Ring expansion/homologation-aldehyde condensation cascade using tert-trihalomethylcarbinols

Article abstract of DOI:10.1021/ol061953q

Treatment of cyclic tert-trihalomethylcarbinols with CrCl₂ in THF/HMPA in the presence of aryl or aliphatic aldehydes initiates a cascade sequence of one carbon ring expansion-olefination affording conjugated exocyclic ketones. Acyclic tert-trihalomethylcarbinols undergo a comparable cascade of one carbon homologation-olefination.

Full text of DOI:10.1021/ol061953q

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4645-4647
Ring Expansion/Homologation
Condensation Cascade Using
tert-Trihalomethylcarbinols
−Aldehyde
J. R. Falck,*,† Anyu He,† L. Manmohan Reddy,† Abhijit Kundu,† Deb K. Barma,†
A. Bandyopadhyay,† Sukanta Kamila,† Radha Akella,† Romain Bejot,‡ and
Charles Mioskowski*,‡
Departments of Biochemistry and Pharmacology, UniVersity of Texas Southwestern
Medical Center, Dallas, Texas 75390, and Laboratoire de Synthe`se Bio-Organique,
UMR 7175 - LC1, Faculte´ de Pharmacie, UniVersite´ Louis Pasteur, 74 Route du Rhin,
BP 24, 67 401 Illkirch, France
j.falck@utsouthwestern.edu; mioskow@aspirine.u-strasbg.fr
Received August 7, 2006
ABSTRACT
Treatment of cyclic tert-trihalomethylcarbinols with CrCl2 in THF/HMPA in the presence of aryl or aliphatic aldehydes initiates a cascade
sequence of one carbon ring expansion olefination affording conjugated exocyclic ketones. Acyclic tert-trihalomethylcarbinols undergo a
comparable cascade of one carbon homologation olefination.
−
−
Trihalomethylcarbinols and their derivatives are a diverse1
and readily accessible class of functionalized alcohols.2 Their
reduction, inter alia, electrochemical,3 zerovalent metals/
metal salts,4 or aqueous Cr(II),5 principally induces elimina-
tion to the corresponding 1,1-dihaloolefin. However, our
laboratories recently observed that sec-trihalomethylcarbinol
derivatives follow a different reaction manifold when reduced
with Cr(II) salts in THF leading stereoselectively to (Z)-R-
haloenol esters and (Z)-â-haloenol ethers.6 We consequently
examined the behavior under similar conditions of tert-
trihalomethylcarbinols in the presence of aldehydes and
report herein a cascade sequence7 of one carbon ring
expansion/homologation-olefination affording conjugated
ketones.8
The cascade sequence was optimized using carbinol 19
(X ) Cl) and benzaldehyde 2 as the test system. The best
yield of adduct 310 was obtained using CrCl2 (6 equiv) in
THF/HMPA (2:1) at 40 °C (Table 1, entry 1). Using the
tribromo version of 1 (X ) Br), the results were identical,
† University of Texas Southwestern.
‡ Universite´ Louis Pasteur.
(1) For example, see: (a) Kiehlmann, E.; Loo, P.-W. Can. J. Chem. 1969,
47, 2029-2037. (b) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1992, 33,
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J. R.; Mioskowski, C. Angew. Chem., Int. Ed. 2005, 44, 2008-2011.
(7) For a definition of cascade reactions and extensive examples, see:
Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131-
163.
(8) Review: Hesse, M. Ring Enlargement in Organic Chemistry; VCH:
New York, 1991.
(9) (a) Sibille, S.; d'Incan, E.; Leport, L.; Perichon, J. Tetrahedron Lett.
1986, 27, 3129. (b) Shono, T.; Kise, N.; Masuda, M.; Suzumoto, T. J. Org.
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1982, 23, 1609-1612.
(4) (a) Kiehlmann, E.; Bianchi, R. J.; Reeve, W. Can. J. Chem. 1969,
47, 1521-1527. (b) Ranu, B. C.; Samanta, S.; Das, A. Tetrahedron Lett.
2002, 43, 5993-5995. (c) Li, J.; Xu, X.; Zhang, Y. Tetrahedron Lett. 2003,
44, 9349-9351. (d) Farkas, J.; Kourim, P.; Sorm, F. Collect. Czech. Chem.
Commun. 1959, 24, 2230-2236.
(5) For seminal studies regarding the reactivity of polyhalogenated
substrates with Cr(II), see: Wolf, R.; Steckhan, E. J. Chem. Soc., Perkin
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10.1021/ol061953q CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/01/2006

(entry 3, 6 f 710), and electron-rich (entry 4, 8 f 9,10 and
entry 5, 10 f 1111) aldehydes. In all, only exocyclic olefins
were generated including 5, the thermodynamically less-
stable positional isomer. Notably, the yield of the adduct, as
demonstrated in the condensation of 1 with 10 (entry 5),
could be ameliorated utilizing a modest excess (1.5 equiv)
of carbinol. Electron-deficient aldehydes were also suitable
substrates, e.g., 12 f 13 (entry 6). Contrary to expectations,8
the ring enlargement-olefination of 14 favored 15,12 the
product of migration of the less-substituted carbon, over 1613
by a 5:1 ratio (entry 7). Other ring sizes could be accom-
modated as well: cyclobutyl carbinol 17 evolved cyclopen-
tenone 1810 (entry 8), and cyclohexyl carbinol 199b furnished
cycloheptenone 2010 (entry 9). To gain some insight into the
influence of relative stereochemistry and conformation on
the efficiency of the ring expansion process, the conforma-
tionally constrained erythro/threo-pairs 21/22 (entry 10) and
24/25 (entry 11) were subjected to the standard reaction
conditions. The erthyro-isomers 21 and 24, whose trichlo-
romethyls are equatorially disposed, afforded significantly
greater yields of the expected adducts 23 and 26, respectively,
consistent with better orbital overlap in the transition state.
Simple elimination to the corresponding 1,1-dichloroolefin
accounted for the majority of the remaining material balance
in all of these cases. Finally, comparable homologation-
olefinations could be achieved using acyclic trihalocarbinols,
as evident by the isolation of 28 in good overall yield from
the commercial carbinol 27 (entry 12).
Table 1. Ring Expansion/Homologation-Aldehyde
Condensation Cascadea
Although the mechanistic details have not been established,
at least two pathways seem plausible in light of the existing
data (Scheme 1). Initial metalation of the trihalomethyl
Scheme 1. Proposed Cascade Mechanism
a Trihalocarbinol (1 mmol) was added to a stirring suspension of CrCl2
(6 mmol) and aldehyde (1 mmol) in THF/HMPA (2:1, 7 mL) at 40 °C for
4 h, quenched with water, and purified. b Structure and relative stereo-
chemistry confirmed by X-ray analysis of the (p-tolylsulfonyl)hydrazone.
c Used 1.5 equiv of carbinol. d Structure and relative stereochemistry
confirmed by X-ray analysis.
except that the reaction only required 2 h instead of the 4 h
when X ) Cl. The output of 3 did not improve using a lower
THF/HMPA ratio (i.e., 1:1), and it decreased linearly as the
ratio increased in favor of THF. Other solvents or their
combinations, e.g., THF only, DMF, EtOAc, dioxane, and
HMPA, were not satisfactory. There was also a strict
dependence on the amount of CrCl2; 5 and 4 equiv gave 3
in 51% and 30% yields, accordingly. Efforts to use fewer
equivalents of CrCl2 by coupling the reaction to a regenera-
tion system showed promise but clearly need further
improvement. For instance, under conditions otherwise
identical to entry 1, CrCl2 (1 equiv)/Mn powder (8 equiv)
and CrCl2 (1 equiv)/Fe powder (10 equiv) gave rise to 3 in
58% and 42% yields, respectively.
moiety generates the key dihalochromium intermediate 29.
A second round of metalation leads to 30,6 which rearranges
to dichromium ketone 31. The latter may exist as the
dichromium enolate 37. Either would be expected to add
rapidly to the aldehyde and collapse to the final product,
33. Alternatively, R-elimination of 29 forms carbene 34 and
hence R-haloenol 35, its rearrangement product. Addition
to the aldehyde culminates in 33 via reduction of adduct 36.
When an equimolar mixture of 2-chlorocyclohexanone and
(11) Sanchez, I. H.; Larraza, M. I.; Rojas, I.; Kuri Brena, F.; Flores, H.
J.; Jankowski, K. Heterocycles 1985, 23, 3033.
(12) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759.
(13) Kutulya, L. A.; Kuz’min, V. E.; Stel’makh, I. B.; Khandrimalova,
T. V.; Shtifanyuk, P. P. J. Phys. Org. Chem. 1992, 5, 308.
We were gratified to find that the cascade was also
applicable to aliphatic (entry 2, 4 f 510), R,â-unsaturated
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Org. Lett., Vol. 8, No. 20, 2006

2 was added to excess CrCl2 in THF/HMPA (2:1), 3 was
isolated in only 34% yield. This suggests that the keto
tautomer of 35, i.e., 38, does not make a significant
contribution to product formation.
Acknowledgment. Financial support provided by the
Robert A. Welch Foundation and NIH (GM31278, DK38226).
Supporting Information Available: Synthetic proce-
dures, analytical data, X-ray files, and 1H/13C spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL061953Q
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