Primary 1-Arylcyclopropylamines from aryl cyanides with diethylzinc and titanium alkoxides

Article abstract of DOI:10.1021/ol034021k

(Matrix presented) 1-Aryl-substituted primary cyclopropylamines are conveniently prepared from aromatic nitriles and diethylzinc. The yields range from 40 to 56% for donor-substituted (five examples) to 62-82% for non- and acceptor-substituted substrates

Full text of DOI:10.1021/ol034021k

ORGANIC
LETTERS
2003
Vol. 5, No. 5
753-755
Primary 1-Arylcyclopropylamines from
Aryl Cyanides with Diethylzinc and
Titanium Alkoxides†
Stefan Wiedemann, Daniel Frank, Harald Winsel, and Armin de Meijere*
Institut fu¨r Organische Chemie der Georg-August-UniVersita¨t Go¨ttingen,
Tammannstrasse 2, 37077 Go¨ttingen, Germany
armin.demeijere@chemie.uni-goettingen.de
Received January 7, 2003
ABSTRACT
1-Aryl-substituted primary cyclopropylamines are conveniently prepared from aromatic nitriles and diethylzinc. The yields range from 40 to
56% for donor-substituted (five examples) to 62−82% for non- and acceptor-substituted substrates (nine examples).
The titanium-mediated reductive cyclopropanation of N,N-
dialkylcarboxamides is now a well-established procedure for
the synthesis of a wide range of N,N-dialkylaminocyclopro-
panes.1,2 While alkyl-substituted primary cyclopropylamines
can be prepared from thus accessible N,N-dibenzylcyclo-
propylamines by catalytic hydrogenation,3 this deprotection
obviously cannot be applied to alkenyl-substituted derivates.
Not only the alkenyl substituents but also the conjugated
cyclopropyl groups are hydrogenated with ring opening under
such conditions, and this behavior is also observed for
arylcyclopropylamines.4 It was apparent early on that a
titanium-mediated reductive cyclopropanation of nitriles
would provide direct access to primary cyclopropylamines.
However, early attempts to apply the established conditions
for the conversion of carboxamides1-3 to nitriles gave the
corresponding primary cyclopropylamines only in poor
yields.4,5 In the meantime, Szymoniak et al. found that good
yields can be achieved from aliphatic nitriles with alkyl-
magnesium halides and titanium tetraisopropoxide when the
reaction mixture is treated with 2 equiv of BF3‚Et2O before
workup,6 and R-alkoxy- as well as dialkylamino-substituted
aliphatic nitriles are converted to the corresponding primary
cyclopropylamines in good yields even without addition of
a Lewis acid.7 At the same time, we had turned our attention
to the possible use of organozinc instead of Grignard reagents
in the titanium-mediated cyclopropanation of carboxamides8
as well as nitriles, and we report here our first results with
nitriles and diethylzinc in the presence of methyltitanium
triisopropoxide.
† Part 90 in the series “Cyclopropyl Building Blocks for Organic
Synthesis.” For Part 89, see: Liu, C.; Tamm, M.; No¨tzel, M. W.; de Meijere,
A.; Schilling, J. K.; Kingston, D. G. I. Tetrahedron Lett. 2003, in press.
Part 88: Tebben, G.-D.; Stratmann, C.; Rauch, K.; Williams, C. M.; de
Meijere, A. Org. Lett. 2003, in press.
(1) (a) Chaplinski, V.; de Meijere, A. Angew. Chem. 1996, 108, 491-
492. (b) Chaplinski, V.; Winsel, H.; Kordes, M.; de Meijere, A. Synlett
1997, 111-114.
Before any nitriles were tried, the conditions for the use
of diethylzinc instead of ethylmagnesium bromide were
optimized for the conversion of dibenzylformamide (1) to
N,N-dibenzylcyclopropylamine (2) (Scheme 1).
Under standard conditions, the expected cyclopropylamine
(2) was obtained in a yield of only 21%.5 This was attributed
(2) Reviews: (a) de Meijere, A.; Kulinkovich, O. G. Chem. ReV. 2000,
100, 2789-2834. (b) de Meijere, A.; Kozhushkov, S. I.; Savchenko, A. I.
In Titanium and Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-
VCH: Weinheim, Germany, 2002; pp 390-434.
(5) (a) Winsel, H. Diplomarbeit, Universita¨t Go¨ttingen, Go¨ttingen,
Germany, 1997. (b) Winsel, H. Dissertation, Universita¨t Go¨ttingen, Go¨t-
tingen, Germany, 2000.
(6) Bertus, P.; Szymoniak, J. Chem. Commun. 2001, 1792-1793.
(7) Bertus, P.; Szymoniak, J. J. Org. Chem. 2002, 67, 3965-3968.
(8) For cyclopropanations of N,N-dialkylcarboxamides with functional-
ized organozinc reagents, see: Wiedemann, S.; Marek, I.; de Meijere, A.
Synlett 2002, 879-882.
(3) de Meijere, A.; Williams, C. M.; Kourdioukov, A.; Sviridov, S. V.;
Chaplinski, V.; Kordes, M.; Savtchenko, A. I.; Stratmann, C.; Noltemeyer,
M. Chem. Eur. J. 2002, 8, 3789-3801.
(4) Stecker, B. Dissertation, Universita¨t Go¨ttingen, Go¨ttingen, Germany,
2002.
10.1021/ol034021k CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/04/2003

Scheme 1a
Scheme 2a
a For details, see Table 1.
to the lower nucleophilicity of diethylzinc9 compared to
ethylmagnesium bromide, and consequently the addition of
sodium isopropoxide (NaOiPr) was tested.
Indeed, the yield increased to 52 and even 89% with 1
and 2 equiv, respectively, of NaOiPr being present (Table
1, entries 2 and 3). Similar yields were obtained with 2 equiv
Table 1. Reductive Cyclopropanation of Dibenzylformamide
(1) with Diethylzinc under various conditions (see Scheme 1)
entry
additive (equiv)
Et2Zn (equiv)
yield (%)
1
2
3
4
5
6
7
8
9
-
2
2
2
2
2
2
2
1
21
52
89
84
10
82
76
82
43
a For details, see Table 2.
NaOiPr (1)
NaOiPr (2)
LiOiPr (2)
NaOMe (2)
NaOEt (2)
NaOtBu (2)
NaOiPr (2)
NaOiPr (2)
The obvious solution to this problem would be to favor
formation of the saturated azatitanacyclopentane intermediate
6 by addition of a better nucleophile to the reaction mixture.
Indeed, with added lithium iodide (2.5 equiv) and slow
addition of Et2Zn to avoid formation of the intermediate 8,
the yield of 1-phenylcyclopropylamine (4a) went up to 62%.
With this improved protocol, various 1-arylcyclopropyl-
amines 4 were obtained from aryl cyanides in moderate to
good yields (Table 2). Acceptor-substituted aromatic nitriles
0.5
of LiOiPr, NaOEt, and NaOtBu (entries 4, 6, and 7) but not
with NaOMe, probably due to the poorer solubility of the
formed titanium methoxide. With NaOiPr as an additive, the
amount of diethylzinc could be lowered to 1 equiv without
a significant loss in yield, but with 0.5 equiv of Et2Zn, the
yield dropped to 43% (Table 1, entries 8 and 9). The added
alkoxide converts diethylzinc to a zincate complex of type
[Et2Zn(OiPr)2]2- as corroborated by an 1H NMR spectrum,10
and the latter is much more nucleophilic than the uncoor-
dinated diethylzinc.9
With the optimized protocol, benzonitrile (3a) was con-
verted to 1-phenylcyclopropylamine (4a) in 25% yield, the
major side products being propiophenone 7 (18%) and
3-amino-3-phenylpentane 9 (15%). Quenching the reaction
with D2O afforded all three products in their deuterated forms
(Scheme 2). Thus, the azatitanacyclopentene 5 must be the
intermediate en route to 4 and 7, the latter being formed by
direct hydrolysis of 5 without ring contraction. Apparently,
5 can undergo insertion with a second molecule of the
titanacyclopropane intermediate to yield a 1-aza-2,8-
dititanabicyclo[3.3.0]octane 8, which upon hydrolysis or
deuteriolysis yields 3-amino-3-phenylpentane (9) or its
dideuterated analogue, the bisalkylation product of benzoni-
trile (3a).
Table 2. Various 1-Arylcyclopropylamines from Aromatic
Nitriles, Diethylzinc, and Methyltitanium Triisopropoxide (See
Scheme 2)
nitrile 3
Ar
yield 4 (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
Ph
62
54
53
56
47
40
65
75
72
73
73
75
80
82
71
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
2-MeO-C6H4
2,4-(MeO)2-C6H3
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
3-CF3-C6H4
3-tBuO2C-C6H4
3-NC-C6H4
2-Py
3-Py
2-Naph
(9) (a) Tochtermann, W. Angew. Chem 1966, 78, 355-375; Angew.
Chem., Int. Ed. Engl. 1966, 5, 351-371. (b) Uchiyama, M.; Kameda, M.;
Mishima, O.; Yokoyama, N.; Koike, M.; Kondo, Y.; Sakamoto, T. J. Am.
Chem. Soc. 1998, 120, 4934-4946.
(10) Cf.: Mobley, T. A.; Berger, S. Angew. Chem. 1999, 111, 3256-
3258; Angew. Chem., Int. Ed. 1999, 38, 3070-3072.
consistently gave better yields than donor-substituted ones.
Yields were particularly high for 1-pyridylcyclopropylamines
4m,n (80 and 82%, respectively).11 Nitro groups are incom-
patible with these conditions;12 thus, 4-nitrobenzonitrile did
754
Org. Lett., Vol. 5, No. 5, 2003

not give any of the corresponding 1-(4-nitrophenyl)cyclo-
propylamine.
Acknowledgment. This work was supported by the
Niedersa¨chsisches Ministerium fu¨r Wissenschaft und Kunst
and the Fonds der Chemischen Industrie. The authors are
indepted to Witco GmbH for a generous gift of diethylzinc,
Prof. Paul Knochel, Mu¨nchen, for valuable discussions, and
Dr. Burkhard Knieriem, Go¨ttingen, for his careful proofread-
ing of the final manuscript.
Under the same conditions, aliphatic nitriles such as
acetonitrile and phenylacetonitrile gave the corresponding
primary cyclopropylamines in poor yields only (12 and 16%,
respectively). This new protocol for the synthesis of 1-aryl-
cyclopropylamines thus ideally complements the recently
published methods of Szymoniak et al., which with one
exception provide only 1-alkyl-substituted primary cyclo-
propylamines from aliphatic nitriles.6,7
Supporting Information Available: Experimental pro-
cedures as well as physical and spectroscopic data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(11) 1-(2-Pyridyl)cyclopropylamine has also been obtained from 2-cy-
anopyridine and ethylmagnesium bromide in the presence of Ti(OiPr)4 by
Szymoniak et al., yet in lower yield (54%). Cf. ref. 7.
(12) For a review on organozinc reagents, see: Knochel, P.; Singer, R.
D. Chem. ReV. 1993, 93, 2117-2188.
OL034021K
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