Asymmetric synthesis of cyclopropylamines starting from N-sulfinyl α-chloro ketimines

Article abstract of DOI:10.1021/ol0622054

(Chemical Equation Presented) Treatment of novel chiral N-sulfinyl α-chloro ketimines with Grignard reagents resulted in the synthesis of chiral N-(1-substituted cyclopropyl)-tert-butanesulfinamides in acceptable to good yields and diastereoselectivity vi

Full text of DOI:10.1021/ol0622054

ORGANIC
LETTERS
2007
Vol. 9, No. 2
187-190
Asymmetric Synthesis of
Cyclopropylamines Starting from
N-Sulfinyl
r-Chloro Ketimines
Bram Denolf,† Sven Mangelinckx,†,‡ Karl W. Tornroos,§ and Norbert De Kimpe*,†
1
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent
UniVersity, Coupure Links 653, B-9000 Ghent, Belgium, and Department of Chemistry,
UniVersity of Bergen, Allegaten 41, N-5007 Bergen, Norway
norbert.dekimpe@ugent.be
Received September 6, 2006
ABSTRACT
Treatment of novel chiral N-sulfinyl
r-chloro ketimines with Grignard reagents resulted in the synthesis of chiral N-(1-substituted cyclopropyl)-
tert-butanesulfinamides in acceptable to good yields and diastereoselectivity via 1,3-dehydrohalogenation and subsequent addition of the
Grignard reagent to the intermediate cyclopropylideneamine. Only in the case of allylmagnesium chloride did the reaction lead to aziridines
in high yield. Further deprotection toward N-unprotected 1-substituted cyclopropylamines was established, and the absolute configuration
was determined.
The use of cyclopropylamines and their stereoselective
synthesis are of considerable interest in recent years.1 Besides
their occurrence as pharmaceutical or agrochemical subunits,
the highly strained cyclopropylamines are also synthesized
for their use as chiral resolving agents or as synthetic
intermediates for further reactions.2 Additionally, the poten-
tial to control local conformation by restricting the number
of rotational degrees is progressively applied in computa-
tional modeling systems. Hence, the need for such small,
chiral molecules is of great interest.3
reagents with R-halo imines is unprecedented. It has been
established that the moderate reactivity and stereoselectivity,
often observed when N-alkyl imines are used, can substan-
tially be improved by using the corresponding N-sulfinyl
imines.5 A lot of work in this area has been performed by
the Ellman6 and Davis groups.7 Despite the good results
leading to numerous publications, almost no attention has
been given to N-sulfinyl R-halo imines. Only few halo-
genated N-sulfinyl imines have been synthesized, and the
few examples reported have not been thoroughly studied
toward their reactivity.8 However, the potential of halo-
From earlier research, it is known that the synthesis of
cyclopropylamines can be achieved in acceptable yield upon
treatment of N-alkyl R-halo imines with alkoxides.4 However,
the cyclopropylamine synthesis via reaction of Grignard
(3) (a) Armstrong, A.; Scutt, J. N. Org. Lett. 2003, 5, 2331. (b) Wang,
M.-X.; Feng, G.-Q. Tetrahedron Lett. 2000, 41, 6501. (c) de Meijere, A.;
Ernst, K.; Zuck, B.; Brandl, M.; Kozhushkov, S. I.; Tamm, M.; Yufit, D.
S.; Howard, J. A. K.; Labahn, T. Eur. J. Org. Chem. 1999, 3105.
(4) Aelterman, W.; Giubellina, N.; Stanoeva, E.; De Geyter, K.; De
Kimpe, N. Tetrahedron Lett. 2004, 45, 441. (b) De Kimpe, N.; Sulmon, P.;
Boeykens, M. Tetrahedron 1991, 47, 3389. (c) De Kimpe, N.; Sulmon, P.;
Brunet, P. J. Org. Chem. 1990, 55, 5777.
* To whom correspondence should be addressed.
† Ghent University.
‡
Postdoctoral Fellow of the Research Foundation-Flanders (FWO).
§ University of Bergen.
(1) de Meijere, A. Chem. ReV. 2003, 103, 931.
(5) Cogan, D. A.; Lui, G.; Ellman, J. A. Tetrahedron 1999, 55, 8883.
(6) a) Ellman, J. A. Pure Appl. Chem. 2003, 75, 39. (b) Ellman, J. A.;
Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984 and references
cited therein.
(7) Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003 and
references cited therein.
(2) (a) Wessjohann, L. A.; Brandt, W.; Thiemann, T. Chem. ReV. 2003,
103, 1625. (b) Gnad, F.; Reiser, O. Chem. ReV. 2003, 103, 1603. (c) Dolbier,
W. R.; Battiste, M. A. Chem. ReV. 2003, 103, 1071. (d) Pietruszka, J. Chem.
ReV. 2003, 103, 1051. (e) Reichelt, A.; Martin, S. F. Acc. Chem. Res. 2006,
39, 433.
10.1021/ol0622054 CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/03/2007

genated imines as starting material to synthesize aziridines
or cyclopropylamines, among other interesting compounds,
in a simple and straightforward manner has been described
extensively.9 Chiral R-halo imines have not been used in this
respect. In addition, N-sulfinyl deprotection, under mild
conditions, after reaction, providing unprotected cyclopro-
pylamines or aziridines is advantageous for further reaction.
In this paper, the chiral synthesis of 1-alkyl- and 1-aryl-
cyclopropylamines is elaborated for the first time starting
from R-halo imines (Scheme 1).
All ketimines (RS)-2a-c were obtained as exclusively
E-isomers and could be stored for long periods (>1 year) of
time at low temperature (-40 °C).
These new chiral ketimines (RS)-2 were tested for their
reactivity upon treatment with Grignard reagents. Therefore,
addition of 1.05 equiv of PhMgCl to ketimine (RS)-2a,
dissolved in CH2Cl2, at -78 °C and subsequent stirring for
4 h at this temperature, afforded N-sulfinyl 1-phenylcyclo-
propylamine (RS,R)-5a in 10% yield with excellent dia-
stereoselectivity (95:5 dr) after aqueous NH4Cl workup. Yet,
most of the starting ketimine (43%) was recovered under
these conditions (Table 1, entry a). As reported in Table 1,
Scheme 1. Purpose of the Research
Table 1. Synthesis of Cyclopropylamine 5a via Addition of
PhMgCl Across N-Sulfinyl R-Chloro Ketimine (RS)-2a
N-Sulfinyl R-chloro ketimines (RS)-2, a new class of
functionalized N-sulfinyl imines, were synthesized via
condensation of R-chloro ketones 1 with (RS)-tert-butane-
sulfinamide in the presence of 2 equiv of Ti(OEt)4 (Scheme
2). Ketimines (RS)-2a,b were synthesized in high yields (82-
entry PhMgCl (equiv)
T (°C)
-78
-78
-78
-40
-78
-78/-40
-78/-40
-78/rt
-78/-40/rt
time (h) yielda (%) (dr)b
a
b
c
1.05
2.2
3
4
4
4
10 (95:5)
28 (96:4)
17 (-)
d
e
f
g
h
i
2.2
2.2
2.2
2.2
2.2
2.2
4
8
59 (80:20)
47 (95:5)
70 (95:5)
71 (92:8)
27 (82:18)
67 (95:5)
2/4
0.4/4
2/4
2/4/12
Scheme 2. Synthesis of N-Sulfinyl R-Chloro Ketimines (RS)-2
a Determined by a mass balance after chromatography. b Determined by
NMR analysis of the reaction mixture.
changing temperature, time, and the amount of Grignard
reagent added resulted in a substantial improvement of the
isolated yields of the formed cyclopropylamine (RS,R)-5a.
Judging from the reaction mechanism (vide infra), 2 equiv
of Grignard reagent is consumed in the synthesis of 1-phenyl-
cyclopropylamine 5a. Subsequently, higher amounts of
Grignard reagent were added (Table 1, entries a-c). If more
than 2.2 equiv of PhMgCl were added, yields of cyclo-
propylamine (RS,R)-5a formed dropped. Side reactions
became more pronounced and were detrimental for purifica-
tion by flash chromatography. Extended reaction times did
improve the yields significantly (entry b vs e). However,
changing the temperature turned out to be a more promising
alternative. Better results were obtained if the reaction was
performed at -40 °C, under the sole condition that the
reagent was added at -78 °C (Table 1, entries d,f-i).
Addition of 2.2 equiv of PhMgCl at -40 °C afforded the
cyclopropylamine (RS,R)-5a in reasonable yield (59%) but
with inferior diastereoselectivity. Again, the purification by
flash chromatography was more tedious and disadvantageous
for the isolated yield of the cyclopropylamine (RS,R)-5a.
Changing the solvent (toluene, Et2O, and THF) or the
concentration did not improve the yield or the diastereo-
selectivity of the reaction.
91%) when stirred for 48 h at reflux temperature in dry THF,
while ketone 1c had to be stirred at 98 °C for 48 h in
isooctane to form ketimine (RS)-2c in 89% yield (Scheme
2). The ketimines (RS)-2 were isolated after removal of the
titanium species after aqueous workup, and after distillation
to remove the small excess of ketones 1 used. The latter
ketones were synthesized according to literature procedures.10
No epimerization at the sulfinyl center occurred during the
synthesis of imines 2 as was checked for with lanthanide
shift reagent Eu(hfc)3.
(8) (a) Davis, F. A.; Nolt, M. B.; Wu, Y.; Prasad, K. R.; Li, D.; Yang,
B.; Bowen, K.; Lee, S. H.; Eardley, J. H. J. Org. Chem. 2005, 70, 2184.
(b) Davis, F. A.; Prasad, K. R.; Nolt, B.; Wu, Y. Org. Lett. 2003, 5, 925.
(c) Lacoˆte, E.; Malacria, M. C. R. Acad. Sci. Paris 1998, 191.
(9) (a) Concellon, J. M.; Riego, E.; Rivero, I. A.; Ochoa, A. J. Org.
Chem. 2004, 69, 6244. (b) Florio, S.; Troisi, L.; Capriati, V.; Suppa, G.
Eur. J. Org. Chem. 2000, 3793. (c) Nguyen, Van, T.; De Kimpe, N.
Tetrahedron 2000, 56, 7299. (d) Aelterman, W.; Abbaspour Tehrani, K.;
Coppens, W.; Huybrechts, T.; De Kimpe, N.; Tourwe´, D.; Declercq, J.-P.
Eur. J. Org. Chem. 1999, 239.
(10) De Kimpe, N.; Verhe´, R. In The chemistry of R-haloketones,
R-haloaldehydes and R-haloimines; Patai, S., Rappoport, Z., Eds.; Wiley:
New York, 1988.
188
Org. Lett., Vol. 9, No. 2, 2007

The best results were obtained if 2.2 equiv of PhMgCl
were added across ketimine (RS)-2a in dichloromethane at
-78 °C. Subsequent stirring for 2 h at -78 °C and 4 h at
-40 °C afforded 1-phenylcyclopropylamine (RS,R)-5a after
aqueous NH4Cl workup in high yield (70%) and excellent
diastereoselectivity (95:5 dr).
In order to explore the scope of the Grignard addition
reaction across ketimine (RS)-2a, a variety of different
Grignard reagents were evaluated. The optimized reaction
conditions, found in the addition reaction of PhMgCl across
ketimine (RS)-2a, were applied for EtMgCl, EtMgBr, and
vinylMgBr upon addition of N-sulfinyl R-chloro ketimine
(RS)-2a (Scheme 3), affording the substituted N-sulfinyl
Better yields of 2-allylaziridine (RS,R)-7 were obtained if
the Grignard reagent was added in a small excess (1.05 equiv
instead of 2.2 equiv) and the mixture stirred for longer
periods at -78 °C (5 h).
The steric bulk of ketimines (RS)-2b,c, upon treatment with
Grignard reagents, resulted in good diastereoselectivities of
the cyclopropylamines formed (Table 2). However, the yields
Table 2. Addition of Grignard Reagents to N-Sulfinyl
R-Chloro Ketimines 2b,c
Scheme 3. Addition of Grignard Reagents to Chiral
N-Sulfinyl R-Chloro Ketimine 2a
entry imine
R′
Ph
product yielda (%) (dr)b
yieldc (%)
a
b
c
2b
2b
2b
2b
2c
2c
2c
8a
8b
8c
50 (95:5)
57 (79:21)
62 (91:9)
91 (95:5)
44 (96:4)
42 (81:19)
83 (93:7)
(Rs,R)-8a (38)
(Rs,R)-8b (30)
(Rs,S)-8c (37)
(Rs,R)-9 (84)
(Rs,R)-10a (31)
(Rs,R)-10b (23)
(Rs,R)-11 (65)d
Et
vinyl
allyl
Ph
Et
allyl
d
e
f
9
10a
10b
11
g
a Determined by a mass balance of the reaction mixture. b Determined
by NMR analysis of the reaction mixture. c Determined by a mass balance
after chromatography. d Cyclopropylamine (RS,R)-10d was isolated in 2%
yield.
cyclopropylamines (RS,R)-5b and (RS,S)-5c in high yield
(77-82%) with good diastereoselectivity (79:21-91:9).
Changing EtMgCl to EtMgBr resulted in the formation
of a less complicated reaction mixture. Still, with reference
to the other nucleophiles used, the stereoselectivity of the
addition of EtMgBr was lower (Scheme 3). As a result, both
diastereomers 5b were obtained.
The cyclopropylamines (RS,R)-5a,b and (RS,S)-5c formed
were isolated as a single compound after flash chromatog-
raphy. Consequently, the yields dropped significantly during
purification. Only 1-phenylcyclopropylamine (RS,R)-5a could
be obtained by recrystallization of the reaction mixture in
diethyl ether. Upon treatment of ketimine (RS)-2a with 2.2
equiv of allylMgCl in dichloromethane at -78 °C for 2 h
and subsequent reaction for 4 h at -40 °C, N-(1-allylcyclo-
propyl)-tert-butanesulfinamide (RS,R)-5d was not formed.
Ketimine (RS)-2a was attacked at the imine function without
preceding R-deprotonation. The intermediate â-halo N-
sulfinamide 6 was in situ ring closed toward the correspond-
ing N-sulfinyl 2-allylaziridine (RS,R)-7. A closely related
synthesis of chiral aziridines by the use of Grignard reagents
and N-sulfinyl R-chloro aldimines has recently been de-
scribed by us.11
of the cyclopropylamines isolated dropped significantly.
Troublesome purification by flash chromatography was
inevitable. Though various solvent mixtures were used, all
attempts to isolate and identify the side products failed. Upon
treatment of ketimine (RS)-2b in dichloromethane with 1.05
equiv of allylMgCl the 2-allylaziridine 9 was isolated in 84%
yield and 95:5 dr after completion of the reaction at -78 °C
(6 h). Noteably, some of the 1-allylcyclopropylamine (RS,R)-
1
8d was observed by H NMR (3%) but the formed side
product could not be isolated. Reaction of ketimine (RS)-2c
with 1.05 equiv of allylMgCl at -78 °C afforded 1-allylspiro-
[2.5]octan-1-amine (RS,R)-10d after flash chromatography
in low yield (2%) in addition to 2-allylazaspiro[2.5]octane
(RS,R)-11 (65%).
It is proposed that the cyclopropanation reaction proceeds
via a Favorskii-type reaction mechanism (Scheme 4).12
Hence, the first equivalent of Grignard reagent acts as a base,
an unprecedented reaction in this field. A proton in R-position
of the imino function of ketimines (RS)-2 is abstracted, the
resulting 1-azaallylic anion 12-13 undergoing chloride
expulsion to produce the intermediate N-(cyclopropylidene)-
(11) Denolf, B.; Mangelinckx, S.; To¨rnroos, K. W.; De Kimpe, N. Org.
Lett. 2006, 8, 3129.
(12) De Kimpe, N.; Sulmon, P.; Moe¨ns, L.; Schamp, N.; Declercq, J.-
P.; Van Meerssche; M. J. Org. Chem. 1986, 51, 3839.
Org. Lett., Vol. 9, No. 2, 2007
189

absolute configuration had to be determined. From the X-ray
diffraction analysis of the formed cyclopropylamine (RS,S)-
5c the absolute configuration of the structure was undoubt-
edly characterized as (RS,S)-N-(tert-butanesulfinyl)cyclopropyl-
amine 5c. This configuration can be predicted via a chelation-
controlled transition state A (Figure 1), which is the general
intermediate proposed for additions to non-functionalized
N-sulfinyl imines.5,6,14
Scheme 4. Proposed Favorskii-Type Reaction Mechanism
tert-butanesulfinamide 14, which is attacked by the second
equivalent of Grignard reagent across the reactive imino
function of 14 giving rise to cyclopropylamine 5, 8, or 10
after aqueous NH4Cl workup. The highly strained Favorskii-
type intermediate 14, in combination with the bulky tert-
butanesulfinyl group, results in the formation of an enantio-
enriched cyclopropylamine 5, 8, or 10.
All attempts to isolate the intermediate N-cyclopropylidene
sulfinamide 14 failed. Addition of different bases (1.05 equiv
of PhMgCl, BuLi, or NaH) yielded a complex reaction
mixture wherein the cyclopropyl protons in 1H NMR, or the
imino function, specific at 1800 cm-1 in IR, were not
observed. By use of Ellman’s procedure,13 the intermediate
aza enolate 12-13 of imine 2a (R ) Me) was trapped with
benzaldehyde affording N-[2-chloro-1-(2-hydroxy-2-phenyl-
ethyl)-2-methylpropylidene]-tert-butanesulfinamide in a 2:1
mixture of diastereomers.
The chiral N-sulfinyl allylaziridines (RS,R)-9 and -11 and
N-sulfinyl cyclopropylamines 5, 8, and 10 could be depro-
tected by simple treatment with a saturated solution of dry
HCl in 1,4-dioxane. Stirring for 15 min at room temperature
afforded the HCl salts of the aziridines 16 and 17 or the
cyclopropylamines 18-20 in high yield (>85%) and purity
(85-95%) (Scheme 5).
Figure 1. Proposed transition states during the reaction
Though it is was not possible to prove the absolute
configuration of allylaziridines 16 and 17, the (RS,R)-
stereochemistry is assumed in analogy with the stereochem-
istry obtained during the synthesis of similar aziridines from
chiral aldimines.11 The reversal of stereochemical outcome
of the reaction is attributed to the R-coordinating ability of
the chlorine atom as is depicted in Figure 1 (transition state
B and C) and is analogous to the results obtained with other
N-sulfinyl imines containing an R-coordinating group, such
as a nitrogen or oxygen atom.14a,15
In conclusion, an efficient synthesis of N-sulfinyl R-chloro
ketimines was developed. Upon treatment of N-sulfinyl
R-chloro ketimines (RS)-2 with Grignard reagents, chiral
N-(1-substituted cyclopropyl)-tert-butanesulfinamides 5, 8,
and 10 were synthesized in acceptable to good yields with
good diastereoselectivity via 1,3-dehydrohalogenation to a
cyclopropylideneamine intermediate which underwent ad-
dition of organomagnesium nucleophiles with high selectiv-
ity. Only in the case of allylmagnesium chloride did the
reaction lead to aziridines (RS,R)-7, 9, and 11 in high yield.
Further deprotection toward the N-unprotected cyclopropyl-
amines 18-20 was established and the absolute configuration
was determined.
Scheme 5. Sulfinyl Deprotection in 1,4-Dioxane‚HCl
Acknowledgment. Research funded by a Ph.D. grant of
the Institute for the Promotion of Innovation through Science
and Technology in Flanders (IWT-Vlaanderen).
Supporting Information Available: Experimental details
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0622054
(13) (a) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 6518. (b) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc.
2003, 125, 11276.
(14) (a) Davis, F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396. (b)
Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001, 66, 8772.
(15) (a) Fujisawa, T.; Kooriyama, Y.; Shimizu, M. Tetrahedron Lett.
1996, 37, 3881. (b) Kuduk, S. D.; DiPardo, R. M.; Chang, R. K.; Ng, C.;
Bock, M. G. Tetrahedron Lett. 2004, 45, 6641.
Without any of the cyclopropylamines (R)-18-20 or
aziridines (R)-16 and -17 being reported in literature, the
190
Org. Lett., Vol. 9, No. 2, 2007