Microwave-promoted michael addition of azaheterocycles to α,β-unsaturated esters and acid under solvent-free conditions

Article abstract of DOI:10.1055/s-0031-1290164

Regioselective Michael addition of N-9 adenine to ethyl acrylate under microwave activation in solid-liquid solvent-free phase-transfer catalysis using TBAB as catalyst and DABCO as base was extended to tert-butyl acrylate and acrylic acid. Under these conditions and in the presence of a catalytic amount of KOH, first Michael addition of indole and indolylmaleimide to acrylates is also reported. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290164

LETTER
▌791
Letter
Microwave-Promoted Michael Addition of Azaheterocycles to α,β-Unsaturat-
ed Esters and Acid under Solvent-Free Conditions
Michael Addition of Azaheterocycles to α,β-Unsaturated Esters and Acid
Lilian Dubois, Francine C. Acher, Isabelle McCort-Tranchepain*
Université Paris Descartes, Sorbonne Paris Cité, UMR 8601 CNRS, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques,
45 Rue des Saints-Pères, 75270 Paris Cedex 06, France
Fax +33(1)4286218387; E-Mail: isabelle.mccort@parisdescartes.fr
Received: 09.11.2011; Accepted after revision: 04.01.2012
solution7,8 and under solvent-free conditions.9,10 Some ste-
Abstract: Regioselective Michael addition of N-9 adenine to ethyl
rically hindered substituents in α,β-position of the
acrylate under microwave activation in solid-liquid solvent-free
Michael acceptors have been studied but with few alkoxy
groups (Me, Et, n-Bu). tert-Butyl acrylate has only been
phase-transfer catalysis using TBAB as catalyst and DABCO as
base was extended to tert-butyl acrylate and acrylic acid. Under
these conditions and in the presence of a catalytic amount of KOH, reported to react with 6-chloropurine in water leading re-
gioselectively to the N-9-alkylated product in 76% yield.7
first Michael addition of indole and indolylmaleimide to acrylates is
also reported.
We have been particularly interested in the regioselective
Key words: microwave irradiation, Michael addition, azahetero-
addition of N-9 adenine 1 to 4a described by Khalafi-
cycles, phase-transfer catalysis, green chemistry
Nezhad et al.9 in the presence of 1,4-diazabicy-
clo[2.2.2]octane (DABCO), a catalytic amount of TBAB
under microwave and solvent-free conditions, leading to
Alkylation of purines and indoles usually results in the
compound 5a in 72% yield. To the best of our knowledge,
formation of regioisomeric mixtures. Treatment of 6-sub-
such conditions have never been described to N-1 position
stituted- and 2,6-disubstituted-purines with a base such as
neither of indole 2 nor of bisindolylmaleimide 3 with
Michael acceptors 4a–c.
sodium hydride followed by addition of an alkylating
agent normally produces both 7-and 9-alkylpurines,1 ex-
Herein, we report the results concerning the Michael ad-
cept with 6-(heteroaryl)purine where regiospecific N-9-
dition assisted by microwave irradiation of azaheterocy-
cles 1–3 to ethyl and tert-butyl acrylates (4a,b) and acrylic
acid (4c) under solvent-free conditions leading to the cor-
responding derivatives in good yields depending on the
presence of an additive base (Scheme 1).
alkylation occured.2 Therefore, functionalization at N-6 or
C-8 positions of adenine and derivatives is usually per-
formed with N-9-alkylated product to provide the desired
compounds with better regioselectivities and yields.3 In-
dole can also suffer from a lack of regioselectivity during
N-1-alkylation with formation of the C-3 regiomeric
product but can usually be controlled by reaction in basic
medium.4
W
W
Z
Z
X
X
base, TBAB
MW
CO2R
+
In the course of our ongoing work on ATP mimics, we
were interested in functionalizing adenine 1 and alkylat-
ing the nitrogen atom of other azaheterocycles, such as in-
dole 2 and bisindolylmaleimide 3 (Scheme 1).5 Michael
addition to α,β-unsaturated carbonyl compounds seems to
be a mean of choice to get a short linker bearing a protect-
ed group that can be functionalized afterwards to intro-
duce molecular diversity.
N
N
H
Y
Y
1: W = NH2; X = Y = Z = N
2: W = H; X = Y = Z = C
3: W = H; X = Y = C;
4a: R = Et
4b: R = t-Bu
4c: R = H
CO2R
Z = indolylmaleimide
Scheme 1
Performing conjugate addition of adenine 1 to 4a, under
the standard conditions reported by Khalafi-Nezhad,9 led
to the N-9-alkylated 5a in 78% yield (Scheme 2 and Table
1, entry 1). Ethyl ester hydrolysis of 5a was performed in
HCl (3 N) to furnish the deprotected compound 5c.
For this purpose, microwave irradiation allows perform-
ing reactions faster and in higher yields than in a conven-
tional thermal method.6 The phase-transfer catalyst
tetrabutylammonium bromide (TBAB) is a highly micro-
wave-absorbent material that is able to restitute heating
around 100 °C in nonpolar reaction mixtures as well as to
create a homogeneous medium in solvent-free reactions.
We were also interested in synthesizing functionalized
ethenonucleobases for their fluorescent properties. N-1,N-
6-Amino cyclization of adenine 5a with chloroacetalde-
hyde in a sodium acetate buffer led to the alkylated etheno
derivative 6a11 that went back to adenine 5c during the
previous acidic hydrolysis conditions of the ethyl ester.
Microwave-assisted Michael addition of N-9 adenine 1 to
α,β-unsaturated esters has been reported recently in
SYNLETT 2012, 23, 791–795
Advanced online publication: 09.02.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290164; Art ID: ST-2011-D0648-L
© Georg Thieme Verlag Stuttgart · New York

792
L. Dubois et al.
LETTER
N
N
NH2
N
NH2
N
NH2
N
N
N
N
N
N
N
N
N
N
N
a
N
N
N
a
a
N
c
N
N
H
CO2Et
N
(CH2)2
CO2R
(CH2)2
CO2R
1
4a
5a
CO2R
CO2R
b
b
6b: R = t-Bu
6c: R = H
5b: R = t-Bu
5c: R = H
b
b
5c: R = H
6a: R = Et
Scheme 3 Reagents and conditions: (a) ClCH2CHO, NaOAc,
45 °C, 48 h, 68% from 5b and 52% from 5c; (b) TFA–CH2Cl2, r.t., 2
h, 87% from 5b, and 80% from 6b.
Scheme 2 Reagents and conditions: (a) DABCO, TBAB, 200 W,
8 min, 78%; (b) HCl (3 N), reflux, 4 h, 87%; (c) ClCH2CHO, NaOAc,
45 °C, 48 h, 75%.
Due to the variety and potent activity exhibited by indole
derivatives, we then studied the microwave-assisted
Michael addition of indole 2 to acrylates 4 (Table 2) since
only one example has been reported in solution but with a
C-3-substituted indole.16 In conventional solution reac-
tion, such Michael acceptors have proved to N-alkylated
indole 2 in basic medium,17 whereas Brønsted acid18 and
Lewis acid19 catalysts promoted the C-3 alkylation. Inter-
estingly, Michael addition of indole to ethyl 2-(dieth-
ylphosphoryl)acrylate in AcOH led to C-3-alkylated
compounds and in basic medium to a mixture of both N-
and C-3-alkylated products.20 Under microwave irradia-
tion, Michael addition of indole to β-nitrostyrene in water
underwent in C-3 position,21 whereas to alkyl halide N-
alkylation occurred under phase-transfer catalysis.22
To overcome this disadvantage, we extended the above
reaction to the anhydrous acid-sensitive protected and un-
protected Michael acceptors 4b and 4c, respectively (Ta-
ble 1, entries 2 and 3). Interestingly, under the same
conditions, compounds 5b and 5c were obtained in quite
comparable yields from 1 in a 15 mmol scale-up,12–14
whereas reactions in a tenfold lesser quantity, yields
dropped drastically to 17–26%, using a standard vessel.
Hence, steric hindrance induced either by the bulky tert-
butyl group or by the carboxylate salt showed no influ-
ence during the reaction, allowing the first preparation in
one step of the useful synthon N-propanoic acid (5c).
These encouraging results, added to the fact that ethyl ac-
rylate 4a has a particularly unpleasant smell, led us to
work specifically with the Michael acceptors 4b and 4c.
In the Khalafi-Nezhad’s conditions9 but with a slight ex-
cess of DABCO with respect to indole2, only 10% reacted
with 4b (Table 2, entry 1) leading regioselectively to 7b.
Indole 2 with a lower acidity than adenine would need a
prolonged reaction time and/or a stronger base due to its
lowest concentration of the anionic form in the reaction
mixture. The presence of four equivalents of both KOH
and K2CO3, a base mixture previously used with alkyl ha-
lide,22 improved the conversion to 48% and significantly
reduced the reaction time to 1.5 minutes until spark ap-
peared (Table 2, entry 2). We could not conclude if the
modest yield of compound 7b was due to a lack of reac-
tivity in this particular heterogeneous mixture or to aza-
retro-Michael addition in thermal and basic conditions.23
Using only KOH as additive base and lowering the
amount to 0.4 equivalents dramatically enhance the for-
mation of 7b to 83% yield (Table 2, entry 3).24,25 We as-
sume that under microwave activation, TBAB first reacts
with KOH to produce tetrabutylammonium hydroxide
(TBAOH), as it was postulated in solution.26 TBAOH
seemed to be a highly microwave-absorbent material
since the rise in temperature occurred much faster, reduc-
ing the reaction time and promoting the reaction in a more
efficient manner.
Table 1 Michael Addition of Adenine 1 to Acrylates 4
NH2
NH2
N
N
N
DABCO, TBAB
8 min, 200 W
N
N
CO2R
+
N
H
N
N
1
4
5
CO2R
Entry
4
R
5
Yield (%)
1
2
4a
4b
4c
Et
5a
78a (26)b
71a (17)b
72a (22)b
t-Bu
5b
5c
3c
H
a Reaction conditions: 1 (15 mmol), molar ratio 1/4/DABCO/TBAB
= 1:1.5:1:0.2.
b Reactions performed with1 (1.5 mmol).
c In this reaction a molar ratio of 1/DABCO = 1:2 was used.
In order to check the relevance of using the tert-butylac-
rylate 4b in comparison with the acrylic acid (4c) during
the synthesis of compound 6c, the alkylated compounds
5b and 5c were subjected to the amino cyclization in the
conditions previously used for 5a (Scheme 3) leading to
the etheno derivatives 6b and 6c.15 Compounds 5b and 6b
were then subjected to anhydrous acidic conditions, lead-
ing to the corresponding acid derivatives 5c and 6c in
good yields.
These conditions applied to the ethyl ester 4a furnished
the alkylated indole 7a but only in 56% yield, probably
due to some saponification during the workup, since ana-
lytical control of the crude product showed only traces of
the starting material 2 (Table 2, entry 4). In the presence
of the acrylic acid (4c), although no alkylated product 7c
Synlett 2012, 23, 791–795
© Georg Thieme Verlag Stuttgart · New York

LETTER
Michael Addition of Azaheterocycles to α,β-Unsaturated Esters and Acid
793
Table 2 Michael Addition of Indole 2 to Acrylates 4a
DABCO, TBAB, additives
200 W
+
CO2R
N
N
H
7
2
4
CO2R
Entry
4
Additive (molar ratio)
Time (min)
7
R
Yield (%)
1
2
3
4
4b
4b
4b
4a
4c
none
10
1.5
1
7b
7b
7b
7a
7c
t-Bu
t-Bu
t-Bu
Et
10
48
83
56c
0
KOH (4), K2CO3 (4)
KOH (0.4)
KOH (0.4)
KOH (0.8)
1.5
1
5b
H
a Reaction conditions: 2 (15 mmol), molar ratio 2/4/DABCO/TBAB = 1:1.5:1.2:0.2.
b In this reaction a molar ratio of 2/DABCO = 1:2.4 was used.
c Unoptimized conditions.
has been isolated, Michael addition did occur, but was fol- nished peaks at 262, 390, and 518 indicating the presence
lowed by in situ retro-Michael reaction under basic condi- of some unalkylated compounds at N-9 position.
tions and microwave activation (Table 2, entry 5), as
Under the standard conditions,9 no reaction occurred be-
tween the Michael donor 3 and acrylate 4c until one
equivalent of TBAB was used in combination with 500 W
already demonstrated to occur from adeninylpropionic
acid under thermal and pressure conditions.27
We then applied the best conditions reported in Table 2 microwave activation, leading to the substituted bisin-
(entry 3) to Michael addition of adenine 1 to 4b. In these dolylmaleimides 8c and 9c (Table 3, entry 1). Likewise,
basic conditions, the N-9-alkylated compound 5b was ob- the 2-(trimethylsilyl) ethoxymethyl (SEM) NH-
tained in 62% yield along with a mixture of byproducts re- bisindolylmaleimide5 reacted under these conditions, but
sulting from nonregioselective and multialkylations. led predominantly to the unprotected compound 3. Vari-
Although these minor byproducts were not independently ous attempts to regioselectively produce the monoalkylat-
isolated, mass spectra allowed identifying from mono- to ed 8b failed, even in the presence of KOH (0.4 equiv,
penta-alkylated products. Indeed, positive ionization Table 3, entry 2). Nevertheless, under these conditions,
showed peaks corresponding to the mono- (264), di- the reaction took place with a catalytic amount of TBAB
(392), tri- (520), tetra- (648), and penta- (776) alkylated with 200 W power microwave activation, supporting our
compounds, whereas detection by negative mode fur- hypothesis of the formation of TBAOH.
Table 3 Michael Addition of Bisindolylmaleimide 3 to Acrylates 4b and 4c
Me
Me
N
N
O
O
O
O
CO2R
4b,c
R1 = (CH2)2CO2R; R2 = H R1 = R2 = (CH2)2CO2R
8b: R = t-Bu
8c: R = H
9b: R = t-Bu
9c: R = H
TFA, CH2Cl2
r.t., 2 h, 84%
DABCO, TBAB
additive, MW
N
N
N
N
R1
R2
H
H
3
Entry
MW power, time Reagents (molar ratio)
8
Yield (%)
9
Yield (%)
1
2
3
500 W, 20 min
200 W, 10 min
200 W, 10 min
4c (3), TBAB (1), DABCO (5)a
8c
27
9
9c
9b
9b
37
25c
71
4b (1), TBAB (0.2), DABCO (1.2), KOH (0.4)b
4b (2.4), TBAB (0.2), DABCO (1.2), KOH (0.8)b
8b
8b
0
a Reactions performed with 3 (0.85 mmol).
b Reactions performed with 3 (5 mmol).
c Along with 60% of recovered starting material.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 791–795

794
L. Dubois et al.
LETTER
(10) (a) Zare, A.; Hasaninejad, A.; Beyzavi, M. H.; Parhami, A.;
Moosavi, Zare. A. R.; Khalafi-Nezhad, A.; Sharghi, H. Can.
J. Chem. 2008, 86, 317. (b) Zare, A.; Hasaninejad, A.;
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(13) Procedure for the Synthesis of 9-(2-tert-Butoxycarbonyl-
ethyl)adenine (5b)
Thus, the resulting intermediate 8b seems to be more re-
active towards the alkylation than the starting material 3.
This result is quite different of what is usually observed in
solution concerning monoprotection of symmetric bisin-
dolylmaleimide. On the other hand, the bisalkylatedin-
dolylmaleimide 9b was obtained alone in 71% yield with
an excess of Michael acceptor 4b (Table 3, entry 3) and
easily converted into 9c.
We have shown that previously reported conjugate addi-
tion of adenine 1 to ethyl acrylate (4a) assisted by micro-
wave activation can be extended to Michael acceptors,
tert-butyl acrylate (4b), and acrylic acid (4c), as well as to
other Michael donors, indole (2) and bisindolylmaleimide
(3) in the presence of a catalytic amount of KOH, provid-
ing a regioselective access in good yields to the corre-
sponding N-ethyl and tert-butylpropanoate and propanoic
acid derivatives that can be further functionalized. In
these environmentally friendly conditions, aza-Michael
addition with acrylic acid had never been reported yet.
Furthermore, N-ethyl and tert-butyl propanoate are also
versatile protective groups of azaheterocycles since after
ester hydrolysis, N-propanoic acid can easily undergo
subsequent retro-Michael addition under basic conditions
and thermal or microwave activation.
Adenine 1 (2.027 g, 15 mmol), DABCO(1.681 g, 15 mmol),
TBAB (967 mg, 3 mmol) were ground until a homogeneous
mass was obtained, then 4b (3.27 mL, 22.5 mmol) was
added. The reaction mixture was stirred using a dark
magnetic bar for 30 min before irradiation at 200 W in a
microwave oven. The reaction mixture was suspended in
CHCl3 (450 mL) and washed with H2O (3 × 250 mL). The
organic layer was dried (MgSO4), filtered, and evaporated
under reduced pressure to give 2.81 g (71%) of 5b as a white
powder.
(14) Spectral and Analytical Data of Compound 5b
Mp 182–184 °C (lit.12 183–185 °C); Rf = 0.6 (CH2Cl2–
MeOH = 9:1). 1H NMR (500 MHz, CDCl3): δ = 8.14 (s, 1H,
H-2), 8.09 (s, 1H, H-8), 7.16 (s, 2H, NH2), 4.34 (t, J = 7.0
Hz, 2H, CH2N), 2.85 (t, J = 7.0 Hz, 2H, CH2CO), 1.31 (s,
9H, CH3). 13C NMR (500 MHz, DMSO): δ = 169.7 (CO),
155.9 (Cq-Ar), 152.3 (C-2), 149.4 (Cq-Ar), 140.9 (C-8),
118.7 (Cq-Ar), 80.4 (Cq-t-Bu), 39.0 (CH2N), 34.9 (CH2CO),
27.8 (CH3). IR: ν = 3292 (NH2), 1723 (CO) cm–1. MS (ESI+):
m/z (%) = 264.0 (100) [M+H]+. HRMS (ESI+) calcd for
[C12H17N5O2 +H]+: 264.1457; found: 264.1451.
Acknowledgment
The authors are thankful to the Neuropôle Région Ile-de-France
(NeRF) for PhD financial support (L.D.).
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Synlett 2012, 23, 791–795
© Georg Thieme Verlag Stuttgart · New York

LETTER
Michael Addition of Azaheterocycles to α,β-Unsaturated Esters and Acid
795
(23) Boncel, S. A.; Mączka, M.; Walczak, K. Z. Tetrahedron
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(24) Optimized Procedure for the Synthesis of 1-(2-tert-
Butoxycarbonylethyl)indole (7b)
(25) Spectral and Analytical Data of Compound 7b
1H NMR (500 MHz, DMSO): δ = 7.56 (d, J = 8.0 Hz, 1 H,
H-7), 7.50 (d, J = 8.2 Hz, 1 H, H-4), 7.35 (d, J = 3.2 Hz, 1 H,
H-2), 7.14 (t, J = 8.0 Hz, 1 H, H-6), 7.02 (t, J = 8.2 Hz, H-5),
6.42 (d, J = 3.2 Hz, 1 H, H-3), 4.40 (t, J = 6.7 Hz, 2 H,
CH2N), 2.74 (t, J = 6.7 Hz, 2 H, CH2CO), 1.32 (s, 9 H, CH3).
13C NMR (500 MHz, CDCl3): δ = 170.2 (CO), 135.7, 128.7
(Cq-Ar), 127.8 (C-4), 121.4 (C-5), 120.9 (C-7), 119.3 (C-6),
109.1 (C-2), 101.3 (C-3), 80.7 (Cq-t-Bu), 41.7 (CH2N), 36.0
(CH2CO), 27.8 (CH3). IR: ν = 1726 (CO) cm–1. MS (ESI+):
m/z (%) = 246.1 (100) [M+H]+. HRMS (ESI+): m/z calcd for
[C15H19N5O2 +H]+: 246.1489; found: 246.1488.
Indole 2 (1.77 g, 15 mmol), DABCO (1.681 g, 15 mmol),
TBAB (967 mg, 3 mmol) were ground until a homogeneous
mass was obtained, then 4b (3.27 mL, 22.5 mmol) was
added. The reaction mixture was stirred using a dark
magnetic bar for 30 min. KOH (337 mg, 6 mmol) was added,
and the mixture was stirred for further 2 min just before
irradiation at 200 W in a microwave oven. The reaction
mixture was suspended in CH2Cl2 (200 mL), washed with
H2O (3 × 200 mL). The organic layer was dried (MgSO4)
and evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel
(cyclohexane–EtOAc = 99:1) to give 3.06 g (83%) of 7b
as a brown oil.
(26) Wang, M.-L.; Liu, B.-L. J. Chin. Inst. Chem. Eng. 2007, 38,
85.
(27) Lira, E. P.; Huffman, C. W. J. Chem. Soc. 1966, 2188.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 791–795

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