NHCs-mediated benzoates formation directly from aromatic aldehydes and alkyl halides

Article abstract of DOI:10.1016/j.tet.2012.02.079

A NHCs-mediated benzoates formation was developed by treatment of aromatic aldehydes with alkyl halides in the presence of oxygen. Corresponding benzoate derivatives were obtained in high yields up to 99%. The reaction mechanism was also discussed and a NHCs-mediated O-alkylation and subsequent oxidation process was proposed.

Full text of DOI:10.1016/j.tet.2012.02.079

Tetrahedron 68 (2012) 3611e3615
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NHCs-mediated benzoates formation directly from aromatic aldehydes and alkyl
halides
,
a,
Yi Li a, Wenting Du b , Wei-Ping Deng
*
*
a Shanghai Key Laboratory of New Drug Design & School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
b Department of Pharmacy, Zhejiang Medical College, 481 Binwen Road, Hangzhou 310053, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A NHCs-mediated benzoates formation was developed by treatment of aromatic aldehydes with alkyl
halides in the presence of oxygen. Corresponding benzoate derivatives were obtained in high yields up to
99%. The reaction mechanism was also discussed and a NHCs-mediated O-alkylation and subsequent
oxidation process was proposed.
Received 14 January 2012
Received in revised form 22 February 2012
Accepted 28 February 2012
Available online 5 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
N-Heterocyclic carbenes
O-Alkylation
Benzoate derivatives
Aerobic oxidation
1. Introduction
best of our knowledge, it was the first example of NHC-mediated
benzoate formation,10 and this unexpected result may lead to the
Umpolung reaction of various carbonyl compounds catalyzed by
N-heterocyclic carbenes (NHCs) is a valuable and attractive syn-
thetic strategy for a wide range of organic transformations. This
approach normally leads to the formation of nucleophilic acyl anion
intermediates, which can react with various electrophiles, such as
aromatic aldehydes1 (benzoin reaction), Michael acceptors2 (Stetter
reaction) and several other electrophilic reagents, such as ketones,3
aziridines,4 imines,5 and so on.6 However, this umpolung reaction
with sp3-carbon-centered electrophiles, which would provide po-
tential access to the formation of CeC bond, is extremely rare. Re-
cently, we presented the first example of NHCs-mediated
intermolecular nucleophilic acylation of aromatic aldehydes with
benzyl halides.7 Subsequently, Yadav et al.8 reported benzimida-
zolium salt-promoted intermolecular acylation of BayliseHillman
discovery of new NHC-mediated reaction pathway, which could be
further developed to a high efficient and facile new synthetic
method for the benzoates formation. Therefore, we planned to
further investigate the scope and generality of this unexpected side
reaction of benzyl benzoates formation. Further study showed that
the benzoate products can be obtained in excellent yields (up to
99%). Herein, we would like to describe this NHCs-mediated ben-
zoates formation and its reaction mechanism discussion in details.
(BH) bromides and
a-haloketones with aldehydes and a, b-un-
saturated aldehydes (enals). Meanwhile, thiazolium salt catalyzed
umpolung coupling of aldehydes with diarylbromomethanes to
form ketones was reported by Glorius et al.9
It is worth noting, in the reaction of NHCs-mediated nucleo-
philic acylation of aryl aldehydes with benzyl halides, except for the
formation of expected a-aryl ketones under nitrogen atmosphere,
Scheme 1. Nucleophilic acylation of p-bromobenzaldehyde with benzyl bromide in
different conditions.
benzyl benzoates were obtained in moderate yields when the re-
actions were performed at aerobic condition (Scheme 1).7 To the
2. Results and discussion
According to our previous work,7 we continued using p-bro-
mobenzaldehyde and benzyl bromide as model reaction substrates.
* Corresponding authors. Tel./fax: þ86 021 64252431; e-mail addresses:
ddwwtt@163.com (W. Du), weiping_deng@ecust.edu.cn (W.-P. Deng).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.079

3612
Y. Li et al. / Tetrahedron 68 (2012) 3611e3615
Table 2
It was proposed that the presence of molecular oxygen is the key
factor for generating the unexpected ester product, which is con-
sistent with Chen’s4a result.
Effect of the catalysts for the reactiona
Therefore, we further systematically tested this reaction in
open-air atmosphere. It was found that ester 4a was obtained as
exclusive product in the presence of thiazolium salt 3a (100 mol %),
which is similar to that of reported in previous paper7 (Table 1,
entry 2). Next, a variety of solvents and bases were screened under
open-air atmosphere, as shown in Table 1.
Table 1
Optimization of reaction conditions for the formation of compound 4aa
Entry
Catalyst
Base
Solvent
Yieldg (%)
1b
2
3
4
5
6
7
8
9
10
11c
12d
13e
14f
15f
16f
17
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
DBU
DBU
DBU
DBU
DBU
TEA
Li2CO3
Na2CO3
CH3CN
CH3CN
DMF
5 (5a, 63)
53
40
49
30
17
ND
22
40
53
52
73
76
66
83
57
73
Entry
1b
2
3
4
Catalyst
Base
Solvent
Yieldd (%)
3a
3b
3c
3d
3e
3f
3g
3a
3f
K2CO3/18-crown-6
K2CO3/18-crown-6
K2CO3/18-crown-6
K2CO3/18-crown-6
K2CO3/18-crown-6
K2CO3/18-crown-6
K2CO3/18-crown-6
K2CO3/18-crown-6
K2CO3/18-crown-6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
35
33
58
79
18
81
80
99
92
THF
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
5
6
K2CO3
Cs2CO3
7
8c
9c
K2CO3/18-crown-6
K2CO3/18-crown-6
K2CO3/18-crown-6
Cs2CO3/18-crown-6
K2CO3/18-crown-6
K2HPO4/18-crown-6
Ag2O
a
Unless otherwise noted, the reaction was performed under open-air atmo-
sphere, with 1a (0.2 mmol) and 2a (0.4 mmol), in the presence of 100 mol % of 3,
K2CO3 (2.2 equiv), and 18-crown-6 (0.66 equiv) in 4 mL of CH3CN.
b
Compound 3a (20 mol %), K2CO3 (1.25 equiv), and 18-crown-6 (0.375 equiv)
were used.
c
Reactions proceeded in oxygen atmosphere.
Isolated yields.
a
Unless otherwise noted, the reaction was performed under open-air atmo-
sphere, with 1a (0.2 mmol) and 2a (0.4 mmol), in the presence of 100 mol % of 3a
and base (0.4 mmol) in 4 mL of solvent.
d
b
Reaction was conducted under N2 atmosphere.
18-Crown-6 (0.2 equiv).
18-Crown-6 (0.4 equiv).
18-Crown-6 (0.6 equiv).
Bases (2.2 equiv), 18-crown-6 (0.66 equiv) were used.
Isolated yields.
c
oxygen balloon showed that the yield of 4a was dramatically im-
proved to 99%, when thiazolium salt 3a was used (Table 2, entry 8).
Having established the optimal reaction condition, the gener-
ality and scope of substrates with regard to aromatic aldehydes and
various halides were examined. Initially, a comparison of the effect
of leaving groups on halides showed that bromine was more ideal
than chlorine (Table 3, entries 1, 2 and 8, 9). Electron-donating and
withdrawing groups on benzyl bromides were both tolerated in
different positions, providing the corresponding esters in 65e99%
yields (Table 3, entries 3e7). Interestingly, aldehydes bearing
electron-withdrawing groups (Cl, NO2, CF3) afforded corresponding
esters in excellent yields (Table 3, entries 10e13), and electron-
donating substituents on the phenyl ring were less reactive
affording corresponding esters in lower yields (21e67%), even no
reaction with dimethylamino substituent (Table 3, entries 14e17).
Benzaldehyde also afforded the moderate yield (Table 3, entry 18).
Furaldehyde was also tolerant and provided corresponding prod-
ucts in 78% yield (Table 3, entry 19). While aliphatic aldehydes of-
fered none of the desired esters presumably due to their low
reactivities (Table 3, entries 20 and 21).
Moreover, when the substrates 2-bromo-1-phenylethanone and
cinnamyl bromide were tried under our optimal conditions, the
reaction also went smoothly to give corresponding benzoates 4t
and 4u in 59% and 72% yields, respectively (Table 3, entries 22 and
23).1-Bromoheptane was also used to further test the scope of alkyl
halide, and the reaction proceeded very slowly to provide 4v in 78%
yield in 3 days (Table 3, entry 24).
A plausible reaction mechanism was proposed in our previous
paper,7 which is different to recent reports.10 To further clarify the
possible reaction mechanism, we conducted several experiments.
d
e
f
g
Among those tried solvents, CH3CN gave slightly better yields
(Table 1, entries 2e5). DBU was initially considered as a good choice
of base for generating NHC from corresponding thiazolium salt, but
in view of the potential formation of ammonium salts in situ be-
tween benzyl halides and organic bases, a series of inorganic bases
were screened. It was found that stronger basicity led higher
product yield and Cs2CO3 gave optimal yield (Table 1, entries 8e10).
Furthermore, phase transfer catalyst 18-crown-6 was added as
additive considering the insolubility of tried inorganic carbonates.
We were pleased to find that the addition of phase transfer catalyst
18-crown-6 effectively increased the yield of reaction from 40% to
52% (Table 1, entry 11). And the increasing amount of 18-crown-6
gave better yields (Table 1, entries 12 and 13). And 2.2 equiv of
K2CO3 combined with 0.66 equiv of 18-crown-6 led to a further
improvement of yield to 83% (Table 1, entry 15). Other bases like
K2HPO4 and Ag2O were tested as well and showed moderate yields
(Table 1, entries 16 and 17).
Next, a series of NHC salts 3beg were screened as shown in
Table 2. However, it was found that 20 mol % of 3a afforded cor-
responding ester 4a in 35% yield, which suggests turn over number
of this catalyst is very low (Table 2, entry 1) under this reaction
condition. Screening of NHC catalysts turned out that NHC salts 3a,
3d, 3f, and 3g all gave excellent yields, and 3a was chosen for fur-
ther study due to its easy availability. Further investigation of using

Y. Li et al. / Tetrahedron 68 (2012) 3611e3615
3613
Table 3
Scope of substratesa
Entry
R1
R2
X
Yieldc (%)
99 (42d)
1 (a)
2 (a)
3 (b)
4 (c)
5 (d)
6 (e)
7 (f)
8 (g)
p-(Br)Ph
p-(Br)Ph
p-(Br)Ph
p-(Br)Ph
p-(Br)Ph
p-(Br)Ph
p-(Br)Ph
p-(Br)Ph
p-(Br)Ph
m-(Cl)Ph
p-(Cl)Ph
p-(NO2)Ph
p-(CF3)Ph
m-(Me)Ph
p-(Me)Ph
p-(OMe)Ph
p-(NMe2)Ph
Ph
Bn
Bn
Br
Cl
89
99
65
71
80
74
81
79
99
98
99
88
59
67
21
ND
63
78
ND
ND
59
72
78
Scheme 3. NHC-mediated oxidation of p-bromobenzaldehyde and corresponding
esterification.
p-(Me)Bn
p-(NO2)Bn
p-(OMe)Bn
o-(CF3)Bn
o-(CN)Bn
Allyl
Allyl
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Br
Br
Br
Br
Br
Br
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
9 (g)
10 (h)
11(i)
12 (j)
13 (k)
14 (l)
15 (m)
16 (n)
17 (o)
18 (p)
19 (q)
20 (r)
21 (s)
22 (t)
23 (u)
24 (v)b
2-Furyl
tert-Amyl
Cyclohexenyl
p-(Br)Ph
p-(Br)Ph
p-(Cl)Ph
Bn
PhCOCH2
Cinnamyl
Heptyl
a
Reaction condition: aldehydes (0.2 mmol), halides (2.0 equiv), catalyst
(100 mol %), K2CO3 (2.2 equiv), 18-crown-6 (0.66 equiv), CH3CN (4 mL), r.t., oxygen
atmosphere.
b
Reactions proceeded under 50 ꢀC, 3 days.
Isolated yields.
The yield in the parentheses was obtained under the condition of 20 mol % of 3a,
c
d
50 ꢀC.
Scheme 4. Two proposed reaction pathways.
Firstly, O-alkylated substrate 6 was prepared smoothly according to
Miyashita’s method.11 Upon treatment with methyl iodide, the
benzyl ether gave ester 4n in 92% yield (Scheme 2), which implies
that our newly proposed esterification pathway via O-alkylation of
adduct in situ derived from corresponding aldehyde and NHC, and
subsequent oxidation is reasonable (Scheme 4, Path A).
According to our experimental result, two reaction pathways
were proposed for this NHC-mediated benzoates formation, as
shown in Scheme 4.
Interestingly, a byproduct 8 was obtained in 51% yield derived
from the oxidation of NHC catalyst when we attempted to perform
the direct oxidation of p-bromobenzaldehyde using 1.0 equiv of
benzimidazolium salt 3f (Scheme 5), which may account for the low
turn over number of NHC. This assumptionwas further supported by
the isolation of similar thiazole type oxidative product 9 in 31% yield,
accompanied by several unconfirmed compounds, when p-chlor-
obenzaldehyde was treated with 1-bromoheptane in the presence
of thiazolium 3a under optimal reaction condition (Scheme 5).
Scheme 2. Ester formation from O-alkylated substrate 6.
Scheme 5. The formation of oxidative products of 3f and 3a.
On the other hand, it was observed that, 87% of 4-bromobenzoic
acid was generated under the above-mentioned optimal conditions
in absence of benzyl bromide, which is consistent to literature.12
And the desired ester was generated quickly and almost quantita-
tively from 4-bromobenzoic acid in the absence of NHC (Scheme 3).
Therefore, another reaction pathway via aldehyde oxidation, and
subsequent nucleophilic substitution, reported by Liu12a and Hui,10b
cannot be ruled out (Scheme 4, Path B).
3. Conclusion
In summary, we have developed an NHC-mediated direct ben-
zoates formation from corresponding aldehydes and alkyl halides
in excellent yields up to 99% under oxygen atmosphere. In our re-
action system, the easily available thiazolium catalyst 3a was found

3614
Y. Li et al. / Tetrahedron 68 (2012) 3611e3615
to give the optimal result, which allows us to perform such reaction
in good efficiency practically, although stoichiometric amount of
thiazolium salt 3a was necessary. Two possible reaction pathways
were proposed based on the experimental evidence. Further study
on its practical application is still ongoing in our lab.
HRMS (EI): calcd for C15H13BrO3 ([Mþ]): 320.0048, found 320.0050;
IR (KBr)
2917, 2833, 1710, 1263, 1242, 1026, 816 cmꢁ1
n
.
4.2.5. 2-(Trifluoromethyl)benzyl 4-bromobenzoate (4e). Yellow solid
(57.8 mg, 80%). Mp: 47e48 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.95e7.92 (m, 2H), 7.72 (d, J¼7.9 Hz,1H), 7.64e7.56 (m, 4H), 7.47 (t,
4. Experimental section
4.1. General methods
J¼7.5 Hz, 1H), 5.55 (s, 2H); 13C NMR (100 MHz, CDCl3):
d 164.3,
132.9, 131.1, 130.8, 130.2, 192.2, 127.7, 127.4, 127.3, 125.2, 124.5, 121.8,
62.4; HRMS (EI): calcd for C15H10BrF3O2 ([Mþ]): 357.9816, found
357.9815; IR (KBr)
n .
2918, 2858, 1721, 1268, 1158, 1100, 747 cmꢁ1
Melting points were obtained in open capillary tubes using
a micro melting point apparatus SGW X-4, which were un-
calibrated. Mass spectra were recorded by the HP5989A service;
HRMS (EI) spectra were obtained on a Finigann MAT8401 in-
strument. 1H nuclear magnetic resonance (NMR) spectra were
recorded using an internal deuterium lock for the residual protons
4.2.6. 2-Cyanobenzyl 4-bromobenzoate (4f). White solid (46.7 mg,
74%). Mp: 112e114 ꢀC; 1H NMR (400 MHz, CDCl3):
7.95 (d,
J¼8.6 Hz, 2H), 7.73 (d, J¼7.7 Hz, 1H), 7.65e7.58 (m, 4H), 7.49e7.45
(m, 1H), 5.54 (s, 2H); 13C NMR (100 MHz, CDCl3):
164.3, 138.1,
d
d
132.2, 132.0, 130.8, 130.3, 128.6, 128.0, 127.5, 127.4, 116.0, 111.3, 63.4;
in CDCl3
(
dH¼7.26) at ambient temperatures on the following in-
HRMS (EI): calcd for C15H10BrNO2 ([Mþ]): 314.9895, found
struments: Bruker AVANCE DPX-400 (400 MHz). Data are pre-
sented as follows: Chemical shift (in ppm on the scale relative to
dTMS¼0), integration, multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, and m¼multiplet), coupling constant (J/Hz), and in-
terpretation. 13C NMR spectra were recorded by broadband spin
314.9892; IR (KBr) n .
2927, 2833, 2219, 1721, 1263, 1089, 774 cmꢁ1
4.2.7. Allyl 4-bromobenzoate13a (4g, Table 3, entry 8). Pale yellow
solid (39.1 mg, 81%). Mp: 95e96 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.92 (d, J¼8.5 Hz, 2H), 7.58 (d, J¼8.5 Hz, 2H), 6.08e5.98 (m, 1H),
decoupling using an internal deuterium lock for CDCl3
(
d
¼77.2) at
5.41(dd, J1¼1.3, J2¼17.2 Hz, 1H), 5.30 (dd, J1¼0.9, J2¼10.4 Hz, 1H),
4.82 (d, J¼5.7 Hz, 2H).
ambient temperatures on the following instruments: Bruker
AVANCE DPX-400 (100.6 MHz). Chemical shift values are reported
in parts per million on the scale (dTMS¼0). All reagents and solvents
were used as purchased if not otherwise stated.
4.2.8. Benzyl 3-chlorobenzoate13b (4h). Pale yellow oil (48.9 mg,
99%). 1H NMR (400 MHz, CDCl3):
1H), 7.52 (d, J¼9 Hz, 1H), 7.45e7.35 (m, 6H), 5.36 (s, 2H).
d
8.04 (s, 1H), 7.95 (d, J¼7.8 Hz,
4.2. Typical procedure for synthesis of product 4
4.2.9. Benzyl 4-chlorobenzoate13c (4i). Pale yellow solid (48.4 mg,
To a flame-dried 25 mL two-neck flask under positive oxygen
pressure were added aldehyde 1 (0.2 mmol), thiazolium salt 3
(0.2 mmol), K2CO3 (0.44 mmol), 18-crown-6 (0.132 mmol), and
anhydrous oxygen-saturated CH3CN (2 mL). The resulting mixture
was stirred at room temperature for 30 min, followed by addition of
benzyl halide 2 (0.4 mmol) in 2 mL of CH3CN with a funnel. After
completion of the reaction (monitored by TLC), the reaction mix-
ture was filtered and the filtrate was concentrated under reduced
pressure. The residue was purified by PTLC (ethyl acetate/petro-
leum ether¼1/40) to give 4.
98%). Mp: 25e26 ꢀC; 1H NMR (400 MHz, CDCl3):
2H), 7.46e7.36 (m, 7H), 5.36 (s, 2H).
d
8.01 (d, J¼8.5 Hz,
4.2.10. Benzyl 4-nitrobenzoate13d (4j). Pale yellow solid (50.7 mg,
99%). Mp: 82e83 ꢀC; 1H NMR (400 MHz, CDCl3):
d
8.28 (d, J¼9.0 Hz,
2H), 8.24 (d, J¼9.0 Hz, 2H), 7.47e7.37 (m, 5H), 5.41 (s, 2H).
4.2.11. Benzyl 4-(trifluoromethyl)benzoate13e (4k). Pale yellow oil
(49.5 mg, 88%). 1H NMR (400 MHz, CDCl3):
7.70 (d, J¼8.3 Hz, 2H), 7.46e7.34 (m, 5H), 5.39 (s, 2H).
d
8.19 (d, J¼8.1 Hz, 2H),
4.2.1. Benzyl 4-bromobenzoate7 (4a, Table 3, entry 1). White solid
4.2.12. Benzyl 3-methylbenzoate13f (4l). Colorless oil (40.1 mg, 59%).
(57.6 mg, 99%). Mp: 52e53 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.93 (d,
1H NMR (400 MHz, CDCl3):
d
7.89 (d, J¼7.6 Hz, 2H), 7.46 (d, J¼7.2 Hz,
2H), 7.43e7.30 (m, 5H), 5.37 (s, 2H), 2.40 (s, 3H); 13C NMR
(100 MHz, CDCl3): 166.8, 138.3, 136.3, 134.0, 130.4, 130.2, 128.8,
J¼8.5 Hz, 2H), 7.58 (d, J¼8.5 Hz, 2H), 7.46e7.32 (m, 5H), 5.35 (s, 2H).
d
4.2.2. 4-Methylbenzyl 4-bromobenzoate (4b). White solid (60.4 mg,
128.4, 128.4, 128.3, 127.0, 66.8, 21.4.
99%). Mp: 55e56 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.92 (d, J¼8.5 Hz,
2H), 7.56 (d, J¼8.5 Hz, 2H), 7.33 (d, J¼7.9 Hz, 2H), 7.20 (d, J¼7.9 Hz,
2H), 5.31 (s, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3):
165.7,
4.2.13. Benzyl 4-methylbenzoate13g (4m). White solid (45.5 mg,
d
67%). Mp: 45e46 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.97 (d, J¼8.2 Hz,
138.3, 132.8, 131.7, 131.2, 129.3, 129.1, 128.4, 128.1, 66.9, 21.2; HRMS
2H), 7.45 (d, J¼6.9 Hz, 2H), 7.41e7.32 (m, 3H), 7.24 (d, J¼8.0 Hz, 2H),
(EI): calcd for C15H13BrO2 ([Mþ]): 304.0099, found 304.0100; IR
5.35 (s, 2H), 2.41 (s, 3H).
(KBr)
n .
2958, 2916, 1720, 1289, 1121, 800 cmꢁ1
4.2.14. Benzyl 4-methoxybenzoate13h (4n). Pale yellow oil (24.7 mg,
4.2.3. 4-Nitrobenzyl 4-bromobenzoate (4c). White solid (43.4 mg,
65%). Mp: 135e136 ꢀC; 1H NMR (400 MHz, CDCl3):
8.25 (d,
J¼8.6 Hz, 2H), 7.94 (d, J¼8.4 Hz, 2H), 7.62e7.59 (m, 4H), 5.45 (s, 2H);
13C NMR (100 MHz, CDCl3):
165.4, 147.8, 143.0, 132.0, 131.2, 128.7,
128.5, 128.4, 123.9, 65.4; HRMS (EI): calcd for C14H10BrNO4 ([Mþ]):
334.9793, found 334.9796; IR (KBr) 2916, 2854, 1718, 1522, 1263,
1120, 842, 753 cmꢁ1
51%). 1H NMR (400 MHz, CDCl3):
d
8.04 (d, J¼8.9 Hz, 2H), 7.44 (d,
d
J¼11.3 Hz, 2H), 7.41e7.32 (m, 3H), 6.92 (d, J¼8.9 Hz, 2H), 5.34 (s,
2H), 3.86 (s, 3H).
d
4.2.15. Benzyl benzoate13i (4p). Pale yellow oil (26.7 mg, 63%). 1H
n
NMR (400 MHz, CDCl3):
5.36 (s, 2H).
d 8.12e8.03 (m, 2H), 7.59e7.30 (m, 8H),
.
4.2.4. 4-Methoxybenzyl
4-bromobenzoate
(4d). White solid
7.91 (d,
4.2.16. Benzyl furan-2-carboxylate (4q). Pale yellow oil (31.8 mg,
78%). 1H NMR (400 MHz, CDCl3):
7.61e7.56 (m, 1H), 7.49e7.30 (m,
5H), 7.21 (dd, J¼3.5, 0.8 Hz,1H), 6.50 (dd, J1¼3.5, J2¼1.7 Hz,1H), 5.35
(s, 2H); 13C NMR (100 MHz, CDCl3):
158.5, 146.4, 144.6, 135.6,
128.6, 128.4, 128.3, 118.2, 111.9, 66.5; HRMS (EI): calcd for C12H10O3
(45.6 mg, 71%). Mp: 59e60 ꢀC; 1H NMR (400 MHz, CDCl3):
d
d
J¼8.6 Hz, 2H), 7.56 (d, J¼8.6 Hz, 2H), 7.38 (d, J¼8.7 Hz, 2H), 6.91 (d,
J¼8.7 Hz, 2H), 5.28 (s, 2H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
d
164.7,158.7,130.6,130.2,129.1,128.2,127.0,128.8,113.0, 65.8, 54.3;

Y. Li et al. / Tetrahedron 68 (2012) 3611e3615
3615
([Mþ]): 202.0630, found 202.0631; IR (film)
1579, 1478, 1292, 1110, 763, 700 cmꢁ1
n
3040, 2937, 1726,
314.1419, found 314.1421; IR (film)
749, 697 cmꢁ1
n
3025, 2922, 1696, 1491, 759,
.
.
4.2.17. 2-Oxo-2-phenylethyl 4-bromobenzoate13j (4t). White solid
(37.9mg, 59%). Mp:84e85 ꢀC;1HNMR (400 MHz, CDCl3):
8.05e7.91
4.5. Oxidative product 9 from the thiazolium salt 3a
d
(m, 4H), 7.67e7.57 (m, 3H), 7.54e7.48 (m, 2H), 5.57 (s, 2H).
p-Chlorobenzaldehyde was treated with 1-bromoheptane in the
presence of thiazolium 3a under above optimal reaction condition.
After isolation of heptyl 4-chlorobenzoate 4v, the residue was fur-
ther purified by column chromatography (ethyl acetate/petroleum
ether¼1/6) to give product 913k as a white solid (8.1 mg, 31%). Mp:
4.2.18. Cinnamyl 4-bromobenzoate12a (4u). Pale yellow oil
(45.7 mg, 72%). 1H NMR (400 MHz, CDCl3)
d
7.94 (d, J¼8.5 Hz, 2H),
7.59 (d, J¼8.5 Hz, 2H), 7.45e7.27 (m, 5H), 6.74 (d, J¼15.9 Hz, 1H),
6.44e6.31 (m, 1H), 4.98 (dd, J¼6.5, 1.1 Hz, 2H).
47e48 ꢀC; 1H NMR (400 MHz, CDCl3):
d
5.75 (d, J¼1.1 Hz, 1H), 3.27
(s, 3H), 2.13 (d, J¼1.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 173.1,
4.2.19. Heptyl 4-chlorobenzoate10b (4v). Colorless oil (39.5 mg,
132.7, 95.4, 29.5, 15.4; HRMS (EI): calcd for C5H7NOS ([Mþ]):
78%). 1H NMR (400 MHz, CDCl3)
J¼8.8 Hz, 2H), 4.31 (t, J¼6.7 Hz, 2H), 1.81e1.71 (m, 2H), 1.47e1.27
(m, 10H), 0.89 (t, J¼6.7 Hz, 3H).
d
7.98 (d, J¼8.8 Hz, 2H), 7.41 (d,
129.0248, found 129.0247; IR (KBr)
n .
3109, 2946, 1641 cmꢁ1
Acknowledgements
4.3. Formation of O-alkylated substrate 6
This work was supported by the Natural Science Foundation of
China (No. 21002026), the Fundamental Research Funds for the
Central Universities, and the Shanghai Committee of Science and
Technology (No. 11DZ2260600).
To a flame-dried 100 mL round bottom flask, under positive ni-
trogen pressure were added p-methylthiazole (3.0 mmol) and dry
THF (20 mL). The resulting solution was cooled to ꢁ78 ꢀC, butyl
lithium (3.0 mmol) was added dropwise to the cooled reaction.
Solution was stirred at ꢁ78 ꢀC for 45 min. At this time, p-methox-
ybenzaldehyde (6.0 mmol) was added in one portion. After stirring
at ꢁ78 ꢀC for an hour, the dry ice/acetone bath was removed and the
reaction warmed to room temperature. After completion, the re-
action mixture was diluted with water and extracted with ethyl
acetate (50 mLꢂ3). The organics were dried over Na2SO4, filtered,
and concentrated. Recrystallization from ethyl acetate yield the
desired product 5 as a white solid (0.67 g, 48%).
Supplementary data
The 1H NMR and 13C NMR copies of all compounds. Supple-
mentary data related to this article can be found online at
doi:10.1016/j.tet.2012.02.079.
References and notes
To a flame-dried 25 mL Schlenk tube under positive nitrogen
pressure were added 5 (1.0 mmol), dry THF (10 mL), sodium hy-
dride (1.0 mmol), and benzyl bromide (2.0 mmol). The resulting
solution was stirred at room temperature. After completion, the
reaction mixture was concentrated and purified by column chro-
matography (ethyl acetate/petroleum ether¼1/10) to afford the
product 6 as a yellow oil (278.9 mg, 86%). 1H NMR (400 MHz, CDCl3)
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d
7.41e7.26 (m, 7H), 6.91e6.86 (m, 2H), 6.83 (d, J¼0.8 Hz, 1H), 5.67
(s, 1H), 4.61 (dd, J¼20.0, 12.0 Hz, 2H), 3.79 (s, 3H), 2.40 (s, 3H); 13C
NMR (100 MHz, CDCl3): d 172.4, 159.6, 152.6, 137.6, 131.8, 128.5(54),
128.5(46), 127.8, 127.8, 114.0, 113.9, 80.0, 70.8, 55.3, 17.2. IR (film)
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3031, 2927, 2854, 1611, 1516, 1252, 837, 742, 700 cmꢁ1
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To a flame-dried 25 mL two-neck flask under positive oxygen
pressure were added 6 (0.2 mmol) and 4 mL of CH3I. The resulting
solution was stirred at room temperature for 30 h, and then was
concentrated under reduced pressure. The residue was purified by
column chromatography (ethyl acetate/petroleum ether¼1/40) to
give 4n (44.6 mg, 92%).
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4.4. Oxidative product 8 from the benzimidazolium salt 3f
To a flame-dried 10 mL two-neck flask under positive oxygen
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zimidazolium salt 3f (0.20 mmol), K2CO3 (0.44 mmol), 18-crown-6
(0.132 mmol), and anhydrous oxygen-saturated CH3CN (4 mL). Af-
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pH 2e3 with 0.5 N HCl, and extracted with ethyl acetate (10 mLꢂ3).
The organics were dried over Na2SO4, filtered, and concentrated.
The residue was purified by column chromatography (ethyl acetate/
petroleum ether¼1/10) to afford p-bromobenzoic acid as a white
solid (31.1 mg, 77%) and product 8 as a pale yellow solid (31.8 mg,
51%). Product 8: mp: 107e108 ꢀC; 1H NMR (400 MHz, CDCl3):
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ꢀ
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d
7.38e7.22 (m, 10H), 7.02e6.93 (m, 2H), 6.91e6.83 (m, 2H), 5.12 (s,
4H); 13C NMR (100 MHz, CDCl3):
154.6, 136.3, 129.3, 128.8, 127.7,
127.5, 121.4, 108.4, 45.0; HRMS (EI): calcd for C21H18N2O ([Mþ]):
d