An efficient approach to substituted 1,5,7,8,9-pentahydrocyclopenta-[h]-2- benzopyran-3-one derivatives by a palladium-catalyzed tandem reaction of 2,7-alkadiynylic carbonates with 2,3-allenoic acids

Article abstract of DOI:10.1002/anie.200803424

(Chemical Equation Presented) An unexpected palladium(0)-catalyzed cyclization of 1 with 2 leads to derivatives 3 or 4. This reaction allows for broad substrate diversity and proceeds through a proposed sequential process involving regioselective intramolecular carbopalladation.

Full text of DOI:10.1002/anie.200803424

Angewandte
Chemie
DOI: 10.1002/anie.200803424
Cyclization Reactions
An Efficient Approach to Substituted 1,5,7,8,9-Pentahydrocyclopenta-
[h]-2-Benzopyran-3-one Derivatives by a Palladium-Catalyzed Tandem
Reaction of 2,7-Alkadiynylic Carbonates with 2,3-Allenoic Acids**
Xiongdong Lian and Shengming Ma*
Transition-metal-catalyzed cyclization reactions of function-
alized allenes in the presence of organic halides have become
powerful tools for the synthesis of cyclic compounds.[1–5]
Based on this approach, we envisioned that a 1,3,4-trienyl
palladium intermediate I, which is formed from the oxidative
addition and cyclic carbopalladation of 2,7-alkadiynylic
carbonates,[6] might act similarly to the aryl/alkenyl palladium
intermediates formed from the oxidative addition of organic
halides with palladium(0) to trigger the cyclization of 2,3-
allenoic acids 2 to afford butenolides with a 1,3,4-trienyl unit
at the b position (Scheme 1).[7] However, our preliminary
study showed that the reaction of 2,7-alkadiynylic carbonate
1a and 2,3-allenoic acid 2a in the presence of [Pd(PPh3)4]
(5 mol%) in acetonitrile at 608C for one hour failed to afford
the II-type product. Instead, an interesting and unexpected
new product was formed and isolated cleanly (Table 1,
entry 1). The structure of this product was unambiguously
established as the tricyclic product 3a by X-ray diffraction
analysis (Figure 1).[8] Herein, we report our recent observa-
tions in this area.
An assortment of palladium catalysts and solvents were
screened for the transformation (Table 1). When [Pd(PPh3)4]
was used as the catalyst, the reaction proceeded smoothly in
DMSO, DCE, and MeNO2 (Table 1, entries 2–4). Among
them MeNO2 was shown to be the best solvent with 3a
isolated in 87% yield (Table 1, entry 4). Other solvents such
as THF, DMF, N-methyl-2-pyrrolidone, and toluene, were
ineffective (Table 1, entries 5–8). Whereas better results were
not observed by using catalyst systems with Pd(OAc)2/
phosphrous-containing ligand (Table 1, entries 9 and 10).
Bidentate ligands such as dppe and binap resulted in trace
amount of product as determined by TLC analysis (Table 1,
entries 11 and 12).
Scheme 1. Palladium(0)-catalyzed reaction of 2,3-allenoic acids with
aryl or alkenyl halides (above) vs 2,7-alkadiynylic carbonates (below).
X=halide, Z=tether.
[*] X. Lian, Prof. Dr. S. Ma
Figure 1. ORTEP plot of 3a shown with ellipsoids at the 30%
probability level.
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032
(P.R. China)
Fax: (+86)21-6416-7510
E-mail: masm@mail.sioc.ac.cn
Next, the substrate scope of 2,3-allenoic acids 2 and 2,7-
alkadiynylic carbonates 1 (which are N tethered) were
surveyed under the optimized reaction conditions (Table 2,
entries 1-9). Fully decorated 2,3-allenoic acids may be alkyl
(Table 2, entry 1), allyl (Table 2, entry 2), or aryl (Table 2,
entries 3 and 4) substituted. The carbon–carbon triple bond at
the 7 position may be either terminal (Table 2, entries 1–8 and
11) or nonterminal (Table 2, entries 9 and 10). The reaction
[**] Financial support from the State Key Basic Research & Develop-
ment Program (2006CB806105) and the National Natural Science
Foundation of China (20732005) are greatly appreciated. We also
thank J. Chen for reproducing the results presented in Table 2,
entries 2 and 8, and Scheme 2.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803424.
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Table 1: Effect of solvent and catalyst on the cyclization reaction of 2,7-
alkadiynylic carbonate 1a with 2,3-allenoic acid 2a.[a]
Table 2: Palladium-catalyzed cyclization reaction of 2,7-alkadiynylic
carbonates 1 with 2,3-allenoic acids 2.[a]
Entry
Solvent
Catalyst
Yield [%][b] (%)[c]
Entry Products
Yield Entry Products
[%][b]
Yield
[%][b]
1
2
3
MeCN
DMSO
DCE
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
100 (76)
100 (75)
92
4
5
MeNO2
THF
[Pd(PPh3)4]
[Pd(PPh3)4]
100 (87)
25
1
87
74
7
8
74
70
6
7
8
9
10
11
12
DMF
NMP
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
Pd(OAc)2, 10 mol% tfp
Pd(OAc)2, 10 mol% Ph3P
Pd(OAc)2, 5 mol% dppe
Pd(OAc)2, 5 mol% binap
42
23
11
100 (71)
83 (66)
trace
trace
toluene
MeNO2
MeNO2
MeNO2
MeNO2
2
3
4
[a] Under argon, a mixture of 1a (0.3 mmol), 2a (0.33 mmol), palladium
complex (5 mol%), and ligand in solvent (3 mL) was stirred at 608C for
1 h. [b] Determined by 1H NMR spectroscopy with CH2Br2 as the internal
standard. [c] Yield of isolated product. binap=2,2’-bis(diphenylphos-
phino)-1,1’-binaphthyl, DCE=1,2-dichloroethane, DMF=N,N-dimethyl-
formamide, DMSO=dimethyl sulfoxide, dppe=1,2-bis(diphenylphos-
phino)ethane, NMP=N-methyl-2-pyrrolidone, tfp=tri(futan-2-yl)phos-
phine, Ts=4-toluenesulfonyl.
75
73
9
61
10
11
75
54
proceeded smoothly with primary (Table 2, entry 11), secon-
dary (Table 2, entries 5 and 6), and tertiary (Table 2,
entries 1–4 and 7–10) 2,7-diynylic carbonates. The method is
also applicable to oxygen tethered (Table 2, entry 10) or
carbon tethered (Table 2, entry 11) 2,7-alkadiynylic carbo-
nates to form the corresponding tricyclic compounds 3j and
3k.
When optically active 2,7-diynylic tosylamide R-(+)-1h,
which was prepared readily from propionaldehyde in four
steps (Scheme 2, see the Supporting Information for exper-
imental details),[9] was used, its cyclization with 2a under the
standard reaction conditions afforded the optically active
product R-(À)-3l in 73% yield with greater than 99% ee.
In addition, it was observed that when 4-monosubstituted
2,3-allenoic acids 2 f and 2g were used, the reaction yielded
the aromatized tricyclic products 4 (Scheme 3). The structure
of 4b was also confirmed by X-ray diffraction analysis
(Figure 2).[10]
5
6
86
80
[a] The reaction was carried out under argon in a Schlenk tube using 1
(0.3 mmol), 2 (0.33 mmol), and [Pd(PPh3)4] (5 mol%) in MeNO2 (3 mL)
at 608C for 1 h. [b] Yield of isolated product. E=COOEt.
A rationale is proposed for the above transformation
(Scheme 4). Instead of triggering the normal cyclization to
afford the expected product II (see Scheme 1), the carbon–
carbon double bond at the 4 position of the 1,3,4-trienyl
palladium species I would undergo highly regioselective
intermolecular oxypalladation with 2,3-allenoic acid 2 to
À
form an ester C O bond to yield the palladabicyclic
intermediate III. Regioselective intramolecular carbopalla-
dation of the relatively electron-rich carbon–carbon double
bond in the allenoic moiety in III would form the six-
membered lactone ring and the seven-membered pallada-
cycle. Subsequent reductive elimination of intermediate IV
would form tricyclic product 3 and regenerate the catalytically
Figure 2. ORTEP plot of 4b shown with ellipsoids at the 30%
probability level.
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active palladium(0). For a 4-monosubstituted 2,3-allenoic
acid, 3 may readily further aromatize to give the tricyclic 4
with a benzene ring in the center of the molecule.
In conclusion, we have developed an efficient method-
ology for the synthesis of 1,5,7,9-pentahydrocyclopenta[h]-2-
benzopyran-3-one skeletons from easily available 2,3-allenoic
acids[2b,c,11] and 2,7-alkadiynylic carbonates.[6b,c] Owing to the
importance of this versatile skeleton,[12,13] the reaction will be
potentially useful in organic synthesis and medicinal chemis-
try. Furthermore, the transformation revealed here involves
the formation of four bonds within one synthetic operation.
Experimental Section
A typical procedure for the preparation of 3a: 2,3-allenoic acid (2a,
42 mg, 0.33 mmol), [Pd(PPh3)4] (17 mg, 0.015 mmol, 5 mol%), 2,7-
alkadiynoic carbonate (1a, 110 mg, 0.3 mmol), and MeNO2 (3 mL)
were sequentially added to a dried and degassed Schlenk tube under
Ar. The resulting reaction mixture was stirred at 608C for 1 h. When
the reaction was complete (as evident by TLC), removal of the
solvent by evaporation and purification by column chromatography
on silica gel (eluent: CH2Cl2) afforded the pure 3a (109 mg, 87%) as a
colorless solid, m. p. 172–1738C (acetone/diethyl ether 1:10).
1H NMR (300 MHz, CDCl3): d = 7.71 (d, J = 8.4 Hz, 2H), 7.34 (d,
J = 8.4 Hz, 2H), 5.40 (s, 1H), 4.16 (s, 2H), 3.93 (s, 2H), 2.43 (s, 3H),
2.24 (s, 3H), 1.53 (s, 6H), 1.34 ppm (s, 6H); 13C NMR (75.4 MHz,
CDCl3): d = 16.7, 21.4, 26.6, 28.0, 38.6, 50.0, 52.3, 79.8, 122.8, 126.9,
127.6, 127.9, 129.8, 131.5, 132.2, 132.6, 144.1, 150.8, 165.4 ppm; EIMS:
m/z (%): 413 (M+, 15.07), 398 (M+ÀCH3, 4.05), 91 (100); IR (thin
film): n˜ = 1783, 1698, 1597, 1347, 1163 cmÀ1; elemental analysis calcd
for C23H27NO4S: C 66.80, H 6.58, N 3.39; found, C 66.78, H 6.47, N
3.31.
Scheme 2. Synthesis and cyclization of an optically active substrate.
DEAD=diethyl azodicarboxylate, TBAF=tetra-n-butylammonium fluo-
ride, TMS=trimethylsilyl.
Received: July 15, 2008
Published online: September 24, 2008
Keywords: allenoic acids · cyclization · palladium ·
.
tandem reactions
Scheme 3. Cyclization reaction of 2,7-alkadiynylic carbonate 1a with 4-
monosubstituted 2,3-allenoic acids 2.
[1] For reviews, see: a) R. Zimmer, C. U. Dinesh, E. Nandanan,
F. A. Khan, Chem. Rev. 2000, 100, 3067; b) J. A. Marshall, Chem.
Rev. 2000, 100, 3163; c) A. S. K. Hashmi, Angew.
Chem. 2000, 112, 3737; Angew. Chem. Int. Ed.
2000, 39, 3590; d) R. W. Bates, V. Satchareon,
Chem. Soc. Rev. 2002, 31, 12; e) L. K. Sydnes,
Chem. Rev. 2003, 103, 1133; f) L. Brandsma,
N. A. Nedolya, Synthesis 2004, 735; g) X. Lu, C.
Zhang, Z. Xu, Acc. Chem. Res. 2001, 34, 535;
h) A. Hoffmann-Rꢀder, N. Krause, Angew.
Chem. 2004, 116, 1216; Angew. Chem. Int. Ed.
2004, 43, 1196; i) H.-U. Reissig, W. Schade,
M. O. Amombo, R. Pulz, A. Hausherr, Pure
Appl. Chem. 2002, 74, 175; j) S. Ma, Pure Appl.
Chem. 2006, 78, 197; k) S. Ma, Pure Appl. Chem.
2007, 79, 261; l) S. Ma, Chem. Rev. 2005, 105,
2829; m) S. Ma, Aldrichimica Acta 2007, 40, 91.
[2] a) S. Ma in Topics in Organometallic Chemistry
(Ed.: J. Tsuji), Springer, Heidelberg, 2005,
pp. 183 – 210; b) The Chemistry of the Allenes,
Vol. 1 (Ed.: S. R. Landor), Academic Press,
London, 1982; c) Modern Allene Chemistry,
Scheme 4. A possible mechanism for the cyclization reaction of 2,7-alkadiynylic
Vols. 1 and 2 (Eds.: N. Krause, A. S. K.
carbonates with 2,3-allenoic acids catalyzed by [Pd(PPh3)4].
Hashmi), Wiley-VCH, Weinheim, 2004; d) S.
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Communications
Ma in Handbook of Organopalladium Chemistry for Organic
Synthesis (Ed.: E.Negishi), Wiley, New York, 2002, pp. 1491 –
1521.
[8] Crystal data for 3a: Recrystallization from acetone/diethyl ether
(1:10), C23H27NO4S, MW = 413.52, Monoclinic, space group P21/
c, MoK, final R indices [I > 2s(I)], R1 = 0.0633, wR2 = 0.1486, R
indices (all data): R1 = 0.0963, wR2 = 0.1647; a = 12.6156(17) ꢂ,
b = 7.5890(11) ꢂ, c = 23.006(3) ꢂ, a = 90, b = 100.518(3), g =
908, V= 2165.6(5) ꢂ3, T= 293(2) K, wavelength: 0.71073 ꢂ,
Z = 4, reflections collected/unique 12125/4704 (Rint = 0.1281),
number of observation [I > 2s(I)] 2980, parameters 268.
CCDC 675814 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[9] For reports of the kinetic resolution of propargylic alcohols, see:
a) P. Allevi, P. Ciuffreda, M. Anastasia, Tetrahedron: Asymmetry
1997, 8 93; b) D. Xu, Z. Li, S. Ma, Tetrahedron Lett. 2003, 44,
6343.
[10] Crystal data for 4b: Recrystallization from acetone/diethyl ether
(1:10), C29H30BrNO4S, MW = 568.51, Monoclinic, space group
P21/n, MoK, final R indices [I > 2s(I)], R1 = 0.0424, wR2 =
0.0778, R indices (all data): R1 = 0.0984, wR2 = 0.0868; a =
17.4190(17) ꢂ, b = 9.6103(10) ꢂ, c = 31.794(3) ꢂ, a = 908, b =
93.815(2)8, g = 908, V= 5310.5(9) ꢂ3, T= 293(2) K, wavelength:
[3] For recent examples on the chemistry of allenes, see: a) J. Piera,
A. Persson, X. Caldentey, J.-E. Bꢁckvall, J. Am. Chem. Soc. 2007,
129, 14120; b) H. L. Shimp, G. C. Micalizio, Chem. Commun.
2007, 4531; c) E. Skucas, J. F. Bower, M. J. Krische, J. Am. Chem.
Soc. 2007, 129, 12678; d) M. R. Luzung, P. Mauleon, F. D. Toste,
J. Am. Chem. Soc. 2007, 129, 12402; e) H. E. Burks, S. B. Liu, J. P.
Morken, J. Am. Chem. Soc. 2007, 129, 8766; f) A. R. Banaag,
M. A. Tius, J. Am. Chem. Soc. 2007, 129, 5328; g) A. Barbero, P.
Castreno, F. J. Pulido, J. Am. Chem. Soc. 2005, 127, 8022;
h) K. M. Brummond, D. T. Chen, Org. Lett. 2005, 7, 3473; i) G. L.
Hamilton, E. J. Kang, M. Mba, D. F. Toste, Science 2007, 317,
496; j) B. M. Trost, A. McClory, Org. Lett. 2006, 8, 3627; k) R. K.
Dieter, N. Chen, V. K. Gore, J. Org. Chem. 2006, 71, 8755; l) N.
Morita, N. Krause, Eur. J. Org. Chem. 2006, 4634; m) A. S. K.
Hashmi, M. C. Blanco, D. Fisher, J. W. Bats, Eur. J. Org. Chem.
2006, 1387; n) C. J. T. Hyland, L. S. Hegedus, J. Org. Chem. 2006,
71, 8658; o) Z. Zhang, R. Widenhoefer, Angew. Chem. 2007, 119,
287; Angew. Chem. Int. Ed. 2007, 46, 283.
[4] For selected reports from our research group, see: a) F. Yu, X.
Lian, S. Ma, Org. Lett. 2007, 9, 1703; b) Z. Gu, Y. Deng, W. Shu,
S. Ma, Adv. Synth. Catal. 2007, 349, 1653; c) Z. Lu, G. Chai, S.
Ma, J. Am. Chem. Soc. 2007, 129, 14546; d) Z. Gu, X. Wang, W.
Shu, S. Ma, J. Am. Chem. Soc. 2007, 129, 10948; e) P. Lu, S. Ma,
Org. Lett. 2007, 9, 5319; f) X. Jiang, X. Cheng, S. Ma, Angew.
Chem. 2006, 118, 8177; Angew. Chem. Int. Ed. 2006, 45, 8009;
g) S. Ma, L. Lu, Chem. Asian J. 2007, 2, 199; h) Y. Deng, Y. Yu, S.
Ma, J. Org. Chem. 2008, 73, 585; i) X. Cheng, S. Ma, Angew.
Chem. 2008, 120, 4657; Angew. Chem. Int. Ed. 2008, 47, 4581.
[5] For a palladium(II)-catalyzed cyclization of 2,3-allenoic acids in
the presence of propargylic carbonates to afford b-allenyl
butenolides, see: S. Ma, Z. Gu, Y. Deng, Chem. Commun.
2006, 94.
0.71073 ꢂ, Z = 8, reflections collected/unique 27183/9845 (Rint
=
0.0900), number of observation [I > 2s(I)] 4485, parameters 657.
CCDC 675815 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[11] a) H. J. Bestmann, H. Hartung, Chem. Ber. 1966, 99, 1198;
b) A. D. Abell, D. A. Hoult, K. M. Morris, J. M. Taylor, J. O.
Trent, J. Org. Chem. 1993, 58, 1531; c) J.-E. Kang, E.-S. Lee, S.-I.
Park, S. Shin, Tetrahedron Lett. 2005, 46, 7431; d) J. A. Marshall,
M. A. Wolf, E. M. Wallace, J. Org. Chem. 1997, 62, 367; e) S. Ma,
S. Wu, J. Org. Chem. 1999, 64, 9314; f) S. Ma, S. Wu, Chem.
Commun. 2001, 441.
[6] For the cyclic carbopalladation and coupling reaction of 2,7-
alkadiynylic carbonates with typical organometallic reagents,
see: a) J. Tsuji, T. Mandai, Angew. Chem. 1995, 107, 2830;
Angew. Chem. Int. Ed. Engl. 1995, 34, 2589; b) W. Oppolzer, A.
Pimm, B. Stammen, W. E. Hume, Helv. Chim. Acta 1997, 80, 623;
c) R. Grigg, R. Rasul, V. Savic, Tetrahedron Lett. 1997, 38, 1825;
d) F. Wang, X. Tong, J. Cheng, Z. Zhang, Chem. Eur. J. 2004, 10,
5338.
[12] a) D. Nicoletti, A. A. Ghini, R. Furtmꢃller, W. Sieghart, R. H.
Dodd, G. Burton, Steroids 2000, 65, 349; b) T. L. Jacobs, R. B.
Brownfield, J. Am. Chem. Soc. 1960, 82, 4033; c) W. N. Speck-
amp, H. Kesselaar, Tetrahedron Lett. 1974, 15, 3405; d) Y. G.
Lee, Y. Utsumi, K. Ohkata, K. Y. Akiba, Heterocycles 1990, 30,
813.
[13] A. W. Nicholas, M. C. Wani, G. Manikumar, M. E. Wall, K. W.
Kohn, Y. Pommier, J. Med. Chem. 1990, 33, 972.
[7] a) S. Ma, Acc. Chem. Res. 2003, 36, 701; b) S. Ma, Z. Shi, Chem.
Commun. 2002, 540; c) S. Ma, Z. Shi, J. Org. Chem. 1998, 63,
6387.
8258
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