Synthesis of 2H-1-benzopyrans via palladacycles with a metal-bonded stereogenic carbon

Article abstract of DOI:10.1021/ol0201456

(graph presented) Stable oxapalladacycles have been prepared and converted into a series of highly functionalized 2H-1-benzopyrans via regioselective insertion of activated alkynes.

Full text of DOI:10.1021/ol0201456

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3679-3681
Synthesis of 2H-1-Benzopyrans via
Palladacycles with a Metal-Bonded
Stereogenic Carbon
Janelle L. Portscheller and Helena C. Malinakova*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-7582
hmalina@ukans.edu
Received July 29, 2002
ABSTRACT
Stable oxapalladacycles have been prepared and converted into a series of highly functionalized 2H-1-benzopyrans via regioselective insertion
of activated alkynes.
Palladium-catalyzed cascade reactions belong among the
most powerful tools for the construction of carbon-carbon
bonds.1 Recently, new pathways for these transformations
have been observed and rationalized by proposing pallada-
cycles as intermediates.2 In this context, systematic explora-
tion of the chemistry of stable palladacycles3 holds great
synthetic promise. We envisioned that palladacycles could
be prepared from achiral substrates with concomitant genera-
tion of a metal-bonded stereogenic carbon4 and subsequently
serve as templates for the introduction of the stereogenic
center into valuable organic targets.
to carbons C-2, C-3, and C-4 of the benzopyran skeleton, a
feat that is difficult to accomplish by traditional methods.5
The two-step protocol offers a new solution to the synthetic
challenge posed by numerous biologically active compounds6
featuring a benzopyran core with a stereogenic C-2 carbon.
In contrast to previous reports that pointed to a rather limited
reactivity of palladium-based complexes,3a,7 novel pallada-
cycles I reacted smoothly with activated alkynes bearing a
variety of substituents R1, including alkyl, aryl, and alkenyl
groups (Scheme 1). Results reported herein constitute a
foundation for the future development of catalytic and
asymmetric variants of this protocol.
Herein, we describe a convergent synthesis of highly
substituted 2H-1-benzopyrans based on the above outlined
strategy (Scheme 1). Stable oxapalladacycles I have been
(1) Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH Verlag GmbH: Weinheim, 1998; Chapter 3.
(2) (a) Lautens, M.; Paquin, J.-F.; Piguel, S. J. Org. Chem. 2002, 67,
3972-3974. (b) Larock, R. C.; Tian, Q. J. Org. Chem. 2001, 66, 7372-
7379. (c) Wang, L.; Pan, Y.; Jiang, X.; Hu, H. Tetrahedron Lett. 2000, 41,
725-727. (d) Catellani, M.; Motti, E.; Baratta, S. Org. Lett. 2001, 3, 3611-
3614. (e) Dyker, G. Chem. Ber. 1997, 130, 1567-1578. (f) Catellani, M.;
Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 119-
122. (g) Echavarren, A. M.; Gonzalez, J. J.; Garcia, N.; Gomez-Lor, B. J.
Org. Chem. 1997, 62, 1286-1291.
Scheme 1. Synthetic Strategy
(3) For examples of the preparation of stable palladacycles, see: (a)
Campora, J.; Lopez, J. A.; Palma, P.; del Rio, D.; Carmona, E.; Valerga,
P.; Graiff, C.; Tiripicchio, A. Inorg. Chem. 2001, 40, 4116-4126. (b)
Martin-Matute, B.; Mateo, C.; Cardenas, D. J.; Echavarren, A. M. Chem.
Eur. J. 2001, 7, 2341-2348. (c) Mateo, C.; Fernandez-Rivas, C.; Cardenas,
D. J.; Echavarren, A. M. Organometallics 1998, 17, 3661-3669. (d) van
Belzen, R.; Hoffmann, H.; Elsevier: C. J. Angew. Chem., Int. Ed. Engl.
1997, 36, 1743-1745. (e) Catellani, M.; Chiusoli, G. P. J. Organomet.
Chem. 1988, 346, C27-C30. (f) Diversi, P. Ingrosso, G.; Lucherini, A.;
Murtas, S. J. Chem. Soc., Dalton Trans. 1980, 9, 1633-1637.
prepared and converted into a series of 2H-1-benzopyrans
II via regiocontrolled insertion of activated unsymmetrical
alkynes. In this manner, diverse substituents can be attached
10.1021/ol0201456 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/18/2002

Palladacycles 4-6 were prepared via several alternative
pathways as shown in Scheme 2. Initially, stepwise protocols
palladium(II) complexes 2a-e that were converted into
complexes 3a-e via ligand exchange with Ph3P.10 Com-
plexes 3a and 3b provided palladacycles 5a and 5b in good
to excellent yields (59-86%) upon reaction with appropriate
bases (LDA or t-BuOK). Treatment with t-BuOK (1 M in
THF) proved to be the method of choice (Method A, Scheme
2). Palladacycles 4a-c bearing the TMEDA ligand have been
obtained in 66-73% yields upon treatment of complexes
2a-c with t-BuOK and AgNO3 (Method B, Scheme 2). The
silver salt is not essential for ring closure, and the additive
only facilitates chromatographic purification of highly polar
complexes 4a-c. Conversion of complex 2b into pallada-
cycle 4b was also induced by PhOK. However, the palla-
dacycle bearing the N,N-diethylamide group and the Ph3P
ligand could not be obtained from complex 3c by Method
A. Furthermore, while exchange of the TMEDA ligands with
Ph3P proceeded uneventfully with complexes 4a and 4b
giving palladacycles 5a and 5b (Scheme 2), the analogous
transformation did not occur with palladacycle 4c featuring
the amide group.11 When Ph3P was replaced with the less
sterically demanding 1,2-bis(diphenylphosphino)ethane (dppe)
and 1,4-bis(diphenylphosphino)butane (dppb) ligands, the
exchange reaction afforded the expected palladacycles 5c and
6c in good yields (Scheme 2). Thus, it appears that the
combined steric bulk of the amide group and of the two Ph3P
ligands may also be responsible for the failure of the ring-
closure reaction of complex 3c. None of the methods
described above allowed closure to the palladacyclic ring
when complexes 2d,e and 3d,e (Y ) Ph, CH2OMe) lacking
the electron-withdrawing substituents were employed. At-
tempts to cyclize complexes 2b and 3b by treatment with
less basic reagents (DBN, TEA, K2CO3) were unsuccessful.
Apparently, formation of the Csp3-Pd bond proceeds via
an intramolecular ligand substitution process that requires
the presence of low equilibrium concentrations of enolate
anions.12 Finally, a practical high-yielding one-pot prepara-
tion of palladacycles 5a,b from the aryl iodides 1a,b has
been developed (Method C, Scheme 2), which allowed us
to routinely prepare the palladacycles on a 1 g scale.
Palladacycles 4-6 were obtained as air-stable white solids.
Structure assignments based on spectroscopic data were
Scheme 2. Synthesis of Palladacyclesa
a Method A: t-BuOK, THF, rt, 10 min. Method B: t-BuOK,
AgNO3, THF, rt, 10 min. Method C: (i) Pd2dba3, Ph3P, 55 °C, 30
min, (ii) t-BuOK, THF, rt, 10 min, benzene.
were explored. Iodoethers 1a-e, accessible via O-alkylation
of o-iodophenol,8 were treated with Pd2dba3 and tetrameth-
ylethylenediamine (TMEDA) in benzene9 to yield stable
(4) Palladacycles with a metal-bonded stereogenic carbon, other than
those containing the norbornane skeleton, are rare. See: (a) Hashmi, A. S.
K.; Naumann, F.; Bolte, M. Organometallics 1998, 17, 2385-2387. (b)
Munz, D.; Stephan. C.; Dieck, H. T. J. Organomet. Chem. 1991, 407, 413-
420. However, cyclopalladated and cycloplatinated complexes with a metal-
bonded stereogenic carbon are known and have been prepared in a
nonracemic form. See: (c) Ryabov, A. D.; Panyashkina, I. M.; Polyakov,
V. A.; Fischer, A. Organometallics 2002, 21, 1633-1636. (d) Garcia-Ruano,
J. L.; Gonzalez, A. M.; Barcena, A. I.; Camazon, M. J.; Navarro-Ranninger,
C. Tetrahedron: Asymmetry 1996, 7, 139-148. (e) Spencer, J.; Pfeffer, M.
Tetrahedron: Asymmetry 1995, 6, 419-426. (f) Yoneda, A.; Hakushi, T.
Organometallics 1994, 13, 4912-4918. (g) Pfeffer, M. Recl. TraV. Chim.
Pays-Bas 1990, 109, 567-576.
(5) For the preparation of 2H-1-benzopyrans, see: (a) Goujon, J. Y.;
Zammattio, F.; Pagnoncelli, S.; Boursereau, Y.; Kirschleger, B. Synlett 2002,
322-324. (b) Parker, K. A.; Mindt, T. L. Org. Lett. 2001, 3, 3875-3878.
(c) Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063-4065. (d) Wipf, P.;
Weiner, W. S. J. Org. Chem. 1999, 64, 5321-5324. (e) Grubbs, R. H.;
Chang, S. J. Org. Chem. 1998, 63, 864-866. (f) Hoveyda, A. H.; Harrity,
J. P. A.; Wisser, J. S.; Gleason, J. D. J. Am. Chem. Soc. 1997, 119, 1488-
1489. (g) Issa, Y.; Ramazani, A. Synth. Commun. 1997, 27, 1385-1390.
(h) Bigi, F.; Carloni, S.; Maggi, R.; Muchetti, C.; Sartori, G. J. Org. Chem.
1997, 62, 7024-7027.
(7) Depending on the spectator ligands, alkyne insertions to the known
palladacycles are often limited to reactions with dimethyl acetylenedicar-
boxylate (dmad). See: (a) Mateo, C.; Cardenas, D. J.; Fernandez-Rivas,
C.; Echavarren, A. M. Chem. Eur. J. 1996, 2, 1596-1606. (b) Catellani,
M.; Marmiroli, B.; Chiara-Fagnola, M.; Acquotti, D. J. Organomet. Chem.
1996, 507, 157-162. (c) Liu, D.-H.; Li, C.-S.; Cheng, C.-H. Organome-
tallics 1994, 13, 18-20. For general references on alkyne insertions to group
10 metalacycles, see: (d) Campora, J.; Palma, P.; Carmona, E. Coord. Chem.
ReV. 1999, 193-195, 207-281. (e) Bennett, M. A.; Macgregor, S. A.;
Wenger, E. HelV. Chem. Act. 2001, 84, 3084-3104. (f) Campora, J.;
Llebaria, A.; Moreto, J. M.; Poveda, M. L.; Carmona, E. Organometallics
1993, 12, 4032-4038.
(8) Ramakrishnan, V. T.; Kagan, J. J. Org. Chem. 1970, 35, 2901-2904.
(9) Markies, B. A.; Canty, A. J.; de Graaf, W.; Boersma, J.; Janssen, M.
D.; Hogerheide, M. P.; Smeets, W. J. J.; Spek, A. L.; van Koten, G. J.
Organomet. Chem. 1994, 482, 191-199.
(10) Ludwig, M.; Stro¨mberg, S.; Svensson, M.; A° kermark, B. Organo-
metallics 1999, 18, 970-975.
(6) For selected examples of biologically active 2H-1-benzopyrans, see:
(a) Iwasaki, T.; Mihara, S.-I.; Shimamura, T.; Kawakami, M.; Masui, M.;
Hayasaki-Kajiwara, Y.; Naya, N.; Ninomiya, M.; Fujimoto, M.; Nakajima,
M. J. CardioVasc. Pharmacol. 2001, 37, 471-482. (b) Mannhold, R.;
Cruciani, G.; Weber, H.; Lemoine, H.; Derix, A.; Weichel, C.; Clementi,
M. J. Med. Chem. 1999, 42, 981-991. (c) Tronchet, J. M. J.; Zerelli, S.;
Bernardinelli, G. J. Carbohydr. Chem. 1999, 18, 343-359.
(11) An in situ monitoring of the reaction between amide 4c and Ph3P
(2.2 equiv) via 1H and 31P NMR indicated the presence of an unreacted
complex 4c, along with low concentrations of the desired palladacycle [31P
NMR (202 MHz, CDCl3) δ 24.5 (d, J ) 27.7 Hz, 1 P), 26.7 (d, J ) 27.3
Hz, 1 P)]. However, attempts to isolate this product failed.
3680
Org. Lett., Vol. 4, No. 21, 2002

Table 1. Reaction of Palladacycles with Alkynes
conditions
substrate
alkynea
time (h)
temp (°C)
product
yield (%)
R1
R2
1
2
3
6c
5b
5b
MeO2CCtCCO2Me
MeO2CCtCCO2Me
MeCtCCO2Et
5d
1
80
40
80
7
8
64
95
54
CO2Me
CO2Me
Me
CO2Me
CO2Me
CO2Et
Me
CO2Et
CO2Et
COCH3
CO2Et
CO2Et
6d
9a b
9b
10
11
12
13
14
CO2Et
n-Bu
Ph
4
5
6
7
8
5b
5b
5b
5b
5b
n-BuCtCCO2Et
PhCtCCO2Et
PhCtCCOCH3
C6H9CtCCO2Etc
TMSCtCCO2Et
6
5
6d
5d
7d
80
80
80
80
80
79
76
59
57
36
Ph
C6H9
c
TMS
a 2.2 molar equiv of alkyne was used. b A 6:1 mixture of products 9a and 9b was isolated. c C6H9 ) 1-cyclohexenyl. d Reaction mixture was stirred for
additional 20 h at room temperature.
further corroborated by X-ray crystallographic analyses of
palladacycles 4a and 5c.
lacking the activating substituent (PhCtCPh) afforded only
traces of the expected benzopyran. To determine the regio-
chemistry of the insertion reaction, long-range 1H-13C
connectivities in the benzopyrans 9a and 10-14 obtained
from an HMBC 2D-NMR experiment were examined.14
Palladium(0) was recovered from the reaction mixture in
entry 2 (Table 1) as [(Ph3P)2Pd(dmad)] in 72% yield.15
In conclusion, synthesis of novel palladacycles with a
metal-bonded stereogenic sp3-hybridized carbon has been
described. The utility of the palladacycles as templates for
the preparation of biologically significant targets has been
demonstrated by a remarkably regiocontrolled synthesis of
highly substituted 2H-1-benzopyrans. Studies of a ligand-
induced asymmetry transfer are in progress, and the develop-
ment of a catalytic variant is being pursued.
Complexes 5b and 6c reacted with dimethyl acetylenedi-
carboxylate (dmad) to afford benzopyrans 7 and 8 (Table 1,
entries 1 and 2) in good to excellent yields (64-95%). The
ability of palladacycle 6c stabilized by a bidentate ligand
(dppb) to undergo the insertion reaction is notable.13 Alkyne
insertions with complex 5a had to be run under high dilution
to avoid the formation of unidentified precipitates, while
palladacycles 4a-c and 5c failed to react with dmad.
Palladacycle 5b inserted smoothly a variety of unsymmetrical
alkynes activated by a ketone or an ester group and featuring
alkyl (methyl, n-butyl, entries 3 and 4), phenyl (entries 5
and 6), and 1-cyclohexenyl (entry 7) substituents to afford
benzopyrans 9-13 in 54-79% yields after chromatography
(Table 1). The presence of a sterically bulky trimethylsilyl
group in the alkyne reduced the yield of the corresponding
benzopyran 14 to 36% (entry 8). Benzopyrans 10-14 were
isolated as single regioisomers, and analyses of the crude
reaction mixtures (entries 4-8) by 1H NMR did not provide
any evidence for the formation of regioisomeric products.
A single exception among the unsymmetrical alkynes was
noted in the reaction of ethyl 2-butynoate (entry 3). Ben-
zopyran 9 was isolated in 54% yield as an inseparable
mixture of two regioisomers in a 6:1 ratio (1H NMR and
GC). The major regioisomer 9a was obtained as a pure
compound in a lower yield (31%) after limiting the reaction
time. The observed regioselectivity points to an electronic
control exerted by the alkyne substituents.7e An alkyne
Acknowledgment. Acknowledgment is made to the
donors of the Petroleum Research Fund, administered by the
American Chemical Society, to Kansas NSF EPSCoR and
to Kansas Technology Enterprise Corporation for support
of this research. We thank our colleague Dr. Douglas R.
Powell for his assistance with X-ray crystallography.
Supporting Information Available: Complete descrip-
tions of the synthesis and characterization of all compounds
prepared in this study and X-ray crystallographic studies of
palladacycles 4a and 5c. This material is available free of
charge via Internet at http://pubs.acs.org.
OL0201456
(14) Indicative HMBC correlations for benzopyrans 9a and 13:
(12) Stable arylpalladium(II) enolates have been isolated. See: (a)
Hartwig, J. F.; Culkin, D. A. J. Am. Chem. Soc. 2001, 123, 5816-5817.
Palladium-catalyzed R-arylation of ketones, esters and amides is known.
See: (b) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem.
1998, 63, 6546-6553. (c) Hamada, T.; Chieffi, A.; A° hman, J.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 1261-1268.
(13) The majority of the known alkyne insertion reactions involve
metalacycles bearing monodentate ligands; see refs 3a and 7.
(15) Urata, H.; Suzuki, H.; Moro-oka, Y.; Ikawa, T. J. Organomet. Chem.
1989, 364, 235-244.
Org. Lett., Vol. 4, No. 21, 2002
3681