Tandem Nazarov cyclization-halovinylation of divinyl ketones under Vilsmeier conditions: Synthesis of highly substituted cyclopentadienes

Article abstract of DOI:10.1039/b917703e

A new Vilsmeier reagent-mediated Nazarov cyclization-halovinylation reaction of divinyl ketones was developed to provide a straightforward method for the synthesis of highly substituted cyclopentadienes with the advantages of simplicity of execution, readily available substrates, cheap reagents, and broad range of potential products and applications.

Full text of DOI:10.1039/b917703e

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Tandem Nazarov cyclization–halovinylation of divinyl ketones under
Vilsmeier conditions: synthesis of highly substituted cyclopentadienesw
Mang Wang,* Feng Han, Hongjuan Yuan and Qun Liu*
Received (in Cambridge, UK) 27th August 2009, Accepted 27th November 2009
First published as an Advance Article on the web 13th January 2010
DOI: 10.1039/b917703e
A
new Vilsmeier reagent-mediated Nazarov cyclization–
To our delight, a white solid, which was identified as chlori-
nated cyclopentadiene 2a, was obtained in 10% isolated yield
by treatment of 1a (1.0 mmol) with POCl3 (2.0 eq.) in
10 mL DMF at room temperature for 12 h. The trans-
formation of 1a to 2a not only discloses the role of VR as a
new promoter for Nazarov cyclization,3,4 but also provides the
first straightforward access to highly substituted Cps from
divinyl ketones.1,2,8 Thus, the optimization of the reaction
conditions with respect to the amount of POCl3 and DMF and
the reaction temperature was performed carefully. The best
result was obtained with 2.5 equiv. of POCl3 (in 5.0 mL DMF)
and reacted at 90 1C (entry 1).
Encouraged by the successful synthesis of Cp 2a, a series
of a-(4-methoxylphenyl) divinyl ketones 1a–g were prepared
to explore the scope of this new synthetic strategy under
optimal conditions. Representative results are summarized
in Table 1. In general, this reaction showed broad tolerance
for aromatic R2 substituents. Substrates 1a–f, with either
electron-neutral (entry 1), electron-rich (entries 2 and 3), or
electron-deficient aryls (entries 4–6), afforded the corres-
ponding Cps 2a–f in good to high yields. In the case of 1g
with aliphatic R2, a complex mixture was obtained (entry 7)
even though the reaction was run at room temperature.
Then, divinyl ketones 1 having an o-hindered aromatic
R1 (2-MeOC6H4) or electron-withdrawing aromatic R1
(4-FC6H4) were examined. It was proved that the desired
Cps 2g–k could be obtained in good yields under the identical
conditions by the reactions of the selected 1h–l (entries 8–12).
Furthermore, divinyl ketone 1m having an alkyl substituent
at a-position was also proven to be a suitable precursor
and afforded Cp 2l in 73% yield (entry 13). For signifi-
cant comparison, however, substrate 1n (with R1 = PhCO)
gave a complex mixture under identical conditions (entry 14).9
Next, PBr3–DMF was used as the VR to evaluate the
efficiency of the cyclization–bromovinylation of 1. As shown
in Table 1, entries 15–20, reactions of all selected substrates 1
also proceeded efficiently to give the corresponding bromi-
nated Cps 2m–r in 76–85% yields, respectively. All halo-Cps
2a–r obtained above were well-characterized by their spectra
and analytical data and were further established by X-ray
diffraction studies of 2f.10
halovinylation reaction of divinyl ketones was developed to
provide a straightforward method for the synthesis of highly
substituted cyclopentadienes with the advantages of simplicity of
execution, readily available substrates, cheap reagents, and
broad range of potential products and applications.
Cyclopentadienes (Cps) are members of a diverse class of
fascinating molecules with wide potential in organic and
organometallic chemistry. New and straightforward methods
to access these substrates are therefore always highly desirable;
in particular, an approach for highly substituted Cps remains
a great challenge to synthetic chemists.1,2 In this communica-
tion, a new route for the direct synthesis of highly substituted
halocyclopentadienes (halo-Cps)2g,h is described based on
an unusual type of Nazarov cyclization3,4 and subsequent
halovinylation of easily available divinyl ketones in a single
step under Vilsmeier conditions.
The present study arose from our interest in developing the
synthetic potential of a-alkenoyl ketene dithioacetals
1
(Scheme 1, R3 = R4 = SR), the divinyl ketones with terminal
gem-dialkylthio substituents.5,6 On the basis of previous
reports on the reactions of 1 with Vilsmeier reagents (VRs),6
we envisioned that 1 may be suitable precursors for the straight-
forward preparation of halo-Cps 2 if the Nazarov cyclization,
a powerful tool for the construction of 2-cyclopentenones
from divinyl ketones,3,4 can be initiated by VRs7 and followed
by an extra halovinylation step7 (Scheme 1). Fortunately, the
above designed procedure was successfully achieved and
presented several new chemistries: (1) a new promoter (VRs)
for Nazarov cyclization was used;3,4 (2) an unusual ‘‘interrupted’’
Nazarov cyclization was reported to undergo a Nazarov
cyclization followed by an extra halovinylation involving an
unconventional enol trapping;3 (3) the products obtained were
polysubstituted halocyclopentadienes, a structure type never
before associated with the Nazarov cyclization,3,4 and thus,
(4) a new and straightforward strategy for cyclopentadiene
synthesis from divinyl ketones was established.
To understand the role of Vilsmeier reagents in Nazarov
cyclization, a model reaction of a-cinnamoyl-a-(4-methoxyl-
phenyl) ketene dithioacetal 1a (Table 1) was initially undertaken.z
Department of Chemistry, Northeast Normal University,
Changchun 130024, China. E-mail: wangm452@nenu.edu.cn;
Fax: +86 431 85099759; Tel: +86 431 85099759
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and analytical data. CCDC 734569. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b917703e
Scheme 1 Design of functionalized Cp synthesis.
Chem. Commun., 2010, 46, 2247–2249 | 2247
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Table 1 Synthesis of cyclopentadienes 2 from a-alkenoyl ketene
dithioacetals 1 under Vilsmeier conditionsa
Entry
1
R1
R2
2
X
t/h Yield (%)b
1
2
1a 4-MeOC6H4 C6H5 2a Cl 2.0 86
1b 4-MeOC6H4 4-MeOC6H4 2b Cl 0.5 79
3
4
5
1c 4-MeOC6H4 4-biphenyl
1d 4-MeOC6H4 4-FC6H4
1e 4-MeOC6H4 4-ClC6H4
2c Cl 1.0 80
2d Cl 1.5 78
2e Cl 1.5 77
6
7
8
9
1f 4-MeOC6H4 4-NO2C6H4 2f Cl 3.0 61
c
Scheme 2 Synthesis of 20 and 20 0 from 10 under Vilsmeier conditions.
1g 4-MeOC6H4 t-Bu
1h 2-MeOC6H4 C6H5
—
—
5.0
—
2g Cl 3.0 74
sequence is diverted (III to IV) after the elimination step
(II to III) but before the reprotonation of the enol III.
1i
1j
2-MeOC6H4 4-MeOC6H4 2h Cl 1.5 67
10
11
12
13
14
15
16
17
18
19d
20
2-MeOC6H4 4-ClC6H4
2i
2j
Cl 4.0 66
Cl 4.5 46
1k 4-FC6H4
1l 4-FC6H4
1m Me
C6H5
It is noteworthy that this tandem Nazarov cyclization–
halovinylation process provides various functionalized cyclo-
pentadienes, in which either a halogen or a dithioacetal functional
group are included. To explore the synthetic potential of these
cyclopentadienes 2, the [4 + 2] cycloaddition14 of 2 with
dimethyl acetylene dicarboxylate were tried and an interesting
transformation leading to polyaryls 3 was found. As described
in Table 2, upon treatment of the selected 2a, 2c or 2e
(1.0 mmol) with dimethyl 2-butynedioate (5.0 mmol) in toluene
(5.0 mL) at reflux, polyaryls 3a–c bearing the p-terphenyl or
p-quaterphenyl motif15 were produced in a regiospecific manner
in high yields. It is clear that cyclopentadienes 2 act as cyclo-
pentadienone equivalents8 in [4 + 2] cycloaddition reactions.
4-ClC6H4
C6H5
C6H5
2k Cl 4.5 55
2l
—
Cl 0.5 73
c
1n C6H5CO
—
3.0
—
1a 4-MeOC6H4 C6H5
1b 4-MeOC6H4 4-MeOC6H4 2n Br 3.0 84
1d 4-MeOC6H4 4-FC6H4 2o Br 3.0 85
1f 4-MeOC6H4 4-NO2C6H4 2p Br 3.0 76
2m Br 3.0 81
1h 2-MeOC6H4 C6H5
1m Me C6H5
2q Br 3.5 77
2r Br 0.5 80
a
Reagents and conditions: 1 (1.0 mmol), POCl3 or PBr3 (2.5 mmol),
b
c
DMF (5.0 mL), 90 1C. Isolated yields. A complex mixture was
obtained. 1 h (1.0 mmol), PBr3 (3.0 mmol), DMF (5.0 mL), 60 1C.
d
As presented above, our findings provide the first evidence
that highly substituted Cps can be constructed from divinyl
ketones under Vilsmeier conditions. Moreover, this method is
one of the simplest due to the readily available substrates,
simple procedure and cheap reagents.1,2,8 Pleasingly, Cps 20
and 20 0 could also be prepared from divinyl ketones 10a–c
without ketene dithioacetal functionality, respectively
(Scheme 2). Whereas, the reaction of 10d at 90 1C only give
2-cyclopentenone III0d in 90% yield. The desired penta-
substituted Cp could not been obtained even with prolonged
reaction time at reflux (Scheme 2).11 These results give further
evidence of the VR-promoted Nazarov cyclization and the
scope and limitation for the preparation of persubstituted Cps
through the above mentioned sequence.
In conclusion, a novel tandem Nazarov cyclization-
halovinylation strategy is developed for the synthesis of highly
substituted Cps. The simplicity of execution, readily available
substrates, cheap reagents, and broad range of potential
products and applications1,8 make this synthetic strategy more
efficient and deserving of further attention.
We gratefully acknowledge NNSFC-20972029/20872015,
NENU-STC08007/07007 for funding support of this research.
On the basis of the experimental results and related reports
on Nazarov cyclizations3,4 and reactions under Vilsmeier
conditions,6,7,12 a possible mechanism for the formation of
halo-Cps 2 is proposed in Scheme 3. The reaction begins with
the generation of pentadienyl cation I from divinyl ketones 1
induced by VR (for example, chloromethyleneiminium salt)
which plays the role of an acid to initiate a 4p-electro-
cyclization (I to II).3,4 Then, the elimination of a proton from
oxyallyl cation II leads to the enol intermediate III along with
the release of HCl. Finally, the addition of HCl to enol III12
and subsequent elimination of DMF and proton affords halo-
Cps 2. 2-Cyclopentenone IIIa was detected along with the
formation of Cp 2a by controlling the reaction conditions.13
The above mechanism indicates that the Nazarov cyclization
Scheme 3 Proposed mechanism for tandem Nazarov cyclization–
halovinylation of 1 mediated by Vilsmeier reagent.
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Table 2 Synthesis of polyaryls 3 by [4 + 2] cycloaddition of
cyclopentadienes 2 with dimethyl 2-butynedioatea
(i) F. Dhoro, T. E. Kristensen, V. Stockmann, G. P. A. Yap and
M. A. Tius, J. Am. Chem. Soc., 2007, 129, 7256; (j) N. Ghavtadze,
R. Frohlich and E.-U. Wurthwein, Eur. J. Org. Chem., 2008, 3656;
¨
(k) A. P. Marcus, A. S. Lee, R. L. Davis, D. J. Tantillo and
R. Sarpong, Angew. Chem., Int. Ed., 2008, 47, 6379; (l) W. He,
J. Huang, X. Sun and A. J. Frontier, J. Am. Chem. Soc., 2008, 130,
300; (m) C. J. Rieder, K. J. Winberg and F. G. West, J. Am. Chem.
Soc., 2009, 131, 7504.
5 (a) X. Bi, D. Dong, Q. Liu, W. Pan, L. Zhao and B. Li, J. Am.
Chem. Soc., 2005, 127, 4578; (b) J. Tan, X. Xu, L. Zhang, Y. Li and
Q. Liu, Angew. Chem., Int. Ed., 2009, 48, 2868; (c) Y. Ma,
M. Wang, D. Li, B. Bekturhun, J. Liu and Q. Liu, J. Org. Chem.,
2009, 74, 3116; (d) Z. Fu, M. Wang, Y. Dong, J. Liu and Q. Liu,
J. Org. Chem., 2009, 74, 6105.
6 (a) Y. Liu, D. Dong, Q. Liu, Y. Qi and Z. Wang, Org. Biomol.
Chem., 2004, 2, 28; (b) Y.-L. Zhao, Q. Liu, J.-P. Zhang and
Z.-Q. Liu, J. Org. Chem., 2005, 70, 6913; (c) L. Chen, Y. Zhao,
Q. Liu and C. Piao, J. Org. Chem., 2007, 72, 9259; (d) J. Liu,
D. Liang, M. Wang and Q. Liu, Synthesis, 2008, 3633.
7 (a) O. Meth-Cohn and S. P. Stanforth, in Comprehensive
Organic Synthesis, ed. C. H. Heathcock, Pergamon Press,
New York, 1991, vol. 2, p. 777; (b) C. M. Marson, Tetrahedron,
1992, 48, 3659.
8 Compound 2a can be considered as a potential cyclopentadienone, for
a discussion of the properties and reactivity of cyclopentadienones, see:
(a) M. A. Ogliaruso, M. G. Romanelli and E. I. Becker, Chem. Rev.,
1965, 65, 261; for selected examples of cyclopentadienone synthesis,
see: (b) C. Chen, C. Xi, Y. Jiang and X. Hong, J. Am. Chem. Soc.,
2005, 127, 8024; (c) P. A. Wender, T. J. Paxton and T. J. Williams,
J. Am. Chem. Soc., 2006, 128, 14814.
9 The intramolecular oxa/aza-Michael additions of a-alkenoyl
ketene dithioacetals with R1 = CO2Et or CONHAr under
Vilsmeier conditions were found to afford d-lactones and d-lactams,
respectively. See: J. Liu, M. Wang, F. Han, Y. Liu and Q. Liu,
J. Org. Chem., 2009, 74, 5090.
Entry
2
3
R1
R2
t/h
Yield (%)b
1
2
3
2a
2c
2e
3a
3b
3c
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
C6H5
4-biphenyl
4-ClC6H4
8.0
8.0
9.0
87
91
90
a
Reagents and conditions: 2 (1.0 mmol), dimethyl 2-butynedioate
b
(5.0 mmol), toluene (5.0 mL), reflux. Isolated yields.
Notes and references
z General procedure for the synthesis of cyclopentadienes 2 (taking 2a as
an example): to a well-stirred solution of 1a (354 mg, 1.0 mmol) in
DMF (5.0 mL) was added POCl3 (0.23 mL, 2.5 mmol) in one portion
at room temperature. Then, the reaction mixture was heated to 90 1C
and stirred for 2.5 h. After 1a was consumed (monitored by TLC), the
reaction mixture was poured into water (30 mL), neutralized with
saturated aqueous NaHCO3 to pH 7, and extracted with CH2Cl2
(15 mL ꢁ 3). The combined organic extracts were washed with water
(15 mL ꢁ 3), dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure to yield the crude product, which was purified
by silica gel chromatography (eluent, petroleum ether–diethyl ether:
75/1, v/v) to give 2a (320 mg, 86%) as light yellow crystals.
1 For reviews, see: (a) Metallocenes, ed. A. Togni and R. L. Halterman,
Wiley-VCH, New York, 1998; (b) R. L. Halterman, Chem. Rev.,
1992, 92, 965; (c) E. Winterfeldt, Chem. Rev., 1993, 93, 827;
(d) M. Enders and R. W. Baker, Curr. Org. Chem., 2006, 10, 937.
2 For selected recent examples of cyclopentadiene synthesis, see:
(a) Z. Xi, Q. Song, J. Chen, H. Guan and P. Li, Angew. Chem., Int.
Ed., 2001, 40, 1913; (b) S. Datta, A. Odedra and R.-S. Liu, J. Am.
Chem. Soc., 2005, 127, 11606; (c) W. Zhang, S. Luo, F. Fang,
Q. Chen, H. Hu, X. Jia and H. Zhai, J. Am. Chem. Soc., 2005, 127,
18; (d) J. H. Lee and F. D. Toste, Angew. Chem., Int. Ed., 2007, 46,
912; (e) H. Funami, H. Kusama and N. Iwasawa, Angew. Chem.,
Int. Ed., 2007, 46, 909; (f) Y. Kuninobu, Y. Nishina, T. Matsuki
and K. Takai, J. Am. Chem. Soc., 2008, 130, 14062; Synthesis of
monohalo-Cps is much less documented. For selected examples,
see: (g) R. Breslow and J. W. Canary, J. Am. Chem. Soc., 1991,
113, 3950; (h) K. Ogawa, S. Minegishi, K. Komatsu and
T. Kitagawa, J. Org. Chem., 2008, 73, 5248.
10 Crystal data for 2f: C20H16ClNO3S2, yellow, M = 417.91, mono-
clinic, space group P21/c, a = 6.808(2), b = 16.045(5), c =
18.120(6) A, V = 1967.4(11) A3, a = 90.00, b = 96.286(6),
g = 90.00, Z = 4, T = 273(2) K, F000 = 864, 10 854 reflections
collected, 3885 unique with R(int) = 0.0338, R1 = 0.0603,
wR2 = 0.1416 (I > 2s(I)).
11 It was found that cyclopentenone III0a, independently obtained
from the Nazarov cyclization of 10a mediated by concentrated HCl
(3.0 equiv) in CH2Cl2 at room temperature, could afford cyclo-
pentadienes 20a and 20 0a in 39% and 40% yields, respectively, by
treatment with POCl3 (2.5 equiv) in DMF at ambient conditions
for 1.5 h. For experimental details, see ESI.w
3 For reviews on Nazarov rections, see: (a) H. Pellissier, Tetrahedron,
2005, 61, 6479; (b) A. J. Frontier and C. Collison, Tetrahedron, 2005,
61, 7577; (c) M. A. Tius, Eur. J. Org. Chem., 2005, 2193.
4 For recent examples of Nazarov reactions, see: (a) F. Dhoro and
M. A. Tius, J. Am. Chem. Soc., 2005, 127, 12472; (b) S. Giese, Jr.,
R. D. Mazzola, C. M. Amann, A. M. Arif and F. G. West, Angew.
Chem., Int. Ed., 2005, 44, 6546; (c) G. Liang, Y. Xu, I. B.
Seiple and D. Trauner, J. Am. Chem. Soc., 2006, 128, 11022;
(d) W. He, J. Huang, X. Sun and A. J. Frontier, J. Am. Chem.
Soc., 2007, 129, 498; (e) D. Song, A. Rostami and F. G. West,
J. Am. Chem. Soc., 2007, 129, 12019; (f) G. Liang and D. Trauner,
J. Am. Chem. Soc., 2004, 126, 9544; (g) J. Huang and
A. J. Frontier, J. Am. Chem. Soc., 2007, 129, 8060;
(h) M. Rueping, W. Ieawsuwan, A. P. Antonchick and
B. J. Nachtsheim, Angew. Chem., Int. Ed., 2007, 46, 2097;
12 A. Lilienkampf, M. P. Johansson and K. Wahala, Org. Lett., 2003,
5, 3387.
13 For details, please see ESI.w As a comparison, no reaction was
found when 1a (1.0 mmol) was treated with either concentrated
HCl (3.0 equiv) or dry HCl gas (bubbled into the reaction mixture)
in 5.0 mL of DMF at 90 1C for 3.0 h. These results provided
further support for the proposed mechanism in Scheme 3.
14 For selected recent examples, see: (a) J. Hudon, T. A. Cernak,
J. A. Ashenhurst and J. L. Gleason, Angew. Chem., Int. Ed., 2008,
47, 8885; (b) J. N. Payette and H. Yamamoto, J. Am. Chem. Soc.,
2007, 129, 9536.
15 J.-K. Liu, Chem. Rev., 2006, 106, 2209.
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This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 2247–2249 | 2249