α-Arylation and alkynylation of cyclic -iodoenones using palladium-catalyzed cross-coupling reactions with trifluoroborate salts

Article abstract of DOI:10.1055/s-0029-1218580

An expeditious synthesis of -aryl- and -alkynylcyclohexenones is described and illustrated by palladium-catalyzed cross-coupling reaction of cyclic -iodoenones with potassium aryltrifluoroborate salts. This procedure offers easy access to -arylated and al

Full text of DOI:10.1055/s-0029-1218580

LETTER
427
a-Arylation and Alkynylation of Cyclic a-Iodoenones Using
Palladium-Catalyzed Cross-Coupling Reactions with Trifluoroborate Salts
a
-Arylation and
A
e
lkynylation
m
of Cyclic
a
-Iodoen
i
one
s
lla Gueogjian,a Fateh V. Singh,a Jesus M. Pena,a Monica F. Z. J. Amaral,a Hélio A. Stefani*a,b
Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brazil
Fax +55(11)38154418; E-mail: hstefani@usp.br
b
Departamento de Biofísica, Universidade Federal de São Paulo, São Paulo, SP, Brazil
Received 28 September 2009
palladium-catalyzed Stille cross-coupling reactions of a-
iodoenones or a-tosylenones with corresponding tributyl-
tin compounds.8 Some of a-alkynylenones have been syn-
thesized by palladium-catalyzed cross-coupling reaction
Abstract: An expeditious synthesis of a-aryl- and a-alkynylcyclo-
hexenones is described and illustrated by palladium-catalyzed
cross-coupling reaction of cyclic a-iodoenones with potassium aryl-
trifluoroborate salts. This procedure offers easy access to a-arylated
and alkynylated cyclohexenones functionalized with electron- of a-haloenones with terminal alkynes.2,9 Recently,
donor and -acceptor substituents in good yields.
Krische and his research group have achieved the synthe-
sis of a-arylated enones by phosphine-catalyzed nucleo-
philic reaction of cyclohex-2-enone with arylbismuth
compounds.10 Most of the synthetic approaches for the
synthesis of a-substituted enones, specially a-arylenones
are associated with the palladium-catalyzed cross-
coupling reactions of a-haloenones with organoboronic
acids or esters.11 The organoboronic acids and esters are
associated with some serious drawbacks such as expense,
low stability, and high sensitivity to air and moisture.
Thus, there is a need to develop an expedient route for the
synthesis of these systems that could offer an economical
route with the flexibility of introducing desirable func-
tionalities into their molecular architecture.
Key words: cross-coupling reaction, cyclic a-iodoenones, a-sub-
stituted enones
The introduction of functional groups at the a-position of
a,b-unsaturated enones is a challenging and important
synthetic transformation in organic chemistry. a-Substi-
tuted functionalized a,b-enones are important synthetic
intermediates for the synthesis of several biologically ac-
tive scaffolds1,2 and common structural motifs found in
various natural products.3 In the past two decades, some
a-alkynylenones containing natural products have been
isolated such as harveynone (I),4 tricholomenyns A (II)
and B (III).5 In addition, both naturally occurring com-
pounds harveynone and tricholomenyns have been identi-
fied as novel anticancer agents6 in the past few years.
In the past few years, potassium organotrifluoroborate
salts (RBF3K)12 have received a great deal of attention
with regard to their application in organic synthesis and
have emerged as some of the most important organome-
tallic reagents for Suzuki–Miyaura cross-coupling reac-
tions. These compounds are crystalline solids, stable in air
and moisture, and easily prepared by the addition of inex-
pensive KHF2 to a variety of organoboron intermediates.12
Recently, we have achieved several palladium-catalyzed
cross-coupling and homocoupling reactions using potassi-
um organotrifluoroborate salts.13
O
O
O
O
O
OH
I
OH
OAc
II
O
III
Herein, we report an alternative approach for the synthesis
of a-arylenones by palladium-catalyzed cross-coupling
reaction of 2-iodocyclohex-2-enone 2 with aryltrifluoro-
borates 3. The strength of this coupling approach lies in
the formation of C–C bond and introduction of electron-
donor or -acceptor functionalities into their molecular
structure.
OAc
Figure 1 Structures of a-alkynylenones containing natural products
Most of the synthetic approaches for a-arylation, alkeny-
lation, and alkynylation of a,b-enones at a-position are as-
sociated with transition-metal-catalyzed cross-coupling
of a-organometallics with aryl halides or the complemen-
tary combination of a-halocarbonyl compound with aryl
organometallics, although some other methodologies are
also available.7 In a few reports, the synthesis of a-arylat-
ed and alkynylated a,b-enones have been achieved by the
Our approach to synthesize a-arylenones 2a–m was based
on palladium-catalyzed cross-coupling of a-iodoenone
with potassium aryltrifluoroborate salts 3a–m. The parent
precursor a-iodoenone 2 was conveniently prepared by di-
rect iodination of cyclohex-2-enone 1 with iodine in
CCl4–pyridine (1:1) at 0 °C under nitrogen atmosphere
(Scheme 1).8
SYNLETT 2010, No. 3, pp 0427–0432
1
2.
0
2.
2
0
1
0
Advanced online publication: 22.12.2010
DOI: 10.1055/s-0029-1218580; Art ID: S11309ST
© Georg Thieme Verlag Stuttgart · New York

428
K. Gueogjian et al.
LETTER
O
O
Table 2 Study of Base Effect on Cross-Coupling of a-Iodoenone 2
with Phenyltrifluoroborate Salt 3a
I
CCl4–pyridine (1:1)
0 °C
I2
+
Entry
Base
Yield (%)a
(2 equiv)
(1 equiv)
1
2
3
4
5
Et3N
15
23
35
40
86
1
2
(i-Pr)2NH
NaOH
Cs2CO3
K2CO3
Scheme 1
Initially, we paid our attention to develop an optimum set
of reaction conditions for the palladium-catalyzed cross-
coupling reaction of 2-iodocyclohex-2-enone (2) with po-
tassium aryltrifluoroborates 3. In order to screen this cou-
pling reaction, we selected 2-iodo-cyclohex-2-enone (2)
and potassium phenyltrifluoroborate salt 3a as coupling
partners. To get the best catalyst, we attempted few reac-
tions with some palladium (Table 1, entry 2–5) and non-
palladium (Table 1, entry 6 and 7) catalysts while the
reaction was working successfully only with palladium
catalysts. The reactions were carried out using 3 equiva-
lents of sodium carbonate as base and 1,4-dioxane–water
as solvent while the reaction was stirred for five hours at
80 °C. When the reaction was performed in the absence of
Pd catalyst no product was formed, indicating that the Pd
catalyst is essential to initiate the reaction. The best result
was obtained with PdCl2 (Table 1, entry 2).
a The yields were determined by GC analysis.
(Table 2, entry 4), while a remarkable improvement
(86%) was observed with K2CO3 (Table 2, entry 5).
After determined the optimal catalyst and base, we per-
formed the reaction using different solvent systems
(MeOH, EtOH, i-PrOH, THF, DME, and 1,4-dioxane),
both under anhydrous and aqueous conditions. The sol-
vent mixture 1,4-dioxane–H2O proved to be ideal, giving
the desired product in 86% yield. The outcome of the re-
action was further improved by a decrease in the catalyst
loading from 10 mol% to 5 mol%, which increased the re-
action yield from 86% to 93%.
Encouraged by the establishment of the optimum reaction
conditions, we tested a series of substituted potassium
aryltrifluoroborate salts 3a–n with a-iodoenone 2 under
our standard Suzuki–Miyaura cross-coupling conditions
using 5 mol% of PdCl2, 3 equivalents of K2CO3 in 1,4-di-
oxane–water (5:1) at 80 °C. The corresponding a-aryl-
cyclohex-2-enone derivatives 4a–n were isolated in
moderate to good yields (26–97%).14
Table 1 Study of Catalyst Effect on Cross-Coupling of a-Iodo-
enone 2 with Phenyltrifluoroborate Salt 3a
O
O
catalyst (5 mol%)
K2CO3 (3 equiv)
BF3K
I
+
1,4-dioxane–H2O, N2
80 °C, 5 h
(1 equiv)
(1 equiv)
4a
3a
2
Almost all the reactions of electron-withdrawing aryl tri-
fluoroborate salts with 2-iodo-cyclohex-2-enone proceed-
ed successfully (Table 3, 3b–g). We can discern that
chloro, bromo, fluoro, and trifluoromethyl substituents at
meta or para positions of the aromatic ring exert a moder-
ate to strong influence upon the Suzuki–Miyaura cross-
coupling reaction. The only substituent that was not toler-
ated was a cyano group at the para position of the aromat-
ic ring (Table 3, 3g). 3-Thiophenetrifluoroborate salt (3h)
also provided the cross-coupling product in low yield
(Table 3, 3h).
Entry
Catalysta
–
Yield (%)b
1
2
3
4
5
6
7
n.r.
86
PdCl2
Pd(OAc)2
PdCl2(PhCN)2
Pd(PPh3)4
CuI
56
75
59
n.r.
n.r.
The Suzuki–Miyaura cross-coupling reactions of aryltri-
fluoroborate salts 3 bearing electron-rich functional
groups such as methyl and methoxy at the ortho, meta,
and para positions furnished moderate to high yields of
the desired products (Table 3, 3i and 3k). The presence of
a hydroxy group at the meta position and a protected ami-
no group at the para position of the aromatic ring afforded
11% and 42% yields, respectively (Table 3, 3j and 3l).
Probably due to steric hindrance, the salt 3m was not re-
active under our reaction conditions. An interesting prod-
uct resulting from a double cross-coupling reaction of two
equivalents of 2-iodocyclohex-2-enone (2) with dipotassi-
um phenylene-1,4-bistrifluoroborate salt (3n) was ob-
NiCl2·6H2O
a The amount of 5 mol% of catalyst was used.
b The yields were determined by GC.
After getting the best catalyst, a variety of bases like Et3N,
i-Pr2NEt (Hünig’s base), K2CO3, Cs2CO3, and NaOH
were tested. The reaction with organic bases Et3N and (i-
Pr)2NH was not working nicely and the desired product
observed in 15% and 23% yields, respectively (Table 2,
entry 1 and 2). On the other hand, when inorganic bases
were used, we observed slight increase in yield to 35%
with NaOH (Table 2, entry 3), to 40% with Cs2CO3
Synlett 2010, No. 3, 427–432 © Thieme Stuttgart · New York

LETTER
a-Arylation and Alkynylation of Cyclic a-Iodoenones
429
Table 3 Suzuki–Miyaura Cross-Coupling Reaction of Aryltrifluo-
roborates and 2-Iodocyclohex-2-enone (continued)
tained in low yield (26%) (Table 3). The success of the
reaction was observed to be dependent on the presence of
water as a co-solvent. One possible explanation is the bet-
ter solubility of the potassium aryltrifluoroborate salts in
aqueous medium.15
O
I
R
(1 equiv)
Table 3 Suzuki–Miyaura Cross-Coupling Reaction of Aryltrifluo-
roborates and 2-Iodocyclohex-2-enone
O
2
+
PdCl2 (5 mol%), K2CO3 (3 equiv)
1,4-dioxane–H2O, N2
O
BF3K
80 °C, 5–8 h
I
R
4
(1 equiv)
R
(1 equiv)
3
O
2
+
PdCl2 (5 mol%), K2CO3 (3 equiv)
Entry Aryltrifluoroborate 3 Product 4
Yield (%)a
46
1,4-dioxane–H2O, N2
BF3K
80 °C, 5–8 h
O
BF3K
R
4
S
8
(1 equiv)
S
3
3h
3i
4h
4i
Entry Aryltrifluoroborate 3 Product 4
Yield (%)a
85
O
O
BF3K
O
9
10
11
97
11
74
BF3K
1
3a
4a
CF3
O
BF3K
OH
HO
BF3K
2
72
69
47
46
3j
F3C
4j
3b
OMe
4b
O
BF3K
F
O
BF3K
MeO
3
3k
F
4k
3c
NHCbz
4c
O
O
BF3K
Br
Cl
12
13
42
O
BF3K
CbzHN
4
3l
Br
4l
3d
4d
BF3K
n.r.
O
BF3K
5
3m
Cl
4m
3e
4e
BF3K
CF3
O
F3C
BF3K
14
26
O
O
O
KF3B
6
7
26
3n
CF3
CN
CF3
4n
3f
a Isolated yields.
4f
BF3K
Next we examined the Suzuki-Miyaura cross-coupling
reaction of 2-iodocyclohex-2-enone (2) with alkynyltri-
fluoroborate salts (5) as summarized in Table 4.16 The
cross-coupling reactions of phenyl- and p-methylphenyl-
n.r.
NC
3g
4g
Synlett 2010, No. 3, 427–432 © Thieme Stuttgart · New York

430
K. Gueogjian et al.
LETTER
Table 4 Suzuki–Miyaura Cross-Coupling Reaction of Alkynyltrifluoroborates 5 and a-Iodocyclohexen-2-enone
O
I
O
R
( 1 equiv)
2
+
PdCl2 (5 mol%), K2CO3 (3 equiv)
1,4-dioxane–H2O, N2
80 °C
BF3K
6
R
( 1 equiv)
5
Entry
1
Alkynyl trifluoroborate 5
Product 6
Time (h)
Yield (%)
73
BF3K
O
7
5a
6a
BF3K
O
2
3
20
61
5b
6b
O
BF3K
n.r.
5c
6c
ethynyltrifluoroborate salts (5a and 5b) proceeded
smoothly, and the products were obtained in good yields
[73% (6a) and 61% (6b), respectively; Table 4, entries 1
and 2]. However, no reaction was observed when alkyl-
ethynyltrifluoroborate salt 5c was treated with 2-iodocy-
clohex-2-enone (2, Table 4, entry 3).
Table 5 Suzuki–Miyaura Cross-Coupling of Phenyltrifluoroborates
3a and 2-Iodo-2-enones 7
R
I
(1 equiv)
7
PdCl2 (5 mol%), K2CO3 (3 equiv)
+
R
1,4-dioxane–H2O, N2
80 °C
BF3K
To further investigate the scope and limitations of this
methodology, we carried out the cross-coupling of two
different a-iodoenones (7a and 7b), as summarized in
Table 5.17 Both compounds (8a and 8b) were obtained in
moderate yields.
8
(1 equiv)
3a
Entry a-Iodoenone 7
Product 8
Time Yield
(h)
(%)
In summary, we have developed an alternative synthetic
route for the synthesis of a-arylated and a-alkynylated
enones through the Suzuki–Miyaura coupling reaction of
aryltrifluoroborate salts with a-iodocyclohex-2-enone
catalyzed by palladium. Gratifyingly, almost all sub-
strates tested during our studies gave cross-coupled prod-
ucts in moderate to good yields, with a variety of
substitution patterns being tolerated.
O
O
H
N
I
H
N
1
2
65
N
N
O
O
O
Acknowledgment
O
O
O
The authors gratefully acknowledge financial support from
FAPESP (Grant 07/59404-2) and CNPq (300.613/2007-5) and
fellowships to F.V.S. and K.G. (FAPESP 07/51466-9, 09/50380-2).
O
2
1
50
O
I
Synlett 2010, No. 3, 427–432 © Thieme Stuttgart · New York

LETTER
a-Arylation and Alkynylation of Cyclic a-Iodoenones
431
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(14) General Procedure for the Cross-Coupling Reaction of
Aryltrifluoroborate Salts with 2-Iodocyclohex-2-enone
(Table 3, Entry 1)
To a round-bottomed flask containing phenyltrifluoroborate
salt (0.5 mmol), 2-iodocyclohex-2-enone (0.5 mmol),
K2CO3 (1.5 mmol), and PdCl2 (5 mol%) was added a mixture
of 1,4-dioxane (4 mL) and degassed H2O (1.0 mL). The
reaction mixture was allowed to stir at 80 °C for 5 h. After
this time, the mixture was cooled to r.t., diluted with EtOAc
(10 mL), and washed with sat. aq NH4Cl (3 × 10 mL). The
organic phase was separated, dried over MgSO4, and
concentrated under vacuum. The residue was purified by
flash chromatography on silica gel using hexane–EtOAc
(8:2) as the eluent.
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Selected Spectral and Analytical Data for 2-Phenylcyclo-
hex-2-enone (4a)
Yield 80%. 1H NMR (300 MHz, CDCl3): d = 7.28–7.40 (m,
5 H), 7.06 (t, 1 H, J = 4.1 Hz), 2.53–2.64 (m, 4 H), 2.09–2.17
(m, 2 H). 13C NMR (75 MHz, CDCl3): d = 197.9, 147.9,
140.3, 136.5, 128.5, 127.9, 127.5, 39.0, 26.5, 22.9. LRMS:
m/z (%) = 172 (100) [M+], 144 (64), 130 (26), 115 (82), 103
(16), 71 (12), 63 (14), 51 (15). IR (KBr): n = 1662, 2933,
3016 cm–1. Mp 93–94 °C (lit.13 92–93 °C).
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Alkynyltrifluoroborate Salts with 2-Iodocyclohex-2-
enone (Table 4, Entry 1)
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To a round-bottomed flask containing phenylethynyltri-
fluoroborate salt (0.5 mmol), 2-iodocyclohex-2-enone
(0.5 mmol), K2CO3 (1.5 mmol), and PdCl2 (5 mol%) was
added a mixture of 1,4-dioxane (4 mL) and degassed H2O
(1.0 mL). The reaction mixture was allowed to stir at 80 °C
for 7 h. After this time, the mixture was cooled to r.t, diluted
with EtOAc (10 mL), and washed with sat. aq NH4Cl (3 × 10
mL). The organic phase was separated, dried over MgSO4,
and concentrated under vacuum. The residue was purified by
flash chromatography on silica gel using hexane–EtOAc
(8:2) as the eluent.
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Selected Spectral and Analytical Data for 2-(Phenyl-
ethynyl)cyclohex-2-enone (6a)
Yield 73%. 1H NMR (300 MHz, CDCl3): d = 7.61–7.64 (m,
2 H), 7.24–7.38 (m, 3 H), 6.47 (t, J = 1.89 Hz, 1 H), 2.48–
2.57 (m, 2 H), 2.34–2.44 (m, 2 H), 1.89–1.98 (m, 2 H). 13
NMR (75 MHz, CDCl3): d = 171.5, 153.3, 150.7, 131.4,
128.6 (2 C), 127.2, 123.7 (2 C), 122.4, 105.6, 62.4, 32.5,
C
(13) (a) Singh, F. V.; Milagre, H. M. S.; Eberlin, M. N.; Stefani,
H. A. Tetrahedron Lett. 2009, 50, 2312. (b) Vieira, A. S.;
Ferreira, F. P.; Fiorante, P. F.; Guadagnin, R. C.; Stefani, H.
23.0, 21.0. LRMS: m/z (%) = 196 (100) [M+], 167 (44), 152
(17), 118 (19), 95 (22), 83 (27), 77 (16).
Synlett 2010, No. 3, 427–432 © Thieme Stuttgart · New York

432
K. Gueogjian et al.
LETTER
(17) General Procedure for the Cross-Coupling Reaction of
Phenyltrifluoroborate Salt with 2-Iodoen-2-ones (Table
5, Entry 1)
Selected Spectral and Analytical Data for (S)-1-Benzoyl-
2-isopropyl-5-phenyl-2,3-dihydropyrimidin-4 (1H)-one
(8a)
To a round-bottomed flask containing phenyltrifluoroborate
salt (0.5 mmol), (S)-1-benzoyl-5-iodo-2-isopropyl-2,3-
dihydropyrimidin-4 (1H)-one (0.5 mmol), K2CO3 (1.5
mmol), and PdCl2 (5 mol%) was added a mixture of 1,4-
dioxane (4 mL) and degassed H2O (1.0 mL). The reaction
mixture was allowed to stir at 80 °C for 2 h. After this time,
the mixture was cooled to r.t., diluted with EtOAc (10 mL),
and washed with sat. aq NH4Cl (3 × 10 mL). The organic
phase was separated, dried over MgSO4, and concentrated
under vacuum. The residue was purified by flash
chromatography on silica gel using hexane–EtOAc (8:2) as
the eluent.
Yield 65%. 1H NMR (300 MHz, CDCl3): d = 7.48–7.59 (m,
6 H), 7.42 (dd, J = 7.5, 1.3 Hz, 2 H), 7.27–7.34 (m, 3 H), 6.66
(d, J = 4.4 Hz, 1 H), 5.67 (s, 1 H), 2.36–2.43 (m, 1 H), 1.09
(d, J = 6.7 Hz, 3 H), 1.01 (d, J = 6.9 Hz, 3 H). 13C NMR (75
MHz, CDCl3): d = 168.4, 163.4, 134.3, 133.4, 132.9, 131.4,
128.6 (2 C), 128.2 (2 C), 128.1 (2 C), 128.0, 127.5 (2 C),
116.6, 68.9, 32.8, 18.2, 17.4. LRMS: m/z (%) = 320 (1) [M+],
277 (14), 105 (100), 89 (2), 77 (28), 51 (4), 43 (2). IR: n =
3396, 3053, 2992, 2859, 1652, 1607 cm–1. Mp 173.2–
174.8 °C.
Synlett 2010, No. 3, 427–432 © Thieme Stuttgart · New York

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