Letter pubs.acs.org/OrgLett
Enantioselective Synthesis of 1,2-Diamines Containing Tertiary and Quaternary Centers through Rhodium-Catalyzed DYKAT of Racemic Allylic Trichloroacetimidates Edward T. Mwenda and Hien M. Nguyen* Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States S Supporting Information *
ABSTRACT: The amination of racemic secondary and tertiary allylic trichloroacetimidates possessing β-nitrogen substituents and proximal nitrogen-containing heterocycles, via chiral diene-ligated rhodiumcatalyzed dynamic kinetic asymmetric transformations (DYKAT), provides branched allylic 1,2-diamines with high enantioselectivity. The catalytic system can be applied to the synthesis of 1,2-diamines possessing two contiguous stereocenters with excellent diastereoselectivity. Furthermore, the nitrogen-containing heterocycles suppress competing vinyl azirdine formation, allowing for the high enantioselective syntheses of 1,2-diamines possessing tertiary and quaternary centers.
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the current limitations associated with the synthesis of 1,2diamines possessing tertiary and quaternary centers. Herein, we report an enantioselective synthesis of 1,2-diamines 2 (Figure 1) via rhodium-catalyzed dynamic kinetic asymmetric transformations (DYKAT) of racemic allylic trichloroacetimidates 1 with anilines. Previous developments in our group have provided methods for the facile catalytic asymmetric amination of racemic allylic trichloroacetimidates using chiral diene-ligated rhodium catalysts.8 Following our work and related studies in the area of transition-metal-catalyzed enantioselective amination of allylic electrophiles,9−12 we recognize that allylic substrates, bearing βnitrogen substituents and β-nitrogen-containing heterocycles, could undergo amination to generate 1,2-diamines. However, due to an amino group proximal to the electrophilic site of πallylrhodium complexes 3 and 4 (Figure 1), competing vinyl aziridine intermediates 5 and 6 could be formed, resulting in an erosion of the enantioselectivity of the product 2.13 We hypothesize that it may be possible to address this shortcoming through the judicious choice of protecting and functional groups, that could decrease nitrogen nucleophilicity and, consequently, suppress formation of vinyl aziridine. Overcoming this foreseen challenge would allow access to allylic 1,2-diamine 2 via rhodiumcatalyzed DYKAT reactions.14−16 To validate vinyl aziridine formation, we selected benzoyl protected β-nitrogen substituted allylic trichloroacetimidate 7 (Scheme 1) in our studies. Treatment of 7 with 5 mol % norbornadiene rhodium chloride dimer, [RhCl(NBD)]2, in the absence of aniline nucleophile yielded exclusively vinyl aziridine 8 (Scheme 1a) in 69% yield. Reaction of 7 with p-methoxyaniline
he 1,2-diamines are found in a wide range of bioactive natural products and pharmaceuticals.1 In addition, their enantiopure motifs are utilized as chiral ligands, auxiliaries, and catalysts for enantioselective transformations.1 Because of the privileged nature of the 1,2-diamines, significant efforts have been focused on the development of asymmetric methods for their synthesis.2 To date, enantioselective syntheses of 1,2-diamines (2, Figure 1) bearing a tertiary or quaternary center and an
Figure 1. A proposed approach to the enantioselective synthesis of 1,2diamines 2 via Rh-catalyzed DYKAT.
unsubstituted β-aminomethyl group remain underveloped.3,4 For instance, the asymmetric synthesis of quaternary-containing 1,2diamines3 could be achieved through the addition of azomethine ylides to chiral N-sulfinylketimines.5 However, several factors complicate this method. First, ketimines possessing an αhydrogen are prone to enolize.5b,6 Second, ketimines can exist as a mixture of E- and Z-isomers, and thus differentiation of their enantiotopic faces can be challenging.7 Third, ketimines often require activation by Lewis or Bronsted acids because they are much less reactive than corresponding aldimines.3,5b Thus, there is a need to develop catalytic asymmetric methods that overcome © 2017 American Chemical Society
Received: July 22, 2017 Published: September 6, 2017 4814
DOI: 10.1021/acs.orglett.7b02256 Org. Lett. 2017, 19, 4814−4817
Letter
Organic Letters
MTBE as a solvent and a slightly higher temperature (40 °C) further improved the yield and enantioselectivity (95%, 90% ee) of 14 (entry 5). Furthermore, lowering the catalyst loading to 2 mol % (entry 12) caused no erosion in yield or selectivity. The application to a larger scale (1.4 mmol of 13) was also explored (entry 13), and 1,2-diamine 14 was obtained in similar yield and selectivity (99%, 91% ee). We next sought to examine the substrate scope of the reaction (Table 2). Allylic 1,2-diamines 23−29 were obtained in moderate
Scheme 1. Studies with β-Nitrogen Substituted Imidates
Table 2. Scope of β-Nitrogen and β-Azido Substituted 1,2Diamines Bearing Tertiary and Quaternary Centersa
Table 1. Optimization of the Reaction Conditionsa
entry
[Rh] mol %
1
5
2
5
3
5
4
5
5
5
6
5
7
5
8
5
9
5
10
5
11
5
12 13
2 2
ligand 10 mol % L1 10 mol % L1 10 mol % L1 10 mol % L1 10 mol % L1 10 mol % L1 10 mol % L1 10 mol % L1 10 mol % L1 10 mol % L2 10 mol % L3 4 mol % L1 4 mol % L1
temp (°C)
yieldc (%)
eed (%)
dioxane
25
70
71
dioxane
40
99
88
THF
40
99
82
CPME
40
91
89
MTBE
40
95
90
toluene
40
91
89
PhCF3
40
99
79
CH2Cl2
40
99
84
cyclohexane
40
43
77
MTBE
40
74
67
MTBE
40
99
89
MTBE MTBE
40 40
97 99b
90 91b
solvent
a All reactions were conducted at 0.1 M using 0.15−0.3 mmol of allylic imidate 13 (1 equiv) and p-methoxylaniline 10 (1.5 equiv). bReaction was carried out on a 1.4 mmol scale of 13. cIsolated yield. d Determined by chiral HPLC. a
All reactions were conducted at 0.1 M using 0.15−0.3 mmol of allylic imidates (1 equiv) and anilines (1.5 equiv). bIsolated yield. c Determined by chiral HPLC.
(10, Scheme 1b) was then tested under rhodium-catalyzed DYKAT conditions (vide inf ra, Table 1). The 1,2-diamine 11 was isolated with 21% ee. We next explored tosyl-protected (Ts) substrate 9 (Scheme 1c) since the sulfonamide group attenuates nitrogen nucleophilicity.17 As expected, allylic amine 12 (Scheme 1c) was isolated with improved ee (49%). Collectively, these results support that competing vinyl aziridine plays a role in eroding the enantioselectivity of the product. To overcome the above shortcomings, we predicted that the use of β-phthalimide-substituted allylic trichloroacetimidate 13 (Table 1) could hinder vinyl aziridine formation. We commenced our studies with reaction of 13 and aniline 10 in 5 mol % [RhCl(ethylene)2]2 and 10 mol % L1 at 25 °C for 1 h (entry 1). The desired 1,2-diamine 14 was obtained in 70% yield and 71% ee. After examining each reaction parameter (temperature, solvent, and ligand, entries 2−11), it was determined that use of
to good yields (57−93%) with high enantioselectivities (81−93% ee) when using substrates with fully protected β-nitrogen (entries 1−7). Although the catalytic system tolerates both electrondonating and electron-withdrawing anilines, the use of the more electron-rich aniline nucleophile 20 further improved the enantioselectivity of the product (entry 5 vs entry 6). We hypothesize that the electron-rich aniline accelerates the rate of nucleophilic attack onto the π-allylrhodium complex (Figure 1),15 consequently suppressing vinyl aziridine formation. The βazido group is also well-tolerated, providing allylic 1,2-diamines 30 and 31 (entries 8 and 9) in high yields (88% and 99%) and enantioselectivies (88% ee and 92% ee). 4815
DOI: 10.1021/acs.orglett.7b02256 Org. Lett. 2017, 19, 4814−4817
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nitrogen-containing heterocycles.26 As illustrated in Table 3, amination of allylic imidates 33−38 provided pyrrole, carbazole, and indole-containing diamines 43−48 (entries 1−6) with high enantioselectivities (86−94% ee). Use of triazole-containing substrate 39 (entry 7) provided 49 with 66% ee. To our delight, the method is also amendable to the asymmetric synthesis of congested quaternary-containing 1,2-diamines 50−52 (entries 8−10) in high enantiomeric excess (85−91% ee). Overall, most allylic 1,2-diamines were obtained in good yields. Because of the decomposition of their starting materials, some products (entries 2−4 and 10) were obtained near 50% yield. To determine whether the chiral diene-ligated rhodium complex could influence the diasteresoelectivity of the amination, we investigated L- and D-proline-derived substrates 53 and 54 (Scheme 2)27 which possess the ability to generate two
We next explored the synthesis of allylic 1,2-diamines bearing sterically challenging quaternary centers using 18 as the model compound (entry 10). Our previous results showed that only tertiary allylic imidate substrates bearing β-hydroxy substituents provided high selectivity.8a We questioned whether the sulfonamide could serve as a directing group17 to provide additional chelation control, decreasing conformational flexibility of the π-allylrhodium intermediates and facilitating the transmission of asymmetric induction from the catalyst to the substrate.18 Unfortunately, quaternary-containing 1,2-diamine 32 (entry 10) was formed in only 57% ee, but with excellent yield (99%). We hypothesize that the modest enantioselectivity is likely due to the high energy barrier of π-allylrhodium intermediate isomerization (3 and 4, Figure 1).19 We further investigated the scope with nitrogen-heterocycle containing substrates 33−42 (Table 3). We hypothesize that the
Scheme 2. Diastereoselective Amination of Both L- and DProline Derived Trichloroacetimidate Substrates
Table 3. Scope of Nitrogen-Heterocycle Substituted Allylic 1,2-Diamines Bearing Tertiary and Quaternary Centersa
a−c
contiguous stereogenic centers. In the case of L-proline imidate 53, use of achiral [RhCl(NBD)]2 provided 1,2-diamine 55 (Scheme 2a) with excellent diastereoselectivity (dr > 99:1), while use of chiral diene ligated rhodium catalyst resulted in a 1:1 mixture of 55. In stark contrast, both achiral and chiral rhodium catalysts were effective at promoting the amination of D-proline imidate 54 to provide 56 (Scheme 2b) with excellent diastereomeric ratio (dr > 1:99). The major diastereomer of 55 and 56 could be recrystallized allowing for X-ray crystallographic determination of the allylic carbon to be in the R- and Sconfiguration, respectively (see Supporting Information). In summary, we have developed an efficient asymmetric synthesis of 1,2-diamines bearing tertiary and quaternary centers via rhodium-catalyzed DYKAT of racemic allylic trichloroacetimidates. This catalytic asymmetric system is tolerant of a variety of substrates incorporated with a number of the fully protected βamino groups. We also discovered that nitrogen-containing heterocycles can suppress competing vinyl aziridine formation and enable the synthesis of 1,2-diamines possessing tertiary and quaternary centers with high levels of asymmetric induction. Furthermore, the method is amendable for the synthesis of 1,2diamines possessing two stereocenters with excellent diastereoselectivity.
See Table 2.
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nitrogen lone pairs of pyrrole, carbazole, and indole are involved in the π-system of the aromatic ring and thus would not be available to participate in vinyl aziridine formation. The achievement of this goal would allow access to the important class of bioactive targets incorporated with pyrrole, carbazole, and indole motifs.20−23 In the area of transition-metal-catalyzed allylic amination, methods for the constructions of the nitrogenheterocycle containing 1,2-diamines are limited to palladiumcatalyzed openings of vinyl aziridines with pyrroles24 and iridiumcatalyzed asymmetric allylic amination with indole25 and
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02256. Experimental procedures and spectra data (PDF) X-ray data for compound 55 (CIF) X-ray crystallographic report for compound 55 (PDF) X-ray data for compound 56 (CIF) 4816
DOI: 10.1021/acs.orglett.7b02256 Org. Lett. 2017, 19, 4814−4817
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Organic Letters
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Commun. 2012, 48, 11531. (c) Arnold, J. S.; Nguyen, H. M. Synthesis 2013, 45, 2101. (d) Arnold, J. S.; Mwenda, E. T.; Nguyen, H. M. Angew. Chem., Int. Ed. 2014, 53, 3688. (9) For the most recent review on asymmetric allylic amination reactions of allylic electrophiles, see: Grange, R. L.; Clizbe, E. A.; Evans, P. A. Synthesis 2016, 48, 2911−2968. (10) For selected examples of the transition-metal-catalyzed enantioselective/enantiospecific amination of allylic electrophiles with anilines, see: (a) Evans, P. A.; Robinson, J. E.; Moffett, K. K. Org. Lett. 2001, 3, 3269. (b) Takeuchi, R.; Ue, N.; Tanabe, Y.; Yamashita, K.; Shiga, N. J. Am. Chem. Soc. 2001, 123, 9525. (c) Shu, C.; Leitner, A.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43, 4797. (d) Satyanarayana, G.; Pflasterer, D.; Helmchen, G. Eur. J. Org. Chem. 2011, 2011, 6877. (e) Cai, A.; Guo, W.; Martinez-Rodriguez, L.; Kleij, A. W. J. Am. Chem. Soc. 2016, 138, 14194. (11) For selected examples of kinetic resolution of secondary allylic electrophiles via transition metal-catalyzed amination reactions, see: (a) Vrieze, D. C.; Hoge, G. S.; Hoerter, P. Z.; van Haitsma, J. T.; Samas, B. M. Org. Lett. 2009, 11, 3140. (b) Stanley, L. M.; Bai, C.; Ueda, M.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 8918. (c) Madrahimov, S. T.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 8136. (12) For selected examples of dynamic kinetic resolution of secondary allylic electrophiles via transition metal-catalyzed amination, see: (a) You, S. L.; Zhu, S. Z.; Luo, Y. M.; Hou, X. L.; Dai, L. X. J. Am. Chem. Soc. 2001, 123, 7471. (b) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 3139. (c) Roggen, M.; Carreira, E. M. J. Am. Chem. Soc. 2010, 132, 11917. (d) Lafrance, M.; Roggen, M.; Carreira, E. M. Angew. Chem., Int. Ed. 2012, 51, 3470. (13) Ibuka, T.; Mimura, N.; Aoyama, H.; Akaji, M.; Ohno, H.; Miwa, Y.; Taga, T.; Nakai, K.; Tamamura, H.; Fujii, N.; Yamamoto, Y. J. Org. Chem. 1997, 62, 999. (14) For alternative enyl rhodium intermediate, see: Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581. (15) We have hypothesized that the isomerization of diastereomeric πallylrhodium complexes 3 and 4 occurs faster than subsequent attack by the aniline nucleophile. The asymmetric environment around the rhodium center would determine which enantiomer (2 or ent-2) of the product is kinetically favored. (16) Trost, B. M.; Fandrick, D. R. Aldrichim. Acta 2007, 40, 59. (17) Wilsily, A.; Tramutola, F.; Owston, N. A.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 5794. (18) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307. (b) Rousseau, G.; Breit, B. Angew. Chem., Int. Ed. 2011, 50, 2450. (19) Gellrich, U.; Meibner, A.; Steffani, A.; Kahny, M.; Drexler, H.; Heller, D.; Plattner, D. A.; Breit, B. J. Am. Chem. Soc. 2014, 136, 1097. (20) (a) Cafieri, F.; Fattorusso, E.; Taglialatela-Scafati, O. J. Nat. Prod. 1998, 61, 122. (b) Rane, R.; Sahu, N.; Shah, C.; Karpoormath, R. Curr. Top. Med. Chem. 2014, 14, 253. (21) (a) Aygun, A.; Pindur, U. Curr. Med. Chem. 2003, 10, 1113. (b) O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23, 532. (c) Gupta, L.; Talwar, A.; Chauhan, P. M. S. Curr. Med. Chem. 2007, 14, 1789. (d) Cao, R.; Peng, W.; Wang, Z.; Xu, A. Curr. Med. Chem. 2007, 14, 479. (22) (a) MacMillan, K. S.; Naidoo, J.; Liang, J.; Melito, L.; Williams, N. S.; Morlock, L.; Huntington, P. J.; Estill, S. J.; Longgood, J.; Becker, G. L.; McKnight, S. L.; Pieper, A. A.; De Brabander, J. K.; Ready, J. M. J. J. Am. Chem. Soc. 2011, 133, 1428. (b) Naidoo, J.; De Jesus-Cortes, H.; Huntington, P. J.; Estill, S. J.; Morlock, L. K.; Starwalt, R.; Mangano, T. J.; Williams, N. S.; Pieper, A. A.; Ready, J. M. J. J. Med. Chem. 2014, 57, 3746. (23) Trost, B. M.; Osipov, M.; Dong, G. J. J. Am. Chem. Soc. 2010, 132, 15800. (24) Zhuo, C.-X.; Zhang, X.; You, S.-L. ACS Catal. 2016, 6, 5307. (b) Ye, K.-Y.; Cheng, Q.; Zhuo, C.-X.; Dai, L.-X.; You, S.-L. Angew. Chem., Int. Ed. 2016, 55, 8113. (25) Stanley, L. M.; Hartwig, J. F. Angew. Chem. 2009, 121, 7981. (26) Stanley, L. M.; Hartwig, J. F. J. J. Am. Chem. Soc. 2009, 131, 8971. (27) Chaudhuri, S.; Parida, A.; Ghosh, S.; Bisai, A. Synlett 2016, 27, 215.
X-ray crystallographic report for compound 56 (PDF)
AUTHOR INFORMATION
Corresponding Author
* Email:
[email protected] ORCID
Hien M. Nguyen: 0000-0002-7626-8439 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support was provided by University of Iowa. We thank Dr. Dale Swenson at University of Iowa for X-ray crystallographic analysis.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b02256 Org. Lett. 2017, 19, 4814−4817
