First intermolecular cyclopropanation of Fischer dialkylaminocarbene complexes. Synthesis of 1-aminocyclopropanecarboxylic acid derivatives

Article abstract of DOI:10.1021/ol026896p

(equation presented) The first cyclopropanation reaction of olefins with Fischer dialkylaminocarbene complexes is presented. The reaction yields 1-aminocyclopropanecarboxylic acid derivatives in a single step, usually with high diastereoselectivity. An ap

Full text of DOI:10.1021/ol026896p

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4273-4276
First Intermolecular Cyclopropanation of
Fischer Dialkylaminocarbene
Complexes. Synthesis of
1-Aminocyclopropanecarboxylic Acid
Derivatives
Jose´ Barluenga,* Fernando Aznar, Ignacio Gutie´rrez,
Santiago Garc´ıa-Granda, and M. Amparo Llorca-Baragan˜o
Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”,
Unidad Asociada al C.S.I.C., UniVersidad de OViedo, Julia´n ClaVer´ıa 8,
E-33701 OViedo, Spain, and Departamento de Qu´ımica F´ısica y Anal´ıtica
(X-ray serVice), UniVersidad de OViedo, Julia´n ClaVer´ıa 8, E-33701 OViedo, Spain
barluenga@sauron.quimica.unioVi.es
Received September 13, 2002
ABSTRACT
The first cyclopropanation reaction of olefins with Fischer dialkylaminocarbene complexes is presented. The reaction yields 1-aminocyclo-
propanecarboxylic acid derivatives in a single step, usually with high diastereoselectivity. An approach to the asymmetric version of this
reaction is also presented. The synthetic utility of the procedure is exemplified by the synthesis of both cycles of metanoproline in a single
step. In addition, the synthesis of the first Fischer carbene containing a halocarbonyl group is reported.
Fischer carbene complexes have become valuable tools for
stoichiometric carbon-carbon bond formation over the last
three decades.1 One of the earliest synthetically significant
reactions developed for this class of complexes was the
thermal cyclopropanation of olefins.2 Many of the traditional
limitations of this reaction have recently been overcome: the
lack of diastereoselectivity,3 the somewhat harsh reaction
conditions,4 the cyclopropanation of nonactivated dienes3 and,
more recently, the cyclopropanation of nonconjugated ole-
fins.5 Nevertheless, a long-standing limitation has been the
cyclopropanation reaction of aminocarbene complexes, which
are rather less reactive than their alkoxy counterparts. Apart
from the inertness of aminocarbene complexes, the main
reason for the failure of the reaction with electron-poor
olefins is the low stability of the product, a cyclopropane
that bears an amine and an electron acceptor group in
* Address correspondence to this author at Instituto Universitario de
Qu´ımica Organometa´lica “Enrique Moles”.
(3) Harvey, D. F.; Lund, K. P. J. Am. Chem. Soc. 1991, 113, 8916-
8921.
(1) Recent reviews: (a) Wulff, W. D. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991;
Vol. 5, pp 1065-1113. (b) Wulff, W. D. In ComprehensiVe Organometallic
Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon: Oxford, UK, 1995; Vol. 12, pp 470-547. (c) Hegedus, L. S.
Tetrahedron 1997, 53, 4105-4128. (d) Do¨rwald, F. Z. Metal Carbenes in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 1999. (e) Weyer-
shausen, B.; Do¨tz, K. H. Eur. J. Inorg. Chem. 1999, 1057-1066. (f) de
Meijere, A.; Schirmer, H.; Duetsch, M. Angew. Chem., Int. Ed. 2000, 39,
3964-4002.
(4) (a) Wienand, A.; Reissig, H. U. Tetrahedron Lett. 1988, 29, 2315-
2318. (b) Buchert, M.; Reissig, H. U. Tetrahedron Lett. 1988, 29, 2319-
2320. (c) Wienand, A.; Reissig, H. U. Organometallics 1990, 9, 3133-
3142. (d) Wienand, A.; Reissig, H. U. Chem. Ber. 1991, 124, 957-965.
(e) Buchert, M.; Reissig, H. U. Chem. Ber. 1992, 125, 2723-2729. (f)
Buchert, M.; Hoffmann, M.; Reissiq, H. U. Chem. Ber. 1995, 128, 605-
614.
(5) (a) Barluenga, J.; Ferna´ndez-Acebes, A.; Trabanco, A. A.; Flo´rez, J.
J. Am. Chem. Soc. 1997, 119, 7591-7592. (b) Barluenga, J.; Lo´pez, S.;
Trabanco, A. A.; Ferna´ndez-Acebes, A.; Flo´rez, J. J. Am. Chem. Soc. 2000,
122, 8145-8154.
(2) (a) Fischer, E. O.; Do¨tz, K. H. Chem. Ber. 1970, 103, 1273-1278.
(b) Do¨tz, K. H.; Fischer, E. O. Chem. Ber. 1972, 105, 1356-1278.
10.1021/ol026896p CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/30/2002

adjacent carbons. At the reaction temperature this kind of
compound evolves toward the cyclopropane opening products
(Scheme 1).6 We know of only one case where a cyclopro-
Aminocarbene complexes 1 were treated with an excess
of monosubstituted olefins 2 in refluxing toluene until
complete disappearance of the starting complexes was
observed. The only product isolated from the reaction was
the corresponding cyclopropane 3, usually as a single
diastereomer (Table 1).10 It was found that the reaction
Scheme 1
Table 1. Cyclopropanation Reactions of Carbene Complexes 1
pane has been isolated from the reaction of an aminocarbene
complex with an alkene.7 In this elegant approach, Hegedus
et al. reduced the electron-donor ability of the nitrogen atom
by its inclusion in an aromatic pyrrol ring (Scheme 2), thus
making the complex more similar to an alkoxycarbene.
Scheme 2
The instability of the resulting aminocyclopropanes can
be avoided by reacting the carbene complexes with non-
conjugated olefins. We have recently developed a method
for the cyclopropanation of this type of olefin, its success
being based on the stabilization of reaction intermediate by
intramolecular coordination with a suitably placed donor
group.6 With the purpose of generalizing this reaction, we
recalled the recent publication of two syntheses of (alkoxy-
carbonyl)dialkylaminocarbene complexes,8 in which the ester
oxygen may serve for this kind of coordination. Furthermore,
the cyclopropanes so formed would be 1-aminocyclopro-
panecarboxylic acid (ACC) derivatives, which are interesting
compounds since they are present in a number of natural
and biologically active compounds, and can be used as
conformationally restricted analogues of proteinogenic amino
acids.9 We report herein our results in the cyclopropanation
of nonconjugated olefins with (alkoxycarbonyl)dialkylami-
nocarbene complexes, which turns out to be the first
successful cyclopropanation reaction of a dialkylaminocar-
bene.
tolerates aryl, alkyl, and alkenyl substituents in the olefin
(entries a, b, and d). The diastereoselectivity of the process
is in line with that described for the cyclopropanation of
nonconjugated olefins with alkoxycarbene complexes. In both
cases the substituent of the olefin and the chelating substitu-
ent of the carbene carbon (here the alkoxycarbonyl group)
end preferentially in the same side of the cyclopropane. It is
worth mentioning that the molybdenum analogue of complex
1b failed in producing these cyclopropanes in a variety of
conditions tested. The synthetic potential of this methodology
is enhanced by the possibility of forming ACC derivatives
suitably substituted for the deprotection of both the amino
and the acid functions (Table 1, entry e).
(10) General experimental procedure for the cyclopropanation reaction:
A 0.1 M solution of complex 1 or 8 in toluene was treated with 4 equiv of
the olefin 2 and deoxygenated (3 freeze-pump-thaw cycles). The mixture
was then refluxed while a constant flow of N2 (g) was bubbled through it.
Once all the carbene complex was consumed (as seen by IR monitoring)
the reaction mixture was exposed to the air and sunlight. The reaction was
then filtered through Celite and chromatographed on silica gel. Selected
data: 1H NMR (200 MHz, CDCl3): δ (ppm) 7.31-7.25 (m, 5H, Ph), 2.68
(s, 6H, N(CH3)2), 2.62 (dd, 1H, J ) 9.5, 7.7 Hz, CHPh), 1.93 (dd, 1H, J
) 7.7, 4.6 Hz, 3â-ciclopropane), 1.29 (dd, 1H, J ) 9.5, 4.6 Hz,
3R-ciclopropane), 1.10 (s, 9H, C(CH3)3). 13C NMR (50.3 MHz, CDCl3):
δ (ppm) 169.9 (CO2R), 136.8 (C ipso), 129.2 (2 × CH, Ph), 127.8 (2 ×
CH, Ph), 126.4 (CH, p-Ph), 80.5 (CMe3), 54.0 (CNMe2), 41.4 (N(CH3)2),
35.2 (CHPh), 27.7 (C(CH3)3), 21.2 (CH2). HRMS (IE): calcd 261.1729;
found 261.1743.
(6) (a) Barluenga, J.; Aznar, F.; Mart´ın, A. Organometallics 1995, 14,
1429-1433. (b) Sierra, M. A.; Soderberg, B.; Lander, P. A.; Hegedus, L.
S. Organometallics 1993, 12, 3769-3771. (c) Sierra, M. A.; Manchen˜o,
M. J.; Sa´ez, E.; del Amo, J. C. J. Am. Chem. Soc. 1998, 120, 6812-6813.
(d) Woodgate, P. D.; Sutherland, H. S. J. Organomet. Chem. 2001, 628,
155-168. (e) Rotrekl, I.; Vyklicky´, L.; Dvorak, D. J. Organomet. Chem.
2001, 617-618, 329-333.
(7) Merino, I.; Hegedus, L. S. Organometallics 1995, 14, 2522-2531.
(8) (a) Dvorak, D.; Ludwig, M. Organometallics 1998, 17, 3627-3629.
(b) Dialer, H.; Polborn, K.; Beck, W. J. Organomet. Chem. 1999, 589, 21-
28.
(9) Reviews: (a) Stammer, C. H. Tetrahedron 1990, 46, 2231-2254.
(b) Burgess, K.; Ho, K. K.; Moye-Sherman, D. Synlett 1994, 575-583.
4274
Org. Lett., Vol. 4, No. 24, 2002

The reaction is quite sensitive to the steric size of the
olefin, and trisubstituted substituents are not cyclopropanated
in these conditions. The cyclopropanation of disubstituted
olefins could not be carried out with carbene complex 1a,
but the reaction of complex 1b with cycloheptene affords
bicyclic cyclopropane 5, although in low yield (Scheme 3).
Scheme 3
Figure 1. X-ray structure of halocarbonyl carbene complex 7.
The extension of this reaction to the preparation of
enantiomerically enriched cyclopropanes required the prepa-
ration of carbene complexes bearing chiral auxiliaries. The
synthetic methods developed by Beck et al.8b and Dvorak et
al.8a proved not to be adequate for the preparation of these
complexes. We envisioned a convergent entry to these
compounds by activation and derivatization of the ester
moiety in carbene complex 1a (Table 2). We performed the
corresponding cyclopropanes 9 as a mixture of both cis
diastereoisomers (Table 2).
To the extent of our knowledge, complex 7 is the first
example of a carbene complex bearing an acyl halide moiety
in its structure. To ascertain its structure we carried out an
X-ray diffraction experiment (Figure 1, Table 3). The most
Table 3. Bond Lengths and Angles of the X-ray Structure
bond lengths (Å)
bond and dihedral angles (deg)
Table 2. Synthesis and Cyclopropanation Reactions of Carbene
Complexes 8
Cr1-C9
1.896(4)
1.903(4)
1.904(4)
1.915(4)
2.098(3)
1.804(3)
1.176(4)
1.295(4)
1.471(4)
1.474(4)
1.494(4)
C9-Cr1-C7
C1-Cr1-C7
C6-Cr1-C7
C3-Cr1-C7
C7-N1-C4
C7-N1-C5
C4-N1-C5
C9-Cr1-C7-N1
C5-N1-C7-Cr1
O1-C2-C7-N1
O1-C2-C7-Cr1
93.64(13)
90.99(10)
94.84(13)
88.58(10)
122.6(2)
125.0(3)
112.4(2)
34.4(3)
Cr1-C1
Cr1-C6
Cr1-C3
Cr1-C7
Cl1-C2
O1-C2
N1-C7
N1-C4
N1-C5
C2-C7
-175.7(2)
-92.9(4)
82.9(3)
notable feature is the lack of conjugation between the
halocarbonyl and the carbene functions. On the contrary, the
latter is fully conjugated with the dialkylamino moiety.
Scheme 4
first step (deprotection of the ester) according to a previously
reported procedure,8a and next carried out the activation by
reacting carboxylic acid 6 with oxalyl chloride in CH2Cl2 at
room temperature. Acyl chloride 7 was obtained in nearly
quantitative yield as a pale yellow solid. Then, the reaction
with an appropriate nucleophile afforded chiral carbene
complexes 8. Treatment of these complexes with terminal
olefins in the conditions described above provided the
Org. Lett., Vol. 4, No. 24, 2002
4275

A further step to increase the synthetic utility of the
cyclopropanation reaction would be to carry it out in an
intramolecular manner. When we tried to synthesize the
homoallylaminocarbene 12 by metathesis reaction of dehy-
droamino acid 10 and carbene complex 11 the only isolable
product was ethyl N-benzylhomoprolinate 13 (Scheme 4),
which probably arises from the intramolecular cyclopropa-
nation of aminocarbene 12 in the reaction conditions.
Homoprolinate 13 was easily deprotected following standard
methodology to afford homoproline 14 as chlorhydrate.
In conclusion, we have reported the first cyclopropanation
reaction of Fischer dialkylaminocarbene complexes, which
represents a novel approach to the skeleton of ACC deriva-
tives. Furthermore, we have prepared and characterized by
means of an X-ray diffraction experiment the first example
of a Fischer carbene complex bearing an acyl chloride group.
Acknowledgment. This research was supported by the
Comisio´n Ministerial de Ciencia y Tecnolog´ıa (CICYT) and
European Commission (Fondos FEDER) 1FD97-0632.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new products
described and an X-ray CIF file for complex 7. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL026896P
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Org. Lett., Vol. 4, No. 24, 2002