Microwave-assisted cyanation of 3-bromo-3-(1-hydroxyalkyl)benzo[b]selenophene derivatives

Article abstract of DOI:10.1016/j.mencom.2015.03.013

Microwave-assisted palladium-catalyzed cyanation of 3-bromo-2-(1-hydroxyalkyl)benzo[b]selenophene affords 3-cyano derivatives. Raising the temperature promotes formation of 2-(1-alkenyl)-3-carbamoyl isomers through intramolecular transfer of water.

Full text of DOI:10.1016/j.mencom.2015.03.013

Mendeleev
Communications
Mendeleev Commun., 2015, 25, 119–120
Microwave-assisted cyanation of 3-bromo-
3-(1-hydroxyalkyl)benzo[b]selenophene derivatives
Pavel Arsenyan,* Edgars Paegle and Sergey Belyakov
Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia. Fax: +371 6755 0338; e-mail: pavel@osi.lv
DOI: 10.1016/j.mencom.2015.03.013
Microwave-assisted palladium-catalyzed cyanation of 3-bromo-2-(1-hydroxyalkyl)benzo[b]selenophene affords 3-cyano derivatives.
Raising the temperature promotes formation of 2-(1-alkenyl)-3-carbamoyl isomers through intramolecular transfer of water.
Br
Benzoselenophenes have attracted increasing attention as building
Me
b
locks in both materials science and medicinal chemistry. Although
Me
benzo[b]selenophene heterocyclic system has not been found in
natural compounds so far, it is considered to be a bioisoster of
naphthalene, benzofuran, benzothiophene and indole.1 It has
been shown that benzoselenophene analogues of milfasartan and
eprosartan (compounds used for treatment of hypertension) are
excellent AT1 receptor antagonists and selenium analogues exhibit
higher activity than corresponding benzothiophene derivatives.2
Furthermore, fused selenophene ring containing systems have
attracted much interest due to their potential applicability as organic
semiconductors in various optoelectronic devices.3 According
to literature sources, 3-bromobenzo[b]thiophene was successfully
converted to 3-cyano derivative by palladium mediated treatment
with Zn(CN)2,4(a),(b) reaction with K4[Fe(CN)6],4(c) CuCN,4(d)
NaCN copper catalyzed,4(e) etc. Previously,5(a) we have reported
palladium [Pd2(dba)3/dppf] catalyzed cross-coupling of ethyl
3-bromobenzo[b]selenophene-2-carboxylate and zinc(ii) cyanide
providing the corresponding 3-cyano derivative. Based on the
above idea and our experience with thiophene and selenophene
chemistry,5(b)–(d) the present study was focused on the introduction
of cyano group in the 3-position of 2-hydroxymethyl-3-bromo-
benzo[b]selenophenes 1. Unfortunately, previously elaborated
methodology turned out to be unsuitable for cyanation of in-
activated substrates such as 1a.5(c)
Se
1a
OH
Zn(CN)2
DMF, MW,
170 °C, Ar,
5 min
(1.2 equiv.)
Pd(PPh3)4
(10 mol%)
DMF + H2O
MW, 170 °C, Ar, 5 min
O
NH2
CH2
CN
OH
Me
Me
+
Se
3 (48%)
Se
2a (31%)
Me
HN
H
O
CH2
Me
Se
A
Therefore, we activated the process by employing microwave
irradiation (Scheme 1).† When Pd(PPh3)4 was used as a catalyst,
reaction was complete at 170°C for 5 min to give ~1:1 mixture
of two products: the desired 3-cyano derivative 2a and an unusual
amide 3.‡ Formation of 3 can be explained by rearrangement
of 2-cyano derivative 2a through tricyclic intermediate A (see
Scheme 1
2-(Hydroxymethyl)benzo[b]selenophene-3-carbonitrile 2b: mp 133–
134°C, 64% yield. 1H NMR (400 MHz, CDCl3) d: 2.62 (t, 1H, OH,
3JHH 5.5 Hz), 5.17 (d, 2H, CH2, 3JHH 5.5 Hz), 7.32–7.39 (m, 1H, 6-CH),
7.44–7.50 (m, 1H, 5-CH), 7.84–7.89 (m, 2H, 4,7-CH). 13C NMR
(100.58 MHz, CDCl3) d: 61.6, 105.6, 114.4, 124.1, 125.6, 125.9 (2C),
139.0, 139.5, 165.4. MS (EI, 70 eV), m/z (%): 237 (56) [M]+. Found (%):
C, 50.80; H, 3.00; N, 5.85. Calc. for C10H7NOSe (%): C, 50.87; H, 2.99;
N, 5.93.
†
General method for cyanation of 1a–c. Bromobenzo[b]selenophene
derivative 1 (0.158 mmol), zinc(ii) cyanide (22 mg, 0.190 mmol), tetrakis-
(triphenylphosphine)palladium(0) (18 mg, 0.0158 mmol), and stirring
bar were placed in a microwave vial and dry DMF (4.0 ml) was added
by syringe under argon. The mixture was flushed with argon and then
subjected to microwave irradiation at 140°C (60 W) for 3 min. After
quenching with EtOAc (80 ml) and brine (30 ml), the mixture was stirred
at room temperature for 15 min. The organic phase was separated, washed
with brine (4×30 ml), dried over Na2SO4, and evaporated under reduced
pressure. Crude product was purified by column chromatography using
light petroleum–EtOAc (5:1) as eluent.
2-(1-Hydroxycyclohexyl)benzo[b]selenophene-3-carbonitrile 2c: mp 165
–
1
166°C, 67% yield. H NMR (400 MHz, CDCl3) d: 1.35–1.50 (m, 1H,
4'-CH), 1.63–1.82 (m, 5H, 4'-CH, 3',5'-CH2), 1.92–2.01 (m, 2H, 2',6'-CH),
2.23–2.36 (m, 2H, 2',6'-CH), 2.58 (br.s, 1H, OH), 7.30–7.37 (m, 1H,
6-CH), 7.44–7.50 (m, 1H, 5-CH), 7.82–7.92 (m, 2H, 4,7-CH). 13C NMR
(100.58 MHz, CDCl3) d: 21.8, 24.7, 37.5, 75.6, 102.8, 115.5, 123.9, 125.2,
125.5, 125.7, 137.9, 141.6, 176.9. MS (EI, 70 eV), m/z (%): 305 (85)
[M]+. Found (%): C, 59.05; H, 5.11; N, 4.55. Calc. for C15H15NOSe (%):
C, 59.22; H, 4.97; N, 4.60.
2-(2-Hydroxyprop-2-yl)benzo[b]selenophene-3-carbonitrile 2a: mp 118–
‡
1
2-(Prop-1-en-2-yl)benzo[b]selenophene-3-carboxamide 3 was obtained
119°C, 46% yield. H NMR (400 MHz, CDCl3) d: 1.85 (s, 6H, 2Me),
similarly from 1a except for the irradiation was applied at 170°C for
5 min, and mixture of DCM–EtOAc (5:1) was used as a chromato-
graphy eluent to afford amide 3 in 48% yield as a white amorphous solid,
mp 179–180°C. H NMR (400 MHz, DMSO-d6) d: 2.18 (s, 3H, Me),
5.23–5.26 (m, 1H, =CH), 5.36 (s, 1H, =CH), 7.28–7.34 (m, 1H, 6-CH),
2.72 (br.s, 1H, OH), 7.30–7.37 (m, 1H, 6-CH), 7.43–7.50 (m, 1H, 5-CH),
7.82–7.89 (m, 2H, 4,7-CH). 13C NMR (100.58 MHz, CDCl3) d: 30.5,
74.2, 103.0, 115.2, 123.9, 125.2, 125.6, 125.8, 137.9, 141.4, 176.2. MS (EI,
70 eV), m/z (%): 265 (50) [M]+. Found (%): C, 54.51; H, 4.29; N, 5.14.
Calc. for C12H11NOSe (%): C, 54.56; H, 4.20; N, 5.30.
1
© 2015 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2015, 25, 119–120
N(18)
C(17)
Br
CN
R
Zn(CN)2 (1.2 equiv.)
Pd(PPh3)4 (10 mol%)
R
R
R
C(13)
C(12)
C(4)
DMF, MW,
140 °C, Ar, 3 min
Se
1a–c
Se
OH
OH
C(3)
C(9)
C(11)
C(10)
C(5)
C(6)
2a–c
C(14)
a R = Me
b R = H
C(2)
C(15)
c R + R = (CH2)5
C(8)
C(7)
O(16)
Se(1)
Scheme 2
Figure 1 ORTEP molecular structure of 2c.
Scheme 1). To verify an intermolecular nature of this rearrange-
ment, an alternative experiment was performed by irradiation of
2a in DMF in the presence of water, however, no reaction
occurred. Apparently, the overall process is intramolecular
transfer of a water molecule from 2-hydroxyprop-2-yl moiety to
cyano group.
corresponding 3-cyano derivatives in preparative yields. Under
elevated temperature, product 2a undergoes a rearrangement
through intramolecular transfer of a water molecule to afford
amide 3. Further development of new methods for functionaliza-
tion of benzo[b]selenophenes is currently under study.
When the reaction was performed at 140°C and the reaction
time was shortened to 3 min, the rearrangement was completely
suppressed and 3-cyano derivative 2a was obtained in 46% yield
(Scheme 2). Close yields were achieved when NMP and DMA
were used as solvents. Lowering catalyst loading and further
temperature reduction resulted in poorer yields. Also, previously5(a)
employed Pd2(dba)3/dppf system did not cause the cross-coupling.
Using the optimized conditions, two other substrates 1b,c5(e)
were cyanated to give products 2b,c in 64 and 67% yields,
respectively (see Scheme 2). Structure of 2c has been unam-
biguously confirmed by X-ray analysis§,6 (Figure 1). In crystal
structure of 2c, intermolecular hydrogen bonds of type OH···N
between OH and CN groups with the length of 2.961(3) Å are
responsible for organization of molecule chains.
This work was supported by the Latvian Council of Science
(447/2012).
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In conclusion, microwave-assisted cyanation of inactivated
3-bromo-2-hydroxymethylbenzo[b]selenophenes provides the
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7.95 (br.s, 1H, NH), 7.98–8.02 (m, 1H, 7-CH). 13C NMR (100.58 MHz,
DMSO-d6) d: 23.0, 117.4, 124.5, 124.9, 125.1, 125.3, 133.7, 138.6, 139.1,
140.9, 145.2, 168.1. IR (film, n/cm–1): 3379.34, 3176.81, 1635.66 (C=O),
1404.20, 1280.76, 906.56, 743.57, 540.08. MS (EI, 70 eV), m/z (%): 265
(100) [M]+. Found (%): C, 54.41; H, 4.26; N, 5.19. Calc. for C12H11NOSe
(%): C, 54.56; H, 4.20; N, 5.30.
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§
Crystal data for 2c. C15H15NOSSe (M = 304.25), monoclinic, space group
P21/n, at 173 K: a = 6.7623(2), b = 16.5944(4) and c = 11.5591(4) Å, b =
91.992(1)°, V = 1296.34(7) Å3, Z = 4, m = 2.880 mm–1, dcalc = 1.559 g cm–3,
2qmax = 55.0°, reflections collected 5427, independent reflections 2957
(Rint = 0.027), reflections with I > ns(I) 2548 (n = 3), final R factor 0.029.
Diffraction data were collected on a Bruker-Nonius KappaCCD diffracto-
meter using graphite monochromated MoKa radiation (l = 0.71073 Å).
The structure was solved by direct methods and refined by full-matrix
least squares.6
CCDC 967167 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
Received: 14th July 2014; Com. 14/4423
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