1290
P. V. Ramachandran et al. / Tetrahedron Letters 55 (2014) 1289–1291
could be better reagents. Thus, propanoic acid was enolized with a
mixture of 5/i-Pr2NEt in tetrahydrofuran (THF) at À78 °C, followed
by aldolization of 7a at the same temperature.8 Although 8a was
isolated in pure form with 78% anti-selectivity, the yield was a dis-
mal 9% (Table 1, entry 2), which could be improved to 56% at the
cost of the diastereoselectivity (62% anti) by replacing i-Pr2NEt
with Et3N (Table 1, entry 3). It is noteworthy that B-chlorodialkyl-
boranes do not enolize alkyl propanoates, whereas it is capable of
enolizing dialkylboryl propanoates. On the basis of the demon-
strated influence of solvents on aldol reactions,14 the effect of
diethyl ether, pentane, and dichloromethane on the reaction with
5 was examined (Table 1, entries 3–6). A positive influence of
diethyl ether on the diastereoselectivity was observed (58% yield,
82% anti-selectivity, Table 1, entry 6).
The effect of the leaving halogen group of the dialkylboron ha-
lide was then evaluated (Table 1, entries 6–8). The reaction with B-
bromodicyclohexylborane (Chx2BBr, 9) was carried out in diethyl
ether and the reaction with B-iododicyclohexylborane (Chx2BI,
10) was performed in pentane since 10 is known to cleave ether al-
most instantaneously.15 Although tribromoborane is a commonly
used reagent for ether cleavage, and dialkylbromoboranes typically
cleave ethers over two weeks,15 we were pleased to note that the
aldol reaction with 9 proceeded well in diethyl ether and yielded
86% of the product with an improved (86%) diastereoselectivity
(Table 1, entry 7). When this reaction was carried out under condi-
tions with shorter reaction time (Condition A, Table 1), the yield
improved to 92% with no change in the anti-selectivity (Table 1, en-
try 9). B-Bromobis-exo-2-norbornylborane (11), under similar con-
ditions, provided the same diastereoselectivity in slightly lesser
yield than obtained with 9 (86% anti, 86% yields, Table 1, entry
10). Due to the lower cost and ready availability of cyclohexene, re-
agent 9 was chosen for further studies. Thus, we achieved an effi-
cient protocol for aldol reaction of propanoic acid with Chx2BBr/
Et3N.
1) Chx2BBr/Et3N
Et2O, 0 °C, 45 min.
OH
O
O
Ph
OH
OH
2) PhCHO
-78°C, 30 min.,0 °C, 1 h
3
8a
92%,syn:anti-14:86
Scheme 1. Optimum conditions for aldol reaction of propanoic acid (3).
Table 2
Examination of aldehydes for the anti-selective aldol reaction of propanoic acid (3)
1) Chx2BBr/Et3N, Et2O
0 °C, 45 min.
OH
O
O
R
OH
2) RCHO, - 78 °C,30 min.
0 °C, 1 h
OH
3
8a j
-
No.
RCHO
Aldol
7
R
8
Yielda (%)
syn:antib
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7i
C6H5
8a
8b
8c
8d
8e
8f
8g
8h
8i
92
86
82
85
86
82
82
80
84
86
14:86
15:85
15:85
14:86
6:94
2:98
7:93
10:90
6:94
3:97
4-MeC6H4
4-MeOC6H4
4-FC6H4
(E)-PhCH@CH
2-Thioph
Chx
n-Pr
i-Pr
t-Bu
10
7j
8j
a
Combined isolated yields of syn and anti-isomers.
syn and anti ratios were determined by 1H NMR spectroscopy.
b
With the optimum conditions in hand (shown in bold face in
Table 1) (Scheme 1), the generality of the reaction was examined
by employing a series of aromatic and aliphatic aldehydes. The re-
sults summarized in Table 2 illustrate that electron-rich and -defi-
H
R
CH3
O
CH3
Chx
R
OH
Chx
O
B
cient
aromatic
aldehydes
gave
similar
yields
and
H
OH
O
Chx
O
diastereoselectivities (Table 2, entries 2–4). An
a,b-unsaturated
B
aldehyde, cinnamaldehyde, provided 86% yield and 94:6 selectivity
Chx
Figure 1. Proposed transition state for the formation of anti-aldols via the
Table 1
aldolization of aldehydes with dibora ene-1,1-diolates.
Optimization for anti-selective aldol reaction of propanoic acid (3)
OH
O
OH
O
O
1) R2BX/Et3N, cond.
+
Ph
OH
Ph
OH
in favor of the anti-aldol (Table 2, entry 5). A heteroaromatic alde-
hyde, such as 2-thiophene carboxaldehyde, provided very high
anti-selectivity (98% anti, Table 2, entry 6). All of the aliphatic
aldehydes provided >90% anti-selectivity in 80–86% yields (entries
7–10). While the yields remained similar, the diastereoselectivity
improved with the increase in steric requirements (Table 2, entries
9 and 10). Pivalaldehyde provided 97% diastereoselectivity for the
product aldol.
It is fascinating that the aldol reaction proceeds with high stere-
oselectivities (Table 2), although the ene-1,1-diolates cannot be
classified as E or Z. While the aldol reaction of dimagnesium ene-
1,1-diolates, which led to the conventional Zimmerman–Traxler
transition state,16 gave poor selectivities, the reaction of diborae-
ne-1,1-diolates provided up to 98% selectivity. These selectivities
could be rationalized due to a tighter transition state, common in
boron-mediated aldol reactions,1a involving the bulky cyclohexyl
ligands (Fig. 1). The methyl group of propanoic acid and the R
group of the aldehyde occupy equatorial positions in the proposed
transition state.
OH
Solvent
2) PhCHO, cond.
8a
3
syn-
8a
anti-
No.
R2BX
#
Cond.a
Solvent
Yieldb (%)
syn:antic
1d
2d
3
4
5
6
7
8
9
Chx2BOTf
Chx2BCl
Chx2BCl
Chx2BCl
Chx2BCl
Chx2BCl
Chx2BBr
Chx2BI
6
5
5
5
5
5
9
10
9
A
B
B
B
B
B
B
B
A
A
Et2O
THF
THF
CH2Cl2
Pentane
Et2O
Et2O
Pentane
Et2O
>100e
9
11:89
22:78
38:62
23:77
23:77
18:82
14:86
18:82
14:86
14:86
56
47
49
58
86
90
92
86
Chx2BBr
Nrb2BBr
10
11
Et2O
a
Reaction conditions: A = enolization: 0 °C, 45 min; aldolization: À78 °C, 30 min,
0 °C, 1 h. B = enolization: À78 °C, 1 h, 0 °C, 1 h; aldolization: À78 °C, 1 h, 0 °C, 15 h.
b
Combined isolated yields of syn and anti-isomers.
syn and anti ratios were determined by 1H NMR analysis of the crude reaction
c
mixture.
d
i-Pr2NEt was used as amine.
Crude yield.
e