Synthesis of tetrasubstituted benzenes via rhodium(i)-catalysed ring-opening benzannulation of cyclobutenols with alkynes

Article abstract of DOI:10.1039/c3ob40436f

A formal [4 + 2] annulation occurs between 1,3-disubstituted cyclobutenols and internal alkynes in the presence of rhodium(i) catalysts to afford 1,2,3,5-tetrasubstituted benzenes. These benzannulation products are generated through dehydration of the initially formed cyclohexadienols. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob40436f

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Synthesis of tetrasubstituted benzenes via rhodium(I)-
catalysed ring-opening benzannulation of
cyclobutenols with alkynes†‡
Cite this: Org. Biomol. Chem., 2013, 11,
3424
Received 1st March 2013,
Accepted 18th March 2013
Takanori Matsuda* and Norio Miura
DOI: 10.1039/c3ob40436f
www.rsc.org/obc
A formal [4 + 2] annulation occurs between 1,3-disubstituted
cyclobutenols and internal alkynes in the presence of rhodium(I)
catalysts to afford 1,2,3,5-tetrasubstituted benzenes. These benz-
annulation products are generated through dehydration of the
initially formed cyclohexadienols.
Table 1 Rhodium(I)-catalysed reaction between cyclobutenol 1a and diphenyl-
acetylene (2a)
Polysubstituted benzenes are extremely useful compounds in
many fields of organic chemistry, such as natural product syn-
thesis and materials science. Given their importance, a myriad
of methods have been developed for their synthesis. While
cycloaddition strategies effect the construction of densely sub-
stituted arenes and have proven to be beneficial,1 considerable
room for improvement remains. In particular, there is a need
to develop more effective methods for preparing polysubsti-
tuted benzenes with specific substitution patterns.
Entry
Ligand (mol%)
Conditions
Yielda (%)
Ring opening and expansion reactions of small-ring com-
pounds have been broadly employed in organic synthesis in
order to construct functionalised molecules in an expedient
manner. In recent years, significant progress has been made
in the rhodium(I)-catalysed coupling and reorganisation reac-
tions of cyclobutanols/cyclobutanones,2 which proceed via
ring opening of rhodium(I) cyclobutanolates by β-carbon elim-
ination.3 Considering these ring opening reactions of rhodium(I)
cyclobutanolates, we became interested in the ring opening of
rhodium(I) cyclobutenolates. Herein we report a rhodium(I)-
catalysed ring-opening benzannulation of cyclobutenols with
alkynes that affords tetrasubstituted benzenes after dehy-
dration of the initial annulation products.
1
2
3
4
None
rac-BINAP (6)
PPh3 (12)
Toluene, 110 °C, 2 h
Toluene, 110 °C, 4 h
Toluene, 110 °C, 2 h
1,4-Dioxane, 100 °C, 5.5 h
87
92
51
24b
rac-BINAP (6)
a Isolated yield. b Accompanied by 64% yield of enone 4a.
(2.5 mol%) in toluene at 110 °C for 2 h, 1-butyl-2,3,5-triphenyl-
benzene (3a, C28H26) was obtained, which was produced by
dehydration of a putative initial annulation product (C28H28O)
in 87% yield (entry 1).5–7 The reaction employing rac-BINAP4
as the ligands gave similar results (entry 2), whereas the use of
PPh3 led to a decrease in yield (entry 3). The choice of solvent
was found to be crucial. When the reaction was performed in
1,4-dioxane instead of toluene, the formation of ring-opened
enone 4a predominated over that of benzannulation product
3a (entry 4). The ring opening of 1a was previously reported to
occur thermally (benzene, 80 °C, 12 h) to exclusively afford
enone 5a in 96% yield.8 Thus, the thermal ring opening of
cyclobutenols 1 is potentially competitive with the benzannula-
tion to form 3. Isomerisation of 5a to 4a might have occurred
under the reaction conditions or during isolation.
We began our investigation by exploring the rhodium(I)-cata-
lysed reaction between 1-butyl-3-phenylcyclobut-2-enol (1a)
and diphenylacetylene (2a) (Table 1). When 1a and 2a (1.2
4
equiv. to 1a) were heated in the presence of [Rh(OH)(cod)]2
Department of Applied Chemistry, Tokyo University of Science, 1–3 Kagurazaka,
Shinjuku-ku, Tokyo 162-8601, Japan. E-mail: mtd@rs.tus.ac.jp;
Fax: +81 3 5261 4631
†This paper is dedicated to Professor Teruaki Mukaiyama in celebration of the
40th anniversary of the Mukaiyama aldol reaction.
A plausible mechanism for the formation of 3a from 1a
and 2a is proposed in Scheme 1. Initially, rhodium(I)
‡Electronic supplementary information (ESI) available: Experimental procedures
and characterisation data for new compounds. See DOI: 10.1039/c3ob40436f
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Table 2 Synthesis of 1,2,3,5-tetrasubstituted benzenes via rhodium(I)-catalysed
ring-opening benzannulation of cyclobutenols
1
with symmetrical internal
alkynes 2
Time
Yieldb
(%)
Entry
1
1
2
Methoda (h)
3
Scheme 1 Proposed mechanism for rhodium(I)-catalysed benzannulation.
1b 2a
A
A
A
2.5
93
80
68
cyclobutenolate A, which is generated from 1a and rhodium(I)
hydroxide, undergoes ring opening by β-carbon elimination
with selective cleavage of the C(sp2)–C(sp3) bond.9,10 The
resulting alkenylrhodium(I) species B adds across 2a to give
the dienylrhodium(I) species C,11 which then undergoes intra-
molecular nucleophilic addition to the carbonyl group.12 Upon
protonolysis, the resulting rhodium(I) cyclohexadienolate D
yields cyclohexadienol E, and rhodium(I) hydroxide is con-
sequently regenerated. Cyclohexadienol E thus formed is
dehydrated to furnish 1,2,3,5-tetrasubstituted benzene 3a.13
Several combinations of cyclobutenols 1 and alkynes 2 were
next subjected to the optimal reaction conditions. Table 2
summarises the results obtained with symmetrical internal
alkynes. In cases producing tetraarylbenzenes, dehydration of
the corresponding cyclohexadienols was sluggish under the
reaction conditions. Heating the crude reaction mixture with
silica gel after annulation facilitated dehydration to provide
symmetrical 1,2,3,5-tetraphenylbenzene (3b) in excellent yield
(entry 1). Analogously, 1-(p-tolyl)- and 1-(2-thienyl)-substituted
cyclobutenols (1c and 1d) were converted to the corresponding
arenes (3c and 3d) after treatment with silica gel (entries 2 and
3). Cyclobutenol 1e, having an alkyl substituent at the 3-pos-
ition, exclusively afforded the ring-opened enone; no benz-
annulation with 2a was observed (entry 4). Cyclobutenol 1a
reacted with diphenylacetylenes 2b and 2c possessing electron-
donating substituents at the 4-positions to afford the corre-
sponding tetrasubstituted benzenes 3f and 3g, respectively
(entries 5 and 6). 1,2-Bis[4-(trifluoromethyl)phenyl]ethyne (2d)
failed to react with 1a under the conditions employing rac-
BINAP, whereas the reaction catalyzed by [Rh(OH)(cod)]2 alone
resulted in a clean conversion to the desired product 3h (entry 7).
Aliphatic alkyne 2e (R3 = Pr) could also be used in the benz-
annulation with 1a and 1b (entries 8–10); method A worked
well for the synthesis of 3i (entry 9).
2
3
1c
2a
2
1d 2a
1.5
4
1e
2a
A
24
0
5
6
7
1a
1a
1a
2b
2c
2d
B
B
A
4
2.5
2
3f (Ar = 4-MeC6H4)
75
3g (Ar = 4-MeOC6H4) 95
3h (Ar = 4-CF3C6H4)
93
57
8
1a
2e
B
4
9
1a
2e
A
B
2
1
3i
90
36
10
1b 2e
a Method A: 2.5 mol% [Rh(OH)(cod)]2, toluene, 110 °C. The reaction
mixture was further heated for 1 h after the addition of silica gel;
Method B: 2.5 mol% [Rh(OH)(cod)]2, 6 mol% rac-BINAP, toluene,
110 °C. b Isolated yield.
The benzannulation was then examined with unsymmetri-
cal alkynes (Table 3).14 The reaction of 1a with 1-(trimethyl-
silyl)-1-propyne (2f) by method B delivered 1,2,3,5-tetrasubstituted
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Table 3 Rhodium(I)-catalysed [4 + 2] benzannulation with unsymmetrical internal alkynes
Entry
1
1 (R1)
2 (R2, R3)
Methoda
B
3 (Ratiob)
Yieldc (%)
50
1a (Bu)
2f (SiMe3, Me)
2
3
1a
2f
2f
A
B
3k (90 : 10)
93
64
1b (Ph)
4
5
1b
1a
2f
A
A
3l (92 : 8)
87
78
2g (Isopropenyl, Et)
6
1a
2h (Ph, Me)
A
39d
a Method A: 2.5 mol% [Rh(OH)(cod)]2, toluene, 110 °C, 1–2.5 h. The reaction mixture was further heated for 1–3 h after the addition of silica gel;
Method B: 2.5 mol% [Rh(OH)(cod)]2, 6 mol% rac-BINAP, toluene, 110 °C, 3–3.5 h. b Ratio of regioisomers determined by 1H NMR. c Isolated yield.
d Accompanied by 44% yield of enone 4a.
benzene 3k having four different substituents as a single alkynes, good regioselectivity was observed, thereby allowing
isomer in 50% yield (entry 1). The regiochemistry of product access to tetrasubstituted benzenes with four different
3k was determined by NOESY experiments.15 In contrast, the substituents.
use of method A allowed obtaining 3k in high yield, albeit with
diminished regioselectivity (entry 2). 1,3-Diphenylcyclobutenol
(1b) also reacted with 2f and provided 3l; method A gave better
yield than method B with comparable regioselectivity (entries 3
Acknowledgements
and 4). While the reaction of 1a with alkyne 2g gave arene 3m This work was supported by a Grant-in-Aid for Scientific
in good yield and regioselectivity (93 : 7) (entry 5), its reaction Research for Young Scientist (B) (No. 23750115) from the Min-
with 1-phenyl-1-propyne (2h) led to a low yield because of the istry of Education, Culture, Sports, Science and Technology,
competing ring opening of 1a, which extensively occurred with Japan.
this less reactive alkyne (entry 6). The product 3n was isolated
as a mixture of regioisomers in the ratio of 87 : 13.
In conclusion, 1,2,3,5-tetrasubstituted benzenes have been
synthesised by a formal [4 + 2] benzannulation between 1,3-
Notes and references
disubstituted cyclobutenols and internal alkynes using
rhodium(I) complexes as catalysts. The reaction proceeds via
successive ring opening of rhodium(I) cyclobutenolate, alkyne
insertion, carbonyl addition and protonation to afford cyclo-
hexadienols, which subsequently undergo dehydration during
the reaction or over silica gel to furnish the 1,2,3,5-tetrasubsti-
tuted benzenes. For the reactions with unsymmetrical internal
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3426 | Org. Biomol. Chem., 2013, 11, 3424–3427
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2 For rhodium(I)-catalysed ring-opening reactions of cyclobu-
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4 Abbreviations: COD = cycloocta-1,5-diene; BINAP = 2,2′-bis
(diphenylphosphino)-1,1′-binaphthyl.
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14 An attempted reaction with a terminal alkyne, phenyl-
acetylene, failed to occur.
6 For the synthesis of 1,2,3,5-tetrasubstituted benzenes by
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+
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