Phosphine-catalyzed synthesis of highly functionalized coumarins

Article abstract of DOI:10.1021/ol071181d

2-Styrenyl allenoates are converted into cyclopentene-fused dihydrocoumarins through phosphine-catalyzed regio- and diastereoselective [3 + 2] cycloadditions. Remarkably, changing the solvent from THF to benzene promotes the conversion of the 2-(2-nitrostyrenyl) allenoate into a tricyclic nitronate through a previously undocumented mode of phosphine catalysis. This nitronate was subjected to efficient face-, regio-, and exo-selective 1,3-dipolar cycloadditions to provide tetracyclic coumarin derivatives.

Full text of DOI:10.1021/ol071181d

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3069-3072
Phosphine-Catalyzed Synthesis of
Highly Functionalized Coumarins
Christopher E. Henry and Ohyun Kwon*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles,
607 Charles E. Young DriVe East, Los Angeles, California 90095-1569
ohyun@chem.ucla.edu
Received May 19, 2007
ABSTRACT
2-Styrenyl allenoates are converted into cyclopentene-fused dihydrocoumarins through phosphine-catalyzed regio- and diastereoselective [3
2] cycloadditions. Remarkably, changing the solvent from THF to benzene promotes the conversion of the 2-(2-nitrostyrenyl) allenoate into
+
a tricyclic nitronate through a previously undocumented mode of phosphine catalysis. This nitronate was subjected to efficient face-, regio-,
and exo-selective 1,3-dipolar cycloadditions to provide tetracyclic coumarin derivatives.
Coumarins are heterocycles that are frequently encountered
in natural products1 and used widely in medicinal compounds
(e.g., warfarin).2 Functionalized coumarins also find applica-
tions in perfumary,3 as fluorescent materials,4 and as dyes
in laser technology.5 Not surprisingly, considerable effort has
been exerted toward the synthesis of coumarins through the
use of Perkin, Pechmann, Wittig, Reformatsky, Claisen, and
Knoevenagel reactions.6 These traditional methods, however,
generally require harsh reaction conditions, often resulting
in low product yields. More recently, transition-metal-
catalyzed reactions have been reported for the synthesis of
coumarins,7 but these examples have been limited to products
possessing simple substituents. As part of a program geared
toward the design and development of nucleophilic phosphine
catalysis for the synthesis of a diverse array of small organic
molecules, here we report the expeditious intramolecular
phosphine-catalyzed transformation of 2-styrenyl allenoates
into highly functionalized coumarins.8
Phosphine-catalyzed annulation of activated alkenes and
alkynes is a highly attractive synthetic method for preparing
a variety of carbocycles and heterocycles from readily
available starting materials.9,10 In particular, much effort has
been devoted to the [3 + 2] cycloaddition of allenoates with
(1) (a) Coumarins: Biology, Applications, and Mode of Action; O’Kennedy,
R., Thornes, R. D., Eds.; John Wiley & Sons: New York, 1997. (b) Murray,
R. D. H.; Mendez, J.; Brown, S. A. The Natural Coumarins: Occurrence,
Chemistry, and Biochemistry; Wiley: New York, 1982.
(2) Yu, D.; Suzuki, M.; Xie, L.; Morris-Natschke, S. L.; Lee, K.-H. Med.
Res. ReV. 2003, 23, 322.
(3) Clark, G. S. Perfum. FlaVor. 1995, 20, 23.
(4) (a) Zahradnik, M. The Production and Application of Fluorescent
Brightening Agents; Wiley: New York, 1982. (b) Furuta, T.; Wang, S.-H.;
Dantzker, J. L.; Dore, T. M.; Bybee, W. J.; Callaway, E. M.; Denk, W.;
Tsien, R. Y. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 1193. (c) Brun, M.-P.;
Bischoff, L.; Garbay, C. Angew. Chem., Int. Ed. 2004, 43, 3432.
(5) Sekar, N. Colourage 2003, 50, 55.
(6) (a) Perkin, W. H.; Henry, W. J. Chem. Soc. 1875, 28, 10. (b)
Pechmann, V. H.; Duisberg, C. Chem. Ber. 1884, 17, 929. (c) Maercker,
A. Org. Synth. 1934, 14, 270. (d) Shriner, R. L. Org. React. 1942, 1, 15.
(e) Cairns, N.; Harwood, L. M.; Astles, D. P. J. Chem. Soc., Perkin Trans.
1 1994, 3101. (f) Jones, F.; Piermatti, O.; Pizzo, F. Heterocycles 1996, 43,
1257.
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(b) Kadnikov, D. V.; Larock, R. C. Org. Lett. 2000, 2, 3643. (c) Rayabarapu,
D. K.; Sambaiah, T.; Cheng, C.-H. Angew. Chem., Int. Ed. 2001, 40, 1286.
(8) (a) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716.
(b) Zhu, X.-F.; Henry, C. E.; Wang, J.; Dudding, T.; Kwon, O. Org. Lett.
2005, 7, 1387. (c) Zhu, X.-F.; Schaffner, A.-P.; Li, R. C.; Kwon, O. Org.
Lett. 2005, 7, 2977. (d) Tran, Y. S.; Kwon, O. Org. Lett. 2005, 7, 4289. (e)
Zhu, X.-F.; Henry, C. E.; Kwon, O. Tetrahedron 2005, 61, 6276. (f)
Dudding, T.; Kwon, O.; Mercier, E. Org. Lett. 2006, 8, 3643. (g) Mercier,
E.; Fonovic, B.; Henry, C. E.; Kwon, O.; Dudding, T. Tetrahedron Lett.
2007, 48, 3617. (h) Castellano, S.; Fiji, H. D. G.; Kinderman, S. S.;
Watanabe, M.; de Leon, P.; Tamanoi, F.; Kwon, O. J. Am. Chem. Soc.
2007, 129, 5843. (i) Zhu, X.-F.; Henry, C. E.; Kwon, O. J. Am. Chem. Soc.
2007, 129, 6722.
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346, 1035. (c) Lu, X.; Du, Y.; Lu, C. Pure Appl. Chem. 2005, 77, 1985.
10.1021/ol071181d CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/13/2007

R,â-unsaturated carbonyl compounds to form cyclopentenes,11
e.g., this process has been applied to natural product
synthesis12 and an enantioselective variant of the reaction
has been developed;13 in addition, thorough mechanistic
studies have been reported by Yu and co-workers and by
us.14 Unfortunately, unlike the [3 + 2] cycloadditions of
allenoates with imines to form dihydropyrroles,15 intermo-
lecular annulations between allenoates and alkenes generally
suffer from the formation of a mixture of regioisomeric
cyclopentenes. For example, Lu’s original report indicated
that the [3 + 2] annulation between ethyl allenoate and
methyl acrylate furnished a 4:1 mixture of regioisomeric
cyclopentenes, favoring R-addition of the phosphonium
dienolate intermediate to the acrylate in a Michael-type
manner.11a In contrast, in Fu’s asymmetric phosphine ca-
talysis of allenes with â-substituted enones to form cyclo-
pentenes, the preference for R-addition of the allenoates to
activated (non-â-substituted) alkenes was reversed to
γ-addition.13c
For many C-C bond-forming processes, exclusive regi-
oselectivity is achieved when the reactions are performed
intramolecularly.16 We sought to apply this principle to an
intramolecular variant of the allene/alkene [3 + 2] cycload-
dition of substrate 1a (eq 1). Compound 1a was synthesized
from salicylaldehyde through a Wittig reaction17 followed
by coupling with 3-butynoic acid under the influence of
Mukaiyama’s reagent;18,19 presumably, the initial 3-butynoate
product isomerized to the allenoate under the coupling
reaction conditions.20 Treatment of 1a with 20 mol % of
tributylphosphine in THF at room temperature for 6 h
produced 2a in 96% isolated yield as a single diastereoiso-
mer.21 Thus, this catalytic reaction provided a tricyclic
dihydrocoumarin structure directly from a cinnamyl allenoate
through a regioselective annulation process.
This reaction proved to be effective for transforming
various other commercially available salicylaldehyde deriva-
tives into cyclopentene-fused dihydrocoumarins (Table 1).
Table 1. Syntheses of Cyclopentene-Fused Dihydrocoumarins
2a
entry
R (1)
H (1a)
3-methyl (1b)
3-methoxy (1c)
4-methoxy (1d)
5-methoxy (1e)
5-fluoro (1f)
yield (%)b product (2) yieldc (%)
1
2
3
4
5
6
7
8
72
64
77
71
73
45
38
45
2a
2b
2c
2d
2e
2f
96
98
74
94
70
91
93
(10) For recent examples, see: (a) Kumar, K.; Kapur, A.; Ishar, M. P.
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Pyne, S. T.; Amornraksa, K.; Wouters, R.; Van der Linden, I.; Biesmans,
I.; Lesage, A. S. J.; Skelton, B. W.; White, A. H. J. Org. Chem. 2002, 67,
227. (d) Liu, B.; Davis, R.; Joshi, B.; Reynolds, D. W. J. Org. Chem. 2002,
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I.; Endo, T. Org. Lett. 2003, 5, 129. (g) Jung, C.-K.; Wang, J.-C.; Krische,
M. J. J. Am. Chem. Soc. 2004, 126, 4118. (h) Du, Y.; Feng, J.; Lu, X. Org.
Lett. 2005, 7, 1987. (i) Zhao, G.-L.; Min, S. Org. Biomol. Chem. 2005, 3,
3686. (j) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234. (k)
Nair, V.; Biju, A. T.; Mohanan, K.; Suresh, E. Org. Lett. 2006, 8, 2213.
(11) (a) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906. (b) Shu, L.-
H.; Sun, W.-Q.; Zhang, D.-W.; Wu, S.-H.; Wu, H.-M.; Xu, J.-F.; Lao, X.-
F. Chem. Commun. 1997, 79. (c) O’Donovan, B. F.; Hitchcock, P. B.;
Meidine, M. F.; Kroto, H. W.; Taylor, R.; Walton, D. R. M. Chem. Commun.
1997, 81. (d) Xu, Z.; Lu, X. Tetrahedron Lett. 1999, 40, 549. (e) Ung, A.
T.; Schafer, K.; Lindsay, K. B.; Pyne, S. G.; Amornraksa, K.; Wouters, R.;
Van der Linden, I.; Biesmans, I.; Lesage, A. S. J.; Skelton, B. W.; White,
A. H. J. Org. Chem. 2002, 67, 227. (f) Du, Y.; Lu, X.; Yu, Y. J. Org.
Chem. 2002, 67, 8901. (g) Lu, X.; Lu, Z.; Zhang, X. Tetrahedron 2006,
62, 457.
(12) (a) Du, Y.; Lu, X. J. Org. Chem. 2003, 68, 6463. (b) Wang, J.-C.;
Krische, M. J. Angew. Chem., Int. Ed. 2003, 42, 5855. (c) Pham, T. Q.;
Pyne, S. G.; Skelton, B. W.; White, A. H. J. Org. Chem. 2005, 70, 6369.
(13) (a) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J.
Am. Chem. Soc. 1997, 119, 3836. (b) Pakulski, Z.; Demchuk, O. L.; Frelek,
J.; Luboradzki, R.; Pietrusiewicz, K. M. Eur. J. Org. Chem. 2004, 3913.
(c) Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1426. (d)
Scherer, A.; Gladysz, J. A. Tetrahedron Lett. 2006, 47, 6335. (e) Jean, L.;
Marinetti, A. Tetrahedron Lett. 2006, 47, 2141. (f) Wallace, D. J.; Sidda,
R. L.; Reamer, R. A. J. Org. Chem. 2007, 72, 1051.
5-bromo (1g)
5-nitro (1h)
2g
2h
9d
a See the Supporting Information for details. b Isolated yield for the
formation of 1. c Isolated yield for the formation of 2. d The allenoate
hydrolyzed to form the 2-hydroxycinnamate; the resulting phenol was added
to the starting cinnamyl allenoate at the â-carbon atom in 81% yield.
Both electron-withdrawing and -donating substituents on the
benzene ring were compatible with the reaction conditions
(entries 1-7). A substrate containing a nitro substituent
provided the lowest product yield (entry 8); this result is
consistent with our previous findings for [4 + 2] allenoate/
arylimine annulations.8a
Next, we turned our attention to establishing the role
played by the activating substituent on the alkene moiety.
Although 2-(2-phenylsulfonyl)styrenyl allenoate 1i readily
(19) Use of the common (peptide) coupling reagents [DCC, TCT, Hf-
(IV) salts, HBTU, HATU, and PyBroP] failed to provide the allenoate
product. Presumably, the product allenoate is susceptible to nucleophilic
attack by either a base present in the reaction medium or the byproducts
derived from the coupling reagents. See the Supporting Information for
details regarding the isolation and characterization of the product of
N-hydroxybenzotriazole addition to the allenoate when using HBTU.
(20) Eglinton, G.; Jones, E. R. H.; Mansfield, G. H.; Whiting, M. C. J.
Chem. Soc. 1954, 3197.
(14) (a) Xia, Y.; Liang, Y.; Chen, Y.; Wang, M.; Jiao, L.; Huang, F.;
Liu, S.; Li, Y.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 3470. (b) Reference
8g.
(15) (a) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (b) Xu, Z.;
Lu, X. J. Org. Chem. 1998, 63, 5031. (c) 8e.
(16) For an example of γ-selective intramolecular alkyne/alkene [3 +
2] cycloaddition, see: Wang, J.-C.; Ng, S.-S.; Krische, M. J. J. Am. Chem.
Soc. 2003, 125, 3682.
(17) Bunce, R. A.; Schilling, C. L. Tetrahedron 1997, 53, 9477.
(18) Mukaiyama, T.; Usui, M.; Shimada, E. Chem. Lett. 1975, 1045.
(21) The connectivity and relative stereochemistry of this compound were
assigned through NMR spectroscopic analyses. See the Supporting Informa-
tion for details.
3070
Org. Lett., Vol. 9, No. 16, 2007

underwent the annulation reaction to produce the tricyclic
coumarin derivative 2i in 63% yield (eq 2),22 the nitrostyrenyl
derivative 1j did not provide the desired annulation product
when subjected to the optimized reaction conditions (20 mol
% PBu3, THF, rt). Catalysis using the less-nucleophilic PPh3
produced the desired annulation product in moderate yield
(48%), accompanied by a minor product 3 (12%). In an
attempt to further improve the yield of the [3 + 2] annulation
product, we examined the use of some other common organic
solvents. Surprisingly, the reaction of the nitrostyrenyl
derivative 1j with PPh3 in benzene provided the nitronate 3
as the major product in 58% yield, in addition to a 14% yield
of the cyclopentene adduct 2j.23 The corresponding reaction
catalyzed by the even-less-nucleophilic tris(p-fluorophenyl)-
phosphine furnished 3 in a slightly improved yield (62%;
19% 2j).
Table 2. 1,3-Dipolar Cycloadditions of Nitronate 3a
Having synthesized this nitronate, we tested its synthetic
utility in 1,3-dipolar cycloadditions to form highly function-
alized coumarin derivatives (Table 2). Nitronates are versatile
1,3-dipoles that undergo reactions with neutral, electron-rich,
and electron-poor dipolarophiles.24 Indeed, when we treated
nitronate 3 with allyl bromide, we obtained the tetracyclic
coumarin derivatives 4a and 5a in 97% isolated yield as a
7:1 mixture of exo and endo products (entry 1). The
connectivity and relative stereochemistry of the nitroso
acetals 4a and 5a, as well as 4d, were confirmed through
X-ray crystallographic analysis.25 This reaction exhibited
exclusive facial and regioselectivity as well as good exo
selectivity. Both electron-rich and -poor alkenes underwent
[3 + 2] cycloadditions with 3 in excellent yields (93-94%)
aSee the Supporting Information for details. b Isolated yield. c Complex
mixture of products. d Mostly recovered starting material.
with high exo selectivity (exo/endo ) 9-11:1; entries 2 and
3). Trans-disubstituted alkenes were viable substrates (entries
4 and 5), but cis-disubstituted alkenes were recalcitrant to
the reaction (entries 6 and 7). In all the examples, the carbon
atom bearing the activating substituent formed a bond to the
oxygen atom of the nitronate 1,3-dipole. The product nitroso
acetals possess up to four stereogenic centers and are replete
with functional groups. Their Raney nickel-catalyzed N-O
bond cleavages producing corresponding amino alcohols and
their application to the syntheses of alkaloid natural products
are well documented.26
(22) NOE analyses confirmed the trans stereochemistry of the [3 + 2]
annulation product. See the Supporting Information for details.
(23) See the Supporting Information for the syntheses of 1i and 1j.
(24) For reviews on the preparation and use of nitronates, see: (a)
Takaeuchi, Y.; Furusaki, F. In AdVances in Heterocyclic Chemistry;
Katritzky, A. R., Boulton, A. J., Eds.; Academic: New York, 1977; Vol.
21, p 207. (b) Shipchandler, M. T. Synthesis 1979, 666. (c) Torsell, K. B.
G. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; VCH:
Weinheim, 1988. (d) Breuer, E.; Aurich, H. G.; Nielsen, A. Nitrones,
Nitronates, and Nitroxides; Wiley: New York, 1990; p 105. (e) Do¨pp, H.;
Do¨pp, D. In Modern der Organischen Chemie (Houben-Weyl), 4th ed.;
Klamann, D., Hagemann, H., Eds.; Georg Thieme: Stuttgart, 1990; Vol.
E14b/1, p 880.
(25) Crystallographic data for 4a, 5a, and 4d have been deposited with
the Cambridge Crystallographic Data Centre as supplementary numbers
CCDC 602367-602369. These data can be obtained online free of charge
(or from the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or deposit@
ccdc.cam.ac.uk).
Scheme 1 provides two possible mechanisms that account
for the formation of nitronate 3. We excluded the possibility
(26) Denmark, S. E.; Cottell, J. J. In The Chemistry of Heterocyclic
Compounds: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H.,
Eds.; Wiley-Interscience: New York, 2002; pp 83-167.
Org. Lett., Vol. 9, No. 16, 2007
3071

8 yields 12. A subsequent 1,4-proton transfer in 12 provides
13, which generates the nitrodiene 14 upon expulsion of
triphenylphosphine. Finally, 6π electrocyclic ring closure of
nitrodiene 14 provides the nitronate 3. To the best of our
knowledge, the literature lacks examples of the proposed 6π
electrocyclization. The closest precedent is a 6-π-electron
5-atom electrocyclization of nitrosostyrenes to benzonitr-
onates found in an indole synthesis from nitrobenzenes via
reductive cyclization.28
Scheme 1. Proposed Mechanisms for the Formation of
Nitronate 3
In summary, we have discovered two diverting reaction
modalities for the nucleophilic phosphine-mediated reactions
of 2-styrenyl allenoates. Tertiary phosphines in THF facili-
tated intramolecular [3 + 2] annulation to provide cyclo-
pentene-fused dihydrocoumarins in excellent to good yields
with exclusive diastereoselectivity. The reaction of 2-(2-
nitrostrenyl)allenoate 1j with triphenylphosphine in benzene,
on the other hand, led to the formation of the tricyclic
nitronate 3 through an unprecedented mode of catalysis. We
have demonstrated the synthetic potential of this nitronate
through its 1,3-dipolar cycloadditions with a number of
dipolarophiles. The reactions described herein are simple and
efficient approaches toward the syntheses of structurally
complex coumarins and add to the number of recently
discovered phosphine-catalyzed annulation reactions of al-
lenoate precursors. Our future efforts will focus on intramo-
lecular phosphine catalysis of other allenoates derived from
salicylaldehydes and their application to the synthesis of
coumarin-containing natural products.
of a Diels-Alder reaction occurring between the nitroalkene
and the allene based on our observation that the reaction
did not proceed in the absence of a phosphine.27 Attempts
to facilitate the Diels-Alder reaction under thermal or Lewis
acid catalysis conditions resulted only in recovery of the
starting material. Accordingly, we propose mechanisms
involving phosphine as a catalyst. Nucleophilic addition of
triphenylphosphine to allenoate 1j produces the zwitterionic
intermediate 6. Intramolecular Michael addition of the allylic
anion to the nitroalkene in 6 leads to the cyclized intermediate
7. Proton transfer of the most acidic proton, i.e., the one
positioned R to the carbonyl group, yields the allylic anion
8. 1,5-Proton transfer in 8 furnishes 9, which undergoes
6-endo cyclization to form 10. Expulsion of the phosphine
from 10 produces the nitronate 11, which can isomerize to
the nitronate 3. In the other scenario, 1,4-proton transfer in
Acknowledgment. This work was supported by the NIH
(R01GM071779) and UCLA. C.E.H. is a recipient of a
USPHS national research service award (GM08496). We
thank Dr. Saeed Khan for performing the X-ray crystal-
lographic analyses. O.K. thanks Dr. Kendall N. Houk for
helpful discussions.
Supporting Information Available: Representative ex-
perimental procedures and spectral data for all new com-
pounds. Crystallographic data for compounds 4a, 4d, and
5a (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(27) For reviews on hetero-Diels-Alder reaction of nitroalkenes, see:
(a) Perekalin, V. V.; Lipina, E. S.; Berestovitskaya, V. M.; Efremov, D. A.
Nitroalkenes: Conjugated Nitro Compounds; Wiley: New York, 1994; p
131. (b) Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137.
OL071181D
(28) Davis, I. W.; Guner, V. A.; Houk, K. N. Org. Lett. 2004, 6, 743.
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