addition, we turned our attention to the concept of a
polyhalomethyltitanium synthesisbasedupon a titaniumÀ
magnesium bimetallic-mediated oxidative addition of the
halides. Effecting such elaborations by use of TiCl4ÀMg
may have the advantages of (1) extending the addition to
various carbonyl compounds such as aldehydes and en-
olizable ketones and (2) enhancing synthetic efficiency by
elaboration of bromoform to both dibromomethyl- and
tribromomethyltitanium reagents. Herein we record pro-
tocols whereby the TiCl4ÀMg-promoted direct coupling
of bromoform with carbonyl compounds can be directed
not only to dibromomethyl carbinols, which served as the
precursors of terminal alkynes6a and acetylenic alcohols6b,c
as well as important intermediates for ketone homologa-
tion and ring expansion,7 but also to tribromomethylcar-
binols, which are important building blocks for synthesis
of conjugated ketones8a and R- and β-bromoenol ethers.8b
Initial studies centered on the TiCl4ÀMg-promoted
CHBr2-transfer reactions. The direct coupling of2-methyl-
cyclohexanone 1a with CHBr3 promoted by TiCl4ÀMg
was chosen to test the feasibility of the process (Table 1).
When 1a (1.0 mmol) and CHBr3 (0.3 mL, 3.3 equiv) are
treated with TiCl4 (1 equiv) and magnesium powder
(5 equiv) in ClCH2CH2ClÀDME (1 mL) at 0À25 °C,
1-(dibromomethyl)-2-methylcyclohexanol 1b was indeed
produced but only in less than 30% conversions after 3 h
(entry 1). The desired dibromomethylcarbinol 1b was
found to be admixed with a trace of vinyl bromide 1d.
Increasing the amount of Mg dramatically improved the
dibromomethylcarbinol formation, with the yield varying
from 35% to 50% (entries 2 and 3). Most revealing was the
effect of the electron-pair-donor (EPD) additives on this
process. Replacing DME with THF proves most satisfac-
tory, giving an 85% yield of adduct 1b (entry 4). A NOE
difference experiment indicates a diequatorial orientation
of dibromomethyl and methyl substituents in 1b, substan-
tiating a highly stereocontrolled HCBr2 transfer. More
gratifyingly, the reaction directly scales up; thus, dibromo-
methylcarbinol 1b was obtained in 75% yield on a
10-mmol scale using 6 mmol of TiCl4 and 55 mmol of Mg.
It seemed reasonable to expect that the direct coupling of
CÀBr bond with a presumed TiCl4ÀMg complex accounts
for the generation of an active diibromomethyltitanium
species and the formation of 1-(dibromomethyl)-2-methyl-
cyclohexanol 1b. Notably, addition to a substituted cyclo-
hexanone 1a takes place with complete stereoselectivity.
Assuming that steric hindrance to attack is controlling, the
stereochemistry possessing the methyl group trans to the
CBr3 unit is assigned. Having established the feasibility of
Table 1. Reaction Conditions for the TiCl4ÀMg-Promoted
CHBr2 Transfer to Ketone 1a
entry
TiCl4/Mg (equiv)
EPD additive
yielda (%) 1b
1
2
3
4
5
1:5
DME
DME
DME
THF
THF
22b,c
35b,c
50b,c
87b,c
75b,c
1:8
1:10
1:10
6:55d
a Isolated yield. b Plus ∼50% recovered starting ketone. c Plus 5À7%
vinyl bromide 1d. d The reaction was performed on a 10 mmol scale.
the HCBr2-transfer reaction, its generality with respect to
the structure of the ketone was established. Reaction of
cyclopentanone and cycloheptanone with CHBr3 under
the standard conditions gave the desired adducts 2b (85%)
and 3b (82%), respectively (Table 2, entries 1 and 2).
Changing the ketone to acyclic ketones 4a and 5a led to
equally gratifying results (entries 3 and 4) with formation
of dibromomethyl alcohols 4b and 5b. The CHBr2 transfer
onto the unsaturated ketone 6a was equally effective by
replacing THF with DME (entry 5). The aromatic ketones
7a and 8a also gave satisfactory results with CHBr3ÀMgÀ
TiCl4ÀTHF (entries 6 and 7). On the other hand, using the
readily enolizable ketones9 also gave satisfactory results.
Thus, either 2-indanone 9a or β-tetralone 10a reacted
efficiently with CHBr3-derived dibromomethyltitanium
reagent to give the desired coupling products 9b (71%)
and 10b (62%), respectively (entries 8 and 9). The success-
ful application of TiCl4ÀMg-promoted CHBr2 transfer to
the readily enolizable 2-indanone and β-tetralone high-
lights the weakly basic nature of this system. More gratify-
ingly, increasing the degree of steric hindrance at the
carbonyl group does not impede coupling reaction. Thus,
reacting 2,6-dimethylcyclohexanone 11a and camphor-
derived ketoester 12a with CHBr3ÀMgÀTiCl4ÀTHF
produced the adducts 11b and 12b, respectively (entries
10 and 11). Notably, the ester group was completely un-
affected. Aldehydes, which are particularly prone to re-
duction to give alcohols, can also lead to equally gratifying
results by replacing THF with DME. Thus, in the reaction
ofaliphatic aldehydes(1 mmol) with CHBr3, use of 1 mmol
of TiCl4, 10 mmol of Mg, and 1 mL of DME also led to
smooth coupling, giving the desired adduct in 73À75%
yield (entries 12 and 13). The unsaturated aldehyde gave an
analogous result (entry 14). Exposing the aromatic alde-
hydes to the CHBr3ÀTiCl4ÀMgÀDME system also gave
(6) (a) Wang, Z.; Yin, J.; Campagna, S.; Pesti, J. A.; Fortunak, J. M.
J. Org. Chem. 1999, 64, 6918. (b) Smith, A. B., III; Adams, C. M.;
Kozmin, S. A.; Paone, D. V. J. Am. Chem. Soc. 2001, 123, 5925. (c)
Kowalski, C. J.; Haque, M. S.; Fields, K. W. J. Am. Chem. Soc. 1985,
107, 1429.
(7) Ward, H. D.; Teager, D. S.; Murray, R. K., Jr. J. Org. Chem.
1992, 57, 1926.
(8) (a) Falck, J. R.; He, A.; Reddy, L. M.; Kundu, A.; Barma, D. K.;
Bandtopadhyay, A.; Kamila, S.; Akella, R.; Bejot, R.; Mioskowski, C.
Org. Lett. 2006, 8, 4645. (b) Bejot, R.; Tisserand, S.; Reddy, L. M.;
Barma, D. K.; Baati, R.; Falck, J. R.; Mioskowski, C. Angew. Chem.,
Int. Ed. Engl. 2005, 44, 2008.
(9) (a) Johnson, C. R.; Tait, B. D. J. Org. Chem. 1987, 52, 281. (b)
Acetoacetic ester fails to react with CHBr3-derived dibromomethyltitanium
reagent to give the desired coupling product. (c) This TiCl4ÀMgÀCHBr3 is
also suitable for the CHBr2 transfer to 2-chlorocyclohexanone; see the
Supporting Information.
B
Org. Lett., Vol. XX, No. XX, XXXX