Enantioseiective aryiative cyclization of allenyl aldehydes with arylboronic acids under Pd(II)-diphosphine catalysis

Article abstract of DOI:10.1021/ol702966j

A Pd(OAc)₂-SEGPHOS combination catalyzes the first enantioseiective aryiative cyclization of allenyl aldehydes with aryiboronic acids to provide c/s-fused fiveand six-membered cyclic homoallylic alcohols. The excellent diastereoand enantioselectivity and the fact that the reaction proceeds at room temperature in the absence of any additives make the process highly practical.

Full text of DOI:10.1021/ol702966j

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1047-1050
Enantioselective Arylative Cyclization of
Allenyl Aldehydes with Arylboronic
Acids under Pd(II)-diphosphine Catalysis
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
hirokazu@mail.pharm.tohoku.ac.jp
Received December 8, 2007
ABSTRACT
A Pd(OAc)2−SEGPHOS combination catalyzes the first enantioselective arylative cyclization of allenyl aldehydes with arylboronic acids to
provide cis-fused five- and six-membered cyclic homoallylic alcohols. The excellent diastereo- and enantioselectivity and the fact that the
reaction proceeds at room temperature in the absence of any additives make the process highly practical.
Organoboron reagents are generally nontoxic, commercially
available, stable, and compatible with various functional
groups, and they are often employed for a wide variety of
transition metal-catalyzed carbon-carbon bond formations.1
Compared with organometallics such as Li, Mg, and Zn, the
boron reagents are favorable for the alkylative cyclization
reaction of unsaturated carbon-carbon bonds containing
carbonyl groups to provide structurally complex cyclic
compounds because their lower nucleophilicity causes no
competitive 1,2-addition to the carbonyl groups.2 In addition
to the alkyne-aldehyde cyclization,3 we have recently
developed Pd0/monophosphine-catalyzed alkylative cycliza-
tion of 3,4- and 4,5-dienals, leading to 3-substituted 3-cy-
clopentenols and cyclohexenols.4 However, this catalyst
turned out to be unsuitable for the cyclization of 5,6-dienal
1a and provided five-membered cyclic alcohols 2aA and 3aA
in poor yield and selectivity (Scheme 1, top). In our hands,
Scheme 1. Pd(PPh3)4- and Pd(OAc)2(dppe)-Catalyzed
Arylative Cyclization of Allenyl Aldehyde 1a
(1) (a) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169-196. (b)
Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829-2844. (c) Hayashi,
T. Bull. Chem. Soc. Jpn. 2004, 77, 13-21. (d) Miura, T.; Murakami, M.
Chem. Commun. 2007, 217-224.
(2) (a) Shintani, R.; Okamoto, K.; Otomaru, Y.; Ueyama, K.; Hayashi,
T. J. Am. Chem. Soc. 2005, 127, 54-55. (b) Miura, T.; Sasaki, T.;
Nakazawa, H.; Murakami, M. J. Am. Chem. Soc. 2005, 127, 1390-1391.
(c) Miura, T.; Shimada, M.; Murakami, M. Synlett 2005, 667-669. (d)
Matsuda, T.; Makino, M.; Murakami, M. Angew. Chem., Int. Ed. 2005, 44,
4608-4611. (e) Miura, T.; Shimada, M.; Murakami, M. Angew. Chem.,
Int. Ed. 2005, 44, 7598-7600. (f) Miura, T.; Shimada, M.; Murakami, M.
Tetrahedron 2007, 63, 6131-6140.
reaction conditions for Pd2+- or Rh1+-catalyzed intermolecu-
lar coupling of allenes, aldehydes, and arylboronic acids5
(3) (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.
(4) Tsukamoto, H.; Matsumoto, T. T.; Kondo, Y. J. Am. Chem. Soc.
2008, 130, 388-389.
10.1021/ol702966j CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/23/2008

were not applicable to the intramolecular reaction. On the
other hand, Lu’s6 and our groups7 independently discovered
that diphosphine-ligated Pd2+ catalysts promoted cis-selective
arylative cyclization of alkyne-carbonyl compound through
transmetalation of the Pd2+ catalysts with arylboronic acids
and successive insertions of the alkyne and the intramolecular
carbonyl group into the C-Pd bonds. Employment of Pd-
(OAc)2(dppe)8 instead of Pd(PPh3)4 for the cyclization of 1a
greatly improves the yield and selectivity to provide cis-
addition product 2aA exclusively (Scheme 1, bottom). The
availability of chiral diphosphine ligands invokes develop-
ment of its asymmetric process, which has never been
achieved by these and other reagents.9,10 Herein, we describe
the first enantioselective arylative cyclization of 5,6- and 6,7-
dienals with arylboronic acids under Pd2+-diphosphine
catalysis.
reaction in CH3CN leading to formation of (3R,4R)-2aB in
45% ee (entry 5). To improve the enantioselectivity, further
ligand screening of chiral diphosphines shown in Figure 1
were conducted.
This effort began by investigating solvent effects on the
asymmetric arylative cyclization of 1a with p-acetylphenyl-
boronic acid (4B) in the presence of Pd(OAc)2-(S,S)-
CHIRAPHOS complex as a catalyst (Table 1). In contrast
Table 1. Solvent Effects on Asymmetric Arylative Cyclization
of 1a with 4B Using Pd(OAc)2-(S,S)-CHIRAPHOS Complex
Figure 1. Chiral diphosphine ligands screened in the asymmetric
cyclization of 1a with 4A. Reaction with 1.5 equiv of 4A, 10 mol
% of Pd(OAc)2 and diphosphine at rt. Major enantiomer was
(3S,4S)-2aA except for CHIRAPHOS and DIPAMP. (a) Reaction
at 0 °C. (b) Phenylated product 2aF was also obtained in 22, 17,
and 5% yield for BINAP, H8-BINAP, and SEGPHOS, respectively.
(c) p-Methylphenylated product 2aC was also obtained in 19%
yield.
entry
solvent
CH2Cl2
1,4-dioxane
THF
time (h)
yield (%)
ee (%)a
1
2
3
1
2
2
quant
quant
99
13
-10
12
Employment of C2-tethered CHIRAPHOS, NORPHOS,
DIPAMP, C3-tethered BDPP, C4-tethered DIOP, and PHA-
NEPHOS with Pd(OAc)2 for the cyclization of 1a with
p-methoxyphenylboronic acid (4A) gives 2aA in poor to
moderate enantioselectivity (Figure 1). In contrast to these
diphosphine ligands, BINAP and its analogues11 containing
an axially chiral biaryl structure dramatically improve the
enantioselectivity of the cyclization. However, the use of
BINAP and TolBINAP as the ligands is accompanied by
the formation of a considerable amount of phenylated product
2aF and p-methylphenylated product 2aC (Table 2), respec-
tively. These byproducts should be generated by aryl-aryl
exchange12 between p-methoxyphenyl group and the diphos-
phine bound to the Pd center prior to the allene insertion
step. (S)-SEGPHOS turns out to be the best ligand to afford
4
5
6b
DMF
CH3CN
t-BuOH
2
3
34
96
88
84
38
45
24
a The ee values were determined by chiral HPLC, and the major
enantiomer was determined by Mosher’s method as (3R,4R) except for entry
2. b Reaction at 50 °C.
to the cyclization reactions recently developed by us,3,4,7 the
reaction proceeds even at room temperature and is retarded
by use of protic solvents (entries 1-5 vs 6). The solvent
also affects the enantioselectivity of the cyclization, with
(5) (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. (c) Hopkins, C. D.; Malinakova, H. C. Org. Lett. 2006, 8,
5971-5974. (d) Bai, T.; Ma, S.; Jia, G. Tetrahedron 2007, 63, 6210-
6215.
(10) Ni0-catalyzed alkylative cyclization with organozinc reagents: (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.
(11) (a) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345-350.
(b) Akutagawa, S. Appl. Catal., A 1995, 128, 171-207. (c) Berthod, M.;
Mignani, G.; Woodward, G.; Lemaire, M. Chem. ReV. 2005, 105, 1801-
1836.
(12) (a) Macgregor, S. A. Chem. Soc. ReV. 2007, 36, 67-76. (b) Kong,
K.-C.; Cheng, C.-H. J. Am. Chem. Soc. 1991, 113, 6313-6315. (c)
Segelstein, B. E.; Butler, T. W.; Chenard, B. L. J. Org. Chem. 1995, 60,
12-13. (e) Goodson, F. E.; Wallow, T. I.; Novak, B. M. J. Am. Chem.
Soc. 1997, 119, 12441-12453.
(6) (a) Song, J.; Shen, Q.; Xu, F.; Lu, X. Org. Lett. 2007, 9, 2947-
2950. (b) Yang, M.; Zhang, X.; Lu, X. Org. Lett. 2007, 9, 5131-5133.
(7) Tsukamoto, H.; Kondo, Y. Org. Lett. 2007, 9, 4227-4230.
(8) (a) Marson, A.; van Oort, A. B.; Mul, W. P. Eur. J. Inorg. Chem.
2002, 3028-3031. (b) Bianchini, C.; Meli, A.; Oberhauser, W. Organo-
metallics 2003, 22, 4281-4285.
(9) Pd0-catalyzed arylative cyclization with aryl iodides and distannane
or In: (a) Ha, Y.-H.; Kang, S.-K. Org. Lett. 2002, 4, 1143-1146. (b) Kang,
S.-K.; Lee, S.-W.; Jung, J.; Lim, Y. J. Org. Chem. 2002, 67, 4376-4379.
See also silylative and stannylative cyclization: (c) Kang, S.-K.; Ha, Y.-
H.; Ko, B.-S.; Lim, Y.; Jung, J. Angew. Chem., Int. Ed. 2002, 41, 343-
345. (d) Yu, C.-M.; Youn, J.; Lee, M.-K. Org. Lett. 2005, 7, 3733-3736.
1048
Org. Lett., Vol. 10, No. 6, 2008

Table 2. Asymmetric Arylative Cyclization of 1a with 4B-K
Table 3. Asymmetric Arylative Cyclization of 1b-g with 4Ba
Using Pd(OAc)2/SEGPHOS Catalytic System
entry
R
2a
time (h) yield (%) ee (%)a
1
2
3
4
5
6
7b
8
9
10
11c,d
p-Me-C6H4 4C
m-Me-C6H4 4D
o-Me-C6H4 4E
C6H5 4F
p-Br-C6H4 4G
p-Ac-C6H4 4B
p-Ac-C6H4 4B
m-NO2-C6H4 4H
2-thiophene 4I
3-thiophene 4J
2aC
2aD
2aE
2aF
2aG
2aB
2aB
2aH
2aI
7
10
48
6
4
3
12
4
4
4
4
90
93
83
90
92
quant
96
85
85
97
97
95
97
97
98
98
97
89
95
81
2aJ
78
58
(E)-â-styrene 4K 2aK
a The ee values were determined by chiral HPLC. b Reaction with 3 mol
% of catalysts. c Reaction with 20 mol % of catalysts. d Trans isomer 3aK
was also obtained in 7% yield (56% ee).
the maximum optical yield of (3S,4S)-2aA (93% ee)13 and
minimize the formation of 2aF.14
Arylboronic acids with electron-donating (Table 2, entries
1-3) or -withdrawing (entries 5-8) groups serve as nucleo-
philes in this process, which leads to exclusive formation of
cyclized products 2aB-H in high yields and enantioselec-
tivity.15 In contrast to the Pd0-catalyzed alkylative cyclization
of 3,4- and 4,5-dienals,4 electron-rich boronic acids require
longer reaction times than their electron-deficient counter-
parts. The cyclization with o-methylphenylboronic acid (4E)
is significantly slow but preserves high enantioselectivity
(entry 3). The catalyst loading can be reduced from 10 to 3
mol % (entry 6 vs 7). These cyclization reactions also occur
with heteroarylboronic acids 4I-J (entries 9, 10). However,
alkenylboronic acid 4K provides the cyclized product 2aK
in lower yield, diastereo-, and enantioselectivity (entry 11).
Arylative cyclization reactions of allenyl aldehydes 1b-d
containing Boc-protected nitrogen, ether oxygen, and tertiary
carbon with 4B require longer times but provide homoallylic
alcohols 2b-dB in good yields with high ee values (Table
3, entries 1-3). Allenyl aldehyde 1e with a longer tether
also undergoes the stereoselective cyclization to give cis-
fused six-membered cyclic alcohol 2eB in excellent yield
and enantioselectivity (entry 4). The use of 1,1-disubstituted
allene-aldehyde 1f leads to formation of enantiomerically
a Reaction with 1.5 equiv of 4B and 20 mol % of Pd(OAc)2 and (S)-
SEGPHOS in CH3CN at rt. Ar ) C6H4-p-Ac. b The ee values were
determined by chiral HPLC. c Reaction with 10 mol % of catalysts.
d Reaction at 50 °C.
pure 2fB containing a quaternary carbon center (entry 5).
The cyclization of methyl ketone 1g requires higher reaction
temperature and decreases the optical yield of 2gB (entry
6).
The plausible mechanism for the arylative cyclization is
outlined in Scheme 2. Transmetalation of diphosphine-ligated
Pd2+ catalyst 5 with arylboronic acid 4 leads to arylpalla-
dium(II) intermediate 6. Polar solvents such as acetonitrile
would facilitate dissociation of an acetate anion from 6 to
generate a cationic arylpalladium(II) 7.16 Regio- and stereo-
selective carbopalladation17 of allene 1 with 7 from the less
hindered side of distal allene π-system would produce anti-
η3-allylpalladium(II) 8a kinetically. The anti isomer 8a could
(16) The less polar solvent would make the acetate anion remain
coordinated on the Pd2+ species and change the tetracoordinate intermediate
9b into different intermediates unfavorable for the enantioselective cycliza-
tion (Table 1). We also observed that enantioselectivities of the cyclization
of 1a with 4B using Pd(CH3CN)2(BF4)2 as a cationic Pd2+ source hardly
depended on reaction solvents. Mikami, K.; Hatano, M.; Akiyama, K. Top.
Organomet. Chem. 2005, 14, 279-321 and references therein.
(17) Regioselective carbopalladation of allenes usually produce C2-
carbon-substituted π-allylpalladium(II): (a) Cazes, B. Pure Appl. Chem.
1990, 62, 1867-1878. (b) Ma, S. Pure Appl. Chem. 2006, 78, 197-208.
(c) Ma, S. Acc. Chem. Res. 2003, 36, 701-712. (d) Bates, R. W.; Satcharoen,
V. Chem. Soc. ReV. 2002, 31, 12-21. (e) Zimmer, R.; Dinesh, C. U.;
Nandanan, E.; Khan, F. A. Chem. ReV. 2000, 100, 3067-3125. (f) Balme,
G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003, 4101-4111.
(13) The absolute configurations of major enantiomers were determined
by Mosher’s method. (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa,
H. J. Am. Chem. Soc. 1991, 113, 4092-4096. (b) Dale, J. A.; Dull, D. L.;
Mosher, H. S. J. Org. Chem. 1969, 34, 2543-2549. (c) Dale, J. A.; Mosher,
H. S. J. Am. Chem. Soc. 1973, 95, 512-519.
(14) SEGPHOS, having a narrower dihedral angle than BINAP, would
accelerate the allene insertion into the Ar-Pd bond and minimize the aryl-
aryl exchange. Shimizu, H.; Nagasaki, I.; Matsumura, K.; Sayo, N.; Saito,
T. Acc. Chem. Res. 2007, 40, 1385-1393.
(15) In contrast to 4A, the boronic acids 4B-K were exclusively
incorporated into the products.
Org. Lett., Vol. 10, No. 6, 2008
1049

Scheme 2. Possible Mechanism for the Arylative Cyclization
of 1a
Scheme 3. Transition States (TS) for 9b and 9b′
enantioselectivity with ketone 1g could be attributed to a
methyl group intruding into the phenyl ring of SEGPHOS
in 9b (R ) Me).
In summary, we have developed the first enantioselective
arylative cyclization reactions of allenyl aldehydes with
arylboronic acids under Pd2+-diphosphine catalysis. The
excellent diastereo- and enantioselectivity and the fact that
the reaction proceeds at room temperature in the absence of
any additives make the process highly practical. Cyclic
homoallylic alcohol products generated in these reactions
should be useful intermediates in hetero- and carbocycle
synthesis since they contain a rich array of preparatively
important functional groups. Further studies probing the
detailed mechanism and expanding the scope of the cycliza-
tion process are underway.
be converted to syn isomer 8b through π-σ-π isomeriza-
tion, but the equilibrium would favor 8a again due to its
release from allylic 1,2-strain inherent in 8b.17a Then,
isomerization of η3-allylpalladium(II) 8a into η1-allylpalla-
dium(II) can form six-membered cyclic transition states 9a
and 9b18 for the intramolecular allylation of the carbonyl
leading to trans- and cis-addition products, respectively. Cis-
specific addition9 indicates that the transition state 9b is more
favorable than 9a having ring strain and this is transformed
into the alkoxopalladium(II) 10. Transmetalation of 10 (or
protonation of 10 prior to the transmetalation) with 4
reproduces the arylpalladium(II) 7 along with the cis-addition
product 2. Furthermore, the stereochemical outcome would
indicate that the enantioselectivity results from severe steric
repulsion between the axial aryl group in 9b′ and an
equatorial phenyl group in (S)-SEGPHOS, a factor which is
not present in transition state 9b (Scheme 3). A loss of
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. BINAP,
TolBINAP, XylBINAP, H8-BINAP, and SEGPHOS were
supplied by Takasago International Corporation.
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) (a) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207-2293. (b)
Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763-2793.
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