Pd-catalyzed sequential reactions via allene intermediate for the synthesis of polycyclic frameworks containing 2,3-dihydrofuran units

Article abstract of DOI:10.1021/ol801139b

(Chemical Equation Presented) A stepwise process involving Sonogashira coupling, propargyl allenyl isomerization, and consecutive [4 + 2] cyclization has been realized, leading to an efficient synthesis of polycyclic compounds containing a 2,3-dihydrofuran unit. Most attractive for synthetic interest is the finding that up to four stereogenic centers could be generated in one step with high stereoselectivity.

Full text of DOI:10.1021/ol801139b

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3283-3286
Pd-Catalyzed Sequential Reactions via
Allene Intermediate for the Synthesis of
Polycyclic Frameworks Containing
2,3-Dihydrofuran Units
Ruwei Shen† and Xian Huang*,†,‡
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310028, P. R. China, and
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China
huangx@mail.hz.zj.cn
Received May 18, 2008
ABSTRACT
A stepwise process involving Sonogashira coupling, propargyl allenyl isomerization, and consecutive [4 + 2] cyclization has been realized,
leading to an efficient synthesis of polycyclic compounds containing a 2,3-dihydrofuran unit. Most attractive for synthetic interest is the
finding that up to four stereogenic centers could be generated in one step with high stereoselectivity.
Sequential reaction represents an elegant and efficient way
to access novel and complex molecules from simple, readily
available starting materials.1 These reactions often involve
a series of inter- or intramolecular processes wherein the
product of one reaction is programmed to be the substrate
for the next. Therefore, the consecutive transformations of
the involved intermediates finally incorporate the powerful
sequences into a designed scheme,1,2 which are now routinely
employed to construct core skeletons of many important
natural products.3
lished in the past decades.5,6 Intramolecular [4 + 2]
cycloaddition of ene-allenes provides a convenient route
for the construction of complex ring systems.4,7,8 Compared
with traditional intramolecular Diels-Alder reaction, the
(4) (a) Patai, S. The Chemistry of Ketenes, Allenes, and Related
Compounds; John Wiley & Sons: New York, 1980. (b) Schuster, H. F.;
Coppola, G. M. Allenes in Organic Synthesis; John Wiley & Sons: New
York, 1984. (c) Landor, S. R. The Chemistry of Allenes; Academic Press:
New York, 1982; Vols. 1-3. (d) Krause, N.; Hashmi, A. S. K. Modern
Allene Chemistry; Wiley-VCH: Weinheim, 2004; Vols. 1-2.
(5) (a) Ma, S. Chem. ReV. 2005, 105, 2829. (b) Marshall, J. A. Chem.
ReV. 1996, 96, 31. (c) Yamamoto, Y.; Radhakrishnan, U. Chem. Soc. ReV.
1999, 28, 199. (d) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A.
Allenes have shown impressive synthetic potentials in
organic chemistry.4 Many novel reactions were well estab-
Chem. ReV. 2000, 100, 3067. (e) Marshall, J. Chem. ReV. 2000, 100, 3163
.
(6) (a) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2000, 39, 3590. (b)
Ma, S. Acc. Chem. Res. 2003, 36, 701. (c) Lu, X.; Zhang, C.; Xu, Z. Acc.
Chem. Res. 2001, 34, 535. (d) Tius, M. A. Acc. Chem. Res. 2003, 36, 284.
(e) Barbero, A.; Pulido, F. J Acc. Chem. Res. 2004, 37, 817. (f) For recent
examples, see: Lambert, T. H.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 13646. (g) Wender, P. A.; Croatt, M. P.; Deschamps, N. M.
Angew. Chem., Int. Ed. 2006, 45, 2459. (h) Makino, T.; Itoh, K. J. Org.
Chem. 2004, 69, 395. (i) Hamaguchi, H.; Kosaka, S.; Ohno, H.; Tanaka,
H. Angew Chem., Int. Ed. 2005, 44, 1513. (j) Jiang, X.; Cheng, X.; Ma, S
Angew. Chem., Int. Ed. 2006, 45, 8009. (k) Feldman, K. S.; Iyer, M. R.
J. Am. Chem. Soc. 2005, 127, 4590. (l) Ma, S.; Gu, Z. J. Am. Chem. Soc.
2006, 128, 4942. (m) Jiang, X.; Ma, S. J. Am. Chem. Soc. 2007, 129, 11600.
(n) Brummond, K. M.; Chen, H.; Mitasev, B.; Casarez, A. D. Org. Lett.
† Zhejiang University.
‡ Shanghai Institute of Organic Chemistry.
(1) (a) Ho, T. L. Tandem Organic Reactions; John Wiley & Sons: New
York, 1992. (b) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reaction
in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(2) (a) Posner, G. H. Chem. ReV. 1986, 86, 831. (b) Parsons, P. J.;
Penkett, C. S.; Shell, A. J. Chem. ReV. 1996, 96, 195. (c) Padwa, A.;
Weingarten, M. D. Chem. ReV. 1996, 96, 223. (d) Tietze, L. F. Chem. ReV.
1996, 96, 115
.
(3) For the most recent reviews, see: (a) Arns, S.; Barriault, L. Chem.
Commun. 2007, 2211. (b) Tietze, L. F.; Modi, A Med. Res. ReV. 2000, 20,
304. (c) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G Angew. Chem., Int.
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10.1021/ol801139b CCC: $40.75
Published on Web 07/10/2008
2008 American Chemical Society

attendance of allene motif enhances the diversity of reaction
possiblity. Typically, four kinds of reaction patterns can be
envisioned: one CdC bond of the allene acts as dienophile
to react with the intramolecular diene unit (Figure 1, types
and CuI.13 With the assistance of suitable base, we envi-
sioned that the formed coupling product 3a could isomerize
to produce an ene-allene intermediate in which diene and
dienophile units were well installed for a subsequent intra-
molecular [4 + 2] cycloaddition. As expected, the reaction
proceeded efficiently to give 3a first, and gratifyingly, we
observed with interest that the reaction afforded a fused
tricyclic compound 4a in 19% yield after 5 h. The following
testing experiment shown that 3a could be completely
converted to 4a with excessive Et3N (Scheme 1).
Figure 1. [4 + 2] cycloaddition models for ene-allenes.
Scheme 1
a and b).7 Alternatively, the vinylallene serves as diene to
undergo cycloaddition with another double or triple bonds
to give cyclic compounds (types c and d).8 More importantly,
due to the unusual facilitation of cycloadditon and unique
geometry of allenes, these reactions often proceed efficiently
in highly stereoselective control, thus providing an attractive
tool for the stereoselective synthesis of polycyclic molecules
including natural products such as compactin9 and ster-
purene.10
In this context, we consider that the development and
application of sequential reactions via allene intermediate
would be an attractive, useful, and in some cases advanta-
geous way to access a variety of interesting and useful
polycyclic molecules.11 As an interest in devising novel
sequential reactions,12 herein we reported a versatile pal-
ladium-catalyzed sequential reaction, wherein the in situ-
generated ene-allene would wisely undergo intramolecular
[4 + 2] cyclization, leading to a facile synthesis of fused
polycyclic scaffolds from 3-iodocyclohex-2-enone 1 and
propargyl allyl ether 2.
Our further studies show that a combination of Et3N and
THF in 1:3 as solvents was appropriate; 5 mol % of
PdCl2(Ph3P)2 and 3 mol % of CuI were sufficient. A clean
and complete conversion was observed in 16 h with 75%
yield of 4a isolated (Table 1, entry 1). Other triamine bases
Table 1. Amine Base Effects on the Sequential Reactiona
We initiated our study by attempting the reaction of 1a
and 2aa in the presence of a catalytic amount of PdCl2(Ph3P)2
entry
solvent
base
Et3N
(n-C4H9)3N
Et2NH
pyrrolidine
i-Pr2NH
TMEDA
Et3N
yieldb (%)
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
THF
Toluene
MeCN
75
72
c
c
c
68
74
71
(7) For type a, see: (a) Cauwberghs, S. G.; De Clercq, P. J. Tetrahedron
Lett. 1988, 29, 6501. (b) Padwa, A.; Meske, M.; Murphree, S. S.; Watterson,
S. H.; Ni, Z. J. Am. Chem. Soc. 1995, 117, 7071. (c) Padwa, A.; Filipkowski,
M. A.; Meske, M.; Watterson, S. H.; Ni, Z. J. Am. Chem. Soc. 1993, 115,
3776. (d) Ma, S.; Lu, P.; Lu, L.; Hou, H.; Wei, J.; He, Q.; Gu, Z.; Jiang,
X.; Jin, X Angew. Chem., Int. Ed. 2005, 44, 5275. (e) For type b, see:
Saxton, H. M.; Sutherland, J. K.; Whaley, C. J. Chem. Soc., Chem. Commun.
1987, 1449. (f) Yoshida, M.; Hiromatsu, M.; Kanematsu, K. J. Chem. Soc.,
Chem. Commun. 1986, 1168. (g) Kanematsu, K.; Sugimoto, N.; Kawaoka,
M.; Yeo, S.; Shiro, M. Tetrahedron Lett. 1991, 32, 1351. (h) Himbert, G.;
Henn, L. Angew. Chem., Int. Ed. 1982, 21, 620. (i) Hayakawa, K.; Yodo,
M.; Ohsuki, S.; Kanematsu, K. J. Am. Chem. Soc. 1984, 106, 6735. (j)
Hayakawa, K.; Nagatsugi, F.; Kanematsu, K. J. Org. Chem. 1988, 53, 860.
(8) (a) For type c, see: Bartlett, A. J.; Laird, T.; Ollis, W. D. J. Chem.
Soc., Chem. Commun. 1974, 496. (b) Curtin, M. L.; Okamura, W. H. J.
Org. Chem. 1990, 55, 5278. (c) For type d, see: Reich, H. J.; Eisenhart,
E. K. J. Org. Chem. 1984, 49, 5282. (d) Reich, H. J.; Eisenhart, E. K.;
Olson, R. E.; Kelly, M. J. J. Am. Chem. Soc. 1986, 108, 7791. (e) Wender,
P. A.; Jenkins, T. E.; Suzuki, S. J. Am. Chem. Soc. 1995, 117, 1843.
(9) Keck, G. E.; Kachensky, D. F. J. Org. Chem. 1986, 51, 2487.
(10) Krause, N. Liebigs Ann. Chem. 1993, 521.
Et3N
a Reactions were carried out using 1a (0.5 mmol), 2aa (0.6 mmol),
PdCl2(PPh3)2 (5 mol %), and CuI (3 mol %) in 3 mL of solvent and 1 mL
of amine at rt for 16 h. b Isolated yields. c No product was obtained.
such as tributylamine (entry 2, 72% yield) and TMEDA
(entry 6, 68% yield) could also be applied to the reaction,
but secondary amines, e.g., diethylamine, pyrrolidine, and
diisopropylamine, which were frequently employed in the
Sonogashira coupling reactions, were turned out to be totally
disfavored (entries 3-5), which apparently indicates that the
reaction was very sensitive to the type of amine base. The
reaction could also be conducted in toluene or MeCN with
comparable yield observed (entries 7 and 8).
(11) (a) Yamaguchi, Y.; Tatsuta, N.; Hayakawa, K.; Kanematsu, K.
J. Chem. Soc., Chem. Commun. 1989, 470. (b) Lee, M.; Morimoto, H.;
Kanematsu, K. Tetrahedron 1996, 52, 8169. (c) Wu, H.-J.; Ying, F.-H.;
Shao, W.-D. J. Org. Chem. 1995, 60, 6168. (d) Ducere, J. P.; Agati, V.;
Faure, R. J. Chem. Soc., Chem. Commun 1993, 270. (e) Hayakawa, K.;
Aso, K.; Shiro, M.; Kanematsu, K. J. Am. Chem. Soc. 1989, 111, 5312.
(12) (a) Huang, X.; Shen, R.; Zhang, T. J. Org. Chem. 2007, 72, 1534.
(b) Huang, X.; Xie, M. J. Org. Chem. 2002, 67, 8895. (c) Huang, X.; Xie,
M. Org. Lett. 2002, 4, 1331. (d) Huang, X.; Xiong, Z. Chem. Commun.
2003, 1714.
(13) Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551.
Org. Lett., Vol. 10, No. 15, 2008
3284

can be a para-substituted phenyl group either with an
electron-donating or electron-withdrawing group (entries
2-6). When Ar ) p-FC6H4, the reactions seem to proceed
more efficiently and give higher yields probably because of
electronic reasons (entries 5 and 6). In contrast, the presence
of a substituent on the ortho position of the benzene ring of
propargyl cyclohexenyl ether negatively affected the reaction.
For example, when Ar ) o-BrC6H4, it failed to afford the
expected product (entry 7). The stereochemistry of these
compounds was unambiguously established by the NOESY
study of 5f (Supporting Information). Significantly, although
there were four stereocenters formed in the reaction, only
one pair of enantiomorphs was produced. A controlled
experiment also revealed the reaction steps and its highly
stereoselective fashion. The reaction of 1a and 2bb, which
was quenched by diluted HCl within 30 min, afforded the
coupling product 3b as a mixture of four stereoisomers in
87% yield. Then treatment of 3b in toluene and Et3N over
20 h ultimately gave 5c in 68% yield as a single diasteromer
(eq 1).
Table 2. Sequential Reaction for the Synthesis of Tricycles 4a
2a
entry
1 (R1)
R2
Ar
4
yieldb(%)
1
1b (Me)
1b
1b
1b
1a (H)
1a
1b
1b
1b
1a
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
C6H5 (2aa)
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
73
80
68
79
65
76
81
71
85
81
85
75
80
2
p-MeC6H4 (2ab)
o-BrC6H4 (2ac)
p-FC6H4 (2ad)
o-BrC6H4 (2ac)
p-MeC6H4 (2ab)
m-BrC6H4 (2ae)
o-MeOC6H4 (2af)
C6H5 (2ag)
3c
4
56
6
7
8c
9
10
11
12
13
C6H5 (2ag)
1b
1a
1a
p-FC6H4 (2ah)
p-MeC6H4 (2ai)
p-FC6H4 (2ah)
a Unless otherwise specified, the reaction was carried out at rt for 16-20
h. b Isolated yields. c Reactions were carried out at 70 °C.
The results summarized in Table 2 prove that this
sequential reaction indeed provides a straightforward entry
to a variety of fused tricyclic compounds with a 2,3-
dihydrofuran unit in moderate to good yields (65%-85%).
The reaction proceeded well at room temperature when Ar
was a meta- or para-substituted phenyl group, but a higher
temperature was required when an ortho-substituted phenyl
group was employed (Table 2, entries 3, 5, and 8).
Further expanding the reaction scope to include propargyl
cyclohexenyl ether such as 2ba led us a tetracyclic compound
5a in 46% yield wherein the double bonds did not migrate
to conjugate with the carbonyl group. A better yield was
obtained using toluene as solvent (Table 3, entry 1). Our
preliminary results on these transformations show that Ar
Interestingly, tetracyclic compounds 6a and 6b with five
stereocenters were readily obtained by direct reduction of
the carbonyl group of 5c upon treatment with NaBH4 (eq
2). Compounds 6a and 6b were easily separated by classical
chromatography, and their structures were determined by
spectroscopic analysis (1H, 13C, DEPT, COSY, NOESY and
HMQC NMR experiments, IR, EIMS, HRMS, see the
Supporting Information).
A possible mechanism is proposed as depicted in Scheme
2. Oxidative addition of 1 to the Pd(0) species, followed by
transmetalation of the copper acetylide and reductive elimi-
nation, affords the coupling product 3. The excessive Et3N
may promote a propargyl allenyl isomerization14 to generate
the ene-allene intermediate 10. When R is an allyl group
or 2-substituted allyl group, 10 may undergo an intra-
molecular [4 + 2] cycloaddition and subsequent CdC
migration to give tricycle 4 (path a); when R is cyclohexenyl
group, a highly diastereoselective [4 + 2] reaction is ready
to conclude the reaction to furnish the tetracycle 5 (path b).
Based on the experiment results, it is worthy to note the
following. (1) Et3N facilitates both the coupling reaction and
Table 3. Sequential Reaction for the Synthesis of Tetracycles 5
entry
1
2b (Ar)
time (h)
5
yielda (%)
1
2
3
4
5
6
7
1a 2ba (C6H5)
1b 2bb (p-MeC6H4)
1a 2bb
1a 2bc (p-ClC6H4)
1a 2bd (p-FC6H4)
1b 2bd
18
24
20
16
10
10
5a
5b
5c
5d
5e
55 (46b)
63
58
63
71
5f, NOESY 76
c
(14) (a) Braun, R. U.; Ansorge, M; Mu¨ller, T. J. J. Chem. Eur. J. 2006,
12, 9081. (b) Liu, Y.; Song, Z.; Yan, B Org. Lett. 2007, 9, 409. (c) Hergueta,
A. R.; Moore, H. W. J. Org. Chem. 2002, 67, 1388. (d) Kel’in, A. V;
Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074. (e)
D’Souza, D. M; Rominger, F.; Mu¨ller, T. J. J. Angew. Chem. Int. Ed. 2005,
44, 153 For review, see: ref 4d, Vol. 1, Chapter 1.
1b 2be (o-BrC6H4)
a Isolated yields. b Reactions were run in THF. c No product was obtained
either at room temperature for 24 h or under reflux for 18 h.
Org. Lett., Vol. 10, No. 15, 2008
3285

as well as in a large number of biologically important natural
products.16 For example, Panepophenanthrin,16d which was
found to be a potential inhibitor of the ubiquitin-activating
enzyme in the ubiquitin-proteasome pathway (UPP) to
regulate important cellular functions, possesses a skeleton
very similar to those of tetracycles 5. Considering the mild
reaction conditions, easily available starting materials and
highly stereoselective fashion, our protocol for the synthesis
of these analogues should be potentially useful.
Scheme 2
.
Proposed Mechanism for the Pd-Catalyzed
Sequential Reaction
Finally, the reactions were also successfully applied to
3-iodobutenolides such as 1c and 1d, providing an efficient
method to construct a class of novel framworks both with
dihydrofuran and butenolide units. Several examples are
presented in Scheme 4.
Scheme 4
the propargyl allenyl isomerization, and the observations that
the reactions became reluctant when Ar was ortho-substituted
may indicate that the steric effects play a negative role in
the later process. (2) An attempt to shorten the reaction time
to identify intermediate 10 was made but failed, which may
suggest that it is highly reactive. However, the reaction of
1a and 2c led to a mixture of 7a in 65% yield together with
7b in 10% yield (Scheme 3). The formation of 7b might be
In conclusion, we have realized a series of reactions
including Sonogashira coupling, propargyl-allenyl isomer-
ization, and [4 + 2] cycloaddition combined via an allene
intermediate, affording an efficient and stereoselective
synthesis of polycyclic skeletons. Most promising for
potential synthetic application was the finding that up to four
adjacent stereocenters could be produced with high selectivity
in one step. Experiments designed to further explore the
reaction scope as well as mechanism study concerning the
stereoselectivity are currently underway.
Scheme 3
from a competitive ene pathway of a similar intermediate
as 10. Thus, the interesting discovery of this reaction should
be an evidence for the existence of the allene intermediate
in the reaction sequence. (3) The stereoselective formation
of compounds 5 may be attributed to the fact that an exo
transition state TS2 is more favored in the Diels-Alder step
than an endo-type TS1 (Scheme 2). This transition-state
selection indicates that the steric interactions rather than
electronic factors play a crucial role in this case.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Project Nos. 20732005
and 20332060) and The Academician Foundation of Zhejiang
Province is gratefully acknowledged.
Supporting Information Available: Spectroscopic data
for 4a-n, 5a-e, 6a,b, 7a,b, and 8a-g. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL801139B
Moreover, it should be mentioned that the general structure
of these obtained tri- and tetracyclic compounds exists
frequently in many pharmacologically interesting molecules15
(16) (a) Harinantenaina, L.; Asakawa, Y.; De Clercq, E. J. Nat. Prod.
2007, 70, 277. (b) van Brunt, M. P.; Standaert, R. F. Org. Lett. 2000, 2,
705. (c) Rho, J.-R.; Lee, H.-S.; Shin, H. J.; Ahn, J.-W.; Kim, J.-Y.; Sim,
C. J.; Shin, J. J. Nat Prod. 2004, 67, 1748. (d) Sekizawa, R.; Ikeno, S.;
Nakamura, H.; Naganawa, H.; Matsui, S.; Iinuma, H.; Takeuchi, T. J. Nat.
Prod. 2002, 65, 1491.
(15) (a) Schulte, G.; Scheuer, P. J.; McConnel, O. J. HelV. Chim. Acta
1980, 63, 2159. (b) Ottinger, H.; Soldo, T.; Hofmann, T. J. Agric. Food
Chem. 2001, 49, 5383.
3286
Org. Lett., Vol. 10, No. 15, 2008