Functionalized cyclobutanes via heck cyclization

Article abstract of DOI:10.1021/ol701697r

(Chemical Equation Presented) Heck-type 4-exo-trig cyclization of linear 2-enol triflate-1,5-hexadienes provides functionalized methylene cyclobutanes, intramolecular palladium coordination can initiate β-hydride elimination leading to 1,2-dimethylene cyc

Full text of DOI:10.1021/ol701697r

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4431-4434
Functionalized Cyclobutanes via Heck
Cyclization
Anna Innitzer, Lothar Brecker, and Johann Mulzer*
Institut fu¨r Organische Chemie der UniVersita¨t Wien, Wa¨hringerstrasse 38,
1090 Wien, Austria
johann.mulzer@uniVie.ac.at
Received July 18, 2007
ABSTRACT
Heck-type 4-exo-trig cyclization of linear 2-enol triflate-1,5-hexadienes provides functionalized methylene cyclobutanes. Intramolecular palladium
coordination can initiate -hydride elimination leading to 1,2-dimethylene cyclobutane derivatives, which are obtained with high selectivity if
â
substrates having a geminal diphenyl group at C are used. In parallel, formal 5-endo-trig cyclization and
â-hydride elimination form 1-methylene
r
cyclopent-2-en derivatives.
Intramolecular Heck reactions have become a powerful tool
for the construction of cyclic natural products.1 Thus, the
cyclization of 2-halo-1,(n-1)-alkadienes and related com-
pounds provides access to ring sizes from three to nine.
However, the formation of cyclobutanes through intra-
molecular Heck reaction has been scarcely observed,2-5
although the resulting functionalized cyclobutanes would be
highly valuable key intermediates in total synthesis.6 Herein
we report novel Heck-type 4-exo-trig cyclizations of enol
triflates which are accompanied by a variety of competing
reactions, depending on the substitution pattern of the
substrate and on the conditions applied (Scheme 1, Table
1).7
By using substrates with gem-disubstituted quaternary
carbons, we hoped to increase the tendency toward ring
formation according to the well-known Thorpe-Ingold
effect. We assume that the reaction starts with an oxidative
addition converting 1 into key intermediate 2. From there,
two competing processes A and B are possible: a 4-exo-
trig cyclization to form 3 as well as direct carbonylation of
2 to ester 9 (Scheme 1). From cyclobutyl intermediate 3,
three routes can be envisioned: syn-palladium hydride
(1) Selected reviews include: (a) Sarlah, D.; Bulger, P. G.; Nicolaou,
K. C. N. Angew. Chem., Int. Ed. 2005, 44, 4442. (b) Dounay, A. B.;
Overman, L. E. Chem. ReV. 2003, 103, 2945. (c) Link, J. T. Org. React.
2002, 60, 157. (d) Bra¨se, S.; De Meijere, A. In Handbook of Organo-
palladium Chemistry for Organic Synthesis; Negishi, E., Ed.; John Wiley
& Sons, Inc.: New York, 2002; Vol. 1, p 1223. (e) Liu, F.; Liou, S.; Ma,
S.; Cope´ret, C.; Negishi, E. Chem. ReV. 1996, 96, 365.
(2) (a) Khan, F. A.; Czerwonka, R.; Reissig, H.-U. Eur. J. Org. Chem.
2000, 3607. (b) Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Bull. Chem.
Soc. Jpn. 1999, 72, 2345. (c) Han, X.; Larock, R. C. J. Org. Chem. 1999,
64, 1875. (d) Bra¨se, S. Synlett 1999, 1654. (e) Carpenter, N. E.; Kucera, D.
L.; Overman, L. E. J. Org. Chem. 1989, 54, 5846. (f) Sukirthalingam, S.;
Sridharan, V.; Grigg, R. Tetrahedron Lett. 1991, 32, 3855.
(3) (a) Ang, K. H.; Bra¨se, S.; Steinig, A. G.; Meyer, F.; Llebaria, A.;
Voigt, K.; De Meijere, A. Tetrahedron 1996, 52, 11503. (b) Narula, C. K.;
Mak, K. T.; Heck, R. F. J. Org. Chem. 1983, 48, 2792.
(4) Renaldo, A. F.; Overman, L. E. J. Am. Chem. Soc. 1990, 112, 3945.
(5) Gajewski, J. J.; Benner, C. W.; Stahly, B. N.; Hall, R. F.; Sato, R. I.
Tetrahedron 1982, 38, 853.
(6) For natural products containing cyclobutanes, see, for example: (a)
Wang, Y. H.; Hou, A. J.; Chen, D. F.; Weiller, M.; Wendel, A.; Staples, R.
J. Eur. J. Org. Chem. 2006, 15, 3457. (b) Snider, B. B.; Lu, Q. Synth.
Commun. 1997, 27, 1583. (c) Okauchi, T.; Kakiuchi, T.; Kitamura, N.;
Utsunomiya, T.; Ichikawa, J.; Minami, T. J. Org. Chem. 1997, 62, 8419.
(d) Jefferies, P. R.; Worth, G. K. Tetrahedron 1973, 29, 903.
(7) Enol triflates were prepared in a five- (compounds 1a-1g) or six-
step (compounds 1h and 1i) sequence using standard chemical methods.
Details on the experimental procedures are given in the Supporting
Information.
10.1021/ol701697r CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/27/2007

Scheme 1. Selected Pathways for Palladium-Mediated
Formation of Cyclobutanes in the Presence of Carbon Monoxide
Table 1. Product Distribution for Enol Triflates 1a-1e
substrate
condna productsb
1a
R1, R2, R3 ) Me, R4 ) H
I
9a
(60%) (5%)
9a 7a
(9%) (56%)
9a 7a
(3%) (65%)
7a
II
III
III
III
III
III
1b
1c
1d
1e
R1, R2 ) Me, R3 ) Et, R4 ) H
R1, R2 ) Me, R3 ) i-Pr, R4 ) H
R1 ) OBn, R2 ) H, R3, R4 ) Me
R1, R3, R4 ) Me, R2 ) H
-
7b
(60%)
7c
-
(65%)
-
9d
(75%)
9e
-
(70%)
a
Conditions I: 1 equiv of substrate in a 0.06 M solution, MeOH/DMF
(2:1), 0.1 equiv of Pd(PPh3)2Cl2, 3.2 equiv of NEt3, CO atmosphere, 50
°C, 18 h. II: 1 equiv of substrate in a 0.06 M solution, MeOH/DMF (2:1),
0.1 equiv of Pd(PPh3)2Cl2, 0.2 equiv of PPh3, 3.2 equiv of NEt3, CO
atmosphere, 50 °C, 18 h. III: 1 equiv of substrate in a 0.06 M solution,
MeOH/DMF (2:1), 0.1 equiv of Pd(PPh3)4, 3.2 equiv of NEt3, CO
atmosphere, 50 °C, 2-18 h. b Percentage refers to yield of isolated product.
no products formed from the reverse order of transformations,
i.e., first carbonyl insertion then cyclization, were observed.9b
Performing the reaction of 1a in the absence of CO leads to
an inseparable mixture of compounds 6a and 8a (1:1) via
â-hydride elimination from intermediates 3a and 4a, respec-
tively (pathways C/D and F). For enol triflate 1a, bidentate
ligands such as diphenylphosphinoferrocene (dppf) and 1,2-
bis(diphenylphosphino)ethane (dppe) were also tried. Dppf
did not react at all, and for dppe the results were the same
as those for PPh3, with or without the addition of CO.
elimination (pathway F) to produce 1,2-dimethylene cyclo-
butane (8) or, alternatively carbonylation to generate cyclo-
butane ester 7 (pathway E). Cyclopropane formation fol-
lowed by homoallyl rearrangement8 can provide the formal
5-endo-trig product9 (pathway C/D). Alternatively, a direct
conversion of 2 into 5 cannot be excluded.
The competition between pathways A and B was studied
first (Table 1). Thus, when subjecting 1a to conditions I,
the acyclic ester 9a is the main product. Only negligible
amounts of the cyclization product 7a are found. Addition
of PPh3 (conditions II) strongly increases the product ratio
in favor of 7a. These phosphine ligands obviously promote
the intramolecular Heck reaction, and in fact, when using
Pd(PPh3)4 as the only catalyst (conditions III), cyclobutane
ester 7a is formed in 65% yield with d.e. > 98%.10
Apparently, these are the best conditions determined for the
tandem Heck cyclization carbonylation pathway A/E.11 It is
noteworthy that this is the first example providing methyl-
enecyclobutylacetates through such a cascade. Interestingly,
Under conditions III, 1b and 1c are smoothly converted
into 7b,c (d.e. > 98%). No acyclic esters 9b,c are formed.
Both 1b and 1c have an alkyl substituent at Câ and two
geminal methyl groups at CR. The position of the methyl
groups is crucial for the cyclization, which obviously fails
if there is only one substituent at CR. Thus, 1d and 1e, which
carry two methyl groups at Câ and only one substituent at
CR, furnish acyclic esters 9d and 9e exclusively. A possible
rationalization lies in the conformational effect exerted by
the bulky palladium substituent. For 1d,e, the corresponding
organopalladium intermediate 2d,e will adopt conformation
10 to avoid steric interference with substituent R4. Hence,
Pd addition to the second olefin is inhibited, and ester 9 is
formed. For 1b,c, conformer 11 should be favored to avoid
(8) For related formation of formal 6-endo products see: (a) Beletskaya,
I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009. (b) Owczarczyk, Z.;
Lamaty, F.; Vawter, E. J.; Negishi, E. J. Am. Chem. Soc. 1992, 114, 10091.
(9) For other examples of formal 5-endo trig Heck cyclizations, see: (a)
Vital, P.; Norrby, P. O.; Tanner, D. Synlett 2006, 3140. (b) Sakoda, K.;
Mihara, J.; Ichikawa, J. Chem. Commun. 2005, 4684. (c) Ackermann, L.;
Kaspar, L. T.; Geschrei, C. J. Chem. Commun. 2004, 2824. (d) Watanabe,
T.; Arai, S.; Nishida, A. Synlett 2004, 907. (e) Chen, C.; Lieberman, D. R.;
Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1997, 62,
2676. (f) O’Connor, B.; Zhang, Y.; Negishi, E. Tetrahedron Lett. 1988,
29, 3903.
(11) For tandem carbopalladation of alkenes terminated by carbonylation,
see: (a) Cope´ret, C.; Negishi, E. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons,
Inc.: New York, 2002; Vol. 1, p 1431 and references therein. (b) Grigg,
R.; Sridharan, V. J. Organomet. Chem. 1999, 576, 65.
(10) Stereochemical assignment was confirmed by NOESY experiments.
See Supporting Information.
4432
Org. Lett., Vol. 9, No. 22, 2007

Pd-R2 repulsions. This facilitates Pd addition to the double
bond and therefore results in the formation of 7 (Scheme
2).
via â-hydride elimination. In the absence of CO (conditions
IV), the dimethylene cyclobutanes (8f-i) are the main
products. Remarkably, under conditions III and IV, 1f and
1g also form the formal 5-endo cyclization products 6f and
6g in appreciable amounts. However, despite the quaternary
center at CR, no 1,2-migration of the alkenyl palladium
intermediate 2 was observed.12
Scheme 2. Conformation of the Acyclic Pd Intermediates
Optimal for Heck Cyclization and Premature Trapping with CO,
Respectively
Possibly, in these cases, palladium intermediate 3 does
not coordinate with CO, which may be rationalized by an
intramolecular coordination of the oxygen atom to pal-
ladium.13 Thus Pd species such as 12 or 13 may be formed,
in which complexation of CO to the metal center is
disfavored (Figure 1). Enol triflates (1h and 1i) with two
To extend the lifetime of intermediate 3, we decided to
examine substrates in which electron-donating substituents
might stabilize the palladium species via complexation and,
hence, retard or inhibit the insertion of CO. In fact, the
presence of an ether group at CR or Câ (Table 2, 1f and 1g)
Figure 1. Intramolecular palladium coordinations of (a) 1f, (b)
1g, and (c) 1h leading to â-elimination and formation of 1,2-
dimethylene cyclobutanes.
geminal phenyl groups at CR exclusively react to 1,2-
dimethylene-cyclobutanes 8h and 8i (Table 2), in the
presence or absence of CO. A presumptive intermediate is
14 in which, as in 12 and 13, palladium coordination to one
of the phenyl groups prevents CO complexation.
Table 2. Product Distribution for Enol Triflates 1f-1i
The 1,2-dimethylene cyclobutanes 8 are suitable substrates
for Diels-Alder reactions. As an example, compound 8h
was treated with benzoquinone as a dienophile (Scheme 3).
substrate
condna
III
productsb
8fc 6fc
(22%) (15%) (25%)
1f
R1, R3 ) Me, R2 ) OPMB
R1, R2 ) Me, R3 ) OMe
R1, R2 ) Ph, R3 ) Me
R1, R2 ) Ph, R3 ) i-Pr
9fc
IV
III
IV
III
IV
IV
-
8fc
(25%) (35%)
8gc 6gc
6fc
Scheme 3. Cycloaddition-Electrocyclic Ring-Opening
Cascade
1g
1h
9gc
(22%) (20%) (17%)
-
8g
6g
(30%) (30%)
8h
(70%)
8h
(87%)
8i
-
-
1i
(75%)
a
Conditions III: see Table 1. Conditions IV: 1 equiv of substrate in a
0.06 M solution, MeOH/DMF (2:1), 0.1 equiv of Pd(PPh3)4, 3.2 equiv of
b
NEt3, argon atmosphere, 50 °C, 2-18 h. Unless stated otherwise,
c
A cascade reaction occurred to produce 16 as the only
product. Obviously, the primary Diels-Alder adduct 15 has
undergone an electrocyclic ring opening.
percentage refers to yield of isolated product. Yield determined by 1H
NMR.
leads to a competition among pathways B, C/D, and F. Under
conditions III, the acyclic esters (9f and 9g) are obtained in
substantial amounts; however, no CO insertion occurs at the
stage of intermediate 4. Instead, the 1,2-dimethylene cyclo-
butanes 8f (1:1 diastereomeric mixture) and 8g are generated
(12) (a) Ebran, J. P.; Hansen, A. L.; Gøgsig, T. M.; Skrydstrup, T.
J. Am. Chem. Soc. 2007, 129, 6391. (b) Hansen, A. L.; Ebran, J. P.;
Ahlquist, M.; Norrby, P.-O.; Skrydstrup, T. Angew. Chem., Int. Ed. 2006,
45, 3349.
(13) Review: (a) Oestreich, M. Eur. J. Org. Chem 2005, 783. (b) Jeong,
S.; Chen, X.; Harran, P. G. J. Org. Chem. 1998, 63, 8640.
Org. Lett., Vol. 9, No. 22, 2007
4433

In conclusion, we have explored the vinyl triflate 1/Heck-
type reaction manifold. All the reactions suggested in Scheme
1 have been detected, and in some cases there is considerable
selectivity in favor of one pathway. Specifically, the forma-
tion of cyclobutane esters 7 and 1,2-dimethylene cyclo-
butanes 8 may be of particular synthetic value. To explain
the different reaction pathways for individual substrates,
detailed mechanistic investigations are currently being
undertaken and will be reported in due course.
Acknowledgment. The authors thank Susanne Felsinger
(University of Vienna) for NMR. Robert Saf (TU Graz) is
thanked for mass spectrometry.
Supporting Information Available: Experimental pro-
cedures and NMR spectra for all new compounds provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL701697R
4434
Org. Lett., Vol. 9, No. 22, 2007