Stereoselective construction of substituted chromans by palladium-catalyzed cyclization of propargylic carbonates with 2-(2-Hydroxyphenyl)acetates

Article abstract of DOI:10.1021/ol901964z

Highly substituted chromans have been constructed In a highly stereoselective manner by a palladium-catalyzed reaction of propargylic carbonates with 2-(2-hydroxyphenyl)acetates. Enantioselective reactions also successfully proceeded to give the optically active chromans with high enantioselectivity.

Full text of DOI:10.1021/ol901964z

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4752-4755
Stereoselective Construction of
Substituted Chromans by
Palladium-Catalyzed Cyclization of
Propargylic Carbonates with
2-(2-Hydroxyphenyl)acetates
Masahiro Yoshida,* Mariko Higuchi, and Kozo Shishido
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokushima, 1-78-1
Sho-machi, Tokushima 770-8505, Japan
yoshida@ph.tokushima-u.ac.jp
Received August 24, 2009
ABSTRACT
Highly substituted chromans have been constructed in a highly stereoselective manner by a palladium-catalyzed reaction of propargylic
carbonates with 2-(2-hydroxyphenyl)acetates. Enantioselective reactions also successfully proceeded to give the optically active chromans
with high enantioselectivity.
Transition-metal-catalyzed reactions of propargylic compounds
have received considerable attention and have been extensively
studied as a result of their versatile and specific reactivity.1 The
palladium-catalyzed reaction of propargylic compounds with
soft nucleophiles is one of the most successful chemical
processes developed to date.2-5 For example, a substrate
having two nucleophilic moieties within the molecule reacted
with propargylic carbonate via palladium catalysis to generate
the π-allylpalladium intermediate, which further reacted with
the other nucleophilic part intramolecularly to afford the
cyclized product (Scheme 1). In our studies on the palladium-
catalyzed reaction of propargylic compounds with soft
nucleophiles,4e,5 we focused on the nucleophilic activity of
2-(2-hydroxyphenyl)acetates. By introducing a nucleophilic
oxygen and a carbon moiety within the substrate, we thought
that substituted chromans, common structures in many phar-
maceutical and agricultural compounds,6 could be construc-
ted in one step. Herein, we describe the palladium-catalyzed
reaction of propargylic carbonates 1 with 2-(2-hydroxyphenyl)-
acetates 2, in which functionalized chromans 3 have been
constructed in a highly stereoselective manner (Scheme 2).
(3) For recent examples of palladium-catalyzed reactions of propargylic
compounds with nucleophiles, see: (a) Kozawa, Y.; Mori, M. Tetrahedron
Lett. 2001, 42, 4869. (b) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2002,
43, 1499. (c) Ohno, H.; Hamaguchi, H.; Ohata, M.; Tanaka, T. Angew.
Chem., Int. Ed. 2003, 42, 1749. (d) Kozawa, Y.; Mori, M. J. Org. Chem.
2003, 68, 8068. (e) Tsubakiyama, M.; Sato, Y.; Mori, M. Heterocycles 2004,
64, 27. (f) Ambrogio, I.; Cacchi, S.; Fabrizi, G. Org. Lett. 2006, 8, 2083.
(g) Duan, X.-H.; Guo, L.-N.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. Org. Lett.
2006, 8, 5777. (h) Guo, L.-N.; Duan, X.-H.; Bi, H.-P.; Liu, X.-Y.; Liang,
Y.-M. J. Org. Chem. 2007, 72, 1538. (i) Bi, H.-P.; Liu, X.-Y.; Gou, F.-R.;
Guo, L.-N.; Duan, X.-H.; Liang, Y.-M. Org. Lett. 2007, 9, 3527. (j) Bi,
H.-P.; Liu, X.-Y.; Gou, F.-R.; Guo, L.-N.; Duan, X.-H.; Shu, X.-Z.; Liang,
Y.-M. Angew. Chem., Int. Ed. 2007, 46, 7068. (k) Ohno, H.; Okanao, A.;
Kosaka, S.; Tsukamoto, K.; Ohata, M.; Ishihara, K.; Maeda, H.; Tanaka,
T.; Fujii, N. Org. Lett. 2008, 10, 1171. (l) Bi, H.-P.; Guo, L.-N.; Gou, F.-
R.; Duan, X.-H.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2008, 73, 4713.
(1) Tsuji, J. Palladium Reagents and Catalysts: InnoVations in Organic
Synthesis; Wiley: New York, 1995; p 453.
(2) (a) Tsuji, J.; Watanabe, I.; Minami, I.; Shimizu, I. J. Am. Chem.
Soc. 1985, 107, 2196. (b) Minami, I.; Yuhara, M.; Watanabe, H.; Tsuji, J.
J. Organomet. Chem. 1987, 334, 225. (c) Tsuji, J.; Mandai, T. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2589
.
10.1021/ol901964z CCC: $40.75
Published on Web 09/21/2009
 2009 American Chemical Society

Scheme 1
.
Reactivity of Propargylic Compounds with Soft
Nucleophiles
Table 1. Effect of Solvent and Ligand in the Reaction of 1a
with 2a
entry
solvent
ligand
DPPF
DPPF
DPPF
DPPB
DPPPentane
Tol-BINAP
yield of 3aa (%)
Scheme 2. Palladium-Catalyzed Reaction of Propargylic
Carbonates 1 with 2-(2-Hydroxyphenyl)acetates 2
1
2
3
4
5
6
dioxane
DMF
DMSO
DMSO
DMSO
DMSO
18
78
99
81
86
44
Scheme 3. Hydrolysis of 3aa
The initial reactions were attempted using 1,3-diphenyl-
prop-2-ynyl methyl carbonate (1a) and methyl 2-(2-hydrox-
yphenyl)acetate (2a). When 1a and 2a were subjected to the
reaction in the presence of 5 mol % Pd2(dba)3·CHCl3 and
20 mol % 1,1′-bis(diphenylphosphino)-ferrocene (DPPF) in
dioxane at 120 °C for 5 min, the substituted chroman 3aa
containing the trans stereochemistry with the (Z)-alkenyl
moiety was obtained in 18% yield as a single stereoisomer
(Table 1, entry 1). After experimenting with various solvents
and ligands (entries 2-6), we found that the yield of 3aa
was dramatically improved to 99% when the reaction was
carried out in DMSO (entry 3). The structure of the resulting
product 3aa was confirmed by an X-ray crystallographic
analysis of the carboxylic acid 4, which was prepared by
hydrolysis of 3aa (Scheme 3).
Having identified a useful set of reaction conditions, we
next carried out a study of the substrate scope (Table 2).
Benzyl 2-(2-hydroxyphenyl)acetate (2b) successfully reacted
with 1a to produce the chroman 3ab in 99% yield (entry 1).
When the reaction of substrates 2c and 2d having a methoxy
group at the 2- and 4-positions on the benzene ring was
carried out, the corresponding products 3ac and 3ad were
obtained in 80% and 88% yields, respectively (entries 2 and
3). The naphthyl-substituted substrate 2e also reacted with
1a to deliver the product 3ae in 51% yield (entry 4). The
reaction of di-4-fluorophenyl-substituted propargylic carbon-
ate 1b with 2b uneventfully proceeded to afford the chroman
3bb in 66% yield (entry 5). Similarly, the propargylic acetate
1c,7 containing two 4-methoxyphenyl groups, was converted
to the corresponding product 3cb in 95% yield (entry 6).
Since in all cases the resulting products 3aa-3ae and
3bb-3cb had been obtained as a single stereoisomer, it was
determined that the reaction had proceeded in a highly
stereoselective manner.
Next we evaluated the reactivity of the propargylic
carbonate 1d, which has no substituent at the terminal alkynyl
position (Scheme 4). Thus the reaction of 1d with 2a
proceeded to give the desired chroman 3da in 26% yield,
along with the isomerized product 5 in 26% yield (Scheme
4).8
(4) (a) Labrosse, J.-R.; Lhoste, P.; Sinou, D. Tetrahedron Lett. 1999,
40, 9025. (b) Labrosse, J.-R.; Lhoste, P.; Sinou, D. Org. Lett. 2000, 2, 527.
(c) Damez, C.; Labrosse, J.-R.; Lhoste, P.; Sinou, D. Tetrahedron Lett. 2003,
44, 557. (d) Duan, X.-H.; Liu, X.-Y.; Guo, L.-N.; Liao, M.-C.; Liu, W.-
M.; Liang, Y.-M. J. Org. Chem. 2005, 70, 6980. (e) Yoshida, M.; Higuchi,
M.; Shishido, K. Tetrahedron Lett. 2008, 49, 1678.
A plausible mechanism, which may account for the highly
stereoselective nature of this process, is shown in Scheme
5. On reacting with the palladium catalyst, the propargylic
carbonate 1 undergoes decarboxylation to give the π-prop-
(5) (a) Yoshida, M.; Nemoto, H.; Ihara, M. Tetrahedron Lett. 1999, 40,
8583. (b) Yoshida, M.; Ihara, M. Angew. Chem., Int. Ed. 2001, 40, 616. (c)
Yoshida, M.; Fujita, M.; Ishii, T.; Ihara, M. J. Am. Chem. Soc. 2003, 125,
4874. (d) Yoshida, M.; Fujita, M.; Ihara, M. Org. Lett. 2003, 5, 3325. (e)
Yoshida, M.; Komatsuzaki, Y.; Nemoto, H.; Ihara, M. Org. Biomol. Chem.
2004, 3099. (f) Yoshida, M.; Ihara, M. Chem.sEur. J. 2004, 2886. (g)
Yoshida, M.; Morishita, Y.; Ihara, M. Tetrahedron Lett. 2005, 46, 3669.
(h) Yoshida, M.; Murao, T.; Sugimoto, K.; Ihara, M. Synlett 2006, 1923.
(6) (a) Dean, F. M. Naturally Occurring Oxygen Ring Compounds;
Butterworths: London, 1963. (b) Ellis, G. P.; Lockhart, I. M. Chromans
and Tocopherols; Wiley: New York, 1977. (c) Saengchantara, S. T.;
Wallace, T. W. Nat. Prod. Rep. 1986, 3, 465.
(7) When the corresponding propargylic carbonate was examined, the
reaction resulted in the decomposition of the substrate, presumably because
of the instability of the carbonate moiety caused by the electron-donating
effect of the methoxy groups.
(8) We also attempted other non-symmetrical substrates such as aryl-
and alkyl-substituted substrates at the terminal alkynyl and propargylic
position, but complex mixtures including regio- and stereoisomers were
produced in each cases.
Org. Lett., Vol. 11, No. 20, 2009
4753

likely the result of steric factors that influence the relative
energies of the competing transition states TS A and TS B.
It was expected that the transition state TS A, leading to the
product 3, would have lower energy because of the absence
of steric repulsion between the ester and aryl groups that is
present in TS B, which would furnish the diastereomer 3′.10
Table 2. Reactions Using Various Substrates 1a-c and 2b-d
We next turned our attention to the application of this
process to an enantioselective reaction. Although numbers
of asymmetric reactions of allylic compounds with nucleo-
philes are known, examples of palladium-catalyzed asym-
metric reactions using propargylic compounds with nucleo-
philes are limited.4b,c,5c In the reaction we designed, an
asymmetric center is formed via the achiral π-allylpalladium
intermediate 8, and it is anticipated that the absolute
configuration of the newly formed stereogenic center could
be controlled by chiral palladium catalysts. To achieve this
enantioselective process, we first examined the reactions of
1a with 2b under various conditions (Table 3). When the
reaction was carried out in the presence of 5 mol %
Pd2(dba)3·CHCl3, 20 mol % (S)-BINAP in DMSO at 120
°C, the optically active chroman (3R,4S)-3ab formed in 62%
yield with 71% ee (entry 1).11
Table 3. Enantioselective Cyclization of 1a with 2b
entry
ligand
temp (°C)
yield (%)
ee (%)a
a The reaction was carried out in the presence of 2 equiv of K3PO4.
1
2
3
4
(S)-BINAP
120
120
120
120
120
80
62
59
78
53
51
55
59
71
68
70
52
91
90
96
(S)-Tol-BINAP
(S)-H8-BINAP
(S)-DM-BINAP
(S)-SEGPHOS
(S)-SEGPHOS
(S)-SEGPHOS
Scheme 4. Reaction of 1d with 2a
5
6
7b
60
a Enantiomeric excess was determined by HPLC using a chiral column.
b The reaction was carried out for 3 h.
After several attempts using various chiral phosphine
ligands (entries 2-5), we discovered that when (S)-SEG-
PHOS was used, the enantiomeric excess increased to 91%
(entry 5). Better results were obtained under low reaction
temperature (entries 6 and 7), and (3R,4S)-3ab was produced
in 96% ee by carrying out the reaction at 60 °C for 3 h (entry
7).
argylpalladium complex 6,9 which further reacts with the
2-(2-hydroxyphenyl)acetate 2 to lead to the anti-π-allylpal-
ladium intermediate 8. Complex 8 is then subjected to the
intramolecular attack of the enolate to produce the chroman
3, which contains the trans stereochemistry and the (Z)-
alkenyl moiety. The observed high diastereoselectivity is
In conclusion, the effort described above has led to the
development of the palladium-catalyzed reaction of propar-
(10) As another hypothesis, the initially produced cis-product 3′ was
epimerized to the thermodynamically preferred trans product 3.
(11) The absolute configuration was determined to be 3R,4S by Kusumi’s
PGME method: Nagai, Y.; Kusumi, T. Tetrahedron Lett. 1995, 36, 1853.
See Supporting Information.
(9) Tsutsumi, K.; Ogoshi, S.; Nishiguchi, S.; Kurosawa, H. J. Am. Chem.
Soc. 1998, 120, 1938.
4754
Org. Lett., Vol. 11, No. 20, 2009

Scheme 5. Proposed Reaction Mechanism
gylic carbonates with 2-(2-hydroxyphenyl)acetates. The
process produces substituted chromans having the trans
stereochemistry with the (Z)-alkenyl moiety in a highly
stereoselective manner. Enantioselective reactions success-
fully proceeded in the presence of SEGPHOS to give the
optically active chromans with high enantioselectivity.
Biologically active compounds having similar chroman
structures have been reported,6 and our methodology would
provide a new and significant protocol for the synthesis of
these compounds.
Acknowledgment. This study was supported in part by a
Grant-in-Aid for the Encouragement of Young Scientists (B)
from the Japan Society for the Promotion of Science (JSPS)
and the Program for the Promotion of Basic and Applied
Research for Innovations in the Bio-oriented Industry (BRAIN).
Supporting Information Available: Experimental pro-
cedures and compound characterization data, including CIF
file. This material is available free of charge via the Internet
at http://pubs.acs.org.
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