Rhenium-catalyzed regioselective synthesis of phenol derivatives from 1,3-diesters and terminal alkynes

Article abstract of DOI:10.1246/cl.2010.894

Treatment of malonates without a substituent at the active methylene moiety with terminal alkynes gave salicylates regioselectively. In contrast, when malonates bearing a substituent at the active methylene moiety were used, cyclic β-keto esters were generated regioselectively. Treatment of the formed cyclic β-keto esters with In(OTf)₃ gave phenol derivatives via decarboxylation.

Full text of DOI:10.1246/cl.2010.894

doi:10.1246/cl.2010.894
894
Published on the web July 14, 2010
Rhenium-catalyzed Regioselective Synthesis of Phenol Derivatives
from 1,3-Diesters and Terminal Alkynes
Yoichiro Kuninobu,* Takashi Iwanaga, Mitsumi Nishi, and Kazuhiko Takai*
Division of Chemistry and Biochemistry, Graduate School of Natural Science and Technology,
Okayama University, Tsushima, Kita-ku, Okayama 700-8530
(Received June 7, 2010; CL-100536; E-mail: kuninobu@cc.okayama-u.ac.jp, ktakai@cc.okayama-u.ac.jp)
Treatment of malonates without a substituent at the active
Table 1. Reactions between dimethyl malonate (1a) and several
alkynes 2a
methylene moiety with terminal alkynes gave salicylates regiose-
lectively. In contrast, when malonates bearing a substituent at the
active methylene moiety were used, cyclic ¢-keto esters were
generated regioselectively. Treatment of the formed cyclic ¢-keto
esters with In(OTf)3 gave phenol derivatives via decarboxylation.
OH
O
Re2(CO)10 (2.5 mol%)
MS4A (200 wt%-Re cat.)
O
O
R
OMe
+
R
MeO
OMe
toluene, 135 °C, 24 h
1a
2
3
R
Entry
R
Conversion/%b
Yield/%c
1
2
3
4
5
6
4-MeOC6H4 2b
70
60
56
36
67
86
3d 47 (67)
3e 40 (67)
3f 44 (79)
3g 30 (83)
3h 36 (54)
[2 + 2 + 2] Cycloaddition is an efficient and powerful
method to synthesize multisubstituted aromatic compounds. For
example, cyclotrimerization of alkynes is well known.1 However,
it is usually difficult to introduce substituents regioselectively
when unsymmetrical alkynes are used. In particular, reactions
between two or three kinds of alkynes usually produce complex
mixtures because it is difficult to control pair- and regioselectivity.
Very recently, our group2 and Tsuji, Nakamura, and co-workers3
independently reported the manganese-catalyzed regioselective
synthesis of benzoates from ¢-keto esters and two equivalents of
terminal alkynes (eq 1). In these reactions, the two substituents,
which are introduced from terminal alkynes, are located at the
para-position. During our investigation of the reactions between
other active methylene compounds and alkynes, we found that
phenol derivatives were formed by the reactions between
malonates and alkynes in the presence of a rhenium catalyst.
4-MeC6H4
4-CF3C6H4
4-BrC6H4
2-MeC6H4
nC10H21
2c
2d
2e
2f
2g
48 (56)
[64:36]d
3i + 3i′
OH
O
OH O
nC10H21
OMe
OMe
+
nC10H21
nC10H21
nC10H21
3i
3i′
a2 (2.5 equiv). bDetermined by 1H NMR. cIsolated yield. Isolated yield based on
conversion is reported in parentheses. dThe ratios between 3i and 3i¤ are reported in
square blacket.
Next, several alkynes were investigated (Table 1). Alkynes
with an electron-donating or -withdrawing group, 2b-2d, afforded
the corresponding salicylates 3d-3f in 67%-79% yields (Entries
1-3). The corresponding salicylate bearing a bromine atom, 3g,
was obtained in 83% yield without losing the bromine atom
(Entry 4). This enables the construction of further derivatives
through cross-coupling reactions. The yield was not decreased
when arylacetylene having a methyl group at the ortho-position,
2f, was used (Entry 5). In the case of an aliphatic alkyne, 2g, a
mixture of two regioisomers was generated (Entry 6). The reaction
did not proceed with diphenylacetylene.
In the case of malonates with a substituent at the active
methylene moiety, the product changed markedly from the
products obtained from malonates without a substituent at the
active methylene moiety. Treatment of diethyl 2-methylmalonate
(4a) with phenylacetylene (2a) in the presence of a catalytic
amount of a rhenium complex, Re2(CO)10, in toluene at 135 °C for
24 h, gave cyclic ¢-keto ester 5a in 74% yield (81% conversion)
(eq 3).6-8 In this reaction, [2 + 2 + 2] cycloaddition between 1
equivalent of 4a and 2 equivalents of 2a proceeded regioselec-
tively, and the two phenyl groups were introduced at the 2- and 5-
positions of 5a.
R1
O
MnBr(CO)5 (5.0 mol%)
MS4A (115 wt%-Mn cat.)
R3
O
O
OR2
HCl
ð1Þ
R3
OR2 +
R1
Et2O
R3
neat, 80 °C, 24 h
Treatment of dimethyl malonate (1a) with phenylacetylene
(2a) in the presence of a rhenium complex, Re2(CO)10, as a
catalyst in toluene at 135 °C for 24 h, gave methyl salicylate 3a in
46% yield (61% yield based on conversion) and 1a was recovered
in 24% yield (eq 2).4 In this reaction, [2 + 2 + 2] cycloaddition
of 1 equivalent of 1a and 2 equivalents of 2a proceeded
regioselectively and two phenyl groups of 3a orient at para-
positions relative to each other. In this reaction, cyclotrimerization
of 2a and insertion of 2a into a carbon-carbon single bond of 1a5
did not occur. The following yields were calculated based on the
conversion yields. Using diethyl malonate (1b) or dibutyl
malonate (1c), the corresponding salicylates 3b and 3c were
formed in 95% and 85% yields, respectively. However, diphenyl
malonate did not produce the corresponding salicylate.
OH
O
Re2(CO)10 (2.5 mol%)
MS4A (200 wt%-Re cat.)
O
O
Ph
OR
O
O
+
Ph
ð2Þ
RO
OR
O
O
toluene, 135 °C, 24 h
Ph
Re2(CO)10 (2.5 mol%)
1
2a (2.5 equiv)
3
Ph
OEt
+
Ph
ð3Þ
EtO
OEt
R
Conversion/%a
Yield/%b
R
Conversion/%a
33
Yield/%b
toluene, 135 °C, 24 h
Ph
74%
4a
2a (2.5 equiv)
Me 1a
Et 1b
76
57
3a 46 (61)
3b 54 (95)
5a
nBu
1c
3c 28 (85)
After the reaction as shown in eq 3, Lewis acid, such as
aDetermined by 1H NMR. bIsolated yield. Isolated yield based on conversion is
reported in parentheses.
indium triflate In(OTf)3, was added without isolation of the cyclic
¢-keto ester 5a.9 As a result, the ethoxycarbonyl group was
Chem. Lett. 2010, 39, 894-895
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

895
Table 2. Reactions between diethyl 2-methylmalonate (4a) and
several alkynes 2a
nium intermediate; (3-a) intramolecular nucleophilic addition to
give cyclic intermediate A.12 Another possible route for the
formation of cyclic intermediate A is path B: (1-b) formation of a
rhenacyclopentene intermediate by oxidative cycloaddition be-
tween a 1,3-diester, an alkyne, and a rhenium catalyst; (2-b)
insertion of second alkyne into the rhenium-carbon bond of the
formed rhenacyclopentene intermediate. After the formation of
cyclic intermediate A, (4) a salicylate is produced by the elimi-
nation of an alcohol when R2 = H. In the case of R2 = Me, (5) a
cyclic ¢-keto ester is generated via the elimination of an alcohol.
In summary, we have succeeded in the regioselective synthesis
of salicylates from 1,3-diesters without a substituent at the active
methylene moiety and terminal alkynes using a rhenium catalyst,
Re2(CO)10. On the other hand, using 1,3-diesters bearing a
substituent at the active methylene moiety, phenol derivatives
were obtained. In these reactions, two substituents from terminal
alkynes are introduced at the para-positions.13 We hope that these
reactions will become a useful method to regioselectively
synthesize phenol derivatives.
OH
1) Re2(CO)10 (2.5 mol%)
toluene, 135 °C, 24 h
O
O
R
+
R
EtO
OEt
2) In(OTf)3 (3.0 mol%)
150 °C, 24 h
R
4a
2
6
Entry
R
Conversion/%b
Yield/%c
1
2
3
4
4-MeOC6H4 2b
4-MeC6H4 2c
4-CF3C6H4 2d
4-BrC6H4 2e
68
82
86
58
6b
6c
6d
6e
47 (69)
54 (66)
47 (55)
12 (21)
a2 (2.5 equiv). bDetermined by 1H NMR. cIsolated yield. Isolated yield based on
conversion is reported in parentheses.
Path A
OH
O
OH
O
O
O
R3
R3
R1O
(2-a) Re
R3
OR1
R1O
OR1
R2
R3
R2
R3
R1O
OR1
(1-a)
Re
R2
alkenylrhenium
intermediate
(3-a)
− Re
References and Notes
1
a) D. B. Grotjahn, in Comprehensive Organometallic Chemistry II,
ed. by L. S. Hegedus, E. W. Abel, F. G. A. Stone, G. Wilkinson,
Pergamon, Oxford, 1995, Vol. 12, pp. 741-770. b) H.
Bonnemann, W. Brijoux, in Transition Metals for Organic
Synthesis, ed. by M. Beller, C. Bolm, Wiley-VCH, Weinheim,
2004, Vol. 1, pp. 171-197.
Y. Kuninobu, M. Nishi, S. Yudha S., K. Takai, Org. Lett. 2008, 10,
3009.
H. Tsuji, K.-i. Yamagata, T. Fujimoto, E. Nakamura, J. Am. Chem.
Soc. 2008, 130, 7792.
Investigation of several catalysts: ReBr(CO)5, 4%. No reaction:
[ReBr(CO)3(thf)]2, Mn2(CO)10, MnBr(CO)5, Cr(CO)6, Mo(CO)6,
Fe2(CO)9, Fe3(CO)12, Ru3(CO)12, Ir4(CO)12, Rh4(CO)12, Co2-
(CO)8.
a) Y. Kuninobu, A. Kawata, K. Takai, J. Am. Chem. Soc. 2006,
128, 11368. b) Y. Kuninobu, A. Kawata, M. Nishi, H. Takata, K.
Takai, Chem. Commun. 2008, 6360.
When the reaction was carried out at 180 °C, only 3a was formed
in 63% yield.
Investigation of several catalysts: ReBr(CO)5, 17%; [ReBr-
(CO)3(thf)]2, 22%. No reaction: Mn2(CO)10, MnBr(CO)5,
Cr(CO)6, Mo(CO)6, W(CO)6, Fe2(CO)9, Fe3(CO)12, Ru3(CO)12,
Ir4(CO)12, Rh4(CO)12, Co2(CO)8.
HO OR1
Path B
(2-b)
HO OR1
O
O
R3
R2
R3
R3
CO2R1
R2
R3
CO2R1
R3
Re
R1O
OR1
OH
(1-b)
− Re
2 = Me
R2
A
2 = H
− R1
rhenacyclopentene
intermediate
R
R
− R1
OH
(4)
OH
2
3
4
(5)
O
O
OH O
R3
R3
R3
In(OTf)3
OR1
OR1
R3
R3
R3
Scheme 1. Proposed mechanism for the formation of phenol
derivatives 3 and 6.
5
eliminated from 5a, and phenol derivative 6a was obtained in 73%
yield (79% conversion) (eq 4).10,11
6
7
OH
1) Re2(CO)10 (2.5 mol%)
toluene, 135 °C, 24 h
O
O
Ph
ð4Þ
+
Ph
EtO
OEt
2) In(OTf)3 (3.0 mol%)
Ph
4a
2a (2.5 equiv)
150 °C, 24 h
6a 73%
8
9
Investigation of several solvents: neat 3a 32%, 4a 8%;
CH2ClCH2Cl 3a 39%, 4a 10%; THF 3a 19%, 4a trace; CH3CN
3a 0%, 4a 0%; N,N-dimethylformamide (DMF) 3a 0%, 4a 0%.
Investigation of several catalysts: Fe(OTf)3, 6a 66%; In(OTf)3, 6a
78%; Cu(OTf)2, 6a 71%; AgOTf, 6a 58%.
Next, several terminal alkynes were investigated (Table 2).
Terminal alkynes with an electron-donating group, 2b and 2c,
provided phenol derivatives 6b and 6c in 69% and 66% yields,
respectively (Entries 1 and 2), whereas the yield of phenol
derivative was slightly decreased when terminal alkyne bearing an
electron-withdrawing group, 2d, was employed (Entry 3). The
corresponding phenol derivative 6e was generated in low yield
using 4-bromophenylacetylene (2e) (Entry 4). The corresponding
phenol derivatives were not formed using o-tolylacetylene (2f) and
diphenylacetylene, and 1-dodecyne (2g) gave a complex mixture.
When salicylates 3 and phenol derivatives 6 are formed,
intermediate A is a key intermediate. There are two possible
pathways to produce intermediate A (Scheme 1). In path A, the
sequence is as follows: (1-a) formation of an alkenylrhenium
intermediate by nucleophilic addition of a 1,3-diester to an alkyne,
which is activated by a rhenium catalyst; (2-a) insertion of second
alkyne into the rhenium-carbon bond of the formed alkenylrhe-
10 Phenol derivative 6a was obtained in 92% yield by the treatment
with 3.0 mol % of In(OTf)3 after the isolation of the cyclic ¢-keto
ester 5a.
11 When ¢-keto ester 5a was treated at 150 °C for 24 h with
powdered NaOH instead of In(OTf)3, decarboxylation of the ¢-
keto ester proceeded to give 6a in 41% yield (cf. In(OTf)3, 58%).
In contrast, the decarboxylation did not occur with NaI.
12 Very recently, Nakamura’s group reported theoretical calculations
on the regioselective formation of benzoates from ¢-keto esters
and two equivalents of terminal alkynes. The results suggest that
the reactions proceed via a similar route as shown in Scheme 1,
Path A. See: N. Yoshikai, S. Zhang, K.-i. Yamagata, H. Tsuji, E.
Nakamura, J. Am. Chem. Soc. 2009, 131, 4099.
13 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2010, 39, 894-895
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/