Ti(II)-mediated conversion of α-heterosubstituted (O, N, S) nitriles to functionalized cyclopropylamines. Effect of chelation on the cyclopropanation step

Article abstract of DOI:10.1021/jo025634y

α-Alkoxy, amino-, and thio nitriles undergo a Ti(II)-mediated coupling with Grignard reagents to afford heterofunctionalized cyclopropylamines. A chelation effect appears to be generally responsible for the spontaneous contraction of the intermediate azatitanacycle leading to cyclopropane. By using the described reaction, 1-aminocyclopropanecarboxylic acids were prepared in four steps, in good overall yields, from the readily available benzyloxyacetonitrile.

Full text of DOI:10.1021/jo025634y

J . Org. Chem. 2002, 67, 3965-3968
3965
Sch em e 1
Ti(II)-Med ia ted Con ver sion of
r-Heter osu bstitu ted (O, N, S) Nitr iles to
F u n ction a lized Cyclop r op yla m in es. Effect
of Ch ela tion on th e Cyclop r op a n a tion Step
Philippe Bertus and J an Szymoniak*
Re´actions Se´lectives et Applications, CNRS, and Universite´
de Reims, 51687 Reims Cedex 2, France
jan.szymoniak@univ-reims.fr
Received February 20, 2002
makes it possible to synthesize N,N-dialkylcyclopropyl-
amines from amides. Recently, we have reported a new
access to primary amines from nitriles.7 In our reaction,
the cyclopropane ring is formed efficiently via a Lewis
acid mediated contraction of the intermediate azatitana-
cycle (Scheme 1, eq 1).8
For example, cyclopropylamine 2 was obtained in 70%
yield from benzyl cyanide (1) in THF or Et2O when BF3‚
OEt2 was used. Interestingly, in the absence of BF3‚OEt2,
2 was also formed but the yields were markedly lower,
i.e., 7% in THF and 31% in Et2O. We anticipated that
weak acid species (Mg, Ti) always present in the reaction
mixture would operate slightly in this case.
By studying the feasibility of preparing 1-(alkoxy-
methyl)-substituted cyclopropylamines from R-alkoxy
nitriles (O-protected cyanohydrins), we noticed that these
reactions proceeded efficiently even in the absence of an
additional Lewis acid. This contrasted not only with the
reactions involving the nonfunctionalized nitriles,7 but
also those involving â-alkoxy nitriles. A striking example
is given through the comparison of the two reactions
using R- and â-benzyloxy nitriles 3 and 5 (Table 1, entries
1 and 2).
Both reactions were carried out in Et2O or THF and
employed 1.1 equiv of Ti(O-i-Pr)4 and 2 equiv of EtMgBr.
Thus, in the absence of BF3‚OEt2, R-benzyloxy nitrile 3
was converted to 4 in 74% yield, while only 5% yield of 6
was obtained starting from the â-benzyloxy nitrile 5 in
Et2O.9 Similar yields of 4 and 6 were obtained in THF.
Significantly, the subsequent addition of BF3‚OEt2 did
not increase the yield of 4 (entry 1) but markedly
increased the yield of 6 (54%, entry 2).
Abstr a ct: R-Alkoxy, amino-, and thio nitriles undergo a Ti-
(II)-mediated coupling with Grignard reagents to afford
heterofunctionalized cyclopropylamines. A chelation effect
appears to be generally responsible for the spontaneous
contraction of the intermediate azatitanacycle leading to
cyclopropane. By using the described reaction, 1-amino-
cyclopropanecarboxylic acids were prepared in four steps,
in good overall yields, from the readily available benzyloxy-
acetonitrile.
Cyclopropylamines have attracted much attention due
to their synthetic potential1 and biological properties.2
In particular, 1-(alkoxymethyl)-substituted cyclopropyl-
amines can be considered as useful intermediates for the
synthesis of 1-aminocyclopropanecarboxylic acids (ACCs).3
Furthermore, the 1-(1-aminoalkyl)-substituted cyclopro-
pylamine moiety is encountered in biologically active
compounds.4 Here, we present a new straightforward
access to such O-, N-, and also S-heterofunctionalized
cyclopropylamines.
Despite their interest, most of the synthetic approaches
to cyclopropylamines are rather specific and require
multistep reactions.1 Among the simpler methods, two
titanium-mediated reactions have been reported. Thus,
the de Meijere5 variant of the Kulinkovich reaction6
* To whom correspondence should be addressed. Fax: +33 326913166.
(1) Vilsmaier, E. In The Chemistry of the Cyclopropyl Group;
Rappoport, Z., Ed.; Wiley: New York, 1987; pp 1341-1454.
(2) (a) Liu, H. W.; Walsh, C. T. In The Chemistry of the Cyclopropyl
Group; Rappoport, Z., Ed.; Wiley: New York, 1987; pp 959-1026. (b)
Salau¨n, J . Top. Curr. Chem. 2000, 207, 1-67. (c) Suckling, C. J . Angew.
Chem., Int. Ed. Engl. 1988, 27, 537-552. (d) Carbocyclic Three- and
Four-membered Ring Systems. In Methods of Organic Chemistry; de
Meijere, A., Ed.; Thieme: Stuttgart, 1997; Houben-Weyl, Vol. E17a-
f.
(3) For the biological activity and the synthesis of these important
series of compounds, see: (a) Alami, A.; Calmes, M.; Daunis, J .;
J acquier, R. Bull. Soc. Chim. Fr. 1993, 130, 5-24. (b) Burgess, K.;
Ho, K.-K.; Moye-Sherman, D. Synlett 1994, 575-583.
(4) (a) Ko, S. S.; Delucca, G. V.; Duncia, J . V.; Kim, U. T.; Wacker,
D. A.; Zheng, C. WO Patent 2001098270; Chem. Abstr. 2001, 136,
69739. (b) Biftu, T.; Feng, D. D.; Liang, G.-B.; Ponpipom, M. M.; Qian,
X.; Girotra, N.; Fisher, M. H.; Wyvratt, M. J . WO Patent 2001034150;
Chem. Abstr. 2001, 134, 366803. (c) See also: Vergne, F.; Aitken, D.
J .; Husson, H. P. J . Org. Chem. 1992, 57, 6071-6075.
(5) Chaplinski, V.; de Meijere, A. Angew. Chem., Int. Ed. Engl. 1996,
35, 413-414. (b) Chaplinski, V.; Winsel, H.; Kordes, M.; de Meijere,
A. Synlett 1997, 111-114. (c) Williams, C. M.; Chaplinski, V.;
Schreiner, P.; de Meijere, A. Tetrahedron Lett. 1998, 39, 7695-7698.
(d) Kordes, M.; Winsel, H.; de Meijere, A. Eur. J . Org. Chem. 2000,
3235-3245. (e) See also: Lee, J .; Cha, J . K. J . Org. Chem. 1997, 62,
1584-1585.
The formation of 4 from 3 in the absence of BF3‚OEt2
can be rationalized by assuming a five-membered chelate,
as depicted in Scheme 1 (eq 2). When the chelation is
involved, the intermediate azatitanacycle would contract
efficiently even in the presence of weak Lewis acid
species. In contrast, when a five-membered chelate
cannot be formed, the contraction step would be efficient
neither for 5 nor for the nonfunctionalized nitriles. It
should be noticed that analogous chelation-promoted
addition of Grignard reagents to R-alkoxy imines is
known.10 Moreover, the dialkylation of nitriles similarly
operates from O-protected cyanohydrins.11
(7) Bertus, P.; Szymoniak, J . Chem. Commun. 2001, 1792-1793.
(8) In contrast to the Kulinkovich and de Meijere reactions, in which
the intermediate oxatitanacycle contracts spontaneously without
requiring an additional Lewis acid, see refs 5 and 6.
(9) Starting from 5, 1-benzyloxy-3-pentanone was the major product
formed (60% yield) on hydrolysis.
(6) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevsky, D. A.;
Prityckaja, T. S. Zh. Org. Khim. 1989, 25, 2244-2245. (b) Kulinkovich,
O. G.; Sviridov, S. V.; Vasilevsky, D. A. Synthesis 1991, 234. (c)
Kukinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789-2834.
10.1021/jo025634y CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/27/2002

3966 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
Sch em e 2a
Ta ble 1. Syn th esis of Cyclop r op yla m in es fr om Nitr iles
a
Reagents: (i) (Boc)2O, NaOH, t-BuOH, H2O; (ii) H2, Pd 5% on
C, MeOH; (iii) KMnO4, NaOH, t-BuOH, H2O.
employing R-alkoxy nitriles and higher Grignard re-
agents proceeded without an additional Lewis acid as
well. The examples are given in entries 5-7 of Table 1.
Noteworthy is the easy preparation of the bicyclic cyclo-
propylamine 13. In such cases, mixtures of diastereo-
meric cyclopropylamines 11-13a ,b can easily be sepa-
rated by flash chromatography.12
The described method also allows to prepare N-func-
tionalized cyclopropylamines (1,2-diamines bearing a
cyclopropane ring) directly from R-aminonitriles. Differ-
ent compounds can be obtained as depicted in Table 1
(entries 8-10), among them pyridine-containing diamine
18. Finally, the title reaction could also be applied to the
synthesis of alkyl- and arylthio-substituted cyclopropyl-
amines 20 and 22 (entries 11 and 12). For these reactions,
however, synthetically useful yields require the use of
an additional Lewis acid, likely due to the relative
softness of the thio nitriles 19 and 21 (Mg and Ti species
being supposed weak and hard Lewis acids).
By using the title reaction, the readily available
benzyloxyacetonitrile (3)13 is revealed to be suitable
starting material for the synthesis of natural and non-
natural 1-aminocyclopropanecarboxylic acids.14 Three
examples are given in Scheme 2.
Boc-protected ACC (25)15a was obtained in four steps,
in 59% total yield from 3, by cyclopropanation, protection
of the amino group, debenzylation, and oxidation of the
resulting alcohol.16 In an analogous way, Boc-protected
coronamic (28a )15b and allo-coronamic (28b)15c acids were
(10) Franz, T.; Hein, M.; Veith, U.; J a¨ger, V.; Peters, E.-M.; Peters,
K.; von Schnering, H. G. Angew. Chem., Int. Ed. Engl. 1994, 33, 1298-
1301.
(11) (a) Gauthier, R.; Axiotis, G. P.; Chastrette, M. J . Organomet.
Chem. 1977, 140, 245-255. (b) Charrette, A. B.; Gagnon, A.; J anes,
M.; Mellon, C. Tetrahedron Lett. 1998, 39, 5147-5150.
(12) The relative stereochemistry of the diastereoisomers was
established by NOE experiments as well as by transformation of 11a ,b
to the known products 27a ,b.
(13) Benzyloxyacetonitrile can be obtained in one step from sodium
cyanide, formaldehyde, and benzyl cyanide; see ref 17a.
(14) Similarly, 3-benzyloxypropionitrile (5) can be used to prepare
â-aminocyclopropanecarboxylic acids.
a
b
Isolated yields. Yields in parentheses refer to an addition of
2 equiv of BF3‚OEt2, 30 min after the addition of Grignard reagent.
c Reaction performed in THF.
(15) (a) Naturally occurring ACC is the precursor of ethylene, a
phytohormone responsible for fruit ripening; see: Pirrung, M. C. Acc.
Chem. Res. 1999, 32, 711-718. (b) Coronamic acid is the constituent
of the bacterial toxin coronatine in Pseudomonas coronafacience var.
atropurpurea; see: Ichiara, A.; Shiraishi, K.; Sato, H.; Sakamura, S.;
Nishiyama, K.; Sakai, R. Furusaki, A.; Matsumoto, T. J . Am. Chem.
Soc. 1977, 99, 636-637. (c) allo-Coronamic acid is a competitive
inhibitor of the ethylene biosynthesis, producing 1-butene; see: Hoff-
man, N. E.; Yang, S. F.; Ichiara, A.; Sakamura, S. Plant Physiol. 1982,
70, 195-199.
Different R-alkoxy or -aryloxy nitriles and Grignard
reagents can be employed to perform the reaction. The
cyclopropanation occurred smoothly, in the absence of a
Lewis acid, with the O-protected propanal cyanohydrin
7 (entry 3, Table 1). Starting from the less coordinating
R-phenoxy nitrile 9, however, a better yield was achieved
when BF3‚OEt2 was added (entry 4). The reactions

Notes
J . Org. Chem., Vol. 67, No. 11, 2002 3967
1.55-1.81 (m, 2 H), 1.75 (s, 2 H, NH2), 2.65 (dd, J ) 8.6, 4.7 Hz,
1 H), 4.52 (d, J ) 11.8 Hz, 1 H), 4.78 (d, J ) 11.8 Hz, 1 H),
7.24-7.40 (m, 5 H); 13C NMR (CDCl3, 125 MHz) δ 9.5, 11.0, 15.9,
25.3, 34.8, 71.0, 86.0, 127,5, 127.6, 128.3, 138.9; MS (EI 70 eV)
m/z 177 (4), 114 (64), 91 (100). Anal. Calcd for C13H19NO‚HCl:
C, 64.59; H, 8.34; N, 5.79. Found: C, 64.57; H, 8.27; N, 5.68.
1-(P h en oxym eth yl)cyclop r op yla m in e (10): pale yellow oil;
80% yield (261 mg); Rf 0.30 (acetone); IR (neat) 3363, 1599, 1495,
simply obtained from 3 through the diastereomeric
benzyloxy cyclopropylamines 11a and 11b. Other 1-(ben-
zyloxymethyl)-substituted cyclopropylamines, readily avail-
able by our method, are potentially useful for the
syntheses of various 1-aminocyclopropanecarboxylic ac-
ids.
In summary, in the presence of Ti(O-i-Pr)4, R-alkoxy,
amino, and thio nitriles readily react with Grignard
reagents to afford functionalized cyclopropylamines. The
chelation effect appears as responsible for the spontane-
ous contraction of the intermediate azatitanacycle leading
to cyclopropane. The described procedure should be a
method of choice for the easy preparation of these useful
series of compounds.
1241 cm-1 1H NMR (CDCl3, 250 MHz) δ 0.60-0.68 (m, 2 H),
;
0.71-0.78 (m, 2 H), 2.00 (s, 2 H, NH2), 3.82 (s, 2 H), 6.85-7.00
(m, 3 H), 7.23-7.32 (m, 2 H); 13C NMR (CDCl3, 63 MHz) δ 12.6,
33.7, 76.1, 114.5, 120.8, 129.5; MS (EI 70 eV) m/z 163 (M•+, 47),
146 (12), 108 (32), 77 (42), 70 (100). Anal. Calcd for C10H13NO‚
HCl: C, 60.15; H, 7.07; N, 7.01. Found: C, 60.05; H, 6.96; N,
6.72.
(E)-1-(Ben zyloxym eth yl)-2-eth ylcyclop r op yla m in e (11a ):
pale yellow oil; 43% yield (175 mg); Rf 0.16 (Et2O); IR (neat) 3362,
1
2958, 1454 cm-1; H NMR (CDCl3, 500 MHz) δ 0.14 (t, J ) 5.2
Exp er im en ta l Section
Hz, 1 H), 0.70 (dd, J ) 8.8, 4.7 Hz, 1 H), 0.86-0.92 (m, 1 H),
0.97 (t, J ) 7.3 Hz, 3 H), 1.10-1.20 (m, 1 H), 1.36-1.42 (m, 1
H), 1.90 (s, 2 H, NH2), 3.41 (d, J ) 9.9 Hz, 1 H), 3.48 (d, J ) 9.9
Hz, 1 H), 4.52 (d, J ) 12.0 Hz, 1 H), 4.55 (d, J ) 12.0 Hz, 1 H),
7.23-7.40 (m, 5 H); 13C NMR (CDCl3, 125 MHz) δ 14.1, 18.5,
22.7, 27.8, 37.4, 72.9, 75.0, 127.4, 127.5, 128.2, 138.3; MS (EI
70 eV) m/z 176 (12, M - Et), 114 (27), 91 (100). Anal. Calcd for
Gen er a l Meth od s. Et2O and THF were distilled from sodium
benzophenone ketyl under argon. All Grignard reagents were
titrated in THF by menthol in the presence of o-phenanthroline
prior to use. Commercially available Ti(O-i-Pr)4, BF3‚OEt2, and
nitrile 17 were distilled under argon. Nitriles 3, 5, 7, 9, 14, 19,
and 21 were prepared following the reported procedures.17
Gen er a l P r oced u r e for th e Syn th esis of Cyclop r op yl-
a m in es 4, 8, 11-13, 15-16, a n d 18. To a solution of the nitrile
(2 mmol) in Et2O (6 mL) were added successively, at room
temperature, Ti(O-i-Pr)4 (0.65 mL, 2.2 mmol) and a Grignard
reagent (4 mmol, 1-2 M in ether). After the mixture was stirred
for 0.5 h, water (ca. 1 mL) was added and the mixture extracted
with ether. The combined ether layers were dried over anhy-
drous sodium sulfate, filtered, and concentrated under reduced
pressure. The resulting crude material was purified by flash
chromatography on silica gel.
Gen er a l P r oced u r e for th e Syn th esis of Cyclop r op yl-
a m in es 6, 10, 20, a n d 22. Ad d ition of a Lew is Acid . To a
solution of the nitrile (2 mmol) in Et2O (6 mL) were added
successively at room temperature Ti(O-i-Pr)4 (0.65 mL, 2.2 mmol)
and a Grignard reagent (4 mmol, 1-2 M in ether). After the
mixture was stirred for 0.5 h, BF3‚OEt2 (0.51 mL, 4 mmol) was
added at once. Stirring was continued over a period of 10 min.
A solution of 10% NaOH (ca. 1 mL) was added, and the mixture
was treated as above.
C
13H19NO‚HCl: C,64.59; H,8.34; N, 5.79. Found: C,64.60; H,
8.24; N, 5.82. (Z)-1-(Ben zyloxym eth yl)-2-eth ylcyclop r op yl-
a m in e (11b): pale yellow oil; 18% yield (75 mg); Rf 0.38 (Et2O);
IR (neat) 3372, 2958, 1454 cm-1; H NMR (CDCl3, 500 MHz) δ
1
0.22 (t, J ) 5.1 Hz, 1 H), 0.59 (dd, J ) 8.9, 4.4 Hz, 1 H), 0.60-
0.68 (m, 1 H), 0.99 (t, J ) 7.5 Hz, 3 H), 1.40-1.55 (m, 2 H), 1.78
(s, 2 H, NH2), 3.25 (d, J ) 9.9 Hz, 1 H), 3.35 (d, J ) 9.9 Hz, 1
H), 4.56 (s, 2 H), 7.23-7.40 (m, 5 H); 13C NMR (CDCl3, 63 MHz)
δ 14.3, 17.3, 21.2, 25.0, 37.4, 72.5, 79.3, 127.4, 127.6, 128.2, 138.4;
MS (EI 70 eV) m/z 176 (11, M - Et), 114 (28), 91 (100).
(E)-1-(Ben zyloxym eth yl)-2-ben zylcyclopr opylam in e (12a):
pale yellow oil; 41% yield (219 mg); Rf 0.19 (Et2O); IR (neat) 3363,
1
1603, 1453 cm-1; H NMR (CDCl3, 250 MHz) δ 0.40 (t, J ) 5.6
Hz, 1 H), 0.88 (dd, J ) 9.1, 5.0 Hz, 1 H), 1.22-1.35 (m, 1 H),
1.90 (s, 2 H, NH2), 2.48 (dd, J ) 15.2, 8.3 Hz, 1 H), 2.83 (dd, J
) 15.2, 6.3 Hz, 1 H), 3.50 (d, J ) 10.0 Hz, 1 H), 3.59 (d, J ) 10.0
Hz, 1 H), 4.58 (d, J ) 12.0 Hz, 1 H), 4.62 (d, J ) 12.0 Hz, 1 H),
7.15-7.40 (m, 10 H); 13C NMR (CDCl3, 125 MHz) δ 19.0, 26.5,
35.2, 37.8, 73.1, 75.1, 125.8, 127.6, 127.7, 128.2, 128.3, 128.4,
138.3, 141.6; MS (EI 70 eV) m/z 267 (M•+, 2), 176 (56), 146 (24),
91 (100). (Z)-1-(Ben zyloxym et h yl)-2-b en zylcyclop r op yl-
a m in e (12b): pale yellow oil; 23% yield (123 mg); Rf 0.67 (Et2O);
1-(Ben zyloxym eth yl)cyclop r op yla m in e (4): colorless oil;
74% yield (262 mg); Rf 0.18 (Et2O); IR (neat) 3361, 2855, 1453
1
cm-1; H NMR (CDCl3, 250 MHz) δ 0.46-0.55 (m, 2 H), 0.55-
1
IR (neat) 3373, 1603, 1453 cm-1; H NMR (CDCl3, 250 MHz) δ
0.68 (m, 2 H), 1.75 (s, 2 H, NH2), 3.38 (s, 2 H), 4.58 (s, 2 H),
7.28-7.40 (m, 5 H); 13C NMR (CDCl3, 63 MHz) δ 12.4, 33.8, 72.7,
78.1, 127.4, 127.6, 128.3, 138.2; MS (EI 70 eV) m/z 177 (M•+, 1),
105 (8), 91 (100). Anal. Calcd for C11H15ON‚HCl: C, 61.82; H,
7.55; N, 6.55. Found: C, 61.58; H, 7.44; N, 6.45.
0.47 (t, J ) 5.4 Hz, 1 H), 0.73 (dd, J ) 9.1, 5.0 Hz, 1 H), 1.00-
1.11 (m, 1 H), 1.80 (s, 2 H, NH2), 2.88 (dd, J ) 15.2, 6.7 Hz, 1
H), 2.89 (dd, J ) 15.2, 7.5 Hz, 1 H), 3.29 (d, J ) 9.9 Hz, 1 H),
3.46 (d, J ) 9.9 Hz, 1 H), 4.53 (s, 2 H), 7.15-7.40 (m, 10 H); 13
C
NMR (CDCl3, 125 MHz) δ 17.5, 24.1, 33.7, 37.6, 72.6, 79.3, 125.7,
127.5, 127.7, 128.2, 128.3, 128.3, 138.4, 142.3; MS (EI 70 eV)
m/z 267 (M•+, 2), 176 (60), 146 (18), 91 (100).
1-(2-Ben zyloxyeth yl)cyclop r op yla m in e (6): yellow oil;
54% yield (206 mg); Rf 0.24 (acetone); IR (neat) 3357, 2857, 1454
1
cm-1; H NMR (CDCl3, 500 MHz) δ 0.43-0.46 (m, 2 H), 0.56-
(E)-6-(Ben zyloxym eth yl)bicyclo[3.1.0]h ex-6-ylam in e (13a):
pale yellow oil; 39% yield (168 mg); Rf 0.45 (MeOH); IR (neat)
3362, 2949, 1453 cm-1; 1H NMR (CDCl3, 250 MHz) δ 1.25-2.00
(m, 10 H), 3.51 (s, 2 H), 4.57 (s, 2 H), 7.22-7.40 (m, 5 H); 13C
NMR (CDCl3, 125 MHz) δ 25.8, 27.3, 33.7, 41.3, 71.7, 73.1, 127.6,
127.8, 128.4, 138.4; MS (CI+, NH3) m/z 218 (M + 1, 42), 112 (100).
(Z)-6-(Ben zyloxym eth yl)bicyclo[3.1.0]h ex-6-yla m in e (13b):
pale yellow oil; 6% yield (27 mg); Rf 0.33 (Ether); ir (neat) 3374,
0.59 (m, 2 H), 1.69 (s, 2 H, NH2), 1.74 (t, J ) 6.3 Hz, 2 H), 3.69
(t, J ) 6.3 Hz, 2 H), 4.52 (s, 2 H), 7.29-7.38 (m, 5 H); 13C NMR
(CDCl3, 125 MHz) δ 14.4, 33.1, 40.0, 69.1, 73.1, 127.6, 127.8,
128.4, 138.4; MS (CI+, NH3) m/z 192 (M + 1, 1), 106 (9), 84 (100).
1-(1-Ben zyloxyp r op yl)cyclop r op yla m in e (8): colorless oil;
73% yield (299 mg); Rf 0.21 (Et2O); IR (neat) 3372, 2961, 1454
1
cm-1; H NMR (CDCl3, 250 MHz) δ 0.25-0.35 (m, 1 H), 0.52-
0.61 (m, 2 H), 0.74-0.81 (m, 1 H), 1.02 (t, J ) 7.4 Hz, 3 H),
2926, 1453 cm-1 1H NMR (CDCl3, 500 MHz) δ 1.20-1.95 (m,
;
10 H), 3.26 (s, 2 H), 4.55 (s, 2 H), 7.23-7.41 (m, 5 H); 13C NMR
(CDCl3, 125 MHz) δ 24.9, 27.4, 29.1, 41.3, 72.7, 78.8, 127.6, 127.7,
128.4, 138.5; MS (CI+, NH3) m/z 218 (M + 1, 12), 112 (100).
1-(N-Ben zyl-N-eth ylam in om eth yl)cyclopr opylam in e (15):
pale yellow oil; 64% yield (261 mg); Rf 0.30 (Acetone); IR (neat)
3357, 2963, 1261 cm-1; 1H NMR (CDCl3, 500 MHz) δ 0.34-0.36
(m, 2 H), 0.58-0.60 (m, 2 H), 1.05 (t, J ) 7.1 Hz, 3 H), 1.86 (s,
2 H, NH2), 2.39 (s, 2 H), 2.63 (q, J ) 7.1 Hz, 2 H), 3.65 (s, 2 H),
7.24-7.37 (m, 5 H); 13C NMR (CDCl3, 63 MHz) δ 11.3, 12.9, 32.0,
47.2, 58.1, 62.1, 126.7, 128.2, 128.7, 140.2; MS (EI 70 eV) m/z
204 (M•+, 5), 148 (60), 134 (71), 91 (100).
(16) The synthesis of 1-aminocyclopropanecarboxylic acids from N,N-
dialkylamides was recently reported by de Meijere et al. (see ref 5d).
The method we described here is short (see ref 13), high yielding, and
may be applied to the preparation of diastereomerically pure com-
pounds.
(17) (a) Kachinsky, J . L. C.; Salomon, R. G. J . Org. Chem. 1986, 51,
1393-1401. (b) MacGregor, J . H.; Pugh, C. J . Chem. Soc. 1945, 535-
536. (c) Cazes, B.; J ulia, S. Tetrahedron 1979, 35, 2655-2660. (d) Yang,
T.-K.; Hung, S.-M.; Lee, D.-S.; Hong, A.-W.; Cheng, C.-C. Tetrahedron
Lett. 1989, 30, 4973-4976. (e) Tokuyama, H.; Kuboyama, T.; Amano,
A.; Yamashita, T.; Fukuyama, T. Synthesis 2000, 1299-1304. (f) Ono,
T.; Tamaoka, T.; Yuasa, Y.; Matsuda, T.; Nokami, J .; Wakabayashi,
S. J . Am. Chem. Soc. 1984, 106, 7890-7893. (g) McManus, J . M.;
Herbst, R. M. J . Org. Chem. 1959, 24, 1464-1467.
(E)-1-(N-Ben zyl-N-eth yla m in om eth yl)-2-eth ylcyclop r o-
p yla m in e (16a ): pale yellow oil; 45% yield (210 mg); Rf 0.19

3968 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
(acetone); IR (neat) 2962, 1677 cm-1; 1H NMR (CDCl3, 250 MHz)
δ 0.08 (dd, J ) 4.9, 3.7 Hz, 1 H), 0.71-0.85 (m, 2 H), 0.95 (t, J
) 7.1 Hz, 3 H), 1.02 (t, J ) 7.1 Hz, 3 H), 1.05-1.15 (m, 1 H),
1.42-1.57 (m, 1 H), 1.98 (s, 2 H, NH2), 2.30 (d, J ) 12.7 Hz, 1
H), 2.48-2.62 (m, 2 H), 2.68 (d, J ) 12.7 Hz, 1 H), 3.45 (d, J )
13.7 Hz, 1 H), 3.77 (d, J ) 13.7 Hz, 1 H), 7.25-7.40 (m, 5 H);
13C NMR (CDCl3, 63 MHz) δ 11.4, 14.2, 20.4, 22.3, 26.3, 35.4,
46.8, 57.8, 57.9, 126.7, 128.1, 128.7, 140.2; MS (CI+) m/z 233 (M
+ 1, 40), 136 (100). (Z)-1-(N-Ben zyl-N-eth yla m in om eth yl)-
2-eth ylcyclop r op yla m in e (16b): pale yellow oil; 27% yield (126
63 MHz) δ 12.8, 28.3, 35.2, 69.8, 80.2; MS (CI+, NH3) m/z 188
(M + 1, 3), 149 (16), 131 (26), 72 (100). Anal. Calcd for C9H17
-
NO3: C, 57.73; H, 9.15; N, 7.48. Found: C, 57.66; H, 9.43; N,
7.19.
(E)-(N-ter t-Bu toxyca r bon yl)-1-(ben zyloxym eth yl)-2-eth -
ylcyclop r op yla m in e (26a ). The title compound was prepared
from 11a (1.43 g, 7 mmol) using the procedure described for 23:
colorless oil; 91% yield (1.94 g); Rf 0.33 (petroleum ether/ethyl
acetate 9:1); IR (neat) 3335, 1717 cm-1 1H NMR (CDCl3, 500
;
MHz) δ 0.43 (t, J ) 5.4 Hz, 1 H), 0.93-1.06 (m, 2 H), 1.01 (t, J
) 7.1 Hz, 3 H), 1.12-1.21 (m, 1 H), 1.42 (s, 9 H), 1.51-1.56 (m,
1 H), 3.48 (d, J ) 9.8 Hz, 1 H), 3.62-3.68 (m, 1 H), 4.50 (d, J )
12.2 Hz, 2 H), 4.55 (d, J ) 12.2 Hz, 2 H), 5.15 (s, 1 H, NH),
7.26-7.36 (m, 5 H); 13C NMR (CDCl3, 125 MHz) δ 13.9, 18.3,
22.5, 27.4, 28.4, 36.8, 71.7, 73.1, 79.1, 127.5, 127.6, 128.3, 138.4,
155.5; MS (CI+, NH3) m/z 306 (M + 1, 2), 250 (8), 249 (14), 232
(62), 100 (100).
mg); Rf 0.33 (acetone); IR (neat) 2962, 1677 cm-1 1H NMR
;
(CDCl3, 250 MHz) δ 0.15 (t, J ) 5.0 Hz, 1 H), 0.43 (dd, J ) 9.0,
4.3 Hz, 1 H), 0.48-0.58 (m, 1 H), 0.95 (t, J ) 7.4 Hz, 3 H), 1.02
(t, J ) 7.1 Hz, 3 H), 1.40-1.54 (m, 2 H), 1.79 (s, 2 H, NH2), 2.18
(d, J ) 12.6 Hz, 1 H), 2.52 (d, J ) 12.6 Hz, 1 H), 2.48-2.70 (m,
2 H), 3.50 (d, J ) 13.6 Hz, 1 H), 3.70 (d, J ) 13.6 Hz, 1 H),
7.25-7.40 (m, 5 H); 13C NMR (CDCl3, 63 MHz) δ 11.2, 14.3, 17.3,
21.5, 26.2, 35.7, 46.9, 57.9, 63.6, 126.7, 128.1, 128.7, 140.2; MS
(EI 70 eV) m/z 232 (M•+, <1), 148 (10), 134 (26), 91 (100).
1-(P yr id in -2-yl)cyclop r op yla m in e (18): yellow oil; 57%
yield (153 mg); Rf 0.23 (acetone); IR (neat) 3361, 1590 cm-1; 1H
NMR (CDCl3, 250 MHz) δ 1.10-1.16 (m, 2 H), 1.20-1.28 (m, 2
H), 2.20 (s, 2 H, NH2), 7.20 (d, J ) 8.2 Hz, 1 H), 7.35 (t, J ) 6.3
(Z)-(N-ter t-Bu toxyca r bon yl)-1-(ben zyloxym eth yl)-2-eth -
ylcyclop r op yla m in e (26b). The title compound was prepared
from 11b (315 mg, 1.54 mmol) using the procedure described
for 23: colorless oil; 96% yield (425 mg); Rf 0.33 (petroleum ether/
1
ethyl acetate 9:1); IR (neat) 3335, 1716 cm-1; H NMR (CDCl3,
500 MHz) δ 0.48-0.50 (m, 1 H), 0.83-0.89 (m, 2 H), 1.01 (t, J )
7.3 Hz, 3 H), 1.19-1.26 (m, 1 H), 1.43 (s, 9 H), 1.55-1.62 (m, 1
H), 3.42 (d, J ) 10.1 Hz, 1 H), 3.48-3.52 (m, 1 H), 4.54 (s, 2 H),
4.95 (s, 1 H, NH), 7.26-7.36 (m, 5 H); 13C NMR (CDCl3, 125
MHz) δ 13.8, 16.9, 21.4, 24.9, 28.3, 37.2, 72.8, 75.1, 79.2, 127.5,
127.6, 128.3, 138.5, 156.0; MS (CI+, NH3) m/z 306 (M + 1, 3),
250 (20), 249 (38), 232 (100).
Hz, 1 H), 7.82 (t, J ) 7.6 Hz, 1 H), 7.20 (d, J ) 4.2 Hz, 1 H); 13
C
NMR (CDCl3, 63 MHz) δ 19.7, 37.6, 118.0, 120.2, 136.1, 148.6,
165.2; MS (EI 70 eV) m/z 134 (M•+, 34), 133 (100), 105 (35), 79
(85). Anal. Calcd for C8H10N2‚HCl: C, 56.31; H, 6.50; N, 16.42.
Found: C, 56.16; H, 6.63; N, 16.11.
1-(Hexylth iom eth yl)cyclop r op yla m in e (20): yellow oil;
54% yield (202 mg); Rf 0.27 (Et2O); IR (neat) 3353, 2926, 1592,
(E)-[1-(N-ter t-Bu toxycar bon ylam in o)-2-eth ylcyclopr opyl]-
m eth a n ol (27a ).18 The alcohol 27a was prepared from 26a (1.70
mg, 5.6 mmol) using the procedure described for 24: white solid;
93% yield (1.11 g); mp ) 81-82 °C; Rf 0.22 (petroleum ether/
1458 cm-1 1H NMR (CDCl3, 250 MHz) δ 0.45-0.55 (m, 2 H),
;
0.61-0.73 (m, 2 H), 0.88 (t, J ) 6.8 Hz, 3 H), 1.25-1.45 (m, 6
H), 1.51-1.65 (m, 2 H), 1.95 (s, 2 H, NH2), 2.58 (t, J ) 7.2 Hz,
2 H); 13C NMR (CDCl3, 63 MHz) δ 13.8, 14.1, 22.4, 28.4, 29.6,
31.2, 32.0, 32.9, 44.1; MS (EI 70 eV) m/z 187 (M•+, 2), 118 (14),
102 (62), 71 (100). Anal. Calcd for C10H21NS‚HCl: C, 53.67; H,
9.91; N, 6.26. Found: C, 53.33; H, 10.28; N, 6.15.
ethyl acetate 7:3); IR (KBr) 3402, 3283, 1686, 1051 cm-1 1H
;
NMR (CDCl3, 250 MHz) δ 0.50 (t, J ) 5.9 Hz, 1 H), 0.88 (dd, J
) 9.2, 5.3 Hz, 1 H), 0.93-0.98 (m, 1 H), 1.01-1.12 (m, 1 H),
1.03 (t, J ) 7.2 Hz, 3 H), 1.22-1.40 (m, 1 H), 1.43 (s, 9 H), 1.50-
1.68 (m, 1 H), 3.62-3.80 (m, 3 H), 5.09 (s, 1 H, NH); 13C NMR
(CDCl3, 63 MHz) δ 13.9, 18.7, 22.7, 28.3, 28.8, 38.5, 66.8, 80.1,
157.8; MS (CI+, NH3) m/z 216 (M + 1, 3), 160 (10), 159 (30), 100
(100). Anal. Calcd for C11H21NO3: C, 61.37; H, 9.83; N, 6.51.
Found: C, 61.70; H, 10.06; N, 6.28.
1-(P h en ylth iom eth yl)cyclop r op yla m in e (22): yellow oil;
39% yield (140 mg); Rf 0.39 (acetone); IR (neat) 3358, 1583, 1480,
1438 cm-1 1H NMR (CDCl3, 250 MHz) δ 0.42-0.52 (m, 2 H),
;
0.59-0.69 (m, 2 H), 1.82 (s, 2 H, NH2), 3.08 (s, 2 H), 7.15-7.30
(m, 3 H), 7.35-7.42 (m, 2 H); 13C NMR (CDCl3, 63 MHz) δ 14.6,
33.6, 47.3, 126.4, 128.8, 130.4, 136.4; MS (EI 70 eV) m/z 179
(M•+, 72), 146 (54), 110 (100).
(Z)-[1-(N-ter t-Bu t oxyca r b on yla m in o)-2-et h ylcyclop r o-
p yl]m eth a n ol (27b).18 The alcohol 27b was prepared from 26b
(377 mg, 1.24 mmol) using the procedure described for 24: white
solid; 87% yield (230 mg); mp ) 40-42 °C; Rf 0.23 (petroleum
(N-ter t-Bu toxyca r bon yl)-1-(ben zyloxym eth yl)cyclop r o-
p yla m in e (23). To a solution of cyclopropylamine 4 (1.18 g, 5.8
mmol) in t-BuOH (7 mL) and water (10 mL) were added
successively NaOH (0.3 g, 7.5 mmol) and Boc2O (1.63 g, 7.5
mmol). After being stirred for 1 h, the mixture was extracted
with ether. The combined organic layers were dried (MgSO4) and
concentrated. The resulting crude material was purified by flash
chromatography giving a white solid (94% yield, 1.51 g): mp )
61 °C; Rf 0.22 (petroleum ether/ethyl acetate 95:5); IR (neat)
3369, 1687, 1508 cm-1; 1H NMR (CDCl3, 250 MHz) δ 0.70-0.85
(m, 4 H), 1.43 (s, 9 H), 3.48 (s, 2 H), 4.55 (s, 2 H), 5.10 (s, 1 H,
NH), 7.25-7.38 (m, 5 H); 13C NMR (CDCl3, 63 MHz) δ 12.1, 28.3,
33.2, 73.0, 74.4, 79.3, 127.6, 127.8, 128.4, 138.3, 155.6; MS (CI+,
NH3) m/z 278 (M + 1, 2), 221 (44), 204 (100). Anal. Calcd for
ether/ethyl acetate 7:3); IR (neat) 3331, 1690, 1172 cm-1 1H
;
NMR (CDCl3, 500 MHz) δ 0.40 (t, J ) 5.1 Hz, 1 H), 0.93-0.98
(m, 1 H), 1.00-1.06 (m, 1 H), 1.01 (t, J ) 7.3 Hz, 3 H), 1.21-
1.30 (m, 1 H), 1.44 (s, 9 H), 1.49-1.58 (m, 1 H), 3.44-3.50 (m,
1 H), 3.67 (d, J ) 11.4 Hz, 1 H), 3.75 (s, 1 H, OH), 4.92 (s, 1 H,
NH); 13C NMR (CDCl3, 63 MHz) δ 13.8, 18.2, 21.6, 25.5, 28.2,
39.5, 71.1, 80.2, 158.2; MS (CI+, NH3) m/z 216 (M + 1, 5), 160
(34), 159 (36), 100 (100). Anal. Calcd for C11H21NO3: C, 61.37;
H, 9.83; N, 6.51. Found: C, 61.66; H, 10.07; N, 6.30.
Boc-protected amino acids 25 and 28 were obtained by
oxidation;5d the spectroscopic data for compounds 25 (88% yield),
28a (88% yield), and 28b (90% yield) are in accordance with the
literature data.5d,18
C
16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.51; H, 8.31;
N, 4.97.
[1-(N -t er t -Bu t oxyca r b on yla m in o)cyclop r op yl]m e t h -
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
spectra for 4, 6, 8, 10-13, 15, 16, 18, 20, 22-24, 26, and 27.
This material is available free of charge via the Internet at
http://pubs.acs.org.
a n ol (24).5d To a solution of benzyl ether 23 (1.36 g, 4.9 mmol)
in methanol (20 mL) was added palladium 5% on charcoal (60
mg). The suspension was stirred overnight under an atmospheric
pressure of H2. After filtration and evaporation of the solvent,
an analytically pure solid was obtained (97% yield, 887 mg): mp
) 86 °C; Rf 0.22 (petroleum ether/ethyl acetate 95:5); IR (neat)
J O025634Y
1
3341, 1695, 1532 cm-1; H NMR (CDCl3, 250 MHz) δ 0.82 (s, 4
(18) Charrette, A. B.; Coˆte´, B. J . Am. Chem. Soc. 1995, 117, 12721-
12732.
H), 1.43 (s, 9 H), 3.56 (s, 2 H), 5.05 (s, 1 H, NH); 13C NMR (CDCl3,