Synthesis of Benzyl Esters via Functionalization of Multiple C-H Bonds by Palladium Catalysis

Article abstract of DOI:10.1021/acs.orglett.5b02518

A highly efficient, selective synthesis of benzyl esters by palladium catalysis is developed through the bidentate directing group assisted functionalization of multiple C(sp³)-H bonds.

Full text of DOI:10.1021/acs.orglett.5b02518

Letter
pubs.acs.org/OrgLett
Synthesis of Benzyl Esters via Functionalization of Multiple C−H
Bonds by Palladium Catalysis
Danyang Li,† Ming Yu,† Jitan Zhang,† Zhanxiang Liu,*,† and Yuhong Zhang*,†,‡
†ZJU-NHU United R&D Center, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: A highly efficient, selective synthesis of benzyl
esters by palladium catalysis is developed through the
bidentate directing group assisted functionalization of multiple
C(sp3)−H bonds.
Scheme 1. Examples of Catalytic Synthesis of Benzyl Esters
he formation of esters is one of the most fundamental
Ttransformations in organic synthesis due to the potential
utility of esters in fine chemicals, agrochemicals, polymers,
pharmaceuticals, and natural organic molecules.1 Accordingly,
the efficient synthesis of esters has attracted considerable
interest. In general, the nucleophilic reactions of carboxylic
acids and their derivatives with alcohols/halohydrocarbons are
reliable methods for the preparation of esters.2 However, these
protocols require the prefunctionalization of substrates and often
suffer from harsh reaction conditions. To overcome these
disadvantages, much effort has focused on transition-metal-
catalyzed oxidative C−H bond cleavage for the assembly of
esters.3 In particular, the catalytic esterification of benzylic sp3
C−H bonds has recently become a hot topic due to the
importance of benzyl esters,4 and pioneering work on the
synthesis of benzyl esters from toluene has been reported.5 For
instance, the Patel group developed the copper-catalyzed cross
dehydrogenative coupling (CDC) reaction of aryl aldehydes with
toluene for the synthesis of benzyl esters using tert-butyl
hydroperoxide (TBHP) as the oxidant, in which the benzylic
sp3 C−H bond of toluene was oxidized to benzyl alcohol in situ
and dual C−H oxidative cross coupling was achieved.6a Later, the
direct benzylation of carboxylic acids by toluene under oxygen
was reported by Zhang and co-workers using palladium
catalysis.6b In these transformation, the direct esterification of
toluene with aldehydes or carboxylic acids is successfully
achieved (Scheme 1, a). In principle, the most direct route for
access to benzyl esters is the selective benzylation of toluene with
another alkylbenzenes. However, successful esterification
between two different alkylbenzenes is far more elusive: (1)
toluene can react not only with itself but also with another
different alkylbenzene, and (2) the benzylic C−H bond can be
oxidized not only to the corresponding hydroxyl but also to the
corresponding aldehyde.
tion9a and oxidative acetoxylation of benzylic C−H bonds with
the assistance of a bidentate auxiliary.9b We envisioned that the
introduction of a directing group in the alkylbenzenes might
allow the selective oxidation of a benzylic C−H bond to achieve
esterification between two different alkylbenzenes. As the first
attempt, a mixture of picolinoyl-protected toluidine 1a and
toluene 2a was treated with 10 mol % of Pd(OAc)2 catalyst and 2
equiv of Ag2CO3 as an oxidant at 140 °C in air. The esterification
product 3a was indeed obtained in 23% yield after 24 h (Table 1,
entry 1). This catalytic reaction was found to be powerful enough
to generate the benzyl ester through multiple benzylic C−H
bond cleavages. Furthermore, this transformation exhibits high
selectivity: the byproducts of the benzylation of toluene with 1a
and the benzylation of toluene with itself were not observed.
Thus, the selective palladium-catalyzed benzylation of alkylben-
zenes with toluene is achieved with the assistance of a bidentate
auxiliary (Scheme 1, b).
To optimize the reaction conditions, a variety of palladium
catalysts were examined. It was found that the use of Pd(TFA)2
and Pd2(dba)3 also gave the esterification product 3a as the main
product, but in low yields (Table 1, entries 2 and 3). Among the
palladium sources examined, PdCl2 was found to be the most
efficient catalyst (Table 1, entry 4). Silver carbonate was proved
The chelation-assisted transition-metal-catalyzed functionali-
zation of C−H bonds has emerged as a powerful tool for the
construction of C−C and C−X bonds.7 To date, several methods
for the direct, catalytic functionalization of benzylic sp3 C−H
bonds, such as alkenylation and amidation, have been reported.8
Recently, we studied the palladium-catalyzed arylation/oxida-
Received: September 15, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02518
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Letter
a
a b
,
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope of Picolinamides
b
entry
catalyst
oxidant
additive
yield (%)
1
Pd(OAc)2
Pd(TFA)2
Pd2(dba)3
PdCl2
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
K2S2O8
BQ
23
21
2
3
20
4
28
5
PdCl2
NR
NR
NR
32
6
PdCl2
7
PdCl2
TBHP
8
PdCl2
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
HOAc
PivOH
TFA
9
PdCl2
43
10
11
12
13
14
15
PdCl2
trace
55
PdCl2
OTA
OTA
OTA
OTA
OTA
c
PdCl2
64
d
0
e
PdCl2
PdCl2
0
f
48
a
Reaction conditions: 1a (0.2 mmol), 2a (3.0 mL), PdCl2 (0.02
mmol), oxidant (0.4 mmol), and additive (0.4 mmol) under air at 140
b
c
a
b
°C for 24 h. Isolated yield by flash column chromatography. 0.6
Isolated yields are given. Reaction conditions: 1 (0.2 mmol), 2a (3
d
e
mmol of Ag2CO3 was used. Without PdCl2. Under N2 atmosphere.
mL), PdCl2 (0.02 mmol), Ag2CO3 (0.6 mmol), 140 °C, air, 24 h. PA =
2-pyridylacyl.
f
Under O2 atmosphere. PA = 2-pyridylacyl, OTA = o-toluic acid.
to be the best oxidant (Table 1, entry 4). Other oxidants, such as
K2S2O8, benzoquinone (BQ), and tert-butyl hydroperoxide
(TBHP), were entirely ineffective (Table 1, entries 5−7). The
addition of acid was particularly effective, and o-toluic acid was
superior, giving the esterification product 3a in 55% yield (Table
1, entries 8−11). After further investigation, we were pleased to
find that the isolated yield of 3a was improved to 64% by using 3
equiv of Ag2CO3 (Table 1, entry 12). No desired esterification
product was observed in the absence of palladium catalyst (Table
1, entry 13), and the reaction failed in a nitrogen atmosphere
(Table 1, entry 14). In addition, the yield of 3a was decreased
when the reaction was performed under O2 atmosphere. A
possible reason is that the toluene may be oxidized to
benzaldehyde rapidly under the pure O2 atmosphere, which
hinders the generation of ester (Table 1, entry 15).
The directing group was found to be crucial for this
esterification transformation. No reaction occurred when
benzamide I or acetamide II was used as the substrate, illustrating
that bidentate coordination was essential for the reaction. 8-
Aminoquinolinamide III, which possesses the popular directing
group of bidentate 8-aminoquinoline auxiliary, also failed to give
the desired ester, showing the predominant power of
picolinamide as the directing group in this esterification reaction.
With the optimal conditions in hand, we next investigated the
scope of picolinamide arene substrates as shown in Scheme 2. In
general, arenes bearing both electron-donating and electron-
withdrawing groups reacted well under the optimized conditions.
For instance, the electron-rich arenes generated the correspond-
ing benzyl esters in high yields (3a−d). A picolinamide arene
with a phenyl group at the para position participated smoothly in
the reaction to give the desired product in 52% yield (3e).
Notably, C−Cl and C−Br bonds remained intact during the
reaction (3f−k), providing an additional opportunity for further
elaboration of the products by cross-coupling reactions.
Picolinamide arenes with strong electron-withdrawing groups,
such as fluoro, acetyl, and ester groups, were good substrates for
this esterification reaction, affording the corresponding benzyl
esters in good yields (3l−n). The sterically hindered arenes were
slightly disfavored, delivering the corresponding products in
relatively lower yields (3h and 3k). The selectivity of this
transformation was that the three C−H bonds of the methyl
group in picolinamide arenes were thoroughly oxidized to
generate the benzoyl moiety of the esters, and only one C−H
bond in toluene was cleaved to provide the benzyloxy portion in
the formed esters. X-ray crystallographic analysis of 3i further
confirmed the structure of this esterification reaction product
(Figure 1).
Figure 1. ORTEP drawing of 3i.
B
DOI: 10.1021/acs.orglett.5b02518
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We subsequently applied this new esterification method to
Scheme 4. Control Experiments
diverse alkylbenzene substrates, as shown in Scheme 3.
a b
,
Scheme 3. Substrate Scope of Alkylbenzenes
a
b
conditions (eq 7), the oxygen in the ester is proved to originate
from O2 in the air. The addition of a radical scavenger 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO) to the reaction halted
the esterification reaction, indicating that a radical process might
be involved in the reaction. In addition, the benzyl radical was
trapped by TEMPO (see the Supporting Information).
Based on the above observations and previous investigation,
we propose a plausible reaction mechanism for this efficient
esterification transformation as shown in Scheme 5. The initial
Isolated yields are given. Reaction conditions: 1a (0.2 mmol), 2 (3
mL), PdCl2 (0.02 mmol), Ag2CO3 (0.6 mmol), 140 °C, air, 24 h. PA =
2-pyridylacyl.
Gratifyingly, both electron-rich and electron-deficient alkylben-
zenes could be smoothly converted to the desired esters in good
yields (4a−k, 46−71%). The substrates with more than one
methyl group, such as xylene (o-, m-, p-) and mesitylene, were
examined, and an appealing outcome was obtained in the
formation of only monoester product (4a−d). The trans-
formation was compatible with common functional groups,
including methoxy, fluoro, chloro, and trifluoromethyl groups
(4e−j). It is worth mentioning that the relatively bulky
ethylbenzene could be included in the reaction and exhibited
good reactivity (4k).
Scheme 5. Mechanistic Hypothesis
Control experiments were performed to obtain insights into
the reaction mechanism (Scheme 4). When picolinamide
benzylic alcohol 5 or picolinamide benzylic ether 6 was used as
the substrate under the standard conditions, only a trace of the
desired product 3a was observed (eq 1−2). This result
demonstrated that neither picolinamide benzylic alcohol nor its
ether is involved in the formation of the benzyl ester. In addition,
no desired product was observed when 2-(picolinamido)benzoic
acid 7 was used as the substrate (eq 3), showing that
picolinamide carboxylic acid was not the key intermediate for
the formation of the benzyl esters. In contrast, N-(2-
formylphenyl)picolinamide 8 could participate in the reaction
to deliver the desired benzyl ester in 46% yield (eq 4), suggesting
that picolinamide benzaldehyde might be an intermediate in the
esterification. The esterification reaction of 1a with benzylic
alcohol 9 proceeded smoothly to give the product 3a in 76% yield
(eq 5), confirming that toluene served as the source of the
PhCH2O− group. Additionally, the reaction of compound 8 and
9 was performed, and the product 3a was obtained in 51% yield,
implicating that compound 8 and 9 might be involved in the
reaction (eq 6). Because the reaction failed in a nitrogen
atmosphere (Table 1, entry 14) and the 18O-labeled product was
not observed in the existence of H218O under the reaction
picolinamide-assisted palladation leads to the formation of
palladacycle A,10 which is oxidized by the benzyl peroxide radical
to generate the Pd(IV)11 or dimeric Pd(III)12 intermediate B.
The reductive elimination of intermediate B results in
intermediate C, which undergoes the second palladation to
give intermediate D. The subsequent Kornblum−DeLaMare
rearrangement affords intermediate E,13 and the reaction of E
with benzyl alcohol produces intermediate F.14 MALDI-TOF
C
DOI: 10.1021/acs.orglett.5b02518
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Organic Letters
Letter
(4) (a) Pappas, C. S.; Malovikova, A.; Hromadkova, Z.; Tarantilis, P.
A.; Ebringerova, A.; Polissiou, M. G. Carbohydr. Polym. 2004, 56, 465.
(b) Aliboni, A.; D’Andrea, A.; Massanisso, P. J. Agric. Food Chem. 2011,
59, 282.
mass analysis of the reaction mixture proved the formation of
intermediates E and F during the esterification process (see the
Supporting Information). Finally, the β-hydrogen elimination
and reductive elimination of intermediate F delivers the
esterification product (3a) and liberates the Pd(0). The catalytic
Pd(II) is then regenerated by oxidation to initiate the next cycle.
In conclusion, we have developed an efficient new protocol for
the synthesis of benzyl esters via the palladium-catalyzed
selective activation of multiple benzylic C(sp3)−H bonds. The
bidentate system is proved to be crucial to the successful selective
formation of benzyl esters. The oxygen in the ester is proved to
originate from O2 in the air, and the method displays exceptional
compatibility with a wide range of functional groups to give
benzyl esters selectively in good yields. Further investigations of
the detailed mechanism are underway in our laboratory.
(5) (a) Khan, K. M.; Maharvi, G. M.; Hayat, S.; Zia-Ullah; Choudhary,
M. I.; Atta-ur-Rahman, A. Tetrahedron 2003, 59, 5549. (b) Kesavan, L.;
Tiruvalam, R.; Ab Rahim, M. H.; bin Saiman, M. I.; Enache, D. I.;
Jenkins, R. L.; Dimitratos, N.; Lopez-Sanchez, J. A.; Taylor, S. H.;
Knight, D. W.; Kiely, C. J.; Hutchings, G. J. Science 2011, 331, 195.
(c) Liu, H.; Li, Y.; Jiang, H.; Vargas, C.; Luque, R. Chem. Commun. 2012,
48, 8431. (d) Huang, J.; Li, L.-T.; Li, H.-Y.; Husan, E.; Wang, P.; Wang,
B. Chem. Commun. 2012, 48, 10204. (e) Feng, J.; Liang, S.; Chen, S.-Y.;
Zhang, J.; Fu, S.-S.; Yu, X.-Q. Adv. Synth. Catal. 2012, 354, 1287. (f) Liu,
L.; Yun, L.; Wang, Z.; Fu, X.; Yan, C.-H. Tetrahedron Lett. 2013, 54,
5383. (g) Majji, G.; Guin, S.; Gogoi, A.; Rout, S. K.; Patel, B. K. Chem.
Commun. 2013, 49, 3031.
(6) (a) Rout, S. K.; Guin, S.; Ghara, K. K.; Banerjee, A.; Patel, B. K. Org.
Lett. 2012, 14, 3982. (b) Liu, H.; Shi, G.; Pan, S.; Jiang, Y.; Zhang, Y. Org.
Lett. 2013, 15, 4098.
ASSOCIATED CONTENT
■
(7) For selected reviews, see: (a) Giri, R.; Shi, B.-F.; Engle, K. M.;
Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242. (b) Wang, D.-H.;
Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315. (c) Colby, D.
A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (d) Lyons,
T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (e) McMurray, L.;
O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885. (f) Gutekunst,
W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976. (g) Baudoin, O. Chem.
Soc. Rev. 2011, 40, 4902. (h) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q.
Acc. Chem. Res. 2012, 45, 788. (i) Rouquet, G.; Chatani, N. Angew.
Chem., Int. Ed. 2013, 52, 11726.
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02518.
Experimental details, spectral and analytical data, and 1H
NMR and 13C NMR spectra for new compounds (PDF)
X-ray data for 3i (CIF)
AUTHOR INFORMATION
■
(8) For selected examples, see: (a) Dick, A. R.; Hull, K. L.; Sanford, M.
S. J. Am. Chem. Soc. 2004, 126, 2300. (b) Hull, K. L.; Anani, W. Q.;
Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134. (c) Campeau, L.-C.;
Corresponding Authors
*E-mail: liuzhanx@zju.edu.cn.
*E-mail: yhzhang@zju.edu.cn.
Notes
Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3266. (d) Novak
́
,
P.; Correa, A.; Gallardo-Donaire, J.; Martin, R. Angew. Chem., Int. Ed.
́
́
́
2011, 50, 12236. (e) Iglesias, A.; Alvarez, R.; de Lera, A. R.; Muniz, K.
̃
Angew. Chem., Int. Ed. 2012, 51, 2225. (f) McMurtrey, K. B.; Racowski, J.
M.; Sanford, M. S. Org. Lett. 2012, 14, 4094. (g) Liu, B.; Zhou, T.; Li, B.;
Xu, S.; Song, H.; Wang, B. Angew. Chem., Int. Ed. 2014, 53, 4191.
(9) (a) Xie, Y.; Yang, Y.; Huang, L.; Zhang, X.; Zhang, Y. Org. Lett.
2012, 14, 1238. (b) Ju, L.; Yao, J.; Wu, Z.; Liu, Z.; Zhang, Y. J. Org. Chem.
2013, 78, 10821.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding from NSFC (No. 21272205, 21472165) and the
Program for Zhejiang Leading Team of S&T Innovation
(2011R50007) is acknowledged.
(10) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154. (b) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2010, 132, 3965. (c) Zhang, S.-Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.;
Chen, G. J. Am. Chem. Soc. 2013, 135, 2124.
(11) (a) Racowski, J. M.; Dick, A. R.; Sanford, M. S. J. Am. Chem. Soc.
2009, 131, 10974. (b) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc.
2009, 131, 11234.
(12) (a) Powers, D. C.; Geibel, M. A. L.; Klein, J. E. M. N.; Ritter, T. J.
Am. Chem. Soc. 2009, 131, 17050. (b) Powers, D. C.; Ritter, T. Nat.
Chem. 2009, 1, 302. (c) Mazzotti, A. R.; Campbell, M. G.; Tang, P.;
Murphy, J. M.; Ritter, T. J. Am. Chem. Soc. 2013, 135, 14012.
(13) (a) Kornblum, N.; DeLaMare, H. E. J. Am. Chem. Soc. 1951, 73,
880. (b) Zhang, M.; Liu, N.; Tang, W. J. Am. Chem. Soc. 2013, 135,
12434. (c) Zhang, J.; Jiang, J.; Xu, D.; Luo, Q.; Wang, H.; Chen, J.; Li, H.;
Wang, Y.; Wan, X. Angew. Chem., Int. Ed. 2015, 54, 1231.
(14) (a) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41,
3381. (b) Gowrisankar, S.; Neumann, H.; Beller, M. Angew. Chem., Int.
Ed. 2011, 50, 5139.
REFERENCES
■
(1) (a) Otera, J. Esterification: Methods, Reactions, and Applications;
Wiley-VCH: Weinheim, 2003. (b) Riemenschneider, W.; Bolt, H. M.
Esters, Organic. In Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-
VCH: Weinheim, 2005. (c) Carmo, A. C.; de Souza, L. K. C.; da Costa,
C. E. F.; Longo, E.; Zamian, J. R.; da Rocha Filho, G. N. Fuel 2009, 88,
461. (d) Kheang, L. S.; May, C. Y. J. Oil Palm Res. 2012, 24, 1388.
(2) (a) Larock, R. C. Comprehensive Organic Transformations: A Guide
to Functional Group Preparations, 2nd ed.; Wiley-VCH: New York, 1999.
(b) Haslam, E. Tetrahedron 1980, 36, 2409. (c) Swamy, K. C. K.; Kumar,
N. N. B.; Balaraman, E.; Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551.
(d) Luo, F.; Pan, C.; Cheng, J. Synlett 2012, 23, 357.
(3) For selected examples, see: (a) Eames, J.; Watkinson, M. Angew.
Chem., Int. Ed. 2001, 40, 3567. (b) Desai, L. V.; Hull, K. L.; Sanford, M.
S. J. Am. Chem. Soc. 2004, 126, 9542. (c) Chen, M. S.; Prabagaran, N.;
Labenz, N. A.; White, M. C. J. Am. Chem. Soc. 2005, 127, 6970. (d) Dick,
A. R.; Kampf, W. J.; Sanford, S. M. J. Am. Chem. Soc. 2005, 127, 12790.
(e) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790. (f) Wang, D.-H.; Hao, X.-S.; Wu, D.-F.; Yu, J.-Q. Org.
Lett. 2006, 8, 3387. (g) Ye, Z.; Wang, W.; Luo, F.; Zhang, S.; Cheng, J.
Org. Lett. 2009, 11, 3974. (h) Liu, C.; Tang, S.; Zheng, L.; Liu, D.;
Zhang, H.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 5662. (i) Xie, P.; Xie,
Y.; Qian, B.; Zhou, H.; Xia, C.; Huang, H. J. Am. Chem. Soc. 2012, 134,
9902. (j) Rout, S. K.; Guin, S.; Banerjee, A.; Khatun, N.; Gogoi, A.; Patel,
B. K. Org. Lett. 2013, 15, 4106. (k) Rout, S. K.; Guin, S.; Ali, W.; Gogoi,
A.; Patel, B. K. Org. Lett. 2014, 16, 3086.
D
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