Stereochemistry of the Kulinkovich cyclopropanation of nitriles

Article abstract of DOI:10.1021/jo900823h

(Chemical Equation Presented) The stereochemistry of the Kulinkovich cyclopropanation of nitriles with alkenes has been examined by employing (E)-disubstituted alkenes and deuterium-labeled homoallylic alcohols as a stereo-chemical probe. An intramolecula

Full text of DOI:10.1021/jo900823h

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Stereochemistry of the Kulinkovich Cyclopropanation of Nitriles
Dmitry Astashko, Hyung Goo Lee, Denis N. Bobrov, and Jin K. Cha*
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202
jcha@chem.wayne.edu
Received April 21, 2009
The stereochemistry of the Kulinkovich cyclopropanation of nitriles with alkenes has been examined
by employing (E)-disubstituted alkenes and deuterium-labeled homoallylic alcohols as a stereo-
chemical probe. An intramolecular cyclopropanation proceeds with preservation of the olefin
configuration. On the other hand, intermolecular counterparts occur with both preservation and
reversal of the olefin configuration, which corresponds to retention and inversion of configuration at
the Ti-C bond, respectively, in the cyclopropane-forming step. These uncommon stereochemical
outcomes contrast with that of the Kulinkovich cyclopropanation of tertiary amides.
Introduction
cyclopropanation involving a dialkoxytitanacyclopropane or
titanium(II)-alkene complex has broadened the scope of the
Kulinkovich reaction.7 An elegant deuterium labeling study by
Casey and Strotman has established that the titanium homo-
enolate intermediates derived from esters undergo cyclization
with retention of configuration at the Ti-C bond.8 In contrast,
the respective ring closure in the Kulinkovich cyclopropana-
tion of amides entails addition of the Ti-C bond to the
iminium ion intermediates with inversion of configuration in
a W-shaped transition state.8,9 The stereochemical course of
the Kulinkovich cyclopropanation of nitriles is subtle in view
The exploration of cyclopropane’s unique reactivity offers
a useful tool in organic synthesis. The incorporation of a
heteroatom substituent onto the ring enhances reactivity.
For example, hydroxycyclopropanes (cyclopropanols) have
been frequently utilized to exploit their facile ring cleavage.
Kulinkovich and co-workers discovered an efficient method
for preparing cyclopropanols from esters in 1989,1 and the
Kulinkovich cyclopropanation has since been extended to
other carboxylic acid derivatives such as amides and nitriles
to afford the corresponding heteroatom-substituted cyclo-
propanes.2-6 An olefin exchange variant of the Kulinkovich
ꢀ
of the likely intermediacy of imines (vis-a-vis iminium ions)
and has been unexplored. By building on the recently disclosed
cyclopropanation of nitriles with homoallylic alcohols, we
report herein a stereochemical study of the Kulinkovich
cyclopropanation of nitriles.
(1) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pritytskaya,
T. S. Zh. Org. Khim. 1989, 25, 2244.
(2) For reviews, see: (a) Kulinkovich, O. G.; de Meijere, A. Chem. Rev.
2000, 100, 2789. (b) Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100,
2835. (c) Kulinkovich, O. G. Russ. Chem. Bull., Int. Ed. 2004, 53, 1065.
(3) Amides: (a) Chaplinski, V.; de Meijere, A. Angew. Chem., Int. Ed.
Engl. 1996, 35, 413. (b) Lee, J.; Cha, J. K. J. Org. Chem. 1997, 62, 1584.
Compare (c) Masalov, N.; Feng, W.; Cha, J. K. Org. Lett. 2004, 6, 2365.
(4) Carbonates: Lee, J.; Kim, Y. G.; Bae, J. G.; Cha, J. K. J. Org. Chem.
1996, 61, 4878.
Results and Discussion
Our initial approach utilized a disubstituted olefin as the
stereochemical probe by adaptation of Six’s intramolecular
(5) Nitriles: (a) Bertus, P.; Szymoniak, J. Chem. Commun. 2001, 1792. (b)
Bertus, P.; Szymoniak, J. J. Org. Chem. 2002, 67, 3965. (c) Laroche, C.;
Bertus, P.; Szymoniak, J. Tetrahedron Lett. 2003, 44, 2485. (d) For a review,
see: Bertus, P.; Szymoniak, J. Synlett 2007, 1346. (e) Joosten, A.; Vasse, J.-L.;
Bertus, P.; Szymoniak, J. Synlett 2008, 2455. (f) Bertus, P.; Menant, C.;
Tanguy, C.; Szymoniak, J. Org. Lett. 2008, 10, 777.
(7) (a) Lee, J.; Kang, C. H.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996,
118, 291. (b) Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 4198.
(8) Casey, C. P.; Strotman, N. A. J. Am. Chem. Soc. 2004, 126, 1699.
(9) (a) Ouhamou, N.; Six, Y. Org. Biomol. Chem. 2003, 1, 3007. (b)
Madelaine, C.; Six, Y.; Buriez, O. Angew. Chem., Int. Ed. 2007, 46, 8046. (c)
Madelaine, C.; Ouhamou, N.; Chiaroni, A.; Vedrenne, E.; Grimaud, L.; Six,
Y. Tetrahedron 2008, 64, 8878.
(6) Nitriles: Babrov, D.; Kim, K.; Cha, J. K. Tetrahedron Lett. 2008, 49,
4089.
5528 J. Org. Chem. 2009, 74, 5528–5532
Published on Web 06/15/2009
DOI: 10.1021/jo900823h
r
2009 American Chemical Society

Astashko et al.
JOCArticle
cyclopropanation of disubstituted alkene-tethered amides,
which proceeded in modest (20-40%) yields but with stereo-
specificity.9 All known (intramolecular) cyclopropanation
reactions of nitriles were limited to monosubstituted alkenes,
except for one example of a gem-disubstituted alkene.5c
However, we speculated that nitriles could be more amenable
to coupling with disubstituted olefins than amides, as low-
valent titanium species would bind more strongly to nitriles.
Toward this end (E)- and (Z)-substrates 1 and 2 were
subjected to intramolecular cyclopropanation (by the action
of the cyclohexyl Grignard reagent) to produce cyclopropy-
lamines 3 and 4, respectively (Scheme 1). Both cyclopropa-
nation reactions were stereospecific and occurred with
retention of the olefin configuration, and the yields were
higher than the cognate cyclopropanation reactions of
amides. The stereochemical assignment rested on the cou-
SCHEME 1
pling constants between two cyclopropane protons (Jtrans
=
3.7 Hz in 3 vs Jcis = 8.9 Hz in 4), along with NOE
measurements. Little difference in the product yield between
(E)- and (Z)-alkenes was observed. Although details for ring
closure of B to 4 are unknown, a plausible pathway likely
involves C (where metal = Mg or Ti) or an open transition
state (not shown).
The use of a disubstituted alkene as the stereochemical
probe was next extended to intermolecular cyclopropanation
of nitriles by taking advantage of the directing effects of a
homoallylic alcohol. We have recently shown that in situ
formation of a temporary tether to the metal center is
indispensable to the successful implementation of olefin-
exchange mediated cyclopropanation to nitriles.5e,6 Cou-
pling between (E)-homoallylic alcohols 5-7 and nitriles
8a-c was thus examined under previously reported condi-
tions (Table 1 and Scheme 2).10 The aminocyclopropane
products 9a-c/90a-c 11a-c, and 12b were obtained in
modest yields from alcohols 5, 6, and 7, respectively, whereas
significant amounts of uncyclized ketones (e.g., 10a-c)
were also isolated in most cases.10d The latter products
were reduced when TMSOTf was added.6 These examples
represent the first successful cyclopropanation reactions
of disubstituted alkenes with nitriles. Interestingly, the cor-
responding (Z)-olefin isomers of 5-7 was recovered un-
reacted.
TABLE 1. Cyclopropanation of Homoallylic Alcohols with Nitriles
entry
nitrile
TMSOTf, time
% dr; 9:90
10 (%)
The product ratios were influenced by several reaction
variables, such as the structure of homoallylic alcohol or
nitrile substrates, the reaction time (after the reaction mix-
ture was allowed to warm to room temperature), and the
presence of TMSOTf. Cyclopropanation of alcohols 6 and 7
yielded additional diastereomers in contrast with that of 5
(Scheme 2). A secondary alcohol was not examined to
bypass complications arising from low 1,3-diastereocontrol
by the resulting stereocenter.6 The stereochemical assign-
ment of the major isomers rested on the coupling constants
1
2
3
4
5
6
7
8
9
8a
8a
8a
8b
8b
8b
8c
8b
8b
0 equiv, ∼12 h
0 equiv, 24 h
5 equiv, ∼12 h
0 equiv, ∼12 h
0 equiv, 24 h
5 equiv, ∼12 h
0 equiv, ∼12 h
0 equiv, 24 h
5 equiv, ∼12 h
39; 1:4
42; 1:3
50; 1:2
25; 2:1
28; 2:1
35; 2:1
40; 1:6
43; 1:5
55; 1:2
35
37
20
35
33
15
between two cyclopropane protons and was also corrobo-
rated by 11a,b f 13a,b. Most importantly, the formation of
the major isomers from alcohols 6 and 7 entails reversal of
the olefin configuration (i.e., cis products from (E)-alkenes)
owing to inversion of configuration at the Ti-C bond in the
cyclopropane-forming step (i.e., due to the overlap between
the small lobe of the σ(C-Ti) orbital and the π* orbital of the
imine). However, there was no noticeable trend in the
cyclopropanation of cyclopropanol 5 in that the major
isomers arose from either retention (having J = 6.1-6.5
(10) (a) During the development of intermolecular coupling between
nitriles and homoallylic alcohols, the use of MeTi(O-i-Pr)3 (1 equiv) and the
cyclohexyl Grignard reagent (2 equiv) was also found to be satisfactory but
did not offer an advantage over the present procedure (except for 7). (b) In
the case of tertiary alcohol 7, however, the pre-formation of the mixed
titanate by the action of MeTi(O-i-Pr)3 was required for the successful
cyclopropanation. (c) Several cyclopropylamine products underwent slow
decomposition during chromatography, which precluded isolation of pure
minor isomers for full characterization. (d) The uncyclized ketones were
isolated in 20-38% and 13% yields from cyclopropanation of 6 and 7,
respectively, but are not shown in Scheme 2 for convenience.
J. Org. Chem. Vol. 74, No. 15, 2009 5529

Astashko et al.
JOCArticle
SCHEME 2
SCHEME 4
SCHEME 3
16b,c. Whereas the structure of a nitrile (8b vs 8c) seems to
affect the degree of stereoselectivity, the major products 16b,
c and 17b,c arise from reversal of the olefin configuration in
accord with inversion of configuration at the Ti-C bond in
the ring-closure step. The minor products involve retention
of the olefin configuration judging from J=8.9-9.2 Hz.
A plausible mechanism starts with initial formation of D
under typical Kulinkovich reaction conditions (Scheme 4).
Subsequent olefin exchange is promoted by a temporary
linker generated from the homoallylic alcohol functionality
to afford bicyclic intermediate G. A dissociative pathway via
E might also be possible.12 As noted earlier, the intermediacy
of F is deemed to be less likely.13 The alternate mode
of coupling leading to H can be envisioned, but its forma-
tion might be slower. (Z)-Disubstituted alkenes would be
Hz between two cyclopropane protons) or reversal (having
J=9.7 Hz) of the olefin configuration. Taken together, these
results suggest a small difference in activation energy be-
tween two stereochemical pathways.
Additional examples were examined by utilizing deuter-
ium-labeled homoallylic alcohols 14 and 15 to probe
subtle factors (including an Rtrans substituent) that affect
the stereochemical outcome of the nitrile cyclopropanation
(Scheme 3).11 As expected, these reactions gave the cyclo-
propylamine products in yields higher than those of the
corresponding disubstituted homologues (Scheme 2). The
stereochemical determination was established by the deter-
mination of J values (5.2-5.7 Hz between the trans cyclo-
propane protons) as well as clean formation of 18b,c from
(12) Under otherwise identical conditions the cyclopentyl Grignard
reagent was known to react with nitriles to give the corresponding bicyclic
aminocyclopropanes.5 This conspicuous difference between cyclohexyl and
cyclopentyl Grignard reagents supports the intermediacy of D and can be
rationalized in terms of different relative rates for ring closure versus olefin
exchange.
(11) (a) Alcohols 14 and 15 were prepared by stereoselective hydrobora-
tion or hydrozirconation of deuterated alkynes to ensure complete deuterium
labeling. (b) The cyclopropanation reactions of nondeuterated substrates
were also undertaken to secure Jtrans for comparison.
(13) Isolation of uncyclized ketones (e.g., 10) is consistent with the
regiochemistry of intermediate G.
5530 J. Org. Chem. Vol. 74, No. 15, 2009

Astashko et al.
JOCArticle
1
recalcitrant to the requisite formation of G presumably as a
result of unfavorable nonbonding interactions with Rcis placed
in the concave face. The involvement of D in place of F is
consistent withthe atypicalreversal in the order of reactivity of
(E)- and (Z)-alkenes toward a transition metal.14,15
(52-62%) of pure cyclopropylamine 3: H NMR (500 MHz,
CDCl3) δ 0.78 (apparent t, J=3.7 Hz, 1H), 1.11 (d, J=6.4 Hz, 3
H), 1.31 (dq, J=6.4, 3.7 Hz, 1H), 1.51 (br s, 2 H), 2.38 (d, J=8.6
Hz, 1H), 2.48 (dd, J=8.3, 3.7 Hz, 1H), 2.87 (d, J=8.6 Hz, 1H),
2.98 (d, J=8.3 Hz, 1H), 3.58 (s, 2H), 7.18-7.28 (m, 5H); 13C
NMR (125 MHz, CDCl3) δ 11.8, 19.1, 30.4, 44.2, 55.2, 59.2,
62.3, 126.7, 128.1, 128.5, 139.4; MS (ESI) m/z 203.36 (M+H+),
204.34 (M +2H+); HRMS calcd for C13H19N2 (M + H+)
203.1548, found 203.1554.
Cyclopropylamine 4 was obtained in 52-62% yield from
nitrile 2 under identical conditions: 1H NMR (500 MHz, CDCl3)
δ 1.04-1.11 (m, 1H), 1.21 (dt, J=8.9, 2.6 Hz, 1H), 1.25 (d, J=6.4
Hz, 3H), 1.85 (br s, 2 H), 2.56 (d, J=9.0 Hz, 1H), 2.79 (d, J=2.6
Hz, 2H), 3.06 (d, J=9.0 Hz, 1H), 3.59 (s, 2H), 7.19-7.35 (m,
5H); 13C NMR (125 MHz, CDCl3) δ 7.3, 23.3, 27.7, 44.6, 52.7,
59.8, 60.2, 126.7, 128.1, 128.3, 139.7; MS (ESI) m/z 203.33 (M+
H+), 204.34 (M+2H+); HRMS calcd for C13H19N2 (M+H+)
203.1548, found 203.1555.
General Procedure for Intermolecular Cyclopropanation of
Nitriles with Alcohols 5, 6, 14, and 15. (A) Without TMSOTf.
A solution of chlorotitanium triisopropoxide (0.12 mL, 0.5 mmol)
in diethyl ether (1.0 mL) was cooled to -78 °C under an atmo-
sphere of nitrogen. A 2 M solution of cyclohexylmagnesium
chlorideindiethyl ether (0.63 mL, 1.26 mmol)was addeddropwise
within 5 min at the same temperature. After the mixture had been
stirred for an additional 45 min, a solution of a homoallylic
alcohol (0.25 mmol) and a nitrile (0.5 mmol) in ether (1.0 mL)
was added in one portion at -78 °C. The reaction mixture was
allowed to slowly warm to rt (∼20 °C) (over approximately 1.5 h),
stirred for an additional 12 or 24 h, and then treated with 10%
NaOH (3 mL) at 0 °C. Two phases separated in 30 min, and the
aqueous layer was extracted with ether (4 ꢀ 5 mL). The combined
organic extracts were dried with Na2SO4. The solvent was re-
moved under reduced pressure. Purification of the concentrate by
silica gel chromatography using a MeOH-CH2Cl2 gradient gave
the corresponding cyclopropylamine products.
Three possible modes of ring closure, I, J, and K, can be
envisioned, where intervention of an iminium ion intermedi-
ate is not obligatory for the formation of a cyclopropane
ring. The first two trigger frontside attack (i.e., retention of
configuration) of the Ti-C bond at the imine. On the other
hand, K is poised to cyclize via a sterically less encumbered
W-shaped transition state with inversion of configuration at
the Ti-C bond.8 This inversion of configuration results in
the cis relationship between Rtrans and the alcohol-tethered
side chain from an (E)-alkene substrate. Possible interactions
between the imine nitrogen and the metal center favor the
formation of the seven-membered titanate intermediate to
account for the cis relationship of the primary amine and the
alcohol-tethered side chain.
Conclusion
In summary, an intramolecular cyclopropanation of an
alkene-tethered nitrile proceeds with retention of the olefin
configuration, but intermolecular coupling between a homo-
allylic alcohol and a nitrile is not stereoselective. This
remarkable dichotomy in the stereochemical outcome be-
tween intramolecular and intermolecular cyclopropanations
of nitriles might be attributed to geometrical constraints
imposed by the bicyclic titanate B in the former reaction.16
The remarkable disparity in stereochemistry between intra-
molecular cyclopropanation reactions of nitriles and amides
(bearing an N-alkenyl tether)9 is also noteworthy.
General Procedure for Intermolecular Cyclopropanation of
Nitriles with Alcohols 5 and 6. (B) With TMSOTf. A solution
of chlorotitanium triisopropoxide (0.12 mL, 0.5 mmol) in
diethyl ether (1.0 mL) was cooled to -78 °C under an atmo-
sphere of nitrogen. A 2 M solution of cyclohexylmagnesium
chloride in diethyl ether (0.63 mL, 1.26 mmol) was added drop-
wise within 5 min at the same temperature. After the mixture had
been stirred for an additional 45 min, a solution of a homoallylic
alcohol (0.25 mmol) and a nitrile (0.5 mmol) in ether (1.0 mL)
was added in one portion at -78 °C. The reaction mixture was
allowed to slowly warm to rt (over approximately 1.5 h), stirred
for an additional 3 h, and then recooled to -78 °C. TMSOTf
(0.23 mL, 1.25 mmol) was added in one portion. The reaction
mixture was allowed to slowly warm to rt (∼20 °C), stirred
overnight (∼ 15 h), and then treated with 10% NaOH (3 mL) at
0 °C. Two phases separated in 30 min, and the aqueous layer was
extracted with ether (4 ꢀ 5 mL). The combined organic extracts
were dried with Na2SO4. The solvent was removed under
reduced pressure. Purification of the concentrate by silical gel
chromatography using MeOH-CH2Cl2 gradient gave the cor-
responding cyclopropylamine products.
Experimental Section
Representative Procedure for Intramolecular Cyclopropana-
tion of Olefin-Tethered Nitriles. To a solution of nitrile 1 (0.1 g,
0.5 mmol) and titanium(IV) isopropoxide (0.16 mL, 0.55 mmol)
in diethyl ether (3 mL) under an atmosphere of nitrogen was
added at rt (∼20 °C) slowly (over a period of 1 h) a 2 M solu-
tion of cyclohexylmagnesium chloride in diethyl ether (0.6 mL,
1.2 mmol). The reaction mixture was stirred for an additional 2
h, treated with 10% NaOH (0.6 mL) at 0 °C, and allowed to stir
for 1 or 2 h. Inorganic precipitates were filtered off through a
pad of Celite, and the filter cake was washed thoroughly with
ether. The combined filtrates were washed with brine and dried
with Na2SO4. The solvent was removed under reduced pressure.
Purification of the residue by silical gel chromatography using a
gradient (0:100 to 1:5 MeOH-CH2Cl2) afforded 53-63 mg
(14) In recent examples of intramolecular cyclopropanation reactions of
(E)- and (Z)-disubstituted alkenes bearing amide groups, faster reactions
were presumed for (Z)-isomers.9c
(15) (a) These putative intermediates in Scheme 4 have eluded isolation for
full characterization. For a computational study on the related Kulinkovich
cyclopropanation of esters, see: Wu, Y.-D.; Yu, Z.-X. J. Am. Chem. Soc. 2001,
123, 5777. (b) The reactivity of the Kulinkovich reagent is conceptually related
to that of the Negishi reagent: Negishi, E.; Huo, S. In Titanium and Zirconium
in Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim, 2002; pp 1-49.
See also : Buchwald, S. L.; Watson, B. T.; Wannamaker, M. W.; Dewan, J. C.
J. Am. Chem. Soc. 1989, 111, 4486.
(16) (a) The atypical dichotomy is indicative of a small difference in
activation energy between two modes of the final cyclization step: complex-
ation between the titanium metal and the imine functional group predisposes
to retention of configuration; on the other hand, inversion of configuration is
favored on grounds of stericeffects. (b) It isinteresting to notethat an idealized
W-shaped transition state is unattainable for the bicyclic titanate B, which
might help reinforce ring closure with retention of configuration.
1
Cyclopropylamine 90a (Major Isomer). H NMR (400 MHz,
C6D6) δ 0.24 (ddd, J=8.1, 6.1, 3.7 Hz, 1H), 0.38-0.48 (m, 2H),
0.50 (apparent q, J=6.1 Hz, 1H), 0.89-0.94 (m, 2H), 0.92 (t, J=
7.3 Hz, 3H), 0.95 (s, 3H), 1.08 (m, 1H), 1.23 (m, 1H), 1.65 (dd,
J=15.0, 8.1 Hz, 1H), 1.87 (dd, J=15.0, 3.7 Hz, 1H), 2.32 (br s,
3H); 13C NMR (125 MHz, C6D6) δ 13.0, 13.8, 14.5, 22.7, 23.3,
29.6, 32.6, 36.2, 36.9, 55.0; MS (ESI) m/z 170.36 (M + H+);
HRMScalcd for C10H20NO (M+H+) 170.1545, found 170.1539.
1
Cyclopropylamine 9a (Minor Isomer). H NMR (400 MHz,
C6D6) δ 0.34-0.43 (m, 3H), 0.63 (dt, J=9.7, 4.1 Hz, 1H), 0.85-
0.95(m, 2H), 0.90(t, J=7.3Hz, 3H), 1.09 (s, 3H), 1.23(dq, J=7.3,
J. Org. Chem. Vol. 74, No. 15, 2009 5531

Astashko et al.
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3.2 Hz, 2H), 1.28 (dd, J=14.6, 4.1 Hz, 1H), 1.87 (ddd, J=14.6,
9.7, 1.6 Hz, 1H), 2.10 (br s, 3H); HRMS calcd for C10H20NO
(M+H+) 170.1545, found 170.1543.
cyclopropylamine products as a mixture of isomers. 12b (major
isomer): 1H NMR (500 MHz, C6D6) δ 0.63 (dt, J=9.2, 7.0 Hz,
1H), 0.73 (dt, J=9.2, 4.7 Hz, 1H), 0.88 (t, J=7.3 Hz, 3H), 1.15 (s,
3H), 1.16 (s, 3H), 1.17 (brs, 3H), 1.27-1.34 (m, 2H), 1.49 (dd, J =
13.4, 4.7 Hz, 1H), 1.54 (dd, J = 13.4, 9.2 Hz, 1H), 2.36 (d, J=13.7
Hz, 1H), 2.59 (d, J=13.7 Hz, 1H), 7.03-7.11 (m, 4H), 7.12-7.18
(m, 1H); 13C NMR (125 MHz, C6D6) δ 14.6, 17.1, 21.8, 22.8, 28.7,
29.2, 30.6, 37.0, 39.4, 49.4, 70.0, 126.6, 128.6, 129.7, 139.9; MS
(ESI) m/z 263.37 (M+H+), 264.38 (M+2H+); HRMS calcd for
C16H27N2O (M+H+) 263.2123, found 263.2115.
Preparation of Cyclopropylamine 12b by Cyclopropanation
with MeTi(O-i-Pr)3. To a solution of methyltitanium triisoprop-
oxide (0.07mL, 0.3mmol)indiethylether(1.0 mL)undernitrogen
was added at rt dropwise (over 5 min) a solution of alcohol 7
(38.4 mg, 0.3 mmol) in ether (0.5 mL). After the mixture had been
stirred for 30 min, a solution of nitrile 8b (29.5 mg, 0.25 mmol) in
ether (0.5 mL) was added in one portion, followed by slow
addition (over 1 h by using a syringe pump) of a 2 M solution
of cyclohexylmagnesium chloride in ether (0.25 mL, 0.5 mmol).
The reaction mixture was stirred at rt for an additional 3 h and
then treated with 10% NaOH (3 mL) at 0 °C. Two phases
separated in 30 min, and the aqueous layer was extracted with
ether (4 ꢀ 5 mL). The combined organic extracts were dried with
Na2SO4. The solvent was removed under reduced pressure.
Purification of the concentrate by silical gel chromatography
using a MeOH-CH2Cl2 gradient (1:100 to 1:10) afforded the
Acknowledgment. We thank NSF (CHE-0615604) and
NIH (GM35956) for generous financial support.
Supporting Information Available: Full characterization
data for all new cyclopropyl amines and copies of their 1H and
13C NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
5532 J. Org. Chem. Vol. 74, No. 15, 2009