Rhodium-catalyzed cyclopropanation of alkenes with dimethyl diazomalonate

Article abstract of DOI:10.1002/adsc.200800027

The outstanding ability of dirhodium α,α,α′, α′-tetramethyl-1,3-benzenedipropanoate [Rh₂(esp) ₂; esp=α,α,α′,α′-tetramethyl-1,3- benzene-dipropanoate] to catalyze the cyclopropanation of a wide range of alkenes with malonate-derived carbenoids under mild reaction conditions is reported in this communication. The experimental protocol is remarkably simple, uses readily accessible and stable dimethyl diazomalonate with very low catalyst loading. More importantly, the alkene is employed as a limiting reagent.

Full text of DOI:10.1002/adsc.200800027

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DOI: 10.1002/adsc.200800027
Rhodium-Catalyzed Cyclopropanation ofAlkenes with Dimethyl
Diazomalonate
Francisco Gonzµlez-Bobes,a,* Michal D. B. Fenster,a Susanne Kiau,a
a
Laxma Kolla,a Sergei Kolotuchin,a andMaxime Soumeillant
a
Process Research andDevelopment, Bristol-Myers Squibb Research andDevelopment, 1 Squibb Drive, P.O. Box 191,
New Brunswick, New Jersey 08903-019, USA
Fax : (+1)-732-227-3928; e-mail: francisco.gonzalezbobes@bms.com
Received: January 15, 2008; Published online: March 31, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The outstanding ability of dirhodium
a,a,a’,a’-tetramethyl-1,3-benzenedipropanoate
constituting an important limitation for the use of the
methodology for more elaborate alkenes. The relative
A
G
stability of diazomalonates has limited their use as
[1,4]
dipropanoate] to catalyze the cyclopropanation of a
wide range of alkenes with malonate-derived carbe-
noids under mild reaction conditions is reported in
this communication. The experimental protocol is
remarkably simple, uses readily accessible and
stable dimethyl diazomalonate with very low cata-
lyst loading. More importantly, the alkene is em-
ployedas a limiting reagent.
carbenoidprecursors,
thus, the scope of the reac-
tion of alkenes with diazomalonates has yet to be re-
ported.
While developing the synthesis of a drug candidate,
we desired access to an intermediate 1,1-cyclopropyl
diester. We initiated our work toward identifying a
suitable catalytic system for the cyclopropanation of
olefins with diazomalonates to overcome the limita-
tions described above. Herein we present the first
report of a simple catalytic system for the use of di-
À
Keywords: alkenes; carbenoids; C C bondforma-
tion; cyclopropanes; diazo compounds; rhodium
azomalonates as carbenoidprecursors, which is effec-
tive in the preparation of a wide range of malonate-
derived cyclopropanes under remarkably mild condi-
tions. There are additional advantages to this system
which include: minimization of organic by-products;
slow addition of the carbenoid is not required; the
olefin is usedas the limiting reagent; andvery low
The cyclopropyl moiety is foundin a variety of mole-
cules of biological andpharmaceutical interest. The
reactivity of cyclopropane derivatives also makes catalyst loading is employed (Scheme 1) [esp=
them versatile intermediates in the preparation of a a,a,a’,a’-tetramethyl-1,3-benzenedipropanoate].[5]
range of natural andsynthetic products. Cyclopropa-
We initially exploredthe reactivity of various com-
nation of olefins arguably represents the most mercially available achiral rhodium catalysts[6] with a
straightforwardandconvergent approach to synthe-
size this important class of compounds. In this regard,
catalysts that allow for the addition of various carbe-
noids to alkenes, including several chiral catalysts that
enable enantioselective versions of these reactions,
have been developed.[1] Despite significant achieve-
ments in the field,[2] the metal-catalyzedcyclopropa-
nation reaction of alkenes with malonate-derived car-
benoids remains a significant synthetic challenge. Al-
though iodonium-ylides derived from malonates have
been usedsuccessfully in cyclopropanation of ole-
fins,[3] these processes result in the formation of one
equivalent of iodobenzene as a by-product, and typi-
cally require high temperatures. Furthermore, the
olefin is usedin large excess, or even as a solvent,
challenging susbtrate, pentafluorostyrene. This elec-
Scheme 1.
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813

Francisco Gonzµlez-Bobes et al.
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tron-poor alkene should more readily distinguish the benzylic positions. Increasing the steric bulk in the al-
performance of the catalysts.
lylic position of the terminal olefin did not negatively
impact the outcome of the cyclopropanation reaction
(entry 6). Cyclic alkenes reactedsmoothly rendering
It was anticipatedfurther that an effective catalytic
system for this substrate wouldbe suitable for a wide
range of alkenes.[7] Our observations from the initial cyclopropanation adducts in good yields (entries 7–9).
[8]
screen are summarizedin Table 1.
Both Rh2(esp)2 andRh
acetate] ledto higher conversions than other rhodium
Interestingly, the outcome of the reaction of b-meth-
A
N
E
alkene. While the cis-isomer afforded exclusively the
cis-cyclopropane product in high yield (entry 10), the
[9]
catalysts typically usedfor relatedtransformations.
Rh2(esp)2 was chosen for further development on the trans-isomer ledto a complex mixture of proudcts
G
basis of its significantly lower cost.[10]
We then examinedthe scope of the Rh
lyzedcyclopropanation on an array of diversely sub-
stitutedstyrene-type derivatives. We were pleasedto
findthat the optimizedconditions (Scheme 1) could
be appliedsuccessfully to a range of substrates of di-
verse steric andelectronic attributes (Table 2).
from which the trans-cyclopropane was isolatedin
[12]
2(esp)2-cata- 28% yield(entry 11).
cis- and trans-internal olefins
also showedmarkedly different reactivity (entries 12–
14). Whereas the cis-isomers of 1,3-dichloro-1-pro-
pene (entry 12) and4-octene (entry 13) producedpre-
dominantly the cyclopropanation adducts, albeit in
lower yieldthan terminal olefins, trans-4-octene gen-
The Rh2(esp)2 catalytic system we developed for erateda mixture of products with the cyclopropane
N
styrenyl alkenes was also effectively appliedwithout
major modifications to a range of other olefins, in-
present only as a minor component (entry 14).[13]
The nitrile group is known to react with carbenoids
cluding non-conjugated aliphatic alkenes (Table 3).[11] in a [3+2] fashion, leading to the formation of oxa-
Terminal olefins (entries 1–5) afforded the corre- zoles. Although reaction of substrates containing ni-
sponding cyclopropanes in good to excellent yields trile functionality did lead to competing oxazole side-
without any evidence of C-H insertion at the allylic or products with the Rh
2(esp)2 catalytic system,[14] these
G
cyclopropanations are higher yielding than those pre-
viously described (Scheme 2).[15]
Another remarkable feature of the Rh2(esp)2 cata-
A
Table 1. Catalyst effect.
lyst was observedupon reaction of 1-phenylpropyne.
The corresponding cyclopropene was obtained as the
major product (Scheme 3). To the best of our knowl-
edge this is the first report of a rhodium-catalyzed cy-
clopropenation of an internal alkyne with a diazomal-
onate.[16,17]
In conclusion, we have demonstrated that cyclopro-
panation of an unprecedented array of alkenes with
diazomalonates can be accomplished through the use
[a]
Entry
Catalyst
Rh2(TFA)4
Yield[%]
1
2
3
4
A
11
22
89
97
of the Rh2(esp)2 catalyst. The experimental protocol
A
Rh2(OAc)4
Rh2(TPA)4
Rh2(esp)2
ACHTREUNG
is remarkably simple, uses readily accessible and
stable diazomalonate, and, in sharp contrast with pre-
viously reportedsystems, uses only stoichiometric
amounts of alkene substrates. We also believe that
AHCTREUNG
AHCTREUNG
[a]
CalibratedGC yield vs. an internal standard.
[a]
Table 2. Products from the Rh2(esp)2-catalyzedcyclopropanation of styrene-type alkenes.
A
[a]
CalibratedGC yield vs. an internal standard.[a] Isolatedyields.
0.8 mol% of catalyst was used.
[b]
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Adv. Synth. Catal. 2008, 350, 813 – 816

Rhodium-Catalyzed Cyclopropanation of Alkenes with Dimethyl Diazomalonate
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Table 3. Rh2(esp)2-catalyzedcyclopropanation of alkenes.
A
Entry Alkene
1
Product
Yield [%][a]
91
2
3
4
87
72
83
5
6
95
91
Scheme 2.
7
72
Scheme 3.
8
82[b]
89
Experimental Section
General Protocol (Table 2, Table 3 and Scheme 2)
In the air, Rh2(esp)2 (2 mg, 2.5 5 mmol, 0.1 mol%) was placed
G
9
in a 100-mL three-neckedflask equippedwith a stir bar. The
flask was cappedandpurgedwith nitrogen (three vacuum/re-
filling cycles). CH2Cl2 (2.5 mL) was added by syringe leading
to a pale green homogenous solution. The alkene (2.5 mmol,
1 equiv.) was added and the reaction mixture was then cooled
in a water/ice bath. After 5 min, a solution of diazodimethyl-
malonate (514 mg, 3.25 mmol, 1.3 equiv.) in CH2Cl2 (2.5 mL)
was added by syringe. The resulting solution was kept in the
bath for 10 min andthen stirredat room temperature. After
2 h, the reaction mixture was treatedwith a saturatedsolu-
tion of aqueous thiourea (50 mL) anddilutedwith 25 mL of
CH2Cl2. The mixture was stirredfor 30 min andthen trans-
ferredinto a separatory funnel. The aqueous layer was ex-
tractedwith CH 2Cl2 (3”25 mL). The combinedorganic
layers were washedwith brine (100 mL), driedover anhy-
drous sodium sulfate, filtered and concentrated under
vacuum. The residue was then purified by column chromatog-
raphy on silica gel with the solvent systems indicated (see
Supporting Information for details).
10
87[b]
11
28[c]
12
13
14
43
41
<5
Supporting Information
[a]
Isolatedyields.
14 h; 0.5 mol% of catalyst was used.
1 mol% of catalyst was used.
Complete experimental procedures and full characterization
data for all the compounds reported are given in the Sup-
porting Information.
[b]
[c]
the availability of chiral rhodium catalysts structurally
relatedto the Rh 2(esp)2 may leadto new andexciting
Acknowledgements
AHCTREUNG
opportunities for asymmetric cyclopropanation reac-
We thank Professor Justin Du Bois, Professor Phil S. Baran,
Dr. Richard M. Corbett, Dr. David A. Conlon, Dr. James P.
tions.[18]
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Francisco Gonzµlez-Bobes et al.
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Sherbine and Dr. David R. Kronenthal for helpful discus-
sions. Dr. Charles Pathirana and Dr. Baoning Su are ac-
knowledged for 2D-NMR experiments.
tion processes, showing similar reactivity to Rh2
see: H. Lebel, K. Huard, Org. Lett. 2007, 9, 639–642.
[10] 1 mmol of Rh2(esp)2 =US $198 (Aldrich catalog, based
on the price for a 500 mg sample). 1 mmol of Rh2
(TPA)4 =US $1886 (TCI catalog, basedon the price for
A
AHCTREUNG
AHCTREUNG
a 100 mg sample).
References
[11] A trisubstitutedolefin, (2-methylprop-1-enyl)benzene,
produced only trace amounts of cyclopropane. Allyl
phenyl sulfide and allyl phenyl sulfone yielded essen-
tially no cyclopropane (<10%). Electron-rich olefins
such as 2,3-dihydropyran and benzofuran produced
mixtures of products under these conditions. Attempts
to isolate the cyclopropanes by column chromatogra-
phy on silica gel were unsuccessful. No attempts to op-
timize the reaction for each particular substrate have
been carriedout.
[1] a) M. P. Doyle, M. A. McKervey, T. Ye, Modern Cata-
lytic Methods for Organic Synthesis with Diazo Com-
pounds: From Cyclopropanes to Ylides, Wiley, New
York, 1998; b) Small Ring Compounds in Organic Syn-
thesis VI, Springer, Berlin, 2007, p 2000; c) H. Lebel, J.-
F. Marcoux, C. Molinaro, A. B. Charette, Chem. Rev.
2003, 103, 977–1050.
[2] Remarkable progress towards the development of re-
latedasymmetric reactions using malonate-derivedcar-
benoids has been reported recently by different re-
search groups. A detailed discussion of these results is
beyondthe scope of this communication. For leading
references, see: a) A. Ghanem, F. Lacrampe, V. Schur-
ing, Helv. Chim. Acta 2005, 88, 216–239; b) P. Müller,
A. Ghanem, Chirality 2005, 17, 44–50; c) P. Müller, A.
Ghanem, Org. Lett. 2004, 6, 4347–4350; d) P. Müller,
Y. Allenbach, E. Robert, Tetahedron: Asymmetry 2003,
14, 779–785; e) M. P. Doyle, W. Hu, Arkivoc 2003, 15–
22; f) M. P. Doyle, S. B. Davies, W. Hu, Org. Lett. 2000,
2, 1145–1147; g) H. M. L. Davies, Eur. J. Org. Chem.
1999, 2459–2469; h) H. M. L. Davies, P. R. Bruzinski,
M. J. Fall, Tetrahedron Lett. 1996, 37, 4133–4136.
[3] a) P. Dauban, L. Saniere, A. Tarrade, R. H. Dodd, J.
Am. Chem. Soc. 2001, 123, 7707–7708; b) G. Georga-
kopoulou, C. Kalogiros; L. P. Hadjiarapoglou, Synlett
2001, 1843–1845; c) P. Müller, D. Fernµndez, Helv.
Chim. Acta 1995, 78, 947–958.
[12] The relative stereochemistry of the cyclopropanes has
been unequivocally establishedby 2D NMR experi-
ments.
[13] a) No attempts to optimize each individual substrate
have been conducted. In the reaction of trans-4-octene,
À
the C H insertion product at the allylic position was
isolatedas the major product. See Supporting Informa-
tion for more details. A similar observation has been
previously reported: see ref.[3b]; b) During the prepara-
tion of this manuscript Davies andco-workers reported
À
a systematic study on the balance between allylic C H
insertion andcyclopropanation: H. M. L. Davies, M. G.
Coleman, D. L. Ventura, Org. Lett. 2007, 9, 4971–4974.
[14] In the cyclopropanation reaction of 4-cyanostyrene
(Table 2) the corresponding oxazole side-product was
isolatedin 24% yield. See Supporting Information.
[15] Rh2(OAc)4-catalyzedcyclopropanation of buten-3-ni-
C
trile under similar experimental conditions has been re-
portedto proceedin 21% yield, see: R. D. Connel, M.
Tebbe, A. R. Gangloff, P. Helquist, B. Škermark, Tetra-
hedron 1993, 49, 5445–5449. Our system gave a 61%
combined yield of cyclopropanated adducts.
[4] a) C. G. Hamaker, J.-P. Djukic, D. A. Smith, L. K. Woo,
Organometallics 2001, 20, 5189–5199; b) H. M. L.
Davies, S. A. Panaro, Tetrahedron 2000, 56, 4871–4880;
c) P. Müller, S. Tohill, Tetrahedron 2000, 56, 1725–1731;
d) J. Lim, Y. H. Kim, J. Chem. Soc. Perkin Trans. 1
1999, 3239–3241; see also ref.[3c]
[16] a) There is scant data available for the metal-catalyzed
cyclopropenation of internal alkynes using malonate-
derived carbenoids; for an isolated copper-catalyzed
example, see: R. Breslow, R. Winter, M. Battiste, J.
Org. Chem. 1959, 24, 415–416; b) the cyclopropene
[5] The Rh2(esp)2 catalyst was designed by Du Bois and
T
À
co-workers andwas originally usedfor C H activation
reactions; for leading references, see: a) K. W. Fiori, J.
Du Bois, J. Am. Chem. Soc. 2007, 129, 562–568; b) M.
Kim, J. V. Mulcahy, C. G. Espino, J. Du Bois, Org. Lett.
2006, 8, 1073–1076; c) C. G. Espino, K. W. Fiori, M.
Kim, J. Du Bois, J. Am. Chem. Soc. 2004, 126, 15378–
15379; for a recent example of the use of this catalyst
for the cyclopropanation of alkenes with nitromethane-
derived iodonium ylides, see: d) H. T. Bonge, T.
Hansen, Synlett 2007, 55–59.
was obtainedin 52% yieldwhen 0.1 mol% of Rh 2(esp)2
E
was used; c) the reaction was performed using 25 mmol
of olefin. 4.3 grams of cyclopropene were isolated.
[17] For leading references on rhodium-catalyzed cyclopro-
penation of terminal alkynes: a) Y. Lou, T. P. Remarch-
uk, E. J. Corey, J. Am. Chem. Soc. 2005, 127, 14223–
14230; b) Y. Lou, M. Horikawa, R. A. Kloster, N. A.
Hawryluk, E. J. Corey, J. Am. Chem. Soc. 2004, 126,
8916–8918; c) H. M. L. Davies; G. L. Lee, Org. Lett.
2004, 6, 1233–1236; for some selectedapplications of
cyclopropenes, see: d) M. Rubin, M. Rubina, V. Ge-
vorgyan, Chem. Rev. 2007, 107, 3117–3179; e) M.
Rubin, M. Rubina, V. Gevorgyan, Synthesis 2006,
1221–1245; f) F. Zhang, J. M. Fox, Org. Lett. 2006, 8,
2965–2968; g) S. Chuprakov, M. Rubin, V. Gevorgyan,
J. Am. Chem. Soc. 2005, 127, 3714–3715.
[6] Under these conditions several Cu-based catalysts gave
no cyclopropanation products.
[7] We have observedsimilar catalytic reactivity for other
substrates.
[8] Experimental results were very similar in different
chlorinatedsolvents (CH 2Cl2, 1,2-dichloroethane or
PhCl). Toluene andbenzonitrile ledto lower yields of
cyclopropane. No reaction was observedin DMF.
[18] Du Bois andco-workers have already reportedchiral
[9] Rh2
G
rhodium catalysts structurally related to Rh2
U
catalyst for N C bondformation through C H activa-
reference ref.[5a]
816
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