Transesterification for synthesis of carboxylates using aldehydes as acyl donors via C-H and C-O bond activations

Article abstract of DOI:10.1021/jo3012573

A new type of transesterification between aryl, heteroaryl, alkyl N-heteroarene-2-carboxylates and various aldehydes by C-H and C-O bond activations has been developed for the synthesis of versatile carboxylates. A possible mechanism containing oxidative addition of acyl-O bond in parent ester and radical cleavage of sp2 C-H bond in aldehyde is proposed.

Full text of DOI:10.1021/jo3012573

Note
pubs.acs.org/joc
Transesterification for Synthesis of Carboxylates Using Aldehydes as
Acyl Donors via C−H and C−O Bond Activations
Yong-Sheng Bao,† Chao-Yue Chen,† and Zhi-Zhen Huang*,†,‡,§
†Key Laboratory of Mesoscopic Chemistry of Ministry of Education, School of Chemistry and Chemical Engineering, Nanjing
University, Nanjing 210093, PR China
‡Department of Chemistry, Zhejiang University, Hangzhou 310028, PR China
§State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, PR China
S
* Supporting Information
ABSTRACT: A new type of transesterification between aryl,
heteroaryl, alkyl N-heteroarene-2-carboxylates and various aldehydes
by C−H and C−O bond activations has been developed for the
synthesis of versatile carboxylates. A possible mechanism containing
oxidative addition of acyl−O bond in parent ester and radical cleavage
of sp2 C−H bond in aldehyde is proposed.
Table 1. Optimization of Transesterification Reaction
ransesterifications as classic organic reactions are widely
1
between Phenyl 2-Pyridinecarboxylate 1a and 4-
Tapplied in organic synthesis and chemical industry. In
a
Nitrobenzaldehyde 2a
some circumstances for ester syntheses, they are more
advantageous than esterification from carboxylic acids and
alcohols. For example, some parent carboxylic acids are labile or
sparingly soluble in organic solvents.1a Transesterifications are
performed mainly by the reactions between esters and alcohols
under the catalysis of acids or bases. In recent years, main
yield
b
efforts are devoted to develop Lewis acids,2 organic and
a
entry
catalyst
Pd(OAc)2
ligand
PPh3
oxidant
solvent
(%)
inorganic bases2 and N-heterocyclic carbene (NHC)2 as
efficient catalysts for improvement of the transesterifications of
carboxylic acids with alcohols. Recently, aldehydes were found
to be used as elegant acylating reagents via C−H bond
activations.3 However, to the best of our knowledge, there is no
report on the transesterification of esters with aldehydes, while
there are numerous literatures on the transesterifications of
esters with alcohols.1,2 Therefore, we envisioned to utilize
aldehydes as acyl donors to develop a new type of
transesterification for the efficient synthesis of a broad scope
of esters under neutral and mild conditions.
b
c
1
TBP
TBP
TBP
TBP
TBP
TBP
O2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
35
0
2
Pd(PPh3)4
Pd(PPh3)2(OAc)2
Cu(OAc)2
FeCl3
PPh3
3
32
0
4
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PBu3
PCy3
5
0
6
Ru(PPh3)3Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
0
7
trace
0
8
−
9
TBHP
TBHP
TBHP
TBHP
52
49
63
37
10
11
12
Boc-Val-
OH
Initially, phenyl pyridine-2-carboxylate 1a with a pyridine
moiety as a coordinating group and 4-nitrobenzaldehyde 2a was
chosen as a parent ester and an acyl donor reagent, respectively,
exploring and optimizing the new transesterification reaction
via C−O and C−H bond activations. We are pleased to find
that under the catalysis of Pd(OAc)2 (10 mol %) and PPh3
using tert-butyl peroxide (TBP) as an oxidant, the desired
transesterification product, phenyl 4-nitrobenzoate 3aa was
isolated after refluxing the 1a and 2a in toluene (Table 1, entry
1). Then, various palladium and other transition metal catalysts
were screened in the reaction (entries 2−6). Among them,
Pd(OAc)2 proved to be best in the yield of ester 3aa. Then,
tert-butyl hydroperoxide (TBHP) and O2 as an oxidant were
examined instead of TBP in the reaction. The experiment
indicated that TBHP resulted in better yield than TBP while
using O2 reduced the yields of 3aa remarkably (entries 7−9). It
13
14
15
16
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
dppe
dppe
dppe
dppe
TBHP
TBHP
TBHP
TBHP
toluene
t-BuOH
CH3CN
dioxane
74
trace
39
trace
a
Conditions: 1a (0.25 mmol), 2a (1.5 equiv), transition metal catalyst
b
(10 mol %), oxidant (1.5 equiv), 115 °C, 48 h. Isolated yield.
was noteworthy that no desired ester 3aa was obtained without
any oxidant (entry 8). A series of ligands were also screened in
the reaction, and using dppe (15 mol %) led to the best yield of
74% (entry 13). Other solvents, such as t-BuOH, 1,4-dioxane or
Received: June 21, 2012
Published: August 24, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
a
Table 2. Transesterification of Pyridine-2-carboxylates 1 with Aromatic or Aliphatic Aldehydes 2 for Versatile Carboxylates 3
a
b
Reaction conditions: 1 (0.25 mmol), 2 (1.5 equiv), Pd(OAc)2 (10 mol %) and TBHP (1.5 equiv), 115 °C, 48 h. Isolated yield.
CH3CN led to a trace amount of or low yields of ester 3aa
(entries 14−16). Therefore, the optimized reaction should be
performed under the catalysis of Pd(OAc)2 (10 mol %) and
dppe (15 mol %) using TBHP (1.5 equiv) as an oxidant at
reflux in toluene.
Under the optimized reaction conditions, the scope of the
transesterification reaction between various pyridine-2-carbox-
ylates 1 and aldehydes 2 was investigated. It was found that not
only aryl pyridine-2-carboxylates 1a−c but also alkyl pyridine-2-
carboxylates 1d−i underwent the transesterification smoothly
with both aromatic and aliphatic aldehydes 2a−l to afford the
desired versatile carboxylates 3 up to 90% yield (Table 2). Our
experiment indicated that electron-withdrawing groups on the
benzene rings of aromatic aldehydes 2a−e are more beneficial
to this reaction than electron-donating groups on those of
aromatic aldehydes 2f, 2i, and 4-methoxybezaldehyde 2f led to
the lowest yield of the corresponding carboxylic ester 3bf (41%
yield). Although hydroxybenzaldehyde 2i contains a hydroxy
group, it did not conduct the common transesterification
reaction with pentafluorophenyl pyridine-2-carboxylate 1c to
exchange pentafluorophenoxy group in 1c with formylphenoxy
group of 2i. The 2i kept to perform this new type of
transesterification, exchanging 2-picolinyl group in 1c with 4-
hydroxybenzoyl group of 2i. Naphthaldehyde 2j as well as
benzaldehyde derivatives performed the transesterification
reaction expediently to give the corresponding naphthoic
ester 3cj in 71% yield. Using furan-2-carbaldehyde 2k as a
heteroaromatic aldehyde resulted in desired furan-2-carboxylic
ester 3ck albeit in comparatively lower yield. Interestingly,
bromo substituted thiophene-2-carbaldehyde 2l, which contains
an easily cleaved C−Br bond by palladium catalysts, still led to
5-bromo-thiophene-2-carboxylic ester 3cl in a satisfactory yield.
Further experiment showed that quinolyl pyridine-2-carbox-
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Note
Scheme 1. Transesterification of Other N-Heteroarene-2-carboxylates 1k−m with Aldehydes 2a,2c for Carboxylates 3cc, 3ha,
3ca
ylate 1j could also undergo the transesterification smoothly to
give desired heteroaryl carboxylic ester 3jc.
that the oxygen of alkoxy group in product ester 3 should come
from alkoxy group in pyridine-2-carboxylate 1 and rule out that
from other oxygen sources. Thus, pyridine-2-carboxylate 1
should be subjected to an oxidative addition of acyl-oxygen
bond with palladium catalyst. Our experiment showed that if 2-
pyridyl group in 1a was replaced by 4-pyridyl, 4-nitrophenyl or
phenyl group, the transesterification could not occur. This
result suggested that nitrogen in this position could promote
and control the acyl−oxygen cleavage by palladium catalyst.
Moreover, when tetramethylpiperidinyloxy (TEMPO), a radical
scavenger, was added into the reaction system of phenyl
pyridine-2-carboxylate 1a with 4-nitrobenzaldehyde 2a, no
desired ester 3aa was isolated. Instead, we captured most of 4-
nitrobenzoyl radical in its ester form with TEMPO.4 This
means that aldehyde should participate in the transesterification
reaction in the species of acyl radical.
Therefore, the possible mechanism of the transesterification
reaction is postulated as follows (Scheme 3). Initially,
Pd(OAc)2 could coordinate with pyridine-2-carboxylate 1 to
form an intermediate 4. In the presence of ligand, palladium in
4 may perform an intramolecular oxidative addition with acyl-
oxygen bond, generating a Pd (IV) intermediate 5. On the
other hand, after TBHP dissociates into a butoxy radical and a
hydroxy radical, aldehyde 2 is deprived of its hydrogen by the
Moreover, when other N-heteroarene-2-carboxylates, quino-
line-2-carboxylate 1k, 1l and pyrazine-2-carboxylate 1m were
employed instead of the corresponding pyridine-2-carboxylate
1c, 1h, the transesterification reaction also proceeded
expediently to afford the same aryl or alkyl carboxylates 3cc,
3ha or 3ca, respectively (Scheme 1).
In order to gain insight into the transesterification reaction,
we carried out preliminary studies on mechanistic pathway. We
prepared 18O-labeled pyridine-2-carboxylate 1i′ by using H218O
as isotopic source. The transesterification reaction of 18O-
labeled 1i′ with aromatic aldehyde 2b led to desired ester 3i′b
without the decrease of 18O-labeling purity in MS under the
above optimized conditions (Scheme 2). Such a result means
Scheme 2. Transesterification Reaction of 18O-Labeled
Pyridine-2-carboxylate 1i′
Scheme 3. Possible Mechanism of the Transesterification
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Note
4-Acetylphenyl 4-Cyanobenzoate 3bb.8 Yield: 70% (46.4 mg); 1H
NMR (300 MHz, CDCl3) δ (ppm) 8.32 (d, J = 8.5 Hz, 2H), 8.08 (d, J
= 8.7 Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 2.64
(s, 3H); MS (EI) m/z (%) 264.9 (M+, 3), 136.0(4), 129.9 (100),
120.9(17), 101.9(33), 42.9(2).
butoxy radical to generate an acyl radical.5 The acyl radical and
the hydroxy radical undergo an oxidative addition with
Pd(OAc)2 to form Pd (IV) intermediate 6. Subsequently, the
intermediate 5 and 6 perform transmetalation to generate Pd
(IV) intermediate 7 and 8, respectively. The reductive
elimination of 7 results in the desired ester 3, with regenerating
Pd(OAc)2. MS analysis of the mixture after the reaction of 1c
with 2c under the optimized conditions indicates that there
probably existed benzyl pyridine-2-carboxylate 1d′ and 2-
benzylpyridine.6 Thus, the intermediate 8 may perform a
ligand-exchange with benzyl alcohol, which is formed by the
oxidation of toluene, generating intermediate 9. The reductive
elimination 9 results in pyridine-2-carboxylate 1d′, with
regenerating Pd(OAc)2.
In summary, we found an unprecedented transesterification
reaction of N-heteroarene-2-carboxylates 1 with aldehydes 2 by
C−H and C−O bond activations for the synthesis of a broad
scope of carboxylates 3 under neutral and mild conditions. By
using Pd(OAc)2 as a catalyst and TBHP as an oxidant, various
aryl, heteroaryl, alkyl N-heteroarene-2-carboxylates 1a−m could
perform the transesterification smoothly with aromatic,
heteroaromatic and aliphatic aldehydes 2a−l to furnish versatile
carboxylates 3 up to 90% yield. The transesterification reaction
has good generality and tolerates various functional groups,
such as nitro, cyno, hydroxy, acetyl, fluoro, chloro, bromo,
trifluoromethyl and methoxy group. Neither N-heteroarene-2-
carboxylate 1 nor aldehyde 2 is necessary to be largely excess in
this reaction. 18O-isotopic labeling and radical inhibiting
experiments indicate that the mechanistic pathway may
undergo the two key steps of oxidative addition of acyl−O
bond in parent ester 1 and radical cleavage of sp2 C−H bond in
aldehyde 2.
4-Acetylphenyl 4-Chlorobenzoate 3bc.9 Yield: 75% (51.4 mg); 1H
NMR (300 MHz, CDCl3) δ (ppm) 8.14 (d, J = 8.6 Hz, 2H), 8.06 (d, J
= 8.7 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 2.63
(s, 3H); MS (EI) m/z (%) 273.9 (M+, 1), 140.9(50), 138.8 (100),
135.9(3), 120.9(14), 110.9(48), 42.9(3).
4-Acetylphenyl 4-Bromobenzoate 3bd. Yield: 56% (44.5 mg); mp
1
150−152 °C; H NMR (300 MHz, CDCl3) δ (ppm) 8.08 (d, J = 2.4
Hz, 2H), 8.05 (d, J = 2.5 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 7.33 (d, J
= 8.7 Hz, 2H), 2.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
196.9, 164.0, 154.5, 135.0, 132.1, 131.7, 130.1, 129.3, 128.0, 121.9,
26.6; Anal. Calcd. For C15H11BrO3: C, 56.45; H, 3.47%. Found: C,
56.27; H, 3.64%; MS (EI) m/z (%) 317.9(M+, 0.33), 184.8(80), 182.8
(100), 154.8(13), 135.9(2), 120.9(7).
4-Acetylphenyl 4-(Trifluoromethyl)benzoate 3be. Yield: 75%
(57.7 mg); mp 102−104 °C; 1H NMR (300 MHz, CDCl3) δ
(ppm) 8.33 (d, J = 8.2 Hz, 2H), 8.07 (d, J = 8.7 Hz, 2H), 7.80 (d, J =
8.3 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 2.64 (s, 3H). 13C NMR (75
MHz, CDCl3) δ (ppm)196.8, 163.5, 154.3, 135.6, 135.1, 132.3, 130.7,
130.1, 125.8, 125.7, 125.3, 121.8, 26.6; MS (EI) m/z (%) 307.9 (M+,
4), 289.0(5), 172.9 (100), 144.9(84), 120.9(7), 94.9(6), 42.9(2). Anal.
Calcd. For C16H11F3O3: C, 62.34; H, 3.60%. Found: C, 62.44; H,
3.81%.
4-Acetylphenyl 4-Methoxybenzoate 3bf.9 Yield: 41% (27.7 mg);
1H NMR (300 MHz, CDCl3) δ (ppm) 8.16 (d, J = 8.9 Hz, 2H), 8.05
(d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H),
3.91 (s, 3H), 2.63 (s, 3H); MS (EI) m/z (%) 270.0(M+, 0.15),
135.9(6), 134.9 (100), 120.9(8), 106.9(6).
4-Acetylphenyl Butyrate 3bg.10 Yield: 63% (32.4 mg); H NMR
1
(300 MHz, CDCl3) δ (ppm) 8.00 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.8
Hz, 2H), 2.62−2.54 (m, 5H), 1.89−1.72 (m, 2H), 1.06 (t, J = 7.4 Hz,
3H); MS (EI) m/z (%) 206.0 (M+, 4), 136.9(64), 135.9(13), 120.9
(100), 70.9(94), 43.0(53).
EXPERIMENTAL SECTION
■
2,3,4,5,6-Pentafluorophenyl 4-Nitrobenzoate 3ca.11 Yield: 90%
Preparation of N-Heteroarene-2-carboxylates (1a−m). A
mixture of N-heteroarene-2-carboxylic acid (10 mmol), alcohol or
phenol (10 mmol), DMAP (4-(dimethylamino)pyridine, 1 mmol) and
1-ethyl-3-(3-dimethylaminopropyl) carbodiamide hydrochloride
(EDC·HCl, 10 mmol) in THF (50 mL) was stirred overnight at 25
°C. The resulting mixture was filtered, and the filtrate was evaporated
in vacuo. The residue was purified by flash column chromatography
(silica gel, ethyl ether/petroleum ether = 1:3 as eluent), affording a
corresponding N-heteroarene-2-carboxylic ester 1a−m.
1
(74.9 mg); H NMR (300 MHz, CDCl3) δ (ppm) 8.42−8.39 (m,
4H); MS (EI) m/z (%) 183.9(18), 154.9(9), 149.9(100), 135.9(10),
119.9(62), 116.9(7), 103.9(97), 75.9(41).
2,3,4,5,6-Pentafluorophenyl 4-Cyanobenzoate 3cb.12 Yield: 80%
(62.6 mg); 1H NMR (300 MHz, CDCl3) δ (ppm) 8.32 (d, J = 8.5 Hz,
2H), 7.87 (d, J = 8.5 Hz, 2H); MS (EI) m/z (%) 183.8(5), 154.8(6),
129.9(100), 101.9(63), 74.9(6).
2,3,4,5,6-Pentafluorophenyl 4-Cholrobenzoate 3cc.13 Yield: 89%
(71.6 mg); 1H NMR (300 MHz, CDCl3) δ (ppm) 8.15 (d, J = 8.7 Hz,
2H), 7.54 (d, J = 8.7 Hz, 2H); 19F NMR (400 MHz, CDCl3) δ (ppm)
−152.23 to −152.63 (m, 2F), −157.60 (t, J = 21.7 Hz, 1F), −161.94 to
−162.38 (m, 2F); MS (EI) m/z (%) 184.0(0.22), 141.0(17),
139.0(100), 111.0(49).
General Procedure for the Transesterification Reaction. A
mixture of N-heteroarene-2-carboxylate 1 (0.25 mmol), Pd(OAc)2
(5.6 mg, 0.025 mmol, 10 mol %) and dppe (14.9 mg, 0.0375 mmol, 15
mol %) in toluene (1 mL) was sealed in a 40 mL-vial. The reaction
mixture was heated at 115 °C for 10 min. Then, aldehyde 2 (0.375
mmol) and TBHP (33.8 mg, 0.375 mmol) were added, and the
resulting mixture was refluxed for 36−48 h. After cooling to room
temperature, the mixture was filtered, and the filtrate was evaporated in
vacuo. The residue was purified by flash column chromatography
(silica gel, ethyl acetate/petroleum ether = 1:3 to 1:8 as an eluent) to
afford the desired carboxylic ester 3.
2,3,4,5,6-Pentafluorophenyl 4-(Trifluoromethyl)benzoate 3ce.14
Yield: 81% (72.1 mg); 1H NMR (300 MHz, CDCl3) δ (ppm) 8.34 (d,
J = 8.2 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H); MS (EI) m/z (%) 336.8(5),
172.9(100), 154.8(7), 144.9(90), 124.9(7), 94.9(9), 74.9(5).
2,3,4,5,6-Pentafluorophenyl Benzoate 3ch.15 Yield: 72% (51.8
1
mg); H NMR (300 MHz, CDCl3) δ (ppm) 8.27−8.16 (m, 2H),
Phenyl 4-Nitrobenzoate 3aa.7 Yield: 74% (44.9 mg); H NMR
1
7.77−7.67 (m, 1H), 7.62−7.51 (m, 2H). ; MS (EI) m/z (%)
183.8(100), 154.8(8), 135.9(82), 116.9(38), 104.9(20).
(300 MHz, CDCl3) δ (ppm) 8.44−8.33 (m, 4H), 7.52−7.42 (m, 2H),
7.37−7.28 (m, 1H), 7.26−7.20 (m, 2H); MS (EI) m/z (%) 242.9 (M+,
6), 149.9(100), 119.9(88), 103.9(20), 93.9(12), 91.9(13), 75.9(9).
2,3,4,5,6-Pentafluorophenyl 4-Hydroxybenzoate 3ci.16 Yield: 45%
(34.2 mg); 1H NMR (300 MHz, CDCl3) δ (ppm) 8.11 (d, J = 8.4 Hz,
2H), 6.96 (d, J = 8.5 Hz, 2H); MS (EI) m/z (%) 184.0(58),
136.0(38), 121.1 (100), 93.1(16).
7
1
Phenyl 4-Cyanobenzoate 3ab. Yield: 69% (38.4 mg); H NMR
(300 MHz, CDCl3) δ (ppm) 8.32 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 8.5
Hz, 2H), 7.50−7.41 (m, 2H), 7.36−7.27 (m, 1H), 7.25−7.18 (m, 2H);
MS (EI) m/z (%) 222.9 (M+, 20), 129.9(77), 101.9 (100), 93.9(7).
2,3,4,5,6-Pentafluorophenyl 2-Naphthoate 3cj.17 Yield: 71%
(60.1 mg); 1H NMR (300 MHz, CDCl3) δ (ppm) 8.82 (s, 1H),
8.17 (d, J = 8.5 Hz, 1H), 8.08−7.85 (m, 3H), 7.76−7.51 (m, 2H);19F
NMR (400 MHz, CDCl3) δ (ppm) −152.25 to −152.49 (m, 2F),
−157.97 (t, J = 21.7 Hz, 1F), −162.14 to −162.57 (m, 2F);MS (EI)
m/z (%) 155.1(100), 127.1(99), 101.1(2), 77.1(3).
7
1
Phenyl 4-Chlorobenzoate 3ac. Yield: 68% (39.4 mg); H NMR
(300 MHz, CDCl3) δ (ppm) 8.15 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.7
Hz, 2H), 7.48−7.39 (m, 2H), 7.33−7.27 (m, 1H), 7.25−7.18 (m, 2H);
MS (EI) m/z (%) 231.9 (M+, 2), 140.9(31), 138.8 (100), 110.9(23).
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Note
2,3,4,5,6-Pentafluorophenyl Furoate 3ck.11 Yield: 51% (35.4 mg);
1H NMR (300 MHz, CDCl3) δ (ppm) 7.76 (d, J = 0.9 Hz, 1H), 7.51
(d, J = 3.6 Hz, 1H), 6.66 (dd, J = 3.6, 1.7 Hz, 1H); MS (EI) m/z (%)
183.8(100), 135.8(56), 116.9(25), 94.9(38).
(%) 283.1 (M+,9), 141.0(55), 139.0 (100), 127.9(44), 126.9(35),
111.0(59); MS (ESI) m/z 284.05 [M + H]+.
18O-Isotopic Labeling and Radical Inhibiting Experiments.
18O-Isotopic Labeling Experiment. Preparation of (18O) Phenethyl 2-
Pyridinecarboxylate 1i′. A mixture of phenethyl bromide (9.2 g, 50
mmol), AgNO3 (4.25 g, 25 mmol) and H218O (1.0 g, about 50 mmol)
was stirred at 50 °C for 12 h. The resulting mixture was filtered, and
the filtrate was purified by flash column chromatography (silica gel,
ethyl ether/petroleum ether = 1:3 as eluent), affording 18O-isotopic
phenethyl alcohol. Then the mixture of the phenethyl alcohol (1.24 g,
10 mmol), pyridine-2-carboxylic acid (1.23 g, 10 mmol), DMAP (0.12
g, 1 mmol) and EDC·HCl (1.92 g, 10 mmol) in THF (50 mL) was
stirred overnight at 25 °C. The resulting mixture was filtered, and the
filtrate was evaporated in vacuo. The residue was purified by flash
column chromatography (silica gel, ethyl ether/petroleum ether = 1:3
as eluent), affording the desired 18O-phenethyl pyridine-2-carboxylate
1i′.
2,3,4,5,6-Pentafluorophenyl 5-Bromo-2-thiophenecarboxylate
3cl.18 Yield: 65% (60.4 mg); H NMR (300 MHz, CDCl3) δ (ppm)
1
7.81 (d, J = 4.1 Hz, 1H), 7.21 (d, J = 4.1 Hz, 1H); 19F NMR (400
MHz, CDCl3) δ (ppm) −152.06 to −152.35 (m, 2F), −157.28 (t, J =
21.7 Hz, 1F), −161.90 to −162.21 (m, 2F); MS (EI) m/z (%)
190.9(85), 188.9(100), 184.0(6), 160.9(5).
Benzyl 4-Nitrobenzoate 3da.19 Yield: 51% (32.8 mg); H NMR
1
(300 MHz, CDCl3) δ (ppm) 8.33−8.18 (m, 4H), 7.50−7.30 (m, 5H),
5.41 (s, 2H); MS (EI) m/z (%) 257.1 (M+, 44), 227.1(9), 150.0 (100),
134.0(17), 120.0(68), 91.1(95).
Benzyl 4-Cyanobenzoate 3db.20 Yield: 53% (31.4 mg); H NMR
1
(300 MHz, CDCl3) δ (ppm) 8.17 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.2
Hz, 2H), 7.48−7.34 (m, 5H), 5.39 (s, 2H); MS (EI) m/z (%) 236.9
(M+, 45), 129.9 (100), 101.9(19), 90.9(45).
The experimental procedure is similar to the general procedure of
the transesterification reaction, affording desired 18O-phenethyl 4-
cyanobenzoate 3i′b: 1H NMR (400 MHz, CDCl3) δ (ppm) 8.09 (d, J
= 8.5 Hz, 2H), 7.72 (d, J = 3.0 Hz, 2H), 7.36−7.30 (m, 2H), 7.30−
7.19 (m, 3H), 4.57 (t, J = 6.9 Hz, 2H), 3.09 (t, J = 6.9 Hz, 2H); MS
(EI) m/z (%) 130.0(100), 104.1(61), 91.1(23), 77.0(4); MS (ESI) m/
z: 252.05 [M − H]−.
Radical Inhibiting Experiment. A mixture of phenyl 2-pyridine-
carboxylate 1a (60.8 mg, 0.25 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol,
10 mol %), dppe (14.9 mg, 0.0375 mmol, 15 mol %) in toluene (1
mL) was sealed in a 40-mL vial. The reaction mixture was heated at
115 °C for 10 min. Then 4-nitrobenzaldehyde 2a (56.6 mg, 0.375
mmol), TEMPO (58.9 mg, 0.375 mmol) and TBHP (33.8 mg, 0.375
mmol) were added, and the resulting mixture was refluxed for 48 h.
After cooling to room temperature, the mixture was filtered, and the
filtrate was evaporated in vacuo. The residue was purified by flash
column chromatography (silica gel, ethyl ether/petroleum ether =
1:5), affording 4-nitrobenzoyl-TEMPO ester 11 in about 70% yield.
2,2,6,6-Tetramethyl-piperidin-1-yl 4-Nitrobenzoate 11.26 1H
NMR (300 MHz, CDCl3) δ (ppm) 8.40−8.29 (m, 2H), 8.29−8.17
(m, 2H), 1.85−1.44 (m, 6H), 1.28 (s, 6H), 1.12 (s, 6H); MS(ESI) m/
z 329.05 [M + Na]+.
Benzyl 4-(Trifluoromethyl)benzoate 3de.21 Yield: 55% (38.5 mg);
1H NMR (300 MHz, CDCl3) δ (ppm) 8.19 (d, J = 8.1 Hz, 2H), 7.71
(d, J = 8.2 Hz, 2H), 7.50−7.33 (m, 5H), 5.40 (s, 2H); MS (EI) m/z
(%) 280.1 (M+, 15), 173.0 (100), 145.0(43), 91.1(41).
4-(Trifluoromethyl)benzyl 4-Nitrobenzoate 3ea. Yield: 53% (43.1
mg); mp 95−97 °C; 1H NMR (300 MHz, CDCl3) δ (ppm) 8.35−8.20
(m, 4H), 7.68 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 5.46 (s,
2H); 13C NMR (75 MHz, CDCl3) δ (ppm) 164.4, 150.8, 139.2, 135.1,
130.9, 130.8 (q, JC−F =32.6 Hz)), 128.8, 128.4, 125.8(q, JC−F = 3.75
Hz), 123.9 (q, JC−F =272 Hz), 123.7, 66.6; Anal. Calcd. For
C15H10F3NO4: C, 55.39; H, 3.10; N, 4.31%. Found: C, 55.59; H,
3.40; N, 4.21%; MS (EI) m/z (%) 324.9 (M+, 3), 308.9(5), 294.9(17),
158.9(61), 149.9 (100), 119.9(46).
4-(Trifluoromethyl)benzyl 4-Cyanobenzoate 3eb. Yield: 54%
1
(41.2 mg); mp 77−79 °C; H NMR (300 MHz, CDCl3) δ (ppm)
8.18 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.2 Hz,
2H), 7.56 (d, J = 8.1 Hz, 2H), 5.45 (s, 2H). 13C NMR (100 MHz,
CDCl3) δ (ppm) 164.6, 139.3, 133.6, 132.3, 130.8 (q, JC−F =32.6 Hz),
130.2, 128.4, 125.7 (q, JC−F = 3.75 Hz), 123.9 (q, JC−F =272 Hz),
117.8, 116.8, 66.5; Anal. Calcd. For C16H10F3NO2: C, 62.96; H, 3.30;
N, 4.59%. Found: C, 63.16; H, 3.50; N, 4.37%; MS (EI) m/z (%)
304.9 (M+, 24), 158.9(60), 129.9 (100), 101.9(32).
2-Chlorobenzyl 4-Nitrobenzoate 3fa.22 Yield: 54% (39.3 mg); H
1
ASSOCIATED CONTENT
■
NMR (300 MHz, CDCl3) δ (ppm) 8.38−8.16 (m, 4H), 7.54−7.48
(m, 1H), 7.47−7.41 (m, 1H), 7.39−7.28 (m, 2H), 5.51 (s, 2H); MS
(EI) m/z (%) 290.9(M+, 0.09), 255.9(100), 225.9(15), 149.9(54),
126.9(16), 124.9(73), 119.9(65).
S
* Supporting Information
1
Spectra of H NMR, 13C NMR, 19F NMR and MS. This
material is available free of charge via the Internet at http://
pubs.acs.org.
2-Methoxybenzyl 4-Nitrobenzoate 3ga.22 Yield: 58% (41.6 mg);
1H NMR (300 MHz, CDCl3) δ (ppm) 8.33−8.18 (m, 4H), 7.46−7.30
(m, 2H), 7.04−6.89 (m, 2H), 5.46 (s, 2H), 3.87 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 164.67, 157.75, 150.51, 135.84, 130.81, 130.05,
129.97, 123.49, 120.50, 110.62, 63.22, 55.48; MS (EI) m/z (%) 286.9
(M+, 11), 149.9(7), 136.9 (100), 120.9(40), 119.9(11), 90.9(73).
2-Methoxybenzyl 4-Cyanobenzoate 3gb.22 Yield: 56% (37.4 mg);
1H NMR (300 MHz, CDCl3) δ 8.17 (d, J = 6.8 Hz, 2H), 7.73 (d, J =
6.8 Hz, 2H), 7.43−7.30 (m, 2H), 7.04−6.86 (m, 2H), 5.44 (s, 2H),
3.86 (s, 3H); MS(EI) m/z (%) 266.9 (M+, 9), 136.9(100), 129.9(72),
120.9(17), 101.9(24), 90.9(55).
AUTHOR INFORMATION
Corresponding Author
*Fax: (+86)25-83686231. E-mail: huangzz@nju.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from National Natural Science Foundation of
China (No. 21072091) and MOST of China (973 program
2011CB808600) is gratefully acknowledged.
Butyl 4-Nitrobenzoate 3ha.23 Yield: 47% (26.2 mg); H NMR
1
(300 MHz, CDCl3) δ (ppm) 8.34−8.16 (m, 4H), 4.38 (t, J = 6.6 Hz,
2H), 1.87−1.69 (m, 2H), 1.58−1.39 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H);
MS (EI) m/z (%) 222.9 (M+, 0.76), 149.9(79), 119.9 (100),
103.9(21), 91.9(26), 75.9(14), 56.0(38).
REFERENCES
■
Phenethyl 4-Cyanobenzoate 3ib.24 Yield: 50% (31.4 mg); 1H
NMR (400 MHz, CDCl3) δ (ppm) 8.09 (d, J = 8.5 Hz, 2H), 7.72 (d, J
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119.1(3), 104.1 (100), 102.0(27), 91.1(45), 77.0(16), 44.0(5).
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