A new five-membered ring forming process based on palladium(0)-catalyzed arylative cyclization of allenyl enones

Article abstract of DOI:10.1021/ol800509z

(Chemical Equation Presented) A palladium(0)/monophosphine catalyst promotes a novel arylative cyclization reaction of C1-, C2-, and C3-tethered allenyl enones with arylboronic acids to produce five-membered ring containing products. The regioselectivity of the process, associated with aryl group introduction into the allene moiety, depends on the length of the tether. This finding suggests that the cyclization reaction does not proceed through a carbopalladation pathway but rather via a route involving palladacycle-forming or anti-Wacker -type oxidative addition to the Pd⁰ catalyst.

Full text of DOI:10.1021/ol800509z

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2633-2636
A New Five-Membered Ring Forming
Process Based on
Palladium(0)-Catalyzed Arylative
Cyclization of Allenyl Enones
Hirokazu Tsukamoto* and Yoshinori Kondo
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity,
Aramaki-aza aoba 6-3, Aoba-ku, Sendai 980-8578, Japan
hirokazu@mail.pharm.tohoku.ac.jp
Received March 6, 2008
ABSTRACT
A palladium(0)/monophosphine catalyst promotes a novel arylative cyclization reaction of C1-, C2-, and C3-tethered allenyl enones with arylboronic
acids to produce five-membered ring containing products. The regioselectivity of the process, associated with aryl group introduction into the
allene moiety, depends on the length of the tether. This finding suggests that the cyclization reaction does not proceed through a carbopalladation
pathway but rather via a route involving palladacycle-forming or “anti-Wacker”-type oxidative addition to the Pd0 catalyst.
Transition-metal-catalyzed carbocyclization reactions of func-
tionalized allenes serve as powerful one-step methods to
prepare carbocycle and heterocycle containing, highly sub-
stituted alkenes,1–6 which are potentially useful intermediates
in the synthesis of natural and pharmaceutically interesting
substances.
We recently developed a new process for the synthesis of
3-substituted 3-cyclohexen-1-ols 3 that relys on Pd0/mono-
phosphine-catalyzed alkylative cyclization of allene-
aldehydes 1 with organoboron reagents 6 (Scheme 1, left).2a
Scheme 1.
Pd0-Catalyzed Alkylative Cyclization of
(1) Reviews on transition-metal-catalyzed cyclizations of allenes: (a)
Ma, S. Pure Appl. Chem. 2006, 78, 197–208. (b) Ma, S. Acc. Chem. Res.
2003, 36, 701–712. (c) Bates, R. W.; Satcharoen, V. Chem. Soc. ReV. 2002,
31, 12–21. (d) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem.
ReV. 2000, 100, 3067–3125. (e) Hashmi, A. S. K. Angew. Chem., Int. Ed.
2000, 39, 3590–3593. (g) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J.
Org. Chem. 2003, 4101–4111. (h) Hoffmann-Ro¨der, A.; Krause, N. Org.
Allene-Aldehydes and -Enones
Biomol. Chem. 2005, 3, 387–391
.
(2) Pd-catalyzed cyclizations of allene-aldehydes: (a) Tsukamoto, H.;
Matsumoto, T.; Kondo, Y. J. Am. Chem. Soc. 2008, 130, 388–389. (b)
Tsukamoto, H.; Matsumoto, T.; Kondo, Y. Org. Lett. 2008, 10, 1047–1050.
(c) Ha, Y.-H.; Kang, S.-K. Org. Lett. 2002, 4, 1143–1146. (d) Kang, S.-K.;
Lee, S.-W.; Jung, J.; Lim, Y. J. Org. Chem. 2002, 67, 4376–4379. (e) Yu,
Initial circumstantial evidence suggested that the cyclization
reaction proceeds through a pathway involving (1) intramo-
lecular electrophilic addition of the carbonyl group in 1 to
the allene, coordinated to electron-rich Pd0 (so-called “anti-
C.-M.; Youn, J.; Lee, M.-K. Org. Lett. 2005, 7, 3733–3736
.
(3) Ni-catalyzed cyclizations of allene-aldehydes: (a) Montgomery, J.;
Song, M. Org. Lett. 2002, 4, 4009–4011. (b) Song, M.; Montgomery, J.
Tetrahedron 2005, 61, 11440–11448. (c) Kang, S.-K.; Yoon, S.-K. Chem.
Commun. 2002, 2634–2635
.
10.1021/ol800509z CCC: $40.75
Published on Web 05/30/2008
2008 American Chemical Society

Wacker”-type oxidative addition),7 (2) concomitant trans-
metalation with the organoboron reagent, and (3) reductive
elimination. However, due to the similar regioselectivity
associated with carbopalladation,1,2b–d,8 it is difficult to rule
out a mechanism for this process that involves sequential
insertion of the allene and carbonyl moiety into the
carbon-palladium(II) bond.9–11
Fortunately, during the course of studies designed to
uncover the origin of the “anti-Wacker”-type oxidative
addition, we discovered that this catalytic system promotes
a cyclization reaction of the allene-enone 2 that follows a
different regiochemical course to provide the cyclopentene
5 rather than cyclohexene 4 (Scheme 1, right).
Below, we describe the results of an investigation of the
effects of the length of tethers on the different regiochemical
modes of cyclization seen in Pd0/monophosphine-catalyzed
arylative cyclization reactions of allene-containing electron-
deficient alkenes. The findings suggest that the regiochemical
course of the carbocyclization process can be rationalized
by invoking palladacycle-forming or “anti-Wacker”-type
oxidative addition to the Pd0 catalyst. To the best of our
knowledge, the carbocyclization reactions of 1,2,5- and 1,2,6-
trienes desribed in this report are the first examples of metal-
catalyzed cyclization reactions of this type.12
The arylative cyclization of (2E)-5,5-dimethyl-1-phenyl-
2,6,7-octatrien-1-one (7), using a slight excess of phenyl-
boronic acid (6a), takes place in the presence of 5 mol % of
Pd(PPh3)4 at 80 °C to provide cyclopentene 8a in good yield
(Table 1, entry 1). In contrast to related allene-aldehyde
cyclizations,2a the use of methanol as solvent and microwave
irradiation are not essential for this process (e.g., 1,4-dioxane
Table 1. Arylative, Alkenylative, and Reductive Cyclization of 7
entry
6
product
yield (%)
1
C6H5B(OH)2 6a
6a
8a
8a
8b
8c
8d
8e
8f
8g
8h
8i
68
61
62
70
68
76
77
75
69
75
70
80
80
25d
2a,b
3
p-MeO-C6H4B(OH)2 6b
p-Me-C6H4B(OH)2 6c
o-Me-C6H4B(OH)2 6d
m-Me-C6H4B(OH)2 6e
p-F-C6H4B(OH)2 6f
p-Cl-C6H4B(OH)2 6g
p-Ac-C6H4B(OH)2 6h
p-OHC-C6H4B(OH)2 6i
m-NO2-C6H4B(OH)2 6j
4
5
6b
7
8
9
10b
11b
12
13
14c
15e
8j
(E)-PhCHdCHB(OH)2 6k 8k
3-thiophene-B(OH)2 6l
2-thiophene-B(OH)2 6m
Et3B 6n
8l
8m
8n, 8′n (R ) H) 54f(1:1) g
a Reaction in 1,4-dioxane. b Reaction for 2 h. c Reaction for 6 h. d 8′n
(R ) H) and 8o (R ) OMe) were also obtained in 11% and 29% yields,
respectively. e 1.6 equiv of 6n was used. f 8o was also obtained in 24%
g
1
yield. The ratio was determined by H NMR.
can be used as solvent) (entries 1 and 2). Importantly, the
reaction does not take place in the absence of the palladium
catalyst or in the presence of Pd(OAc)2(dppe) as a Pd2+
source.
Arylboronic acids containing electron-donating (entries
3-6) or -withdrawing groups (entries 7-11) serve as
nucleophiles in this process, as exemplified by the formation
of 8b-j in high yields. Alkenylative cyclization also occurs
with 7 to provide 1,4-diene 8k (entry 12). However, the two
nucleophiles 2-thiopheneboronic acid and triethylborane
display different behavior in contrast with that of other
substrates for the allene-aldehyde cyclization. For example,
cyclization reaction of 7 with 2-thiopheneboronic acid (6m)
is sluggish, even though its isomer 6l reacts in a normal
fashion (entries 13 and 14).13 Also, triethylborane (6n),
possessing ꢀ-hydrogens, does not undergo ethylative cy-
clization but rather produces the reduction products 8n and
8′n (R ) H) as a 1:1 mixture (entry 15).
Reaction of the 1,1-disubtituted allene-enone 9 leads to
formation of the tetrasubstituted alkene containing cyclo-
pentene 18 (Table 2, entry 1). Use of a PdCp(η3-allyl)/P(c-
Hex)3 combination7b in place of Pd(PPh3)4 promotes con-
version of the 1,3-disubstituted allene 10 to cyclized product
19 as a mixture of diastereomers (entry 2). The aldehyde
and methyl ketone appended alkenes 11 and 12, as well as
the phenyl ketone analogue 7, undergo Pd(PPh3)4-catalyzed
cyclization to produce the corresponding products 20 and
(4) Pd-catalyzed cyclizations of 1,2,7-trienes: (a) Zhu, G.; Zhang, Z.
Org. Lett. 2004, 6, 4041–4047. (b) Doi, T.; Yanagisawa, A.; Nakanishi, S.;
Yamamoto, K.; Takahashi, T. J. Org. Chem. 1996, 61, 2602–2603. (c) Doi,
T.; Yanagisawa, A.; Yamamoto, K.; Takahashi, T. Chem. Lett. 1996, 1085–
1086. (d) Doi, T.; Takasaki, M.; Nakanishi, S.; Yanagisawa, A.; Yamamoto,
K.; Takahashi, T. Bull. Chem. Soc. Jpn. 1998, 71, 2929–2935. (e) Ohno,
H.; Miyamura, K.; Mizutani, T.; Kadoh, Y.; Takeoka, Y.; Hamaguchi, H.;
Tanaka, T. Chem. Eur. J. 2005, 11, 3728–3741
.
(5) Ni-catalyzed cyclizations of 1,2,7-trienes: Chevliakov, M. V.;
Montgomery, J. J. Am. Chem. Soc. 1999, 121, 11139-11143.
(6) Pd-catalyzed cyclizations of allene-ynecarboxylate: (a) Gupta, A. K.;
Rhim, C. Y.; Oh, C. H. Tetrahedron Lett. 2005, 46, 2247–2250. (b) Oh,
C. H.; Park, D. I.; Jung, S. H.; Reddy, V. R.; Gupta, A. K.; Kim, Y. M.
Synlett 2005, 2092–2094
.
(7) (a) Tsukamoto, H.; Ueno, T.; Kondo, Y. J. Am. Chem. Soc. 2006,
128, 1406–1407. (b) Tsukamoto, H.; Ueno, T.; Kondo, Y. Org. Lett. 2007,
9, 3033–3036
.
(8) Pd-catalyzed intermolecular coupling reactions of allenes, aldehydes,
and arylboronic acids based on carbopalladation: (a) Hopkins, C. D.;
Malinakova, H. C. Org. Lett. 2004, 6, 2221–2224. (b) Hopkins, C. D.; Guan,
L.; Malinakova, H. C. J. Org. Chem. 2005, 70, 6848–6862
.
(9) Arylpalladium(II) species, formed by oxidative addition of arylbo-
ronic acid to palladium(0), are proposed to be intermediates in the Pd0-
catalyzed carbonylations of the boronic acids. (a) Ohe, T.; Ohe, K.; Uemura,
S.; Sugita, N. J. Organomet. Chem. 1988, 344, C5-C7. (b) Cho, C. S.;
Ohe, T.; Uemura, S. J. Organomet. Chem. 1995, 496, 221–226.
(10) The only example of the opposite regioselectivity of intermolecuar
carbopalladation is seen in reactions of allenes substituted with sulfones.
(a) Fu, C.; Ma, S. Org. Lett. 2005, 7, 1605–1607. The opposite regiose-
lectivity of intramolecular carbopalladation of allenes is reported in the
following. (b) Grigg, R.; Rasul, R.; Redpath, J.; Wilson, D. Tetrahedron
Lett. 1996, 37, 4609–4612. (c) Oppolzer, W.; Pimm, A.; Stammen, B.;
Hume, W. E. HelV. Chim. Acta 1997, 80, 623–639, See also ref 4a–d.
(11) Pd2+-diphosphine catalysts that are applicable to the carbopalla-
dation pathway do not promote the reactions described herein. Tsukamoto,
H.; Kondo, Y. Org. Lett. 2007, 9, 4227–4230, See also ref 2b.
(13) Organoboron reagents 6m,n do not serve as good nucleophiles in
direct cross-coupling reactions with allylic alcohols. (a) Tsukamoto, H.;
Sato, M.; Kondo, Y. Chem. Commun. 2003, 1200–1201. The 2-thienyl group
is used as dummy ligand in the Hiyama cross-coupling reaction. (b) Hosoi,
K.; Nozaki, K.; Hiyama, T. Chem. Lett. 2002, 138–139.
(12) There is only one example of allylmetalation of a 1,2,6-triene.
Nishikawa, T.; Shinokubo, H.; Ohshima, K. Org. Lett. 2003, 5, 4623–4626.
2634
Org. Lett., Vol. 10, No. 13, 2008

16 provides the cis-fused cyclopentane 25 containing an exo
(1-aryl)ethenyl group (entry 8). On the other hand, 1,2,5-triene
17 undergoes cyclization in the presence of Pd(PPh3)4 to afford
cyclopentene 26, in which the aryl group and ꢀ-carbon of the
enone are connected to the respective central sp- and terminal
sp2-carbons of the allene (entry 9).
Table 2. Arylative Cyclization of Trienes 9-17 with 6ca
A plausible mechanism for the arylative cyclization of allenyl
enone 7 is displayed in Scheme 2. In this pathway, the catalytic
Scheme 2
.
Possible Mechanism for the Arylative Cyclization of
7, 16, and 17
a Reaction with 1.2 equiv of 6c and 5 mol % of catalyst in MeOH at 80
°C. Pd(PPh3)4 (entries 1, 3, 4, 9) or PdCp(η3-C3H5)-P(c-Hex)3 (1:3) (entries
2, 5-8) was used as the catalyst. Ar ) C6H4-p-Me. b Reaction in 1,4-dioxane
in place of MeOH. c Cyclohexene 27 was also obtained in 9% yield.
d Cyclohexene 28 was also obtained in 6% yield. e Small amount of the
trans isomer was observed.
cycle is initiated by coordination and oxidative addition of both
the allene and enone moieties in 7 to Pd0 to form either [3,3,0]-
or [3,5,0]bicyclic palladacycles 30 and 31 (Scheme 2, top).
Transmetalation and protonation with the boronic acid 6, taking
place in either order, followed by reductive elimination of 32
at the less hindered allylic carbon regenerates the Pd0 catalyst
along with the cyclization product 8.
Formation of methyl ether 8o in reactions performed in
the absence of nucleophiles (Scheme 3, left) and incorpora-
21 (entries 3 and 4). Again, the Pd0 catalyst ligated with
P(c-Hex)3, a more σ-donating phosphine, is a more effective
catalyst for the arylative cyclization of less electron-
withdrawing ester-substituted alkene 13 (entry 5). Cyclization
reactions of the malonate 14 and nitro alkene 15 produce
major amounts of the respective cyclopentenes 23 and 24
along with minor quantities of the corresponding cylohexenes
27 and 28 (entries 6 and 7).14
Scheme 3. Cyclization of 7 in CD3OD and in the absence of 6a
The effects of tether length on the cyclization process were
examined. Pd/P(c-Hex)3-catalyzed reaction of the 1,2,7-triene
tion of a deuterium into the R-position of phenyl ketone in
8a in the reaction carried out in methanol-d4 (Scheme 3,
right) gives support to the mechanism for formation of 30
and 31.15
(14) In contrast to those promoted by Pd/P(c-Hex)3, Pd(PPh3)4-catalyzed
cyclizations of 14 and 15 provide cyclohexenes 27 and 28 as major products
along with minor amounts of cyclopentenes 23 and 24. These electron-
deficient alkenes should not form π-complexes readily with the Pd0 catalyst
that are ligated with less-σ-donating PPh3.
Org. Lett., Vol. 10, No. 13, 2008
2635

At this time, it is not possible to rule out an alternative
mechanism involving formation of π-allylpalladium 34 via
oxidative addition of the enone moiety in 7 to Pd0 followed
by insertion of the allene to generate intermediate 32 (Scheme
2, middle).16 However, reaction of 1,2,5-triene 38, containing
an internal enone, does not afford cyclopentene 40 by way
of intramolecular allene insertion of π-allylpalladium 42.
Rather, cyclohexene 39 is generated through an “anti-
Wacker”-type 6-endo cyclization (Scheme 4).17 The different
much higher tendency for Pd0 catalysts to form π-complexes
with electron-deficient alkenes rather than with the carbonyl
group. Palladacycle formation would be slowed by both
methyl substitution at the terminal allene carbon and the
presence of a less potent electron-withdrawing group at the
alkene. In contrast, the formation of palladacycles would be
promoted by the use of more σ-donating P(c-Hex)3 ligands
in place of PPh3 (Table 2, entries 2 and 5-7). The cyclization
of 1,2,7-triene 16 would proceed through the alkenylpalla-
dium intermediate 36, containing a cis-fused cyclopentane
ring, and provide the cis addition product 25 in contrast to
trans-selective cyclization of 5,6-dienals2a (Table 2, entry
8, and Scheme 2, bottom, left). On the other hand, “anti-
Wacker”-type cyclization would dominate in reaction of
1,2,5-triene 17, which, owing to the presence of a short tether,
cannot form a palladacycle (Table 2, entry 9, and Scheme
2, bottom, right).
Scheme 4. Arylative Cyclization of 1,2,5-Trienes 38
In summary, the studies described above have led to the
development of a Pd0-catalyzed arylative cyclization reaction
of allenyl enones with arylboronic acids that form five-
membered ring products. The cyclization reactions proceed
through pathways involving palladacycle-forming or “anti-
Wacker”-type oxidative additions to the Pd0 catalyst, the
relative efficiencies of which depend on the tether length in
the allenyl enones. The results of this study also suggest that
“anti-Wacker”-type oxidative additions observed in the
allene-aldehyde cyclization originate from the low tendency
for the Pd0 catalyst to form π-complexes with carbonyl
groups. Finally, the five-membered ring products generated
in these reactions should be versatile intermediates in
carbocycle synthesis since they contain a rich array of
preparatively important functional groups. Studies of trans-
formations of the functionalized cyclic compounds are
underway.
behavior of organoboron reagents 6m,n in reactions of
allene-aldehydes versus allene-enones (Table 1, entries 14
and 15) reflects the participation of different palladium
intermediates, i.e., σ-alkenyl- versus π-allylpalladium species,
respectively.18
The change from “anti-Wacker”-type oxidative addition
to palladacycle-forming addition is the consequence of the
(15) We also demomstrated that the reaction conditions did not transform
8a into 8a-d.
(16) It is reported that the oxidative addition of enone to the Pd0 occurs
in the presence of strong Brønsted or Lewis acid. (a) Ogoshi, S.; Yoshida,
T.; Nishida, T.; Morita, M.; Kurosawa, H. J. Am. Chem. Soc. 2001, 123,
1944–1950. (b) Ogoshi, S.; Morita, M.; Kurosawa, H. J. Am. Chem. Soc.
2003, 125, 9020–9021. See also: (c) Hanzawa, Y.; Yabe, M.; Oka, Y.;
Taguchi, T. Org. Lett. 2002, 4, 4061–4063. (d) Marshall, J. A.; Herold,
M.; Eidam, H. S.; Eidam, P. Org. Lett. 2006, 8, 5055–5508.
(17) We also observed that 1,2,6-triene 43 containing an allylic alcohol
or its regioisomer 44 did not afford the cyclization product 45 through a
π-allylpalladium intermediate.13a
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 pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) The difference results from the slower reductive elimination from
π-allylpalladium(II) than that from σ-alkenylpalladium(II). ꢀ-Hydrogen
elimination prior to reductive elmination would promote reductive cycliza-
tion of 7, leading to the formation of 8n and 8′n.
OL800509Z
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Org. Lett., Vol. 10, No. 13, 2008