Triflic anhydride-mediated tandem formylation/cyclization of cyanoacetanilides: a concise synthesis of glycocitlone alkaloids

Article abstract of DOI:10.1016/j.tetlet.2009.09.073

A method is presented for the concise synthesis of 3-formyl-4-hydroxyquinolin-2(1H)-ones through triflic anhydride-mediated tandem formylation/cyclization of cyanoacetanilides. This tandem process was successfully used for the rapid syntheses of glycocitl

Full text of DOI:10.1016/j.tetlet.2009.09.073

Tetrahedron Letters 50 (2009) 6665–6667
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Tetrahedron Letters
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Triflic anhydride-mediated tandem formylation/cyclization
of cyanoacetanilides: a concise synthesis of glycocitlone alkaloids
*
*
Yusuke Kobayashi , Takashi Harayama
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A method is presented for the concise synthesis of 3-formyl-4-hydroxyquinolin-2(1H)-ones through tri-
flic anhydride-mediated tandem formylation/cyclization of cyanoacetanilides. This tandem process was
successfully used for the rapid syntheses of glycocitlones A and C.
Received 21 August 2009
Revised 11 September 2009
Accepted 14 September 2009
Available online 17 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Substituted 4-alkoxy- and 4-hydroxyquinolin-2(1H)-ones
1
this compound (entries 1–3). Three equivalents of Tf2O were
required to obtain 5a in good yield (entry 4 vs entry 6). It is impor-
tant to note that 5a was isolated as a precipitate by the simple
aqueous workup, and a gram-scale reaction can be conducted eas-
ily (entry 5).
We next performed several experiments to gain mechanistic
insights into the tandem reaction (entries 7–10). When 6a was
treated with trifluoromethanesulfonic acid (TfOH) instead of
Tf2O, no reaction occurred and unreacted 5a was recovered (entry
7).10 The treatment of 6a with a combination of TfOH (2.0 equiv)
and Tf2O (1.0 equiv) resulted in almost the same result as that in
entry 6 (entry 8), indicating that a Brönsted-acid-catalyzed Hou-
ben–Hoesch reaction11,12 did not occur in the tandem reaction
(Fig. 1) such as glycocitlones A–C (2–4)1 are widely found among
quinoline alkaloids of rutaceous plants.2 Compound 1 also form a
valuable class of biologically active molecules,3 including human
immunodeficiency virus type 1 (HIV-1) integrase inhibitors3a and
hepatitis C virus (HCV) inhibitors.3b,e Therefore, a diversity-ori-
ented strategy4 for the preparation of this class of compounds in
a practical and concise manner would be very useful for drug
discovery.
In our view, the development of an efficient method for the syn-
thesis of 3-formyl-4-hydroxyquinolin-2(1H)-ones
5 would be
invaluable for the diversity-oriented synthesis of 1 since 5 possess
hydroxy and formyl functionality that can help in the synthesis of a
wide range of compounds5 (Scheme 1). We expect that 5 can be
prepared from cyanoacetanilides 6 and N,N-dimethylformamide
(DMF) by simultaneous cyclization and functionalization,6,7 which
is a powerful and direct approach to prepare diverse derivatives
from a simple precursor. This approach would dramatically reduce
the consumption of solvents, reagents, and energy, as compared to
the stepwise preparation of 5.3f,8
Herein, we report a concise and practical method to obtain 5
from 6 through tandem formylation/cyclization. The salient fea-
tures of our method are as follows: (1) a variety of cyanoacetani-
lides are readily available,9 (2) multiple C–C bond formation
allows for the rapid synthesis of functionalized quinolinones 5
from simple starting materials, and (3) facile isolation of 5 is
accomplished by a simple aqueous workup.
Figure 1. 4-Alkoxy- and 4-hydroxyquinolin-2(1H)-ones.
We first examined the reaction of cyanoacetanilide 6a in DMF
(Table 1). We found that the use of trifluoromethanesulfonic anhy-
dride (Tf2O) in the tandem reaction yielded 3-formyl-4-hydroxy-
quinolin-2(1H)-one 5a in 71% yield (entry 4). Other reagents such
as POCl3, (COCl)2, and SOCl2 were found to be incapable of yielding
* Tel.: +81 87 894 5111; fax: +81 87 894 0181 (Y.K.); tel.: +81 87 894 5111; fax:
+81 87 894 0181 (T.H.).
E-mail addresses: ykobayashi@kph.bunri-u.ac.jp (Y. Kobayashi), harayama@
kph.bunri-u.ac.jp (T. Harayama).
Scheme 1. Synthetic strategy.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.073

6666
Y. Kobayashi, T. Harayama / Tetrahedron Letters 50 (2009) 6665–6667
Table 1
Survey of the reaction conditionsa
Entry
Substrates (R)
Reagentb (equiv)
Yield of 5ac
1
2
3
6a (CN)
6a
6a
6a
6a
6a
6a
6a
POCl3 (3.0)
(COCl)2 (3.0)
SOCl2 (3.0)
Tf2O (3.0)
Tf2O (3.0)
Tf2O (1.0)
TfOH (3.0)
Tf2O (1.0) + TfOH (2.0)
Tf2O (3.0)
0d
0d
0d
4
71
84
26
n.r.f
29
n.r.f
0d
5e
6
7
8
9g
10
6a
7 (CO2Et)
Tf2O (3.0)
a
Unless otherwise noted, all reactions were carried out with 3.0 mmol of sub-
strates in N,N-dimethylformamide (3.0 mL, 13 equiv).
b
Scheme 2. Plausible mechanism.
Tf = trifluoromethanesulfonyl.
Isolated yields.
See the Supplementary data.
15 mmol of 6a was employed.
No reaction occurred.
The reaction was carried out in N,N-dimethylacetamide (DMA).
c
d
e
6a with the Vilsmeier reagent13 is likely to be an initial step in
the tandem reaction14 (Scheme 2). The introduction of an iminium
substituent in a geminal position relative to the CN group may
increase the electrophilicity of the CN group15 and promote Tf2O-
mediated cyclization (A?B and/or C?D).
Once the optimum conditions were identified, we examined the
substrate scope of the reaction with cyanoacetanilides 6b–j (Table
2). The tandem reaction of 6b and 6c in which the para positions
f
g
and that Tf2O played a crucial role in the cyclization step. Further-
more, both DMF and the CN functionality of the substrate were
found to be essential for the formation of 5a (entries 9 and 10).
These results suggest that the reaction of the active methylene of
Table 2
Substrate scope of cyanoacetanilides 6a,b
Entry
6 (R1, R2)
Products
Yieldc (%)
1
2
3
4
5
6b (p-Me, Me)
6c (p-OMe, Me)
6d (p-Cl, Me)
6e (p-Br, Me)
6f (p-CF3, Me)
5b
5c
5d
5e
5f
79
69
80
68
61
6
6g (m-Me, Me)
5g
+ 5g0
78d (5g:5g0 = 35:65)e
7
8
6h (o-Me, Me)
6i (o-OMe, Me)
6j
5h
5i
5j
80
69
9
82
a
b
c
All reactions were carried out with 3.0 mmol of substrates in N,N-dimethylformamide (3.0 mL, 13 equiv).
Tf = trifluoromethanesulfonyl.
Isolated yields.
The ratio between 5g and 5g0 is given in parentheses.
The ratio was determined by a 1H NMR experiment.
d
e

Y. Kobayashi, T. Harayama / Tetrahedron Letters 50 (2009) 6665–6667
6667
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Scheme 3. Synthesis of glycocitlones.
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were substituted with electron-donating methyl or methoxy groups
took place smoothly to afford quinolinones 5b and 5c in 79% and 69%
yields, respectively (entries 1 and 2). Unlike the Houben–Hoesch
reaction, which requires electron-rich arene substrates and dry gas-
eous HCl to afford decent yields of ketones, the tandem reaction can
be successfully carried out with arenes bearing electron-withdraw-
ing substituents (entries 3–5).14e,16 The halogenated products 5d
and 5e could in principle be further functionalized through transi-
tion-metal-catalyzed coupling reactions. Interestingly, cyanoace-
tanilide 6g afforded regioisomers 5g and 5g0 in 78% combined yield
upon cyclization primarily ortho to the methyl group (ratio of para
to ortho: 35:65) (entry 6). Further, it is noteworthy that ortho-substi-
tuted cyanoacetanilides 6h and 6i were also effective in the tandem
reactions(entries7and8)sincetheproduct5icanbe usedinthesyn-
thesis of quinoline alkaloids (vide infra). Moreover, when this meth-
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Ag2O in MeCN gave aldehydes 8a and 8i. Subsequently, the Horn-
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sponding
a,b-unsaturated esters 9a and 9i. These esters were
then treated with MeMgBr to obtain glycocitlones A (2) and C (4).
In conclusion, we have presented an efficient method for the
conversion of cyanoacetanilides 6 into 3-formyl-4-hydroxyquino-
lin-2(1H)-ones 5; the method involves a novel Meth-Cohn-type
reaction.14 The method is simple and it has the potential to be used
for the synthesis of a wide variety of functionalized quinolin-
2(1H)-ones. Further, the use of the method in synthetic applica-
tions is under investigation and will be reported in due course.
Acknowledgment
This work was supported in part by a Grant-in-Aid for Young Sci-
entists (start-up) from Japan Society for the Promotion of Science.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.073.
16. For the Pd-catalyzed addition of C-H to nitrile, see: Zhou, C.; Larock, R. C. J. Am.
Chem. Soc. 2004, 126, 2302–2303.
References and notes
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