General access to chiral n -alkyl terminal aziridines via organocatalysis

Article abstract of DOI:10.1021/ol101276x

(Figure Presented) A three step, one-pot protocol involving enantioselective α-chlorination of aldehydes, subsequent reductive amination with a primary amine, and S_N2 displacement to afford chiral N-alkyl terminal aziridines in 40-65% yield (74-87%/step) and, in most cases, >90% ee is reported.

Full text of DOI:10.1021/ol101276x

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3276-3278
General Access to Chiral N-Alkyl
Terminal Aziridines via Organocatalysis
Olugbeminiyi O. Fadeyi, Michael L. Schulte, and Craig W. Lindsley*
Departments of Chemistry and Pharmacology, Vanderbilt Institute of Chemical
Biology, Vanderbilt UniVersity Medical Center, NashVille, Tennessee 37232
craig.lindsley@Vanderbilt.edu
Received June 3, 2010
ABSTRACT
A three step, one-pot protocol involving enantioselective r-chlorination of aldehydes, subsequent reductive amination with a primary amine,
and SN2 displacement to afford chiral N-alkyl terminal aziridines in 40-65% yield (74-87%/step) and, in most cases, >90% ee is reported.
Aziridines represent an important class of nitrogen het-
erocycles with a wide range of synthetic utility and
prevalence in natural products.1 Despite their value,
synthetic routes to aziridines are limited in terms of
generality and diversity of the N-substituent. Classical
methods for the synthesis of terminal aziridines include
nitrene transfer to olefins,2 carbene methodology,3 aza-
Darzens approaches,4 addition/elimination sequences,5 and
ylide-mediated strategies.6 For many of these tactics, the
N-substituent is typically a p-toluenesulfonyl moiety or
other electron-withdrawing group.1,2 The synthesis of chiral
terminal aziridines with diversity at the N-substituent is
extremely rare.1 One recent example was reported for the
synthesis of terminal diarylaziridines by the enantioselective
reductive amination of R-chloroketones.7 Here, we report a
general one-pot protocol for the enantioselective synthesis
of N-alkyl terminal aziridines via organocatalysis.
We recently reported on a one-pot protocol for the
enantioselective R-fluorination of aldehydes, followed by
reductive amination to produce pharmaceutically relevant
chiral ꢀ-fluoroamines (Figure 1, eq 1).8,9 Previously, both
MacMillan11 and Jørgensen12 disclosed the enantioselective
R-chlorination of aldehydes via organocatalysis. Based on
this precedent and our chiral ꢀ-fluoroamine work, we
envisoned a three-step, one-pot protocol involving enanti-
(1) For a recent review on the asymmetric synthesis of aziridines, see:
Pellissier, H. Tetrahedron 2010, 66, 1509.
(2) Li, Z.; Cosner, K. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1993, 115,
5326.
(3) Badea, F.; Condeiu, C.; Gherighiu, M.; Iordache, A.; Simion, C.
ReV. Roum. Chim. 1992, 37, 393.
(4) Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R. J. Org.
Chem. 2003, 68, 2410.
(5) Barros, M. T.; Matias, P. M.; Maycock, C. D.; Ventura, M. R. Org.
Lett. 2003, 5, 4321.
(6) Davis, F. A.; Zhou, P.; Liang, C.-H.; Reddy, R. E. Tetrahderon:
Asymmetry 1995, 6, 1511.
Figure 1
. Organocatalytic approach to chiral ꢀ-fluoroamines and
envisioned route to chiral N-alkyl terminal aziridines.
(7) Malkov, A. V.; Stoncˇıus, S.; Kocoˇvsky´, P. Angew. Chem. 2007, 119,
3722.
10.1021/ol101276x  2010 American Chemical Society
Published on Web 06/16/2010

oselective R-chlorination of aldehydes, subsequent reductive
amination with a primary amine, and SN2 displacement to
afford previously unattainable chiral terminal aziridines with
a wide range of N-substituents (Figure 1, eq 2). Overall, this
new approach represents the effective addition of a primary
amine across an olefin to form aziridines and is a notable
extension of the Linchpin SOMO catalysis concept to access
chiral epoxides reported by MacMillan.10
Scheme 2
.
Enantioselective R-Chlorination of
Hydrocinnamaldehyde*
For a one-pot protocol involving a reductive amination
step, we could not use the MacMillan R-chlorination
chemistry, as that route employed a chloroquinone as the
chlorinating agent and acetone as a solvent.11 The Jørgensen
route was attractive, as NCS was the chlorinating agent, and
the optimized solvent was DCE.12 We first set out to
determine if this proposal would allow access to racemic
N-alkyl terminal aziridines. Thus, DL-proline-catalyzed R-chlo-
rination of 1 with NCS 2, followed by reductive amination
with benzylamine and subsequent base-induced SN2 cycliza-
tion with KOH in THF/H2O at 65 °C, did provide racemic
aziridine 3 in 70% yield (Scheme 1) for the three step, one-
pot protocol (average of 90% per step). Importantly, KOH
was critical for the production of 3, as a screen of organic
(ie., Et3N, pyridine, DBU, KO-t-Bu) and inorganic bases (ie.,
NaH, K2CO3) provided less than 50% conversion to 3.13
* All reactions were 0.05 mmol scale. Enantiomeric ratios were measured
using chiral stationary-phase HPLC. a 5 mol % catalyst loading. ND ) not
determined. b Reaction performed at -20 °C for 24 h.
afforded comparable conversion (>95%), but lower enanti-
oselectivity (56-90% ee).
Scheme 1
.
One-Pot Protocol for Racemic N-Alkyl Terminal
Aziridines
With optimal R-chlorination conditions in hand, we
attempted the three step, one-pot protocol to deliver 3
enantioselectively. Utilizing the protocol in Scheme 1, but
replacing DL-proline with 5m, we were disappointed to find
that this approach afforded 3 in comparable yield, but in less
than 40% ee. Thus, we investigated the most probable source
of epimerization in the sequence: the room-temperature
reductive amination step. Molecular sieves proved essential,
and we found a direct correlation between enantioselectivity
and temperature. As shown in Scheme 3, reducing the
temperature for the reductive amination step to -78 °C
resulted in the enantioselective synthesis of aziridine 3 in
71% yield for the three steps (∼90% per step) and 94% ee.
As expected, the (S,S)-5m catalyst afforded the opposite
enantiomer of 3 in good yield (74%) and excellent enanti-
oselectivity (95% ee).
Efforts now focused on developing an enantioselective
one-pot protocol. To ensure we had optimal conditions for
the enantioselective R-chlorination of 1, we elected to survey
a set of 15 organocatalysts 5a-o employing NCS as the
chlorinating agent and DCM as the solvent. This study
demonstrated that the Jørgensen11 catalyst 5m was indeed
optimal, affording 4 in >97% conversion. In order to
determine the degree of enantioselectivity by chiral HPLC,
4 was reduced to the corresponding ꢀ-chloroalcohol 6 and
found to possess 95% ee (Scheme 2). Organocatalysts 5k,
5l, 5n, and 5o never before employed for this transformation
Scheme 3
.
One-Pot Protocol for Chiral N-Alkyl Terminal
(8) Fadeyi, O. O.; Lindsley, C. W. Org. Lett. 2009, 11, 943.
(9) For the initial disclosures of organocatalytic R-fluorination of
aldehydes, see: (a) Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 8826. (b) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjaersgaard,
A.; Jørgensen, K. A. Angew Chem., Int. Ed. 2005, 44, 3703. (c) Steiner,
D. D.; Mase, N.; Barbas, C. F., III Angew Chem., Int. Ed. 2005, 44, 3706.
(10) Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C.
Angew Chem., Int. Ed. 2009, 48, 5121.
Aziridines
(11) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2004, 126, 4108.
(12) (a) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jør-
gensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790. (b) Marigo, M.;
Bachmann, S.; Halland, N.; Braunton, A.; Jørgensen, K. A. Angew Chem.
Int. Ed. 2004, 43, 5507.
As shown in Scheme 4, the reaction scope is general with
respect to both aldehyde and amine, providing chiral terminal
(13) See the Supporting Information for full details.
Org. Lett., Vol. 12, No. 14, 2010
3277

Scheme 4
.
Substrate Scope of Enantioselective N-Alkyl
Scheme 5
.
Two-Pot Protocol for Chiral N-Alkyl Terminal
Terminal Aziridines*
Aziridines*
* All reactions were 0.50 M in substrate and proceeded to complete
conversion. a Yield after chromatography. b Enantiomeric excess determined
by chiral HPLC or SFC analysis.
Finally, modest improvements in yield and comparable
enantioselectivty were observed if we performed a workup
after the R-chlorination step. The addition of pentane to the
crude reaction mixture precipitated both the succinimide and
organocatalyst 5m. Removal of the pentane, concentration,
resupsension in CH2Cl2, and proceeding with the reductive
amination and base-induced cyclization steps now provided
N-alkyl terminal aziridines in 51-75% yield and >90% ee
(Scheme 5); however, isolation proved more facile.
In summary, we have developed a three step, one-pot
protocol for the general enantioselective synthesis of terminal
N-alkyl aziridines via organocatalysis. This new methodology
provides access to aziridines that were previously difficult
to prepare, utilizing aldehydes and amines for which
thousands are commercially available.
* All reactions were 0.50 M in substrate and proceeded to complete
conversion. a Yield after chromatography. b Enantiomeric excess detremined
by chiral HPLC or SFC analysis. c Diastereomeric ratio determined via NMR
experiments using chiral solvating agents (Pirkle alcohol).14 d Because
homoaldol product formation occurred at -20 °C with use of 5m, catalyst
5o was used.
Acknowledgment. We acknowledge the Department of
Pharmacology for support of this research and Mr. Chris-
topher J. Denicola (Vanderbilt Program in Drug Discovery)
for technical assistance with chiral HLPC and chiral
SFC. M.L.S. acknowledges the Vanderbilt Institute of
Chemical Biology (VICB) for a predoctoral fellowship.
N-alkyl aziridines 4-17 in overall yields of 40-65%
(74-87% per step) and, in most cases, >90% ee for the three
step, one-pot protocol. Determining the enantioselectivity
required classical reversed-phase chiral HPLC, SFC, or NMR
chiral shift reagents.13
Supporting Information Available: Complete experi-
mental procedures, compound characterization, chiral HPLC/
SFC analysis, and supplemental tables. This material is free
of charge via the Internet at http://pubs.acs.org.
(14) Pirkle, W. H.; Sikkenga, D. L.; Pavlin, M. S. J. Org. Chem. 1977,
42, 384.
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