Microwave-assisted palladium(0)-catalyzed alkylative cyclization of allenyl aldehydes leading to 3-substituted 3-cycloalken-1-ols

Article abstract of DOI:10.1021/ja076080p

We have developed an efficient synthetic method for 3-substituted 3-cyclohexenols and -cyclopentenol based on Pd0-catalyzed alkylative, arylative, alkenylative, alkynylative, and borative cyclization reaction of allene-carbonyl compounds. Microwave irradi

Full text of DOI:10.1021/ja076080p

Published on Web 12/20/2007
Microwave-Assisted Palladium(0)-Catalyzed Alkylative Cyclization of Allenyl
Aldehydes Leading to 3-Substituted 3-Cycloalken-1-ols
Hirokazu Tsukamoto,* Tomotaka Matsumoto, and Yoshinori Kondo
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity, Aramaki-aza aoba 6-3,
Aoba-ku, Sendai 980-8578, Japan
Received August 13, 2007; E-mail: hirokazu@mail.pharm.tohoku.ac.jp
Scheme 1. Alkylative Cyclization of Functionalized Allenes 1
and 4
Transition-metal-catalyzed cyclization of functionalized allenes
serves as a powerful one-step method to prepare carbo- and
heterocycles containing highly substituted olefin groups,1-3 which
should be useful intermediates for natural and pharmaceutical
product synthesis. Palladium(0) catalysts with organic halides have
been often employed for the cyclization reactions, most of which
proceed through carbopalladation of the allene moiety and are
focused on the arylative ones of allenes 1 bearing a nucleophilic
functionality leading to exo- or endo-olefin-containing cyclic
compounds 2 and 3.1 Furthermore, addition of reducing metals to
the above reaction conditions allows cyclization of allenes 4 bearing
an electrophilic carbonyl group leading to exo-alkenyl-containing
homoallylic cycloalkanols 5.2 However, its counterpart process
leading to endo-olefin-containing homoallylic alcohols 6 has never
been developed3 because in situ assembled η1-allylmetal generated
by the carbopalladation and subsequent transmetalation could not
form a six-membered cyclic transition state with the intramolecular
carbonyl group.4 In addition, alkylative cyclization employing
nickel(0) catalysts and organozinc reagents5 should not be applicable
to transformation of allenyl aldehydes 4 into 6 owing to oxidative
addition forming a metallacycle composed of Ni0 and 4.6,7 Herein,
we disclose a Pd0-catalyzed alkylative, arylative, alkenylative,
alkynylative, and borative cyclization reaction of 4 based not on
carbopalladation but on our original “anti-Wacker”-type cyclization8
to provide homoallylic alcohols 6 (Scheme 1).
At first, we examined the arylative cyclization of allenyl aldehyde
4a under the best reaction conditions for that of alkynals8 (1.5 equiv
of 7A, 2 mol % of Pd(PPh3)4, MeOH, 65 °C). As compared with
the alkynal cyclization, the reaction rate is faster and gives
3-cyclohexenol 6aA in lower yield along with a considerable
amount of hydroarylated product 8aA (Table 1, entry 1).9 The
formation of 8aA can be reduced by increasing the reaction
temperature to 80 °C and completely suppressed by microwave
irradiation10,11 (entries 2 and 3). Importantly, no reaction takes place
in the absence of the palladium catalyst.
Arylboronic acids with electron-donating or -withdrawing groups
serve as nucleophiles, and electron-rich boronic acids give higher
yields than their electron-deficient counterparts (entries 3-12).
These cyclization reactions also occur with heteroaryl- and alk-
enylboronic acids 7K-N (entries 13-16). Trialkylboranes 7O,P
possessing â-hydrogens participate in this process without undergo-
ing competitive â-hydride elimination (entries 17 and 18). Fur-
thermore, a combination of terminal alkyne and catalytic amount
of CuI serves as an alkynylmetal and provides enyne alcohol 6aQ
in good yield (entry 19).12 Remarkably, use of an excess bis-
(pinacolato)diboron (7R) leads to exclusive formation of borated
alcohol 6aR prior to dimerization with 4a (entry 20).
Table 1. Pd(PPh3)4-Catalyzed Cyclizations of 4a
entrya
7
6
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17d
18d
19d,e
20d,f
p-Me-C6H4-B(OH)2 7A
7A
7A
p-Me2N-C6H4-B(OH)2 7B
p-MeO-C6H4-B(OH)2 7C
C6H5-B(OH)2 7D
p-Cl-C6H4-B(OH)2 7E
p-OHC-C6H4-B(OH)2 7F
o-OHC-C6H4-B(OH)2 7G
p-F3C-C6H4-B(OH)2 7H
p-NC-C6H4-B(OH)2 7I
m-NO2-C6H4-B(OH)2 7J
2-furan-B(OH)2 7K
3-furan-B(OH)2 7L
trans-propenyl-B(OH)2 7M
cis-propenyl-B(OH)2 7N
Et3B 7O
6aA
6aA
6aA
6aB
6aC
6aD
6aE
6aF
6aG
6aH
6aI
54 (24)b
69 (10)b
86 (trace)b
90
quant.
84
85
80
82
78
88
65
94
93
6aJ
6aK
6aL
6aM
6aN
6aO
6aP
6aQ
6aR
82
79c
quant.
80
78
octyl-9-BBN 7P
PhCCH-cat. CuI 7Q
(BPin)2 7R
85
a Reaction at 65 °C (entry 1) and 80 °C (entry 2) for 1 h with oil bath
heating, and at 80 °C for 10 min with microwave irradiation (entries 3-20).
b 8aA is also obtained in the yields shown in parentheses. c Small amount
of 6aM is contained. d Reaction with 2 equiv of nucleophiles. e Reaction
with 4 mol % of Pd(PPh3)4 and 4 mol % of CuI. f Pin ) pinacolato.
in high yield (entry 1). Axial chirality of 1,3-disubstituted allene
4c can be transferred into cyclized product 6cC, which informs us
about the reaction mechanism mentioned below (entry 2). Allenyl
ketone 4d requires higher temperature and longer time but provides
tertiary homoallylic alcohol 6dC in good yield (entry 3). In contrast
to alkynal cyclization, allenyl aldehydes 4e and 4f containing
Next, the arylative cyclization reactions of other allenes 4b-g
with 7C were examined (Table 2). 1,1-Disubstituted allene aldehyde
4b affords tetrasubstituted alkene containing 3-cyclohexenol 6bC
9
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J. AM. CHEM. SOC. 2008, 130, 388-389
10.1021/ja076080p CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Pd(PPh3)4-Catalyzed Arylative Cyclizations of 4b-ga
preparatively important functional groups. Studies expanding the
scope of the cyclization process are underway.
Acknowledgment. This work was partly supported by a Grant-
in-Aid from the Japan Society for Promotion of Sciences (No.
18790003) and Banyu Pharmaceutical Co. Ltd. Award in Synthetic
Organic Chemistry, Japan.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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Scheme 2. Possible Mechanism for the Arylative Cyclization of 4c
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conformationally more flexible methylene and shorter tethers also
undergo efficient cyclization reactions (entries 4 and 5). However,
this catalytic system is less suitable for the cyclization of allenyl
aldehyde 4g with a longer tether than the previously reported ones2,5
(entry 6).
The high efficiency of chirality transfer from the starting optically
active 4c to 6cC (Table 2, entry 2)13 supports trans-specific addition
of 7C to the aldehyde across the distal allene π-system, which would
result from an intramolecular electrophilic addition of the carbonyl
group in 4c to the allene coordinated by electron-rich Pd0 (anti-
Wacker-type oxidative addition)8,15 and concomitant transmetalation
with 7C followed by reductive elimination (Scheme 2). It is worth
noting that both regiochemistry and stereochemistry of addition of
the catalyst and the carbonyl to the allene moiety are opposite to
those of the Ni0-catalyzed allene aldehyde coupling reported by
Jamison.7
In summary, we have developed an efficient synthetic method
for 3-substituted 3-cyclohexenols and -cyclopentenol from allene
carbonyl compounds. Microwave irradiation turns out to increase
not only the reaction rate but also the product yield and to suppress
formation of hydroarylation byproducts observed in the same
catalytic system.9 In addition to sp2- and sp3-carbonucleophiles, sp-
carbon and boron nucleophiles also participate in this process. We
also obtain proof of the reaction mechanism involving not carbo-
palladation but anti-Wacker-type cyclization. Cyclic homoallylic
alcohols generated in these reactions should be versatile intermedi-
ates in carbocycle synthesis since they contain a rich array of
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(11) We also observed that employment of arylboronic esters led to exclusive
formation of 6aA. In situ formation of methyl arylboronate might be
accelerated by microwave irradiation.
(12) Use of alkynylboronic esters resulted in protonation of the esters.
(13) In addition to this result, no competitive addition to the formyl group in
7F (Table 1, entry 9),14 no reductive cyclization using 7O,P (Table 1,
entries 17 and 18), and less efficiency and anti selectivity of the cyclization
of 4g (Table 2, entry 6) would also exclude the carbopalladation pathway.
(14) Grigg reported Pd0-catalyzed coupling reaction of 2-haloaryl aldehydes
with external allene: (a) Anwar, U.; Grigg, R.; Rasparini, M.; Savic, V.;
Sridharan, V. Chem. Commun. 2000, 645-646. (b) Gai, X.; Grigg, R.;
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(15) Reaction of 4a in MeOH without nucleophiles gives 3-cyclohexenols 10-
12, which would result from carbopalladation of 4a with a cyclic
alkenylpalladium intermediate such as 9a.
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