4-Aryl- and 4-vinyl-2,2-dialkyl-3-chromenes from tertiary 3-(o-bromophenyl)propynols via a palladium-catalyzed hydroarylation/ hydrovinylation-cyclization sequence

Article abstract of DOI:10.1055/s-2006-939048

4-Aryl- and 4-vinyl-2,2-dialkyl-3-chromenes were prepared from tertiary 3-(o-bromophenyl)propynols and aryl iodides or vinyl triflates through a one-pot process, which involves the addition of t-BuONa, dppf and, where appropriate, fresh Pd(OAc)₂

Full text of DOI:10.1055/s-2006-939048

LETTER
909
4-Aryl- and 4-Vinyl-2,2-Dialkyl-3-chromenes from Tertiary 3-
(o-Bromophenyl)propynols via a Palladium-Catalyzed Hydroarylation/
Hydrovinylation–Cyclization Sequence
4
-Substituted Chr
o
n
m
ene
s
from
t
3-(
o
-B
o
romophenyl)
n
propynols io Arcadi,a Sandro Cacchi,*b Giancarlo Fabrizi,b Fabio Marinelli,*a Mirella Verdecchiaa
a
Dipartimento di Chimica, Ing. Chimica e Materiali, via Vetoio, 67100 L’Aquila, Italy
b
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi ‘La Sapienza’,
P. le A. Moro 5, 00185 Rome, Italy
E-mail: sandro.cacchi@uniroma1.it; E-mail: fmarinel@univaq.it
Received 27 October 2005
eral trend towards improving the environmental accept-
ability of synthetic processes and that one of the more
convenient strategies is limiting the number of distinct
steps, we decided to investigate the development of a sim-
Abstract: 4-Aryl- and 4-vinyl-2,2-dialkyl-3-chromenes were pre-
pared from tertiary 3-(o-bromophenyl)propynols and aryl iodides or
vinyl triflates through a one-pot process, which involves the addi-
tion of t-BuONa, dppf and, where appropriate, fresh Pd(OAc)2 to
the crude mixture resulting from the hydroarylation or hydrovinyla- plified one-pot procedure, with beneficial effects on costs,
tion step [Pd(OAc)2, Et3N, HCOOH, Bu4NCl, toluene]. In general,
time, energy, raw materials, and waste.
4-aryl- and 4-vinyl-2,2-dialkyl-3-chromenes are obtained with high
regioselectivity and overall yields range from satisfactory to high.
The presence of the 2,2-dimethyl-3-chromene motif in a
variety of biologically active compounds has led to a
continuing interest in the chromene ring system.7 The 2,2-
dimethyl-3-chromene motif is commonly found in
potassium channel activators with smooth-muscle relax-
ant activity in a variety of cardiovascular and bronchopul-
monary diseases (cromakalim,8 Ro 31-6930,9 and several
other compounds with the 2,2-dimethyl-3-chromene moi-
ety have been tested10). The chromene scaffold is present
in a novel class of selective non-steroidal glucocorticoid
receptor (GR) antagonists.11 Moreover, chromenes con-
taining substituents at the C-4 position may act as potent
retinoic acid receptor a-selective antagonists12 and 4-aryl-
4H-chromenes have been recently identified as potent
apoptosis inducers.13
Vinyl triflates tend to give higher yields than aryl iodides.
Key words: chromenes, palladium catalysis, cyclization, hydro-
vinylation, hydroarylation
The palladium-catalyzed hydroarylation and hydrovinyl-
ation of disubstituted alkynes with aryl and vinyl halides
or triflates represents a valuable tool for the addition of a
carbon sp2 unit and a hydrogen to a carbon–carbon triple
bond.1 With unsymmetrical alkynes, steric and coordinat-
ing effects appear to play a major role in controlling the
regioselectivity of the process. Solvents2 and other reac-
tion parameters such as temperature, the presence or ab-
sence as well as the nature of phosphine ligands, and the
nature of the sp2 donor have also been found to influence
the regiochemical outcome. In general, the reaction is
stereoselective and overall cis-addition derivatives are
usually obtained as the main products. Therefore, the ad-
dition to alkynes with suitable nucleophilic and electro-
philic centers close to the acetylenic system can be
followed by a cyclization step. We have taken advantage
of this addition–cyclization strategy to develop new
versatile routes to substituted butenolides,3 quinolines,4
coumarins, and chromanols.5
This justifies efforts to develop new more efficient syn-
thetic procedures towards this class of compounds from
readily available starting materials by simple procedures.
Herein we report the results of this study.
Readily available tertiary 3-(o-bromophenyl)propynols 1
appeared to us particularly suited for the development of
a one-pot protocol for the preparation of chromene deriv-
atives containing 4-aryl and 4-vinyl substituents. The
whole process would proceed through a palladium-cata-
lyzed hydroarylation/hydrovinylation–cyclization, with
the cyclization step involving an intramolecular Buch-
wald–Hartwig C–O bond-forming reaction (Scheme 1).
Disubstituted alkyne 1a (R1 = R2 = Me) and 1-chloro-3-
iodobenzene 2a were selected as the model system.
Compound 1a – prepared in 93% yield by chemoselective
Sonogashira cross-coupling of commercially available
1-bromo-2-iodobenzene with 2-methyl-3-butyn-2-ol at
room temperature, in DMF, in the presence of
PdCl2(PPh3)2, CuI and i-Pr2NH as the base – was reacted
with 2.4 equivalents of 2a under conditions previously
developed by us to give regio- and stereoselectively the
hydroarylated alkene 3a (Scheme 2).
More recently, we reported the synthesis of chromene
derivatives through the hydroarylation/hydrovinylation–
cyclization of tertiary 3-(o-acetoxyaryl)- and 3-(o-ben-
zoyloxyaryl)propynols.6 Though this process gives good
overall yields with a variety of aryl iodides and vinyl trif-
lates, it requires a stepwise protocol involving the protec-
tion of the starting material, isolation of hydroarylation/
hydrovinylation products, deprotection of the phenolic
oxygen, and cyclization. Therefore, considering the gen-
SYNLETT 2006, No. 6, pp 0909–0915
0
4.
0
4.
2
0
0
6
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939048; Art ID: G00706ST
© Georg Thieme Verlag Stuttgart · New York

910
A. Arcadi et al.
LETTER
R3
Pd(OAc)2 (0.05 equiv)
R2
R1
Bu3N (3.6 equiv)
HCOOH (2.6 equiv)
Bu4NCl (1 equiv)
R2
Pd cat.
Me
OH
Cl
R1
+
R3X
HO
Me
+
Br
OH
3
R3
THF (5 mL)
60 °C, 7 h
65%
Br
2
1
Br
I
2a
1a
Cl
Pd cat.
Cl
R2
R1
O
Pd(OAc)2 (0.05 equiv)
dppf (0.05 equiv)
4
NaOt-Bu (2 equiv)
Scheme 1
Me
Me
OH
Me
toluene (2.5 mL)
110 °C, 6 h
O
Me
Br
3a
Compound 3a was isolated as a single isomer. Its stereo-
chemistry (Z; cis adduct) and regiochemistry are in agree-
ment with our previous studies1 and were assigned by
NOESY experiments. Compound 3a (0.29 mmol) was
next converted to the corresponding chromene derivative
4a under the conditions developed by Buchwald et al.14
for intramolecular C–O bond formation (Scheme 2).
4a (79%)
Scheme 2
This procedure, which omits the isolation of addition
products, was extended to include other substrates
(Table 1). Two different procedures were used for the hy-
droarylation/hydrovinylation step; Procedure A15 (applied
to aryl iodides): Pd(OAc)2, Bu3N, HCOOH, Bu4NCl,
THF, 60 °C and Procedure B16 (applied to vinyl triflates):
Pd(OAc)2, HCOOK, DMF, 40 °C.
Subsequently, we found that 4a could be conveniently
prepared through a process in which the cyclization step
is carried out on the crude mixture resulting from the hy-
droarylation step, after extraction and evaporation of the
solvent. Using this procedure, 4a was isolated in a slightly
higher overall yield (56%) than that obtained via the step-
wise protocol (51%).
Table 1 Palladium-Catalyzed Synthesis of 4-Aryl- and 4-Vinyl-2,2-dialkyl-3-chromenes 4a
Entry Alkyne 1
R3X 2
Procedure Time (h)b Chromene 4
Yield (%)c
Cl
Me
OH
Cl
Me
1
1a
1a
1a
1a
2a
2b
2c
2d
A
A
B
B
7 (6)
16 (7)
19 (22)
17 (5)
4a 56
I
Br
Me
Me
O
COMe
2
3
4
4b 57
MeOC
I
Me
Me
O
OMe
OMe
4c
40
OTf
Me
Me
O
Ph
4d 40
Ph
OTf
Me
Me
O
Synlett 2006, No. 6, 909–915 © Thieme Stuttgart · New York

LETTER
4-Substituted Chromenes from 3-(o-Bromophenyl)propynols
911
Yield (%)c
50
Table 1 Palladium-Catalyzed Synthesis of 4-Aryl- and 4-Vinyl-2,2-dialkyl-3-chromenes 4a (continued)
Entry Alkyne 1
R3X 2
Procedure Time (h)b Chromene 4
CF3
F3C
6
1b
1b
2e
2f
A
A
40 (15)
4e
4f
I
HO
Br
O
F
F
5
6
25 (9)
58
I
O
Cl
1b
2g
A
A
3 (16)
4g 55
Cl
I
O
NHCOMe
7
1b
2h
20 (24)
4h 77
MeOCHN
I
O
a All reactions were conducted under a nitrogen atmosphere. Procedure A (aryl iodides): 1 (1 equiv), 2 (2.4 equiv), Bu3N (3.6 equiv), HCOOH
(2.6 equiv), Bu4NCl (1 equiv), Pd(OAc)2 (0.05 equiv), THF, 60 °C, work-up, then t-BuONa (2 equiv), Pd(OAc)2 (0.05 equiv), dppf (0.05 equiv),
toluene, 110 °C. Procedure B (vinyl triflates): 1 (1.2 equiv), 2 (1 equiv), HCOOK (2 equiv), Pd(OAc)2 (0.05 equiv), DMF, 40 °C, work-up, then
as for procedure A.
b Figures in parentheses refer to the cyclization step.
c Overall isolated yields for isolated products.
Though the results shown in Table 1 were interesting, pro-
COMe
viding distinct advantages over our previous procedure,6
to simplify further the synthetic protocol, we attempted
5
Br
the preparation of chromenes 4 from 1 through a pseudo-
domino process17 which would avoid the work-up step.
Figure 1
However, under the best hydroarylation conditions devel-
oped, no cyclization products were observed with our Therefore, we decided to return to the procedure requiring
model system even with prolonged reaction times or in- a work-up between the two transformations with the task
creasing the temperature after completion of the hy- of making it more attractive synthetically by omitting the
droarylation step. Even attempts to combine cyclization work-up step. After some experimentation we were
with hydroarylation conditions met with failure, for exam- pleased to find that the reaction of 1a with 2 equivalents
ple, when 1a was treated with 2 equivalents of p-iodoace- of p-iodoacetophenone 2b, 3 equivalents of Et3N, 2 equiv-
tophenone, 2 equivalents of HCOOK, 2 equivalents of t- alents of HCOOH, and 0.025 equivalents of Pd(OAc)2 in
BuONa, 0.05 equivalents of Pd(OAc)2, 0.05 equivalents
of dppf in toluene at 110 °C for 18 hours, no evidence of
toluene at 60 °C for 16 hours, in the absence of phosphine
ligands,19 resulted in the formation of the hydroarylation
the chromene product was observed, the main product be- product with almost complete conversion of the starting
ing the diarylalkyne 5 (formed via removal of the alcohol alkyne and that the direct addition of 4 equivalents of t-
group as acetone followed by a coupling reaction)18 in BuONa, 0.025 equivalents of Pd(OAc)2, and 0.05 equiv of
36% isolated yield. It is very likely that incompatibilities dppf to the reaction mixture (without work-up) led to the
between the two mechanistically unrelated catalytic cy- isolation of 4b in 57% overall yield after 6 hours at
cles prevent any pseudo-domino process.
110 °C.
Synlett 2006, No. 6, 909–915 © Thieme Stuttgart · New York

912
A. Arcadi et al.
LETTER
Control experiments were performed to evaluate the ef- 45% yield). Higher catalyst loading in both the hydroaryl-
fectiveness of this protocol and some of the more signifi- ation and cyclization steps did not improve the yield sig-
cant results are as follows. The presence of dppf was nificantly (Table 2, entry 2). Omitting the addition of
found to hamper the hydroarylation step. Indeed, the hy- fresh Pd(OAc)2 in the cyclization step led to the isolation
droarylation derivative, 3b, was isolated in only 42% of chromene 4b in low yield (Table 2, entry 3), most like-
yield when the hydroarylation of 1a with 2b was carried ly due to the irreversible precipitation of the majority of
out using 3 equivalents of Et3N, 2 equivalents of HCOOH, the catalyst during hydroarylation.
0.05 equivalents of Pd(OAc)2, and 0.05 equivalents of
dppf in toluene at 60 °C for 24 hours (1a was recovered in
Table 2 Palladium-Catalyzed One-Pot Synthesis of 4-Aryl- and 4-Vinyl-2,2-dialkyl-3-chromenes 4a
Entry Alkyne
R3X
Bu4NCl (equiv) Pd
Pd
Time (h)b Chromene 4
Yield (%)c
1st step (equiv) 2nd step (equiv)
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
1a
2b
2b
2b
2b
2a
2a
2e
–
–
–
1
1
–
1
0.025
0.05
0.05
0.05
0.05
0.025
0.05
0.025
16 (7)
16 (24)
16 (7)
16 (7)
4b
4b
4b
4b
57
59
17
57
51
56
60
0.05
–
–
–
5.5 (27) 4a
0.025
–
24 (24)
7 (25)
4a
CF3
Me
Me
O
4i
8
9
1b
1b
1b
1b
1b
1b
1b
2e
2e
2e
2f
1
–
1
1
1
1
1
1
0.05
–
8 (15)
44 (22)
18 (6)
48 (28)
6 (15)
23 (4)
8 (15)
24 (7)
4e
4e
4e
4f
24
50
49
46
57
16
77
50
0.025
0.025
0.025
0.025
0.05
0.025
0.025
0.025
0.025
–
10
11
12
13
14
15
2g
2g
2h
2f
4g
4g
4h
0.025
0.025
0.025
0.025
Me
OH
Et
F
Br
1c
Me
Et
O
4j
d
16
17
18
19
20
1b
1a
1a
1a
1a
2f
–
1
–
1
1
0.025
0.05
0.025
–
16 (–)
–
2c
2c
2d
2d
5.5 (18) 4c
71
e
0.025
0.05
0.025
–
24 (–)
–
4 (17)
4 (42)
4d
4d
23
60
0.025
0.025
Synlett 2006, No. 6, 909–915 © Thieme Stuttgart · New York

LETTER
4-Substituted Chromenes from 3-(o-Bromophenyl)propynols
913
Table 2 Palladium-Catalyzed One-Pot Synthesis of 4-Aryl- and 4-Vinyl-2,2-dialkyl-3-chromenes 4a (continued)
Entry Alkyne
R3X
Bu4NCl (equiv) Pd
Pd
Time (h)b Chromene 4
Yield (%)c
85
1st step (equiv) 2nd step (equiv)
21
22
23
1a
1a
1b
1
1
1
0.025
0.025
0.025
0.025
0.025
0.025
7 (16)
7 (16)
6 (15)
4i
t-Bu
OTf
2i
2i
4j
4k
82
81
OTf
2j
Me
Me
Me
OTf
Me
2k
a All reactions were run under a nitrogen atmosphere. Reagents and conditions: Pd(OAc)2 (0.025 or 0.05 equiv), Et3N (3 equiv), HCOOH (2
equiv), Bu4NCl (0 or 1 equiv), alkyne and aryl iodide (1 equiv and 2 equiv; 60 °C) or alkyne and vinyl triflate (1.2 equiv and 1 equiv; 50 °C);
then, Pd(OAc)2 (0 or 0.025 equiv), dppf (0.05 equiv), and NaOt-Bu (4 equiv) were added and the temperature was increased to 110 °C.
b Figures in parentheses refer to the reaction time of the cyclization step.
c Overall yields given for isolated products.
d No hydroarylation product was observed and 1c was recovered in 70% yield.
e No hydrovinylation product was observed and 1a was recovered in 84% yield.
Since chloride anions are reported to have a beneficial hydrovinylation step followed by an intramolecular C–O
effect on palladium-catalyzed reactions,20 stabilizing low- bond-forming reaction] and can be conducted as a one-pot
ligated palladium(0) species,21 the hydroarylation–cy- process, simply adding NaOt-Bu and dppf and, where
clization sequence was attempted in the presence of one appropriate, fresh Pd(OAc)2 to the crude mixture resulting
equivalent of Bu4NCl without further addition of from the hydroarylation/hydrovinylation step. In general,
Pd(OAc)2. Only NaOt-Bu and dppf were added to the 4-substituted 2,2-dialkyl-3-chromenes are obtained with
crude mixture resulting from the hydroarylation step. Un- high regioselectivity and overall yields range from satis-
der these conditions, 4b was isolated in 57% yield factory to high. Vinyl triflates tend to give higher yields
(Table 2, entry 4).
then aryl iodides.
This procedure appeared particularly convenient and was
extended to other substrates. However, it was found to
give satisfactory results in some cases (Table 2, entries 4,
5, 7 and 17) but to be ineffective in others (Table 2, entries
8 and 13).
Acknowledgment
Work carried out in the framework of the National Project ‘Stereo-
selezione in Sintesi Organica. Metodologie e Applicazioni’ suppor-
ted by the Ministero dell’Università e della Ricerca Scientifica e
Tecnologica and by the University ‘La Sapienza’.
Even when Bu4NCl was omitted and fresh Pd(OAc)2
(along with NaOt-Bu and dppf) were added after comple-
tion of the hydroarylation step, chromene products were
isolated in good yields in some cases (Table 2, entries 1,
2, 6, and 9) and in poor yields in others (Table 2, entries
16 and 18).
References and Notes
(1) Cacchi, S.; Fabrizi, G. In Handbook of Organopalladium
Chemistry for Organic Synthesis, Vol. 1; Negishi, E., Ed.;
John Wiley & Sons: New York, 2002, 1335–1360.
(2) Cacchi, S.; Fabrizi, G.; Goggiamani, A. J. Mol. Catal. A:
Chem. 2004, 214, 57.
(3) (a) Arcadi, A.; Bernocchi, E.; Burini, A.; Cacchi, S.;
Marinelli, F.; Pietroni, B. Tetrahedron 1988, 44, 481.
(b) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Pace, P.
Eur. J. Org. Chem. 1999, 3305. (c) Arcadi, A.; Bernocchi,
E.; Burini, A.; Cacchi, S.; Marinelli, F.; Pietroni, B.
Tetrahedron Lett. 1989, 30, 3465.
Eventually, it appears that the most general procedure re-
quires the presence of Bu4NCl and the addition of fresh
Pd(OAc)2, NaOt-Bu, and dppf in the second step.22 Some
of the results obtained by this procedure are shown in
Table 2; clearly, there is room for further optimization.
In conclusion, we have demonstrated that tertiary 3-(o-
bromophenyl)propynols can be useful precursors for the
preparation of 4-aryl- and 4-vinyl-2,2-dialkyl-3-
chromenes. The synthesis, which can provide a new ver-
satile entry into this class of compounds, involves two un-
related palladium-catalyzed reactions [a hydroarylation or
(4) (a) Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P.
Tetrahedron 1996, 52, 10225. (b) Cacchi, S.; Fabrizi, G.;
Goggiamani, A.; Moreno-Mañas, M.; Vallribera, A.
Tetrahedron Lett. 2002, 43, 5537.
Synlett 2006, No. 6, 909–915 © Thieme Stuttgart · New York

914
A. Arcadi et al.
LETTER
(15) Hydroarylation/Hydrovinylation–Cyclization of 1;
(5) Cacchi, S.; Fabrizi, G.; Moro, L.; Pace, P. Synlett 1997,
1367.
Procedure A
(6) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Pace, P.
Eur. J. Org. Chem. 2000, 4099.
To a stirred solution of 1a (0.160 g, 0.67 mmol) and 2b
(0.395 g, 1.61 mmol) in THF (5 mL) were added Bu3N
(0.572 mL, 2.41 mmol), BuN4Cl (0.198 g, 0.67 mmol), and
Pd(OAc)2 (0.008 g, 0.035 mmol). The solution was stirred
under nitrogen for 3 min. Then, HCOOH (0.066 mL, 1.74
mmol) was added. The reaction mixture was stirred at 60 °C
under nitrogen for 24 h, then cooled, and extracted with 0.1
M HCl (100 mL) and Et2O (3 × 50 mL). The combined
organic layers were washed with 5% NaHCO3 (30 mL),
dried over Na2SO4, and concentrated under reduced
pressure. The residue was dissolved in toluene (5 mL),
Pd(OAc)2 (0.008 g, 0.035 mmol), dppf (0.019 g, 0.035
mmol), and t-BuONa (0.129 g, 1.34 mmol) were added and
the reaction mixture was stirred at 110 °C under nitrogen for
16 h. After cooling, the mixture was extracted with 0.5 M
NH4Cl (100 mL) and EtOAc (3 × 50 mL). The combined
organic layers were dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by
chromatography (silica gel; n-hexane–EtOAc, 98:2) to give
4b (0.117 g, 61%); mp 113–115 °C. IR (KBr): 1690, 1610,
1270 cm–1. 1H NMR (CDCl3): d = 7.99 (d, J = 8.4 Hz, 2 H),
7.45 (d, J = 8.4 Hz, 2 H), 7.21–7.13 (m, 1 H), 6.97–6.78 (m,
3 H), 5.67 (s, 1 H), 2.63 (s, 3 H), 1.50 (s, 6 H). 13C NMR
(CDCl3): d = 197.7, 153.3, 143.3, 136.3, 134.1, 130.0, 129.5,
128.9, 128.4, 128.3, 125.3, 120.7, 117.1, 75.7, 27.5, 26.7.
EI-MS: m/z (%) = 263 (100) [M+ – CH3].
(7) For some recent references, see: (a) Goujon, J.-Y.;
Zammatio, F.; Chrétien, J.-M.; Beaudet, I. Tetrahedron
2004, 60, 4037. (b) Kidwai, M.; Saxena, S.; Khan, M. K. R.;
Thukral, S. S. Bioorg. Med. Chem. Lett. 2005, 15, 4295.
(c) Youn, S. W.; Eom, J. I. Org. Lett. 2005, 7, 3355.
(d) Shi, Y. L.; Shi, M. Org. Lett. 2005, 7, 3057. (e)Nevado,
C.; Echavarren, A. M. Chem. Eur. J. 2005, 11, 3155.
(f) Lee, Y. R.; Choi, J. H.; Yoon, S. H. Tetrahedron Lett.
2005, 46, 7539. (g) van Otterlo, W.; Ngidi, E. L.; Kuzvidza,
S.; Morgans, G. L.; Moleele, S. S.; de Koning, C. B.
Tetrahedron 2005, 61, 9996. (h) Zhao, G. L.; Shi, Y. L.; Shi,
M. Org. Lett. 2005, 7, 4527.
(8) Evans, J. M.; Stemp, G. Chem. Ber. 1991, 27, 439.
(9) (a) Attwood, M. R.; Jones, P. S.; Paciorek, P. B.; Redshaw,
S. Life Sci. 1991, 48, 803. (b) Attwood, M. R.; Churcher, I.;
Dunsdon, R. M.; Hurst, D. N.; Jones, P. S. Tetrahedron Lett.
1991, 32, 811.
(10) See, for example: (a) Buckle, D. R.; Arch, J. R. S.; Fenwick,
A. E.; Houge-Frydrych, C. S. V.; Pinto, I. L.; Smith, D. G.;
Taylor, S. G.; Tedder, J. M. J. Med. Chem. 1990, 33, 3028.
(b) Bergmann, R.; Eiermann, V.; Gericke, R. J. Med. Chem.
1990, 33, 2759. (c) Bergmann, R.; Gericke, R. J. Med:
Chem. 1990, 33, 492. (d) Gericke, R.; Harting, G.; Lues, I.;
Shittenhelm, C. J. Med. Chem. 1991, 34, 3074. (e) Cassidy,
F.; Evans, J. M.; Hadley, M. S.; Haladij, A. H.; Leach, P. E.;
Stemp, G. J. Med. Chem. 1992, 35, 1623. (f) Satoh, Y.;
Stanton, J. L.; Hutchison, A. J.; Libby, A. H.; Kowalsky, T.
J.; Lee, W. H.; White, D. H.; Kimble, E. F. J. Med. Chem.
1993, 36, 3580. (g) Atwal, K. S.; Grover, G. J.; Ahmed, S.
Z.; Ferrara, F. N.; Harper, T. W.; Kim, K. S.; Sleph, P. G.;
Dzwonczyk, S.; Russel, A. D.; Moreland, S.; McCullough, J.
R.; Normandin, D. E. J. Med. Chem. 1993, 36, 3971.
(11) Akritopoulou-Zanze, I.; Patel, J. R.; Hartandi, K.;
Brenneman, J.; Winn, M.; Pratt, J. K.; Grynfarb, M.; Goos-
Nisson, A.; Von Geldern, T. W.; Kym, P. R. Bioorg. Med.
Chem. Lett. 2004, 14, 2079.
(16) One-Pot Hydroarylation/Hydrovinylation–Cyclization
of 1; Procedure B
To a stirred solution of 1a (0.143 g, 0.60 mmol) and 2d
(0.153 g, 0.50 mmol) in DMF (2 mL) were added Pd(OAc)2
(0.006 g, 0.026 mmol) and HCOOK (0.084 g, 1.00 mmol).
The reaction mixture was stirred at 40 °C under nitrogen for
17 h, then cooled, and extracted with 5% NaHCO3 (100 mL)
and Et2O (3 × 50 mL). The combined organic layers were
dried over Na2SO4 and concentrated under reduced pressure.
The residue was dissolved in toluene (5 mL), Pd(OAc)2
(0.006 g, 0.026 mmol), dppf (0.014 g, 0.026 mmol), and
t-BuONa (0.096 g, 1.00 mmol) were added and the reaction
mixture was stirred at 110 °C under nitrogen for 5 h. After
cooling, the mixture was extracted with 0.5 M NH4Cl (100
mL) and EtOAc (3 × 50 mL). The combined organic layers
were dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by chromatography
(silica gel; n-hexane–EtOAc, 99:1) to give 4d (0.063 g,
40%); mp 55–57 °C. IR (KBr): 1610, 1480, 1450, 1260
cm–1. 1H NMR (CDCl3): d = 7.32–7.07 (m, 7 H), 6.90–6.81
(m, 2 H), 5.83 (br s, 1 H), 5.47 (s, 1 H), 2.95–2.80 (m, 1 H),
2.38–1.80 (m, 6 H), 1.42 (s, 3 H), 1.40 (s, 3 H). 13C NMR
(CDCl3): d = 153.3, 146.8, 136.3, 135.5, 128.8, 128.4, 126.8,
126.5, 126.3, 126.1, 125.2, 121.9, 120.5, 116.9, 75.5, 39.8,
33.6, 30.0, 29.2, 27.6, 27.5. EI-MS: m/z (%) = 316 (2) [M+],
301 (100) [M+ – CH3].
(12) Teng, M.; Duong, T. T.; Johnson, A. T.; Klein, E. S.; Wang,
L.; Khalifa, B.; Chandraratna, R. A. S. J. Med. Chem. 1997,
40, 2445.
(13) (a) Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Wang,
Y.; Zhao, J.; Jia, S.; Herich, J.; Labreque, D.; Storer, R.;
Meerovitch, K.; Bouffard, D.; Rej, R.; Denis, R.; Blais, C.;
Lamothe, S.; Attardo, G.; Gourdeau, H.; Tseng, B.;
Kasibhatla, S.; Xiong Cai, S. J. Med. Chem. 2004, 47, 6299.
(b) Kasibhatla, S.; Gourdeau, H.; Meerovitch, K.; Drewe, J.;
Reddy, S.; Qiu, L.; Zhang, H.; Bergeron, F.; Bouffard, D.;
Yang, O.; Herich, J.; Lamothe, S.; Xiong Cai, S.; Tseng, B.
Mol. Cancer Ther. 2004, 11, 1365. (c) Gordeau, H.;
Leblond, L.; Hamelin, B.; Desputeau, C.; Dong, K.;
Kianicka, I.; Custeau, D.; Boudreau, C.; Geerts, L.; Xiong
Cai, S.; Drewe, J.; Labreque, D.; Kasibhatla, S.; Tseng, B.
Mol. Cancer Ther. 2004, 11, 1375. (d) Kemnitzer, W.;
Kasibhatla, S.; Songchun Jiang, S.; Zhang, H.; Zhao, J.; Jia,
S.; Xu, L.; Crogan-Grundy, C.; Denis, R.; Barriault, N.;
Vaillancourt, L.; Charron, S.; Dodd, J.; Attardo, G.;
Labrecque, D.; Lamothe, S.; Gourdeau, H.; Tseng, B.;
Drewea, J.; Caia, S. X. Bioorg. Med. Chem. Lett. 2005, 15,
4745.
(17) Poli, G.; Giambastiani, G. J. Org. Chem. 2002, 67, 9456.
(18) Carpita, A.; Lessi, A.; Rossi, R. Synthesis 1984, 571.
(19) Ahlquist, M.; Fabrizi, G.; Cacchi, S.; Norrby, P.-O. Chem.
Commun. 2005, 4196.
(20) Fagnou, K.; Lautens, M. Angew. Chem. Int. Ed. 2002, 41, 26.
(21) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314.
(22) One-Pot Synthesis of Chromenes without Work-up after
Hydroarylation/Hydrovinylation
(14) (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1996, 118, 10333. (b) Kuwabe, S.-i.; Torraca, K. E.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 12202.
To a stirred solution of 1a (0.161 g, 0.67 mmol) and 2j
(0.145 g, 0.56 mmol) in toluene (3 mL) were added Et3N
(0.234 mL, 1.68 mmol), BuN4Cl (0.166 g, 0.56 mmol), and
Pd(OAc)2 (0.003 g, 0.014 mmol). The solution was stirred
under nitrogen for 5 min and then HCOOH (0.042 mL, 1.12
Synlett 2006, No. 6, 909–915 © Thieme Stuttgart · New York

LETTER
4-Substituted Chromenes from 3-(o-Bromophenyl)propynols
915
mmol) was added. The reaction mixture was stirred at 50 °C
chromatography (silica gel; n-hexane–EtOAc, 99:1) to give
4j (0.124 g, 82%) as an oil. IR: 1630, 1500, 1470, 1280
cm–1. 1H NMR (CDCl3): d = 7.08–7.01 (m, 2 H), 6.85–6.78
(m, 2 H), 5.68 (t, J = 8.2 Hz, 1 H), 5.39 (s, 1 H), 2.34–2.21
(m, 4 H), 1.60–1.44 (m, 8 H), 1.41 (s, 6 H). 13C NMR
(CDCl3): d = 153.3, 139.0, 136.6, 129.5, 128.7, 127.0, 126.9,
125.4, 120.4, 116.7, 75.6, 29.9, 28.6, 28.4, 27.8, 26.6, 26.3.
EI-MS: m/z (%) = 268 (7) [M+], 253 (100) [M+ – CH3].
under nitrogen for 7 h, then Pd(OAc)2 (0.003 g, 0.014
mmol), dppf (0.016 g, 0.029 mmol), and NaOt-Bu (0.216 g,
2.25 mmol) were added, the temperature was raised to
110 °C and the reaction mixture was stirred under nitrogen
for 16 h. After cooling, the mixture was extracted with 0.5 M
NH4Cl (100 mL) and EtOAc (3 × 50 mL). The combined
organic layers were dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by
Synlett 2006, No. 6, 909–915 © Thieme Stuttgart · New York