Cascade synthesis of (E)-2-alkylidenecyclobutanols

Article abstract of DOI:10.1021/ol901985c

A facile, one-pot reaction cascade condenses 1,1,1-trichloroalkanes with α,β-unsaturated ketones to unexpectedly furnish moderate to good yields of (E)-2-alkylidenecyclobutanols.

Full text of DOI:10.1021/ol901985c

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4764-4766
Cascade Synthesis of
(E)-2-Alkylidenecyclobutanols
J. R. Falck,*,† Anish Bandyopadhyay,† Narender Puli,† Abhijit Kundu,†
L. Manmohan Reddy,† Deb K. Barma,† Anyu He,† Hongming Zhang,‡
Dhurke Kashinath,§ and Rachid Baati*,§
Departments of Biochemistry and Pharmacology, UniVersity of Texas Southwestern
Medical Center, Dallas, Texas 75390, Department of Chemistry, Southern Methodist
UniVersity, Dallas Texas 75275, and UniVersity of Strasbourg, Faculty of Pharmacy
CNRS-UMR 7199, 74 Route du Rhin, 67401 Illkirch, France
j.falck@utsouthwestern.edu; baati@bioorga.u-strasbg.fr
Received August 26, 2009
ABSTRACT
A facile, one-pot reaction cascade condenses 1,1,1-trichloroalkanes with r,ꢀ-unsaturated ketones to unexpectedly furnish moderate to good
yields of (E)-2-alkylidenecyclobutanols.
In recent years, our laboratories1 and others2 have introduced
an assortment of organochromium reagents and exploited
their unique physical/chemical properties for access to a wide
range of natural products and high value targets.3 In
continuation of these studies, we sought to extend the utility
of select chromium reagents via in situ transmetalation and
subsequent reaction with electrophiles. In one such example,
chromium carbenoid 2 was generated from 1,1,1-trichloro-
alkane 1 using excess anhydrous CrCl2, except both copper
cyanide and an R,ꢀ-unsaturated ketone 3 were present. We
anticipated the (E)-vinylchromium(III) intermediate 2 would
undergo transmetalation and subsequent 1,4-conjugate ad-
dition with 3. Unexpectedly, however, (E)-2-alkylidenecy-
clobutanol 4 was isolated as the major product in moderate
to good yields (Scheme 1).
† University of Texas Southwestern Medical Center.
‡ Southern Methodist University.
§ University of Strasbourg.
(1) Review: (a) Baati, R.; Falck, J. R.; Mioskowski, C. Actualite Chim.
2009, 326, 25. (b) Baati, R.; Mioskowski, C.; Kashinath, D.; Kodepelly,
S.; Lu, B.; Falck, J. R. Tetrahedron Lett. 2009, 50, 402. (c) Bejot, R.; He,
A.; Falck, J. R.; Mioskowski, C. Angew. Chem, Int. Ed. 2007, 46, 1719.
(d) Falck, J. R.; Bejot, R.; Barma, D. K.; Bandyopadhyay, A.; Joseph, S.;
Mioskowski, C. J. Org. Chem. 2006, 71, 8178. (e) Falck, J. R.; He, A.;
Reddy, L. M.; Kundu, A.; Barma, D. K.; Bandyopadhyay, A.; Kamila, S.;
Akella, R.; Bejot, R.; Mioskowski, C. Org. Lett. 2006, 8, 4645. (f) Baati,
R.; Mioskowski, C.; Barma, D.; Kache, R.; Falck, J. R. Org. Lett. 2006, 8,
2949. (g) Bejot, R.; Tisserand, S.; Reddy, L. M.; Barma, D. K.; Baati, R.;
Falck, J. R.; Mioskowski, C. Angew. Chem., Int. Ed. 2005, 44, 2008. (h)
Barma, D. K.; Kundu, A.; Zhang, H.; Mioskowski, C.; Falck, J. R. J. Am.
Chem. Soc. 2003, 125, 3218. (i) Barma, D. K.; Kundu, A.; Baati, R.;
Mioskowski, C.; Falck, J. R. Org. Lett. 2002, 4, 1387. (j) Baati, R.; Barma,
D. K.; Falck, J. R.; Mioskowski, C. J. Am. Chem. Soc. 2001, 123, 9196.
(2) Recent examples: (a) Takai, K.; Toshikawa, S.; Inoue, A.; Kokumai,
R.; Hirano, M. J. Organomet. Chem. 2007, 692, 520. (b) Concellon, J. M.;
Mejica, C. Eur. J. Org. Chem. 2007, 5250. (c) Nakagawa, M.; Saito, A.;
Soga, A.; Yamamoto, N.; Taguchi, T. Tetrahedron Lett. 2005, 46, 5257.
(d) Takenaka, N.; Xia, G.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126,
13198. (e) Berkessel, A.; Menche, D.; Sklorz, C. A.; Schroder, M.; Paterson,
I. Angew. Chem., Int. Ed. 2003, 42, 1032.
Scheme 1. Synthesis of (E)-2-Alkylidenecyclobutanols
Alkylidenecyclobutanols, and the cyclobutanols which are
readily derived from them, appear as substructures4 in many
architecturally interesting and/or bioactive natural products.5
They also display unique reaction manifolds that make them
useful as synthetic intermediates.6 Access to these strained
(3) Pospisil, J.; Mueller, C.; Fu¨rstner, A. Chem.sEur. J. 2009, 15, 5956.
10.1021/ol901985c CCC: $40.75
Published on Web 09/17/2009
 2009 American Chemical Society

ring systems is generally restricted to [2 + 2]-cycloadditions,7
ring expansions, or contractions of the corresponding ho-
mologues,8 Wittig9 and, to a lesser extent, via intramolecular
alkylations.10
Scheme 2. 1,4-Conjugate Adduct
To better understand the implications of this unusual
cascade reaction, we investigated its scope and possible
mechanism and report our findings herein. The reaction
parameters were systematically optimized using 1,1,1-
trichloroalkane 5, R,ꢀ-unsaturated ketone 6, CrCl2 (6 equiv),
and CuCN (1.2 equiv) as the benchmark system. Yields of
7 were best in THF (Table 1, entry 1), somewhat lower in
e.g., NiCl2, BF3·Et2O, and KCN, were likewise unhelpful as
were higher (70 °C) or lower (4 °C) reaction temperatures.
The amount of CrCl2 could be reduced from 6 equiv to 1
equiv using Mn(0) powder as a regeneration agent,11
although the yield of 7 declined to 24%. Substoichiometric
amounts of CuCN also led to significantly lower yields.
Table 1. Synthesis of (E)-2-Alkylidenecyclobutanolsa
Both allylic 8 (entries 2 and 3) and benzylic 12 (entry 4)
trichloroalkanes behaved analogously to 5 and afforded
adducts 9, 11, and 13, respectively, from ketones 6 and 10.12
Importantly, the cascade was compatible with silyl ether 14
(entries 5-8), electron-rich napthalene 16 (entry 6), and even
the aryl bromide 18 (entry 7). X-ray analysis (see Supporting
Information) of adduct 17, following desilylation, confirmed
its identity and the E-olefinic geometry. The latter was a key
insight that must be accommodated by any proposed annu-
lation process (vide infra).
It should be noted that benzylic trichloromethylcarbinols,
e.g., 20 (entry 8), which are readily prepared from aldehydes,
were also suitable precursors for the casacde, albeit with
slightly diminished yields of adduct.13 Addition to R-sub-
(6) (a) Kabalka, G. W.; Yao, M.-L. Tetrahedron Lett. 2003, 44, 7885.
(b) Fujiwara, T.; Iwasaki, N.; Takeda, T. Chem. Lett. 1998, 741. (bb)
Anderson, E. A.; Alexanian, E. J.; Sorensen, E. J. Angew. Chem., Int. Ed.
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N.; Novack, A. R. J. Am. Chem. Soc. 2005, 127, 11206. (e) Fu, N.-Y.;
Chan, S.-H.; Wong, H. N. C. The Application of Cyclobutane Derivatives
in Organic Synthesis. In Chemistry of Cyclobutanes; Rappoport, Z.,
Liebman, J. F., Eds.; John Wiley & Sons Ltd.: Chichester, UK, 2005; Vol.
1, pp 357-440.
(7) (a) Carreira, E. M.; Hastings, C. A.; Shepard, M. S.; Yerkey, L. A.;
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2003, 44, 3329. (b) Bernard, A. M.; Floris, C.; Frongia, A.; Piras, P. P.
Synlett 1998, 668.
a See ref 12 for general procedure.
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Soc. 1995, 117, 5503.
(10) (a) Krohn, K.; Boerner, G. J. Org. Chem. 1994, 59, 6063. (b) Avila-
Zarraga, J. G.; Maldonado, L. A. Chem. Lett. 2000, 512. (c) Other synthetic
methodology: Okuma, K.; Kamahori, Y.; Tsubakihara, K.; Yoshihara, K.;
Tanaka, Y.; Shioji, K. J. Org. Chem. 2002, 67, 7355. (d) Mubarak, M. S.;
Jennermann, T. R.; Ischay, M.; Peters, D. G. Eur. J. Org. Chem. 2007, 32,
5346. (e) Barbero, A.; Cuadrado, P.; Garcia, C.; Rincon, J. A.; Pulido, F. J.
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DME, CH3CN, and dioxane, and poor in DMF, HMPA,
DMSO, and EtOAc. The reaction was also highly dependent
upon the copper salt. CuCN was superior to all others for
producing alkylidenecyclobutanols; little, if any, 7 or con-
jugate addition was observed with CuI, CuBr, CuCl, PhSCu,
or CuTc, whereas CuOTf gave a 35% yield of the 1,4-adduct
28 but no alkylidenecyclobutanol (Scheme 2). Adjuvants,
(11) Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349.
(12) A mixture of 1,1,1-trichloroalkane 1 (0.2 mmol) and R,ꢀ-unsaturated
ketone 3 (0.24 mmol, 1.2 equiv) in dry tetrahydrofuran (5 mL) was added
to a stirring, room temperature suspension of CrCl2 (1.2 mmol, 6 equiv;
Aldrich Chem. Co.) and CuCN (0.24 mmol, 1.2 equiv) in dry tetrahydrofuran
(5 mL) under an argon atmosphere. After 12 h, the reaction mixture was
quenched with saturated aqueous ammonium oxalate (3 mL) and extracted
with Et2O (3 × 30 mL). The combined ethereal extracts were washed with
water (2 × 40 mL), dried over anhydrous sodium sulfate, and concentrated
under reduced pressure. The residue was purified by SiO2, column
chromatography using a gradient of hexane to hexane/ethyl acetate (10:1)
affording 2-alkylidenecyclobutanol 4 in the indicated yields (Table 1).
(4) (a) Zheng, Y.-B.; Lu, C.-H.; Zheng, Z.-H.; Lin, X.-J.; Su, W.-J.;
Shen, Y.-M. HelV. Chim. Acta 2008, 91, 2174. (b) Vasas, A.; Hohmann,
J.; Forgo, P.; Szabo, P. Tetrahedron 2004, 60, 5025. (c) Fujiwara, Y.;
Naithou, K.; Miyazaki, T.; Hashimoto, K.; Mori, K.; Yamamoto, Y.
Tetrahedron Lett. 2001, 42, 2497.
(5) Hansen, T. V.; Stenstrom, Y. Naturally Occurring Cyclobutanes. In
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Science Ltd.: New York, NY, 2001; Vol. 5, pp 1-38.
Org. Lett., Vol. 11, No. 20, 2009
4765

stituted R,ꢀ-unsaturated ketone 22 proceeded smoothly to
furnish 23 as a 1:1.8 diastereomeric mixture (entry 9), and
notably, the polymerization-prone exocyclic ketone 24 was
transformed into fused bicyclic 25 (entry 10). In contrast,
analogous efforts using the ꢀ-substituted analogue 26 (R )
Me, Ph) failed to give any 27 (entry 11).
While the mechanistic details remain undefined at present,
we speculate that one-electron reduction of enone 314 to enol
radical 29 occurs concurrently with the production of
R-halovinylidene chromium carbenoid 2 (Scheme 3).1j
ously identified internal proton return process1j,16 or adventi-
tious water, gives 32 from which 4 is obtained by intramo-
lecular ketone vinylation.17
In summary, we have demonstrated a convergent, (E)-
selective synthesis of 2-alkylidenecyclobutanols based upon
mechanistically unique, synergistic chemistry not achievable
using either CrCl2 or CuCN alone.
Acknowledgment. Financial support provided by the
Robert A. Welch Foundation and NIH (GM31278). The
ANR (Agence National pour la Recherche) is acknowledged
for a grant to D.K.
Supporting Information Available: Experimental pro-
cedures, spectral data of all new compounds, and crystal
structure data of 17 (after desilylation) in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 3. Proposed Mechanism
OL901985C
(14) Comparable enone Cr(II)-reductions are well precedented: (a) Takai,
K.; Morita, R.; Toratsu, C. Angew. Chem., Int. Ed. 2001, 40, 1116. (b)
Toratsu, C.; Fujii, T.; Suzuki, T.; Takai, K. Angew. Chem., Int. Ed. 2000,
39, 2725. (c) Montgomery, D.; Reynolds, K.; Stevenson, P. J. Chem. Soc.,
Chem. Commun. 1993, 363.
(15) Gossage, R. A.; van de Kuil, L. A.; van Koten, G. Acc. Chem.
Res. 1998, 31, 423.
(16) As would be predicted for an internal proton return (IPR) process,
there was no change in the yield of 4 if 1.2 equiv of water was intentionally
added at the beginning of the reaction. Also, there was no deuterium
incorporation into 4 using THF-d8 as solvent or when the final reaction
mixture was quenched with D2O. Utilization of 2,2-dideuterated 1 led to 4
fully deuterated at the vinyl but nowhere else in the molecule.
(17) Vinyl chromium reagents add to ketones with retention of config-
uration: Trost, B. M.; Pinkerton, A. B. J. Org. Chem. 2001, 66, 7714.
Subsequent copper-mediated Kharasch-type addition15 and
loss of copper chloride from the resultant adduct 30 deliver
(E)-vinylchromium 31. Enol quench, perhaps by the previ-
(13) Baati, R.; Barma, D. K.; Falck, J. R.; Mioskowski, C. Tetrahedron
Lett. 2002, 43, 2183.
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