New annulations via platinum-catalyzed enyne cyclization and cyclopropane cleavage

Article abstract of DOI:10.1021/ol0486573

(Chemical Equation Presented) Oxidative ring opening of 3-oxabicyclo[4.1.0]hept-4-enes, formed by the intramolecular Pt(II)-catalyzed cyclopropanation of enol ethers by alkynes, gives oxepane derivatives. Alternatively, the acid-catalyzed opening of the c

Full text of DOI:10.1021/ol0486573

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3191-3194
New Annulations via Platinum-Catalyzed
Enyne Cyclization and Cyclopropane
Cleavage
Cristina Nevado, Catalina Ferrer, and Antonio M. Echavarren*
Institute of Chemical Research of Catalonia (ICIQ), 43007 Tarragona, Spain, and
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid,
28049 Madrid, Spain
aechaVarren@iciq.es
Received July 13, 2004
ABSTRACT
Oxidative ring opening of 3-oxabicyclo[4.1.0]hept-4-enes, formed by the intramolecular Pt(II)-catalyzed cyclopropanation of enol ethers by
alkynes, gives oxepane derivatives. Alternatively, the acid-catalyzed opening of the cyclopropane ring leads to dihydrobenzofurans or 3,4-
dihydro-2H-chromenes.
Enynes 1 (Z ) NTs or O) react with PtCl2 as a catalyst in
nonpolar solvents to give 3-aza or 3-oxabicyclo[4.1.0]hept-
4-ene derivatives 2 (Scheme 1).1,2,3 This cyclopropanation
This novel cyclopropanation provides a ready entry into
bicyclic systems bearing a strained three-membered ring
conjugated to an enol ether or an enamine. However, the
synthetic potential of ring systems such as 2 has not yet been
examined. We decided to explore the cyclization of substrates
1 bearing an enol ether function that would lead to
intermediates 2 with an alkoxy substituent at R2, which could
Scheme 1
(1) (a) Fu¨rstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122,
6785-6786. (b) Fu¨rstner, A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc.
2001, 123, 11863-11869. (c) Blum, J.; Berr-Kraft, H.; Badrieh, Y. J. Org.
Chem. 1995, 60, 5567-5569.
(2) (a) Me´ndez, M.; Mun˜oz, M. P.; Nevado, C.; Ca´rdenas, D. J.;
Echavarren, A. M. J. Am. Chem. Soc. 2001, 123, 10511-10520. (b) Nevado,
C.; Charruault, L.; Michelet, V.; Nieto-Oberhuber, C.; Mun˜oz, M. P.;
Me´ndez, M.; Rager, M.-N.; Geneˆt, J. P.; Echavarren, A. M. Eur. J. Org.
Chem. 2003, 706-713.
(3) (a) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002, 102, 813-
834. (b) Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 215-236. (c) Diver,
S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317-1382. (d) Echavarren,
A. M.; Nevado, C. Chem. Soc. ReV. 2004, in press.
of the alkene by the alkyne likely proceeds via platinum
cyclopropyl carbenes as intermediates1,2 and is therefore
mechanistically related to the skeletal rearrangement and the
alkoxycyclization of enynes catalyzed by electrophilic transi-
tion metals.3
10.1021/ol0486573 CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/10/2004

facilitate the selective cleavage of the cyclopropane4 leading
to seven-membered rings. Here we report results that
illustrate the facile oxidative cleavage with DDQ or CAN
to give seven-membered ring double acetals. In addition, a
novel benzannulation has been found to take place by simply
heating the cyclopropane derivatives in the presence of a
protic acid.
Enynes 3-5 are readily assembled in two steps by the
addition of R-lithiated enol ethers to aldehydes, followed by
propargylation of the resulting secondary alcohols. Cycliza-
tion of 3-5 was cleanly carried out with 5 mol % PtCl2 in
toluene (Table 1).5 Although the cyclizations were performed
The reactions of 3-5 proceeded with total regiocontrol
by 6-endo-dig cyclization, as a result of the terminal
substitution at the alkyne and the electronegative character
of the tether.5 In addition, these reactions are highly
stereoselective.8 A single diastereomer was observed in the
crude reaction mixtures, with the exception of the reaction
of 5a, in which 8a was formed along with its C-2 epimer in
a 5:1 ratio. The cyclization presumably proceeds via η2-
alkyne-PtCl2 complex 9, by formation of two carbon-carbon
bonds from the face of the alkene opposite to the R2
substituent (Scheme 2). Platinum carbene 10 probably
evolves by a â-hydrogen elimination1 to give enol ether 11.
Table 1. Platinum-Catalyzed Cyclization of Enynes 3-5a
Scheme 2
Being electron-rich systems, oxidative cleavage of the
cyclopropane bond activated by the alkoxy substituent was
attempted first (Scheme 3).9-11 Epoxidation of the enol
double bond of 6a under a variety of conditions does not
trigger the cleavage of the cyclopropane ring and gives 12
when the reaction was carried out in MeOH. In addition,
3,4-dihydro-2H-chromene 19a was also obtained (see below).
Inspection of the solid structure of 6b8 reveals a preference
for the attack of electrophilic MCPBA at the convex face,
T
time
(h)
product
entry
enyne
R1
R2
(°C)
(yield, %)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
4a
4b
4c
5a
5b
Me
Me
Et
Ph
80
50
45
80
80
0
80
50
80
70
80
80
6
2
4
12
48
17
4
24
1
6a (84)
6b (97)
6c (79)
6d (72)
6e (52)
6f (61)
6g (74)
7a (58)
7b (70)
7c (71)
8a (73)c
8b (54)
1-Napht
Ph
Ph
Ph
(6) Reaction of 3a with AuCl3 (5 mol %) in toluene at 80 °C gives 6a
(40%), along with allene a resulting from 1,2-H shift and Claisen
rearrangement: Nevado, C.; Echavarren, A. M. Tetrahedron 2004, 60, in
press.
Me
Me
Me
Me
Et
Me
Me
Me
CHdCHMe
CHdCHPh
i-Pr
Ph
p-Tol
t-Bu
10
11
12b
1.5
2
2
Ph
i-Pr
a Reactions carried out with 5 mol % PtCl2. b Reaction performed in the
presence of 4 Å ms. c Mixture (5:1) of C-2 epimers.
(7) Skeletal rearrangement of enynes catalyzed by PtCl4: Oh, C. H.;
Bang, S. Y.; Rhim, C. Y. Bull. Korean Chem. Soc. 2003, 24, 887-888.
(8) Relative configuration of 6b was determined by X-ray diffraction.
(9) Review: Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko,
J.; Hudlicky, T. Chem. ReV. 1989, 89, 165-198.
(10) Recent leading references on the oxidative opening of cyclopropanes
with metal oxidants: (a) Booker-Milburn, K. I.; Thompson, D. F. J. Chem.
Soc., Perkin Trans. 1 1995, 2315-2321. (b) Booker-Milburn, K. I.; Baker,
A.; Brailsford, W.; Cox, B.; Mansley, T. E. Tetrahedron 1998, 54, 15321-
15344. (c) Takemoto, Y.; Yamagata, S.; Furose, S.; Hayase, H.; Echigo,
T.; Iwata, C. Chem. Commun. 1998, 651-652. (d) Kirihara, M.; Ichinose,
M.; Takizawa, S.; Momose, T. Chem. Commun. 1998, 1691-1692. (e)
Takemoto, Y.; Ibuka, T.; Furuse, S.; Hayase, H.; Echigo, T.; Iwata, C.;
Tanaka, T. Chem. Commun. 1999, 2515-2516. (f) Nakamura, M.; Inoue,
T.; Nakamura, E. J. Organomet. Chem. 2001, 624, 300-306. (g) Booker-
Milburn, K. I.; Jones, J. L.; Sibley, G. E. M.; Cox, R.; Meadows, J. Org.
Lett. 2003, 5, 1107-1109.
routinely in toluene at 80 °C, some of these reactions also
proceed at 0-50 °C (Table 1, entries 2, 3, 6, and 8), which
proved to be particularly convenient for substrates such as
6f that decomposed at higher temperatures. The cyclizations
could also be performed with PtCl4 as a catalyst.6 No skeletal
rearrangement of enynes 3-5 was observed under these
conditions.3,7
(4) Leading references: (a) Park, S.-B.; Cha, J. K. Org. Lett. 2000, 2,
147-149. (b) Braun, N. A.; Spitzner, D. Tetrahedron Lett. 1996, 37, 9187-
9188. (c) Kura, K.; Ryu, I.; Kambe, Sonoda, N. J. Am. Chem. Soc. 1992,
114, 1520-1521. (d) Murai, S.; Aya, T.; Sonoda, N. J. Org. Chem. 1973,
38, 4354-4356.
(5) Pt(II)- and Au(III)-catalyzed methoxycyclization of enol ethers with
alkynes: Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. Chem. Eur. J.
2003, 9, 2627-2635.
(11) Oxidations of cyclopropane acetals with DDQ or chloranil: (a) Oku,
A.; Yamauchi, Y.; Schroeder, M. Chem. Lett. 2001, 1194-1195. (b) Oku,
A.; Takahashi, H.; Asmus, S. M. J. Am. Chem. Soc. 2000, 122, 7388-
7389. (c) Oku, A.; Abe, M.; Iwamoto, M. J. Org. Chem. 1994, 59, 7445-
7452.
3192
Org. Lett., Vol. 6, No. 18, 2004

2). DDQ has been previously used for the opening of
cyclopropanone acetals, although trapping of the intermediate
radical cation initially formed by the quinone radical anion
of DDQ was observed in most cases.11
Scheme 3a
The reactions of 6 and 7 with DDQ or CAN provide
stereoselectively double acetals 14 and 15, respectively,
although in the cases of 6c and 6d the oxidation with DDQ
also gave hemiacetals 16a,b as minor products (Table 2,
entries 5 and 6). Under these conditions, 8a,b gave only
complex mixtures.
A rationale for this transformation is provided in Scheme
4 on the basis of a single electron-transfer oxidation of 6
Scheme 4
a Reagents and conditions: (a) MCPBA (1 equiv), MeOH, 0 °C,
7 h [12 (80%) + 19a (15%)]. (b) Pb(OAc)4 (1.5 equiv), HOAc, rt,
12 h [13 (28%) + 19a (15%)].
which is followed by opening of the epoxide by methanol.
On the other hand, reaction of 6a with Pb(OAc)4 in HOAc
gave 13 (28%) and 19a (15%). In the transformation of 6a
into 13, oxidative cleavage of the cyclopropane ring is
followed by the formation of a second cyclopropane in a
rare example of electrophilic cyclopropanation at the expense
of a methyl group.12
and 7 to form radical cations 17, which would be trapped
by water and further oxidized to form 18. Intermediates 18
could cyclize to form triclyclic derivatives 14 and 15.
Alternatively, trapping of oxonium ion 18 by water would
give 16.
Successful cleavage of the cyclopropane was achieved with
DDQ or CAN as the oxidants in aqueous solvents (Table
In some of the oxidations of 6a,b, 3,4-dihydro-2H-
chromenes 19a and 19b were observed as secondary
products. This intriguing transformation, which corresponds
to a dehydration reaction, could be simply performed by
heating 6a-e with aqueous HCl in THF or with p-TsOH in
toluene to give 3,4-dihydro-2H-chromenes 19a-e (Scheme
Table 2. Oxidation of 6 and 7 with DDQ or CAN
Scheme 5a
entry substrate conditionsa time (h) product(s) (yield, %)
1
2
3
4
5
6
7
8
6a
6a
6b
6b
6c
6d
7a
7b
a
b
a
b
a
a
a
b
2
1
1
1
2
2
2
1
14a (60)b
14a (60)c
14b (54)
14b (58)d
14c (63) + 16a (18)
14d (58) + 16b (24)
15a (84)
15b (83)
a Reagents and conditions: (a) aq HCl, THF, reflux, 2-14 h
[19a (72%); 19b (72%); 19c (64%)]. (b) p-TsOH (1 equiv), toluene,
70-110 °C, 2-30 min [19d (80%); 19e (52%); 20a (95%); 20b
(82%)].
a Conditions a: DDQ (2 equiv), 10:1 CH2Cl2-H2O, 40 °C. Conditions
b: CAN (1 equiv), 10:1 MeCN-H2O, 70-90 °C. b 19a (24%) was also
obtained. c 19a (8%) was also obtained. d 19b (23%) was also obtained.
Org. Lett., Vol. 6, No. 18, 2004
3193

5). Similarly, heating of 7a,b with p-TsOH in toluene gave
dihydrobenzofurans 20a,b in good yields.
Scheme 7
This new benzannulation reaction probably proceeds by
retro-hetero-Diels-Alder opening of 6 and 7 to form 21,13,14
followed by an acid-catalyzed aldol-type cyclization and
dehydration of 22 to afford 3,4-dihydro-2H-chromenes 19
or dihydrobenzofurans 20 (Scheme 6).15
Scheme 6
has also been uncovered from enynes, which are modularly
assembled from an enol ether, an aldehyde, and a propargyl
bromide.
Acknowledgment. We are grateful to the MCyT (Project
PB97-0002-C2) and the ICIQ Foundation for support of this
research. We also acknowledge the CAM and the AGAUR
for predoctoral fellowships to C.N. and C.F., respectively,
and to Johnson Matthey PLC for a loan of PtCl2.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0486573
(14) In the case of 6d, reaction with p-TsOH gave 5,6-diphenyl-3,4-
dihydro-2H-chromene as a byproduct (ca. 5%), the result of an unexpected
rearrangement. Rearrangement products (5,6-disubstituted 3,4-dihydro-2H-
chromenes) were observed as minor products (15:1 ratio) when the
cyclizations of substrates 19a and 19c were carried out with p-TsOH in
toluene instead of aqueous HCl. Formation of these rearranged products
could be explained by E/Z isomerization of 21 to 21′, followed by Michael
addition to form i, which could open to give ii. Aldol-type cyclization of ii
as in Scheme 6 forms 5,6-disubstituted 3,4-dihydro-2H-chromenes.
In summary, the cyclopropane ring of 3-oxabicyclo[4.1.0]-
hept-4-enes, obtained by PtCl2-catalyzed cyclization of 3 and
4, can be oxidatively cleavaged to form oxepanes 14 and 15
(or hemiacetals 16). This transformation is an alternative to
the yet unknown alkoxycyclization of 1,6-enynes by endo-
dig pathway that, in the case of 6 and 7, should have afforded
23 and 24 (Scheme 7).5 A new benzannulation that gives
3,4-dihydro-2H-chromenes 19 or 2,3-dihydrobenzofurans 20,
with a substituent pattern difficult to obtain by other methods,
(12) This transformation is presumably initiated by the cleavage of the
cyclopropane to form an organolead intermediate. For reviews on electro-
philic cyclopropanation: (a) Wessjohann, L. A.; Brandt, W.; Thiemann, T.
Chem. ReV. 2003, 103, 1625-1647. (b) Taylor, R. E.; Engelhardt, F. C.;
Schmitt, M. Tetrahedron 2003, 59, 5623-5634.
(13) Retro-Diels-Alder reactions of bicyclo[4.1.0]hept-4-enes: Sellers,
S. F.; Dolbier, W. R.; Koroniak, H.; Al-Fekri, D. M. J. Org. Chem. 1984,
49, 1033-1036.
(15) Curiously, a 3,4-dihydro-2H-chromene was formed by acid-catalyzed
reaction of 13-methoxy-trioxadispiro[4.1.5.3]pentadecane by a mechanism
that resembles that proposed for the 21 f 19 and 20 transformation. See:
Dorta, R. L.; Mart´ın, A.; Sua´rez, E. J. Org. Chem. 1997, 62, 2273-2274.
3194
Org. Lett., Vol. 6, No. 18, 2004