Palladium-catalyzed enantiospecific reaction of propargylic carbonates with phenols: Cascade chirality transfer

Article abstract of DOI:10.1021/ol0351753

(Matrix presented) A cascade chirality transfer process has been achieved by the palladium-catalyzed reaction of substituted propargylic carbonates with phenols. The reaction proceeds in a highly enantiospecific manner to produce chiral cyclic carbonates, which supports the existence of the π-propargylpalladium intermediate in the reaction mechanism. The (E)- and (Z)-selectivity of the products can be controlled by choice of the phosphine ligand.

Full text of DOI:10.1021/ol0351753

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3325-3327
Palladium-Catalyzed Enantiospecific
Reaction of Propargylic Carbonates with
Phenols: Cascade Chirality Transfer
Masahiro Yoshida,* Mika Fujita, and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku UniVersity, Aobayama, Sendai, 980-8578, Japan
mihara@mail.pharm.tohoku.ac.jp
Received June 25, 2003
ABSTRACT
A cascade chirality transfer process has been achieved by the palladium-catalyzed reaction of substituted propargylic carbonates with phenols.
The reaction proceeds in a highly enantiospecific manner to produce chiral cyclic carbonates, which supports the existence of the
π-propargylpalladium intermediate in the reaction mechanism. The (E)- and (Z)-selectivity of the products can be controlled by choice of the
phosphine ligand.
Palladium-catalyzed reactions of propargylic compounds with
soft nucleophiles serve as a useful method for the construc-
tion of carbon-carbon and carbon-heteroatom bonds.1 In
these processes, allenylpalladium complexes are formed
initially, and these complexes undergo secondary reactions
with nucleophiles to form π-allylpalladium intermediates.
Since the first report by Tsuji in 1985,2 a large variety of
reactions in this family have been developed and applied in
the preparation of various organic substances.1,3 However,
to the best of our knowledge, studies examining stereochem-
ical features of these processes have not been reported. Thus,
in contrast to the well-known palladium-catalyzed allylation
process, which proceeds via the formation of a π-allylpal-
ladium complex followed by addition of a nucleophile with
overall retention of configuration,4 the stereochemical course
of the palladium-catalyzed nucleophilic substitution reac-
tions of asymmetric propargylic substrates is unknown
(Scheme 1).5
Scheme 1
(1) For reviews on palladium-catalyzed reactions of propargylic com-
pounds, see: (a) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140. (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.
(2) Tsuji, J.; Watanabe, H.; Minami, I.; Shimizu, I. J. Am. Chem. Soc.
1985, 107, 2196.
(3) For recent examples of similar types of palladium-catalyzed reactions
of propargylic carbonates with nucleophiles, see: (a) Fournier-Nguefack,
C.; Lhoste, P.; Sinou, D. Synlett 1996, 553. (b) Yoshida, M.; Nemoto, H.;
Ihara, M. Tetrahedron Lett. 1999, 40, 8583. (c) Labrosse, J.-R.; Lhoste, P.;
Sinou, D. Tetrahedron Lett. 1999, 40, 9025. (d) Labrosse, J.-R.; Lhoste,
P.; Sinou, D. Org. Lett. 2000, 2, 527. (e) Kozawa, Y.; Mori, M. Tetrahedron
Lett. 2001, 42, 4869. (f) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2002,
43, 1499. (g) Damez, C.; Labrosse, J.-R.; Lhoste, P.; Sinou, D. Tetrahedron
Lett. 2003, 44, 557.
Recently studies in our laboratory have uncovered a novel
palladium-catalyzed cascade reaction of propargylic carbon-
10.1021/ol0351753 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/06/2003

Table 1. Palladium-Catalyzed Reaction of Racemic
Propargylic Carbonates 1a-d with p-Methoxyphenol 2aa,b
Table 2. Palladium-Catalyzed Reaction of Chiral Propargylic
Carbonates 1a,b with Phenols 2a-ea
entry
substrate
ligand
product
yield (%)c
Z:E
yield
ee (%)e,f
3a a e
3a a
4a a e
4a a
4a a
3ba f
3ca f
66
47
40
42
20 (30)
81
32 (47)
tr
10:1g
1:3.3g
6.4:1h
8:1h
Z only
3.7:1g
Z only
entry substrate
phenol
product (%) Z,S:E,Rd Z,S/E,R
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1c
1d
dppe
dppp
dppb
dppf
1b
2c
3b
4c
5b
6c
7b
8b
9b
10c
(S)-1a 2a R′ ) 4-methoxy 3a a
(S)-1a 2a R′ ) 4-methoxy 3a a
(S)-1a 2b R′ ) 2-methoxy 3a bg
(S)-1a 2b R′ ) 2-methoxy 3a b
(S)-1a 2c R′ ) 4-methyl
(S)-1a 2c R′ ) 4-methyl
(S)-1a 2d R′ ) 4-fluoro
(S)-1a 2e 1-naphthol
66 10:1
47 1:3.3
65 7:1
36 E,R only 92
72 5.5:1
36 E,R only 94
54 Z,S only 94
51 2.9:1
81 3.7:1
95/95
95/95
94/94
d
PPh3
3a cg
3a c
95/95
dppe
dppe
dppe
3a d h
3a eg
93/93
98/98
(S)-1b 2a R′ ) 4-methoxy 3ba
(S)-1b 2a R′ ) 4-methoxy 3ba
a Reactions are carried out in the presence of 5 mol % Pd2(dba)3‚CHCl3
and 20 mol % ligand in dioxane at 50 °C for 10-24 h under CO2
atmosphere. b PMP ) p-methoxyphenyl. c The yields in parentheses are
based on recovered starting material. d Using 40 mol % of PPh3. e The
stereochemistry of each product was determined by using the NOESY
technique. See Supporting Information. f The stereochemistry of each
product was tentatively assigned by comparison of its NMR spectra with
(Z)- and (E)-3aa. g Ratios were determined by the isolation of each isomer.
h Ratios were determined by 1H NMR integration of methine proton on the
epoxide ring.
41 E,R only 95
a All reactions are carried out in the presence of 5 mol % Pd2(dba)3‚CHCl3
and 20 mol % ligand in dioxane at 50 °C for 8-24 h under CO2 atmosphere.
b dppe was used as a ligand. c dppp was used as a ligand. d All isomers
were isolated. e Enantiomeric excesses are determined by using chiral HPLC
(CHIRALPAK OD-H or OJ-H). f Absolute configurations of (Z,S)- and
(E,R)-3aa were each determined by using Kusumi’s method, and other
products were tentatively assigned on the basis of specific rotation. g The
stereochemistry of the products were tentatively assigned by comparisons
with the NMR spectra of (Z)- and (E)-3aa. h Stereochemistry was determined
by using the NOESY technique.
ates with phenols, which involves a CO2 elimination-
fixation step and affords phenoxy-substituted cyclic carbon-
ates.6 In continuing investigations in this area, we have
discovered that reactions of chiral substrates, which possess
asymmetric propargylic centers, proceed in a highly enan-
tiospecific manner to give chiral cyclic carbonates via an
overall cascade chirality transfer process. Below we describe
the preliminary result of this effort.
Our initial studies focused on reactions of racemic prop-
argylic carbonates 1a-d, which possess substituents at the
propargylic position (Table 1). Reaction of the methyl-
substituted substrate 1a with p-methoxyphenol 2a in the
presence of 5 mol % Pd2(dba)3‚CHCl3 and 20 mol % dppe
in dioxane at 50 °C under a CO2 atmosphere for 12 h yields
the cyclic carbonates (Z)- and (E)-3aa in a 10:1 ratio and
66% yield (entry 1). Interestingly, we found that the
stereochemical course of this reaction is reversed (Z:E )
1:3.3 in entry 2) when dppp is used as the ligand. When
dppb, dppf, and PPh3 are employed as ligands, the reaction
does not yield cyclic carbonates. Rather, the (Z)-epoxide 4aa
is generated selectively (entries 3-5). Reaction of the pentyl-
substituted substrate 1b in the presence of dppe produces
(Z)- and (E)-3ba in 81% yield and a 3.7:1 ratio (entry 6).
Substrate 1c, which has a phenyl group at the propargylic
position, reacts to afford 3ca in low yield (32% and 47%
yield based on recovered starting material, in entry 7).
Finally, only a trace amount of products is generated by the
reaction of 1d, which has a bulky cyclohexyl group at the
propargylic center (entry 8).
We next examined the reactions enantiomerically enriched,
chiral propargylic carbonates (Table 2). When substrate (S)-
1a (95% ee), prepared from (S)-3-butyn-2-ol, is subjected
to reaction with p-methoxyphenol 2a in the presence of 5
mol % Pd2(dba)3‚CHCl3 and 20 mol % dppe, chiral cyclic
carbonates (Z)- and (E)-3aa are produced with 10:1 Z-
selectivity (entry 1). The absolute configurations of (Z)- and
(E)-3aa were determined to be S and R, respectively, by their
conversion into and NMR analysis of their MTPA esters (see
Supporting Information). It is noteworthy that the enantio-
meric excess of both (Z,S)- and (E,R)-3aa is 95%. The results
clearly show that cascade reactions of chiral propargylic
substrates occur with complete transferring chirality. In
addition, reaction of (S)-1a in the presence of dppp selec-
tively affords (E,R)-3aa without any loss of enantiomeric
purity (entry 2). Similar highly enantiospecific cascade
reactions take place between 1a and various phenols 2b-e
to afford the corresponding cyclic carbonates (Z,S)- and
(4) For reviews on stereochemical studies of palladium-catalyzed reac-
tions of allylic compounds, see: (a) Tsuji, J. Tetrahedron 1986, 42, 4361.
(b) Consiglio, G.; Waymouth, R. M. Chem. ReV. 1989, 89, 257. (c) Trost,
B. M. Angew. Chem., Int. Ed. Engl. 1989, 28, 1173. (d) Heumann, A.;
Re´glier, M. Tetrahedron 1995, 51, 975. (e) Trost, B. M.; Vranken, D. L.
V. Chem. ReV. 1996, 96, 395.
(5) It is known that chiral allenes can be synthesized from the palladium-
catalyzed reaction of chiral propargylic compounds via stereoselective SN2′
attack of palladium catalyst; see: (a) Elsevier: C. J.; Stehouwer, P. M.;
Westmijze, H.; Vermeer, P. J. Org. Chem. 1983, 48, 1103. (b) Marshall, J.
A.; Adams, N. D. J. Org. Chem. 1997, 62, 367. (c) Dixneuf, P.; Guyot, T.;
Ness, M. D.; Roberts, S. M. Chem. Commun. 1997, 2083. (d) Konno, T.;
Tanikawa, M.; Ishihara, T.; Yamanaka, H. Chem. Lett. 2000, 1360.
(6) (a) Yoshida, M.; Ihara, M. Angew. Chem., Int. Ed. Engl. 2001, 40,
616. (b) Yoshida, M.; Fujita, M.; Ishii, T.; Ihara, M. J. Am. Chem. Soc.
2003, 125, 4874.
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Org. Lett., Vol. 5, No. 18, 2003

Scheme 2. Proposed Reaction Mechanism
(E,R)-3ab-ae (entries 3-8). Substrate (S)-1b (98% ee),
allenylpalladium complex.1,2 On the basis of NMR studies,
Ogoshi and Kurosawa have recently proposed an alternate
mechanism for this process that involves the intermediacy
of a π-propargylpalladium complex.7c,d Our finding that
reactions of chiral propargylic substrates are highly enan-
tiospecific offers strong support for the Ogoshi-Kurosawa
mechanism. Accordingly, if reactions of the chiral propar-
gylic carbonates (S)-1 proceed via a route involving the
intermediacy of palladium-carbene complexes 13, complete
loss of stereochemical integrity would be observed.
In conclusion, the effort described above has led to the
discovery of a palladium-catalyzed cascade chirality transfer
reaction occurring between chiral propargylic carbonates and
phenols. The process yields cyclic carbonate products in a
highly enantiospecific manner. Furthermore, the stereose-
lectivity of these reactions can be altered by the choice of
the phosphine ligand. Continuing studies probing the scope,
mechanism, and synthetic applications of this reaction are
now in progress.
having a pentyl propargylic substituent, is also converted
stereoselectively and enantiospecifically to (Z,S)- and (E,R)-
3ba (98% ee in entriy 9 and 95% ee in entry 10).
A plausible mechanism, which accounts for the highly
enantiospecific nature of these processes, is shown in Scheme
2. In the first step of the reaction, regio- and stereoselective
anti SN2′ attack of the palladium catalyst5 on propargylic
carbonate (S)-1 takes place to yield the chiral allenylpalla-
dium complex 5. Next, transformation of complex 5 to
π-propargylpalladium complex 6 (an equilibrium process),7
is followed by selective addition of phenol to the central
carbon of π-propargyl moiety to form the chiral palladacy-
clobutene 7. Complex 7 is then converted to the allylpalla-
dium complex 8 by intramolecular proton transfer without
loss of the chirality. The complex 8 is delocalized to afford
π-allylpalladium complexes 9 and 10, and CO2 fixation
followed by cyclization from these complexes via 11 and
12 produces the cyclic carbonate (E,R)-3 and (Z,S)-3,
respectively. The cause of the phosphine ligand effect (dppe
vs dppp) on stereochemistry is not clear, but it could be
associated with an alteration of the π-σ-π equilibrium4
between π-allylpalladium complexes 9 and 10.8
Acknowledgment. This study was supported in part by
Grant-in-Aid for Encouragements for Young Scientists (B)
from the Japan Society for the Promotion of Science (JSPS)
(for M.Y.) and Scientific Research on Priority Areas (A) from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
It has been postulated that palladium-catalyzed reactions
of propargylic substrates with soft nucleophiles proceed via
a pathway in which formation of a palladium-carbene
intermediate is preceded by nucleophilic addition to the
Supporting Information Available: Experimental pro-
cedures and characterization data for all products; data for
NOESY correlations of (Z)- and (E)-3aa, 4aa, and (Z)-3ad;
procedure for determining the absolute configuration of (Z,S)-
and (E,R)-3ga. This material is available free of charge via
the Internet at http://pubs.acs.org.
(7) (a) Ogoshi, S.; Tsutsumi, K.; Kurosawa, H. J. Organomet. Chem.
1995, 493, C19. (b) Tsutsumi, K.; Ogoshi, S.; Nishiguchi, S.; Kurosawa,
H. J. Am. Chem. Soc. 1998, 120, 1938. (c) Tsutsumi, K.; Kawase, T.;
Kakiuchi, K.; Ogoshi, S.; Okada, Y.; Kurosawa, H. Bull. Chem. Soc. Jpn.
1999, 72, 2687. (d) Ogoshi, S.; Kurosawa, H. J. Synth. Org. Chem. Jpn.
2003, 61, 14.
(8) Åkermark has reported changes in the syn/anti ratio of π-allylpal-
ladium complexes by using various ligands: Sjo¨gren, M.; Hansson, S.;
Norrby, P.-O.; Åkermark, B. Organometallics 1992, 11, 3954.
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