Rhodium-catalyzed one-pot intermolecular [2 + 2 + 2] trimerization/ asymmetric intramolecular [4 + 2] cycloaddition of two aryl ethynyl ethers and 5-alkynals

Article abstract of DOI:10.1021/ol3027158

It has been established that a cationic Rh(I)/(R)-H₈-BINAP complex catalyzes the one-pot intermolecular [2 + 2 + 2] trimerization/ asymmetric intramolecular [4 + 2] cycloaddition of two aryl ethynyl ethers and 5-alkynals to produce annulated 1,

Full text of DOI:10.1021/ol3027158

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rhodium-Catalyzed One-Pot
Intermolecular [2 þ 2 þ 2] Trimerization/
Asymmetric Intramolecular [4 þ 2]
Cycloaddition of Two Aryl Ethynyl Ethers
and 5‑Alkynals
Yuta Miyauchi,† Keiichi Noguchi,‡ and Ken Tanaka*,†,§
Department of Applied Chemistry, Graduate School of Engineering, and Instrumentation
Analysis Center, Tokyo University of Agriculture and Technology, Koganei, Tokyo
184-8588, Japan, and JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
tanaka-k@cc.tuat.ac.jp
Received October 1, 2012
ABSTRACT
It has been established that a cationic Rh(I)/(R)-H8-BINAP complex catalyzes the one-pot intermolecular [2 þ 2 þ 2] trimerization/asymmetric
intramolecular [4 þ 2] cycloaddition of two aryl ethynyl ethers and 5-alkynals to produce annulated 1,4-cyclohexadienes possessing two
stereogenic centers.
One-pot catalyses, which allow the preparation of com-
plex organic molecules from simple starting materials, are
highly attractive methods in modern organic synthesis.1 If
such one-pot reactions proceed by using a single catalyst, it
is obviously more advantageous than the use of binary
catalysts. Our research group has reported that cationic
Rh(I) complexes are highly effective catalysts for a wide
variety of [2 þ 2 þ 2] cycloaddition reactions2 via metalla-
cycle intermediates.3 As a recent example, we developed
the cationic Rh(I) complex-catalyzed chemo-, regio-, and
(3) For reviews of the Rh-catalyzed [2 þ 2 þ 2] cycloaddition, see: (a)
Shibata, Y.; Tanaka, K. Synthesis 2012, 44, 323. (b) Tanaka, K.
Heterocycles 2012, 85, 1017. (c) Tanaka, K. Synlett 2007, 1977. (d)
Fujiwara, M.; Ojima, I. In Modern Rhodium-Catalyzed Organic Reac-
tions; Evans, P. A., Eds.; Wiley-VCH: Weinheim, Germany, 2005; p 129.
(4) Miyauchi, Y.; Kobayashi, M.; Tanaka, K. Angew. Chem., Int. Ed.
2011, 50, 10922.
(5) For other examples of the Rh-catalyzed [2 þ 2 þ 2] cycloaddition
of alkynes with carbonyl compounds, see: (a) Bennacer, B.; Fujiwara,
M.; Lee, S.-Y.; Ojima, I. J. Am. Chem. Soc. 2005, 127, 17756. (b) Tanaka,
K.; Otake, Y.; Wada, A.; Noguchi, K.; Hirano, M. Org. Lett. 2007, 9,
2203. (c) Tsuchikama, K.; Yoshinami, Y.; Shibata, T. Synlett 2007, 1395.
(d) Tanaka, K.; Otake, Y.; Sagae, H.; Noguchi, K.; Hirano, M. Angew.
Chem., Int. Ed. 2008, 47, 1312. (e) Tanaka, K.; Tanaka, R.; Nishida, G.;
Hirano, M. Synlett 2008, 2017. (f) Otake, Y.; Tanaka, R.; Tanaka, K.
Eur. J. Org. Chem. 2009, 2737. (g) Suda, T.; Noguchi, K.; Tanaka, K.
Angew. Chem., Int. Ed. 2011, 50, 4475. For the Rh-catalyzed reductive
coupling of acetylene gas and aldehydes, see: (h) Kong, J. R.; Krische,
M. J. J. Am. Chem. Soc. 2006, 128, 16040.
† Department of Applied Chemistry.
‡ Instrumentation Analysis Center.
§ JST, ACT-C.
(1) For selected recent reviews, see: (a) Albrecht, Ł.; Jiang, H.;
ꢀ
Jorgensen, K. A. Angew. Chem., Int. Ed. 2011, 50, 8492. (b) Toure,
B. B.; Hall, D. G. Chem. Rev. 2009, 109, 443. (c) Nicolaou, K. C.; Chen,
J. S. Chem. Soc. Rev. 2009, 38, 2993. (d) Arns, S.; Barriault, L. Chem.
´
Commun. 2007, 2211. (e) Tejedor, D.; Garcıa-Tellado, F. Chem. Soc.
Rev. 2007, 36, 484. (f) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1.
(2) For selected recent reviews, see: (a) Weding, N.; Hapke, M.
ꢀ
Chem. Soc. Rev. 2011, 40, 4525. (b) Domınguez, G.; Perez-Castells, J.
´
Chem. Soc. Rev. 2011, 40, 3430. (c) Inglesby, P. A.; Evans, P. A. Chem.
Soc. Rev. 2010, 39, 2791. (d) Perreault, S.; Rovis, T. Chem. Soc. Rev.
2009, 38, 3149. (e) Galan, B. R.; Rovis, T. Angew. Chem., Int. Ed. 2009,
48, 2830. (f) Tanaka, K. Chem.;Asian J. 2009, 4, 508. (g) Varela, J. A.;
ꢀ
Saa, C. Synlett 2008, 2571. (h) Shibata, T.; Tsuchikama, K. Org. Biomol.
Chem. 2008, 1317. (i) Heller, B.; Hapke, M. Chem. Soc. Rev. 2007, 36,
1085.
r
10.1021/ol3027158
XXXX American Chemical Society

stereoselective intermolecular [2 þ 2 þ 2] trimerization of
two aryl ethynyl ethers with carbonyl compounds leading
to aryloxy-substituted dienyl esters.4ꢀ8 Based on this
result, we designed the following Rh(I) complex-catalyzed
one-pot reaction (Scheme 1).9 If the chiral cationic Rh(I)
complex-catalyzed intermolecular [2 þ 2 þ 2] trimerization
of two aryl ethynyl ethers 1 with the formyl group of
5-alkynal 2 rather than the alkyne moiety proceeds chemo-,
regio-, and stereoselectively, the corresponding dienyne 3
would be generated. Subsequently, if the same chiral
cationic Rh(I) complex is able to catalyze the asymmetric
intramolecular [4 þ 2] cycloaddition of the dienyne 3,10ꢀ12
the corresponding annulated 1,4-cyclohexadiene 4,
possessing two stereogenic centers, would be generated.
However, the transition-metal-catalyzed asymmetric in-
tramolecular [4 þ 2] cycloaddition of a dienyne, possessing
the trisubstituted diene moiety, has not been reported.13
Therefore, the reactivity and enantioselectivity of densely
functionalized dienynes in the latter asymmetric transfor-
mation is interesting. However, we were successful with the
above-mentioned asymmetric one-pot reaction by using a
cationic Rh(I)/(R)-H8-BINAP catalyst.
Scheme 1
(6) For examples of the [2 þ 2 þ 2] cycloaddition of alkynes with
carbonyl compounds catalyzed by other transition metals, see: (a)
Tsuda, T.; Kiyoi, T.; Miyane, T.; Saegusa, T. J. Am. Chem. Soc. 1988,
110, 8570. (b) Yamamoto, Y.; Takagishi, H.; Itoh, K. J. Am. Chem. Soc.
2002, 124, 6844. (c) Tekevac, T. N.; Louie, J. Org. Lett. 2005, 7, 4037. (d)
Tekevac, T. N.; Louie, J. J. Org. Chem. 2008, 73, 2641.
(7) For other examples of the Rh-catalyzed [2 þ 2 þ 2] cycloaddition
involving alkynyl ethers, see: (a) McDonald, F. E.; Zhu, H. Y. H.;
Holmquist, C. R. J. Am. Chem. Soc. 1995, 117, 6605. (b) Clayden, J.;
Moran, W. J. Org. Biomol. Chem. 2007, 5, 1028. (c) Alayrac, C.;
Schollmeyer, D.; Witulski, B. Chem. Commun. 2009, 1464. (d) Komine,
Y.; Kamisawa, A.; Tanaka, K. Org. Lett. 2009, 11, 2361. (e) Oberg,
K. M.; Lee, E. E.; Rovis, T. Tetrahedron 2009, 65, 5056. (f) Komine, Y.;
Tanaka, K. Org. Lett. 2010, 12, 1312. (g) Komine, Y.; Miyauchi, Y.;
Kobayashi, M.; Tanaka, K. Synlett 2010, 3092.
(8) For examples of the [2 þ 2 þ 2] cycloaddition involving alkynyl
ethers catalyzed by other transition metals, see: (a) Funk, R. L.;
Vollhardt, K. P. C. J. Am. Chem. Soc. 1979, 101, 215. (b) Funk, R. L.;
Vollhardt, K. P. C. J. Am. Chem. Soc. 1980, 102, 5253. (c) Hillard, R. L.,
III; Parnell, C. A.; Vollhardt, K. P. C. Tetrahedron 1983, 39, 905. (d)
Semmelhack, M. F.; Park, J. Organometallics 1986, 5, 2550. (e) Tsuda,
T.; Kunisada, K.; Nagahama, N.; Morikawa, S.; Saegusa, T. Synth.
Commun. 1989, 19, 1575.
Table 1. Optimization of Reaction Conditions for One-Pot
Transformation of 1a and 2a Leading to 4aaa
(9) For our previous reports of the cationic Rh(I) complex-catalyzed
one-pot reactions, see: (a) Okazaki, E.; Okamoto, R.; Shibata, Y.;
Noguchi, K.; Tanaka, K. Angew. Chem., Int. Ed. 2012, 51, 6722. (b)
Okamoto, R.; Okazaki, E.; Noguchi, K.; Tanaka, K. Org. Lett. 2011, 13,
4894. (c) Kobayashi, M.; Suda, T.; Noguchi, K.; Tanaka, K. Angew.
Chem., Int. Ed. 2011, 50, 1664. (d) Tanaka, K.; Okazaki, E.; Shibata, Y.
J. Am. Chem. Soc. 2009, 131, 10822.
(10) For examples of the transition-metal-catalyzed asymmetric in-
tramolecular [4 þ 2] cycloaddition of dienynes, see: Rh: (a) Shintani, R.;
Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem., Int. Ed. 2007, 46,
7277. (b) Aikawa, K.; Akutagawa, S.; Mikami, K. J. Am. Chem. Soc.
2006, 128, 12648. (c) Gilbertson, S. R.; Hoge, G. S.; Genov, D. G. J. Org.
Chem. 1998, 63, 10077. Ir: (d) Shibata, T.; Takasaku, K.; Takesue, Y.;
Hirata, N.; Takagi, K. Synlett 2002, 1681. The Rh-catalyzedasymmetric
intermolecular [4 þ 2] cycloaddition of 1,3-dienes with an electron-
deficient alkyne was also reported. See: (e) Shibata, T.; Fujiwara, D.;
Endo, K. Org. Biomol. Chem. 2008, 6, 464. See also ref 10a.
2a
3aa
4aa
entry
ligand
(equiv) conditions % yieldb % yield,b dr, % ee
1
2
3
4
5
6
(R)-H8-BINAP
(R)-H8-BINAP
(R)-BINAP
1
1
1
1
1
2
rt, 1 h
43
0
0
(11) For examples of the transition-metal-catalyzed nonasymmetric
intramolecular [4 þ 2] cycloaddition of dienynes, see: Rh: (a) Jolly, R. S.;
Leudtke, G.; Sheehan, D.; Livinghouse, T. J. Am. Chem. Soc. 1990, 112,
4965. (b) Gilbertson, S. R.; Hoge, G. S. Tetrahedron. Lett. 1998, 39,
2075. (c) Paik, S.-J.; Son, S. U.; Chung, Y. K. Org. Lett. 1999, 1, 2045. (d)
Wang, B.; Cao, P.; Zhang, X. Tetrahedron. Lett. 2000, 41, 8041. (e)
Motoda, D.; Kinoshita, H.; Shinokubo, H.; Oshima, K. Angew. Chem.,
Int. Ed. 2004, 43, 1860. (f) Yoo, W.-J.; Allen, A.; Villeneuve, K.; Tam, W.
Org. Lett. 2005, 7, 5853. (g) Lee, S. I.; Park, S. Y.; Park, J. H.; Jung, I. G.;
Choi, S. Y.; Chung, Y. K. J. Org. Chem. 2006, 71, 91. (h) Saito, A.; Ono,
T.; Hanzawa, Y. J. Org. Chem. 2006, 71, 6437. (i) Gomez, F. J.; Kamber,
N. E.; Deschamps, N. M.; Cole, A. P.; Wender, P. A.; Waymouth, R. M.
Organometallics 2007, 26, 4541. Ni: (j) Wender, P. A.; Jenkins, T. E.
J. Am. Chem. Soc. 1989, 111, 6432. (k) Wender, P. A.; Smith, T. E.
J. Org. Chem. 1996, 61, 824. Au: (l) Furstner, A.; Stimson, C. C. Angew.
Chem., Int. Ed. 2007, 46, 8845. (m) Kim, S. M.; Park, J. H.; Chung, Y. K.
Chem. Commun. 2011, 47, 6719. Pd: (n) Kumar, K.; Jolly, R. S.
80 °C, 24 h
80 °C, 24 h
80 °C, 24 h
80 °C, 24 h
80 °C, 24 h
46, >99:1, >99 (ꢀ)
38, >99:1, 97 (ꢀ)
<5
0
(R)-Segphos
0
(S)-xyl-H8-BINAP
(R)-H8-BINAP
0
48, >99:1, 98 (þ)
67, >99:1, >99 (ꢀ)
0
a [Rh(cod)2]BF4/ligand (0.010 mmol), 1a (0.10 mmol), 2a (0.10 mmol),
and (CH2Cl)2 (2.0 mL) were used. b Isolated yield from 1a.
We first investigated the reaction of ethynyl 2-naphthyl
ether (1a) and tosylamide-linked 5-alkynal 2a in the pre-
sence of a cationic Rh(I)/(R)-H8-BINAP complex at rt
(Table 1, entry 1). Although the desired intermolecular
€
Tetrahedron. Lett. 1998, 39, 3047. Fe: (o) Furstner, A.; Majima, K.;
Martin, R.; Krause, H.; Kattnig, E.; Goddard, R.; Lehmann, C. W.
J. Am. Chem. Soc. 2008, 130, 1992.
(12) For a review of the Rh-catalyzed [4 þ 2] carbocyclization, see:
Robinson, J. E. In Modern Rhodium-Catalyzed Organic Reactions;
Evans, P. A., Eds.; Wiley-VCH: Weinheim, Germany, 2005; p 241.
(13) Only one example of the transition-metal-catalyzed nonasym-
metric intramolecular [4 þ 2] cycloaddition of a dienyne, possessing the
trisubstituted diene moiety, has been reported by using a cationic Rh(I)/
N-heterocyclic carbene complex as a catalyst. See: Reference 11g.
B
Org. Lett., Vol. XX, No. XX, XXXX

[2 þ 2 þ 2] trimerization between two alkynes 1a and the
formyl group of 2a proceeded to give dienyne 3aa in
moderate yield14 with complete regio- and stereoselectiv-
ity, the subsequent asymmetric intramolecular [4 þ 2]
cycloaddition did not proceed. Pleasingly, when the same re-
action was carried out at 80 °C for 24 h, the expected [4 þ 2]
cycloaddition product 4aa was obtained in moderate yield
with complete diastereo- and enantioselectivity (entry 2).
Other biaryl bisphosphine ligands were also tested (entries
3ꢀ5), which were less effective than H8-BINAP. Finally,
increasing the amount of 2a further improved the product
yield (entry 6).
Table 2. Rh-Catalyzed Asymmetric One-Pot Reactions of
Alkynes 1 and Alkynals 2 Leading to Cyclohexadienes 4a
With the optimized reaction conditions in hand, the
scope of this asymmetric one-pot reaction was examined
(Table 2). Withrespect toaryl ethynyl ethers, electronically
and sterically different aryl ethynyl ethers 1aꢀd could be
employed (entries 1ꢀ4).15 With respect to 5-alkynals,
various tosylamide-linked 5-alkynals 2bꢀd could be em-
ployed (entries 5ꢀ7).16 Nosylamide- and oxygen-linked
5-alkynals 2e and 2f also reacted with 1a to give cyclohex-
adienes 4ae and 4af (entries 8 and 9). Importantly, all the
reactions proceeded with almost complete regio-, diastereo-,
and enantioselectivity. The relative and absolute configura-
tions of (ꢀ)-4ac were determined to be 5R,7aS by X-ray
crystallographic analysis.17
The reaction of 1a and 5-alkynone 2g was also examined
(Scheme 2). The expected dienyne 3ag, generated through
the trimerization step, possesses a tetrasubstituted diene
moiety; however, the transition-metal-catalyzed [4 þ 2]
cycloaddition of such a sterically demanding dienyne has
not been reported. Pleasingly, the desired one-pot reaction
proceeded to give the corresponding cyclohexadienes 4ag
and 4ag0 with high yields and ee values, although diaster-
eoselectivity was moderate.18
(14) In the reactions of Table 1, the homo-[2 þ 2 þ 2] cycloaddition of
1a leading to benzene 7 and the homodimerization of 2a leading to ester 8
were observed as side reactions. For the formation of 8, see: Tanaka, R.;
Noguchi, K.; Tanaka, K. J. Am. Chem. Soc. 2010, 132, 1238.
a Reactions were conducted using [Rh(cod)2]BF4/(R)-H8-BINAP
(0.020 mmol), 1 (0.20 mmol), and 2 (0.40 mmol) in (CH2Cl)2 (2.0 mL)
at 80 °C for 16 h. b Isolated yield from 1.
Transformations of the present asymmetric one-pot
reaction product 4aa were examined briefly (Scheme 3).
Aryl ester 4aa could be converted to the correspond-
ing methyl ester 5 by treatment with NaOMe in
MeOH. Oxidation of 4aa with m-CPBA afforded the
corresponding epoxide 6 with complete diastereo-
selectivity.
Scheme 4 depicts a plausible mechanism for this rho-
dium-catalyzed one-pot transformation. Two aryl ethynyl
ethers 1 react with rhodium to generate rhodacyclopenta-
diene A. Insertion of the formyl group of 5-alkynal 2 into A
generates rhodacycle B.19 Reductive elimination of rho-
dium affords pyrane C. Subsequent electrocyclic ring
opening affords dienyne 3, which reacts with rhodium
(15) Alkyl ethynyl ethers could not be employed in the presence of the
Lewis acidic cationic Rh(I) complex due to their instability.
(16) Although the reaction of 1a and a terminal 5-alkynal was
examined, the corresponding cyclohexadiene was generated in low yield
and could not be isolated in a pure form due to the formation of a
complex mixture of byproducts.
(17) See the Supporting Information.
(18) The opposite stereochemistry at the bridged carbon atoms of
(ꢀ)-4ag and (þ)-4ag0 was confirmed by treatment of these 1,4-cyclohex-
adienes with DBU leading to an enantiomeric pair of 1,3-cyclohexa-
dienes, (ꢀ)-9 and (þ)-9.
(19) For a discussion about the facile insertion of the carbonyl group
to the rhodacycle A, see: Reference 4.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2
Scheme 4
Scheme 3
Scheme 5
again to generate rhodacyclopentene D. Of the two possi-
ble intermediates D-1 and D-2, D-1 would be more favor-
able due to the absence of the steric interaction between the
equatorial phenyl group of (R)-H8-BINAP and the alkenyl
group (R0). This mechanism is consistent with the forma-
tion of (5R,7aS)-(ꢀ)-4ac. 1,3-Allylic migration affords
rhodacycle E. Reductive elimination of rhodium affords
cyclohexadiene 4.20,21
The intermediacy of dienyne 3 in this one-pot reaction is
confirmed by the reaction of the isolated dienyne 3aa
(Scheme 5). Treatment of 3aa with the cationic Rh(I)/(R)-
H8-BINAP catalyst at 80 °C indeed afforded the cyclohex-
adiene 4aa.
In conclusion, it has been established that a cationic
Rh(I)/H8-BINAP complex catalyzes the one-pot intermo-
lecular [2 þ 2 þ 2] trimerization/asymmetric intramolecular
[4þ 2] cycloaddition of two aryl ethynyl ethers and 5-alkynals
to produce annulated 1,4-cyclohexadienes. Future work
will focus on further utilization of the cationic Rh(I)
catalysts for the development of novel one-pot reactions.
Acknowledgment. This work was supported partly by a
Grant-in-Aid for Scientific Research (No. 20675002) from
MEXT and ACT-C from JST, Japan. We thank Takasago
International Corporation for the gift of H8-BINAP,
Segphos, and xyl-H8-BINAP, and Umicore for generous
support in supplying a rhodium complex.
(20) For a mechanistic proposal of the Rh-catalyzed intramolecular
[4 þ 2] cycloaddition of dienynes, see: References10aꢀ10c.
(21) A possible explanation for the formation of two diastereomers
4ag and 4ag0 is as follows. At rt, the reaction of 1a and 2g affords
E-dienyne 3ag as a predominant stereoisomer. At 80 °C, equilibration
between E-dienyne 3ag and Z-dienyne 3ag0 occurs in the presence of the
cationic Rh(I) catalyst. (For the cationic Rh(I) complex-catalyzed E/Z
isomerization of enones, see: Tanaka, K.; Shoji, T.; Hirano, M. Eur.
J. Org. Chem. 2007, 2687.) Although E-dienyne 3ag may be thermo-
dynamically more stable, the cyclization of 3ag may be slow as a result of
the steric interaction between the methyl and aryloxyvinyl groups in
intermediate F. In contrast, the cyclization of thermodynamically less
stable Z-dienyne 3ag0 may be fast as a result of the formation of less
sterically demanding intermediate F0. The formation of 4ag and 4ag0
through different rhodacycles F and F0, respectively, is consistent with
their different ee values.
Supporting Information Available. Experimental pro-
cedures, compound characterization data, and an X-ray
crystallographic information file. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX