Indium-Mediated Blaise-Type Reaction of Bromomalonates with Nitriles and Isocyanates

Article abstract of DOI:10.1055/s-0035-1561973

The indium-mediated Blaise-type reaction of bromomalonates with nitriles and isocyanates is described. The choice of the solvent is crucial for the successful reaction; the dependency on dichloromethane proved to be nonplussed. The reaction with nitriles

Full text of DOI:10.1055/s-0035-1561973

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
E. Babaoglu et al.
Letter
Synlett
Indium-Mediated Blaise-Type Reaction of Bromomalonates with
Nitriles and Isocyanates
Emre Babaoglu
Klaus Harms
Gerhard Hilt*
O
O
In
(1.5 equiv)
In
EtO
OEt
PhCN
O
O
CH2Cl2
40 °C, 24 h
(1.5 equiv)
CH2Cl2
40 °C, 24 h
O
O
H2N
O
Ph
O
67%
N
OEt
O
Fachbereich Chemie, Philipps-Universität Marburg,
Hans-Meerwein-Straße 4, 35043 Marburg,
Germany
EtO
OEt
MeO
1. 2-furylCN
O
N
H
In
Br
2. 2-MeOC6H4NCO
(1.5 equiv)
73%
EtO
OEt
PhNCO
Hilt@chemie.uni-marburg.de
CH2Cl2
40 °C, 24 h
O
NH
Ph
85%
Received: 15.02.2016
Accepted after revision: 10.03.2016
Published online: 24.03.2016
O
R1
O
R2
R2
Zn
Zn
In
EtO
H2N
Blaise
reaction
EtO
+
DOI: 10.1055/s-0035-1561973; Art ID: st-2016-b0108-l
N
R1
O
Br
Abstract The indium-mediated Blaise-type reaction of bromom-
alonates with nitriles and isocyanates is described. The choice of the
solvent is crucial for the successful reaction; the dependency on di-
chloromethane proved to be nonplussed. The reaction with nitriles led
to the corresponding β-enamino diesters in moderate to good yields.
The conversion with isocyanates generated carbamoyl malonates in
good to excellent yields. Both reactions tolerated various functional
groups regarding the electronic nature. Also, steric hindrance in the
starting materials, as caused by mesityl isocyanate or diisopropyphenyl
isocyanate, was well tolerated. In addition, a sequential three-compo-
nent one-pot reaction sequence is described for the formation of 2,4-
dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates enabling future in-
vestigations in this field.
O
R1
O
O
O
previous
work
EtO
OEt
EtO
EtO
OEt
OEt
+
R1
O
Br
O
R1
N
O
this
work
EtO
OEt
+
H2N
R1
Br
Scheme 1
To the best of our knowledge, zinc-mediated reactions
of bromomalonates with nitriles are unknown. Therefore,
we intended to expand our interest towards nitriles as un-
saturated starting materials in metal-mediated reactions
with bromo-functionalized starting materials.
Key words Blaise reaction, bromomalonates, indium, isocyanates, ni-
triles, pyrimidines
The Blaise reaction1 is originally a reaction of a bromoa-
cetate with a nitrile for the synthesis of β-ketoesters. Never-
theless, under careful hydrolysis, β-enamino esters can be
obtained as well (Scheme 1). The enamino esters are im-
portant intermediates for a number of very promising fol-
low-up reactions to access a number of interesting func-
tional-group assemblies. However, a major drawback of the
Blaise reaction are the rather low yields2 whereas the reac-
tion rates can be improved by ultrasonic irradiation.3 Also,
the scope of the Blaise reaction remained rather narrow
over the last centuries and is restricted towards bromoace-
tates as starting materials. In recent years, significant im-
provements were reported for the application of the Blaise
reaction in tandem transformations to access more com-
plex products.4
In a previous investigation, we realized the zinc-mediat-
ed carbon–carbon bond formation of a bromomalonate
with alkynes (Scheme 1)5 and follow-up reactions of the in
situ generated organo-zinc species.6 One key observation
for this reaction was the solvent dependency. The reaction
failed in THF as solvent, whereas dichloromethane proved
to be the optimal solvent for this transformation. As men-
tioned above, the Blaise reaction of bromomalonates has
not been described, and we propose that the in situ gener-
ated zinc-ester enolate species are not nucleophilic enough
to undergo a reaction with moderately active electrophiles.
This result could successfully be reproduced in our labora-
tory in THF as well as CH2Cl2 as solvent, and no product for-
mation from bromomalonates was observed.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
E. Babaoglu et al.
Letter
Synlett
In our ongoing investigation, we substituted zinc with
metallic indium.7 While the reaction in THF failed again, the
transformation in CH2Cl2 as solvent at 40 °C in a sealed tube
under inert atmosphere gave the desired product 1a in
moderate yields (Scheme 2).8
the in situ generated indium reagent from bromomalonate
had to react with the dinitrile starting material for the for-
mation of 1l. Accordingly, we were not surprised to isolate
only 17% of 1l as a highly polar product from benzo-1,4-di-
nitrile. A similar 2:1 adduct was expected for the reaction
with benzo-1,2-dinitrile, however, only the isoindole deriv-
ative 1k could be obtained as product. Although 1k was
only isolated in 21% yield. The unusual structure of the
product and the straightforward approach to access such a
molecule is highly appealing for investigations in perspec-
tive.
O
O
R1
O
O
In
(2.0 equiv)
EtO
OEt
EtO
OEt
+
CH2Cl2
40 °C, 24 h
N
Br
H2N
O
R1
(1.5 equiv)
1
O
O
O
O
O
In a second set of experiments, we applied the indium-
mediated Blaise-type reaction conditions to the addition to
isocyanates (Scheme 3).9 The results for these conversions
are significantly better than for the nitrile substrates, which
are presumably based on their higher electrophilicities. Ac-
cordingly, the products of electron-rich (2b,c), electron-de-
ficient (2d),10 simple aliphatic (2g), sterically more de-
manding aliphatic (2h), and congested aromatic isonitriles
(2e,f) could be isolated in good to excellent yields.
EtO
OEt
EtO
H2N
OEt
EtO
H2N
OEt
H2N
1c 48%
1a
1b
67%
68%
OMe
Br
O
O
O
O
O
O
EtO
OEt
EtO
OEt
EtO
H2N
OEt
O
H2N
H2N
1f 62%
1e
N
54%
1d
68%
CO2Me
CN
O
O
O
O
O
O
O
R1
+
O
O
In
N
C
O
EtO
H2N
OEt
EtO
OEt
O
EtO
OEt
Me
(2.0 equiv)
EtO
OEt
EtO
O
OEt
CH2Cl2
40 °C, 24 h
H2N
1g 94%
H2N
1i 17%
Br
HN
R1
O
1h 19%
CO2Et
2
(1.5 equiv)
O
O
O
OEt
O
O
O
O
O
O
O
O
O
NH2
EtO
OEt
EtO
CCl3
EtO
HN
OEt
EtO
HN
OEt
EtO
HN
OEt
OEt
O
EtO
OEt
H2N
H2N
2a
2b
2c
O
O
1j
42%
N
EtO
85%
96%
80%
17%
1l
MeO
O
H2N
1k 21%
O
O
O
O
Scheme 2
Me
O
O
O
EtO
HN
OEt
EtO
OEt
EtO
OEt
2d
O
2e
To achieve complete conversion, a slight excess of me-
tallic indium as well as a slight excess of the nitrile were
used and after 24 hours reaction time the reaction mixture
was quenched by addition of water to yield the adducts of
type 1 after workup.
HN
O
63%
2f
80%
HN
Me
Me
97%
iPr
iPr
O
O
Me
O
O
O
O
Me
EtO
EtO
OEt
The reaction could be expanded to a number of aromat-
ic nitriles. Electron-withdrawing functional groups (1a,b)
as well as an electron-donating functional group were ap-
plicable (1c). The best result was obtained for the 2-furan-
carbonitrile, where the desired product 1g could be isolated
in an excellent yield of 94%. Aliphatic nitriles were much
more problematic, resulting in low yields for butryronitrile
(1i) and ethyl cyanoacetate (1h). However, the application
of trichloroacetonitrile as nitrile component led to an ac-
ceptable yield of 42% of product 1j. Noteworthy, additional
bromo substituents (1b) were well accepted under the re-
action conditions and no proto-debromination was ob-
served. We then applied dinitriles as substrates in the indi-
um-mediated Blaise-type reaction. As mentioned above,
good results were obtained when the nitrile was used in
excess, however, for this transformation two equivalents of
OEt
2h
79%
HN
O
2g
HN
90%
nBu
Scheme 3
These two sets of reactions intrigued us to investigate
the possibility for a sequential three-component reaction.
Two scenarios were envisaged (Scheme 4): first reaction of
the indium reagent with a more reactive isocyanate to-
wards A and quenching of the secondary indium intermedi-
ate C with a less reactive nitrile for the formation of the het-
erocycle 3. The second scenario is the reverse process,
where first the reaction with a nitrile is conducted towards
intermediate B and then conversion with the more reactive
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
E. Babaoglu et al.
Letter
Synlett
isocyanate to generate D which will undergo a 1,3-H-shift
towards the heterocycle of type 4. It has to be mentioned
that the products of type 4 were reported by Lee and co-
workers9 who reacted bromoacetate with zinc and nitriles
in a traditional Blaise reaction and reacted the correspond-
ing zinc intermediate of type B first with isocyanates and
then with triphosgene to obtain the products of type 4 (4a
was synthesized in up to 73% yield).
tigated in the future to overcome this bottleneck in the
straightforward three-component synthesis of interesting
heterocyclic compounds.
Finally, we were interested to disclose the role of indi-
um-based Lewis acids as possible catalysts in the indium-
mediated Blaise-type reaction. Therefore, the readily avail-
able indium halides were applied, and under otherwise
identical reaction conditions, no conversion was observed
with indium trichloride and indium tribromide (Scheme 5).
On the other hand, when indium triiodide was applied, 49%
of product 1a was isolated after 24 hours reaction time.12
O
O
R1
R2
N
C
O
EtO
OEt
In
In
Br
N
O
O
O
O
O
Ph
N
O
O
O
O
InX3
EtO
OEt
EtO
OEt
+
CH2Cl2
40 °C, 24 h
EtO
In
OEt
EtO
In
OEt
R1
Br
H2N
Ph
1a
N
R1
N
R2
InCl3: 0%
lnBr3: 0%
InI3: 49%
A
B
N
C
O
R2
then
then
Scheme 5
N
O
O
N
O
O
Interestingly, the reaction led to a significant formation
of iodine, indicated by a deep purple color of the reaction
mixture. Under all reaction conditions described above, no
significant colored solution was observed. Accordingly, the
proposal emerged that indium triiodide was not stable un-
der the reaction conditions and led to the decomposition of
indium triiodide to metallic indium and iodine. When InI3
was heated to reflux in CH2Cl2, no iodine formation was ob-
served. Also, the addition of the benzonitrile or the product
(1a, Scheme 5) to this mixture did not result in a color
change. However, when bromomalonate was added, the im-
mediate formation of iodine was observed. After 24 hours
reaction time in the absence of benzonitrile, the formation
of iodomalonate (>95%) was detected (GC–MS analysis). On
a 1.00 mmol scale besides iodomalonate also the formation
of 0.83 mmol iodine was determined by titration of the io-
dine.13 Accordingly, the InI3 decomposed to iodine and me-
tallic indium.
R1
O
OEt
N
OEt
R2
N
O
N
O
R2
C
R1
D
OH
O
O
O
R1
O
N
OEt
N
OEt
O
R2
N
R1
N
H
R2
3
4
O
O
O
O
O
Ph
O
Ph
O
N
OEt
N
OEt
N
OEt
MeO
O
O
N
Ph
O
N
N
H
H
H
4a 17%
4b 73%
4c 70%
Scheme 4
The conversion of the in situ generated organoindium
species with nitriles and the subsequent quenching with
isocyanates (pathway A → C → 3) did not lead to the desired
products of type 3 as expected. Thus, the organoindium
species A is not nucleophilic enough to react with the ni-
trile to heterocycles of type 3. However, when the alterna-
tive reaction sequence for the synthesis of 2,4-dioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylates was investi-
gated, the desired product 4b11 and 4c derived from 2-cy-
anofurane could be isolated in good yields. Unfortunately,
when the less reactive benzonitrile was applied, the corre-
sponding pyrimidine derivative 4a could only be isolated in
17% yield. This considerable drop in efficiency will be inves-
In summary, we showed that the indium-mediated
Blaise-type reaction of bromomalonate could be realized
and the corresponding β-enamino esters were obtained.
The reaction with isocyanates gave the desired carbamoyl
malonates in good to excellent yields, and a sequential
three-component reaction was established to obtain two
2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates in
good yields. Finally, a Lewis acid mediated reaction mecha-
nism could be excluded and hints to a purely metal-induced
reaction could be reported.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561973.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
E. Babaoglu et al.
Letter
Synlett
References
(10) Synthesis of Diethyl 2-[(4-Acetylphenyl)carbamoyl]malonate
(2d)
(1) (a) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 478.
(b) Rao, H. S. P.; Rafi, S.; Padmavathy, K. Tetrahedron 2008, 64,
8037.
The reactions were carried out in sealed tubes under argon
atmosphere. Metallic indium pellets (2.00 mmol, 2.00 equiv)
were sliced to smaller pieces and evacuated in a sealed tube for
15 min, then suspended with dry CH2Cl2 (1.0 mL). To the sus-
pension was added diethyl bromomalonate (263 mg, 1.00
mmol, 1.00 equiv; 92% purity,) and 4-acetylphenyl isocyanate
(242 mg, 1.50 mmol). The clear reaction mixture was heated to
40 °C for 24 h. The reddish-brown suspension was cooled to
room temperature, poured into water (30 mL) and extracted
with CH2Cl2 (3 × 15 mL). The combined organic layers were
dried over Mg2SO4 and filtered off. The solvent was removed
under reduced pressure, and the crude product was purified by
flash chromatography on silica gel (eluent: pentane–EtOAc =
5:1 → 3:1) to afford the malonyl amide 2d (203 mg, 0.63 mmol;
63%); yellow solid, mp 85–86 °C; Rf = 0.13 (pentane–EtOAc =
3:1).
(2) Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833.
(3) Lee, A. S.-Y.; Cheng, R.-Y. Tetrahedron Lett. 1997, 38, 443.
(4) (a) Chun, Y. S.; Lee, K. K.; Ko, Y. O.; Shin, H.; Lee, S. Chem.
Commun. 2008, 5098. (b) Chun, Y. S.; Ko, Y. O.; Shin, H.; Lee, S.
Org. Lett. 2009, 11, 3414. (c) Chun, Y. S.; Ryu, K. Y.; Ko, Y. O.;
Hong, J. Y.; Hong, J.; Shin, H.; Lee, S. J. Org. Chem. 2009, 74, 7556.
(d) Ko, Y. O.; Chun, Y. S.; Kim, Y.; Kim, S. J.; Shin, H.; Lee, S. Tetra-
hedron Lett. 2010, 51, 6893. (e) Kim, J. H.; Lee, S. Org. Lett. 2011,
13, 1350. (f) Chun, Y. S.; Lee, J. H.; Kim, J. H.; Ko, Y. O.; Lee, S. Org.
Lett. 2011, 13, 6390. (g) Chun, Y. S.; Kim, J. H.; Choi, S. Y.; Ko, Y.
O.; Lee, S. Org. Lett. 2012, 14, 6358. (h) Chun, Y. S.; Xuan, Z.; Kim,
J. H.; Lee, S. Org. Lett. 2013, 15, 3162. (i) Kim, J. H.; Bouffard, J.;
Lee, S. Angew. Chem. Int. Ed. 2014, 53, 6435. (j) Sakthivel, K.;
Srinivasan, K. J. Org. Chem. 2014, 79, 3244. (k) Xuan, Z.; Kim, J.
H.; Lee, S. J. Org. Chem. 2015, 80, 7824. (l) Rao, H. S. P.;
Muthanna, N. Eur. J. Org. Chem. 2015, 1525. (m) Kim, J. H.; Ko, Y.
O.; Bouffard, J.; Lee, S. Chem. Soc. Rev. 2015, 44, 2489.
IR (neat): 3306, 3195, 3117, 2990, 2942, 2907, 1740, 1670,
1596, 1525 cm–1. 1H NMR (300 MHz, CDCl3-d1): δ = 9.56 (s, 1 H),
7.84 (d, 3J =8.8 Hz, 2 H), 7.59 (d, 3J =8.8 Hz, 2 H), 4.44 (s, 1 H),
4.20 (q, 3J =7.1 Hz, 4 H), 2.48 (s, 3 H), 1.21 (t, 3J =7.1 Hz, 6 H). 13
C
(5) Miersch, A.; Hilt, G. Chem. Eur. J. 2012, 18, 9798.
NMR (75 MHz, CDCl3-d1): δ = 197.0, 165.4, 160.6, 141.6, 133.3,
129.6, 119.4, 62.9, 59.7, 26.3, 13.8. HRMS (APCI+–TOF): m/z [M +
H]+ calcd for C16H20NO6: 322.1285; found: 322.1286.
(6) (a) Miersch, A.; Harms, K.; Hilt, G. Chem. Commun. 2014, 50,
542. (b) Miersch, A.; Kohlmeyer, C.; Hilt, G. Synthesis 2013, 45,
3228.
(11) Synthesis of Ethyl 6-(Furan-2-yl)-3-(2-methoxyphenyl)-2,4-
dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4b)
The reactions were carried out in sealed tubes under argon
atmosphere. Metallic indium pellets (2.00 mmol, 2.00 equiv)
were sliced to smaller pieces and evacuated in a sealed tube for
15 min, then suspended with dry CH2Cl2 (1 mL). To the suspen-
sion was added diethyl bromomalonate (263 mg, 1.00 mmol,
1.00 equiv; 92% purity) and 2-furonitrile (140 mg, 1.50 mmol,
1.50 equiv). The clear reaction mixture was heated to 40 °C for
24 h. To the reddish-brown suspension was added 4-acetylphe-
nyl isocyanate (350 mg, 3.00 mmol, 3.00 equiv) and heated to
40 °C for 24 h. The reddish suspension was cooled to room tem-
perature, diluted with EtOAc, poured into water (30 mL), and
extracted with EtOAc (3 × 15 mL). The combined organic layers
were dried over Mg2SO4 and filtered off. The solvent was
removed under reduced pressure, and the crude product was
purified by flash chromatography on silica gel (eluent:
pentane–EtOAc = 1:1 → 0:1) and recrystallized (pentane–EtOAc
= 5:1) to afford the pyrimidinone 4b (259 mg, 0.73 mmol; 73%);
yellowish solid, mp 215–216 °C; Rf = 0.29 (pentane–EtOAc = 1:1).
IR (neat): 3127, 2957, 2838, 1738, 1697, 1650, 1602, 1550,
1499, 1459, 1434 cm–1. 1H NMR (300 MHz, CDCl3-d1): δ = 10.01
(s, 1 H), 7.44 (d, J =1.6 Hz, 1 H), 7.40–7.30 (m, 1 H), 7.23–7.10
(m, 1 H), 7.01 (m, 1 H), 7.05–6.90 (m, 2 H), 6.39 (dd, J =3.7, 1.8
Hz, 1 H), 4.31 (q, 3J =7.1 Hz, 2 H), 3.70 (s, 3 H), 1.27 (t, 3J =7.1 Hz,
3 H). 13C NMR (75 MHz, CDCl3-d1): δ = 164.4, 160.6, 155.1,
151.2, 146.2, 143.1, 137.7, 130.7, 129.9, 122.7, 121.0, 116.2,
113.1, 112.0, 104.6, 62.3, 55.9, 14.2. HRMS data could not be
obtained. The identity of the product was confirmed by X-ray
analysis; see Supporting Information.
(7) (a) Hashmi, A. S. K. J. Prakt. Chem. 1998, 340, 84. (b) Chen, Y. H.;
Knochel, P. Angew. Chem. Int. Ed. 2008, 47, 7648. (c) Chen, Y. H.;
Sun, M.; Knochel, P. Angew. Chem. Int. Ed. 2009, 48, 2236.
(d) Hilt, G.; Smolko, K. I. Angew. Chem. Int. Ed. 2001, 40, 3399.
(e) Hilt, G. Angew. Chem. Int. Ed. 2003, 42, 1720. (f) Smolko, K. I.;
Waloch, C.; Hilt, G. Tetrahedron Lett. 2002, 43, 1437. (g) Ranu, B.
C.; Guchhait, S. K.; Sarkar, A. Chem. Commun. 1998, 2113.
(8) Synthesis of Diethyl 2-[Amino(furan-2-yl)methylene]malonate
(1g)
The reactions were carried out in sealed tubes under argon
atmosphere. Metallic indium pellets (2.00 mmol, 2.00 equiv)
were sliced to smaller pieces and evacuated in a sealed tube for
15 min, then suspended with dry CH2Cl2 (1.0 mL). To the sus-
pension was added diethyl bromomalonate (263 mg, 1.00
mmol, 1.00 equiv; 92% purity) and 2-furonitrile (140 mg, 1.50
mmol). The clear reaction mixture was heated to 40 °C for 24 h.
The reddish-brown suspension was cooled to room tempera-
ture, poured into water (30 mL), and extracted with CH2Cl2 (3 ×
15 mL). The combined organic layers were dried over Mg2SO4
and filtered off. The solvent was removed under reduced pres-
sure, and the crude product was purified by flash chromatogra-
phy on silica gel (eluent: pentane–EtOAc = 5:1 → 3:1) to afford
the enamino diester 1g (239 mg, 0.94 mmol, 94%); yellowish
solid, mp 33–34 °C; Rf = 0.32 (pentane–EtOAc = 3:1).
IR (neat): 3414, 3301, 3134, 2981, 2904, 1697, 1663, 1604,
.
1580, 1516, 1474 cm–1 1H NMR (300 MHz, CDCl3-d1): δ = 7.40
(dd, J =1.7, 0.5 Hz, 1 H), 9.04–5.40 (m, 2 H), 6.69 (dd, J =3.6, 0.5
Hz, 1 H), 6.37 (dd, J =3.6, 1.8 Hz, 1 H), 4.09 (q, 3J =7.1 Hz, 4 H),
1.17 (t, 3J =7.4 Hz, 3 H), 1.12 (t, 3J =7.4 Hz, 3 H). 13C NMR (75
MHz, CDCl3-d1): δ = 168.2, 167.8, 149.3, 147.3, 144.1, 112.9,
111.9, 92.3, 60.9, 59.8, 14.2, 13.8. HRMS (APCI+–TOF): m/z [M +
H]+ calcd for C12H16NO5: 254.1023; found: 254.1022.
(12) Almarzoqi, B.; George, A. V.; Isaacs, N. S. Tetrahedron 1986, 42,
601.
(13) The in situ generated iodine was complexed with starch and
titrated with Na2S2O3 solution, see: Strähle, J.; Schweda, E.
Jander/Blasius: Lehrbuch der Analytischen und Präparativen
Anorganischen Chemie, 14th ed.; Hirzel: Stuttgart, 1995, 283.
(9) Chun, Y. S.; Xuan, Z.; Kim, J. H.; Lee, S. Org. Lett. 2013, 15, 3162.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D