Addition of Diazoalkanes to Enynes Promoted by a Ruthenium Catalyst: Simple Synthesis of Alkenyl Bicyclo[3.1.0]hexane Derivatives

Article abstract of DOI:10.1002/anie.200352477

[C*_pRuCl(cod)] (C*_p=C₅Me ₅, cod=cyclooctadiene) promotes the reaction of 1,6-enynes with an excess of diazoalkane in dioxane in one step to afford selectively 1-alkenyl bicyclo[3.1.0]hexane derivatives (see scheme, X=O, NTs; Y=CO₂Et; R¹=H, Me; R²=H; Ts=p-toluenesulfonyl). This novel reaction involves the stereoselective formation of three C-C bonds and a cyclopropanation step.

Full text of DOI:10.1002/anie.200352477

Communications
Enyne Cyclization
Addition of Diazoalkanes to Enynes Promoted by
a Ruthenium Catalyst: Simple Synthesis of
Alkenyl Bicyclo[3.1.0]hexane Derivatives**
Florian Monnier, Dante Castillo, Sylvie DØrien,
Loïc Toupet, and Pierre H. Dixneuf*
Molecular catalysts are currently playing a key role in
innovative synthetic methods.[1] They promote the synthesis
of complex, useful molecules, through highly simplified
pathways that involve the combination of simple substrates
and the formation of several consecutive bonds with high
selectivity.[2,3] The activation of these molecules under mild
[*] Prof. P. H. Dixneuf, F. Monnier, D. Castillo, Dr. S. DØrien
Institut de Chimie de Rennes, UMR 6509
CNRS-UniversitØ de Rennes
OrganomØtalliques et Catalyse
Campus de Beaulieu, 35042, Rennes (France)
Fax: (+33)2-2323-6939
E-mail: pierre.dixneuf@univ-rennes1.fr
Dr. L. Toupet
Groupe Mati›re CondensØe et MatØriaux, UMR 6626
CNRS-UniversitØ de Rennes
Campus de Beaulieu, 35042, Rennes (France)
[**] This work was supported by the CNRS and the Minist›re de la
recherche. The authors are grateful to the latter for a PhD grant to
FM and, for additional support, to the European Union through the
Cost Program D17, and the Region Bretagne, through a PRIR
program (169AOC), and to Institut Universitaire de France for
membership (PHD).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200352477
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conditions are also opening the way to transform stoichio-
metric reactions into catalytic ones such as the Pauson–
Khand[4] or Nicholas[5] reactions. Enynes have recently been
at the center of general, useful catalytic transformations. In
the presence of alkene metathesis catalysts, they lead to a
variety of functional alkenyl cycloalkenes with the 1,3-diene
moiety.[6] The research groups of Trost, Murai, and Fürstner
have shown that enynes constitute the basis of straightforward
routes to bicyclo[3.1.0]hexane[7,8] or bicyclo[4.1.0]heptane[9]
derivatives in the presence of PdII centers,[8] [RuCl2Ln][7] or
[PtCl2][9–11] catalysts. One aspect that these transformations
have in common is the initial electrophilic activation of the
triple bond, which favors its coupling with the double bond
and leads to either bicyclic alkylidene–metal[7,8] or stabilized
by cationic carbenoid resonance [9] intermediates.
Recently, the ruthenium catalyzed double addition of
diazoalkanes to alkynes, has offered a direct route to 1,3-
dienes.[12] The attempt to apply this reaction to enynes has
actually led to the discovery of a new catalytic reaction that
contrasts with the above electrophilically initiated trans-
formations of enynes.[7–9]
The major diastereoisomer of 4b was purified by chro-
matography over silica gel. Crystals of this diastereoisomer
that were suitable for X-ray crystal-structure analysis were
Herein we report the novel one-step reaction of enynes
with diazoalkanes, catalyzed by [(Cp*RuCl(cod)] ([Rh];
Cp* = C5Me5, cod = cyclooctadiene). The reaction involves
obtained in a mixture of pentane and diethyl ether
(Figure 1.)[15] The structure reveals the relative spacial
substituent positions on the cyclopropane moiety: both Z
trimethylsilylvinyl and methyl groups are cis and this obser-
vation is confirmed by NMR experiments (hmqc, hmbc,
NOESY) for the derivatives 2 and 4.
À
the selective formation of three C C bonds including a
cyclopropanation step and directly leads to 1-alkenyl bicy-
clo[3.1.0]hexane derivatives [Eq. (1)]. This highly stereo-
selective reaction has potential in synthesis as alkenylcyclo-
propanes easily give access to 5-membered cycles.[13]
The reaction of enyne 1a with an excess of trimethylsi-
lyldiazomethane in dioxane in the presence of 5 mol% of
[Cp*RuCl(cod)] under inert atmosphere does not lead to the
ꢀ
expected diazoalkane carbene double addition to the C C
bond,[12] but selectively affords the bicyclic 1-alkenyl bicy-
clo[3.1.0]hexane product 2a in 70% yield after 24 h at 608C
and with complete conversion of 1a [Eq. (2)]. Under the same
conditions the enyne 1b led to 2b, which was isolated in 85%
Figure 1. ORTEP drawing of the molecular structure of the major dia-
stereoisomer of 4b. Thermal ellipsoids are set at the 50% probability
level.
yield (Z/E = 3:1).[14] For the C C bond disubstituted ether 1c,
=
the reaction was slower and 2c was isolated in only 40% yield
as a mixture of diastereoisomers (9:1). All compounds 2
formed as a mixture of Z > E isomers but the cyclopropana-
tion is highly stereoselective.
The enynes that contain nitrogen are more reactive. The
reaction of 3a with N2CHSiMe3 after 1 h at 608C led to 4a in
95% yield (Z/E = 4:1) [Eq. (2)] (Ts = p-toluenesulfonyl). It is
The above catalytic reaction seems general, as it is not
=
inhibited by different substitutions on the C C bond of the
starting enynes. The only observed limitation is related to the
disubstituted triple bond of the starting enyne 1d. In that case,
the reaction affords the compound 5, which results from
classical cyclopropanation of the double bond. This result
ꢀ
suggests that an enyne with sterically hindered C C bond
=
noteworthy that in this case substitutions at the C C bond in
inhibits the coordination of the catalyst to the advantage of
=
enynes 3b and 3c do not affect either reaction time or yield,
and the formation of the bicyclo[3.1.0]hexane derivatives 4b
(80%) and 4c (85%) is observed. In the case of enyne 3b, the
diastereoisomers 4b (d.r. = 3:1) are formed and had only a Z
the C C bond [Eq. (3)].
Ethyl diazoacetate and phenyldiazomethane are less
reactive than trimethylsilyldiazomethane and require more
energetic conditions. Thus, the reaction of 1b, 3a and 3c to
afford derivatives 6, 7a, and 7c, respectively, in yields of 60–
=
configuration of the C C bond.
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75% requires three equivalents of N2CHCO2Et in dioxane at
1008C for 5–24 h [Eq. (4)]. Under these conditions the
reaction affords exclusively the E isomer.
The reaction of 1b with an excess of N2CHPh at 608C in
dioxane and after 24 h led to 8 isolated in 50% yield. This
relatively low yield is related to the parallel formation of
stilbene by decomposition of the phenyldiazomethane
[Eq. (5)].
Scheme 1. Catalytic cycle.
the same catalyst,[12] or as shown for the first step of
stoichiometric addition of metal carbenes to enyne.[19] This
is also supported by the reaction inhibition of disubstituted
ꢀ
hindered enyne C C bond (1d to 5, [Eq. (3)]). The formation
of intermediates D and E corresponds to alkene and enyne
metathesis key steps. The novelty of this catalytic reaction is
related to the last step: a promoted reductive elimination
from E to give 2, rather than the classical formation of the
enyne metathesis product the alkenylcycloalkene F. On
interaction of ruthenium–carbene moiety with an alkene,
this reductive elimination step is favoured[20] probably
because of the steric hindrance of the C5Me5–Ru group, as
we showed that [Cp*RuCl(cod)] also catalyzed the same
reaction but afforded derivatives of 2 in lower yield.
In the reaction reported here, the diazoalkane carbene,
which is known to involve a variety of functional groups, is not
involved in the cyclopropane ring but in the pendent chain.
Thus, this new reaction leading to alkenyl cyclopropane
derivatives has a broad spectrum of applications in synthesis.
These results show that the catalyst [Cp*RuCl(cod)]
selectively transforms 1,6-enynes into 1-alkenyl bicy-
clo[3.1.0]hexanes and the stereochemistry of the alkene
group depends on the nature of the diazoalkane and thus
reaction conditions. For the enynes 1a, 1b, 3a with
N2CHSiMe3 the isomer Z is the major product formed at
608C and N2CHCO2Et preferentially leads to the E isomer at
1008C.
It is noteworthy that the stoichoimetric reaction of enynes
1
=
with metal–carbene complexes, [(OC)5M C(OR)R ] deriva-
Experimental Section
tives of chromium[16] and molybdenum,[17] have been shown to
lead to the synthesis of alkenyl bicyclo[3.1.0]hexane deriva-
tives.[18] Thus the above reaction appears to be the first
catalytic version of the Hoye–Harvey reaction.[16,17]
General procedure for the catalytic synthesis of 2,4–8: [Cp*Ru-
Cl(cod)] (0.0625 mmol, 5 mol%) was added to a solution of enyne
(1.25 mmol, 1 equiv) and diazoalkane (2–4 equiv) in 1 mL of degassed
dioxane at 60–1008C under an inert atmosphere. The reaction
mixture was stirred for between 1 h to 48 h according to the natures
of the enyne and diazoalkane. The solvent was then removed under
vacuum, and the products were isolated by column chromatography
on silica gel to give bicyclic products (1-alkenyl bicyclo[3.1.0]hexane).
The yields are based on the enyne. All compounds were fully
characterized by spectroscopic methods (see Supporting Informa-
The mechanism of the reaction can be explained accord-
ing to Scheme 1. The initial step is expected to involve the
=
formation of a Ru CHR moiety from the diazoalkane and its
coupling with the alkyne to form C, as postulated for the first
step of the catalytic double diazoalkane addition to alkyne by
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Chemie
À3
tion). Selected data for 7c: 1H NMR (200.131 MHz, CDCl3): d = 0.89
(d, 1H, J = 5.3Hz, CH 2); 1.16 (s, 3H, Me); 1.26 (t, 3H, J = 7.1 Hz,
CH3) ; 1.29 (d, 1H, J = 5.3Hz, CH 2); 2.44 (s, 3H, Me); 2.80 (d, 1H, J =
9.1 Hz, CH2N); 3.10 (d, 1H, J = 9.0 Hz, CH2N); 3.60 (d, 2H, J =
9.1 Hz, CH2N); 4.16 (q, 2H, J = 7.1 Hz, OCH2); 5.68 (d, 1H, J =
15.8 Hz, = CH); 6.66 (d, 1H, J = 15.8 Hz, = CH); 7.34 (d, 2H, J =
8.0 Hz, Ph); 7.68 ppm (d, 2H, J = 8.0 Hz, Ph). 13C NMR
(50.329 MHz, CDCl3): d = 166.5, 147.3, 144.2, 133.3, 130.2, 128.1,
120.1, 60.8, 55.1, 51.7, 33.4, 33.3, 23.2, 22.0, 15.8, 14.7. HRMS: m/z
calcd for (C18H23NO4S) [M+] 349.1347, found 349.1348; FTIR (KBr):
104.157(1)8,V= 1902.8(1) Š
,
Z = 4,
Dx = 1.220 Mg.mÀ3
,
l(MoKa) = 0.71073Š, m = 2.42 cmÀ1, F(000) = 752, T= 120 K.
The sample (0.25 ” 0.12 ” 0.12 mm) is studied on a NONIUS
Kappa CCD with graphite monochromatized MoKa radiation.
The cell parameters are obtained with Denzo and Scalepack
(Otwinowski & Minor , 1997) with ten frames (psi rotation: 18
per frame). The data collection (Nonius, 1999) (2qmax = 548, 23 0
frames through 1.88 omega rotation and 20 s per frame, range
HKL: H 0.17, K 0.9, L À25.24) gives 27966 reflections. The data
reduction with Denzo and Scalepack (Otwinowski and Minor,
1997) leads to 4323 independent reflections from which 3489
with I > 2.0s(I). The structure was solved with SIR-97 (Altomare
et al., 1998) which reveals the non hydrogen atoms of the
molecule. After anisotropic refinement, many hydrogen atoms
may be found with a Fourier Difference. The whole structure
was refined with SHELXL97: G. M. Sheldrick, SHELXS-97,
Program for the Solution of Crystal Structures, University of
Göttingen, Göttingen (Germany), 1997 by the full-matrix least-
square techniques (use of F square magnitude; x, y, z, bij for Si, S,
O, C, and N atoms, x, y, z in riding mode for H atoms ; 208
variables and 3489 observations with I > 2.0s(I); calcd w = 1/
[s2(Fo2)+(0.098P)2+1.48P] in which P = (Fo2+2Fc2)/3with thÀe3
n = 2928, 1707, 1637, 1598 cmÀ1. Elemental analysis calcd (%) for
~
C18H23NO4S: C 61.87, H 6.63; found: C 61.87, H 6.71.
Received: July 25, 2003[Z52477]
Keywords: cyclization · diazo compounds · enynes ·
.
heterocycles · ruthenium
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[14] The double-bond stereochemistry of all products obtained with
trimethylsilyldiazomethane was based on larger coupling con-
stants between the two vinyl protons for the trans (18–19 Hz)
with respect to the cis (14–15 Hz) isomer and was confirmed by
X-ray structure of 4b.
[15] Crystal structure analysis: SSiNC18H27O2, Mr = 349.56, mono-
clinic, P21/a, a = 13.5714(2), b = 7.3787(1), c = 19.5966(4) Š, b =
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