Triflic acid promoted tandem ring-closure-aryl-migration of 2-amino chalcone epoxide: A new synthetic route to azaisoflavones

Article abstract of DOI:10.1055/s-0030-1258091

An unprecedented TfOH-promoted tandem ring-closure-aryl-migration of 2′-amino chalcone epoxide leading to 3-aryl-4(1H)-quinolones (azaisoflavones) was achieved. The outcome of the reaction was confirmed by NMR analysis and rationalized through the intermediacy of a phenonium ion. This synthetic protocol furnishes azaisoflavones straightforwardly from simple starting materials under mild conditions. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258091

LETTER
1635
Triflic Acid Promoted Tandem Ring-Closure–Aryl-Migration of 2¢-Amino
Chalcone Epoxide: A New Synthetic Route to Azaisoflavones
A
NewRoute to
h
zaisoflavon
a
es ndrasekaran Praveen,a Kannabiran Parthasarathy,b Paramasivan T. Perumal*a
a
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
Analytical Research & Development, Orchid Chemicals & Pharmaceuticals Ltd., Research & Development Centre,
Sholinganallur, Chennai 600 119, India
b
Fax +91(44)24911589; E-mail: ptperumal@gmail.com
Received 25 March 2010
R
[Au]
Abstract: An unprecedented TfOH-promoted tandem ring-clo-
sure–aryl-migration of 2¢-amino chalcone epoxide leading to 3-
aryl-4(1H)-quinolones (azaisoflavones) was achieved. The out-
come of the reaction was confirmed by NMR analysis and rational-
ized through the intermediacy of a phenonium ion. This synthetic
protocol furnishes azaisoflavones straightforwardly from simple
starting materials under mild conditions.
R
O
O
O
O
[Au]
NH2
O
NH2
O
1
Key words: 2¢-amino chalcone epoxide, triflic acid, sequential
ring-opening aryl-migration, phenonium ion, azaisoflavones
OH
_
[Au]
O
R
R
N
H
– [Au]
N
2¢-Amino chalcone epoxide is a little known but potential-
ly useful synthetic intermediate, that can readily engage in
a range of transformations.1–5 The synthesis of these com-
pounds mainly relies on the reaction of the corresponding
amino chalcones with alkaline H2O2.2 Despite their easy
preparation and the density of functional groups, the syn-
thetic utility of these intermediates has scarcely been in-
vestigated. Among the few reactions, the acid-promoted
ring-opening of 2¢-amino chalcone epoxide is particularly
attractive,3 since the resulting 3-hydroxy-2-aryl-tetrahy-
dro-4(1H)-quinolone is densely functionalized and can
potentially serve as a synthetic precursor. However, there
were no reports for the Lewis acid mediated ring-opening
of 2¢-amino chalcone epoxide. Recently, the synthetic ap-
plications of gold complexes and Brønsted acids in cy-
clization reactions were described.6 In the context of our
ongoing efforts to develop new methodologies for
heterocycles7 under gold catalysis,7b–f we envisaged that
the trans-2¢-amino chalcone epoxide 1 might undergo a
domino pathway consisting of gold-catalyzed epoxide
ring-opening followed by nucleophilic attack of the teth-
ered amino group leading to 3-hydroxy-2-aryl-tetrahydro-
4(1H)-quinolone (2; Scheme 1).
+H2
2
Scheme 1 Projected reaction
O
O
O
OH
catalyst
CH2Cl2, r.t.
N
NH2
H
1a
2a
Scheme 2 Screening of catalysts
for 24 hours at reflux temperature. The use of 15 mol% of
AgOTf as co-catalyst along with 5 mol% of AuCl3 led to
the formation of a trace amount of new product (entry 2).8
Interestingly, when 1.0 equivalent of AgOTf alone was
used, the yield of the product was improved to 25%, albeit
in 24 hours (entry 3).
Structural assignment of the product indicated that the
reaction took a completely different course, and did not
lead to the expected compound 2a. 1H NMR spectra of the
new compound in DMSO-d6 exhibited two doublets at
dH = 8.16 and 12.06 ppm with coupling constants of 1J =
Compound 1a was first chosen as a model substrate to val-
idate the approach described above, using dichlo-
romethane as solvent (Scheme 2).
1
6.1 and J = 5.7 Hz, respectively. Upon D2O exchange,
the peak at dH = 12.06 ppm disappeared, leaving the peak
at dH = 8.16 ppm as a singlet. This observation indicated
the presence of one labile proton (-NH) and an aryl proton
To this end, treatment of 1a with 5 mol% of AuCl3 in
dichloromethane at room temperature was attempted
(Table 1, entry 1). Unfortunately, no progress in the reac-
tion was observed, even when the reaction was carried out
adjacent to each other. A 2D H–1H COSY experiment
1
showed an intense corrrelation between the protons at
dH = 8.16 and 12.06 ppm. In the 13C NMR spectrum, a
peak at dC = 174.7 ppm corresponds to the presence of an
a,b-unsaturated carbonyl carbon. In the mass spectrum, a
peak at m/z = 222 [M + H]+ corresponded to the loss of one
molecule of H2O. In the IR spectrum, a peak at 3454 cm–1
SYNLETT 2010, No. 11, pp 1635–1640
x
x
.x
x
.2
0
1
0
Advanced online publication: 11.06.2010
DOI: 10.1055/s-0030-1258091; Art ID: G09410ST
© Georg Thieme Verlag Stuttgart · New York

1636
C. Praveen et al.
LETTER
TfOH was used (entry 5). This may be attributed to the
stoichiometric amount of H2O formed (1.0 mol of H2O /
1.0 mol of chalcone epoxide) in the reaction, and to the
acidity of the system dropping significantly.10 This low
acidity prevents further transformations from being cata-
lyzed. By performing the same reaction with 0.5 equiva-
lents of TfOH at 0 °C, we were able to isolated the
intermediate 2a (entry 6).11 To assess the efficacy of
TfOH over other acids, the reaction was carried out with
different Brønsted acids. PTSA led to the formation of the
product 3a in low yield (entry 6), whereas methanesul-
phonic acid and trifluoroacetic acid did not led to the for-
mation of the desired product at all (entries 7 and 8,
respectively). However, the latter resulted in the forma-
tion of 3-hydroxy-2-phenyl-4(1H)-quinolone (2a) in 40%
yield (entry 8). These findings suggested that TfOH is su-
perior to other acids in effecting this novel transformation.
Since TfOH is a commonly used superacid (H0 = –14.1)
for effective catalysis of many transformations,12 its use is
preferable to that of other acids with similar acid strengths
(e.g., H2SO4, ClSO3H, FSO3H), furthermore, because it
does not promote oxidative side reactions,13 TfOH was
chosen as the acid of choice for further studies. Moreover,
the synthesis of azaisoflavone by this method seemed to
be superior to other protocols,14 including the thermal re-
arrangement of 3-(b-styryl)-2,1-benzisoxazoles,14a oxida-
tive rearrangement of 2¢-acetamidochalcones with
Tl(NO3)3,14b thermolysis of 3-(propenyl)-1,2,3-benzotri-
azin-4(3H)-ones,14c and Tl(OTs)3-promoted oxidation of
tetrahydro-4(1H)-quinolones.14d On the basis of the above
results, coupled with the fact that azaisoflavones are asso-
ciated with important biological activities such as NO pro-
duction inhibition,15 EGFR tyrosine kinase inhibition,16
and anti-platelet applications, the scope of the reaction
was tested with other substrates.
Table 1 Screening of Catalysts for the Synthesis of Azaisoflavone
3a
Entry
Catalyst (equiv)
AuCl3 (0.05)
AuCl3 (0.05)/AgOTf (0.15)
AgOTf (1.0)
Yield (%)a
b
1
–
2
traceb
25
3
4
TfOH (1.0)
65
5
TfOH (3.0)
90
6
TfOH (0.5)
80c,d
20
7
PTSA (3.0)
8
MeSO3H (3.0)
TFA (3.0)
–
9
40c
a Isolated yield.
b The reaction was carried out at reflux temperature.
c 3-Hydroxy-2-phenyl-(4H)-quinolone (2a) was obtained.
d The reaction was carried out at 0 °C for 10 min.
O
N
H
Figure 1 3-Phenyl-4(1H)-quinolone 3a
revealed the presence of an NH functionality. All these
findings confirmed the structure of the new product as
3-phenyl-4-(1H)-quinolone (3a; Figure 1).
Having established the structure, we next set out to im-
prove the yield of the product 3a. As expected, the yield
of the product was improved to 65%, when 1.0 equivalent
of TfOH was used, instead of AgOTf (entry 4).9 The yield
was further improved to 90%, when 3.0 equivalents of
Table 2 TfOH-Promoted Synthesis of Azaisoflavones from 2¢-Amino Chalcone Epoxidea
Entry
2¢-Amino chalcone epoxide (1)
Azaisoflavone (3)b
Time (h)
0.30
Yield (%)c
O
O
O
1
90
N
H
NH2
1a
3a
O
O
O
2
3
0.20
0.20
94
92
N
H
NH2
1b
3b
O
O
O
N
H
NH2
1c
3c
Synlett 2010, No. 11, 1635–1640 © Thieme Stuttgart · New York

LETTER
A New Route to Azaisoflavones
1637
Table 2 TfOH-Promoted Synthesis of Azaisoflavones from 2¢-Amino Chalcone Epoxidea (continued)
Entry
2¢-Amino chalcone epoxide (1)
Azaisoflavone (3)b
Time (h)
0.20
Yield (%)c
OMe
O
O
O
OMe
4
91
NH2
N
H
1d
3d
3e
3f
Cl
O
Cl
O
O
5
6
7
8
9
0.45
0.40
1.0
85
87
79
73
81
NH2
N
H
1e
1f
Cl
O
O
O
Cl
NH2
N
H
F
O
F
O
O
NH2
N
H
1g
1h
1i
3g
3h
3i
F
O
O
O
0.50
0.45
F
NH2
N
H
Br
O
Br
O
O
NH2
N
H
Br
O
O
O
Br
10
11
0.50
1.10
84
80
NH2
N
H
1j
3j
OMe
O
F
O
O
OMe
NH2
F
N
H
1k
3k
Synlett 2010, No. 11, 1635–1640 © Thieme Stuttgart · New York

1638
C. Praveen et al.
LETTER
Table 2 TfOH-Promoted Synthesis of Azaisoflavones from 2¢-Amino Chalcone Epoxidea (continued)
Entry
12
2¢-Amino chalcone epoxide (1)
Azaisoflavone (3)b
Time (h)
1.30
Yield (%)c
NO2
O
O
O
NO2
78
NH2
N
H
1l
3l
a All reactions were carried out at 0 to 25 °C in dichloromethane using 3.0 equiv of TfOH.
b All products were characterized by IR, 1H NMR, 13C NMR and mass spectroscopy.
c Isolated yield.
Thus, under the optimized conditions,17 substrates with Protonation of the hydroxyl group of 2 leads to the inter-
electron-releasing substituents 1a–d reacted to give prod- mediate 6. Anchimeric assistance by the C2-aryl group of
ucts 3a–d with yields ranging from good to excellent 6 results in the formation of the phenonium ion18 7 (in res-
(Table 2, entries 1–4) after a shorter reaction time. In onance stabilization with 7¢). Migration of the aryl group
comparison, the electron-withdrawing counterparts 1e–l from the C2 to the C3 position was facilitated by the elec-
gave moderate to good yields of products 3e–l (Table 2, tron-donating amino group, which pushes electron density
entries 5–12) but required longer reaction times. This can from the aryl group towards the C3 position, leading to the
be ascribed to the greater stabilization of the phenonium intermediate 8. Deprotonation at the a-carbon results in
ion intermediate by the electron-releasing substituents the formation of 3-aryl-4(1H)-quinolone 3.
compared to their electron-withdrawing counterparts
(Scheme 3). A tentative mechanism is given in Scheme 3,
which involves the initial protonation of the trans-2¢-ami-
no chalcone epoxide 1 that results in the protonated inter-
To support the intermediacy of 2a in Scheme 4, a control
reaction of 2a (prepared by the literature procedure1) with
TfOH was carried out, which led to the formation of 3a
(Scheme 4). This observation confirmed the formation of
mediate 4. Subsequent nucleophilic attack of the tethered
intermediate 2a along the reaction path.
amino group leads to the formation of the six-membered
To confirm the participation of the phenonium ion in the
intermediate 5, which, upon deprotonation, affords 2-aryl-
reaction mechanism, cis-1,2,3,4-tetrahydro-3-hydroxy-2-
3-hydroxy-tetrahydro-4(1H)-quinolone (2), where the
phenyl-4(1H)-quinolone (2a¢) was prepared4 and reacted
aryl and hydroxyl groups are located trans to each other.11
under the optimized reaction conditions (Scheme 5).
O
O
O
O
..
OH
..
OH
..
O
..
O
H+
+
H
..
NH2
..
NH2
– H+
..
N
N
+
H2
H
H+
1
R
4
R
2
5
R
R
O
O
O
O
O
OH2
H
R
+
..
..
– H+
– H2O
..
..
+
N
N
N
+
N
H
H
H
N
H
H+
R
R
3
8
7'
7
R
6
Scheme 3 Proposed mechanism for the formation of azaisoflavone 3
O
O
O
O
OH
TfOH (3.0 equiv)
n-BuOH
90 °C, 70% yield
CH2Cl2, 0 °C to r.t.
N
H
N
H
NH2
1a
ref. 1
2a
3a
Scheme 4 Control reaction of 2a with TfOH
Synlett 2010, No. 11, 1635–1640 © Thieme Stuttgart · New York

LETTER
A New Route to Azaisoflavones
1639
O
O
O
O
OH
TfOH (3.0 equiv)
CH2Cl2, 0 °C to r.t.
AcOH
120 °C, 10 min
38%
N
H
NH2
N
H
ref. 4
1a
2a'
3a
Scheme 5 Reaction of cis-1,2,3,4-tetrahydro-3-hydroxy-2-phenyl-4(1H)-quinolone (2a¢) with TfOH
Similarly, the reaction of 1a with AgOH did not led to any
product formation at all. Having observed this, we decided
to use TfOH as the catalyst
However, the expected product 3a was not obtained,
which indicates that the hydroxyl and the migrating aryl
groups must be in the trans-configuration for the reaction
to occur. The exclusive reaction of the trans-isomer over
the cis-isomer can be reasonably rationalized by consider-
ing stereoelectronic effects, which suggest that the migrat-
ing aryl group cannot accommodate the requisite anti-
periplanar orientation with the leaving hydroxyl group.
Participation of a free carbocation was ruled out as an al-
ternative, because it is energetically unfavorable for a car-
bocation to reside on a carbon a to the carbonyl group.
These observations revealed that the phenonium cation is
indeed the reaction intermediate that is involved in this
novel migration.
(10) It is well-known that the acid strength of TfOH is
significantly altered by H2O, see: (a) Saito, S.; Sato, Y.;
Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1994, 116, 2312.
(b) Olah, G. A.; Batamack, P.; Deffieux, D.; Török, B.;
Wang, Q.; Molnár, ; Prakash, G. K. S. Appl. Catal., A 1996,
146, 107.
(11) The ring-opening of trans-chalcone epoxide 1a with TfOH
(0.5 equiv) gave trans-1,2,3,4-tetrahydro-3-hydroxy-2-
phenyl-4 (1H)-quinolone (2a). The spectral data and
stereochemistry of the product was consistent with the
literature value (ref. 1).
(12) (a) Dumeunier, R.; Markó, I. E. Tetrahedron Lett. 2004, 45,
825. (b) Loh, T.-P.; Hu, Q.-Y.; Ma, L.-T. Org. Lett. 2002, 4,
2389. (c) Olah, G. A.; Wu, A.-h. Synthesis 1991, 407.
(d) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.;
To conclude, an unprecedented synthesis of azaisofla-
vones via TfOH-promoted tandem ring-closure–aryl-
migration of 2¢-amino chalcone epoxide is reported. Clar-
ification of the reaction mechanism and further applica-
tion of this chemistry for the synthesis of bioactive
molecules is currently under study.
Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179.
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Acknowledgment
C.P. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi, India for the research fellowship and K.P.
thanks Orchid Chemicals and Pharmaceuticals Ltd., Chennai, India.
(13) (a) Olah, G. A.; Prakash, G. K. S.; Sommer, J. Superacids;
John Wiley & Sons: New York, 1985. (b) Puglici, A.; Lee,
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Ann. Chem. 1993, 8, 927. (c) Barker, A. J.; Paterson, T. Mc.
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References and Notes
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(7) (a) Praveen, C.; Kumar, K. H.; Muralidharan, D.; Perumal,
P. T. Tetrahedron 2008, 64, 2369. (b) Praveen, C.;
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it was not characterized.
(16) Traxler, P.; Green, J.; Mett, H.; Séquin, U.; Furet, P. J. Med.
Chem. 1999, 42, 1018.
(17) Representative procedure for the synthesis of
azaisoflavones (3a–k): To a stirred solution of 2¢-amino
chalcone epoxide 1a (239 mg, 1.0 mmol) in anhydrous
CH2Cl2 (1 mL) were added trifluoromethanesulphonic acid
(452 mg, 3.0 mmol), dropwise at 0 °C. After completion of
the reaction as indicated by TLC, the reaction mixture was
quenched with ice-cold water and adjusted the pH to 7.5 with
NaHCO3, extracted with CH2Cl2 (3 × 15 mL), and the
organic extract was dried with anhydrous sodium sulphate.
(9) The reaction of 1a with AgOTf (1.0 equiv) in wet CH2Cl2
resulted in the formation of 3a in 45% yield. It was thought
that AgOTf is hydrolyzed to AgOH and TfOH and the
resulting TfOH effects the formation of the product.
Synlett 2010, No. 11, 1635–1640 © Thieme Stuttgart · New York

1640
C. Praveen et al.
LETTER
reaction intermediates, see: (a) Protti, S.; Dondi, D.;
Removal of the solvent under reduced pressure gave the
crude product, which was purified by column chromatog-
raphy (EtOAc–petroleum ether, 6:4) to afford the pure
product 3a as a brown solid. Mp 258–260 °C (Lit.19 257 °C).
IR (KBr): 3454, 1621, 1561, 1515, 1356, 1292, 753, 697 cm–
1. 1H NMR (400 MHz, DMSO-d6): d = 7.27 (t, J = 7.4 Hz,
1 H), 7.34–7.42 (m, 3 H), 7.59 (d, J = 8.0 Hz, 1 H), 7.65 (t,
J = 8.0 Hz, 1 H), 7.73 (d, J = 7.4 Hz, 2 H), 8.16 (d, J =
6.1 Hz, 1 H), 8.21 (d, J = 7.9 Hz, 1 H), 12.06 (d, J = 5.7 Hz,
1 H, D2O exchangeable). 13C NMR (100 MHz, DMSO-d6):
d = 118.2, 119.7, 123.3, 125.6, 125.8, 126.4, 127.9, 128.5,
131.5, 136.2, 138.1, 139.3, 174.7. MS (ESI): m/z = 222 [M
+ H]+. Anal. Calcd for C15H11NO: C, 81.43; H, 5.01; N, 6.33.
Found: C, 82.01; H, 5.03; N, 6.35
Fagnoni, M.; Albini, A. Eur. J. Org. Chem. 2008, 2240.
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references cited therein.
(19) Wislicenus, W.; Börner, K.; Kurtz, P.; Bilhuber, E. A. Justus
Liebigs Ann. Chem. 1917, 413, 206.
(18) For discussion on the participation of phenonium ions as
Synlett 2010, No. 11, 1635–1640 © Thieme Stuttgart · New York