Catalytic synthesis of coumarins via direct annulations of α,β-unsaturated aldehydes and salicylaldehydes

Article abstract of DOI:10.1055/s-0030-1259691

The first organocatalytic approach towards substituted coumarins is reported. Catalytic amounts of in situ generated N-heterocyclic carbenes (NHC) catalyze a one-pot redox esterification of α,β-unsaturated aldehydes with simultaneous aldol condensation. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259691

LETTER
635
Catalytic Synthesis of Coumarins via Direct Annulations of a,b-Unsaturated
Aldehydes and Salicylaldehydes
Catalytic
S
ynthesis
l
of Cou
r
m
arinsike Gross,a,b Patrick J. Gross,a,b Min Shi,*b Stefan Bräse*a
a
Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
E-mail: stefan.braese@kit.edu
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, P. R. of China
E-mail: mshi@mail.sioc.ac.cn
Received 4 December 2010
large excess of a,b-unsaturated aldehydes 2 and in only
Abstract: The first organocatalytic approach towards substituted
coumarins is reported. Catalytic amounts of in situ generated N-
heterocyclic carbenes (NHC) catalyze a one-pot redox esterification
of a,b-unsaturated aldehydes with simultaneous aldol condensation.
moderate yields.7
Herein we report our systematic development of an orga-
nocatalytic methodology for the synthesis of several cou-
marins 4 (Scheme 2).
Key words: domino reactions, heterocycles, umpolung
R2
O
R2
X
N
N
R3
R3
The application of N-heterocyclic carbenes (NHC) as cat-
alysts and promoters in organic synthesis enables various
highly valuable synthetic transformations.1 Of particular
interest is the inversion of classical reactivity (Umpol-
ung),2 which include benzoin3 and Stetter reactions.4
More recent examples are synthesis of g-butyrolactones,5
b-lactones5a and other esters,5b and g-lactams.6
3
+
toluene
K2CO3, heating
H
O
OH
O
O
R1
R1
1
2
4
Scheme 2 One-pot synthesis of substituted coumarins 47
Coumarins are naturally occurring benzopyran deriva-
tives with interesting pharmacological properties.8 One
example is their potential to bind to and activate canna-
binoid receptors.9 Recently, we described the synthesis
and biological evaluation of several coumarin derivatives,
employing our previously reported NHC-promoted meth-
odology.10 This way, novel lead structures with high bind-
ing activity were identified, showing selectivity towards
the cannabinoid receptors CB1 and CB2. In a typical pro-
cedure salicylaldehyde (1a) and 2.5 equivalents of ac-
rolein (2a, R2 = H) were treated with 1.0 equivalent of
NHC precursor 3a [R3 = Me, X = (MeO)2PO2] to furnish
26% yield of coumarin 4aa (R1, R2 = H).7 Similar reaction
conditions with cinnamaldehyde (2b, R2 = Ph) furnished
only 18% of the product 4ab (R1 = H, R2 = Ph).7 The use
of other a,b-unsaturated aldehydes 2 with R2 representing
an alkyl group had yet been unsuccessful.
The use of NHC for synthesis of coumarins C was de-
scribed by our group in 2007 (Scheme 1).7a It should be
noted that depending on the reaction parameters, a,b-
unsaturated carbonyl compounds and salicylaldehydes
give different reaction products like A or B.7b,c
O
OH
O
R1
O
amine base
(R2 = Me)
A
O
O
oxide base
R1
R2
+
R2
R1
O
OH
stoich.
NHC
B
(R1 = H,
Aryl
R
2 = aryl)
Due to these shortcomings, we decided to further investi-
gate the reaction, to render it more applicable for further
synthesis of pharmacological interesting coumarins. Our
aim was to lower the loading of NHC precursor 3 to cata-
lytic amounts, to widen the scope of substrates to b-alkyl
a,b-unsaturated aldehydes like crotonaldehyde (2c,
R2 = Me) and to optimize yields.
O
O
C
Scheme 1 Reaction of salicylaldehydes with a,b-unsaturated alde-
hydes
Earlier we reported the synthesis of benzyl-substituted
coumarins 4 (R2 = Ar) in a one-pot reaction, albeit with
stoichiometric amounts of NHC precursors 3 (Scheme 2),
We started our screening with salicylaldehyde (1a,
R1 = H) and slight excess (1.5 equiv) of crotonaldehyde
(2c, R2 = Me) under the previously described conditions
(K2CO3, toluene, reflux) with different imidazolium and
imidazolidinium salts. The best results were obtained with
bis(2,6-diisopropylphenyl)imidazolium chloride (3b,
R3 = 2,6-diisopropylphenyl, X = Cl), significantly superi-
SYNLETT 2011, No. 5, pp 0635–0638
x
x.
x
x.
2
0
1
1
Advanced online publication: 25.02.2011
DOI: 10.1055/s-0030-1259691; Art ID: G34410ST
© Georg Thieme Verlag Stuttgart · New York

636
U. Gross et al.
LETTER
or to the previously used 1,3-dimethyl imidazolium spe- tion had some influence on the yield (entries 2 and 3).
cies 3a. These findings are in compliance with results Bromine and iodine substituents could be introduced in
reported for similar reactions: large substituents at the good yields (entries 4–6), enabling further elaboration of
NHC shield reaction intermediates, thus avoiding undes- the coumarins, for example, by cross-coupling, which is
ired side reactions.5 The commercially available, inexpen- important for further pharmacological evaluation. Naph-
sive imidazolium salt 3b was used for further thyl derivative 4gc and biphenyl derivative 4hc were
optimization. With 1.0 equivalent of 3b, coumarin 4ac formed only in moderate yields (entries 7 and 8). In case
was obtained in 74% yield (Table 1, entry 1). Lowering of 4hc this could be explained by steric hindrance of the
the loading of catalyst precursor 3b diminished the yield phenol group due to the adjacent phenyl substituent. Us-
to 58% (entry 2). This could be slightly improved by slow ing 4-diethylaminosalicylaldehyde 1c, only starting mate-
addition of crotonaldehyde over six hours (entry 3). Next, rial was recovered (entry 9). The electron-deficient 5-
different solvents (entries 4 and 5) and bases (entries 6–8) nitrosalicylaldehyde 1j led to decomposition (entry 10).
were screened. The application of Cs2CO3 proved to be This is either due to the decreased nucleophilicity of the
superior to the previously employed K2CO3. Further sol- intermediate phenolate or due to a higher reactivity of the
vent screening, employing Cs2CO3 as base, revealed o-xy- aldehyde function towards side reactions.
lene at 120 °C to be the solvent of choice, furnishing 81%
yield (entry 12). Lowering the amount of base to 0.2
equivalents had detrimental effect, diminishing the yield
to 56% (entry 13).
Table 2 Reaction of Different Substituted Salicylaldehydes 1a–j
with Crotonaldehyde 2c
R4
O
R4
3b (20 mol%)
Cs2CO3 (1.0 equiv)
o-xylene, 120 °C
R3
R2
R3
R2
Table 1 Optimization of the Catalytic One-Pot Synthesis of Cou-
marin 4ac
+
H
O
OH
O
O
R1
1a–j
R1
4ac–hc
N
N
Cl
2c
(1.5 equiv)
O
Entry R1
R2
H
H
H
H
H
H
R3
H
H
H
Br
Br
I
R4
H
Product
4ac
4bc
4cc
Yield (%)
3b
conditions
+
1
2
H
81
74
37
42
79
67
36
33
0
H
O
OH
O
4ac
O
1a
2c
(1.5 equiv)
OMe
H
H
3
OMe
H
Entry 3b
Base (equiv) Solvent
Temp Yield
(%)
(equiv)
1.0
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
4
OMe
H
4dc
4ec
1
2
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
toluene
toluene
toluene
THF
reflux 74
reflux 58
reflux 63a
reflux 67
5
H
6
H
H
4fc
3
7
H
(–HC=CH–)2
H
4gc
4hc
4ic
4
8
Ph
H
H
H
H
5
THF–toluene (1:1) reflux 50
9
NEt2
H
H
H
6
Na2CO3 (1.0) toluene
KOt-Bu (1.0) toluene
Cs2CO3 (1.0) toluene
Cs2CO3 (1.0) THF
reflux 65
reflux 25
reflux 68
reflux 29
10
H
NO2
H
4jc
0
7
Finally we tested the applicability of the optimized cata-
lytic methodology to different a,b-unsaturated aldehydes
(Table 3). With acrolein (2a, R1, R2 = H) under our opti-
mized reaction conditions, but lower temperature (60 °C,
due to the higher volatility of acrolein), only 27% of the
coumarin 4aa were obtained (entry 1).
8
9
10
11
12
13
Cs2CO3 (1.0) THF–toluene (1:1) reflux 57
Cs2CO3 (1.0) benzene
Cs2CO3 (1.0) o-xylene
Cs2CO3 (0.2) o-xylene
reflux 34
120 °C 81
120 °C 56
Using 3.0 equivalents of acrolein, which were added sub-
sequently in three portions over six hours, the yield could
be increased to 40% (entry 2). The reaction proceeds also
with cinnamaldehydes 2c,d, albeit in only moderate yield
(entries 3 and 4). With prenal (2e, R1, R2 = Me) and citral
(2f, R1 = C6H11, R2 = Me) no conversion was observed
(entry 5, 6), indicating that b,b-disubstituted aldehydes
are no suitable substrates in this reaction.
a Slow addition of crotonaldehyde over 6 h.
After the optimization of the reaction conditions,11 we in-
vestigated the scope of the reaction, employing substitut-
ed salicylaldehydes 1a–j (Table 2). Methoxy groups on
the salicylaldehyde core are tolerated, although their posi-
Synlett 2011, No. 5, 635–638 © Thieme Stuttgart · New York

LETTER
Catalytic Synthesis of Coumarins
637
clization of the alkoxy group of 9 onto the activated car-
bonyl group would lead to a b-lactone, as observed by
Glorius et al. for related structures.5 In our case, another
reaction pathway is possible due to the presence of the
phenol group in the substrate: tautomerization of 9 to a
phenolate enables lactonization to the d-lactone 10. We
observed only the formation of the latter, the six-mem-
bered-ring lactone and were not able to isolate any b-lac-
tone. Finally, elimination of water under the basic reaction
conditions, furnishes coumarin 4b.
Table 3 Reaction of Salicylaldehyde 1a with Different a,b-Unsat-
urated Aldehydes 2a–f
R1
R1
O
3b (20 mol%)
Cs2CO3 (1.0 equiv)
o-xylene, 120 °C
R2
R2
+
H
O
OH
O
O
1a
2a–f
(1.5 equiv)
4aa, ab, ad
Entry
R1
R2
H
Product
Yield (%)
1
H
H
4aa
4aa
4ab
4ad
4ae
4af
27a
40b
32
47
0
Altogether, the reaction represents a redox esterification
of a,b-unsaturated aldehydes with simultaneous aldol
condensation. The bond-formation steps are quite unique
for NHC-catalyzed reactions, which usually proceed via
an a1-d1 or a3-d3 Umpolung.
2
H
3
Ph
H
4
2-MeOC6H4
Me
H
In summary, we have developed an organocatalytic meth-
odology for the synthesis of several coumarins. Employ-
ing 20 mol% of an inexpensive NHC precursor, the
reaction of crotonaldehyde, cinnamaldehydes and ac-
rolein with differently substituted salicylaldehydes pro-
ceed in moderate to good yields. This methodology thus
allows the readily construction of a variety of coumarins,
5
Me
Me
6
C6H11
0
a 60 °C.
b Addition of acrolein (3.0 equiv) over 6 h, 60 °C.
The proposed catalytic cycle for the coumarin formation a family of high interest for pharmacological studies.
is outlined in Scheme 3. Deprotonation of imidazolium
ion 3b generates the catalytically active NHC species 7
[R = 2,6-diisopropylphenyl (IPr)], which then adds to cro-
tonaldehyde (2c). Tautomerization of the generated zwit-
terion 5 gives rise to an intermediate, which can be drawn
as dienamine 6a or as its mesomeric homoenolate 6b.
Tautomerization forms the enol 8, which subsequently un-
dergoes a 1,2-addition to salicylaldehyde (1a). The addi-
tion product 9 represents an activated carbonyl group,
which is prone to intramolecular lactonization. In this
step, the catalytically active NHC 7 is regenerated. Cy-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. It contains
all experimental procedures, including those for the preparation of
starting materials, characterization of all compounds and 1H NMR
and 13C NMR spectra.
Acknowledgment
This work was supported by fellowships to U. Gross and P. Gross
from the Karlsruhe House of Young Scientists (KHYS) and the
DFG [Sino-German program GZ 417(362/1)].
~H
R
R
R
O
N
N
N
OH
H
O
OH
H
NR
~H
NR
NR
2c
5
6a
6b
R
N
+ base
3b
NR
R = 2,6-diisopropylphenyl
– base-H
7
O
OH
+ 1a
R
OH
RN
N
– H2O
O
O
O
O
O
O
NR
NR
4ac
10
9
8
Scheme 3 Proposed catalytic cycle for the reaction of a,b-unsaturated aldehydes with salicylaldehydes to coumarins
Synlett 2011, No. 5, 635–638 © Thieme Stuttgart · New York

638
U. Gross et al.
LETTER
Vanderheiden, S.; Bräse, S. Adv. Synth. Catal. 2005, 347,
555. (c) Volz, N.; Bröhmer, M. C.; Bräse, S. Synlett 2009,
550. (d) Bröhmer, M. C.; Volz, N.; Bräse, S. Synlett 2009,
1383. (e) For an account, see: Volz, N.; Bröhmer, M. C.;
Toräng, J.; Nieger, M.; Bräse, S. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 2009, 48, 1699.
References and Notes
(1) (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007,
107, 5606. (b) Díez-Gonzáles, S.; Nolan, S. P.; Marion, N.
Angew. Chem. Int. Ed. 2007, 46, 2988. (c) Nair, V.;
Vellalath, S.; Babu, B. P. Chem. Soc. Rev. 2008, 37, 2691.
(d) Purohit, V. C.; Matla, A. S.; Romo, D. Heterocycles
2008, 76, 949. (e) Droege, T.; Glorius, F. Angew. Chem. Int.
Ed. 2010, 49, 6940. (f) De Sarkar, S.; Studer, A. Angew.
Chem. Int. Ed. 2010, 49, 9266. (g) Thai, K.; Wang, L.;
Dudding, T.; Bilodeau, F.; Gravel, M. Org. Lett. 2010, 12,
5708. (h) Du, G.-F.; He, L.; Gu, C.-Z.; Dai, B. Synlett 2010,
2513. (i) Nair, V.; Vellalath, S.; Babu, B. P.; Varghese, V.;
Paul, R. R.; Suresh, E. Org. Biomol. Chem. 2010, 8, 4861.
(j) Jiang, H.; Gschwend, B.; Albrecht, Ł.; Jørgensen, K. A.
Org. Lett. 2010, 12, 5052.
(2) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239;
Angew. Chem. 1979, 91, 259.
(3) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534.
(4) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639;
Angew. Chem. 1976, 88, 695.
(5) (a) Burstein, C.; Tschan, S.; Xie, X.; Glorius, F. Synthesis
2006, 2418. (b) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7,
905. (c) Zeitler, K. Org. Lett. 2006, 8, 637. (d) Sohn, S. S.;
Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126,
14370. (e) Burstein, C.; Glorius, F. Angew. Chem. Int. Ed.
2004, 43, 6205.
(6) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131.
(7) (a) Toräng, J.; Vanderheiden, S.; Nieger, M.; Bräse, S. Eur.
J. Org. Chem. 2007, 943. (b) Lesch, B.; Toräng, J.;
(8) Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E.
Curr. Med. Chem. 2005, 12, 887.
(9) Khanolkar, A. D.; Lu, D.; Ibrahim, M.; Duclos, R. I.;
Thakur, G. A.; Malan, T. P.; Porreca, F.; Veerappan, V.;
Tian, X.; George, C.; Parrish, D. A.; Papahatjis, D. P.;
Makriyannis, J. A. J. Med. Chem. 2007, 50, 6493.
(10) Behrenswerth, A.; Volz, N.; Toräng, J.; Hinz, S.; Bräse, S.;
Müller, C. E. Bioorg. Med. Chem. 2009, 17, 2842.
(11) Typical Procedure
To a round-bottom flask with reflux condenser under argon
atmosphere were added salicylaldehyde (20 mL, 23 mg, 0.19
mmol), crotonaldehyde (23 mL, 19 mg, 0.28 mmol, 1.5
equiv), 1,3-diisopropyl-imidazolium chloride (7.0 mg, 37
mmol, 20 mol%), Cs2CO3 (60 mg, 0.19 mmol, 1.0 equiv) and
o-xylene (1.0 mL). The reaction mixture was heated to 120
°C for 12 h. Then H2O (10 mL) was added, and the resulting
mixture was extracted with EtOAc (3 × 10 mL). The
combined organic extracts were washed with brine (10 ml),
dried over MgSO4, and evaporated under reduced pressure.
Purification by chromatography on silica gel, eluting with
PE–EtOAc (20:1), yielded the desired product 4ac (26 mg,
81%) as a pale yellow solid.
Synlett 2011, No. 5, 635–638 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.