3 Hz, C-6/12); 142.46 (s, C-19); 129.83 (s, CPh); 128.44 (d, 3JCF = 7.8 Hz, C-10/16); 127.72 (s, CPh); 127.39 (d, 3JCF = 7.9 Hz, 10/16); 127.28 (br, C-11/17); 126.91 (s, CPh); 126.59 (d, 4JCF = 2.6 Hz, C-11/17); 118.07 (d, 2JCF = 23.1 Hz, C-7/13); 117.98 (d, 2JCF = 23.1 Hz, C-7/13); 114.11 (d, 2JCF = 21.1 Hz, C-9/15); 113.00 (d, 2JCF = 21.1 Hz, C-9/15); 88.22 (s, C-18); 68.66 (s, C-1); 68.37 (s, C-5); 50.03 (s, C-2); 30.75 (s, C-3/4); 27.72 (s, C-3/4) ppm.
48 Compound 1b 19F{1H} NMR (CDCl3, 376.27 MHz, 298.1 K): = −113.91 (s, 8/14); −114.52 (s, F-8/14) ppm. MS (HR-DART(+)): m / z 395.1927 ([M+H]+) calculated: 395.1935 (C24H25F2N2O, [M+H]+) Compound 1b GP-1
Nitrile: 4-fluorobenzonitrile (0.57 g, 4.7 mmol, 1.0 eq);
Grignard reagent: 3-fluorophenylmagnesium bromide (1.0 M THF solution, 14 mL, 14 mmol, 3.0 eq).
Conversion: 55%
Yield: 0.94 g, colorless solid (2.3 mmol, 48%).
1H NMR (CDCl3, 399.89 MHz, 297.6 K): = 7.44 - 7.35 (m, 2 H, H-20); 7.35 - 7.18 (br, 2 H, H-7, 13); 7.18 - 7.10 (m, 2 H, H-10/16, 11/17); 7.09 - 6.96 (m, 2 H, H-9/15, 10/16); 6.94 - 6.84 (m, 3 H, H-11/17, 21); 6.83 - 6.75 (m, 1 H, H-9/15); 4.20 (d, 2JHH = 11.82 Hz, 1 H, H-1a/1b); 3.61 (d, 2JHH = 11.79 Hz, 1 H, H-1a/1b); 2.65 (br, 2 H, NH2); 1.68 (br, 1 H, NH); 1.18 (s, 3 H, H-3/4); 0.61 (s, 3 H, H-3/4) ppm. 13C{1H} NMR (CDCl3, 100.55 MHz, 295.0 K): = 162.30 (d, 1JCF = 246.9 Hz, C-22); 161.84 (d, 1JCF = 243.6 Hz, C-8/14); 161.63 (d, 1JCF = 243.7 Hz, C-8/14); 150.91 (d,
49 3JCF = 5.7 Hz, C-6/12); 148.97 (d, 3JCF = 5.7 Hz, C-6/12); 138.09 (d, 4JCF = 3.3 Hz, C-11/17); 131.79 (d, 3JCF = 7.9 Hz, C-20); 128.53 (d, 3JCF = 8.1 Hz, C-10/16); 127.49 (d, 3JCF = 8.1 Hz, C-10/16); 127.18 (br, C-11/17); 126.52 (d, 4JCF = 2.7 Hz, C-11/17); 117.98 (d, 2JCF = 23.2 Hz, C-7/13); 117.88 (d, 2JCF = 23.3 Hz, C-7/13); 114.23 (d, 2JCF = 21.1 Hz, C-9/15); 113.62 (d, 2JCF = 21.1 Hz, C-21); 113.14 (d, 2JCF = 21.1 Hz, 9/15); 88.11 (s, 18); 68.68 (s, 1); 68.23 (s, 5); 50.09 (s, 2); 30.72 (s, C-3/4); 27.67 (s, C-3/4) ppm. 19F{1H} NMR (CDCl3, 376.27 MHz, 295.0 K): = −113.74 (s, F-8/14/22); −114.31 (s, F-8/14/22); −115.11 (s, F-8/14/22) ppm.
Elemental analysis: found: C 69.71%, H 5.74%, N 6.72%, calculated: C 69.89%, H 5.62%, N 6.79%
MS (HR-DART(+)): m / z 413.1826 ([M+H]+)
50
Compound 1c
Compound 1c GP-1
Nitrile: 4-methoxybenzonitrile (0.63 g, 4.7 mmol, 1.0 eq);
Grignard reagent: 3-fluorophenylmagnesium bromide (1.0 M THF solution, 14 mL, 14 mmol, 3.0 eq).
Conversion: 53%
Yield: 0.97 g, colorless solid (2.28 mmol, 48%).
1H NMR (CDCl3, 399.89 MHz, 297.6 K): = 7.43 - 7.28 (m, 3 H, H-7/13, HPh); 7.25 - 6.82 (m, 6 H, HFPh); 6.80 - 6.71 (m, 3 H, H-9/15, HPh); 4.20 (d, 2JHH = 11.9 Hz, 1 H, H-1a/1b); 3.78 (s, 3 H, H-23); 3.59 (d, 2JHH = 11.8 Hz, 1 H, H-1a/1b); 2.53 (br, 2 H, NH2); 1.61 (br, 1 H, NH); 1.16 (s, 3 H, H-3/4); 0.60 (s, 3 H, H-3/4) ppm. 13C{1H} NMR (CDCl3, 100.55 MHz, 295.0 K): = 161.82 (d, 1JCF = 243.5 Hz, C-8/14); 161.58 (d, 1JCF = 243.3 Hz, C-8/14); 158.93 (s, C-22); 151.36 (d, 3JCF = 6.3 Hz, C-6/12); 149.36 (d, 3JCF = 6.6 Hz, C-6/12); 134.46 (s, C-19); 131.14 (s, CPh); 128.41 (d, 3JCF = 8.2 Hz, C-10/16); 127.35 (d, 3JCF = 8.1 Hz, C-10/16); 127.20 (br, C-11/17); 126.59 (d, 4JCF = 2.7 Hz, C-11/17); 118.07 (d, 2JCF = 23.1 Hz, C-7/13); 117.88 (d, 2JCF = 23.0 Hz, C-7/13); 114.00 (d, 2JCF = 21.2 Hz, C-9/15); 112.92 (d, 2JCF = 21.2 Hz, C-9/15); 112.08 (s, CPh); 88.13 (s, C-18); 68.59 (s, C-1); 68.24 (s, C-5); 55.28 (s, C-23); 49.95 (s, C-2); 30.79 (s, C-3/4); 27.75 (s, C-3/4) ppm.
51 Compound 1d 19F{1H} NMR (CDCl3, 376.27 MHz, 295.1 K): = −113.95 (s, 8/14); −114.56 (s, F-8/14) ppm. MS (HR-DART(+)): m / z 425.2027 ([M+H]+) calculated: 425.2041 (C25H27F2N2O2, [M+H]+) Compound 1d GP-1
Nitrile: 4-phenylbenzonitrile (0.85 g, 4.7 mmol, 1.0 eq);
Grignard reagent: 3-fluorophenylmagnesium bromide (1.0 M THF solution, 14 mL, 14 mmol, 3.0 eq).
Conversion: 51%
Yield: 0.78 g, colorless crystals (1.7 mmol, 35%), suitable for single-crystal X-ray
diffraction. 1H NMR (CDCl3, 399.89 MHz, 295.0 K): = 7.65 - 6.90 (m, 16 H, HAr); 6.84 - 6.76 (m, 1 H, H-9/15); 4.25 (d, 2JHH = 11.8 Hz, 1 H, H-1a/1b); 3.64 (d, 2JHH = 11.8 Hz, 1 H, H-1a/1b); 2.70 (br, 2 H, NH2); 1.72 (br, 1 H, NH); 1.20 (s, 3 H, H-3/4); 0.63 (s, 3 H, H-3/4) ppm. 13C{1H} NMR (CDCl3, 100.55 MHz, 295.0 K): = 161.85 (d, 1JCF = 243.8 Hz,
C-52 Compound 1e 8/14); 161.63 (d, 1JCF = 243.5 Hz, C-8/14); 151.02 (br, C-6/12); 149.03 (br, C-6/12); 141.44 (s, C-19/22/23); 140.63 (s, C-19/22/23); 140.27 (s, 19/22/23); 130.32 (s, CPh); 128.85 (s, CPh); 128.50 (d, 3JCF = 8.0 Hz, C-10/16); 127.51 (s, CAr); 127.45 (s, CAr); 127.28 (br, CAr); 127.18 (s, CAr); 126.62 (d, 4JCF = 2.4 Hz, C-11/17); 125.49 (s, CPh); 118.10 (d, 2JCF = 23.2 Hz, C-7/13); 117.94 (d, 2JCF = 23.3 Hz, C-7/13); 114.18 (d, 2JCF = 21.2 Hz, C-9/15); 113.08 (d, 2JCF = 21.1 Hz, C-9/15); 88.24 (s, C-18); 68.67 (s, C-1); 68.36 (s, C-5); 50.10 (s, C-2); 30.72 (s, C-3/4); 27.69 (s, C-3/4) ppm. 19F{1H}-NMR (CDCl3, 376.27 MHz, 295.0 K): = −113.75 (s, 8/14); −114.34 (s, F-8/14) ppm. MS (HR-DART(+)): m / z 471.2248 ([M+H]+) calculated: 471.2248 (C30H29F2N2O, [M+H]+) Compound 1e GP-1
Nitrile: 2-thiophenecarbonitrile (0.44 mL, 4.7 mmol, 1.0 eq);
Grignard reagent: 3-fluorophenylmagnesium bromide (1.0 M THF solution, 14 mL, 14 mmol, 3.0 eq).
Conversion: 46%
Yield: 0.76 g, colorless solid (1.9 mmol, 40%).
1H NMR (CDCl3, 399.89 MHz, 295.0 K): = 7.51 - 7.36 (m, 1 H, H-7/13); 7.34 - 7.04
53 11.8 Hz, 1 H, H-1a/1b); 3.60 (d, 2JHH = 11.8 Hz, 1 H, H-1a/1b); 2.80 (br, 2 H, NH2); 1.78 (br, 1 H, NH); 1.16 (s, 3 H, H-3/4); 0.63 (s, 3 H, H-3/4) ppm. 13C{1H} NMR (CDCl3, 100.55 MHz, 295.0 K): = 161.92 (d, 1JCF = 244.0 Hz, C-8/14); 161.69 (d, 1JCF = 243.8 Hz, C-8/14); 150.36 (d, 3JCF = 6.5 Hz, C-6/12); 148.76 (d, 3JCF = 6.8 Hz, C-6/12); 147.27 (s, C-19); 128.55 (d, 3JCF = 8.1 Hz, C-10/16); 127.81 (s, CTh); 127.80 (d, 3JCF = 8.1 Hz, C-10/16); 126.93 (br, C-11/17); 126.54 (d, 4JCF = 2.8 Hz, C-11/17); 126.36 (s, CTh); 125.56 (s, CTh); 118.07 (d, 2JCF = 23.1 Hz, C-7/13); 117.89 (d, 2JCF = 23.3 Hz, C-7/13); 114.32 (d, 2JCF = 21.2 Hz, C-9/15); 113.26 (d, 2JCF = 21.2 Hz, C-9/15); 88.19 (s, C-18); 69.01 (s, C-1); 68.55 (s, C-5); 49.95 (s, C-2); 30.63 (s, C-3/4); 27.72 (s, C-3/4) ppm. 19F{1H} NMR (CDCl3, 376.27 MHz, 295.0 K): = −113.65 (s, 8/14); −113.96 (s, F-8/14) ppm.
Elemental analysis: found: C 65.83%, H 5.67%, N 7.10%, calculated: C 65.98%, H 5.54%, N 6.99%.
MS (HR-DART(+)): m / z 401.1486 ([M+H]+)
54
Compound 1f
Compound 1f GP-1
Nitrile: benzonitrile (0.48 mL, 4.7 mmol, 1.0 eq);
Grignard reagent: 4-fluorophenylmagnesium bromide (1.0 M THF solution, 14 mL, 14 mmol, 3.0 eq).
Conversion: 42%
Yield: 0.60 g, colorless solid (1.5 mmol, 32%).
1H NMR (CDCl3, 399.89 MHz, 295.4 K): = 7.61 - 7.45 (br, 2 H, H-7/11); 7.42 - 7.29 (m, 4 H, H-7/11, HPh); 7.28 - 7.19 (m, 3 H, HPh); 7.00 - 6.90 (m, 2 H, H-8/12); 6.85 - 6.75 (m, 2 H, H-8/12); 4.26 (d, 2JHH = 11.8 Hz, 1 H, H-1a/1b); 3.64 (d, 2JHH = 11.8 Hz, 1 H, H-1a/1b); 2.76 (br, 2 H, NH2); 1.22 (s, 3 H, H-3/4); 0.61 (s, 3 H, H-3/4) ppm. 13C{1H} NMR (CDCl3, 100.55 MHz, 296.6 K): = 162.09 (d, 1JCF = 247.0 Hz, C-9/13); 161.10 (d, 1JCF = 246.4 Hz, C-9/13); 144.08 (br, C-6/10); 142.68 (s, C-15); 142.22 (br, C-6/10); 132.86 (d, 3JCF = 7.7 Hz, C-7/11); 132.49 (d, 3JCF = 7.5 Hz, C-7/11); 129.64 (s, CPh); 127.62 (s, CPh); 126.90 (s, CPh); 113.86 (d, 2JCF = 20.8 Hz, C-8/12); 113.11 (d, 2JCF = 21.0 Hz, C-8/12); 88.24 (s, C-14); 68.69 (s, C-1); 68.19 (s, C-5); 50.24 (s, C-2); 30.71 (s, C-3/4; 27.76 (s, C-3/4) ppm. 19F{1H} NMR (CDCl3, 376.27 MHz, 295.9 K): = −115.66 (s, 9/13); −116.64 (s, F-9/13) ppm.
