Synthesis of multisubstituted 2-(dihydrofuran-2(3H)-ylidene)acetates via intramolecular carboalkoxylation by platinum-olefin catalyst system

Article abstract of DOI:10.1021/ol702795u

(Chemical Equation Presented) The cyclization of 6-(1-alkoxyethyl)hex-2- ynoates in the presence of a platinum-olefin catalyst system gave the corresponding multisubstituted 2-(dihydrofuran-2(3H)-ylidene)acetates in good to high yields. The Z/E selectivit

Full text of DOI:10.1021/ol702795u

ORGANIC
LETTERS
2008
Vol. 10, No. 2
309-312
Synthesis of Multisubstituted
2-(Dihydrofuran-2(3H)-ylidene)acetates
via Intramolecular Carboalkoxylation by
Platinum−Olefin Catalyst System
Itaru Nakamura,* Ching Siew Chan, Toshiharu Araki, Masahiro Terada, and
Yoshinori Yamamoto
Department of Chemistry, Graduate School of Science, Tohoku UniVersity,
Sendai 980-8578, Japan
itaru-n@mail.tains.tohoku.ac.jp
Received November 21, 2007
ABSTRACT
The cyclization of 6-(1-alkoxyethyl)hex-2-ynoates in the presence of a platinum−olefin catalyst system gave the corresponding multisubstituted
2-(dihydrofuran-2(3H)-ylidene)acetates in good to high yields. The Z/E selectivity is controlled by the electronic property of the ester group;
the 2,2,2-trichloroethyl ester led to the Z isomer, while the phenyl ester gave the E isomer.
The cataytic cyclization reaction for alkynylamines, -alcohols,
and -thiols, which proceeds through intramolecular addition
of N-H, O-H, and S-H bonds to the triple bond, is one of
the most powerful tools to synthesize heterocyclic com-
pounds (eq 1).1 Recently, Lewis acidic transition metal-
catalyzed cyclization of o-alkynylphenyl ethers,2 o-alkynylani-
lines,2a,b,3 and o-alkynylphenyl sulfides4 having a carbon
migrating group (CR3), such as allyl, acyl, p-methoxyphenyl
(MPM), and R-alkoxylalkyl groups, on the heteroatom (Y),
which proceed through a carbon-heteroatom bond addition
have been developed as a synthetic method for 2,3-disub-
stituted benzofurans, indoles, and benzothiophenes (eq 2).
However, these Lewis acidic transition metal-catalyzed
carbon-heteroatom bond addition reactions have rarely
employed substrates which have an alkyl chain between the
alkyne moiety and the heteroatom as its starting material.
To the best of our knowledge, a single known instance is
the platinum-catalyzed cyclization of allylic ethers reported
by Fu¨rstner’s group (eq 3).5 Herein, we report that the
cyclization of 6-(1-alkoxyethyl)hex-2-ynoates 1 in the pres-
(2) Migration of allyl groups: (a) Cacchi, S.; Fabrizi, G.; Pace, P. J.
Org. Chem. 1998, 63, 1001. (b) Fu¨rstner, A.; Davies, P. W. J. Am. Chem.
Soc. 2005, 127, 15024. Propargyl groups: (c) Cacchi, S.; Fabrizi, G.; Moro,
L. Tetrahedron Lett. 1998, 39, 5101. Acyl groups: (d) Shimada, T.;
Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 10546.
R-Alkoxyalkyl group: (e) Nakamura, I.; Mizushima, Y.; Yamagishi, U.;
Yamamoto, Y. Tetrahedron 2007, 63, 8670.
(3) Allyl groups: (a) Arcadi, A.; Cacchi, S.; Del Rosario, M.; Fabrizi,
G.; Marinelli, F. J. Org. Chem. 1996, 61, 9280. (b) Cacchi, S.; Fabrizi, G.;
Moro, L. Synlett 1998, 741. (c) Monterio, N.; Balme, G. Synlett 1998, 746.
R-Alkoxyalkyl groups: (d) Nakamura, I.; Mizushima, Y.; Yamamoto, Y.
J. Am. Chem. Soc. 2005, 127, 15022. (e) Fu¨rstner, A.; Heilmann, E.; Davies,
P. W. Angew. Chem., Int. Ed. 2007, 46, 4760.
(1) For a review, see: (a) Hosokawa, T.; Murahashi, S.-I. In Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; John
Wiley & Sons: New York, 2000; Vol. 3.2.1, p 2169. (b) Hosokawa, T. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E., Ed.; John Wiley & Sons: New York, 2000; Vol. 3.3.1, p 2211. (c)
Gabriele, B.; Salerno, G. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons: New York, 2000;
Vol. I4.4.2, p 2623. (d) Schmalz, H. G.; Geis, O. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; John
Wiley & Sons: New York, 2000; Vol. I.2.1.3, p 2377. (e) Mu¨ller, T. E.;
Beller, M. Chem. ReV. 1998, 98, 675. (f) Brunet, J. J.; Neibecker, D. In
Catalytic Heterofunctionalization; Togni, A., Gru¨tzmacher, H., Eds., Wiley-
VCH Verlag GmbH: Weinheim; 2001; p 91. (g) Nakamura, I.; Yamamoto,
Y. Chem. ReV. 2004, 104, 2127. (h) Zeni, G.; Larock, R. C. Chem. ReV.
2004, 104, 2285.
(4) Nakamura, I.; Sato, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006,
45, 4473.
(5) (a) Fu¨rstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122,
6785. (b) Fu¨rstner, A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc. 2001, 123,
11863.
10.1021/ol702795u CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/22/2007

ence of a platinum-olefin catalyst system gave the corre-
sponding multisubstituted 2-(dihydrofuran-2(3H)-ylidene)-
acetates 2 in good to high yields (eq 4). The stereo
configuration outcome can be controlled by switching the
electronic property of the ester group.
to the alkynyl moiety, in 84% yield with exclusive Z
stereoselectivity (entry 1). The reaction in the absence of
1,5-hexadiene did not proceed at all.6 Interestingly, the
reaction of the substrates 1a, 1b, 1c, and 1d having electron-
deficient ester groups afforded Z isomers as major products
(entries 1-4), while those having a relatively electron-rich
ester, such as 1f, 1g, and 1h, proceeded more slowly and
gave the E isomers, deriving from formal cis-addition of the
acetal C-O bond (entries 6-8). Particularly, the reaction
of the phenyl ester 1h gave (E)-2h in a good yield with an
exclusive E selectivity (entry 8). The stereochemistry of the
product was determined by NOE experiments. Furthermore,
the structure of (Z)-2e was unambiguously determined by
X-ray crystallographic analysis.7
We explored the substrate scope of the platinum-olefin-
catalyzed cyclization of the 2,2,2-trichloroethyl esters (Table
2, eq 6). Regardless of the bulkiness of the acetal moiety,
Table 2. Cyclization of the 2,2,2-Trichloroethyl Ester 1a and
1i-ma
The results of the platinum-olefin catalyzed cyclization
of 5,5-diphenyl-6-(1-ethoxyethyl)hex-2-ynoates 1a-h are
summarized in Table 1 (eq 5). The reaction of the 2,2,2-
entry
1
R2
R3
Et
i-Pr
i-Bu
time/h
2
yield/%b
Z/Ec
1
2
3
4
5
6
1a
1i
1j
1k
1l
1m
Ph
Ph
Ph
1.5
1
3
4
2.5
1
2a
2i
2j
2k
2l
2m
84d
88
78
88
56d
75
100:0
100:0
100:0
53:47
71:29
78:22
-(CH2)5- Et
Me
H
Table 1. Cyclization of 5,5-diphenyl-6-(1-ethoxyethyl)hex-
2-ynoates 1a-ha
Et
Et
a The reaction of 1 was carried out in the presence of 10 mol % of PtCl2
and 40 mol % of 1,5-hexadiene in toluene at 25 °C. b Isolated yield. c The
ratio was determined by 1H NMR. d 1H NMR yield using 1,3-benzodioxole
as an internal standard.
entry
1
R1
time/h
2
yield/%b
Z/Ec
substrates 1a, 1i, and 1j bearing a gem-diphenyl group solely
produced Z isomers (Z)-2a, (Z)-2i, and (Z)-2j, respectively,
in high yields (entries 1-3). The reaction of 1l having a
gem-dimethyl group produced 2l with a good stereoselec-
tivity, while that of 1k having a spirocyclohexyl group
proceeded with poor stereoselectivity (entries 4 and 5). The
substrate 1m, which did not have a geminal substituent in
the tether moiety, was converted to 2m in a good yield with
an acceptable stereoselectivity (entry 6).
1
2
3
4
5d
6d
7d
8d
1a Cl3CCH2
1b p-O2N-C6H4
1c p-Cl-C6H4
1d p-Br-C6H4
1e Me
1.5
3.5
4
4.5
4.5
13
2a
2b
2c
2d
2e
2f
84
83
84
87
54
50
32
69
100:0
96:4
95:5
95:5
31:69
0:100
0:100
0:100
1f
Et
1g p-MeO-C6H4
1h Ph
24
48
2g
2h
a The reaction of 1 was carried out in the presence of 10 mol % of PtCl2
and 40 mol % of 1,5-hexadiene in toluene at 25 °C. b 1H NMR yield using
1,3-benzodioxole as an internal standard. c The ratio was determined by
1H NMR. d At 35 °C.
(6) 1,5-Hexadiene breaks the aggregate structure of polymeric PtCl2,
thereby possibly increasing the number of active sites available for the
reaction. (a) Jensen, K. A. Acta Chem. Scand. 1953, 7, 866. (b) Fu¨rstner,
A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410.
(7) CCDC-667034 contains the supplementary crystallographic data for
(Z)-2e. The data can be obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the Cambridge Crystallographic Data Centre,
12, Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or
deposit@ccdc.cam.ac.uk).
trichloroethyl ester 1a in the presence of 10 mol % of PtCl2
and 40 mol % of 1,5-hexadiene in toluene at 35 °C gave
(Z)-2a, deriving from trans-addition of the acetal C-O bond
310
Org. Lett., Vol. 10, No. 2, 2008

Next we attempted selective synthesis of the E isomers
using substrates having a phenyl ester (Table 3, eq 7). The
other hand, the isolated (Z)-2h was converted to a 62:38
mixture of the Z/E stereoisomers under the reaction condi-
tions, indicating that the Z/E isomerization occurs on the way
of cyclization proceess and the interconversion from Z isomer
to E isomer is a minor reaction pathway in the reaction of
1h, since the ratio of interconversion from (Z)-2h to (E)-2h
was, however, much less than that in the cyclization reaction
of 1h (eq 10 vs Table 1, entry 8), In contrast, the isolated
(E)-2k and (E)-2h remained unchanged under the reaction
conditions, suggesting that the E isomers were thermody-
namically more stable than the Z isomers (eqs 11 and 12).
Table 3. Cyclization of the Phenyl Ester 1h and 1n-ra
entry
1
R2
R3
Et
i-Pr
i-Bu
time/h
2
yield/%b
Z/Ec
1
2
3
4
5
6
1h Ph
1n Ph
1o Ph
1p -(CH2)5- Et
1q Me
1r
48
48
38
43
19
1
2h
2n
2o
2p
2q
2r
69
58
55
56
58d
58
0:100
12:88
18:82
0:100
3:97
Et
Et
H
48:52
a The reaction of 1o-t was carried out in the presence of 10 mol % of
PtCl2 and 40 mol % of 1,5-hexadiene in toluene at 35 °C. b Isolated yield.
c The ratio was determined by 1H NMR. d 1H NMR yield using 1,3-
benzodioxole as an internal standard.
reaction of substrates having a substituent at the tether moiety
(R2) gave the corresponding E isomers as major products
(entries 1-5). In contrast, the reaction of 1r, which did not
have any substituents at R2 afforded a 1:1 mixture of the
E/Z isomers (entry 6).
We extended the present reaction for the synthesis of
substitued dihydroisobenzofurans (eq 8). The reaction of the
trichloroethyl ester of 4-[o-{(1-ethoxyethoxy)methyl}phenyl]-
but-2-ynoic acid 1s gave 2s in 57% yield with a moderate Z
stereoselectivity, while the phenyl ester 1t solely afforded
the E isomer (E)-2t.
To find out if the migration of the R-alkoxyalkyl group
occurs in an intramolecular or intermolecular fashion, we
performed crossover experiment (eq 13). The reaction of a
1:1 mixture of 1b and 1j under the standard reaction con-
ditions gave the corresponding products (Z)-2b and (Z)-2j
in 86 and 90% yields, respectively; the crossover products,
such as (Z)-2a and (Z)-2u, were not detected by GC-mass
and NMR analysis. This result clearly indicates that the
migration of the R-alkoxyalkyl group proceeds in an in-
tramolecular manner.
We also observed isomerization from the Z product to its
corresponding E geometrical isomer in the presence of the
platinum-olefin catalysts.8 The isolated 2,2,2-trichloroethyl
ester (Z)-2k was rapidly converted to a 42:58 mixture of the
Z/E isomers in the presence of the platinum catalyst, indi-
cating that (E)-2k was formed mainly by platinum-catalyzed
isomerization from (Z)-2k in the reaction 1k (eq 9). On the
On the basis of these experiments, we propose a mecha-
nism of this reaction as shown in Scheme 1. A Lewis acidic
Org. Lett., Vol. 10, No. 2, 2008
311

nation of the R-alkoxyalkyl group, leading to fast carbode-
metalation from (Z)-4 to (Z)-2. The E product would also
then be formed via isomerization from the Z product.10 The
reaction pathway for the formation of the E isomer depends
on the substrate’s structure.
Scheme 1. Plausible Mechanism
In conclusion, we are now in a position to synthesize
multisubstituted 2-(dihydrofuran-2(3H)-ylidene)acetates ste-
reoselectively by changing a substituent at the ester moiety.
This present reaction, which proceeds with an addition of
an acetal C-O bond, which we termed carboalkoxylation,
is a useful methodology to synthesize (dihydrofuran-2(3H)-
ylidene)acetates in an efficient and atom-economic manner.
Acknowledgment. This work was supported by Grant-
in-Aid for Scientific Research on Priority Areas (No.
19028005, “Chemistry of Concerto Catalysis”) from Ministry
of Education, Culture, Sports, Science and Technology,
Japan.
platinum catalyst would coordinate to the triple bond of the
substrate 1, forming π-complex 3. Nucleophilc attack of
the oxygen atom of the acetal moiety to the electron-defi-
cient alkynyl moiety would lead to the cyclized intermediate
(Z)-4. [1,3]-Migration of R-alkoxyalkyl group followed by
elimination of the platinum catalyst, so-called carbodemeta-
lation, would give the Z-isomer. In the reaction of the phenyl
esters (1h, 1n-r, and 1t), the isomerization from (Z)-4 to
(E)-4 through the platinum carbene intermediate 5 would
take place.9 Similarly, the following carbodemetalation would
give the E isomer. In the reaction of the 2,2,2-trichloroethyl
ester, a strongly electron-withdrawing group facilitates elimi-
Supporting Information Available: Experimental pro-
cedures and characterization of the products 2. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL702795U
(9) (a) Miki, K.; Nishino, F.; Ohe, K.; Uemura, S. J. Am. Chem. Soc.
2002, 124, 5260. (b) Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. Chem.
Eur. J. 2003, 9, 2627. (c) Harrak, Y.; Blaszykowski, C.; Bernard, M.; Cariou,
K.; Mainetti, E.; Mourie`s, V.; Dhimane, A.-L.; Fensterbank, L.; Malacria,
M. J. Am. Chem. Soc. 2004, 126, 8656. (d) Kusama, H.; Miyashita, Y.;
Takaya, J.; Iwasawa, N. Org. Lett. 2006, 8, 289.
(8) The Z and E isomers did not isomerize in the absence of the platinum
catalysts.
(10) Miura, K.; Itaya, R.; Horiike, M.; Izumi, H.; Hosomi, A. Synlett
2005, 3148.
312
Org. Lett., Vol. 10, No. 2, 2008