Palladium-catalyzed cycloaddition of alkynyl aryl ethers to allenes to form a 2,3-bismethylidene-2,3-dihydro-4h-1-benzopyran framework

Article abstract of DOI:10.1246/cl.130894

Palladium-catalyzed cycloaddition of alkynyl aryl ethers to allenes proceeds through o-CH activation to give 2,3-dihydro- 4H-1-benzopyran derivatives containing 2,3-exo-double bonds. These benzopyran derivatives further cycloadd stereoselectively to dieno

Full text of DOI:10.1246/cl.130894

Received: September 26, 2013 | Accepted: October 16, 2013 | Web Released: October 24, 2013
CL-130894
Palladium-catalyzed Cycloaddition of Alkynyl Aryl Ethers to Allenes
to Form a 2,3-Bismethylidene-2,3-dihydro-4H-1-benzopyran Framework
Yasunori Minami,*1 Mayuko Kanda,2 and Tamejiro Hiyama*1
1Research and Development Initiative, Chuo University, Kasuga, Bunkyo-ku, Tokyo 112-8551
2Faculty of Science and Engineering, Chuo University, Kasuga, Bunkyo-ku, Tokyo 112-8551
(E-mail: yminami@kc.chuo-u.ac.jp, thiyama@kc.chuo-u.ac.jp)
Table 1. Palladium-catalyzed cycloaddition of 1 with hexylallene 2aa
Palladium-catalyzed cycloaddition of alkynyl aryl ethers to
allenes proceeds through o-C-H activation to give 2,3-dihydro-
4H-1-benzopyran derivatives containing 2,3-exo-double bonds.
These benzopyran derivatives further cycloadd stereoselectively
to dienophiles to give condensed polycycles.
O
R2
R1
Pd(OAc)2 (5 mol%)
PCy3 (5 mol%)
Zn (5 mol%)
R2
8
O
H
+
7
6
1
H
R1
R3
R5
toluene, 100 °C, 2 h
Hex
3(a-l)a
R4
2
2a (R3 = Hex, R4 = R5 = H)
The Diels-Alder reaction of 1,2-bismethylidene carbocycles
with dienophiles is a straightforward method to obtain poly-
cyclic homologues, the synthetic method being the long-stand-
ing target of synthetic chemistry.1 Thus, such a conjugated diene
unit is a useful structural motif for polycyclic annulation.
Representative preparative methods for 1,2-exomethylidene
carbocycles are dehydrohalogenation of cyclic substrates having
two adjacent halo- or pseudohalomethyl groups,2 the Ramberg-
Bäcklund reaction of in situ generated allylchloromethyl sul-
fones,3 and metal-mediated and -catalyzed cyclizations of
enynes as well as allenyl alkynes, diynes, and bisallenes.4,5
Among these, metal-catalyzed cyclization appears to be ideal for
the synthesis of multisubstituted 1,2-bismethylidene carbocycles
with high atom-economy. This approach, however, is generally
limited to unimolecular reactions, and its application to
intermolecular cycloadditions remains a challenge.6 In keeping
with the goal of developing such reactions, regioselective
insertion of allenes into C-H bonds of substrates having C-C
triple bonds is a promising method.7 In this respect, we recently
found that an alkynoxy group (-OC¸CR)8 works as a directing
group for C-H activation and a cyclization partner as well.9,10
Herein, we report the palladium-catalyzed activation of an o-C-
H bond of alkynoxyarenes 1 followed by cycloaddition with
allenes 2 to produce a wide range of 2,3-bismethylidene-2,3-
dihydro-4H-1-benzopyrans 3. The cycloadducts are extremely
useful for the Diels-Alder reactions with dienophiles to give
condensed cycles.
The reaction of 4-methoxyphenyl triisopropylsilylethynyl
ether (1a) with 1,2-nonadiene (2a) gave 2,3-bismethylidene-
chromane derivative 3aa in 81% yield as a single regioisomer in
the presence of Pd(OAc)2, PCy3, and Zn (for in situ Pd(II)
reduction) in toluene at 100 °C for 2 h (Table 1, Run 1). The
structure of 3aa was unambiguously determined by NMR
spectroscopy. It should be noted that the internal double bond of
2a readily underwent cycloaddition. The reaction of 1b (R2 =
TBDPS), 1c (R2 = TES), and 1d (R2 = TBDMS) proceeded to
afford 3ba, 3ca, and 3da in moderate to excellent yields (Runs
2-4). In addition, the Me2PhSi-substituted alkynyl ether 1e,
which was reluctant to cycloadd to alkynes, provided the desired
product 3ea in 40% yield (Run 5). The presence of a silyl
substituent, however, is not essential for this reaction to occur: a
bulky carbonaceous group also allows the substrate to undergo
the transformation, as is evidenced by substrate 1f, which
Run
1
R1
R2
3
R1
Yield/%b
1
2
3
4
5
6
7
8
9
1a 4-MeO TIPS
1b 4-MeO TBDPS
1c 4-MeO TES
1d 4-MeO TBDMS
1e 4-MeO SiMe2Ph
3aa 6-MeO
3ba 6-MeO
3ca 6-MeO
3da 6-MeO
3ea 6-MeO
81
>99
82
58
40
64
84
73
77
1f 4-MeO C(OMe)(-CH2-)5 3fa 6-MeO
1g 4-Me
1h 3-Me
1i 2-Me
TIPS
TIPS
TIPS
TIPS
TIPS
3ga 6-Me
3ha 7-Me
3ia 8-Me
3ja
3ka 6-F
10 1j
11 1k 4-F
12 1l 4-CF3 TIPS
aUnless otherwise noted, a mixture of 1 (0.5 mmol), 2a (1.0-1.5
mmol), Pd(OAc)2 (0.025 mmol), PCy3 (0.025 mmol), Zn (0.025
mmol), and toluene (2.0 mL) was heated at 100 °C. bIsolated yields.
TIPS: Sii-Pr3, TBDPS: Sit-BuPh2, TBDMS: Sit-BuMe2, TES: SiEt3.
H
H
77
52
66
3la 6-CF3
despite the presence of the bulky substituent C(OMe)(-CH2-)5
produces 3fa in 64% yield (Run 6). The reaction of 4-
MeOC6H4OC¸CMe, however, resulted in a complex mixture
of products. These results clearly demonstrate that a bulky R2
group is crucial to the success of the reaction, and that silyl
groups are the most effective. The fact that C6H5CH2C¸CTIPS
remained totally intact under similar conditions indicates that the
sole ligation of the oxygen atom or C¸C bond to palladium(0)
does not induce the C-H cleavage reaction. The substituent
effect on the aryl groups was investigated next. Phenyl and
4-, 3-, and 2-tolyl groups did not hamper the cycloaddition
(Runs 7-10). It is worth noting that the reaction of 3-tolyl
substrate 1h provided 3ha in 73% yield as a single regioisomer
(Run 8). Fluorine and trifluoromethyl group did not interfere
with the reaction and gave cycloadducts 3ka and 3la in 52% and
66% yields, respectively (Runs 11 and 12).
Next, various allenes were applied to the cycloaddition
reaction (Table 2). Alkyls with cyano (2b), oxycarbonyl (2c),
silyloxy (2d), and cyclohexyl (2e) tolerated the reaction of either
1b or 1m to give the corresponding products (Runs 1-5). The
reaction of 1c with p-methoxyphenylallene (2f) took place to
give 3cf in 53% yield (Run 6). Internal allenes such as 4,5-
nonadiene (2g) underwent the reaction with 1b under these
conditions, giving 3bg in 71% yield as a mixture of stereo-
Chem. Lett. 2014, 43, 181–183 | doi:10.1246/cl.130894
© 2014 The Chemical Society of Japan | 181

Table 2. Palladium-catalyzed cycloaddition of 1 with 2a
R2
R2
O
O
H
H
R3
1
2
+
+
R5
R1
R1
R3 R4
R5 R4
3
3'
Run
1
2
Time/h Product
Yield/%b
TBDPS
O
H
Figure 1. ORTEP diagram of 6d (one isomer).
R1
R3
1
2
3
4
5
1b 2b
1b 2c
1b 2d
1b 2e
1m 2e
5
5
3bb (R1 = MeO, R3 = (CH2)3CN)
3bc (R1 = MeO, R3 = (CH2)3CO2Me)
3bd (R1 = MeO, R3 = (CH2)4OTBDPS)
3be (R1 = MeO, R3 = c-C6H11)
60
63
elimination and silylpalladation of the less-hindered terminal
double bond.12
15
25
5
67
Pd(OAc)2 (5 mol%)
TBDPS
>99
95
PCy3 (5 mol%)
Zn (5 mol%)
R3
O
3me (R1 = H, R3 = c-C6H11)
H
+
1b
TES
toluene, 100 °C, 2 h
Si
MeO
O
H
(2-3 equiv)
Si R3
6
7
26
2
53
2i (R3 = H, Si = TES)
1c 2f
2j (R3 = H, Si = SiMe2Ph)
2k (R3 = Me, Si = SiPh3)
3b(i-k)
MeO
C6H4-OMe-p
3cf
TBDPS
O
TBDPS
O
TBDPS
O
H
H
R3
H
+
+
ð1Þ
71c
1b 2g
Si
MeO
Pr
MeO
MeO
R3
3'b(i-k) Si
4b(i-k)
Pr
TBDPS
3bg
60% (3bi : 3'bi : 4bi = 80 : 0 : 20)
84% (3bj : 3'bj : 4bj = 60 : 0 : 40)
>99% (3bk : 3'bk : 4bk = 36 : 22 : 42)
O
H
The Diels-Alder reaction of 3 with N-arylmaleimide 5 was
investigated (eq 2). The reaction of 3aa, 3be, and 3me with N-
phenylmaleimide (5a) (X = H) gave the endo-cyclic adducts
6a, 6b, and 6c in 70-91% yields, respectively. Brominated
derivative 5b (X = Br) reacted with 3me to provide 6d in
87% yield. The structure and stereochemistry of 6d were
unambiguously determined by X-ray crystallographic analysis
(Figure 1),11 showing that the reaction proceeded selectively by
approach from only one side, so as to minimize steric hindrance
on R3.
MeO
TBDPS
O
+
8
1b 2h
2
>99
(1.2:1)d
H
MeO
3bh
+
3’bh
aUnless otherwise noted, a mixture of 1 (0.5 mmol), 2 (1.0-1.5 mmol),
Pd(OAc)2 (0.025 mmol), PCy3 (0.025 mmol), Zn (0.025 mmol), and
toluene (2.0 mL) was heated at 100°C. bIsolated yields. cE/Z = 25:75.
dRatio of 3bh/3¤bh.
O
R2
isomers (Run 7). 1,1-Dimethylallene (2h) upon reaction with 1b
also gave a mixture of 3bh and 3¤bh (1.2:1 ratio) in quantitative
yield (Run 8). These results show that sterically biased allenes
tend to form the regioisomer 3¤, as a result of the reaction at the
less-hindered terminal carbon.
N C6H4-X-p
O
O
H
5 (1.1 equiv)
Ar
H
O
R1
R3
N
3
ClCH2CH2Cl
80 °C, 10-19 h
H
O
H
O
The reaction with silylallenes gave a mixture of 3 and 3-
silylmethylchromenes 4 (eq 1). For example, TES- and Me2Ph-
Si-substituted propa-1,2-dienes 2i and 2j reacted with 1b to give
3bi and 3bj together with 3-silylmethylchromenes 4bi and 4bj
in 60% (3bi:4bi = 80:20) and 84% (3bj:4bj = 60:40) yields,
respectively. This indicates that the bulkier silyl substituents
result in higher ratios of 4. In the case of 3-triphenylsilyl-1,2-
butadiene (2k), a mixture of 3bk, 3¤bk, and 4bk was obtained
(36:22:42, >99% total yield). The structure of 4bk was
unambiguously determined by X-ray crystallographic analysis,11
providing evidence that the triphenylsilyl group apparently
migrated to the terminal carbon of allene 2k. In view that 3bj did
not isomerize to 4bj via a 1,3-silicon shift under the catalytic
conditions, it is possible that the insertion of the internal double
bond of allene 2k into the Ar-Pd bond is followed by β-silyl
R2
O
H
ð2Þ
N C6H4-X-p
R1
H
R3
O
6a (R1 = MeO, R2 = TIPS, R3 = Hex, X = H), 70%
6b (R1 = MeO, R2 = TBDPS, R3 = c-C6H11, X = H), 78%
6c (R1 = H, R2 = TBDPS, R3 = c-C6H11 , X = H), 91%
6d (R1 = H, R2 = TBDPS, R3 = c-C6H11 , X = Br), 87%
The one-pot cycloaddition/Diels-Alder reaction sequence
employing 1a, 2a, and 5a can be carried out and 6a was isolated
in 74% overall yield (eq 3). In addition, when a 60:40 mixture of
3bj and 4bj was treated with 5a, only 3bj participated in the
reaction to give 6e in 86% yield, whereas most of 4bj remained
intact (eq 4).
182 | Chem. Lett. 2014, 43, 181–183 | doi:10.1246/cl.130894
© 2014 The Chemical Society of Japan

To get an insight into the mechanism of the cycloaddition,
we carried out the reaction of 1j-d5 with 2c and obtained the
cycloadduct d-3jc, whose structure was determined by 1H NMR.
This paper is dedicated to Professor Teruaki
Mukaiyama in celebration of the 40th anniversary of the
Mukaiyama aldol reaction.
1) 2a (3.0 equiv), Pd(OAc)2 (5 mol%)
References and Notes
PCy3 (5 mol%), Zn (5 mol%)
toluene, 100 °C, 2 h
1
Syntheses of tetracycline and its derivatives are representative examples.
a) K. C. Nicolaou, J. S. Chen, D. J. Edmonds, A. A. Estrada, Angew.
Chem., Int. Ed. 2009, 48, 660. b) A. Takada, Y. Hashimoto, H. Takikawa,
K. Hikita, K. Suzuki, Angew. Chem., Int. Ed. 2011, 50, 2297.
W. J. Bailey, H. R. Golden, J. Am. Chem. Soc. 1953, 75, 4780.
A. G. Yurchenko, A. B. Kyrij, I. R. Likhotvorik, N. N. Melnik, P.
Zaharzh, V. V. Bzhezovski, A. O. Kushko, Synthesis 1991, 393.
For examples, see: a) B. M. Trost, F. J. Fleitz, W. J. Watkins, J. Am.
Chem. Soc. 1996, 118, 5146. b) C. H. Oh, S. H. Jung, C. Y. Rhim,
Tetrahedron Lett. 2001, 42, 8669. c) Y. Nakao, E. Shirakawa, T.
Tsuchimoto, T. Hiyama, J. Organomet. Chem. 2004, 689, 3701. d) H.-Y.
Jang, M. J. Krische, J. Am. Chem. Soc. 2004, 126, 7875. e) K. M.
Brummond, L. You, Tetrahedron 2005, 61, 6180. f) A. Joosten, M.
Soueidan, C. Denhez, D. Harakat, F. Hélion, J.-L. Namy, J.-L. Vasse, J.
Szymoniak, Organometallics 2008, 27, 4152. g) V. Pardo-Rodríguez, J.
Marco-Martínez, E. Buñuel, D. J. Cárdenas, Org. Lett. 2009, 11, 4548.
For reviews, see: a) B. M. Trost, M. U. Frederiksen, M. T. Rudd, Angew.
Chem., Int. Ed. 2005, 44, 6630. b) V. Michelet, P. Y. Toullec, J.-P. Genêt,
Angew. Chem., Int. Ed. 2008, 47, 4268. c) S. I. Lee, N. Chatani, Chem.
Commun. 2009, 371. d) C. Aubert, L. Fensterbank, P. Garcia, M.
Malacria, A. Simonneau, Chem. Rev. 2011, 111, 1954.
a) R. C. Larock, Y. He, W. W. Leong, X. Han, M. D. Refvik, J. M.
Zenner, J. Org. Chem. 1998, 63, 2154. b) P. Lu, S. Ma, Org. Lett. 2007, 9,
5319. c) A. T. Brusoe, E. J. Alexanian, Angew. Chem., Int. Ed. 2011, 50,
6596. d) A. T. Brusoe, R. V. Edwankar, E. J. Alexanian, Org. Lett. 2012,
14, 6096.
For recent selected reports on the reaction of C-H bond with allenes, see:
a) J. Piera, K. Närhi, J.-E. Bäckvall, Angew. Chem., Int. Ed. 2006, 45,
6914. b) Y. Kuninobu, P. Yu, K. Takai, Org. Lett. 2010, 12, 4274. c) D. N.
Tran, N. Cramer, Angew. Chem., Int. Ed. 2010, 49, 8181. d) B. M. Trost,
J. Xie, J. D. Sieber, J. Am. Chem. Soc. 2011, 133, 20611. e) H. Wang, F.
Glorius, Angew. Chem., Int. Ed. 2012, 51, 7318. f) R. Zeng, C. Fu, S. Ma,
J. Am. Chem. Soc. 2012, 134, 9597.
ð3Þ
1a
6a
2) 5a (3.0 equiv), 100 °C, 12 h
74% (one-pot)
2
3
TBDPS
O
O
H
H
5a (3.0 equiv)
3bj + 4bj
+ 4bj
NPh
ð4Þ
4
ClCH2CH2Cl
80 °C, 12 h
MeO
(60:40)
67%
recovered
O
Me2PhSi
6e, 86% (based on 3bj)
The data showed that the original o-deuterium was dis-
tributed among four sites in the product: the C2-silylmethylidene
(containing 40% D), C3-methylidene (19% and 21% D), and
C4-methine (7% D) positions (eq 5). In control experiments, the
reaction of 1a with 2a in the absence of Zn gave 3aa in lower
yields. Of note was the fact that [Pd(PCy3)2] and its combination
with [Pd(dba)2]/PCy3 also showed catalytic activity. These facts
indicate two reaction pathways. One, the o-C-H activation
proceeds via the reaction with an active palladium(0) catalyst to
give an aryl palladium hydride complex,13 which then undergoes
intermolecular insertion of the allene in a manner similar to
reaction with alkynes.9a The deuterium-labeling experiment may
support this mechanism. The incorporation of deuterium into
three separate positions in addition to the C2-silylmethylidene
site may be attributed to β-H elimination-reinsertion after the
initial insertion into the Pd-H bond of the aryl palladium
hydride complex (See the Supporting Information).14 In the
second mechanism, the π-allyl palladium complex may be
formed via the nucleophilic attack of the α-carbon to the internal
carbon of allenes ligating palladium catalysts, followed by the
intramolecular attack of the ortho-carbon of oxyarenes on the
allyl ligands.
5
6
7
8
9
a) R. Tanaka, S. I. Miller, Tetrahedron Lett. 1971, 12, 1753. b) P. J. Stang,
K. A. Roberts, J. Am. Chem. Soc. 1986, 108, 7125. c) M. Shindo,
Tetrahedron 2007, 63, 10.
a) Y. Minami, Y. Shiraishi, K. Yamada, T. Hiyama, J. Am. Chem. Soc.
2012, 134, 6124. b) Y. Minami, K. Yamada, T. Hiyama, Angew. Chem.,
Int. Ed. 2013, 52, 10611.
10 For examples of C-C unsaturated bonds as directing groups, see: a) R.
Takeuchi, H. Yasue, J. Org. Chem. 1993, 58, 5386. b) K. Tanaka, G. C.
Fu, Org. Lett. 2002, 4, 933. c) M. Murakami, T. Itahashi, Y. Ito, J. Am.
Chem. Soc. 2002, 124, 13976. d) N. Chernyak, V. Gevorgyan, J. Am.
Chem. Soc. 2008, 130, 5636. e) M. Tobisu, I. Hyodo, M. Onoe, N.
Chatani, Chem. Commun. 2008, 6013. f) N. Chernyak, V. Gevorgyan,
Adv. Synth. Catal. 2009, 351, 1101. g) N. Chernyak, S. I. Gorelsky, V.
Gevorgyan, Angew. Chem., Int. Ed. 2011, 50, 2342. h) P. Gandeepan,
C.-H. Cheng, J. Am. Chem. Soc. 2012, 134, 5738. i) T. Xu, G. Dong,
Angew. Chem., Int. Ed. 2012, 51, 7567.
O
TIPS
40% D
H/D
H/D
19% D
C6D5
Pd(OAc)2
PCy3, Zn
O
TIPS
1j-d5
ð5Þ
+
toluene
100 °C, 21 h
D4
H/D
H/D
MeOC(O)
21% D
7% D
CO2Me
2c
d-3jc
11 CCDC-917988 (4bk), CCDC-917989 (6c), and CCDC-917990 (6d)
contain the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
12 a) Y. Wakatsuki, H. Yamazaki, M. Nakano, Y. Yamamoto, J. Chem. Soc.,
Chem. Commun. 1991, 703. b) B. Marciniec, Z. Foltynowicz, C.
Pietraszuk, J. Guliński, H. Maciejewski, J. Mol. Catal. 1994, 90, 213. c)
B. Marciniec, C. Pietraszuk, Organometallics 1997, 16, 4320. d) C.
Pietraszuk, H. Fischer, Organometallics 2001, 20, 4641. e) Y. Itami, B.
Marciniec, M. Majchrzak, M. Kubicki, Organometallics 2003, 22, 1835.
f) P. Pawluc, B. Marciniec, G. Hreczycho, B. Gaczewska, Y. Itami,
J. Org. Chem. 2005, 70, 370.
13 a) N. D. Clement, K. J. Cavell, C. Jones, C. J. Elsevier, Angew. Chem.,
Int. Ed. 2004, 43, 1277. The reaction of [Pd(PPh3)4] with bis-silicon(II)-
based SiCSi pincer arene ligand probably forms palladium hydride
complex as a reaction intermediate via oxidative addition, reported by
Inoue, Driess and co-workers. See: b) W. Wang, S. Inoue, E. Irran, M.
Driess, Angew. Chem., Int. Ed. 2012, 51, 3691.
In conclusion, we have demonstrated that the palladium-
catalyzed cycloaddition of alkynyl aryl ethers with allenes is a
viable approach for the synthesis of the benzopyran framework
with 2,3-bismethylidene moieties through C-H activation. It
should be noted that the alkynoxy group behaves both as a
directing group and as the cycloaddition partner during the
reaction. The Diels-Alder reaction of the diene moieties of the
cycloadducts gave the linearly condensed tetracycles. Our
continuing research is currently focusing on extending the
present cycloaddition and understanding the detailed reaction
mechanism.
This work has been supported financially by a Grant-in-Aids
for Scientific Research (S) (No. 21225005 to T.H.) and Young
Scientists (B) (No. 25870747 to Y.M.) from JSPS, and JST,
ACT-C.
14 Supporting Information is available electronically on the CSJ-Journal
Web site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2014, 43, 181–183 | doi:10.1246/cl.130894
© 2014 The Chemical Society of Japan | 183