Rhodium-catalyzed complete regioselective lntermolecular cross-cyclotrimerization of aryl ethynyl ethers and nitriles or isocyanates at room temperature

Article abstract of DOI:10.1021/ol100182u

Chemical Equation Presented We have established that a catlonic rhodium(I)/H₈- BINAP complex catalyzes the complete regioselective intermolecular cross-cyclotrimerizatlon of aryl ethynyl ethers and nitriles or isocyanates leading to 2,4-diaryloxypyrldines or 4,6-diaryloxy-2-pyridones at room temperature.

Full text of DOI:10.1021/ol100182u

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1312-1315
Rhodium-Catalyzed Complete
Regioselective Intermolecular
Cross-Cyclotrimerization of Aryl Ethynyl
Ethers and Nitriles or Isocyanates at
Room Temperature
Yoshiyuki Komine and Ken Tanaka*
Department of Applied Chemistry, Graduate School of Engineering, Tokyo UniVersity
of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
tanaka-k@cc.tuat.ac.jp
Received January 25, 2010
ABSTRACT
We have established that a cationic rhodium(I)/H8-BINAP complex catalyzes the complete regioselective intermolecular cross-cyclotrimerization
of aryl ethynyl ethers and nitriles or isocyanates leading to 2,4-diaryloxypyridines or 4,6-diaryloxy-2-pyridones at room temperature.
The transition-metal-catalyzed chemo- and regioselective
intermolecular cross-cyclotrimerization has received much
attention as a useful method for the synthesis of substituted
arenes because of its high atom economy and convergent
nature.1 Although the intermolecular cross-cyclotrimerization
involving alkynyl ethers is potentially attractive for the
synthesis of aryl ethers, existing examples are quite lim-
ited.2-6 For the reaction using a stoichiometric amount of a
transition metal, Sato and co-workers reported the titanium-
mediated regioselective cross-cyclotrimerization of cyclo-
hexyl trimethylsilylethynyl ether and ethynyl tolyl sulfone.2
For transition-metal-catalyzed reactions,3-5 Saegusa and co-
workers reported the nickel-catalyzed regioselective cross-
cyclotrimerization of ethyl ethynyl ether and carbon dioxide.3
Recently, Rovis and co-workers reported the neutral rhod-
ium(I)/phosphoramidite complex-catalyzed regioselective
cross-cyclotrimerization of terminal alkynes and isocyanates
at elevated temperature (110 °C) that includes a single
example using ethyl ethynyl ether as a terminal alkyne (38%
isolated yield).4 However, the corresponding reaction using
nitriles has not been reported. In this paper, we disclose the
cationic rhodium(I)/H8-BINAP complex-catalyzed complete
regioselective intermolecular cross-cyclotrimerization of aryl
ethynyl ethers and nitriles as well as isocyanates at room
temperature.
(1) For a recent review, see: Galan, B. R.; Rovis, T. Angew. Chem.,
Int. Ed. 2009, 48, 2830.
(2) (a) Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2001, 123,
7925. The zirconium-mediated cross-cyclotrimerization of ethyl ethynyl
ether and 3-hexyne was also reported as a patent; see: (b) Takahashi, T. JP
11263737, 1999; Chem. Abstr. 1999, 131, 228541
(3) Tsuda, T.; Kunisada, K.; Nagahama, N.; Morikawa, S.; Saegusa, T.
Synth. Commun. 1989, 19, 1575
(4) Oberg, K. M.; Lee, E. E.; Rovis, T. Tetrahedron 2009, 65, 5056
.
.
.
(5) Very recently, the nickel-catalyzed [3 + 2 + 2] cycloaddition of
ethyl cyclopropylideneacetate and alkynyl ethers was reported; see: Ya-
masaki, R.; Terashima, N.; Sotome, I.; Komagawa, S.; Saito, S. J. Org.
(6) The homo-cyclotrimerization of di-tert-butoxyacetylene was reported;
see: Semmelhack, M. F.; Park, J. Organometallics 1986, 5, 2550.
Chem. 2010, 75, 480
.
10.1021/ol100182u  2010 American Chemical Society
Published on Web 02/25/2010

Scheme 1
Scheme 3
We recently reported that a cationic rhodium(I)/H8-BINAP
complex is able to catalyze the partially intramolecular
cyclotrimerization of phenol-linked 1,6-diynes and alkynes
or nitriles leading to substituted dibenzofurans or azadiben-
zofurans.7 During the study, we were aware that aryl ethynyl
ethers are stable compounds and can be readily handled
without any special precautions. This feature is contrary to
that of alkyl ethynyl ethers. These backgrounds prompted
us to investigate the cationic rhodium(I)/bisphosphine complex-
catalyzed intermolecular cyclotrimerization using aryl ethynyl
ethers. Aryl ethynyl ethers 3a-e were readily prepared by a
two-step operation starting from commercially available
naphthols 1a,b or phenols 1c-e via aryl dichloroethenyl
ethers 2a-e following our previous synthesis of phenol-
linked 1,6-diynes (Scheme 1).7 These alkynes 3a-e could
be purified by a silica gel column chromatography without
decomposition.
The use of aryl ethynyl ether 3a as a terminal alkyne in a
cross-cyclotrimerization with 4 was examined using the
cationic rhodium(I)/H8-BINAP catalyst. Contrary to our
expectation, a homocyclotrimerization of 3a proceeded
predominantly and a large amount of 4 was recovered.
Furthermore, the unexpected diethyl 3,5-diaryloxyphthalate
5, not the expected diethyl 3,6-diaryloxyphthalate, was
obtained in 14% yield as a major regioisomer (Scheme 3).9
We anticipated that the selective formation of intermediate
B by oxidative coupling of two aryl ethynyl ethers 3a with
rhodium might account for the observed selective formation
of 5 and the rapid homocyclotrimerization of 3a rather than
that of 4 (Scheme 3). Alternatively, the selective formation
of intermediate C by oxidative coupling of 3a and 4 with
rhodium might also account for the observed selectivity
(Scheme 3).
Scheme 2
Scheme 4
Our research group previously reported that the cationic
rhodium(I)/H8-BINAP complex catalyzes the intermolecular
cross-cyclotrimerization of terminal alkynes and diethyl
acetylenedicarboxylate (4) to yield 3,6-disubstituted phtha-
lates in high yields with excellent regioselectivities as shown
in Scheme 2.8 A possible mechanism of this reaction is also
shown in Scheme 2. Regioselective oxidative coupling of
the terminal alkyne and 4 with rhodium leads to rhodacy-
clopentadiene intermediate A. Regioselective insertion of the
terminal alkyne between the sterically less demanding
rhodium-carbon bond followed by reductive elimination
furnishes the 3,6-disubstituted phthalate.8
Based on the above mechanistic consideration, the regi-
oselective intermolecular cross-cyclotrimerization of aryl
ethynyl ethers and nitrogen-containing unsaturated com-
(9) Other regioisomers were generated in <5% yields. A cross-
cyclotrimerization product of one molecule of 3a and two molecules of 4
was not detected at all.
(10) Deiters and co-workers successfully overcame the regioselectivity
problem in the cobalt-catalyzed intermolecular cross-cyclotrimerization of
terminal alkynes and nitriles by employing the solid-supported reaction
system; see: Senaiar, R. S.; Young, D. D.; Deiters, A. Chem. Commun.
2006, 1313.
(11) The cobalt-catalyzed regioselective cross-cyclotrimerization of tert-
butylacetylene and trimethylacetonitrile leading to 2,4,6-tri-tert-butylpyridine
was reported; see: Heller, B.; Sundermann, B.; Buschmann, H.; Drexler,
H.-J.; You, J.; Holzgrabe, U.; Heller, E.; Oehme, G. J. Org. Chem. 2002,
67, 4414.
(7) Komine, Y.; Kamisawa, A.; Tanaka, K. Org. Lett. 2009, 11, 2361.
(8) (a) Tanaka, K.; Shirasaka, K. Org. Lett. 2003, 5, 4697. (b) Tanaka,
K.; Toyoda, K.; Wada, A.; Shirasaka, K.; Hirano, M. Chem.sEur. J. 2005,
11, 1145.
Org. Lett., Vol. 12, No. 6, 2010
1313

Table 1. Effect of Ligands for Rh-Catalyzed Intermolecular
Cross-Cyclotrimerization of Aryl Ethynyl Ether 3a and Nitrile
6aa
Figure 1. Structures of biarylbisphosphine ligands.
dicarboxylate (4) with rhodium followed by regioselective
insertion of 3 would also furnish intermediate C or D,
respectively (Scheme 4).
Thus, we investigated an intermolecular cross-cyclotrim-
erization of aryl ethynyl ether 3a and ethyl cyanoacetate (6a)
in the presence of the cationic rhodium(I)/H8-BINAP cata-
lyst.14 Pleasingly, the expected cross-cyclotrimerization
entry
ligand
catalyst (equiv)
yieldb (%)
1
2
3
H8-BINAP
Segphos
BINAP
BIPHEP
H8-BINAP
0.05
0.05
0.05
0.05
0.025
75
53
39
39
64d
4
5c
a [Rh(cod)2]BF4 (0.010 mmol), ligand (0.010 mmol), 3a (0.20 mmol),
6a (0.10 mmol), and CH2Cl2 (2.0 mL) were used. b Determined by 1H NMR
using 1,4-dimethoxybenzene as an internal standard. c 3a (0.40 mmol) and
6a (0.20 mmol) were used. d Isolated yield.
Table 2. Rh-Catalyzed Intermolecular Cross-Cyclotrimerizations
of Aryl Ethynyl Ethers 3a-e and Nitriles 6a-fa
pounds, nitriles and isocyanates, were investigated. In
general, the regioselective intermolecular cross-cyclotri-
merization of terminal alkynes and nitriles10-14 or isocyan-
ates4,15 is difficult to proceed presumably due to the lack of
regioselectivity in the oxidative coupling and/or insertion
step.16 On the other hand, as shown in Scheme 4, if nitrile
6 is able to react with intermediate B, insertion of the cyano
group between the sterically less demanding rhodium-carbon
bond might regioselectively furnish intermediate C through
the formation of the bond between the nitrogen atom and
the cationic rhodium. Reductive elimination would furnish
2,4-diaryloxypyridine 7 and regenerate the rhodium catalyst.
The reaction using isocyanate 8 would furnish 4,6-diaryloxy-
2-pyridone 9 through the regioselective formation of inter-
mediate D. Alternatively, the selective formation of inter-
mediate E or F by oxidative coupling of aryl ethynyl ether
3 and nitrile 6 or isocyanate 8 instead of diethyl acetylene-
(12) The ruthenium-catalyzed regioselective cross-cyclotrimerization of
methyl propiolate and electron-deficient nitriles leading to 2,3,6-trisubstituted
pyridines was reported; see: (a) Varela, J. A.; Carlos, L.; Saa´, C. J. Org.
Chem. 2003, 68, 8595. (b) Yamamoto, Y.; Kinpara, K.; Saigoku, T.;
Takagishi, H.; Okuda, S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005,
127, 605.
(13) For the regioselective cross-cyclotrimerization of terminal alkynes
and nitriles using a stoichiometric amount of a transition metal, see: (a)
Suzuki, D.; Nobe, Y.; Watai, Y.; Tanaka, R.; Takayama, Y.; Sato, F.; Urabe,
H. J. Am. Chem. Soc. 2005, 127, 7474. (b) Takahashi, T.; Tsai, F.-Y.; Li,
Y.; Wang, H.; Kondo, Y.; Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am.
Chem. Soc. 2002, 124, 5059.
(14) For the rhodium-catalyzed intermolecular cross-cyclotrimerization
of a terminal alkyne and an activated nitrile leading to two regioisomeric
pyridines, see: Tanaka, K.; Suzuki, N.; Nishida, G. Eur. J. Org. Chem.
2006, 3917.
(15) Our research group reported the rhodium-catalyzed intermolecular
cross-cyclotrimerization of terminal alkynes and isocyanates, but the
regioselectivities vary depending on the alkynes used; see: Tanaka, K.;
Wada, A.; Noguchi, K. Org. Lett. 2005, 7, 4737.
(16) For recent reviews of the transition-metal-catalyzed cyclotrimer-
ization for the synthesis of nitrogen heterocycles, see: (a) Varela, J. A.;
Saa´, C. Synlett 2008, 2571. (b) Heller, B.; Hapke, M. Chem. Soc. ReV. 2007,
36, 1085. (c) Yamamoto, Y. Chim. Oggi 2007, 25, 108. (d) Chopade, P. R.;
Louie, J. AdV. Synth. Catal. 2006, 348, 2307. (e) Nakamura, I.; Yamamoto,
Y. Chem. ReV. 2004, 104, 2127. (f) Varela, J. A.; Saa´, C. Chem. ReV. 2003,
103, 3787.
a Reactions were conducted using [Rh(cod)2]BF4 (0.010 mmol),
H8-BINAP (0.010 mmol), 3a-e (0.40 mmol), 6a-f (0.20-4.0 mmol),
and CH2Cl2 (2.0 mL) at rt for 1 h. b Isolated yield.
1314
Org. Lett., Vol. 12, No. 6, 2010

proceeded at room temperature for 1 h to yield 2,4-
diaryloxypyridine 7aa as a single regioisomer in good yield
(Table 1, entry 1).17 The effect of biarylbisphosphine ligands
(Figure 1) was then examined, which revealed that the use
of electron-rich ligands (entries 1 and 2) furnished 7aa in
higher yields than that of electron-deficient ligands (entries
3 and 4). The catalyst loading could be reduced to 0.025
equiv when H8-BINAP was used as a ligand (entry 5).
Table 3. Rh-Catalyzed Intermolecular Cross-Cyclotrimerizations
of Aryl Ethynyl Ethers 3a-e and Isocyanates 8a,ba
The scope of the 2,4-diaryloxypyridine synthesis was then
examined under the above optimal reaction conditions (Table
2).17 Not only ethyl cyanoacetate (6a) but also a series of
activated nitriles 6b-d could react with 3a to give the
corresponding diaryloxypyridines in moderate to good yields
with perfect regioselectivity without using excess nitriles (0.5
equiv, entries 1-4). Consistent with the mechanism shown
in Scheme 4, increasing the amount of 6a to 1 equiv, which
would suppress the competitive homocyclotrimerization of
3a, improved the yield of pyridine 7aa (entry 5).18 Not only
activated nitriles 6a-d but also benzonitrile (6e) and
acetonitrile (6f) could participate in this reaction, although
excess nitriles were used (entries 6 and 7). With respect to
aryl ethynyl ethers, sterically and electronically diverse
alkynes could equally react with activated nitriles 6a,b in
good yields with perfect regioselectivity (entries 8-15).
Regioselective intermolecular cross-cyclotrimerizations of
aryl ethynyl ethers and isocyanates were also investigated
using the cationic rhodium(I)/H8-BINAP catalyst (Table
3).15,17 Pleasingly, n-butyl isocyanate (8a) reacted with aryl
ethynyl ether 3a at room temperature for 1 h to yield the
corresponding 4,6-diaryloxy-2-pyridone 9aa with perfect
regioselectivity, although the product yield was moderate
(entry 1). Increasing the amount of 8a to 2 equiv improved
the yield of 2-pyridone 9aa (entry 2).18 Not only n-butyl
isocyanate (8a) but also benzyl isocyanate (8b, entry 3) could
react with 3a to yield the corresponding pyridone with perfect
regioselectivity, albeit in lower yield. With respect to aryl
ethynyl ethers, sterically and electronically diverse alkynes
3b-e could participate in this reaction, although the product
yields were lower than that using 3a (entries 4-7).
a Reactions were conducted using [Rh(cod)2]BF4 (0.010 mmol),
H8-BINAP (0.010 mmol), 3a-e (0.40 mmol), 8a,b (0.40-0.80 mmol),
and CH2Cl2 (2.0 mL) at rt for 1 h. b Isolated yield.
Future studies will focus on the utilization of aryl ethynyl
ethers in various transition-metal-catalyzed reactions.
In conclusion, we have established that a cationic rhod-
ium(I)/H8-BINAP complex catalyzes the complete regiose-
lective intermolecular cross-cyclotrimerization of aryl ethynyl
ethers and nitriles or isocyanates leading to 2,4-diaryloxy-
pyridines or 4,6-diaryloxy-2-pyridones at room temperature.
Acknowledgment. This work was supported partly by a
Grant-in-Aid for Scientific Research (No. 20675002) from
MEXT, Japan. We are grateful to Takasago International
Corporation for the gift of H8-BINAP and Segphos and
Umicore for generous support in supplying a rhodium
complex.
(17) Homo-cyclotrimerization products of 3a-e were generated as
byproducts in the reactions of Tables 1-3.
(18) Although the slow addition of aryl ethynyl ether 3a to nitrile 6a or
isocyanate 8a and the Rh catalyst over 30 min was also examined, the
yields of the corresponding pyridine 7aa and 2-pyridone 9aa were not
increased.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL100182U
Org. Lett., Vol. 12, No. 6, 2010
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