Functionalized aminocyclopropanes from functionalized organozinc compounds and N,N-dialkylcarboxamides

Article abstract of DOI:10.1055/s-2002-31906

Inter- as well as intramolecular competition experiments have been performed to demonstrate that N,N-dialkylcarboxamides react faster than tert-butyl esters with the titanium intermediates formed from ethylmagnesium bromide and methyltitanium triisopropox

Full text of DOI:10.1055/s-2002-31906

LETTER
879
Functionalized Aminocyclopropanes From Functionalized Organozinc
Compounds and N,N-Dialkylcarboxamides1
F
unctionalized
t
A
min
e
f
a
Institut für Organische Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany
Fax +49(551)399475; E-mail: Armin.deMeijere@chemie.uni-goettingen.de
b
Department of Chemistry and Institute of Catalysis Science and Technology, Technion-Israel Institute of Technology, Technion City,
Haifa, 32000 Israel
Received 15 February 2002
Abstract: Inter- as well as intramolecular competition experiments
have been performed to demonstrate that N,N-dialkylcarboxamides
react faster than tert-butyl esters with the titanium intermediates
formed from ethylmagnesium bromide and methyltitanium triiso-
propoxide to selectively yield cyclopropylamines rather than cyclo-
propanols. Thus, functionalized organozinc reagents including a
series with tert-butyl ester functionalities could be employed under
newly developed conditions to transform N,N-dialkylformamides
into chloroalkyl-substituted N,N-dialkylcyclopropylamines (55–
67%) and tert-butyl (N,N-dialkylaminocyclopropyl)alkanoates
(24–63% yield).
Figure
Since the titanium-mediated reductive cyclopropanation
was originally developed for the conversion of esters to
cyclopropanols,2,3 the selectivity question was first ad-
dressed by some inter- as well as intramolecular competi-
tion experiments.
Key words: cyclopropanes, organometallics, amino acids, organo-
In fact, a 1:1 mixture of N,N-dibenzylformamide (2) and
tert-butyl acetate (3), when treated with ethylmagnesium
bromide and methyltitanium triisopropoxide,5 yielded
only N,N-dibenzylcyclopropylamine (4) (90%), and the
tert-butoxycarbonyl-substituted amides 7 gave the -cy-
clopropanated -(dialkyl)aminobutyric esters 8 selective-
ly, albeit in moderate yields (Scheme 1). Thus, it ought to
be possible to apply functionalized organozinc com-
pounds including those with tert-butyl ester functional-
ities in the titanium-mediated reductive cyclopropanation
of amides.
titanium intermediates, cyclopropylamines
Quite a number of cyclopropyl-group containing amino
acids occur in nature, and most of them have important bi-
ological activities. The simplest one, 1-aminocyclopro-
panecarboxylic acid 1 (R = H) is abundant as the natural
precursor to the plant growth hormone ethylene,2 and der-
ivatives such as 1 (R = Me, Et) are potent inhibitors of the
ethylene forming enzyme (Figure). Aminocyclopropane
moieties are also essential in many pharmacologically rel-
evant compounds such as the widely used broad-spectrum
antibiotics ciprofloxacin (Ciprobay®) and moxifloxacin
(Avalox®). Our previously reported adaptation of the
Kulinkovich protocol for the conversion of esters to
cyclopropanols3,4 to readily transform N,N-dialkylcarbox-
amides to N,N-dialkylcyclopropylamines4–6 can also be
applied to prepare a variety of 2-substituted 1-aminocy-
clopropanecarboxylic acids7 as well as -amino acids con-
taining a cyclopropane moiety.8 However, several steps
are required to transform the functional groups like C=C
double bonds, ether or acetal moieties, which are compat-
ible with the standard conditions for the preparation of
Grignard reagents,9 to a carboxylic acid. Other functional-
ities including ester moieties and halogen substituents are
compatible with the well-examined and easily prepared
organozinc reagents,10 and thus we set out to test the pos-
sible use of various functionally substituted organozinc
compounds for the reductive cyclopropanation of N,N-di-
alkylcarboxamides.
However, none of the original protocols developed for the
use of Grignard reagents4–6 gave the desired aminocyclo-
Scheme 1 A: MeTi(i-PrO)3, EtMgBr, THF, 25 °C, 8 h. – B: R2NH.
– C: Isobutene, H2SO4, Et2O, 25 °C, 24 h. – D: EtMgBr, MeTi(i-
PrO)3, THF, 25 °C, 8 h.
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
1437-2096,E;2002,0,06,0879,0882,ftx,en;G05902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

880
S. Wiedemann et al.
LETTER
propane derivatives from tert-butoxycarbonyl-16 and Another series of optimization experiments revealed that
chloro-substituted organozinc compounds 18.11 Further consistently and reproducibly better yields were obtained
modifications of the reaction conditions were first tested when dimethyldiisopropyloxytitanium (11) was prepared
with commercially available diethylzinc which, under es- from dichlorodiisopropyloxytitanium (9) and two equiva-
tablished conditions, gave cyclopropylamines in yields of lents of methyllithium16 prior to the addition of one equiv-
only up to 25%.12 However, it was found that upon addi- alent of methylmagnesium chloride and the freshly
tion of 2 equivalents of sodium isopropoxide, diethylzinc prepared organozinc compound (Table 1, conditions B).
in tetrahydrofuran in the presence of methyltitanium tri- The additional equivalent of methylmagnesium chloride –
isopropoxide converted N,N-dialkylcarboxamides to N,N- which turned out to be better than an additional equivalent
dialkylcyclopropylamines in yields as high as those of methyllithium – was necessary apparently to form the
achieved with ethylmagnesium halides (up to 89%).13,14 more reactive zincate before transmetallation and/or the
But even these conditions failed when functionalized or- more reactive titanate after transmetallation to titanium.15
ganozinc reagents were employed. Therefore, different ti-
Table 1
tanium derivatives were tested. Indeed, when the
functionalized organozinc was first treated with dichloro-
diisopropyloxytitanium (9), then after 30 minutes an ex-
cess (5 equiv) of methylmagnesium chloride was added,
and finally dibenzylformamide, the (2-dibenzylaminocy-
clopropyl)-substituted tert-butyl acetate 17aa was isolat-
16
n
Cond.a R,R
17
Yield
(%)
trans/cis
ed at best in 49% yield (Table 1, conditions A). Several
other functionally substituted organozinc derivatives were
employed according to this protocol and gave the corre-
sponding cyclopropylamines in moderate yields (21–
61%). Most probably the dichlorodiisopropyloxytitanium
partially transmetallates the functionalized organozinc, as
evidenced by a change in appearance of the reaction mix-
ture from colorless to red. This can be enhanced by the
added methylmagnesium chloride which can react with
the organozinc before transmetallation to form a more ba-
sic zincate, or also with the unreacted dichlorodiisopropy-
loxytitanium with single or twofold exchange of the
chlorine substituents by methyl groups or with the first
formed alkylchlorodiisopropyloxytitanium intermedi-
ate.15 Eventually, an alkylmethyldiisopropyloxytitanium
intermediate 13 will be formed which, by -hydride trans-
fer from the functional alkyl to the methyl group, affords
the functionally substituted titanacyclopropane intermedi-
ate 14 that subsequently reacts in the same manner as the
intermediate in the original reductive cyclopropanation4
of carboxamides (Scheme 2).
a
a
a
a
b
c
1
1
1
1
2
3
A
B
B
B
B
B
Bn, Bn
aa
aa
ab
ac
ba
ca
49
60
63
52
40
24
1.1:1
1.8:1
1.3:1
1.4:1
1.2:1
1.1:1
Bn, Bn
Me, Me
–(CH2)5–
Bn, Bn
Bn, Bn
a A: (1) Cl2Ti(i-PrO)2, THF, –30 °C, 1 h. (2) MeMgCl (5 equiv), THF,
–30 to 20 °C, 8 h; – B: (1) Me2Ti(i-PrO)2, MeMgCl; (2) R2NCHO,
THF, –30 to 25 °C, 8 h.
According to this protocol, various tert-butoxycarbonyl-
and chloroalkyl-substituted cyclopropylamine derivatives
were prepared in yields ranging from 24 to 67% (Table 1
and Table 2).17,18
For the tert-butoxycarbonyl-substituted systems, an in-
crease in the chain length between the functional group
and the metal led to decreasing yields. From bis(4-chlor-
obutyl)zinc, the major product was (2-ethenylcyclopro-
pyl)dibenzylamine (31% yield) formed by subsequent
dehydrochlorination in addition to 27% of the [2-(2 -chlo-
roethyl)cyclopropyl]dibenzylamine (19aa).
Thus, the newly developed protocol makes various func-
tionalized aminocyclopropanes easily accessible in virtu-
ally one operational step. These products are valuable
building blocks for the synthesis of pharmacologically in-
teresting molecules containing aminocyclopropane moi-
eties. Further investigations are continuing towards the
direct synthesis of cyclopropyl-group containing -amino
acids in one or two steps.
Scheme 2
Synlett 2002, No. 6, 879–882 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Table 2
Functionalized Aminocyclopropanes
881
(12) Winsel, H. Diplomarbeit; Universität: Göttingen, 1997.
(13) The added isopropoxide most probably helps to form a
zincate which can more rapidly transfer one of its ethyl
groups to titanium. Wiedemann, S. Part of the forthcoming
Dissertation, Universität Göttingen, 2002.
(14) Wiedemann, S.; Frank, D.; Winsel, H.; de Meijere, A.
unpublished results.
(15) It has been shown that i-PrMgBr reacts faster with RZnX
than with Ti(i-PrO)4. Cf.: Averbuj, C.; Kaftanov, J.; Marek,
I. Synlett 1999, 1939.
18
n
Cond.a R,R
19
Yield
(%)
trans/cis
a
b
b
b
b
c
2
3
3
3
3
4
4
B
A
B
B
B
A
B
Bn, Bn
aa
ba
ba
bb
bc
ca
ca
27b
61
65
67
55
57
61
1.2:1
1.4:1
1.2:1
1.2:1
1.1:1
1.1:1
1.1:1
(16) Reetz, M. T.; Westermann, J.; Steinbach, R.; Wenderoth, B.;
Peter, R.; Ostarek, R.; Maus, S. Chem. Ber. 1985, 118, 1421.
(17) All new compounds were fully characterized by
spectroscopic methods (IR, 1H and 13C NMR, MS) and
elemental analyses. General Procedure B (GPB): To a
solution of Cl2Ti(O-i-Pr)2 (1043 mg, 4.0 mmol) in THF
(5 mL) kept at –30 °C, was added 5.3 mL of a 1.65 M
solution of methyllithium (8.8 mmol) in hexane. Then 1.5
mL of a 3 M solution of methylmagnesium chloride (4.5
mmol) in THF was added, and the mixture was stirred for
1 h at this temperature. After that the previously prepared
solution of the organozinc compound in THF and the N,N-
dialkylcarboxamide (4 mmol) were added, the mixture was
slowly warmed up to r.t. until gas evolution ceased, and
stirred for an additional 8 h. The reaction was quenched by
addition of 2 mL of H2O, and stirring of the mixture
continued until the color of the suspension had turned
yellow. The mixture was filtered, and the solid was washed
with diethyl ether (2 10 mL). The combined organic
phases were dried over Na2SO4. The crude products were
purified by column chromatography. For example (2-
Dibenzylaminocyclopropyl)acetic Acid tert-Butyl Ester
(17aa): From tert-butyl 4-iodobutyrate and N,N-
Bn, Bn
Me, Me
–(CH2)5–
Bn, Bn
c
Bn, Bn
a A: (1) Cl2Ti(i-PrO)2, THF, –30 °C, 1 h. (2) MeMgCl (5 equiv), THF,
–30 to 20 °C, 8 h; – B: (1) Me2Ti(i-PrO)2, MeMgCl; (2) R2NCHO,
THF, –30 to 25 °C, 8 h. –
b In addition, dibenzyl(2-ethenylcyclopropyl)amine was isolated in
31% yield.
Acknowledgement
This work was supported by the Niedersächsisches Ministerium für
Wissenschaft und Kunst, the Deutsche Forschungsgemeinschaft
(SFB 416, Project A3), and the Fonds der Chemischen Industrie.
The authors are indebted to Prof. Paul Knochel, München, for val-
uable discussions, and to Dr. Burkhard Knieriem, Göttingen, for his
careful proofreading of the final manuscript.
dibenzylformamide, following GPB as above, two
diastereomeric products were isolated by column
chromatography (70 g of silica gel, diethyl ether/pentane
1:10).
Fraction I (Rf = 0.83): 300 mg (21%) of cis-(2-dibenzyl-
aminocyclopropyl)acetic acid tert-butyl ester (cis-17aa) as a
colorless oil. IR(film): = 3063, 2977, 2928, 1733, 1494,
1454, 1367, 1152, 1028, 749, 698 cm–1. 1H NMR (250 MHz,
CDCl3): = 0.13 (ddd, 3J = 4.5, 3J = 4.9, 2J = 5.1 Hz, 1 H,
3 -H), 0.73 (ddd, 2J = 5.1, 3J = 6.9, 3J = 8.6 Hz, 1 H, 3 -H),
1.14 (ddddd, 3J = 4.9, 3J = 6.8, 3J = 7.0, 3J = 7.2, 3J = 8.6
Hz, 1 H, 1 -H), 1.34 [s, 9 H, C(CH3)3], 1.96 (ddd, 3J = 4.5,
3J = 6.9, 3J = 7.0 Hz, 1 H, 2 -H), 2.41 (dd, 3J = 6.8, 2J = 16.4
Hz, 1 H, 2-H), 2.48 (dd, 3J = 7.2, 2J = 16.4 Hz, 1 H, 2-H),
3.50 (d, 2J = 13.8 Hz, 2 H, CHHPh), 3.69 (d, 2J = 13.8 Hz, 2
H, CHHPh), 7.35–7.21 (m, 10 H, Ph-C). 13C NMR (62.9
MHz, CDCl3, DEPT): = 12.1 (–, C-3 ), 15.1 (+, C-1 ), 28.0
[+,OC(CH3)3], 33.9 (–, C-2), 40.1 (+, C-2 ), 57.5 (–, NCH2),
80.0 [Cquat, OC(CH3)3], 126.8 (+, Ph-C), 128.0 (+, Ph-C),
129.4 (+, Ph-C), 138.1 (Cquat, Ph-C), 173.5(Cquat, C=O). MS
(EI, 70 eV): m/z (%) = 351(6) [M+], 278(9), 260(4), 236(9),
204(100), 181(2), 158(5),106(4), 91(81). Anal. Calcd for
C23H29NO2: C, 78.60; H, 8.32; N, 3.99. Found: C, 78.44; H,
8.34; N, 4.04.
Fraction II (Rf = 0.58): 542 mg (39%) of trans-(2-dibenzyl-
aminocyclopropyl)acetic acid tert-butyl ester (trans-17aa)
as a colorless oil. IR(film): = 3063, 3028, 2978, 2929,
1732, 1602, 1494, 1454, 1392, 1367, 1257, 1154, 1076,
1029, 955, 750, 699, 620 cm–1. 1H NMR (250 MHz, CDCl3):
= 0.34 (ddd, 2J = 5.3, 3J = 5.3, 3J = 6.7 Hz, 1 H, 3 -H), 0.61
(ddd, 3J = 3.3, 2J = 5.3, 3J = 8.0 Hz, 1 H, 3 -H), 1.04 (ddddd,
3J = 3.4, 3J = 5.3, 3J = 7.2, 3J = 7.2, 3J = 8.0 Hz, 1 H, 1 -H),
1.42 [s, 9 H, C(CH3)3], 1.68 (ddd, 3J = 3.3, 3J = 3.4, 3J = 6.7
Hz, 1 H, 2 -H), 2.02 (dd, 3J = 7.2, 2J = 14.6 Hz, 1 H, 2-H),
References
(1) Part 76 in the series Cyclopropyl Building Blocks for
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E.; Dekker: New York, 1996.
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(11) The functionally substituted dialkylzinc reagents were
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Synlett 2002, No. 6, 879–882 ISSN 0936-5214 © Thieme Stuttgart · New York

882
S. Wiedemann et al.
LETTER
2.07 (dd, 3J = 7.2, 2J = 14.6 Hz, 1 H, 2-H), 3.64 (d, 2J = 13.5
Hz, 2 H, CHHPh), 3.71 (d, 2J = 13.5 Hz, 2 H, CHHPh),
7.35–7.22 (m, 10 H, Ph-C). 13C NMR (62.9 MHz, CDCl3,
DEPT): = 14.2 (–, C-3 ), 17.6 (+, C-1 ), 28.1 [+,
OC(CH3)3], 38.6 (–, C-2), 43.1 (+, C-2 ), 57.7 (–, NCH2),
80.2 [Cquat, OC(CH3)3], 126.8 (+, Ph-C), 128.0 (+, Ph-C),
129.4 (+, Ph-C), 138.6 (Cquat, Ph-C), 172.2 (Cquat, C=O). MS
(EI, 70 eV): m/z (%) = 351(6) [M+], 294(6), 260(5), 250(14),
236(8), 204(100), 186(3), 158(6), 131(4), 106(6), 91(81).
Anal. Calcd for C23H29NO2: C, 78.60; H, 8.32; N, 3.99.
Found: C, 78.81; H, 8.10; N, 3.96.
(18) Diastereomerically pure (E)-1-(2-chloroethyl)-2-ethyl-
cyclopropanols can be obtained from -chloropropionates
and unsubstituted butylmagnesium bromide. Cf.: Sylvestre,
I.; Ollivier, J.; Salaün, J. Tetrahedron Lett. 2001, 42, 4991.
Synlett 2002, No. 6, 879–882 ISSN 0936-5214 © Thieme Stuttgart · New York