Pt-Catalyzed sp3 C-H bond activation of o-alkyl substituted aromatic carboxylic acid derivatives for the formation of aryl lactones

Article abstract of DOI:10.1016/j.tetlet.2005.12.104

Synthesis of aryl lactones from ortho-alkyl substituted aromatic carboxylic acids is described on the basis of sp³ C-H bond activation using either palladium or platinum catalysts. Kinetic isotope studies reveal that the reaction takes place presumably by the chelation assistance of metal catalyst to the carboxylic group followed by the C-H bond activation.

Full text of DOI:10.1016/j.tetlet.2005.12.104

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1375–1379
3
Pt-Catalyzed sp C–H bond activation of o-alkyl
substituted aromatic carboxylic acid derivatives for the
formation of aryl lactones
Ji Min Lee and Sukbok Chang*
Center for Molecular Design and Synthesis, Department of Chemistry and School of Molecular Science (BK21),
Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
Received 26 September 2005; revised 12 December 2005; accepted 22 December 2005
3
Abstract—Synthesis of aryl lactones from ortho-alkyl substituted aromatic carboxylic acids is described on the basis of sp C–H
bond activation using either palladium or platinum catalysts. Kinetic isotope studies reveal that the reaction takes place presumably
by the chelation assistance of metal catalyst to the carboxylic group followed by the C–H bond activation.
Ó 2006 Elsevier Ltd. All rights reserved.
Transition metal-catalyzed activation of carbon–hydro-
gen bonds has been perceived as challenging goals in
We describe herein our initial results on the Pd- and
Pt-catalyzed direct lactonization of o-alkyl substituted
carboxylates, and the preliminary mechanistic studies
on the activation process are also presented.
1
organic synthesis owing to their robust nature. In
3
particular, selective functionalization of sp C–H bonds
is one of the most difficult targets, thus usually requiring
stoichiometric amounts of metal complexes and/or
harsh reaction conditions for that purpose. As a result,
O
2
O
n
cat. Pd(II) or Pt(II)
Oxidant
n
finding a general method to make the unreactive bonds
labile would have a significance impact. Thanks to the
recent appearance of the active late transition metal cat-
alyst systems, functionalization of certain types of ali-
phatic and aromatic C–H bonds has been possible via
either a direct activation manner or a chelation-assisted
OH
H
O
m
m
ð1Þ
3
strategy.
For the one-step synthesis of aryl lactones from o-alkyl
substituted aryl carboxylates, we initially investigated a
wide range of metal catalyst systems in order to optimize
Lactone is an important and ubiquitous building block
in organic synthesis, materials science, polymer areas,
7
reaction conditions. Among the metal complexes exam-
4
and natural products chemistry. Although various
ined, certain types of palladium(II) and platinum(II)
catalysts exhibited discernable activities in the presence
of additional oxidants or co-catalysts leading to the
desired lactone product (Table 1).
methods utilizing either the oxidation of benzylic C–H
bond or insertion of carbon monoxide have been devel-
5
oped, only a few direct approaches have been revealed
for the construction of aryl lactones starting from ortho-
alkyl substituted aromatic carboxylic acids or their
derivatives via the sp C–H bond activation (Eq. 1).
When 2,4,6-trimethylbenzoic acid (1) was applied with
3
6
the use of Pd(OAc) (3, 20 mol %), 5,7-dimethylphtha-
2
lide (2) was isolated in a moderate yield (44%) at
1
00 °C only in the presence of Na CO (1.5 equiv) and
2
3
8
MnO (2.0 equiv, entry 3). It was interesting to observe
2
Keywords: C–H Bond activation; Shilov catalyst system; Aromatic
carboxylates; Lactones; Chelation assistance.
that atmospheric oxygen serves also as an oxidant
although the efficiency of the reaction was lower com-
*
Corresponding author. Fax: +82 42 869 2810; e-mail: sbchang@
kaist.ac.kr
pared to that of MnO (entry 2). Use of toluene solvent
2
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.104

1376
J. M. Lee, S. Chang / Tetrahedron Letters 47 (2006) 1375–1379
a
Table 1. Optimization of the catalyst system in the lactonization of 2,4,6-trimethylbenzoic acid (1)
O
O
OH
conditions
O
1
2
b
c
Entry
Catalyst
Additive
—
Base
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)
3
2
(3)
—
Chlorobenzene
Chlorobenzene
Chlorobenzene
Toluene
Chlorobenzene
Chlorobenzene
Chlorobenzene
DMF
Water
Water
Water
Water
0
30
44
28
<5
<5
<5
0
O
2
(1 atm)
d
Na
Na
Na
Na
—
2
2
2
2
CO
CO
CO
CO
3
3
3
3
3
MnO
MnO
MnO
MnO
MnO
MnO
—
2
2
2
2
2
2
d
d
d
d
d
3
—
3
3
3
Et N
3
Na
—
2
CO
3
K
2
PtCl
4
(4)
0
0
e
e
10
11
12
13
14
15
16
—
4
K
K
2
PtCl
PtCl
6
—
—
—
—
2
6
60
23
56
0
13
31
4
CuCl
CuCl
CuCl
—
2
2
2
(1.0 equiv)
(3.0 equiv)
(3.0 equiv)
4
Water
Water
Chlorobenzene
Chlorobenzene
—
PdCl
—
2
(PPh
3
)
2
Na
Na
2
CO
CO
3
3
Pd(CH CN)
4
BF
4
—
2
3
a
b
c
Palladium catalyst system: 20 mol % of 3, 100 °C, 0.04 M and 9 h, and platinum catalyst system: 10 mol % of 4, 150 °C, 0.01 M, and 24 h.
.5 equiv of base was added.
Isolated yield.
1
d
e
2.0 equiv were used.
30 mol % was employed.
reduced the product yield mainly due to a side reaction,
in which toluene itself is competitively activated to gen-
erate benzyl 2,4,6-trimethylbenzoate (20%) as a side
product in addition to 5,7-dimethylphthalide (2, 28%,
entry 4). Almost no desired product was observed in
the absence of either a palladium catalyst (entry 5) or
base (entry 6). Use of polar solvents such as 1,2-dimeth-
oxyethane or DMF resulted in inhibition of the reaction
catalyst resulted in no conversion (entries 9 and 10).
On the other hand, when the less expensive and more
1
1
practical copper additive was applied instead of a
Pt(IV) cocatalyst, the reaction proceeded with an almost
comparable efficiency (entry 13) compared to that
obtained under the Shilov conditions. Although product
yields were increased depending on the amounts of cop-
per additive, the addition of CuCl2 in more than
3.0 equiv did not improve the reaction efficiency.
(
(
entry 8). Whereas Pd(OAc) provided the highest yield
44%, entry 3) among various palladium catalysts exam-
2
ined, the use of others provided reduced yields under the
same conditions, for example, PdCl (PPh ) in 13% and
To demonstrate the utility of the optimized lactoniza-
tion protocol, a wide range of o-alkyl substituted aro-
matic carboxylic acid derivatives were then examined
under the Pt(II)/Cu(II) systems (Table 2).1 It was
observed that o-toluic acid was also readily reacted
under the conditions to afford phthalide (5) in accept-
able yield (entry 1). When 2-ethylbenzoic acid was
employed, both primary and secondary C–H bonds
were activated, giving 3-methylphthalide (6, 10%) and
3,4-dihydridoisocoumarin (7, 35%), respectively. When
an iso-propyl substituent is positioned ortho to the
carboxylic acid group, the substrate was inert to the
reaction conditions presumably due to steric reasons
(entry 3). 2-Methylnaphthoic acid was subjected under
the reaction condition to give 3(1H)-benzo[e]isobenzo-
furanone in 30% yield (entry 4). It should be mentioned
that the lactonization protocol was also applied to aryl-
acetic analogues in addition to benzoic acid derivatives.
For example, 2,4,6-trimethylphenylacetic acid was sub-
jected to the conditions and the corresponding substi-
tuted 3-isochromanone product was obtained in 35%
2
3 2
Pd(CH CN) BF in 31%. It turned out that the lactoni-
3
4
4
2
zation suffered from decarboxylation under the palla-
dium catalyst system, which limits the improvement on
the yield and substrate scope. In addition, it was
observed that the reaction has rather a narrow range of
temperatures; if the temperature is below 90 °C, no reac-
tion occurs. On the other hand, the substrates undergo
complete decarboxylation at temperatures above
9
1
20 °C.
2
ꢀ
4ꢀ
Since a combination of PtCl4 /PtCl6 in water (Shilov
conditions) has been extensively investigated in the acti-
1
0
vation of unreactive bonds, we next turned our atten-
tion to platinum catalyst system. With the platinum
catalysis, decarboxylation seemed to be minimized to
some degree compared to the corresponding palladium
systems. In fact, when K PtCl was applied in the pres-
2
4
ence of 0.30 equiv of K PtCl in water, the desired lac-
2
6
tone product was obtained up to 60% yield at 150 °C
1
3
(
entry 11). As expected, omission of any one platinum
yield (entry 5). In addition, it is highly interesting to

J. M. Lee, S. Chang / Tetrahedron Letters 47 (2006) 1375–1379
1377
a
Table 2. Lactonization of o-alkyl substituted aromatic carboxylates with the Pt catalyst system
K PtCl (10 mol%)
2
4
O
O
CuCl (3 equiv)
2
OH
O
H O (0.01 M)
2
o
R
150 C, 24 h
R
Entry
1
Substrate
CO H
Product(s)
Isolated yield (%)
2
O
51
O (5)
O
O
CO H
2
+
O
O
2
3
4
45 (6/7 = 1:3.5)
(
6)
(7)
CO H
2
i
-Pr
i
-Pr
No reaction
0
O
CO H
2
O
30
O
5
35
COOH
O
6
7
8
9
R = CO
R = CO
R = CONH
R = CN
2
H
2
2
2
2
56
43
65
20
R
2
Et
2
a
See Ref. 12 for detailed experimental procedure.
note that the lactonization was achieved not only with
carboxylic acids but also with their derivatives including
esters, amides, and nitriles. For example, ethyl mestioate
was converted to 5,7-dimethylphthalide (2) in 43% yield
under the Pt(II)/Cu(II) system (entry 7). More signifi-
cantly, the subject of corresponding benzamide and ben-
zonitrile resulted in 2 although with lower yield in the
later case (entries 8 and 9, respectively). This result sug-
gests that the carboxylic derivatives are hydrolyzed
in situ under the aqueous reaction conditions to the cor-
responding same carboxylic acid that is reacted to afford
chelation effects,16 the measured k /kD values would
H
be nearly the same in both competitive reactions
provided that C–H bond cleavage proceeds without
coordination of the metal to the carboxylic acid group.
On the other hand, if the present reaction involves the
coordination of carboxyl group to the metal center prior
to C–H bond cleavage, the k /kD values in these label-
H
ing experiments should be different.
To make sure that this deuterium experiment is not
complicated by H/D exchange reaction with water,
2,6-dimethylbenzoic acid was applied to the reaction
1
4
the lactone product.
condition under D O. It was found that the deuterium
2
To gain insight into the mechanistic pathway in plati-
num catalysis, especially on the issue whether chelation
of the catalyst to the carboxylic acid group occurs prior
to the activation of C–H bond, we adopted both inter-
and intra-molecular competitive reactions using deute-
rium-labeled 2,6-dimethylbenzoic acids. It is assumed
that, analogous to the conclusion of the recent reports
on the kinetic isotope studies for the elucidation of
was not incorporated into methyl group of the sub-
strate although d-incorporation was observed on the
aromatic ring, thus suggesting that this reaction may
proceed via electrophilic substitution with Pt(II) spe-
cies. On the other hand, no deuterium was incorporated
on the aromatic ring when 2,6-bis(trideuterio-
methyl)benzoic acid was subjected to the reaction condi-
1
5
tions in H O.
2

1378
J. M. Lee, S. Chang / Tetrahedron Letters 47 (2006) 1375–1379
O
O
OH
CH3
O
K PtCl (10 mol%)
2
4
CuCl (3 equiv)
2
No d-incorporation
on benzylic carbon was
observed.
O
o
D O, 150 C
2
H
D
H
ð2Þ
OH
CD3
O
K PtCl (10 mol%)
2
4
D C
CD3
3
CuCl (3 equiv)
2
O
D
o
H O, 150 C
2
D
Values of kinetic isotope effects (KIE) were next mea-
sured in both inter- and intramolecular competition
reaction. When 2,6-bis(trideuteriomethyl)benzoic acid
vation of C–H is considerably assisted by the chelation
effects although the detailed pathway of the activation
itself is not clear at the present stage.
1
8
CH3
CD3
O
O
O
OH
O
OH
CD3
K PtCl (10 mol %)
2
4
+
D C
3
O
+
O
CuCl (3 equiv)
2
o
H
D
ð3Þ
ð4Þ
1
50 C, H O, 2 h
2
H
D
A
B
A/B = 1.41:1
O
OH
CH3
O
CD3
O
K PtCl (10 mol %)
2
4
CD3
+
O
CuCl (3 equiv)
O
2
D
o
1
50 C, H O, 2 h
2
D
C
D
C/D = 1.91:1
and 2,6-dimethylbenzoic acid were applied at the same
Based on the KIE results, a plausible mechanism is ten-
tatively presented in Scheme 1. After initial chelation of
metal center to carboxylic acid oxygen, it is assumed
that the metal activates the adjacent benzylic C–H bond.
Subsequent reductive elimination of the putative inter-
mediate is presumed to complete the catalytic cycle with
concomitant reoxidation of metal from zero oxidation
state to metal(II) state.
1
7
time to the reaction conditions, the kinetic isotope
effects value of the intermolecular competitive reaction
was measured to be k /k = 1.41 ± 0.01 (Eq. 3). This
H
D
is significantly different from that of intramolecular
reaction with 6-methyl-2-tridueteriomethylbenzoic acid
(
k /k = 1.91 ± 0.04, Eq. 4). In each case, the extents
H D
of the deuterium incorporation were determined to be
1
more than 95% based on the H NMR integration. This
result may support that the chelation of platinum metal
to carboxylic group takes place prior to the C–H bond
cleavage on the basis of the previous relevant mechanis-
In summary, we have demonstrated that either platinum
or Pd catalysts can activate sp carbon–hydrogen bond,
converting aromatic benzoic acid derivatives to the cor-
responding lactones in moderate yield. On the basis of
3
1
6
tic studies. As a consequence, it is presumed that acti-
O
LnPtCl2
OH
Oxidant
-
HCl
O
LnPt(0)
O
PtL Cl
n
O
O
O
-
HCl
C-H Activation
O
Reductive
Elimination
PtLn
Scheme 1. Plausible mechanism for the present transdormation.

J. M. Lee, S. Chang / Tetrahedron Letters 47 (2006) 1375–1379
1379
the isotope studies, the lactonization is presumed to
occur via C–H activations. Although the present results
show that it has a rather limited substrate scope with
modest selectivity for the formation of lactones, it is
believed that further studies would lead to better cata-
lysts system.
9. Recently, Pd-catalyzed decarboxylative Heck olefination
of arene carboxylates was reported: Myers, A. G.; Tanaka,
D.; Mannion, M. R. J. Am. Chem. Soc. 2002, 124, 11250–
1
1251.
1
0. (a) Shilov, A. E. Activation of Saturated Hydrocarbons by
Transition Metal Complexes; Riedel, D.: Dordrecht, The
Netherlands, 1984; (b) Crabtree, R. H. Chem. Rev. 1995,
9
5, 987–1007.
1
1
1. Lin, M.; Shen, C.; Garcia-Zayas, E. A.; Sen, A. J. Am.
Chem. Soc. 2001, 123, 1000–1001.
2. Representative experimental procedure using a platinum
catalyst system: In a screwed-cap vial, a solution of
Acknowledgements
This research was supported by Grant No. (R01-2005-
00-10381-0) from the Basic Research Program and
CMDS from the Korea Science and Engineering
Foundation.
2
K PtCl
4
(2.5 mg, 0.006 mmol), 2,4,6-trimethylbenzoic acid
0
(
1, 10 mg, 0.06 mmol), and CuCl (41 mg, 0.18 mmol) in
2
water (0.6 mL, 0.01 M) was heated to 150 °C for 18–24 h.
After the reaction was over, the reaction mixture was
extracted with ethyl acetate and dried over magnesium
sulfate, and the solvent was evaporated under the reduced
pressure. The crude product was chromatographed on
silica gel (hexane) to afford 5,7-dimethylphthalide (2) in
56% yield.
References and notes
1
2
3
. (a) Shilov, A. E.; Shul’pin, G. B. Chem. Rev. 1997, 97,
2
1
2
879–2932; (b) Dyker, G. Angew. Chem., Int. Ed. 1999, 38,
698–1712; (c) Kakiuchi, F.; Murai, S. Acc. Chem. Res.
002, 35, 826–834.
13. Interestingly, when o-tolylacetic acid was employed as a
substrate, we only obtained phthalide in 13% yield instead
of either 3-isochromanone or 4-methyl-3H-benzofuran-2-
one.
14. In the absence of catalyst, benzamide, benzoate and
benzonitrile are completely hydrolyzed to benzoic acid in
water at 150 °C within 1 h.
15. Intermolecular competition experiments: a mixture of 2,6-
bis(trideuteriomethyl)benzoic acid (44 mg), 2,6-dimethyl-
. Kakiuchi, F.; Murai, S. Activation of C–H bonds:
catalytic reactions. In Activation of Unreactive Bonds and
Organic Synthesis; Murai, S., Ed.; Springer: New York,
1
999; pp 47–79.
. For selected recent examples, see: (a) Murahashi, S.-I.;
Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc. 2003,
1
25, 15312–15313; (b) Desai, L. V.; Hull, K. L.; Sanford,
benzoic acid (44 mg, 1 equiv), K PtCl
and CuCl (120 mg, 3 equiv) in H O (6 mL) was heated for
2
2 h at 150 °C (ca. half conversion was made). The crude
products were analyzed by H NMR using an internal
standard (1,4-dimethoxybenzene) to reveal that the lac-
tone product is 41% deuterium-incorporated meaning that
2
4
(12 mg, 10 mol %)
M. S. J. Am. Chem. Soc. 2004, 126, 9542–9543.
. Devon, T. K.; Scott, A. I. In Handbook of Naturally
Occurring Compounds; Academic Press: New York, 1975;
Vol. 1, pp 249–264.
. (a) Grieco, P. A. Synthesis 1975, 67–82; (b) Tsunoi, S.;
Ryu, I.; Sonoda, N. J. Am. Chem. Soc. 1994, 116, 5473–
2
4
5
H D
k /k = 1.41 ± 0.01.
5
7
474; (c) Lee, M.; Chang, S. Tetrahedron Lett. 2000, 41,
507–7510.
Intramolecular competition experiments: a mixture of 6-
methyl-2-trideuteriomethylbenzoic acid (44 mg, 0.3 mmol),
6
. (a) Bertrand, M. P.; Oumar-Mahamat, H.; Surzur, J. M.
Tetrahedron Lett. 1985, 26, 1209–1212; (b) Mahmoodi, N.
O.; Salehpour, M. J. Heterocycl. Chem. 2003, 40, 875–878.
. Recent reports from this laboratory regarding on the
chelation-assisted approaches: (a) Ko, S.; Na, Y.; Chang,
S. J. Am. Chem. Soc. 2002, 124, 750–751; (b) Ko, S.; Lee,
C.; Choi, M.-G.; Na, Y.; Chang, S. J. Org. Chem. 2003,
K
H
2
PtCl (6 mg, 10 mol %) and CuCl (60 mg, 3 equiv) in
4
2
2
O (3 mL) was heated for 2 h at 150 °C (ca. half
H D
conversion was made) to reveal that k /k = 1.91 ± 0.04
(average of three time experiments).
7
16. (a) Jones, W. D. Acc. Chem. Res. 2003, 36, 140–146;
(b) Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N. J.
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17. For the synthesis of 2,6-bis(trideuteriomethyl)benzoic acid
(97% d-incorporated), see: Grossel, M. C.; Perkins, M. J.
J. Chem. Soc., Perkin Trans. 2 1975, 1544–1549; For the
synthesis of 6-methyl-2-trideuteriomethylbenzoic acid
(98% d-incorporated), see: Hignite, C. E.; Tschanz, C.;
Huffman, D. H.; Azarnoff, D. L. J. Label. Compd.
Radiopharm. 1980, 17, 185–190.
18. For related mechanistic studies on the C–H bond activa-
tion by platinum complexes, see: (a) Lebrilla, C. B.; Maier,
W. F. J. Am. Chem. Soc. 1986, 108, 1606–1616; (b)
Siegbahn, P. E. M.; Crabtree, R. H. J. Am. Chem. Soc.
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6
8, 1607–1610; (c) Ko, S.; Han, H.; Chang, S. Org. Lett.
2
003, 5, 2687–2690; (d) Na, Y.; Ko, S.; Hwang, L. K.
Tetrahedron Lett. 2003, 44, 4475–4478; (e) Han, H.; Bae,
I.; Yoo, E. J.; Lee, J.; Do, Y.; Chang, S. Org. Lett. 2004, 6,
4
109–4112.
8
. Representative experimental procedure using a palladium
catalyst system: To a solution of 2,4,6-trimethylbenzoic
acid (1, 20.0 mg, 0.12 mmol), Na
and MnO (16 mg, 0.24 mmol) in chlorobenzene (3.0 mL,
.04 M) was added 20 mol % of Pd(OAc)2 (5.4 mg,
2 3
CO (26 mg, 0.18 mmol)
2
0
0
1
.024 mmol). The reaction mixture was stirred for 9 h at
00 °C and the product was isolated by a silica gel
chromatography (hexane) to give 5,7-dimethylphthalide
(
2) in 44% yield.