2
J. K. Augustine et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 1
1. Et3N (3.0 equiv)
O
(E)
O
CH2Cl2, 25 o
C
TiCl4-mediated synthesis of (E)-
a
,b-unsaturated carboxylic acids
O
O
+
O
2. TiCl4 (1.2 equiv)
2a
98%
O
O
(1.2 equiv)
(1.0 equiv)
(E)
TiCl4, NEt3
R
+
O
OH
R
OH
Scheme 2. Synthesis of tert-butyl cinnamate from tert-butyl acetate.
CH2Cl2, 3-4 h
1
Entry
1
Aldehyde
CHO
Product
Yielda (%)
98
1. TiCl4 (2.1 equiv)
CH2Cl2, 30 min
O
(E)
COOH
O
O
OH
98%
+
1a
O
2. Et3N (2.5 equiv)
1a
CHO
CHO
COOH
COOH
(1.2 equiv)
O
O
O
(1.0 equiv)
2
3
98
99
O
Scheme 3. Synthesis of (E)-cinnamic acid from tert-butyl acetate.
1b
NC
HO
NC
HO
even after prolonged stirring, while the same reaction took just
3 h for complete conversion under the optimized conditions. Sim-
ilarly, TiCl4 or Et3N failed to promote the reaction when used
separately.
The optimized reaction conditions for Ti(IV)-mediated
(E)-olefination were then generalized by reacting acetic acid with
a group of representative aldehydes and the results are summa-
rized in Table 1. Diverse aromatic aldehydes (Table 1, entries 1–
7) and heterocyclic aldehydes (Table 1, entries 8–11) reacted
smoothly with acetic acid in the presence of TiCl4, and gave the
1c
CHO
COOH
4
5
6
97
98
99
1d
F
CHO
CHO
F
COOH
COOH
O
O
1e
Ph
Ph
1f
respective a,b-unsaturated carboxylic acids with high stereoselec-
CHO
COOH
COOH
tivities (>95% E) and excellent yields. While cyclopropane carbox-
aldehyde, a branched aliphatic aldehyde, gave 1l in 94% yield
(Table 1, entry 12), the method did not prove beneficial for straight
chain aliphatic aldehydes as represented by n-butanal (Table 1,
entry 13). As observed by us, n-butanal polymerized under the
optimized reaction conditions yielding no trace of product 1m.
Compounds possessing tert-butyl carboxylate functionality are
practical building blocks in organic synthesis, due to their ease of
deprotection to the subsequent carboxylic acid in acidic medium.
It was of interest to explore if we could extend the methodology
involving Ti(IV)-mediated (E)-olefination for the synthesis of
7
95b
boc
Br
N
H
H2N
1g
N
CHO
Br
N
8
9
98
99
1h
CHO
COOH
O
O
1i
COOH
COOH
CHO
10
11
97
97
tert-butyl
a,b-unsaturated carboxylates. Accordingly, TiCl4
O
1j
O
(1.2 equiv) was added dropwise to a mixture of benzaldehyde
(1.0 equiv), Et3N (3.0 equiv), and tert-butyl acetate (1.2 equiv) in
DCM. The mixture was then stirred for 3 h at room temperature
to afford tert-butyl cinnamate 2a in 98% yield with excellent
(E)-stereoselectivity (Scheme 2). In contrast to the optimized con-
ditions for 1a (Scheme 1) wherein 2.1 equiv of TiCl4 was employed,
the synthesis of tert-butyl cinnamate 2a required only 1.2 equiv of
TiCl4 for complete conversion (Scheme 2).
As opposed to the observations in Scheme 2, cinnamic acid 1a
was obtained in 98% yield when Et3N was added dropwise to a
pre-complexed mixture of benzaldehyde, tert-butyl acetate, and
TiCl4 in DCM (Scheme 3). It is likely that the tert-butyl acetate
underwent hydrolysis prior to the addition of Et3N owing to the
acidic nature of TiCl4. However, 2.1 equiv of TiCl4 was essential
for optimal conversion.
CHO
N
N
1k
CHO
COOH
12
13
94
0
1l
CHO
COOH
1m
a
Isolated yields.
N-Boc protection was lost during the reaction.
b
Diverse aromatic and heterocyclic aldehydes were then reacted
with tert-butyl acetate under the standard conditions (Scheme 2)
to afford tert-butyl a,b-unsaturated carboxylates in excellent yields
By careful investigation we established that acetic acid
(1.2 equiv) could easily be transformed into cinnamic acid 1a in
98% yield with high (E)-stereoselectivity (>95%) by treatment with
benzaldehyde (1.0 equiv) in dichloromethane (DCM) in the pres-
ence of TiCl4 (2.1 equiv) and Et3N (2.5 equiv) at room temperature
(Scheme 1). The product 1a was isolated as white solid following
an aqueous work up. No trace of the (Z)-isomer could be detected
by NMR analysis of the crude reaction mixture, signifying >95% ste-
reochemical purity. The above conditions were most suitable for
the transformation. For instance, when the amount of Et3N was
decreased from 2.5 equiv to 2.0 equiv or decreasing the amount
of TiCl4 from 2.1 equiv to 1.8 equiv led to an incomplete reaction
(Table 2, entries 1–9). The reaction was complete within 2–3 h for all
the substrates tested. The scope of the reaction was then generalized
by treating benzaldehyde with various alkyl acetates in the presence
of TiCl4 and Et3N to afford the respective cinnamates in excellent
yields, and the high stereoselectivity (>95% E) still remained.
In conclusion, a new method has been developed for the prep-
aration of
a
,b-unsaturated carboxylic acids10 and corresponding
esters11 with (E)-stereoselectivity via the TiCl4-mediated olefin-
ation of aldehydes. The method, which uses readily available acetic