Rhodium-catalyzed cyclopropenation of alkynes: Synthesis of trifluoromethyl-substituted cyclopropenes

Article abstract of DOI:10.1002/anie.201000787

(Figure Presented) Make it strained and fluorinated! A rhodium-catalyzed domino diazotization/ cyclopropenation reaction involving trifluoroethylamine hydrochloride and alkynes has been developed for the synthesis of trifluoromethyl cyclopropenes that can be easily functionalized to afford useful CF_3- containing building blocks for drug discovery.

Full text of DOI:10.1002/anie.201000787

Communications
DOI: 10.1002/anie.201000787
Cyclopropenation
Rhodium-Catalyzed Cyclopropenation of Alkynes: Synthesis of
Trifluoromethyl-Substituted Cyclopropenes**
Bill Morandi and Erick M. Carreira*
The trifluoromethyl group is a structural subunit that is
extensively relied upon in the drug discovery process in
medicinal chemistry. However, its introduction during the
course of a synthesis remains a challenge for the organic
chemist.[1] Trifluoromethyl-substituted cyclopropenes are
potentially highly useful subunits whose synthesis and use
have been only sparsely described in the literature.[2] We
recently documented an iron-catalyzed domino diazotization/
cyclopropanation of alkenes that utilizes F3CCH2NH2·HCl as
a precursor for the in situ generation of F3CCHN2 in water.[3]
Herein, we report a rhodium-catalyzed cyclopropenation
reaction of alkynes that proceeds with remarkable efficiency
in aqueous media, to enable the synthesis of a previously
unknown class of trifluoromethyl-substituted cyclopropenes
[Eq. (1)]. Furthermore, we describe a range of possible
transformations for these trifluoromethylcyclopropene build-
ing blocks.
erably less well-developed than the alkene reaction because
of their attenuated reactivity.[5]
Preliminary experiments using our previously described
conditions for the iron-catalyzed cyclopropanation of alkenes
(cat. FeTPPCl, DMAP, H2SO4, NaOAc, 1.5 equiv
CF3CH2NH3Cl, 1.8 equiv NaNO2) and 4-phenyl-1-butyne as
test substrate failed to afford any cyclopropene product.
Attempts with a [Co(salen)] catalyst led to complete recovery
of the starting material. We then screened several rhodium
complexes, and the results are shown in Table 1. The lipo-
Table 1: Catalyst screening.[a]
Entry
Catalyst
Loading [mol%]
Conversion [%][b]
1
2
3
4
5
6
[Fe(TPP)Cl][c]
[Co(salen)][d]
3
5
2.5
2.5
2.5
2.5
n.r.
n.r.
20
32
60
92
[Rh2(OAc)2]
[Rh2(CF3COOÀ)4]
[Rh2(C7H15COOÀ)4]
[Rh2(esp)2]
[a] General procedure: alkyne (0.22 mmol, 1.0 equiv), F3CCH2NH3Cl
(2.0 equiv), NaNO2 (2.4 equiv), NaOAc (20 mol%), H2SO4 (10 mol%),
H2O (1.3 mL). [b] Conversion determined by NMR spectroscopy.
[c] 10 mol% DMAP. [d] 10 mol% N-methylimidazole. n.r.=no reaction.
[Co(salen)]=rac-trans-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohex-
ane diaminocobalt(II). esp=espino, TPP=5,10,15,29-tetraphenyl-
21H,23H-porphine, DMAP=4-(dimethylamino)pyridine.
The in situ conversion of trifluoroethylamine hydrochlo-
ride into trifluoromethyldiazomethane in aqueous media
permits safer handling of this reactive species in the labo-
ratory.[4] To extend the uses of F3CCHN2, we have been
interested in examining a number of other carbene-transfer
reactions, as this could lead to the preparation of novel
building blocks that contain the trifluoromethane unit. It is
important to note that the development of these reactions
require the identification of robust catalysts that are compat-
ible with the strongly oxidizing and acidic conditions that are
required for the generation of the reactive intermediate. Our
interest in the chemistry of alkynes led us to prioritize the
cyclopropenation of this class of starting materials. Further-
more, the cyclopropenation of alkynes in general is consid-
philicity of the ligand that is associated with the metal
complex plays a crucial role in the reaction, as the conversion
increases inversely proportional to the polarity, from the most
polar complex, [Rh2(OAc)4], to the least polar, [Rh2-
(O2CC7H15)4]. We speculate this happens because the more
lipophilic ligands enhance the hydrophobicity of the metal–
carbene complex, ensuring that the reaction proceeds hetero-
geneously, and thus avoiding a quenching of the putative
reactive metal–carbenoid intermediate by water. Further
screening led us to identify the [Rh2(esp)2] catalyst reported
by Du Bois and co-workers[6] as the best catalyst under the
harsh conditions (NaNO2, H2SO4) required for the production
of the diazoalkane, affording almost full conversion of the
starting material. The combined lipophilicity of the ligand
along with its chelating nature likely ensures high stability
under the reaction conditions.
[*] B. Morandi, Prof. Dr. E. M. Carreira
Laboratorium fꢀr Organische Chemie, ETH Zꢀrich
8093 Zꢀrich (Switzerland)
Fax: (+41)1-632-1328
E-mail: carreira@org.chem.ethz.ch
Homepage: http://www.carreira.ethz.ch
[**] We are grateful to the Swiss National Foundation and the SSCI for a
fellowship to B.M.
In the optimized experimental procedure, a mixture of 4-
phenyl-1-butyne, [Rh2(esp)2] (2.5 mol%), CF3CH2NH3Cl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000787.
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(2 equiv), H2SO4 (10 mol%), and NaOAc (20 mol%) at
ambient temperature was treated with an aqueous solution
of NaNO2 (0.8m, 2.4 equiv) by syringe pump addition. The
reaction gave complete conversion, and (2-(3-(trifluorome-
thyl)cycloprop-1-enyl)ethyl)benzene was isolated in 78%
yield. It is important to note that addition of toluene as a
co-solvent led to reduced conversion (50%) of the alkyne into
the cyclopropene product. We hypothesize that the reaction
might proceed on water, because both catalyst and substrate
are insoluble in the aqueous phase.[7] The diazotization
reaction likely transpires in the aqueous phase whilst the
cyclopropenation of the alkyne occurs in the organic alkyne
phase. This hypothesis is supported by the strong coloration of
the alkyne droplets owing to the dissolved violet rhodium
complex.
trifluoromethylated building blocks. It is well worth noting
that although 1,1-trifluoromethyl-alkoxycarbonyl-substituted
cyclopropenes have been previously reported,[2] the cyclo-
propene class described herein has not been previously
documented.
Next, a study of the reactivity[8] of these novel cyclo-
propenes in a variety of chemical transformations was
conducted (Scheme 1). To examine the reactivity of the
Next, the scope of the reaction was probed (Table 2).
Interestingly, unactivated aliphatic alkynes were excellent
substrates for this transformation, affording cyclopropene
adducts in good yields. Furthermore, even the disubstituted
aliphatic substrates reacted successfully. Phenylacetylene did
not furnish the corresponding product under these conditions;
rather, complete decomposition of the starting material into
unidentified products was observed. However, gratifyingly,
methylphenylacetylene afforded the cyclopropene product in
good yield (Table 2, entry 5). Common alcohol protecting
groups are tolerated in the reaction (OBn and OTBS; Table 2,
entries 3, 6, and 7). This method shows a broad substrate
scope and affords a facile and quick access to this new type of
Scheme 1. Transformations of cyclopropene 1.
trifluoromethylcyclopropenes, larger amounts of cyclopro-
pene 1 were required; therefore, the quantities used in the
cyclopropenation reaction were scaled up. Under optimized
preparative conditions, the amount of trifluoroethylamine
hydrochloride was successfully lowered to 1.5 equivalents;
the reaction performed on a 4.4 mmol (572 mg) scale afforded
the product in 75% yield.
Table 2: Scope of the cyclopropenation.[a]
The first transformation we examined was the Diels–
Alder reaction of 1 with 2,3-dimethylbutadiene, which
afforded 2 in 97% yield (Scheme 1).[9c] The efficiency with
which the cycloaddition took place underscores the versatility
of trifluoromethyl-substituted cyclopropenes as a point of
divergence for the preparation of fused-ring systems. Cyclo-
propene 1 was also subjected to reduction with Pd/CaCO3/H2
to furnish cyclopropane 3 with excellent diastereoselectivity
(93:7).[9c] That the product of the reduction is the cis diaster-
eomer provides a complementary approach to our earlier
report regarding the cyclopropanation of mono-substituted
alkenes, which displays high trans-selectivity. Therefore, both
families of cis- and trans-trifluoromethyl-substituted cyclo-
propanes may now be accessed with exceptional diastereo-
control. When 1 was subjected to Heck coupling with para-
bromonitrobenzene, arylated product 4 was isolated in 93%
yield,[10] wherein the double bond in the product had been
incorporated exo to the cylopropane ring. The formation of
the double bond is consistent with a b-hydride elimination
reaction that can only occur in an exo fashion because of
stereoelectronic constraints with regard to the b hydride.
Methylenecyclopropanes have a rich chemistry, which makes
our transformation a useful route to this class of compounds.[8]
Finally, cyclopropenes may be subjected to lithiation and
trapping.[11] We were pleased to observe that cyclopropene 1
was stable upon deprotonation with BuLi, and the lithiated
cyclopropene did not suffer decomposition even upon warm-
Entry
1
Alkyne
Product
Yield[b]
78
2
3
4
5
6
71
71
70
67
69[c]
7
73[c]
[a] General procedure: alkyne (0.22 mmol, 1 equiv), F3CCH2NH3Cl
(2.0 equiv), NaNO2 (2.4 equiv), NaOAc (20 mol%), H2SO4
(10 mol%),H2O (1.3 mL). [b] Yield of isolated product. [c] 1:1 d.r.
TBS=tert-butyldimethylsilyl.
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Communications
ing to room temperature. This observation is in contrast to
Keywords: carbenes · cyclopropenes · rhodium ·
trifluoromethyl group · water
.
what has been reported for cyclopropenes that are stabilized
by electron-withdrawing groups, which lead to formation of a
ring-opened alkyne product.[11] The lithiated cyclopropene
underwent reaction with benzaldehyde at À788C to afford
product 5 in 78% yield.
[1] For general reviews in this area, see: a) P. Kirsch, Modern
Fluoroorganic Chemistry: Synthesis Reactivity, Applications,
Wiley-VCH, Weinheim, 2004; b) M. Schlosser, Angew. Chem.
2006, 118, 5558 – 5572; Angew. Chem. Int. Ed. 2006, 45, 5432 –
5446; c) C. Isanbor, D. OꢀHagan, J. Fluorine Chem. 2006, 127,
303 – 319; d) K. Mꢁller, C. Faeh, F. Diederich, Science 2007, 317,
1881 – 1886; e) S. Purser, P. R. Moore, S. Swallow, V. Gouver-
neur, Chem. Soc. Rev. 2008, 37, 320 – 330.
[2] P. Mꢁller, S. Grass, S. P. Shahi, G. Bernardinelli, Tetrahedron
2004, 60, 4755 – 4763.
[3] B. Morandi, E. M. Carreira, Angew. Chem. Int. Ed. 2010, 49,
938 – 941; Angew. Chem. 2010, 122, 950 – 953.
In summary, we have described the first cyclopropenation
reaction of alkynes with trifluoromethyldiazomethane. The
reaction proceeds in aqueous media under conditions in
which the reactive diazoalkane is generated in situ from
trifluoroethylamine hydrochloride in the presence of H2SO4
and NaNO2. Key to enabling the transformation is the
identification of the rhodium catalyst [Rh2(esp)2] as being
robust and compatible with the harsh reaction conditions. We
have also showcased, in preliminary experiments, the versa-
tility of these previously unknown products for further
organic transformations. Therefore, the trifluoromethylcyclo-
propenes represent a promising class of compounds for the
preparation of new building blocks in medicinal and materials
chemistry. In a broader sense, this work highlights the
opportunities for synthesis in the identification of new
processes and catalysts under acidic, strongly oxidizing, and
aqueous conditions that lead to the in situ generation of
reactive intermediates. Development of other transforma-
tions and asymmetric cyclopropenation reactions are cur-
rently being investigated in our laboratory.
[4] J. R. Fulton, V. K. Aggarwal, J. de Vicente, Eur. J. Org. Chem.
2005, 1479 – 1492.
[5] a) S. Fujimori, E. M. Carreira, Angew. Chem. 2007, 119, 5052 –
5055; Angew. Chem. Int. Ed. 2007, 46, 4964 – 4967; b) T. F.
Knꢂpfel, P. Zarotti, Y. Takashi, E. M. Carreira, J. Am. Chem.
Soc. 2005, 127, 9682 – 9683; c) T. F. Knꢂpfel, E. M. Carreira, J.
Am. Chem. Soc. 2003, 125, 6054 – 6055; d) C. Fischer, E. M.
Carreira, Org. Lett. 2001, 3, 4319 – 4321; e) D. E. Frantz, R.
Fꢃssler, E. M. Carreira, J. Am. Chem. Soc. 2000, 122, 1806 – 1807.
[6] C. G. Espino, K. W. Fiori, M. Kim, J. Du Bois, J. Am. Chem. Soc.
2004, 126, 15378 – 15379.
[7] S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb,
K. B. Sharpless, Angew. Chem. 2005, 117, 3339 – 3343; Angew.
Chem. Int. Ed. 2005, 44, 3275 – 3279.
[8] For reviews on the general reactivity of cyclopropenes and
methylenecyclopropenes, see: a) I. Marek, S. Simaan, A.
Masarwa, Angew. Chem. 2007, 119, 7508 – 7520; Angew. Chem.
Int. Ed. 2007, 46, 7364 – 7376; b) M. Rubin, M. Rubina, V.
Gevorgyan, Synthesis 2006, 1221 – 1245; c) M. Rubin, M.
Rubina, V. Gevorgyan, Chem. Rev. 2007, 107, 3117 – 3179;
d) A. de Meijere, S. I. Kozhushkov, H. Schill, Chem. Rev. 2006,
106, 4926 – 4996.
[9] For selected references, see: a) M. P. Doyle, M. Protopopova, P.
Mꢁller, D. Ene, E. A. Shapiro, J. Am. Chem. Soc. 1994, 116,
8492 – 8498; b) Y. Lou, T. P. Remarchuk, E. J. Corey, J. Am.
Chem. Soc. 2005, 127, 14223 – 14230; c) Y. Lou, M. Horikawa,
R. A. Kloster, N. A. Hawryluk, E. J. Corey, J. Am. Chem. Soc.
2004, 126, 8916 – 8918; d) H. M. L. Davies, G. H. Lee, Org. Lett.
2004, 6, 1233 – 1236; e) P. Panne, J. M. Fox, J. Am. Chem. Soc.
2007, 129, 22 – 23.
Experimental Section
General procedure for cyclopropenation: [Rh2(esp)2] (4.3 mg,
0.0055 mmol) and NaOAc (3.6 mg, 0.044 mmol) were dissolved in
degassed, distilled water (0.8 mL). Then, trifluoroethylamine hydro-
chloride (60 mg, 0.44 mmol) and H2SO4 (1.2 mL, 0.022 mmol) were
added, and the solution was degassed for one minute by sparging with
argon. The alkyne (0.22 mmol) was added next, and NaNO2 (36 mg,
dissolved in 0.5 mL of water) was added by syringe pump over
10 hours. After 4 hours, CH2Cl2 and water were added, and the water
phase was extracted with CH2Cl2 (x3), dried with MgSO4, and
evaporated under reduced pressure. After analysis of the crude NMR
spectrum, the mixture was purified by column chromatography on
silica gel (pentane/diethyl ether) to afford the product.
[10] S. Chuprakov, M. Rubin, V. Gevorgyan, J. Am. Chem. Soc. 2005,
127, 3714 – 3715.
Received: February 9, 2010
Published online: May 5, 2010
[11] L. Liao, N. Yan, J. M. Fox, Org. Lett. 2004, 6, 4937 – 4939.
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