One-pot cycloisomerization/hetero-diels-alder reaction of 1,6-enynes with aldehydes catalyzed by rhodium and a Bronsted acid

Article abstract of DOI:10.1021/ol4005849

A rhodium and Bronsted acid catalyzed one-pot cycloisomerization/ hetero-Diels-Alder reaction of 1,6-enynes with unactivated aldehydes was established under mild conditions. This one-pot catalytic protocol produced a wide variety of annulated dihydropyrans from readily available starting materials in a highly atom economical manner.

Full text of DOI:10.1021/ol4005849

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2120–2123
One-Pot Cycloisomerization/
Hetero-DielsꢀAlder Reaction of
1,6-Enynes with Aldehydes Catalyzed
by Rhodium and a Brønsted Acid
Mana Ishida† and Ken Tanaka*,†,‡
Department of Applied Chemistry, Graduate School of Engineering, 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 March 4, 2013
ABSTRACT
A rhodium and Brønsted acid catalyzed one-pot cycloisomerization/hetero-DielsꢀAlder reaction of 1,6-enynes with unactivated aldehydes was
established under mild conditions. This one-pot catalytic protocol produced a wide variety of annulated dihydropyrans from readily available
starting materials in a highly atom economical manner.
The hetero-Diels-Alder reaction has been utilized for
the convenient synthesis of six-membered heterocycles.
Several examples of [4 þ 2] cycloaddition reactions of
1,3-dienes with aldehydes leading to six-membered oxa-
cyclic compounds have been reported to date.1 However,
the successful examples are largely limited to the use
of electron-deficient aldehydes and/or electron-rich 1,3-
dienes.2 Although a few examples using unactivated alde-
hydes and 1,3-dienes have been reported, these reactions
employed very strong Brønsted3 or Lewis acids4 in order to
activate poorly reactive heterodienophiles. Furthermore,
the product yieldsare insufficient and the substratescopeis
limited. Recently, Matsubara, Kurahashi, and a co-worker
achieved the highly efficient hetero-DielsꢀAlder reaction
of unactivated aldehydes and 1,3-dienes under mild reac-
tion conditions (benzene, 80 °C) by using a cationic Fe(III)
porphyrin complex as a novel Lewis acid catalyst.5 This
mild catalyst system significantly broadened the substrate
scope. However, a few examples of exocyclic 1,3-dienes,
which afford annulated dihydropyrans,6 were tested due to
the poor availability of exocyclic 1,3-dienes.5 Herein, we
disclose the one-pot cycloisomerization/hetero-DielsꢀAlder
reaction of 1,6-enynes with unactivated aldehydes catalyzed
† Tokyo University of Agriculture and Technology.
‡ JST, ACT-C.
(1) For reviews of the hetero DielsꢀAlder reaction, see: (a) Boger,
D. L.; Weinreb, S. M. Hetero-DielsꢀAlder Methodology in Organic
Synthesis; Academic Press: San Diego, 1987. (b) Tietze, L.-F.; Kettschau, G.
Top. Curr. Chem. 1997, 189, 1.
(2) For representative examples, see: (a) Thadani, A. N.; Stankovic,
A. R.; Rawal, V. H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5846.
(b) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003,
424, 146. (c) Bednarski, M.; Danishefsky, S. J. Am. Chem. Soc. 1986,
108, 7060. (d) Bednarski, M.; Danishefsky, S. J. Am. Chem. Soc. 1983,
105, 6968. (e) Bednarski, M.; Maring, C.; Danishefsky, S. Tetrahedron
Lett. 1983, 24, 3451.
(3) (a) Ansell, M. F.; Charalambides, A. A. J. Chem. Soc., Chem.
Commun. 1972, 739. (b) Griengl, H.; Geppert, K. P. Monatsh. Chem.
1976, 107, 675. (c) Aggarwal, V. K.; Vennall, G. P.; Davey, P. N.;
Newman, C. Tetrahedron Lett. 1997, 38, 2569.
(4) (a) Oi, S.; Kashiwagi, K.; Terada, E.; Ohuchi, K.; Inoue, Y.
Tetrahedron Lett. 1996, 37, 6351. (b) Hanamoto, T.; Sugimoto, Y.; Jin,
Z. Y.; Inanaga, J. Bull. Chem. Soc. Jpn. 1997, 70, 1421.
(5) Fujiwara, K.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc.
2012, 134, 5512.
(6) For recent examples of biologically active compounds possessing
annulated dihydropyran cores, see: (a) Stokl, J.; Hofferberth, J.;
Pritschet, M.; Brummer, M. J. Chem. Ecol. 2012, 38, 331. (b) Feng,
C.-L.; Gong, M.-F.; Zeng, Y.-B.; Dai, H.-F.; Mei, W.-L. Molecules
2010, 15, 2473.
r
10.1021/ol4005849
Published on Web 04/22/2013
2013 American Chemical Society

by rhodium and a Brønsted acid under mild conditions. This
unprecedented one-pot catalysis produces a wide variety of
annulated dihydropyrans from readily available starting
materials.
Scheme 2
We previously reported that a cationic Rh(I)/
bisphoshinecomplexcatalyzesthecyclizationof1,6-diynes
with benzoic acid (2) leading to dienyl benzoates under
mild conditions.7 Thus, we attempted the reaction of
1,6-enyne 1a in the presence of a stoichiometric amount
of 2 and a catalytic amount of a cationic Rh(I)/BINAP
[2,20-bis(diphenylphosphino)-1,10-binaphthyl] complex.
Although the expected carboxylative cyclization product
3a was not generated, exocyclic 1,3-diene 4a was generated
in low yield (Scheme 1). When using a catalytic amount of
2, the yield of 4a significantly improved (Scheme 1).
Lewis acidic cationic Rh(I) complex as a catalyst,12 we
anticipated that the same Rh(I) complex would catalyze
the hetero-DielsꢀAlder reaction with an unactivated
aldehyde in one pot. As we expected, the unprecedented
one-pot cycloisomerization/hetero-DielsꢀAlder reaction
of 1,6-enyne 1a with benzaldehyde (7a) proceeded in the
presence of the cationic Rh(I)/BINAP complex (5 mol %)
and 2 (5 mol %) to give annulated dihydropyran 8aa as a
single regioisomer in high yield with high diastereoselec-
tivity (Scheme 3).
Scheme 1
Scheme 3
Chatani, Murai, and co-workers reported the cycloi-
somerization of 1,6-enynes leading to exocyclic 1,3-dienes8
by using a neutral Ir(I) complex and acetic acid.9 Subse-
quently, Yamamoto, Itoh, and co-workers reported the
trapping of the thus generated exocyclic 1,3-dienes8 from
nitrogen-linked 1,6-enynes with N-phenylmaleimide (5) by
the DielsꢀAlder reaction under toluene reflux conditions.10
Thus, we attempted the one-pot cycloisomerization/Dielsꢀ
Alder reaction of 1a with 5.11 Pleasingly, the expected
product 6 was obtained in high yield under mild reaction
conditions (Scheme 2).
On the other hand, Oi and co-workers reported the
hetero-DielsꢀAlder reaction of unactivated aldehydes
and 1,3-dienes under mild reaction conditions (CHCl3,
50 °C) by using a cationic Pd(II)/bisphosphine catalyst.4a
As the one-pot reaction shown in Scheme 2 employs the
The effect of Brønsted acids and counteranions on the
reaction of 1,6-enyne 1a with benzaldehyde (7a) was
examined (Table 1). With respect to Brønsted acids, use
of more acidic sulfonic acid 10 and phosphoric acid 11
increased the yield of the undesired olefin isomerization
product 9a (entries 2 and 3), and use of less acidic phenol
(12) lowered the yield of 8aa due to the formation of
the corresponding [2 þ 2 þ 2] cyclization product as a
byproduct.13 The use of the most acidic sulfonic acid 10
significantly decreased the diastereoselectivity (entry 2).
With respect to counteranions, use of the more ionic [SbF6]
anion afforded a complex mixture of byproducts other
than the desired product 8aa (entry 5), and use of less ionic
[OTf] anion afforded 9a as a major product (entry 6). In
both cases, lower diastereoselectivities were observed. The
neutral Rh(I)/BINAP complex did not catalyze the reac-
tion (entry 7). Thus, use of benzoic acid (2) as the Brønsted
acid and the [BF4] anion as the counteranion is optimal
(entry 1).
With the optimized reaction conditions in hand, we
explored the scope of this one-pot catalysis (Table 2). With
respect to unactivated aldehydes, a variety of aromatic and
heteroaromatic aldehydes 7aꢀf could participate in this
reaction to give the corresponding dihydropyrans 8aaꢀf in
high yields with high diastereoselectivities (entries 1ꢀ6).
Importantly, both electron-rich and -deficient aromatic
aldehydes 7d,e equally reacted with 1a (entries 4 and 5).
Not only aromatic aldehydes but also aliphatic aldehydes
(7) Tanaka, K.; Saito, S.; Hara, H.; Shibata, Y. Org. Biomol. Chem.
2009, 7, 4817.
(8) For examples of the transition-metal-catalyzed cycloisomeriza-
tion of 1,6-enynes leading to exocyclic 1,3-dienes, see: (a) Aubert, C.;
Buisine, O.; Malacria, M. Chem. Rev. 2002, 102, 813. (b) Mori, M.;
Kozawa, Y.; Nishida, M.; Kanamaru, M.; Onozuka, K.; Takimoto, M.
Org. Lett. 2000, 2, 3245. (c) Trost, B. M.; Krische, M. J. Synlett 1998, 1.
(d) Trost, B. M.; Romero, D. L.; Rise, F. J. Am. Chem. Soc. 1994, 116,
4268. (e) Trost, B. M.; Tanoury, G. J. J. Am. Chem. Soc. 1987, 109, 4753.
(f) Trost, B. M.; Tour, J. M. J. Am. Chem. Soc. 1987, 109, 5268.
(9) (a) Chatani, N.; Inoue, H.; Morimoto, T.; Muto, T.; Murai, S.
J. Org. Chem. 2001, 66, 4433. (b) Kezuka, S.; Okada, T.; Niou, E.;
Takeuchi, R. Org. Lett. 2005, 7, 1711.
(10) Yamamoto, Y.; Hayashi, H.; Saigoku, T.; Nishiyama, H. J. Am.
Chem. Soc. 2005, 127, 10804.
(11) For examples of the one-pot cycloisomerization/DielsꢀAlder
€
reaction, see: (a) Van Boxtel, L. J.; Korbe, S.; Noltemeyer, M.; De
Meijere, A. Eur. J. Org. Chem. 2001, 2283. (b) Nakai, Y.; Uozumi, Y.
Org. Lett. 2005, 7, 291.
(12) Our research group recently reported that a cationic Rh(I)/biaryl
bisphoshine complex catalyzes the carbonyl ene reaction; see: Okazaki,
E.; Okamoto, R.; Shibata, Y.; Noguchi, K.; Tanaka, K. Angew. Chem.,
Int. Ed. 2012, 51, 6722.
(13) Ishida, M.; Shibata, Y.; Noguchi, K.; Tanaka, K. Chem.;Eur.
J. 2011, 16, 12578.
Org. Lett., Vol. 15, No. 9, 2013
2121

Table 1. Effect of Brønsted Acids and Counteranions on
Reaction of 1,6-Enyne 1a with Benzaldehyde (7a)a
Table 2. One-Pot Cycloisomerization/Hetero-DielsꢀAlder
Reaction of 1,6-Enynes 1aꢀh with Aldehydes 7aꢀla
a [Rh(cod)2]X (0.010 mmol), BINAP (0.010 mmol), Brønsted acid
(0.010 mmol), 1a (0.20 mmol), 7a (0.22 mmol), and (CH2Cl)2 or CH2Cl2
(2.0 mL) were used. b Isolated yield. c [RhCl(cod)]2 (2.5 mol %) was used.
7gꢀj could be employed, although diastereoselectivities
were low (entries 7ꢀ10). Furthermore, acid-sensitive ben-
zyloxy-substituted aldehydes7k,l smoothly reacted with 1a
(entries 11 and 12). With respect to 1,6-enynes, not only
malonate- (entries 1ꢀ13) but also 1,3-diol-derived ones 1c,
d (entries 14 and 15) were suitable substrates for this
process. In the reaction of tosylamide-linked 1,6-enyne 1e
with 7a, the use of p-toluenesulfonic acid (10) at rt gave
the corresponding dihydropyran 8ea in a higher yield
(entry 17) than the use of 2 at 60 °C (entry 16). Not only
1,6-enynes 1aꢀe possessing the methyl group at the alkyne
terminus but also 1,6-enynes 1f,g possessing the n-butyl or
phenyl group at the alkyne terminus, respectively, reacted
with 7a to give dihydropyrans 8fa and 8ga14 in moderate to
high yields (entries 18 and 19). Unfortunately, the reaction
of terminal 1,6-enyne 1h and 7a did not afford dihydro-
pyran 8ha (entry 20).15
Very recently, Matsubara, Kurahashi, and a co-worker
reported the aza-DielsꢀAlder reaction of unactivated
imines and 1,3-dienes at rt by using a cationic Co(III)
porphyrin complex as a Lewis acid catalyst.16,17 We also
(14) Oligomerization of 4g proceeded as a side reaction.
(15) As the corresponding exocyclic 1,3-diene 4h was generated in ca.
40% yield, the subsequent hetero-DielsꢀAlder reaction of 4h with 7a did
not proceed.
(16) Wakabayashi, R.; Kurahashi, T.; Matsubara, S. Org. Lett. 2012,
14, 4794.
(17) For other examples of the aza-DielsꢀAlder reaction of unac-
tivated imines and 1,3-dienes, see: (a) Tambar, U. K.; Lee, S. K.;
Leighton, J. L. J. Am. Chem. Soc. 2010, 132, 10248. (b) Kobayashi, S.;
Ishitani, H.; Nagayama, S. Synthesis 1995, 1195.
a Reactions were conducted using [Rh(cod)2]BF4 (0.010 mmol),
BINAP (0.010 mmol), 2 (0.010 mmol), 1aꢀh (0.20 mmol), and 7aꢀl
(0.22 mmol) in (CH2Cl)2 (2.0 mL) at 60 °C for 24 h. b Isolated yield.
c A reaction was conducted using 10 in place of 2 at rt. d At 40 °C.
2122
Org. Lett., Vol. 15, No. 9, 2013

Scheme 4
Scheme 6
Scheme 5
Scheme 7
attempted the one-pot cycloisomerization/aza-DielsꢀAlder
reaction by using the cationic Rh(I)/BINAP complex and
Brønsted acids. Gratifyingly, 1,6-enynes 1a,e reacted with
unactivated imine 13 at rt in the presence of 5 mol % of the
cationic Rh(I)/BINAP complex with the more ionic [SbF6]
anion and 10 to give tetrahydropyridine 14a,e as a single
regioisomer in good yields with moderate diastereoselectiv-
ities (Scheme 4). The diastereoselectivity of 14a was de-
creased by using 2 in place of 10 at 60 °C.
Importantly, the annulated dihydropyran product can
serve as a precursor of a nine-membered oxacyclic com-
pound. Ring expansion of the annulated dihydropyran
8aa proceeded by the ruthenium-catalyzed CdC bond
cleavage18 to give nine-membered oxacyclic compound
15 in moderate yield (Scheme 5).
Scheme 6 depicts a plausible mechanism for the present
one-pot catalysis. 1,6-Enyne 1 reacts with rhodium afford-
ing rhodacyclopentene A. The reaction of A with benzoic
acid (2) affords rhodium benzoate B. β-Hydride elimina-
tionfrom B followed by eliminationof benzoicacid affords
exocyclic 1,3-diene 4. Carbonyl activation by the cationic
Rh(I) complex promotes the hetero-DielsꢀAlder reac-
tion through cationic intermediate C to afford annulated
dihydropyran 8.19 Small amounts of HBF4, which ꢀmay be
generated in situ by the reaction of Rh(I)þꢀBF4 com-
plexes and 2, may also catalyze the hetero-DielsꢀAlder
reaction.
complex smoothly catalyzed the reaction in the presence
or absence of benzoic acid (2), while 2 did not catalyze
the reaction at all. The use of HBF4•OEt2 at 60 °C led to a
complex mixture of products, although 8aa was obtained
at rt. However, the yield and diastereoselectivity using
HBF4•OEt2 were lower than those using the cationic
Rh(I)/BINAP complex. Therefore, the hetero-Dielsꢀ
Alder reaction might be mainly catalyzed by the cationic
Rh(I)/BINAP complex and partly catalyzed by small
amounts of in situ generated HBF4.
In conclusion, a rhodium and Brønsted acid catalyzed
one-pot cycloisomerization/hetero DielsꢀAlder reaction
of 1,6-enynes with unactivated aldehydes was established
under mild conditions. This one-pot catalytic protocol
produced a wide variety of annulated dihydropyrans from
readily available starting materials in a highly atom eco-
nomical manner. Future studies will focus on developing
an asymmetric variant of this one-pot catalysis.20
Acknowledgment. This work was supported partly by
Grants-in-Aid for Scientific Research (Nos. 20675002 and
23105512) from MEXT and ACT-C from JST (Japan).
We are grateful to Umicore for the generous support in
supplying rhodium complexes.
In order to determine the active catalyst in the hetero-
DielsꢀAlder reaction step, the reactions of isolated exo-
cyclic1,3-diene4awith 7awere examinedin the presenceof
various catalysts (Scheme 7). The cationic Rh(I)/BINAP
(18) (a) Krishnan, K. S.; Kuthanapillil, J. M.; Rajan, R.; Suresh, E.;
Radhakrishnan, K. V. Eur. J. Org. Chem. 2007, 5847. (b) Molander,
G. A.; Czako, B.; St. Jean, D. J., Jr. J. Org. Chem. 2006, 71, 1172.
(19) Similar cationic intermediate C was proposed in the cationic
Pd(II)/bisphosphine complex-catalyzed hetero-DielsꢀAlder reaction;
see ref 4a.
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
(20) Unfortunately, the reaction of 1a and 7a by using the cationic
Rh(I)/(R)-BINAP catalyst afforded 8aa with <5% ee.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 9, 2013
2123