Efficient assembly of chromone skeleton from 2,3-allenoic acids and benzynes

Article abstract of DOI:10.1021/ol202076c

Chromone derivatives were synthesized from 2,3-allenoic acids and benzynes in moderate to excellent yields under mild conditions. Instead of the cyclic conjugate addition of the intermediate A formed by the nucleophilic addition of allenoic acid with benz

Full text of DOI:10.1021/ol202076c

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5196–5199
Efficient Assembly of Chromone Skeleton
from 2,3-Allenoic Acids and Benzynes
Guobi Chai, Youai Qiu, Chunling Fu, and Shengming Ma*
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry,
Zhejiang University, Hangzhou 310027, Zhejiang, P. R. China
masm@sioc.ac.cn
Received July 31, 2011
ABSTRACT
Chromone derivatives were synthesized from 2,3-allenoic acids and benzynes in moderate to excellent yields under mild conditions. Instead of the
cyclic conjugate addition of the intermediate A formed by the nucleophilic addition of allenoic acid with benzyne, this intermediate undergoes 1,2-
addition with the carbonyl group, which was followed by the ring opening, conjugate addition, and protonolysis to afford chromone derivatives.
This protocol allows the diversity due to the substituent-loading capability of 2,3-allenoic acids as well as benzynes.
Chromones and their derivatives are a class of com-
pounds existing widely in nature, and much attention has
been paid to this class of compounds due to their biological
and pharmacological activities.1 They could serve as anti-
bacterial, antifungal, anticancer, antioxidant, and anti-
HIV agents2 and have been considered as privileged struc-
tures in drug development.3 Although synthetic approaches
to this family of compounds have been extensively inves-
tigated in the past decades,4 general protocols for the
synthesis of polysubstituted chromones with diversified
functionality under mild conditions are still highly desir-
able for further study in this area. Herein we wish to report
an efficient assembly of a chromone sekleton from 2,
3-allenoic acids and benzynes under mild conditions in
moderate to excellent yields.
diversified compounds such as β,γ-unsaturated alkenoates,5aÀc
5-benzylidenecyclohex-2-enones,5d allenols,5e naphthols,5f
and cyclobutenones5g depending on the nature of sub-
strates, nucleophiles, and conditions applied, showing the
diversified reactivities of 2,3-allenoates toward nucleophiles.
On the other hand, benzynes have been proven to be very
useful in the construction of benzo-fused rings since the
formal insertion of benzynes into carbonÀcarbon, carbonÀ
heteroatom, and heteroatomÀhydrogen bonds by accept-
ing a nucleophilic attack has been extensively studied in
recent years.6 These results encouraged us to investigate
the reaction of allenoic acids with benzynes, since the intra-
molecular Michael addition of allenoate-type intermediate
A generated from 2,3-allenoic acids with benzynes would
be a convenient way to synthesize diversified coumarin
products due to the substituent-loading capability of 2,
3-allenoic acids as well as benzynes (Scheme 1). On the
In our recent reports, the nucleophilic addition reactions
of organometallic reagents with 2,3-allenoates afforded
(1) (a) Ellis, G. P., Ed. Chromenes, chromanones, and chromones;
Wiley: New York, 1977. (b) Saengchantara, S. T.; Wallace, T. W. Nat. Prod.
Rep. 1986, 465. (c) Houghton, P. J. Stud. Nat. Prod. Chem. 2000, 21, 123.
(2) For reviews, see: (a) Edwards, A. M.; Howell, J. B. L. Clin. Exp.
Allergy 2000, 30, 756. (b) Havsteen, B. H. Pharmacol. Ther. 2002, 96, 67.
(c) Kim, H. P.; Son, K. H.; Chang, H. W.; Kang, S. S. J. Pharmacol. Sci.
2004, 96, 229. (d) Kosmider, B.; Osiecka, R. Drug Dev. Res. 2004, 63,
200. (e) Grazul, M.; Budzisz, E. Coord. Chem. Rev. 2009, 253, 2588.
(3) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893.
(5) (a) Lu, Z.; Chai, G.; Ma, S. J. Am. Chem. Soc. 2007, 129,
14546. (b) Lu, Z.; Chai, G.; Zhang, X.; Ma, S. Org. Lett. 2008, 10,
3517. (c) Chai, G.; Lu, Z.; Fu, C.; Ma, S. Adv. Synth. Catal. 2009,
351, 1946. (d) Lu, Z.; Chai, G.; Ma, S. Angew. Chem., Int. Ed. 2008,
47, 6045. (e) Chen, B.; Lu, Z.; Chai, G.; Fu, C.; Ma, S. J. Org. Chem.
2008, 73, 9486. (f) Chai, G.; Lu, Z.; Fu, C.; Ma, S. Chem.;Eur. J.
2009, 15, 11083. (g) Chai, G.; Wu, S.; Fu, C.; Ma, S. J. Am. Chem.
Soc. 2011, 133, 3740.
(6) For reviews, see: (a) Sanz, R. Org. Prep. Proced. Int. 2008, 40, 215.
~
ꢀ
ꢀ
(4) Li, N.-G.; Shi, Z.-H.; Tang, Y.-P.; Ma, H.-Y.; Yang, J.-P.; Li,
B.-Q.; Wang, Z.-J.; Song, S.-L.; Duan, J.-A. J. Heterocycl. Chem. 2010,
47, 785.
(b) Pena, D.; Perez, D.; Guitian, E. Angew. Chem., Int. Ed. 2006, 45,
3579. (c) Wenk, H. H.; Winkler, M.; Sander, W. Angew. Chem., Int. Ed.
2003, 42, 502.
r
10.1021/ol202076c
Published on Web 09/14/2011
2011 American Chemical Society

Scheme 1
other hand, it should be noted that Larock et al. reported
the reaction of alkynoic (or alkenoic) acids with arynes.7
Figure 1. ORTEP representation of 3aa.
The formation of 3aa could be explained as follows
(Scheme 2): nucleophilic addition of allenoic acid 1a to
the benzyne would form aryl anion intermediate A1.
Instead of the intramolecular Michael addition to form
coumarin shown in Scheme 1, intermediate A1 undergoes
rearrangement to form o-(1-oxo-2,3-allenyl)phenoxide C1
via cyclic 1,2-addition with the carbonyl group forming B1
and the subsequent four-membered ring-opening process.6,7
Intramolecular oxa-Michael addition of intermediate C1
affords bicyclic intermediate D1, which upon subsequent
hydrolysis would afford chromone 3aa as the final product.
Table 1. Optimization of the Reaction Conditionsa
yieldb (%)
additive
(equiv)
temp
entry solvent
(°C)
3aa 4aa 1a
1
CH3CN CsF (4)
rt
17
82
84
88
95
0
33
9
0
0
2
THF
THF
THF
THF
THF
THF
THF
KF/18-crown-6 (2)
KF/18-crown-6 (2)
KF/18-crown-6 (2)
KF/18-crown-6 (2)
KF (2)
rt
3
40
60
80
80
80
80
80
80
80
80
80
80
80
5
0
4
0
0
Scheme 2
5
0
0
6c
7c
8d,e
9
0
51
0
KF/18-crown-6 (1.5)
KF/18-crown-6 (2)
88
88
37
15
76
76
49
51
5
0
0
0
dioxane KF/18-crown-6 (2)
CH3CN KF/18-crown-6 (2)
toluene KF/18-crown-6 (2)
10
0
0
10
11
12
13
14
15
0
0
0
f
KF/18-crown-6 (2)
0
0
THF
THF
THF
CsF (2)
11
0
14
0
TBAT (2)
TBAF (2)
0
7
a The reaction was conducted with 0.2 mmol of 2,3-allenoic acid, 1.5
equiv of benzyne precusor, and additives in 2 mL of solvent. b Deter-
mined by 1H NMR of crude product using dibromomethane as internal
standard. c The reaction time was 18 h. d The reaction time was 17 h. e 1.2
equiv of precursor 2a were used. f 2-Methyltetrahydrofuran was used as
solvent.
Our initial effort focused on the use of 2-(trimethylsilyl)-
phenyl triflate 2a as a benzyne precusor and 2-methyl-4-
phenyl-2,3-butadienoic acid 1a as a reaction partner in
CH3CN in the presence of CsF. However, instead of the
expected coumarin product, the 2,3-allenoic acid phenyl
ester 4aa was formed as the major product in 33% yield
along with an unexpected new product 3aa in 17% yield
(entry 1, Table 1), which was confirmed to have a chro-
mone skeleton instead of coumarin through careful NMR
spectroscopy, MS, and X-ray diffraction analysis (Figure 1).8
Aftersometrialsand errors, wewerepleased to findthat,
in the presence of KF and 18-crown-6,9 the reaction of 1a
with 2a in THF at room temperature could afford 3aa in
(8) Crystal data for compound 3aa: C17H14O2, MW = 250.28, Mono-
clinic, space group C2/c, Final R indices [I > 2σ(I)], R1 = 0.0372, wR2 =
˚
0.0906, R indices (all data) R1 = 0.0462, wR2 = 0.0961, a = 15.3311(5) A,
o
˚
˚
b = 8.9614(2) A, c = 18.9054(6) A, R = 90°, β = 103.569(4) , γ = 90°,
V = 2524.88(14) A , T = 293(2) K, Z = 8, reflections collected/unique:
3
˚
5765/2315 (Rint = 0.0181), number of observations [>2σ(I)] 1925,
parameters: 173. CCDC 833186.
(9) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211.
(7) Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2010, 12, 3117.
Org. Lett., Vol. 13, No. 19, 2011
5197

82% yield (entry 2, Table 1). Further screening of the
temperature effect revealed that the formation of bypro-
duct 4a could be suppressed at higher temperature and
the yield of 3aa could be further improved to 95% when
the reaction was conducted at 80 °C in a closed vial
(entries 3À5, Table 1). In the absence of 18-crown-6, the
starting material 1a was recovered (entry 6, Table 1).
Reducing the amounts of either KF/18-crown-6 or benzyne
precursor 2a led to lower yields (entries 7 and 8). We tried
to use other solvents with higher boiling points such as 1,4-
dioxane, CH3CN, toluene, and 2-methyltetrahydrofuran
to avoid the use of a pressure vessel; however, lower yields
were observed (entries 9À12, Table 1). The use of another
FÀ source in THF also failed to give better results (entries
13À15, Table 1). Therefore, we defined the reaction of 2,
3-allenoic acid with 1.5 equiv of benzyne precursor in the
presence of 2 equiv of KF/18-crown-6 in THF at 80 °C as
the standard reaction conditions (entry 5, Table 1).
Table 3. Reaction of Substituted Benzyne Precursorsa
Table 2. Reaction of Different Allenoic Acids with Benzyne
Precursor 2aa
1
a The reaction conditions: 0.4 mmol of allenoic acid, 1.5 equiv of
benzyne precursor, and 2.0 equiv of KF/18-crown-6 in 4 mL of THF
were heated in a sealed pressure vessel at 80 °C for 12 h. b Isolated yield.
c 2,3-Allenoic acid aryl ester 4hb was also isolated in a yield of 9%.
entry
R1
R2
R3
yield of 3 (%)b
1
Ph
H
Me (1a)
Me (1b)
Me (1c)
Me (1d)
Pr (1e)
Pr (1f)
3aa (88)
3ba (90)
3ca (76)
3da (78)
3ea (92)
3fa (75)
3ga (89)
3ha (89)
3ia (90)
3ja (92)
3ka (70)
3la (75)
3ma (60)
3na (80)
3aa (91)
2
p-MeC6H4
p-BrC6H4
p-ClC6H4
Ph
H
3
H
4
H
76% and 78% yields, respectively (entries 3 and 4, Table 2).
The reaction can be easily conducted on a scale of 6 mmol of
1a (1.0480 g) in a slightly higher yield (entry 15, Table 2).
In addition to simple benzyne precursor 2a, disubsti-
tuted benzyne precursor 2b may also be used to afford
chromones 3ab and 3hb in good yields (entries 1 and 2,
Table 3). It should be noted that when 3-MeO-substituted
benzyne precursor 2c was utilized, single regioisomers of
corresponding chromones 3ac and 3jc were formed exclu-
sively in excellent yields (entries 3 and 4, Table 3). The
regioselectivity observed here can be rationalized in terms
of steric and electronic effects, both of which favor nucleo-
philic attack at the meta position of the methoxy group
(Scheme 3).6,7 However, the use of 2-Me-substituted
5
H
6
n-C7H15
Ph
H
7
Et
Et
Ph
Ph
Et
Me
H
Me (1g)
Pr (1h)
Me (1i)
Pr (1j)
8
Ph
9
Ph
10
11
12
13
14
15c
Ph
Et
Ph (1k)
Me (1l)
H (1m)
Bn (1n)
Me (1a)
Me
n-C8H17
H
H
Ph
H
a The reaction conditions: a mixture of 0.4 mmol of allenoic acid, 1.5
equiv of benzyne precursor, and 2.0 equiv of KF/18-crown-6 in 4 mL of
THF was heated in a sealed pressure vessel at 80 °C for 12 h. b Isolated
yield. c The reaction was conducted with a 6 mmol (1.0480 g) scale of 1a.
With the optimal conditions in hand, we proceeded to
examine the scope of this transformation (Tables 2 and 3).
Overall, the method works smoothly and a variety of
mono-, di-, and fully substituted 2,3-allenoic acids with
benzyne precursor 2a afforded the corresponding chro-
mones 3aaÀ3na in moderate to excellent yields (entries
1À15, Table 2). The substituent on the allenoic acids could
be aryl, alkyl, and H. It should be noted that CÀBr or CÀCl
bonds were well tolerated with 3ca and 3da being formed in
Scheme 3
5198
Org. Lett., Vol. 13, No. 19, 2011

benzyne precursor 2d led to two separable regioisomers in
a ratio of 1:1.7 (entry 5, Table 3), in which nucleophilic
attack at the ortho position of the methyl group dominates,
showing that the reaction is controlled electronically rather
than sterically (Scheme 3).
In summary, we have developed an efficient and general
method to synthesize polysubstituted chromones with mod-
erate to excellent yields. Because of the mild conditions
utilized and the broad scope, this protocol will be of high
interest in organic synthesis and medicinal chemistry. Further
studies in this area are being conducted in our laboratory.
Acknowledgment. Financial support from the National
Basic Research Program of China (2011CB808700) and
National Natural Science Foundation of China (20732005)
is greatly appreciated. S.M. is a Qiu Shi Adjunct Professor at
Zhejiang University. We thank Mr. B. Chen in our group
for reproducing the results presented in entries 3 and 11 of
Table 2 and entry 4 of Table 3.
Supporting Information Available. General procedure
and spectroscopic data (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
5199