An efficient one-pot synthesis of coumarins mediated by propylphosphonic anhydride (T3P) via the Perkin condensation

Article abstract of DOI:10.1016/j.tetlet.2012.06.037

An efficient one-pot synthesis of coumarins mediated by T3P, a mild and low toxic peptide coupling agent, via the Perkin condensation has been demonstrated.

Full text of DOI:10.1016/j.tetlet.2012.06.037

Tetrahedron Letters 53 (2012) 4422–4425
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient one-pot synthesis of coumarins mediated by propylphosphonic
anhydride (T3P) via the Perkin condensation
John Kallikat Augustine a, , Agnes Bombrun b, Balakrishna Ramappa a, Chandrakantha Boodappa a
⇑
a Syngene International Ltd, Biocon Park, Plot Nos. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560 099, India
b Merck Serono SA, 9 Chemin des Mines, 1202 Geneva, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot synthesis of coumarins mediated by T3P, a mild and low toxic peptide coupling
agent, via the Perkin condensation has been demonstrated.
Received 5 May 2012
Revised 6 June 2012
Accepted 8 June 2012
Available online 15 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Coumarin
Propylphosphonic anhydride
Perkin condensation
Cyclodehydration
Peptide coupling reagent
Coumarins and their derivatives are very important structural
motifs that occur widely in natural products.1 Their synthesis has
attracted considerable attention from organic and medicinal chem-
ists for many years as members of this family have wide applica-
tions in medicinal chemistry,2 being known as anticancer,3
antioxidants,4 anti-HIV,5 enzymatic inhibitors,6 or vasorelaxants.7
Besides the medicinal applications, coumarins have been used in
fluorescent probes,8 triplet sensitizers,9 and cosmetic industries.10
Coumarins can be synthesized by one of such methods as the
Witting reaction, Perkin reaction, Pechmann reaction as well as
the Knoevenagel condensation.11 The classical Perkin condensation
is perhaps the most direct and simple method known for the prepa-
ration of substituted coumarins.12 While this procedure is a suitable
method, it suffers from drawbacks such as limited substrate scope,
the use of strong acids and sometimes the necessity of multi-step
reactions. In an attempt to improve on these procedures, Mashraqui
et al. have described a convenient and single step alternative to the
classical Perkin condensation to provide 3-substituted coumarins by
using Mukaiyama esterification protocol.13 Further optimization
leading to practical methods having broad substrate and functional
group tolerance is still essential and would extend the scope of cou-
marin synthesis.
organic synthesis has generated innovative uses for this reagent
beyond peptide synthesis.15 There are quite a few examples,
wherein, T3P is utilized in molecular rearrangements,16 and dehy-
dration chemistry.17 Recently, T3P has been used as a reagent in
the preparation of a range of functionalized heterocycles.18 Herein,
we report our results on the highly effective T3P mediated one-pot
synthesis of functionalized coumarins via the Perkin condensation.
The preparation of 3a from salicylaldehyde (1a) was chosen as a
model reaction (Table 1). Accordingly, preliminary experiments
were done in n-BuOAc with equimolar amounts of 1a, cyanoacetic
acid (2a), and T3P (50% solution in EtOAc) in the presence of
2.0 equiv of triethylamine (TEA) at room temperature (Table 1,
entry 1). Under these conditions the reaction did not proceed be-
yond intermediate 4a, and the mixture was then heated to
100 °C for 10 h to provide 3a in 19% yield (Table 1, entry 2). Further
raise in the reaction temperature (Table 1, entry 3) and amount of
base (Table 1, entry 4) had no influence on the formation of 3a.
Interestingly, when 2.0 equiv of T3P were used (Table 1, entry 5),
3a was obtained in 97% yield within 7 h of stirring at 100 °C. A
comparable result was obtained in a shorter duration when the
reaction was performed at 120 °C in the presence of 2.0 equiv of
T3P, but could be limited to this substrate (Table 1, entry 6). Micro-
wave irradiation did not prove beneficial for the preparation of 3a
(Table 1, entry 7) as it led to an incomplete reaction even after 2 h
of irradiation at 150 °C. Further, formation of 3a was not observed
when the reaction was performed at 120 °C in the absence of T3P,
instead, the Knoevenagel product 5a was isolated in considerable
amount (Table 1, entry 8).
Propylphosphonic anhydride (T3P) is a prevailing peptide cou-
pling reagent having low toxicity.14 Its versatility as a reagent in
⇑
Corresponding author. Tel.: +91 80 2808 3131; fax: +91 80 2808 3150.
E-mail addresses: john.kallikat@syngeneintl.com, john.kallikat@gmail.com (J.K.
Augustine).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.037

J. K. Augustine et al. / Tetrahedron Letters 53 (2012) 4422–4425
4423
Table 1
Table 2
Screening optimal reaction conditions
T3P mediated coumarin synthesis
R1
HO
CN
OH
R1
CN
O
CHO CN
2a
CN
OH
O
O
O
T3P (2.0 equiv)
CN
O
+
+
R
NC
OH
+
T3P
R
O
O
O
OH
O
O
OH
1a
TEA (2.0 equiv)
3a
O
4a
TEA, n-BuOAc
5a
n-BuOAc
2a
1a-j
3a-j
120 ºC, 6-10 h
Entrya
T3P (mol %)
Time (h)
Temp (°C)
Yield (%)
Entry
1
Substrate
CHO
Product
Yielda (%)
97
3a
4a
5a
CN
1
2
100
100
100
100
200
200
200
0
6
10
10
10
7
5
2
10
25
100
120
100
100
120
150
120
0
19
23
21
97
97
76
0
96
77
72
76
0
0
19
0
0
0
0
0
0
0
0
61
O
3aO
1a OH
3
4b
5
CHO
CN
6
O
OH
O
7c
8d
2
98
O
O 1b
3b
a
b
c
Reaction was monitored by LCMS.
3.0 equiv of TEA were used.
Reaction was performed under MW irradiation.
Reaction was performed in the absence of T3P.
CHO
OH
CN
O
Br
Br
3
4
94
92
3cO
d
1c
O2N
Cl
CHO
CN
O2N
Cl
With optimal conditions in hand (Table 1, entry 5), various
O
O
3d
OH
commercially accessible salicylaldehydes (1a–f) and 2-hydroxya-
rylketones (1g–j) were reacted with 2a to evaluate the scope and
limitations of T3P mediated coumarin synthesis (Table 2). As
shown in Table 2, the conditions were compatible with various
substituents on the aromatic ring and provided the respective cou-
marins in good yields. Electronic disparities between substrates
had no influence on the rate of reaction or yield. While aldehydes
were more reactive and produced the corresponding coumarins in
6–7 h (Table 2, entries 1–6), 7–10 h of heating was required for ke-
tones to react to give the products in good yields (Table 2, entries
7–10). More importantly, this protocol could be applied to sub-
strates having a labile functional group, such as 1j, affording the
corresponding coumarin 3j without the loss of N-Boc group
(Table 2, entry 10). Such novel coumarins are useful synthetic
handles for further derivatization.
The substrate scope of the reaction was further extended to var-
ious substituted acetic acids (Table 3). Accordingly, 1b was reacted
with diverse carboxylic acids (2b–j) in the presence of T3P
(2.0 equiv) under the optimized reaction conditions.19 In general,
as observed from Table 3, the reaction proceeded well for all acetic
acids we tried, and gave good yields of respective coumarins. It is
noteworthy that chloroacetic acid reacted well under the reaction
conditions to give 3-chloro coumarin (3l) in moderate yield
(Table 3, entry 3). Similarly, N-acetyl glycine produced the respec-
tive coumarin in 81% yield (Table 3, entry 6). However, the reaction
did not tolerate the carboxamide functionality, instead, gave the
corresponding nitrile following dehydration mediated by T3P16a
(Table 3, entry 2). In addition to aryl and alkylsulfonyl acetic acids
(Table 3, entries 4 and 5), arylacetic acids (Table 3, entries 7 and 8)
as well reacted easily under the reaction conditions and gave
excellent yields of corresponding 3-substituted coumarins. In most
cases (Tables 2 and 3), the products were isolated by simple aque-
ous work-up, and purified by passing through a small plug of
silica gel.
1d
CN
O
CHO
OH
5
6
94
85
3e O
1e
CHO
OH
CN
O
N
N
O
1f
3f
CN
7
93
O
O
O
3g
O
O
OH
1g
CN
O
8
9
96
92
O
3hO
OH
1h
CN
F
F
F
F
O
O
3i O
OH
1i
boc
N
boc
N
10
88
CN
O
O
3jO
OH
1j
a
Isolated yields.
Trifluoromethyl substituted coumarins are known to be fluores-
cent markers.20 Nevertheless, such applications are limited to 4-
trifluoromethyl substituted coumarins due to their easy access.21
Interestingly, the only two successful but low yielding prepara-
tions of 3-trifluoromethyl substituted coumarins reported so far
involve the reaction of coumarins with bis(trifluoroacety1)
peroxide22 and that of coumarin-3-carboxylic acids with sulfur tet-
rafluoride.23 As illustrated in Table 3, a convenient and high yield-
ing synthesis of 3-trifluoromethyl substituted coumarins could be
achieved by the reaction of 2-hydroxyarylcarbonyls with 3,3,3-tri-
fluoropropionic acid (Table 3, entry 9).
In order to validate the position of T3P in coumarin synthesis, a
control experiment was undertaken. Thus, 3p was prepared via a
stepwise procedure (Scheme 1). The reaction of 1b with phenylace-
tic acid in the presence of T3P (1.0 equiv) and TEA (1.0 equiv) in n-
BuOAc at room temperature for 4 h afforded the intermediate 4b in
96% yield.24 Subsequent heating of 4b at 120 °C in the presence of

4424
J. K. Augustine et al. / Tetrahedron Letters 53 (2012) 4422–4425
Table 3
O
T3P mediated coumarin synthesis: scope of acetic acids
O
OH
O
O
2h
O
O
O
T3P (2.0 equiv)
R
O
R
+
OH
OH
OH
O
T3P, NEt3
O
O
TEA, n-BuOAc
1b
2b-j
n-BuOAc, 25 oC
O
120 oC, 6-10 h
1b
O
3k-r
4b
4 h, 96%
Entry
1
Acid
Product
Yielda (%)
O
NEt3
O
O
O
OH
n-BuOAc, 120 oC
O
O
HO
O
O
18 h
2b
94
H
O
O
O
O
intramolecular
O
O
O
4b
aldol-type condn
3k
O
6
O
O
CN
O
HO
HO
NH2
O
84%
2
3
4
92b
2c
H2O
:NEt3
3b
O
Cl
O
H
Cl
O
O
O
44
H
2d
O
O
O
O
O
3l
O
O
O
O
O
3p
O
S
O
P
O
P
O
P
S
HO
HO
89
O
O
HO
O
O
OH
2e
Pr
Pr
Pr
O
O
O
95%
3m
O
P
Pr
O
S
O
S
O
O
O
O
O
O
Pr
O
O
P
O
P
O
P
P
P
2f
5
6
7
8
9
94
81
95
88
91
O
O
O
O
O
O
Pr
O
O
O
O
OH
Pr
Pr
Pr
O
3n
H
NEt3
H
O
O
H
N
H
N
n-BuOAc, 120 oC
O
HO
HO
7
O
7 h
O
8
O
O
O
2g
Scheme 1. Control experiment and probable mechanism of coumarin synthesis.
3o
O
intermediates 4b, 7, and 8 as shown in Scheme 1. The first
equivalent of T3P could be involved in the generation of ester
intermediate (4b) and subsequent cyclodehydration in the
presence of another equivalent of T3P would lead to coumarin.19
In summary, a convenient and versatile method has been opti-
mized for the synthesis of coumarins25 via the Perkin condensation
mediated by T3P, a mild and low toxic peptide coupling agent. The
method not only employs readily accessible T3P, but also tolerates
diverse 2-hydroxyarylcarbonyls and acetic acids giving access to
distinctively substituted coumarins in good yields. Further, the
reaction conditions are sufficiently mild that could tolerate sensi-
tive functional groups and make the process a practical method
for coumarin synthesis.
2h
O
O
3p
F
F
O
O
HO
HO
2i
O
O
F
O
O
3q
F
F
F
F
F
O
2j
O
3r
Supplementary data
a
Isolated yields.
Dehydration of amide was observed.
Supplementary data (1H NMR, 13C NMR and LCMS report for 3a–
r, 4b and 19F NMR for 3i, 3j, 3q and 3r) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.06.037.
b
TEA (1.0 equiv) for 18 h afforded 84% conversion to 3p via
intramolecular aldol-type condensation as monitored by LC–MS
(Scheme 1). However, when 4b was heated at 120 °C in the
presence of 1.0 equiv each of T3P and TEA, complete consumption
of starting material was realized leading to the formation of 3p in
95% yield within 7 h (Scheme 1). Accordingly, the formation of
coumarin could be envisaged as a chronological coupling and
cyclodehydration process mediated by T3P in one-pot via the
References and notes
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24. Copies of 1H NMR and 13C NMR for compound 4b are available in
Supplementary data.
25. T3P mediated synthesis of coumarins: To a mixture of 2-hydroxyaryl aldehyde/
ketone (1, 0.01 mol) and appropriate acetic acid (2, 0.01 mol) in n-BuOAc
(10 mL) was added T3P (0.02 mol, 50% soln in EtOAc) followed by
triethylamine (0.02 mol). The resulting reaction mixture was stirred at
120 °C for 6–10 h under conventional heating. When the reaction was
completed (monitored by TLC), the mixture was cooled and washed with
saturated NaHCO3 solution (1 Â 10 mL), water and brine. The organic phase
was dried over anhydrous Na2SO4. The solvent was removed under reduced
pressure and the crude product was passed through a small plug of silica to
afford the coumarins (3) in good purity and yield.
Compound 3c: Yield 94%, yellow solid, mp 199.8–202.1 °C; IR (KBr): 3085, 2231,
1728, 1212 cmÀ1 MS (ESI-APCI, negative mode) 251 [M+2-H]+; 1H NMR
;
(DMSO-d6, 400 MHz): dH = 7.50–7.47 (d, J = 8.8 Hz, 1H), 7.95–7.93 (dd, J = 8.8,
2.4 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 8.84 (s, 1H); 13C NMR (DMSO-d6, 400 MHz):
dC = 156.3, 153.1, 151.9, 137.4, 131.6, 119.2, 116.8, 114.2, 103.4.
Compound 3o: Yield 81%, white solid, mp 241.3–242.8 °C; IR (KBr): 3332, 1709,
1676, 1528, 1192 cmÀ1; MS (ESI-APCI, negative mode) 232 [M-H]+; 1H NMR
(DMSO-d6, 400 MHz): dH = 2.15 (s, 3H), 3.89 (s, 3H), 7.18–7.16 (m, 1H), 7.27–
7.20 (m, 2H), 8.57 (s, 1H), 9.76 (s, 1H); 13C NMR (DMSO-d6, 400 MHz):
dC = 170.2, 157.1, 146.2, 138.7, 124.8, 123.5, 120.1, 119.0, 111.9, 55.9, 23.9.
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