L. Lin et al. / Tetrahedron Letters 51 (2010) 3571–3574
3573
Table 2
CH3CN, using different bases such as TEA and DBU, the benzyl 4-
bromobenzoate was obtained in 35% and 45% yields, respectively
The generality and scope of the NHCs-mediated coupling of aromatic aldehydes with
benzylic halidesa
(entries 2 and 3), however, without the desired product
a-aryl
ketone. This unexpected result prompted us to further investigate
the reaction mechanism. We then proposed a possible pathway
accounting for the formation of the unexpected ester product
through the NHCs-mediated reaction of aromatic aldehyde with
benzyl bromide. As shown in Scheme 2, the intermediate I reacts
with benzyl bromide to form a benzyl ether II, which isomerizes
to intermediate III and is then subjected to an oxygen oxidation
to form ester 6 after the NHC departure. It is apparent that the
presence of oxygen is the key factor for generating the unexpected
ester product, which is consistent with Chen’s result.8 This reaction
pathway was confirmed by the synthesis of key intermediate IIf.9
On the other hand, it is well known that the intermediate I easily
isomerizes to the Breslow intermediate via path a, which would re-
O
N
Ar2
Ar1-CHO
3
+
O
Ar1
I
Ar2
Ar2
100 mol%
S
Ar1
5
7f
+
O
11
Ar2
X
DBU, CH3CN, N2
Ar1
O
Ar2
4
6
Entry
R1
R2
X
Yield (%) of 5
Yield (%) of 6
1 (a)
2 (a)
3 (a)
4 (b)
p-(Br)Ph
p-(Br)Ph
p-(Br)Ph
p-(Br)Ph
Ph
Ph
Ph
o-(CN)Ph
Br
Cl
63
22
29
18 (5b)
34 (11b)
47
30
42
50
55
ND
34
ND
ND
5
16
5
ND
act directly with benzyl bromide to form the desired product
a-
OTs
Br
aryl ketone 5. If this is true, we believed that the removal of oxygen
would facilitate the reaction proceeding through path a. Therefore,
the reaction condition for the coupling of p-bromobenzaldehyde
with benzyl bromide at oxygen-free atmosphere was further
5 (c)
6 (d)
7 (e)
8 (f)
9 (g)
p-(Br)Ph
p-(Br)Ph
p-(Br)Ph
p-(Cl)Ph
p-(CF3)Ph
p-(NO2)Ph
Ph
o-(CF3)Ph
p-(Br)Ph
1-Naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
Br
Br
Br
Br
Br
Br
Br
Br
Br
ND
ND
ND
ND
ND
41
ND
ND
ND
screened in order to produce the desired
are summarized in Table 1.
a-aryl ketone. The results
10 (h)
11 (i)
To our delight, when the reaction was conducted under nitro-
gen atmosphere at room temperature, the desired product ketone
5a was obtained in 23% yield along with 17% of ester 6a (entry
4). The yield of ketone 5a increased to 39% surprisingly in 5 min
when the amount of catalyst 7a was increased from 50 mol % to
100 mol % (entries 4 and 5). Screening of the bases turned out that
DBU was the optimal one (entries 5–8). Solvents optimization
found that CH3CN gave the best yield of ketone 5a (entries 5 and
9–11). Screening of NHCs showed that thiazolium salt was more
suitable for this reaction (entries 12–19), and thiazolium salt 7f
gave the best yield up to 63% (entry 16). Therefore, the optimal
12 (m)
13 (n)
p-(OMe)Ph
p-(NMe2)Ph
a
Reaction condition: aromatic aldehydes (1.0 equiv), benzylic halides (2.0 equiv),
NHC (100 mol %), DBU (1.25 equiv), rt, nitrogen atmosphere, 5 min.
bromide.12 Nevertheless, our strategy well complements
Scheidt’s method, in which benzyl bromide was barely reactive
to Breslow intermediate to generate
a-aryl ketones without o-
hydroxy group. More importantly, it is the first example of the
NHCs-mediated intermolecular nucleophilic acylation of aromatic
aldehydes with benzyl halides. Further study focusing on the
optimization and application of this umpolung process is in pro-
gress in our laboratory.
reaction condition for the production of
a-aryl ketone is carried
out in anhydrous acetonitrile at room temperature under nitrogen
atmosphere using thiazolium salt 7f (100 mol %) and DBU as the
base.10
To explore the generality and scope of this reaction, represen-
tative aromatic aldehydes and various benzyl halides were exam-
ined under the above-mentioned optimal condition (Table 2).
Initially, a survey of the effect of benzyl-leaving groups (Br, Cl,
and OTs) showed that bromine was the most ideal leaving group
and gave the highest yield of ketone 5a up to 63% (entries 1–3).
We then investigated the reactivities of four different benzylic
bromides. It was found, in most cases, that benzyl bromides gave
Acknowledgments
This work was supported by the Natural Science Foundation
of Shanghai (No. 08ZR1405900), Shanghai Committee of Science
and Technology (No. 09JC1404500), and ‘111’ Project (No.
B07023).
the corresponding
a-aryl ketones in 22–63% yields (entries 1 and
4–7). Interestingly, 2-(bromomethyl) benzonitrile 4b gave normal
ketone 5b in 18% yield along with a further alkylated ketone 11b
in 34% yield (entry 4). 4-Nitrobenzaldehyde surprisingly afforded
the ester 6h in 41% yield instead of the desired product ketone
due to unclear reason. On the other hand, aldehydes bearing elec-
tron-donating group (EDG) on aromatic ring gave no desired
products presumably due to their low reactivities (entries 12
and 13).
References and notes
1. Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298.
2. (a) Takikawa, H.; Hachisu, H.; Bode, J. W.; Suzuki, K. Angew. Chem. 2006, 118,
3572–3574; (b) Li, Y.; You, S.-L. Chem. Commun. 2008, 2263–2265.
3. He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418–8420.
4. (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606–5655; (b)
Li, G.-Q.; Dai, L.-X.; You, S.-L. Org. Lett. 2009, 11, 1623–1625; (c) Huang, X.-L.;
Chen, Y.-Y.; Ye, S. J. Org. Chem. 2009, 74, 7585; (d) He, J.; Zheng, J.; Liu, J.; She, X.;
Pan, X. Org. Lett. 2006, 8, 4637–4640; (e) Huang, X.-L.; He, L.; Shao, P.-L.; Ye, S.
Angew. Chem., Int. Ed. 2009, 49, 192–195; (f) Wang, X.-N.; Lv, H.; Huang, X. L.;
Ye, S. Org. Biomol. Chem. 2009, 346.
In conclusion, we have developed a new NHCs-mediated syn-
thetic method10 to produce
a-aryl ketones in 22–63% of yields in
5. Suzuki, Y.; Toyota, T.; Miyashita, A.; Sato, M. Chem. Pharm. Bull. 2006, 54, 1653–
1658.
6. Miyashita, A.; Matsuda, H.; Iijima, C.; Higashino, T. Chem. Pharm. Bull. 1990, 38,
1147–1152.
one-pot process from corresponding aldehydes and benzyl ha-
lides under optimal reaction condition. In addition, this reaction
interestingly afforded an unexpected benzyl ester (up to 45%
yield) as major product at aerobic condition. Although, according
to the proposed mechanism shown in Scheme 2, the NHC is the
catalytic active species, we are still using stoichiometric amount
of thiazolium salt, which is similar to Scheidt’s result. This may
attribute to the dimerization of active NHC species11 and unreac-
tive ammonium salt formation in situ from DBU and benzyl
7. Mattson, A. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 4508–4509.
8. Liu, Y. K.; Li, R.; Yue, L.; Li, B. J.; Chen, Y. C.; Wu, Y.; Ding, L. S. Org. Lett. 2006, 8,
1521–1524.
9. According to a modified procedure of Miyashita’s method,13 the benzyl ether
14 was prepared smoothly. Upon treatment with MeI in DMF, the ether 14 gave
ester 6a in 50% yield via the formation of key intermediate IIf and subsequent
air oxidation, without generating any amount of ketone. The intermediate IIf
was not isolated due to its chemical instability.
Lin, Lu
