Palladium-catalyzed novel cycloisomerization: An unprecedented domino oxidative cyclization towards substituted carbocycles

Article abstract of DOI:10.1055/s-2005-872241

Efficient Pd-catalyzed cyclization of homoallylated β-bromo- vinylalcohols via a domino process to carbocycle derivatives in presence of different bases is reported. An unexpected and novel palladium-mediated Heck-type intramolecular oxidative cyclization

Full text of DOI:10.1055/s-2005-872241

LETTER
2135
Palladium-Catalyzed Novel Cycloisomerization: An Unprecedented Domino
Oxidative Cyclization towards Substituted Carbocycles
P
D
alladium-Catalyz
e
e
d
N
ovel
C
v
ycloisomeriz
a
a
tion lina Ray, Sajal K. Mal, Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Fax +91(3222)282252; E-mail: jkray@chem.iitkgp.ernet.in
Received 8 April 2005
Mg to bromoaldehydes (Scheme 1) in tetrahydrofuran
THF) to afford bromo alcohols (1a–6a, Table 1) in good
yield.
Abstract: Efficient Pd-catalyzed cyclization of homoallylated b-
bromo-vinylalcohols via a domino process to carbocycle deriva-
tives in presence of different bases is reported. An unexpected and
novel palladium-mediated Heck-type intramolecular oxidative
cyclization of 1-bromohexa-1-ene-5-yn-3-ol derivatives is also
described.
(
Applying Heck reaction to the compounds 1a–6a under
standard conditions,7 produced substituted cyclohex-
enones (Scheme 2) exclusively through 6-exo-trig cycli-
zation pathways.
Key words: Heck reaction, palladacycles, tandem reactions, oxida-
tion, isomerization
Br
Pd(OAc)2 / PPh3
The formation of carbon–carbon bonds using in situ gen-
erated organometallic reagents is of fundamental impor-
tance in organic synthesis. Palladium catalysts have
bases
DMF or MeCN
1
H OH
TBAC
O
emerged as extremely powerful tools for the construction
2
Scheme 2
of carbon–carbon bonds. Their popularity stems in part
3
a,b
3c,d
3e,f
from their capability to oxidize, reduce, isomerize
as well as to form new bonds. Substituted carbocycles rep- In our previous communication, we opted for HCOONa
resent a common structural component of naturally occur- as the base, but later, we performed the reaction with other
4
ring and biologically active molecules. The cyclization of bases (Na
CO
, K
CO
, NaOAc, Et
N) and acetonitrile as
2
3
2
3
3
unsaturated substrates using an intramolecular Heck reac- solvent. In all these cases we successfully isolated the
tion promoted by organopalladium complexes is of fun- cyclized products. To improve the yield further, we in-
damental importance for the construction of a vast array corporated tetrabutyl ammonium chloride as additive,
of mono- and polycarbocyclic and also polyheterocyclic which was found to be effective in all cases (Table 2).
5
systems and is therefore a highly attractive feature in the
The structure of 6b was unambiguously determined by X-
ray crystallographic analysis (Figure 1).
5
e
synthesis of cyclic natural products. In this context, we
have recently reported a new palladium-promoted domi-
6
no C–C cyclopalladation sequence allowing the facile
one-pot synthesis to cyclopentenones with promising syn-
thetic value. The 1-bromohexa-1,5-diene-3-ol derivatives
underwent Pd-catalyzed oxidative cyclization to function-
alized cyclopentenones in very good yields. In this com-
munication we wish to report the reactivity of new
sensitive substrates towards palladium-catalyzed intra-
molecular Heck reaction, which provides an efficient
route to cyclopentenones and cyclohexenones.
The starting materials were synthesized by addition of the
Grignard reagents derived from 4-bromo-1-butene and
Br
Br
Mg, 4-bromo-1-butene
THF, –78 °C to 0 °C
CHO
H
OH
Figure 1 ORTEP view of the structure 6b
Scheme 1
As we could not isolate any intermediate for this reaction,
we speculate that the mechanism follows the sequence in
Scheme 3. During the search for an intermediate, we syn-
thesized compound I by O-alkylation of 1-(2-bromo-
SYNLETT 2005, No. 14, pp 2135–2140
0
2
.0
9
.2
0
0
5
Advanced online publication: 22.07.2005
DOI: 10.1055/s-2005-872241; Art ID: D09305ST
Georg Thieme Verlag Stuttgart · New York
©

2
136
D. Ray et al.
LETTER
Table 1 Homoallylation of the b-Bromo-vinylaldehydes Using Mg/4-Bromo-1-butenea
Entry
1
Substrate
Product
Time (h)
6.0
Yield (%)b
Br
CHO
69
Br
H
OH
1
2
a
2
3
Br
5.5
5.5
63
Br
CHO
H OH
Br
a
Br
64
CHO
H
OH
3
4
a
a
4
5
6.5
5.5
61
72
Br
Br
CHO
H
OH
Br
CHO
Br
OH
H
5
a
6
CHO
5.5
75
Br
OH
H
Br
6
a
a
Reagents and conditions: b-bromo-vinylaldehydes (1 mmol), 4-bromo-1-butene (1.3 mmol), THF (6–8 mL), Mg metal (1.2 mmol), stirred at
–
78 °C.
b
Yields are of isolated product.
acenaphthylen-1-yl)-but-3-en-1-ol with methyl iodide in
PdBr
Br
PdBr
OH
presence of sodium hydride in 67% yield. Heck reaction
of I (Scheme 4), under identical conditions, produced
compound II in 54% yield, which readily underwent
isomerization and afforded ketone III in presence of
mild acid in 45% yield. This may be considered as partial
evidence in favor of the cyclization followed by iso-
merization.
Pd(0)
Pd(0)
n
n
n
OH
OH
n = 1, 2
HPdBr
HPdBr
n
n
Our continuing interest was then focused towards the suc-
cessive coupling of 1-bromo-hexa-1-ene-5-yn-3-ol deriv-
atives via novel palladium-catalyzed oxidative cyclization
and isomerization. Attempted Heck reaction of substrates
PdBr
OH
OH
n
O
(
entries 1c–8c, Table 3) did not produce the anticipated
Scheme 3 The plausible mechanism
cyclopentanoid moiety containing an exocyclic double
Synlett 2005, No. 14, 2135–2140 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Novel Cycloisomerization
2137
8
Table 2 Palladium-Catalyzed Cyclization
indium-mediated propargylation with propargyl bromide
(
Scheme 5). The propargyl indium reagent generated in
Substrate
Product
Yield (%)a
44
situ readily underwent regioselective addition to the car-
bonyl group of bromo-vinylaldehyde at 0 °C.
1
a
a
Br
Br
CHO
In, propargyl bromide
DMF, 0 °C
O
1
2
3
b
b
b
H
OH
2
38
51
51
Scheme 5
When we subjected the appropriate propargylated b-bro-
mo-vinylalcohols to Pd(OAc) (10 mol%), PPh (0.25
O
2
3
equiv), HCOONa (1 equiv) and DMF, we found the same
-methyl cyclopentenones (Scheme 6, 1d–8d) as the only
3
a
a
3
isolable products (Table 4).
O
Br
Pd(OAc)2 / PPh3
HCOONa
DMF
4
H
OH
O
Scheme 6
O
9
a
It has been previously reported that the alkyne insertion
reactions are terminated by anion capture. In this case, the
alkynyl-palladium9b intermediate formed by intramole-
cular insertion of the unactivated triple bonds could be ter-
minated by hydrogenolysis with formic acid to generate
the terminal alkene, which undergoes isomerization to
thermodynamically stable ketone. All these substrates
(entries 1c–8c) underwent cyclization through the 5-exo-
dig pathway and were reduced through isomerization
4
5
b
b
5
a
a
53
65
O
6
O
7
under the reaction conditions. As the Pd(0)-catalyzed
isomerization is unusual, it may proceed through a Pd(II)
intermediate.10
6
b
We obtained the reduced cyclopentenone as the only
isolable product. However, the cyclization of 1-(1,7-di-
bromo-3,4-dihydro-naphthalen-2-yl)-but-3-yn-1-ol (entry
a
Yield refers to isolated yield. All of the compounds gave satisfactory
H NMR, C NMR spectroscopic and MS spectrometric data.
1
13
11
7
c) failed under the same reaction conditions and we
obtained a complex mixture of products.
In conclusion, we have outlined a palladium-catalyzed
cycloisomerization towards the synthesis of fused car-
bocycles. The developed methodology serves an effective
transition metal-catalyzed protocol for the cyclization of
unactivated alkenes, alkynes via a tandem process. The
palladium acetate–HCOONa protocol could be used for
intramolecular Heck reactions, though the mechanistic
aspects are not yet fully understood. Our efforts are
currently directed towards further exploitation of this
procedure for sequential allylations and cyclizations.
Br
OMe
OMe
O
Pd(0)
bases
H+
I
II
III
Scheme 4
bond but we found the 3-methyl cyclopentenone as the
only isolable product. Attempts to perform the reaction Acknowledgment
using other bases like K CO , Na CO , Et N, were all
unsuccessful resulting in polymeric materials.
2
3
2
3
3
Financial support from DST (New Delhi) and CSIR (New Delhi)
for fellowship to S.M) is gratefully acknowledged. We are also
(
The 1-bromohexa-1-ene-5-yn-3-ol derivatives were thankful to Dr. Manish Bhattacharya, IIT-Kharagpur, India for the
crystal structure.
synthesized from substituted b-bromovinylaldehydes by
Synlett 2005, No. 14, 2135–2140 © Thieme Stuttgart · New York

2
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D. Ray et al.
LETTER
Table 3 Propargylation of the b-Bromo-vinylaldehydes Using In/Propargyl Bromidea
Entry
1
Substrate
Time (h)
Product
4.5
Yield (%)b
Br
CHO
80
78
75
74
79
Br
OH
H
H
1
2
3
4
c
c
c
c
2
3
4
5
Br
Br
5.5
4.0
5.0
5.0
CHO
OH
Br
Br
CHO
H
OH
Br
Br
4c
CHO
H
OH
Br
CHO
Br
OH
H
5
c
6
7
CHO
5.0
82
Br
H
Br
OH
6
c
Br
5.5
5.0
75
78
Br
CHO
Br
H
Br
OH
7
c
8
CHO
HO
Br
H
Br
8
c
a
Reagents and conditions: b-bromo-vinylaldehydes (1 mmol), propargyl bromide (1.3 mmol), DMF, In metal (1.2 mmol), stirred at 0 °C.
Yields are isolated yield.
b
Synlett 2005, No. 14, 2135–2140 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Novel Cycloisomerization
2139
(
(
2) (a) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285.
b) Widenhoefer, R. A. Acc. Chem. Res. 2002, 35, 905.
Table 4 Pd-Catalyzed Cyclization
(
Substrate
Product
Yield (%)a
40
(c) Tan, Z.; Negishi, E.-i. Handbook of Organopalladium
Chemistry for Organic Synthesis, Vol 1; John Wiley and
Sons: New York, 2002, 863–942.
1
c
c
3) (a) Muzart, J. Tetrahedron 2003, 59, 5789. (b) Gibson, S.
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Tetrahedron 2004, 60, 6945. (c) Tobrman, T.; Dvorak, D.
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E.; Cacchi, S.; Marinell, F.; Scarinci, A. Synlett 1991, 177.
O
1
d
2
38
(
e) Ganchegui, B.; Bouquillon, S.; Henin, F.; Muzart, J. J.
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O
(4) (a) Trost, B. M.; Dumas, J.; Villa, M. J. Am. Chem. Soc.
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Coburn, C. A.; Di Grandi, M. J. J. Am. Chem. Soc. 1996,
2
3
d
d
3
c
c
48
42
118, 2843. (c) Hong, C. Y.; Kado, N.; Overman, L. E. J. Am.
O
Chem. Soc. 1993, 115, 11028. (d) Tietze, L. F.; Evers, H.;
Topken, E. Angew. Chem. Int. Ed. 2001, 40, 903.
(e) Nicolaou, K. C.; Gray, D. L. F.; Tae, J. J. Am. Chem. Soc.
4
2004, 126, 613. (f) Willmore, N. D.; Goodman, R.; Lee, H.
H.; Kennedy, R. M. J. Org. Chem. 1992, 57, 1216.
5) (a) Belestkaya, I. P.; Chheprakov, A. V. Chem. Rev. 2000,
100, 3009. (b) Grigg, R.; Millington, E. L.; Thornton-Pett,
M. Tetrahedron Lett. 2002, 43, 2605. (c) Oestreich, M.;
Dennison, P. R.; Kodanko, J. J.; Overman, L. E. Angew.
Chem. Int. Ed. 2001, 40, 1439. (d) Balme, G.; Bouyssi, D.;
Lomberget, T.; Monteiro, N. Synthesis 2003, 2115.
(
O
4
5
d
d
5
c
c
34
40
O
(e) Link, J. Org. React. 2002, 60, 157. (f) Smith, A. B. III;
Jerris, P. J. J. Am. Chem. Soc. 1981, 103, 194.
(
(
6) Mal, S. K.; Ray, D.; Ray, J. K. Tetrahedron Lett. 2004, 45,
277.
6
O
7) General Procedure for the Palladium-Catalyzed
Cyclization.
The appropriate homoallylated or propargylated b-bromo-
vinylalcohols, Pd(OAc) (10 mol%), PPh (0.25 equiv), base
2
3
(1 equiv)[HCOONa (1 equiv) for propargylated compound
only] and DMF (6–8 mL) were placed in a two-neck round-
6
d
bottom flask. After degassing with N the mixture was
2
7
c
c
Messy mixture (7d)
–
heated to 70 °C for 4 h. After cooling, the reaction mixture
8
O
35
was diluted with cold H O and extracted with Et O (4 × 25
2
2
mL), and dried (Na SO ). The solvent was evaporated, and
2
4
the product was isolated by column chromatography (PE–
EtOAc 9:1).
(
(
8) General Procedure for Propargylation.
A mixture of b-bromo vinylaldehyde (1 mmol), propargyl
bromide (1.3 mmol), indium metal (SRL, India) (1.2 mmol),
NaI (3 mmol) in DMF (4–5 mL) was stirred at 0 °C until
completion of the reaction (checked by TLC). The reaction
8
d
a
Yields refers to isolated yield. All of the compounds gave satisfac-
1
13
11
tory H NMR, C NMR spectroscopic and MS spectrometric data.
The structure of 6d was unambiguously determined by X-ray
crystallographic analysis.
mixture was quenched with aq NH Cl solution diluted with
4
H O and extracted with Et O (3 × 25 mL). The solvent was
2
2
removed at r.t. under vacuum.
9) (a) Burns, B.; Grigg, R.; Sridharan, V.; Worakun, T.
Tetrahedron Lett. 1988, 29, 4325. (b) Nuss, J. M.; Levine,
B. H.; Rennels, R. A.; Heravi, M. M. Tetrahedron Lett.
1
991, 32, 5243.
References
(
10) For mechanistic studies on palladium-catalyzed
transformations using phosphine ligands see: (a) Alcazar
Roman L. M., Hartwig J. F.; Organometallics; 2002, 21:
(
1) (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104,
127. (b) Tsuji, J. Transition Metal Reagents and Catalysts:
Innovations in Organic Synthesis; Wiley: New York, 2002.
c) Minami, I.; Yuhara, M.; Watanabe, H.; Tsuji, J. J.
2
491. (b) Roy A. H., Hartwig J. F.; J. Am. Chem. Soc.; 2001,
123: 1232. (c) Alcazar Roman, L. M.; Hartwig, J. F.;
(
Rheingold, A. L.; Liable-Sands, L. M.; Guzei, I. A. J. Am.
Chem. Soc. 2000, 122, 4618. (d) Elsevier, C. J.; Kleijn, H.;
Organomet. Chem. 1987, 334, 225; and references cited
therein.
Synlett 2005, No. 14, 2135–2140 © Thieme Stuttgart · New York

2
140
D. Ray et al.
LETTER
Boersma, J.; Vermeer, P. Organometallics 1986, 5, 716.
3-Methyl-3,4,5,6,7,8-hexahydro-2H-azulen-1-one (3d):
–
1 1
(
e) Wojcicki, A. New J. Chem. 1994, 18, 61. (f) Kurosawa,
H.; Ogoshi, S. Bull. Chem. Soc. Jpn. 1998, 71, 973.
g) Casey, C. P.; Boller, T. M.; Kraft, S.; Guzei, I. A. J. Am.
IR (CHCl ): n = 1685 cm . H NMR (200 MHz, CDCl ):
3
m
a
x
3
d = 1.15 (d, 3 H, J = 6.96 Hz), 1.42–1.67 (m, 6 H), 1.73–1.83
1
3
(
(m, 4 H), 2.26–2.58 (m, 2 H), 2.67–2.7 (m, 1 H). C NMR
Chem. Soc. 2002, 124, 13215. (h) Tsutsumi, K.; Ogoshi, S.;
Nishiguchi, S.; Kurosawa, H. J. Am. Chem. Soc. 1998, 120,
(75 MHz, CDCl ): d = 18.98, 23,09, 26.33, 26.50, 31.13,
3
31.42, 37.04, 43.13, 141.72, 181.02, 208.11. MS (EI, 70 eV):
+
1938. (i) Baize, M. W.; Blosser, P. W.; Plantevin, V.;
m/z = 164 [M ]. Anal Calcd for C H O: C, 80.44; H, 9.82.
1
1
16
Schimpff, D. G.; Gallucci, J. C.; Wojcicki, A.
Found: C, 80.65; H, 9.62.
10-Methyl-9,10-dihydro-8H-fluoranthen-7-one (6b):
Organometallics 1996, 15, 164. (j) Casey, C. P.; Nash, J. R.;
Yi, C. S.; Selmeczy, A. D.; Chung, S.; Powell, D. R.;
Hayashi, R. K. J. Am. Chem. Soc. 1998, 120, 722.
–
1 1
IR (CHCl ): n = 1660 cm . H NMR (200 MHz, CDCl ):
3
max
3
d = 1.55 (d, 3 H, J = 7.12 Hz), 2.06–2.09 (m, 1 H), 2.39–2.78
(m, 3 H), 3.39–3.45 (m, 1 H), 7.53 (m, 2 H), 7.79 (d, 1 H,
J = 8.20 Hz), 7.92–7.98 (m, 2 H), 8.26 (d, 1 H, J = 6.79 Hz).
(
11) Spectral Data of Representative Compounds.
-Methoxy-9-methylene-8,9-dihydro-7H-
7
1
3
cyclopenta[a]acenaphthylene (II):
C NMR (75 MHz, CDCl ): d = 20.38, 29.19, 31.32, 35.68,
3
1
H NMR (200 MHz, C D ): d = 3.01–3.16 (m, 2 H), 3.20 (s,
126.11, 126.21, 126.96, 127.54, 128.41, 128.66, 130.86,
6
6
+
3
H), 4.48 (dd, 1 H, J = 2.87 Hz, J = 2.96 Hz), 5.02 (br s, 1
136.81, 161.66, 196.89. MS (EI, 70 eV): m/z = 234 [M ].
H), 5.49 (br s, 1 H), 7.20–7.31 (m, 3 H), 7.45–7.60 (m, 3 H).
Anal Calcd for C H O: C, 87.15; H, 6.02. Found: C, 88.25;
Anal Calcd for C H O: C, 87.15; H, 6.02. Found: C, 86.92;
H, 5.93.
1
7
14
1
7
14
H, 5.92.
Synlett 2005, No. 14, 2135–2140 © Thieme Stuttgart · New York