LETTER
One-pot Three-component Synthesis of (E)- or anti-Homoallylic Alcohols
603
General procedure for the synthesis of
(7).9 Protocol A.
-homoallylic alcohols
alkyl groups (1-octyl, cyclohexyl, 3-methyl-but-2-yl) ex-
amined as migrating groups. Thus, a single reaction path-
way is accessible for 8 leading to 9, in fluxional Entry 1: (E)-1-Phenyl-4-cyclohexyl-but-3-en-1-ol (7a).
BH3 SMe2 (0.5 mL, 2 M solution in THF, 1 mmol) was added at
equilibrium with 10. The addition of 9 and 10 to an alde-
0 °C to a solution of cyclohexene (0.2 mL, 2 mmol) in THF (2 mL)
hyde selectively produces alcohols 7 and 5, respectively.
and the reaction mixture was vigorously stirred at 0 °C for 1h. Pro-
Exerting a control on the haptotropic rearrangement will
allow to selectively produce 5 or 7, and, to this purpose,
pargyl chloride (0.075 mL, 1 mmol) was added and the mixture was
stirred for an additional hour, until the white precipitate of dicyclo-
we identified two procedures, henceforth referred to as
protocol A and B. In protocol A the aldehyde is added to
the hydroboration mixture before the addition of TE-
BACl. Under these conditions, as soon as the catalytic cy-
cle starts producing 9, addition of 9 to the aldehyde occurs
with a rate higher than the haptotropic rearrangement, and
7 is selectively produced. E/Z Ratios range in the 55/45 –
98/2 interval, depending on the nature of R and R’ groups
(entries 1-8).
hexyl borane dissolved. Benzaldehyde (0.1 mL, 1 mmol) was added
followed by TEBACl (0.012 g) and the mixture was was stirred at
25 °C for 3 h. The reaction mixture was quenched at 0 °C by con-
secutive addition of 3 N NaOH and 30% H2O2 and finally stirred for
30 min. The aqueous layer was extracted with ether (3 5 mL), the
combined organic layers were dried (Na2SO4) and concentrated un-
der reduced pressure. Purification of the residue by flash-chroma-
tography (SiO2, cyclohexane:ether 95:5) afforded 0.19 g (0.82
mmol, 82%) of 7a. 1H NMR (CDCl3, 300 MHz): = 0.98-1.40 (m,
5H), 1.57-1.82 (m, 5H), 1.90-2.05 (m, 1H), 2.34-2.62 (m, 2H), 4.68
(dd, J = 5.1/8.1 Hz, 1H), 5.36 (dt, J = 7.8 /15.6 Hz, 1H), 5.54 (dd,
J = 6.6/15.6 Hz, 1H), 7.22-7.42 (m, 5H); 13C NMR (CDCl3, 75
MHz): = 26.0, 26.1, 33.0, 40.6, 42.7, 73.4, 122.7, 125.7, 127.1,
128.1, 140.7, 143.9; MS (EI): m/z (%) = 124 (26), 107 (100), 82
(18), 79 (63), 77 (37), 67 (13), 55 (7). C16H22O (230.35): calcd C
83.43, H 9.63; found C 83.49, H 9.70.
On the other hand, in protocol B an equilibration time (teq)
between the addition of TEBACl and the aldehyde is
adopted in order to allow the conversion of 9 into the ther-
modynamically more stable 10 to occur. The extension of
teq depends on the rearrangement rate which, in turn,
mainly depends on the nature of the alkyl substituent R.
When R = cyclohexyl conversion of 9 into 10 is complete
in 1 h at 25 °C, while 12 h and 36 h are required when
R = octyl or siamyl, respectively.
General procedure for the synthesis of anti-homoallylic alcohols
5.9 Protocol B.
Entry 12: (1E)-1-Phenyl-4-cyclohexyl-esa-1,5-dien-3-ol (5d).
BH3 SMe2 (0.5 mL, 2 M solution in THF, 1 mmol) was added at
0 °C to a solution of cyclohexene (0.2 mL, 2 mmol) in THF (2 mL)
and the reaction mixture was vigorously stirred at 0 °C for 1 h. Pro-
pargyl chloride (0.065 mL, 1 mmol) was added and the mixture was
stirred for an additional hour, until the white precipitate of dicyclo-
hexyl borane dissolved. TEBACl (0.015 g) was added and the reac-
tion mixture was equilibrated with stirring for 1 h while temperature
was allowed to raise to 20 °C, then cinnamaldehyde (0.25 mL, 2
mmol) was added and the mixture was allowed to react at r.t. for 3
h. The reaction mixture was quenched at 0 °C by the consecutive
addition of 3 N NaOH and 30% H2O2 followed by stirring for 30
min. The aqueous layer was extracted with ether (3 5 mL), the
combined organic phase was dried (Na2SO4) and concentrated un-
der reduced pressure. Purification of the residue by flash-chroma-
tography (SiO2, cyclohexane:ether 95:5) afforded 0.44 g (1.7 mmol,
We wish to emphasize that chemical yields reported in the
Table refer to isolated and cumulative yields of a se-
quence of two hydroboration steps, a quaternization pro-
cess, migration, haptotropic rearrangement, addition to an
aldehyde and final oxidative quenching.
The main difference between the one-pot protocol here re-
ported and the previously reported synthetic procedure
based on the use of propargyl bromide6 lies on the high
stability of 3-chloro-prop-1-en-1-yl borane 6 compared to
3-bromo-prop-1-en-1-yl borane 3. This allows to develop
procedures which are both simpler and more chemoselec-
tive since: i) propargyl chloride has not to be distilled im-
mediately prior to use, ii) products deriving from chloride
migration have been never detected, iii) formation of (E)-
homoallylic alcohols 7 occurs in higher yield (e.g. com-
pare 82% in entry 1 and 55% obtained starting from pro-
pargyl bromide), and iv) a change of solvent is not
required, while THF must be replaced by a pentane-
dichloromethane solution when 7 is prepared from prop-
argyl bromide.
1
86%) of 5d. H NMR (CDCl3, 300 MHz): = 0.92-1.34 (m, 5H),
1.46-1.81 (m, 6H), 1.94-2.01 (m, 1H), 4.31-4.37 (m, 1H), 5.13 (dd,
J = 2.1/17.0 Hz, 1H), 5.26 (dd, J = 2.1/10.5 Hz, 1H), 5.80 (dt,
J = 10.5/17.0 Hz, 1H), 6.24 (dd, J = 7.5/16.0 Hz, 1H), 6.60 (d,
J = 16.0 Hz, 1H), 7.20-7.42 (m, 5H); 13C NMR (CDCl3, 50 MHz):
= 26.38, 26.43, 26.5, 31.8, 37.8, 56.9, 72.3, 118.8, 126.3, 127.4,
128.4, 131.1, 136.5, 136.7; MS (EI): m/z (%) = 133 (100), 115 (14),
103 (11), 91 (8), 81 (8), 77 (16), 67 (8), 55 (34). C18H24O (256.39):
calcd C 84.32, H 9.44; found C 84.27, H 9.47.
In conclusion, the preparation of costitutionally and stere-
ochemically defined homoallylic alcohols 5 and 7 is re-
ported, based on two very simple synthetic procedures
differing in the reagent addition order. The one-pot three
components syntheses developed involve a sequence of
four reactions: i) formation of a dialkylborane, ii) hydrob-
oration of propargyl chloride, iii) quaternization with TE-
BACl, iv) reaction of the resulting allylic boranes with an
aldehyde. Depending on the order of addition of TEBACl
and the aldehyde the overall process may be addressed to-
ward the formation of 5 or 7.
Acknowledgement
This work was supported by M.U.R.S.T.-Rome (National Project
“Stereoselezione in Sintesi Organica. Metodologie e Applicazioni”)
and University of Bologna (funds for selected topics).
References and Notes
(1) Roush, W. R. In Comprehensive Organic Synthesis, Vol 2;
Trost B. M. and Heathcock C. H. Eds.; Pergamon Press:
Oxford, 1991; pp 1-53.
(2) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1987, 26, 489.
(3) Salmon, A.; Carboni, B. J. Organomet. Chem. 1998, 1-2, 31.
Synlett 2001, No. 5, 601–604 ISSN 0936-5214 © Thieme Stuttgart · New York