Synthesis of multisubstituted cyclopentadienes from cyclopentenones prepared via catalytic double aldol condensation and nazarov reaction sequence

Article abstract of DOI:10.1055/s-0030-1260324

The rhenium-catalyzed synthesis of cyclopentenone derivatives via double aldol condensation and successive Nazarov reaction is described. The cyclopentenones were converted to the corresponding cyclopentadienes using organolithium reagents. Cyclopentadien

Full text of DOI:10.1055/s-0030-1260324

LETTER
2585
Synthesis of Multisubstituted Cyclopentadienes from Cyclopentenones
Prepared via Catalytic Double Aldol Condensation and Nazarov Reaction
Sequence
S
ynthesis of Multi
u
substituted
C
t
yclope
a
ntadienes from Cy
N
clopentenones ishina,1 Tomohiro Tatsuzaki, Ayano Tsubakihara, Yoichiro Kuninobu,* Kazuhiko Takai*
Division of Chemistry and Biochemistry, Graduate School of Natural Science and Technology, Okayama University,
Tsushima, Kita-ku, Okayama 700-8530, Japan
Fax +81(86)2518094; E-mail: kuninobu@cc.okayama-u.ac.jp; E-mail: ktakai@cc.okayama-u.ac.jp
Received 20 July 2011
O
Abstract: The rhenium-catalyzed synthesis of cyclopentenone de-
O
rivatives via double aldol condensation and successive Nazarov re-
action is described. The cyclopentenones were converted to the
corresponding cyclopentadienes using organolithium reagents. Cy-
clopentadienes with four different substituents could be synthesized
by stepwise double aldol condensation using a ketone and two types
of aldehydes, followed by treatment with an organolithium reagent.
Re2(CO)10 (5.0 mol%)
toluene, 180 °C, 48 h
PhCHO
+
1a
(1 equiv)
2a
(2 equiv)
Ph
Ph
3a 80%
Scheme 1 Rhenium-catalyzed synthesis of cyclopentenone 3a from
ketone 1a and aldehyde 2a
Key words: rhenium, cyclopentenone, cyclopentadiene, aldol con-
densation, Nazarov cyclization
yield (entry 3).12 Heteroaryl aldehydes, such as 2-furalde-
hyde (2c) and 2-thiophenecarboxaldehyde (2d), also gave
cyclopentenones 3e and 3f in 70% and 82% yields, re-
spectively (entries 4 and 5). If the reaction temperature
was higher than 150 °C, the furyl moiety decomposed,
whereas a thiophenyl group was stable under the present
reaction conditions. When TiCl4(thf)2 was used as a cata-
lyst (see ref. 7), the cyclopentenone 3e was not generated
at all.
Cyclopentadienes are among the most useful precursors
of ligands in organometallic complexes2 and functional
materials.3 A general method for the synthesis of cyclo-
pentadiene derivatives is nucleophilic addition of organo-
metallic reagents to cyclopentadienones followed by
reduction of the formed cyclopentadienols.4 Although cy-
clopentenones also serve as precursors to cyclopenta-
dienes,5 there have been only a few examples reported.6
We report herein the rhenium-catalyzed synthesis of cy-
clopentenones from ketones and aldehydes by double al-
dol condensation and successive Nazarov reaction,7,8 and
its application to the synthesis of cyclopentadiene deriva-
tives.
A proposed mechanism for the formation of cyclopenten-
ones 3 is as follows (Scheme 2): (1) Aldol condensation
between ketone 1 and aldehyde 2 to give a,b-unsaturated
ketone A; (2) formation of dialkenyl ketone B from A and
the second aldehyde 2 by successive aldol condensation;13
and (3) Nazarov reaction of the formed dialkenyl ketone
B to afford cyclopentenone 3.14
Treatment of 3-pentanone (1a) with benzaldehyde (2a) in
the presence of a catalytic amount of a rhenium complex,
Re2(CO)10, gave cyclopentenone derivative 3a in 80%
yield (Scheme 1).9 Examples of catalytic formation of cy-
clopentenone 3 are still rare,6,10 possibly because an a,b-
unsaturated carbonyl compound is formed from 1a and
one equivalent of 2a, which readily undergoes side reac-
tions such as polymerization in the presence of a Lewis
acid.11
Cyclopentenones 3 could be transformed into cyclopenta-
dienes 5 by the reaction of 3 with organolithium reagents
4 and successive protonation and dehydration (Table 2).
The choice of quenching reagent (aq NH4Cl) and dehydra-
tion catalyst (TsOH, 5.0 mol%) was found to be impor-
tant.15 Treatment of tetraphenylcyclopentenone 3b with
cat. Re
R3CHO (2)
O
O
R1
R2
R1
R2
First, the synthesis of several cyclopentenones 3 was in-
vestigated using Re2(CO)10 as a catalyst (Table 1). The
presence of a-phenyl substituents on the ketone starting
materials improved yields and reactivity (entries 1 and 2).
As a result, the corresponding cyclopentenones 3b and 3c
were obtained in good to excellent yields. An excess
amount of acetaldehyde (2b) and a longer reaction time
were necessary to generate cyclopentenone 3d in 71%
first aldol condensation
1
R3
R2
A
O
cat. Re
R3CHO (2)
R1
R3
second aldol condensation
R3
B
O
O
R1
R2
R1
R2
cat. Re
+
Nazarov reaction
R3
R3
R3
R3
SYNLETT 2011, No. 17, pp 2585–2589
x
x
.x
x
.2
0
1
1
3
3'
Advanced online publication: 22.09.2011
Scheme 2 Proposed mechanism for the formation of cyclopenten-
one 3 from ketone 1 and aldehyde 2
DOI: 10.1055/s-0030-1260324; Art ID: U05511ST
© Georg Thieme Verlag Stuttgart · New York

2586
Y. Nishina et al.
LETTER
Table 1 Synthesis of Cyclopentenones 3
O
R1
R2
O
Re2(CO)10 (5.0 mol%)
toluene
R1
R2
+
R3CHO
R3
R3
1
2
3
Entry
1
1
2
2 (equiv) Conditions
3
Yield (%)
91
1b
2a
2
150 °C, 24 h
3b
(R1 = R2 = Ph)
(R3 = Ph)
O
O
1c
79a
Ph
Ph
2
2a
3
180 °C, 24 h
(R1 = Ph, R2 = Me)
[77:23]b
+
Ph
Ph
Ph
Ph
3c'
3c
2b
3
4
1b
1b
5
2
150 °C, 72 h
135 °C, 24 h
3d
3e
71
70
(R3 = Me)
CHO
O
2c
5
1b
2
180 °C, 24 h
3f
82
CHO
S
2d
a Combined yield of olefinic regioisomers.
b The ratio of 3c and 3c¢ is reported in square brackets.
phenyllithium (4a) gave the desired pentaphenylcyclo- 50% yields, respectively, from dimethyldiphenylcycle-
pentadiene (5a), but in low yield (entry 1).16 Methyllithi- pentenones, 3a and 3d (entries 6 and 7). Heteroaryl-
um (4b) functioned as a good nucleophile to give substituted cyclopentenones, 3e and 3f, led to the corre-
methyltetraphenylcyclopentadiene 5b in 57% yield (entry sponding cyclopentadienes 5g and 5h in 49% and 92%
2). Dimethyltriphenyl cyclopentadienes have two regioi- yields, respectively (entries 8 and 9). The Nazarov cy-
somers, 5c and 5d. These cyclopentadienes 5c and 5d clization can produce cyclopentenones 3 as a mixture of
were synthesized from methyltriphenylcyclopentenones olefinic regioisomers, which also leads to an isomeric
3c and 3c¢ with 4b (entry 3), and dimethyldiphenylcyclo- mixture of cyclopentadienes 5. This is not a problem in
pentenone (3a) with 4a (entry 4), respectively. The yield this case because the cyclopentadienes can be converted
of 5d was improved by using Ph3MgLi (4c) as the phenyl into single cyclopentadienyl anions by deprotonation.2
nucleophile (entry 5).17 Regioisomers of trimethyldiphe-
nylcyclopentadienes, 5e and 5f, were obtained in 71% and
Table 2 Synthesis of Cyclopentadienes 5
R4
O
R1
R2
R3
R1
R2
R4Li (4, 1.1 equiv)
1) aq NH4Cl
2) TsOH (5.0 mol%)
CH2Cl2, 25 °C, 1 h
THF, –78 °C, 3 h
R3
R3
R3
3
5
Entry
1
3
4
Product
Yield (%)a
39
Ph
O
Ph
Ph
PhLi
4a
Ph
Ph
Ph
Ph
Ph
Ph
3b
5a
Ph
Ph
Ph
Ph
MeLi
4b
57
2
3b
[68:32]b
+
Ph
Ph
Ph
Ph
5b
5b'
Synlett 2011, No. 17, 2585–2589 © Thieme Stuttgart · New York

LETTER
Synthesis of Multisubstituted Cyclopentadienes from Cyclopentenones
2587
Table 2 Synthesis of Cyclopentadienes 5 (continued)
R4
O
R1
R2
R3
R1
R2
R4Li (4, 1.1 equiv)
1) aq NH4Cl
2) TsOH (5.0 mol%)
CH2Cl2, 25 °C, 1 h
THF, –78 °C, 3 h
R3
R3
R3
3
5
Entry
3
3
4
Product
Yield (%)a
O
O
Ph
Ph
+
Ph
Ph
4b
71c
Ph
Ph
Ph
Ph
Ph
3c
3c'
5c
[3c:3c¢ = 77:23]
Ph
O
4
5
6
4a
40c
60c
Ph
Ph
Ph
Ph
5d
3a
Ph3MgLi
4c
3a
5d
71
3a
4b
4b
[65:35]d
+
Ph
Ph
Ph
Ph
+
Ph
5e
5e'
O
50e
Ph
Ph
Ph
Ph
Ph
7
8
[71:29]f
3d
5f
5f'
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
49e
4b
4b
[54:39:7]g
+
+
O
O
O
O
O
O
O
O
5g
5g'
5g''
3e
O
Ph
Ph
Ph
Ph
Ph
Ph
92e
9
[57:43]h
+
S
S
S
S
S
S
5h
5h'
3f
a Combined yield of olefinic regioisomers.
b The ratio of 5b and 5b¢ is reported in square brackets.
c One isomer represented at least 90% of the product mixture.
d The ratio of 5e and 5e¢ is reported in square brackets.
e The regioisomers could not be separated.
f The ratio of 5f and 5f¢ is reported in square brackets.
g The ratio of 5g, 5g¢ and 5g¢¢ is reported in square brackets.
h The ratio of 5h and 5h¢ is reported in square brackets.
Cyclopentadienes 5 could also be synthesized without iso- tonation and dehydration to give cyclopentadienes 5b and
lation of the cyclopentenones 3. After the formation of 3b 5b¢ in 58% combined yield (Scheme 3).18
from ketone 1b and benzaldehyde (2a), the reaction mix-
ture was treated with methyllithium (4b) followed by pro-
Although a similar methodology was developed previous-
ly,6,10 there have been no reports on incorporation of dif-
Synlett 2011, No. 17, 2585–2589 © Thieme Stuttgart · New York

2588
Y. Nishina et al.
LETTER
O
F
CHO
O
Ph
Ph
O
Re2(CO)10 (5.0 mol%)
2a (1.0 equiv)
Re2(CO)10 (5.0 mol%)
2e (1.0 equiv)
Ph
Ph
+
PhCHO
O
toluene, 150 °C, 24 h
Re2(CO)10 (5.0 mol%)
2a
Ph
Ph
1b
toluene (0.25 M)
150 °C, 24 h
3b
toluene (2.5 M)
180 °C, 24 h
Ph
1a
6a 56%
(2.0 equiv)
1) aq NH4Cl
Ph
Ph Ph
+
Ph
O
O
MeLi (4b, 6.0 equiv)
THF, –78 °C, 3 h
2) CHCl3
25 °C, 1 h
1) aq NH4Cl
n-BuLi (4d, 1.1 equiv)
Ph
Ph
Ph
Ph
+
F
5b
5b'
THF, –78 °C, 3 h
2) TsOH (5.0 mol%)
CH2Cl2, 25 °C, 1 h
Ph
Ph
58% (5b:5b' = 67:33)
Scheme 3 One-pot synthesis of cyclopentadiene 5b
3g
3g'
F
70% (3g:3g' = 40:60)
ferent substituents derived from aldehydes 2 into
cyclopentenones 3. When ketone 1a (2 equiv) was treated
with benzaldehyde (2a) at low concentration for 24 hours,
a,b-unsaturated ketone 6a was obtained in 56% yield
(Scheme 4).19 After the formation of 6a, the second alde-
hyde 2e was added at a higher concentration and temper-
ature, and cyclopentenones having three different
substituents 3g and 3g¢ were formed in 70% yield. In the
case of zirconium- or titanium-catalyzed reactions, two
substituents on cyclopentenones 3 from aldehydes 2 were
always the same (R3 = R4). We found that such stepwise
transformations can be achieved with the rhenium cata-
lyst, Re2(CO)10. We then examined the transformation
into cyclopentadienes 5i by the reaction of the formed cy-
clopentenones 3g and 3g¢ with butyllithium reagent 4d
followed by protonation and dehydration.20 Although
there have been previous reports of the synthesis of mul-
tisubstituted cyclopentadienes, the examples have been
limited in the diversity of the substituents on the cyclo-
pentadiene rings.5,21
n-Bu
n-Bu
n-Bu
+
+
Ph
Ph
Ph
F
F
F
n-Bu
n-Bu
+
+
Ph
Ph
F
F
5i 58% (27:28:20:20:5)
Scheme 4 Synthesis of cyclopentadiene 5i with four different sub-
stituents
References and Notes
In summary, we have demonstrated the rhenium-cata-
lyzed synthesis of cyclopentenones from ketones and two
equivalents of aldehydes by double aldol condensation
and Nazarov cyclization.22,23 By treating the formed cy-
clopentenones with organolithium reagents followed by
protonation and dehydration, the corresponding cyclopen-
tadienes were produced.24,25 Cyclopentadienes with dif-
ferent substituents could be synthesized by this method.
We hope that this methodology will allow access to func-
tionalized cyclopentadienes which can be used in both or-
ganometallic chemistry and organic functional materials
science.
(1) Present address: Research Core for Interdisciplinary
Sciences, Okayama University, Tsushima, Kita-ku,
Okayama 700-8530, Japan.
(2) (a) Comprehensive Organometallic Chemistry II, Vol. 3;
Abel, E. W.; Stone, F. G. A.; Wilkinson, G., Eds.; Elsevier:
Oxford (U.K.), 1995. (b) Comprehensive Organometallic
Chemistry II, Vol. 4; Abel, E. W.; Stone, F. G. A.;
Wilkinson, G., Eds.; Elsevier: Oxford (U.K.), 1995.
(c) Comprehensive Organometallic Chemistry II, Vol. 5;
Abel, E. W.; Stone, F. G. A.; Wilkinson, G., Eds.; Elsevier:
Oxford (U.K.), 1995. (d) Comprehensive Organometallic
Chemistry II, Vol. 6; Abel, E. W.; Stone, F. G. A.;
Wilkinson, G., Eds.; Elsevier: Oxford (U.K.), 1995.
(e) Comprehensive Organometallic Chemistry II, Vol. 7;
Abel, E. W.; Stone, F. G. A.; Wilkinson, G., Eds.; Elsevier:
Oxford (U.K.), 1995. (f) Comprehensive Organometallic
Chemistry II, Vol. 8; Abel, E. W.; Stone, F. G. A.;
Wilkinson, G., Eds.; Elsevier: Oxford (U.K.), 1995.
(g) Comprehensive Organometallic Chemistry II, Vol. 9;
Abel, E. W.; Stone, F. G. A.; Wilkinson, G., Eds.; Elsevier:
Oxford (U.K.), 1995. (h) McKnight, A. L.; Waymouth, R.
M. Chem. Rev. 1998, 98, 2587. (i) Arndt, S.; Okuda, J.
Chem. Rev. 2002, 102, 1953. (j) Deck, P. A. Coord. Chem.
Rev. 2006, 250, 1032.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was partially supported by the Ministry of Education,
Culture, Sports, Science, and Technology of Japan.
(3) There are several examples of applications for
electroluminescence devices. See: (a) Adachi, C.; Tsutsui,
T.; Saito, S. Appl. Phys. Lett. 1990, 56, 799. (b) Ohmori,
Synlett 2011, No. 17, 2585–2589 © Thieme Stuttgart · New York

LETTER
Synthesis of Multisubstituted Cyclopentadienes from Cyclopentenones
2589
Y.; Tada, N.; Fujii, A.; Ueta, H.; Sawatani, T.; Yoshino, K.
(16) The yield of 5a was low because deprotonation of 3b with 1a
occurred predominantly. When the reaction was quenched
with D2O, deuterium was incorporated at the a-position of
the carbonyl group of 3b.
(17) The magnesium ate complex can undergo selective addition
to the carbonyl group. See: Hatano, M.; Matsumura, T.;
Ishihara, K. Org. Lett. 2005, 7, 573.
Thin Solid Films 1998, 331, 89. (c) Sugiyama, K.;
Yoshimura, D.; Miyamae, T.; Miyazaki, T.; Ishii, H.; Ouchi,
Y.; Seki, K. J. Appl. Phys. 1998, 83, 4928. (d) Zhao, Y. S.;
Fu, H.; Hu, F.; Peng, A. D.; Yao, J. Adv. Mater. 2007, 19,
3554.
(4) (a) Chambers, J. W.; Baskar, A. J.; Bott, S. G.; Atwood,
J. L.; Rausch, M. D. Organometallics 1986, 5, 1635.
(b) Burk, M. J.; Calabrese, J. C.; Davidson, F.; Harlow,
R. L.; Roe, D. C. J. Am. Chem. Soc. 1991, 113, 2209.
(c) Martín-Matute, B.; Edin, M.; Bogár, K.; Kaynak, F. B.;
Bäckvall, J.-E. J. Am. Chem. Soc. 2005, 127, 8817.
(d) Mavrynsky, D.; Päiviö, M.; Lundell, K.; Sillanpää, R.;
Kanerva, L. T.; Leino, R. Eur. J. Org. Chem. 2009, 1317.
(5) Kohl, F. X.; Jutzi, P. J. Organomet. Chem. 1983, 243, 119.
(6) There has been a report on zirconium-catalyzed synthesis
of cyclopentenones from ketones and aldehydes and its
application to the preparation of cyclopentadienes. See:
Yuki, T.; Hashimoto, M.; Nishiyama, Y.; Ishii, Y. J. Org.
Chem. 1993, 58, 4497.
(7) For reviews of Nazarov reactions, see: (a) Santelli-Rouvier,
C.; Santelli, M. Synthesis 1983, 429. (b) Pellissier, H.
Tetrahedron 2005, 61, 6479. (c) There have been many
reports on reactions catalyzed by a rhenium complex as a
Lewis acid; however, examples of rhenium-catalyzed
Nazarov reactions are still rare.
(18) Chloroform was used as a proton source. When a catalytic
amount of p-toluenesulfonic acid was used in the
dehydration, the yield of cyclopentadiene 5b decreased.
(19) Monoselective aldol reaction has been limited to a few
examples. See: (a) Iranpoor, N.; Kazemi, F. Tetrahedron
1998, 54, 9475. (b) Cao, Y. Q.; Dai, Z.; Zhang, R.; Chen,
B. H. Synth. Commun. 2005, 35, 1045.
(20) The regioisomers of 5i could not be separated by column
chromatography on silica gel or GPC. The ratio between five
regioisomers of 5i was determined by 1H NMR.
(21) (a) Koschinsky, R.; Köhli, T. P.; Mayr, H. Tetrahedron Lett.
1988, 29, 5641. (b) Batz, C.; Jutzi, P. Synthesis 1996, 1296.
(c) Lee, J. H.; Toste, F. D. Angew. Chem. Int. Ed. 2007, 46,
912.
(22) General Procedure for the Synthesis of Cyclopentenones
3: A mixture of ketone 1 (0.250 mmol), aldehyde 2 (0.500
mmol), Re2(CO)10 (8.2 mg, 0.0125 mmol), and toluene (0.1
mL) was stirred at 150 °C for 24 h in a sealed tube. Then, the
solvent was removed in vacuo and the product was isolated
by column chromatography on silica gel (hexane–EtOAc =
20:1) to give cyclopentenone 3.
(8) Rhenium carbonyl complexes exhibit Lewis acidity. See:
Kuninobu, Y.; Takai, K. Chem. Rev. 2011, 111, 1938.
(9) For investigation of several catalysts: Sc(OTf)3 (5.0 mol%,
150 °C, 24 h), 12%; TiCl4(thf)2 (10 mol%, 120 °C, 16 h),
80%; ZrOCl2·8H2O (10 mol%, 150 °C, 12 h), 63%; AuCl3
(5.0 mol%, 150 °C, 24 h), 4%. No reaction (5.0 mol%, 150
°C, 24 h): InCl3, In(OTf)3, and Cu(OTf)2. These results were
obtained within the scope of this work.
(23) 2,5-Dimethyl-3,4-diphenyl-2-cyclopentene-1-one (3a): 1H
NMR (400 MHz, CDCl3): d = 1.25 (d, J = 7.2 Hz, 3 H), 1.93
(d, J = 1.6 Hz, 3 H), 2.31 (qd, J = 7.2, 2.8 Hz, 1 H), 3.89 (s,
1 H), 6.97–7.23 (m, 10 H). 13C NMR (100 MHz, CDCl3):
d = 10.1, 15.2, 51.2, 56.2, 126.5, 127.4, 128.2, 128.6, 128.8,
135.0, 136.6, 136.8, 141.9, 166.9, 210.8.
(10) There has been a report on titanium-catalyzed synthesis of
cyclopentenones from ketones and aldehydes. See: Tao, X.;
Liu, R.; Meng, Q.; Zhao, Y.; Zhou, Y.; Huang, J. J. Mol. Cat.
A: Chem. 2005, 225, 239.
(11) Rhenium carbonyl complexes function as mild Lewis acids,
which do not decompose a,b-unsaturated carbonyl
compounds. The reactivities are maintained even in the
presence of water. See: Kuninobu, Y.; Ueda, H.; Takai, K.
Chem. Lett. 2008, 37, 878.
(24) General Procedure for the Synthesis of Cyclopentadienes
5: To a mixture of cyclopentenone 3 (0.25 mmol) and THF
(5.0 mL), an Et2O solution of organolithium reagent 4 (0.275
mmol, 1.1 equiv) was added dropwise at –78 °C. Then the
reaction mixture was stirred at –78 °C for 3 h. The reaction
was quenched with aq NH4Cl (3.0 mL), and the mixture was
extracted with EtOAc. The organic layer was dried with
MgSO4, filtered, and concentrated in vacuo. CH2Cl2 (1.0
mL) and TsOH (5.2 mg, 0.0125 mmol, 0.050 equiv) were
added to the mixture, and the mixture was stirred at 25 °C for
1 h. Then, the solvent was removed in vacuo and the product
was isolated by column chromatography on silica gel
(hexane–EtOAc = 50:1) to give cyclopentadiene 5.
(25) 1,2,3,4,5-Pentaphenylcyclopentadiene (5a): 1H NMR (400
MHz, CDCl3): d = 5.08 (s, 1 H), 6.94–6.98 (m, 4 H), 7.00–
7.03 (m, 8 H), 7.08–7.22 (m, 13 H). 13C NMR (100 MHz,
CDCl3): d = 62.7, 126.3, 126.5, 126.7, 127.7, 127.8, 128.4,
128.5, 129.0, 130.1, 135.8, 136.1, 138.1, 144.0, 146.5.
(12) Self-aldol condensation of acetaldehyde (2b) also proceeded
as a side reaction.
(13) Arnold, A.; Markert, M.; Mahrwald, R. Synthesis 2006,
1099.
(14) (a) Walz, I.; Togni, A. Chem. Commun. 2008, 4315.
(b) Wu, Y. K.; West, F. G. J. Org. Chem. 2010, 75, 5410.
(c) Yaji, K.; Shindo, M. Tetrahedron Lett. 2010, 51, 5469.
(15) When the reaction was quenched with aq HCl, the yield of
5a decreased. See: ref 5.
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