Hydrolysis-free synthesis of 3-aminocoumarins

Article abstract of DOI:10.1016/j.tetlet.2007.05.088

A commonly encountered problem in the synthesis of 3-aminocoumarins is the formation of 3-hydroxycoumarins. A solution to this problem, which involves non-aqueous formation of the 3-aminocoumarin system, is described.

Full text of DOI:10.1016/j.tetlet.2007.05.088

Tetrahedron Letters 48 (2007) 5077–5080
Hydrolysis-free synthesis of 3-aminocoumarins
Amit A. Kudale, Jamie Kendall, C. Chad Warford, Natasha D. Wilkins and
Graham J. Bodwell*
Department of Chemistry, Memorial University, St. John’s, NL, Canada A1B 3X7
Received 30 March 2007; revised 11 May 2007; accepted 15 May 2007
Available online 18 May 2007
Abstract—A commonly encountered problem in the synthesis of 3-aminocoumarins is the formation of 3-hydroxycoumarins. A
solution to this problem, which involves non-aqueous formation of the 3-aminocoumarin system, is described.
Ó 2007 Elsevier Ltd. All rights reserved.
The coumarin system is present in a very broad range of
natural and non-natural products of biological interest.1
The 3-aminocoumarin motif, while considerably less
prevalent, can nonetheless be found in a number of
naturally occurring antibiotics, such as novobiocin 1,2
clorobiocin 23 and coumermycin A1 34 (Fig. 1).
antibacterial,6 antiallergic7 and insect-growth regula-
tory.8 Moreover, 3-aminocoumarin and its derivatives
are also known to exhibit interesting photochemical
behavior and have found application as fluorescent
markers.9
Although various methods have been reported for the
synthesis of 3-aminocoumarins or related compounds,10
reproducibility has sometimes been a problem, as
Derivatives of 3-aminocoumarins have been found to
possess biological activity, including CNS depressant,5
OH
OH
O
H
O
H
N
O
N
O
Cl
O
O
OH
OH
O
O
O
O
MeO
MeO
clorobiocin 2
novobiocin 1
O
O
OH
OH
O
H2N
O
NH
O
O
HN
H
H
N
N
O
O
O
O
OH
HO
OH
O
H
O
N
O
O
O
MeO
coumermycin A1
3
OMe
O
OH
O
NH
Figure 1. Natural antibiotics containing 3-aminocoumarin.
Keywords: Salicylaldehydes; 3-Acetamidocoumarins; 3-Aminocoumarins.
*
Corresponding author. Tel.: +1 709 737 8406; fax: +1 709 737 3702; e-mail: gbodwell@mun.ca
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.088

5078
A. A. Kudale et al. / Tetrahedron Letters 48 (2007) 5077–5080
experienced by us and others.11 The final step of these
syntheses is typically the hydrolysis of a 3-acetamido-
coumarin, which can result in the formation of a
3-hydroxycoumarin, both under acidic and basic condi-
tions.12 Herein, we report an efficient and convenient
synthesis of 3-aminocoumarin and several derivatives
bearing a substituent on the carbocyclic ring.
Table 1. Condensation of salicylaldehydes with N-acetylglycine
R
R
N
-Acetylglycine
CHO
OH
NHAc
O
O
NaOAc, Ac O
2
4
5
o
110-120 C
Entry
R
H
6-Br
6-Me
6-NO2
6-OMe
7-OMe
8-OMe
7-OAc
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
46
69
42
69
40
20
69
21b
63
For the parent 3-aminocoumarin (7a), the synthesis
commenced with the conversion of commercially avail-
able (or easily prepared from salicylaldehyde and N-
acetylglycine13) 3-acetamidocoumarin (5a) to Boc-pro-
tected 3-aminocoumarin (6a) using the method of Burk
and Allen14 in 94% yield. This one-pot procedure, which
was originally developed for amino acids, involves an
acylation–deacylation sequence in which an N-acetyl
compound is reacted with di-t-butyl dicarbonate in the
presence of DMAP to give an imide, followed by reac-
tion with hydrazine hydrate to remove the acetyl group.
The resulting t-butyl carbamate (6a) could then be easily
deprotected to give 3-aminocoumarin (7a) in high yield
(99%) under anhydrous conditions through the action
of 15% TFA/CHCl3 (Scheme 1). In our hands, this
method has proved to be very reproducible and we have
prepared up to 15 g of 3-aminocoumarin in a single run.
5g
5h
5i
5,6-Benzo
a Isolated yield, >95% purity by 1H NMR analysis.
b 4-HOC6H4CHO was the starting material in this reaction. The
hydroxyl group undergoes acetylation under the reaction conditions.
the starting material was 4-hydroxysalicylaldehyde
(Table 1, entry 8), O-acylation took place, giving 7-acet-
oxy-3-acetamidocoumarin (5h) as the product.
The next step involved conversion of the acetamide to a
t-butyl carbamate. Burk and Allen’s one-pot protocol
was then employed to afford the Boc-protected 3-amino-
coumarins (6b–i) (Table 2). Under these conditions, the
acetoxy group in compound 5h was converted back to a
hydroxy group (Table 2, entry 8). For the most part, the
yields were high. As above, the yields of the products
with donor groups at the 7-position (Table 2, entries 6
and 8) were comparatively low.
For the synthesis of substituted 3-aminocoumarins,
suitably substituted 3-acetamidocoumarins (5) were
required. Being commercially unavailable, it was
envisaged that these compounds could be prepared from
the corresponding salicylaldehyde and N-acetylgly-
cine.13 Since the yield for parent 3-acetamidocoumarin
(5a) is low (27%) using this method, efforts were made
to optimize the reaction conditions for the conversion
of salicylaldehyde (4a) into compound 5a. After varying
reaction time, temperature, number of equivalents of N-
acetylglycine and sodium acetate, it was found that the
use of 4.0 equiv of sodium acetate and 1.0 equiv of
N-acetylglycine at 110–120 °C for 3.5 h gave the best
yield (46%) for the parent 3-acetamidocoumarin (5a).
Employing the same reaction conditions for a series of
substituted salicylaldehydes (commercially available or
easily prepared by known formylation protocols15)
afforded the corresponding 3-acetamidocoumarins (5b–
i) (Table 1). The yields for these reactions were variable.
Poor yields were obtained when an electron-donating
group was situated para to the aldehyde function of
the starting salicylaldehyde (Table 1, entries 6 and 8).
Otherwise, the yields ranged from 40% to 69%. When
Removal of the Boc-group using 15% TFA/CHCl3 then
afforded the 3-aminocoumarins (7b–i) in generally very
good yields (58–96%) (Table 3). In no case was any
3-hydroxycoumarin detected. Clearly, the use of a t-
butoxycarbonyl protecting group is crucial because it
can be removed under anhydrous conditions. The opti-
mal reaction times for preparing the desired 3-amino-
Table 2. Conversion of 3-acetamidocoumarins (5) into Boc-protected
3-aminocoumarins (6)
1. Boc2O,
DMAP, THF
R
R
NHBoc
O
NHAc
O
O
O
2.H2NNH2.H2O,
MeOH
6
5
Entry
R
Product
Yielda (%)
1. Boc2O,
R
R
N
-Acetylglycine
R
1
2
3
4
5
6
7
8
9
H
6-Br
6-Me
6-NO2
6-OMe
7-OMe
8-OMe
7-OH
5,6-Benzo
6a
6b
94
87
90
93
93
58
92
50
95
CHO
OH
NHAc
O
DMAP, THF
6cb
O
NaOAc, Ac2O
110-120 oC
2. H2NNH2.H2O,
MeOH
6d
4
5
6eb
6fb
6gb
6hb
6ib
R
NH2
NHBoc
O
TFA/CHCl3
O
O
O
7
6
a Isolated yield, >95% purity by 1H NMR analysis.
b New compound. See Ref. 16.
Scheme 1. General synthesis of 3-aminocoumarins 7.

A. A. Kudale et al. / Tetrahedron Letters 48 (2007) 5077–5080
5079
Table 3. Removal of the Boc group
Supplementary data
R
R
NH2
O
NHBoc
1
TFA/CHCl3
Experimental procedures, characterization data and H
and 13C NMR spectra for individual compounds. Sup-
plementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.05.088.
O
O
O
7
6
Entry
R
H
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
99
67
96
89
95
58b
80
96
65
6-Br
6-Me
References and notes
6-NO2
6-OMe
7-OMe
8-OMe
7-OH
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7g
7h
7i
5,6-Benzo
a Isolated yield, >95% purity by 1H NMR analysis.
b 37% 6f recovered after 3 h.
NHBoc
TFA
NHCOCF
O
3
+
7a
O
O
O
CHCl
3
6a
8
NH
O
NHCOCF
O
2
3
TFA/CHCl
3
O
O
7a
8
Scheme 2. Formation of 3-trifluoroacetamidocoumarin 8.
coumarins were found to be generally between 3 and
4.5 h at room temperature. Longer reaction times re-
sulted in a decrease in the yields of desired 3-amino-
coumarins and the formation of the corresponding
3-trifluoroacetamidocoumarin (8) (Scheme 2). For the
parent system, 3-trifluoroacetamidocoumarin (8a)17
was isolated in 14% yield after a reaction time of 31 h.
Yields as high as 35–45% were obtained for substrates
6d and 6e when the reaction was run for 27 h. Evidently,
the 3-aminocoumarin, once formed, is acylated by the
solvent. Indeed, stirring pure 3-aminocoumarin (7a) in
15%. TFA/CHCl3 at room temperature resulted in the
slow formation of compound 8a (tlc analysis). After
stirring for 7 days, roughly equivalent amounts of
compounds 7a and 8a were present in solution (tlc
analysis) and, after a further day’s reaction at reflux, tri-
fluoroacetamidocoumarin (8a) was isolated in 68%
yield.
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In conclusion, we have developed a hydrolysis-free
method for the synthesis of 3-aminocoumarins. It can
be used to prepare multigram quantities of various 3-
aminocoumarins and does not result in the formation
of any 3-hydroxycoumarins.
Acknowledgments
The Natural Sciences and Engineering Research Council
(NSERC) of Canada and AnorMED Inc are gratefully
acknowledged for financial support of this work.
7. Connor, D. T. U.S. Patent, 126,4,287, 1981.

5080
A. A. Kudale et al. / Tetrahedron Letters 48 (2007) 5077–5080
8. Shyamala, B. S.; Ananthalakshmi, P. V.; Raju, V. J. T.;
1717 (m), 1707 (m), 1632 (s), 1616 (s), 1581 (s), 1510 (m)
cmÀ1; MS m/z (%) = 175 (100, M+); HRMS calcd for
C15H17NO4 275.1158, found 275.1149. Compound 6e:
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Mp = 164–165 °C
(EtOAc/hexanes);
dH
(CDCl3,
500 MHz) = 8.24 (s, 1H), 7.42 (s, 1H), 7.23 (d, J =
9.0 Hz, 1H), 6.97 (dd, J = 9.2, 2.6 Hz, 1H), 6.90 (d,
J = 2.7 Hz, 1H), 3.83 (s, 3H), 1.54 (s, 9H) ppm; dC
(CDCl3, 125 MHz) = 158.9, 156.8, 152.7, 144.2, 125.2,
120.8, 120.4, 117.5, 116.8, 109.8, 82.0, 56.0, 28.4 ppm; IR
m = 3416 (m), 1729 (s), 1693 (b), 1583 (s) cmÀ1; MS m/z
(%) = M+ not obs., 191 (100); HRMS calcd for
C15H17NO5 291.1107, found 291.1101. Compound 6f:
Mp = 117–118 °C
(EtOAc/hexanes);
dH
(CDCl3,
500 MHz) = 8.23 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.29
(s, 1H), 6.86 (dd, J = 8.6, 2.6 Hz, 1H), 6.81 (d, J = 1.8 Hz,
1H), 3.85 (s, 3H), 1.53 (s, 9H) ppm; dC (CDCl3,
125 MHz) = 161.0, 159.1, 152.8, 151.2, 128.3, 122.4,
121.4, 113.5, 113.2, 100.9, 81.7, 55.9, 28.4 ppm; IR
m = 3318 (m), 1726 (m), 1699 (s), 1631 (m), 1613 (s),
1575 (m), 1524 (s) cmÀ1; MS m/z (%) = M+ not obs., 191
(100); HRMS calcd for C15H17NO5 291.1107, found
291.1099. Compound 6g: Mp = 97–99 °C (EtOAc/hex-
anes); dH (CDCl3, 500 MHz) = 8.25 (s, 1H), 7.43 (s, 1H),
7.22–7.19 (m, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.97 (d,
J = 8.1 Hz, 1H), 3.96 (s, 3H), 1.53 (s, 9H) ppm; dC
(CDCl3, 125 MHz) = 158.3, 152.7, 147.2, 139.2, 125.1,
125.1, 121.0, 120.6, 119.1, 111.3, 81.9, 56.4, 28.4 ppm; IR
m = 3318 (m), 1729 (s), 1703 (s), 1580 (m), 1532 (m) cmÀ1
;
MS m/z (%) = M+ not obs., 191 (100); HRMS calcd for
C15H17NO5 291.1107, found 291.1110. Compound 6h:
Mp = 177–178 °C
(CH2Cl2/hexanes);
dH
(CDCl3,
500 MHz) = 8.24 (s, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.27
(s, 1H), 6.88 (d, J = 1.5 Hz, 1H), 6.83 (dd, J = 8.2, 2.6 Hz,
1H), 6.42 (s, 1H), 1.53 (s, 9H) ppm; dC (CDCl3,
125 MHz) = 159.6, 157.8, 152.9, 151.1, 128.7, 122.4,
122.0, 114.3, 113.4, 103.2, 82.0, 28.4 ppm; IR m = 3317
(m), 17039 (s), 1681 (s), 1633 (s), 1608 (s), 1535 (s), 1512 (s)
cmÀ1; MS m/z (%) = M+ not obs., 177 (100); HRMS calcd
for C14H15NO5 277.0950, found 277.0951. Compound 6i:
11. (a) Kendall, J. M.Sc. Dissertation, Memorial University of
Newfoundland, 2002; (b) Trivedi, K.; Sethna, S. J. Org.
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Chem. 1956, 21, 601–604.
14. Burk, M. J.; Allen, J. G. J. Org. Chem. 1997, 62, 7054–
7057.
Mp = 192–194 °C
(EtOAc/hexanes);
dH
(CDCl3,
500 MHz) = 9.10 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 7.90–
7.85 (m, 2H), 7.65–7.64 (m, 1H), 7.58–7.55 (m, 1H), 7.49
(s, 1H), 7.44 (d, J = 9.4 Hz, 1H), 1.59 (s, 9H) ppm; dC
(CDCl3, 125 MHz) = 158.8, 152.8, 148.3, 130.9, 130.3,
129.2, 129.0, 127.8, 126.3, 124.8, 122.6, 116.8, 116.6, 114.6,
82.0, 28.5; IR m = 3316 (m), 1701 (s), 1575 (s), 1522 (s)
cmÀ1; MS m/z (%) = M+ not obs., 211 (100); HRMS calcd
for C18H17NO4 = 311.1158, found = 311.1149.
17. Compound 8a: Mp = 132–133 °C (EtOAc/hexanes); dH
(CDCl3, 500 MHz) = 8.81 (s, 1H), 8.70 (s, 1H), 7.59–7.54
(m, 2H), 7.40–7.36 (m, 2H) ppm; dC (CDCl3, 125 MHz) =
158.1, 155.7 (q, JC–F = 39.1 Hz), 150.7, 131.3, 128.5, 126.5,
125.8, 122.2, 119.0, 116.9, 115.3 (q, JCÀF = 288.4 Hz)
ppm; IR m = 3298 (m), 1735 (m), 1694 (s), 1626 (b), 1607
15. (a) Duff, C. J. J. Chem. Soc. 1941, 547; (b) Hofsløkken, N.
U.; Skattebøl, L. Acta Chem. Scand. 1999, 53, 258–262.
16. Compound
6c:
Mp = 133–134 °C;
dH
(CDCl3,
500 MHz) = 8.22 (s, 1H), 7.40 (s, 1H), 7.24 (m, 1H),
7.20 (m, 2H), 2.39 (s, 3H), 1.53 (s, 9H) ppm; dC (CDCl3,
125 MHz) = 159.0, 152.7, 147.9, 134.9, 130.2, 127.4, 124.7,
120.6, 120.0, 116.2, 81.8, 28.4, 21.1 ppm; IR m = 3407 (m),
(s), 1555 (s) cmÀ1
257.0300, found 257.0298.
; HRMS calcd for C11H6F3NO3