A new synthesis of versatile indolyl-3-carbonylnitriles

Article abstract of DOI:10.1016/j.tetlet.2015.07.075

Abstract Indolyl-3-carbonylnitriles are compounds with demonstrated utility as intermediates in organic chemistry. However, their synthesis remains a challenge, requiring the use of toxic sources of cyanide, and often proceeding in low yields. Accordingly, presented here is a new synthesis of these versatile reactants, via dehydration of easily accessible α-oxoacetamides in generally high yields under simple reaction conditions.

Full text of DOI:10.1016/j.tetlet.2015.07.075

Accepted Manuscript
A new synthesis of versatile indolyl-3-carbonylnitriles
Clinton G.L. Veale
PII:
S0040-4039(15)01239-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.07.075
TETL 46564
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
6 May 2015
10 June 2015
24 July 2015
Please cite this article as: Veale, C.G.L., A new synthesis of versatile indolyl-3-carbonylnitriles, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.07.075
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Clinton G. L. Veale

1
Tetrahedron Letters
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A new synthesis of versatile indolyl-3-carbonylnitriles
a,
Clinton G. L. Veale ∗
a
Faculty of Pharmacy, Rhodes University, Grahamstown, 6140, South Africa
ARTICLE INFO
ABSTRACT
Article history:
Received
Indolyl-3-carbonylnitriles are compounds with demonstrated utility as intermediates in organic
chemistry. However, their synthesis remains a challenge, requiring the use of toxic sources of
cyanide, and often proceeding in low yields. Accordingly, presented here is a new synthesis of
these versatile reactants, via dehydration of easily accessible α-oxoacetamides in generally high
yields under simple reaction conditions.
Received in revised form
Accepted
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Carbonyl nitrile
Indole
α-Oxoacetamide
Amide dehydration
—
——
∗
Corresponding author. Tel.: +27-46-603-8096; fax: +27-603-7506; e-mail: c.veale@ru.ac.za

2
1
Janosik successfully synthesized C-5 brominated indolyl-3-
0
The carbonyl nitrile moiety has demonstrated versatility in
organic chemistry, serving as a useful reactant and intermediate
carbonylnitrile (3) over three steps from indole via Vilsmeier-
Haack formylation and subsequent reaction with TMSCN to
yield an unstable O-silylated cyanohydrin which was oxidised
using DDQ.
1–9
in an assortment of organic syntheses. Specifically, the utility
of indolyl-3-carbonylnitriles has been shown through their
application to the synthesis of a variety of indole natural products
1
0–13
(
Figure 1).
However, to date only two methods exist for the
synthesis of indolyl-3-carbonylnitriles. The original method of
Classically, carbonyl nitriles have been synthesized through
the reaction between an electrophilic species, such as an acid
chloride or aldehyde, and an inorganic cyanide source e.g.
1
1
Hogan and Sainsbury occurs through the formation of a glyoxal
chloride intermediate, followed by thermolytic decarbonylation
and subsequent nucleophilic substitution of the resultant acid
chloride with a nitrile anion to yield indolyl-3-carbonylnitrile (1).
This method has been extensively applied to the synthesis of
compound 1, with reasonable success. However, it was found to
Cu(I)CN, KCN or TMSCN, followed by oxidation to regenerate
5,6,16–19
the carbonyl if necessary.
potentially dangerous sources of cyanide, various research groups
In an effort to avoid the use of
have exploited the conversion of activated oximes into nitriles
20,21
1
4
and carbonyl nitriles respectively.
known to dehydrate in the presence of thionyl chloride to give
Moreover, aryl amides are
be inefficient when applied to halogenated indole systems. In
order to access the desired C-6 brominated indolyl-3-
22
the corresponding aryl nitriles and it was reasoned this could
1
5
carbonylnitrile (2), Horne and co-workers opted to directly
possibly be applied to the synthesis of 1 from indolyl-3-α-
oxoacetamide (4). Herein, is described a new two step synthesis
of indolyl-3-carbonylnitriles (1 – 3, 5 – 9) from a variety of
indoles using readily available reagents under facile reaction
conditions, without the requirement of a cyanide source.
brominate 1, proceeding in moderate yield.
Scheme 1. Reagents and conditions: a) (COCl)
2
, Et
2
O, 0 °C, Ar,
1 h, 98%; b) sat. aq. NH
quant.
4
Cl, KOH; c) SOCl
2
, DMF, 0 °C, Ar, 2 h
Fig. 1 Examples of natural products synthesised from indolyl-3-
carbonylnitrile (1)
a
Table 1. Synthesis of carbonyl nitriles 2, 3, 5 – 9, 20 and 21
Starting
material
Yield
b
(%)
Carbonyl
nitrile
Yield
b
(%)
Starting
material
Yield
b
(%)
Carbonyl
nitrile
Yield
b
(%)
Entry
α-Oxoacetamide
Entry
α-Oxoacetamide
1
79
90
96
66
85
90
95
94
7
58
67
72
10
95
90
80
2
3
4
8
9
10
N.A.
N.A.
N.A.
5
40
98
84
97
11
12
0
0
6
a
b
Reaction conditions as per Scheme 1. Isolated yields. N.A. = not applicable.

3
This reaction was initially examined with the synthesis of
2
Acknowledgments
3
compound 4 which proceeded via acylation with oxalylchloride,
followed by the addition of a saturated aqueous solution of
ammonium chloride and potassium hydroxide after one hour
This research project was financially supported by Rhodes
University.
(N.B. a violent reaction occurs). The resultant precipitate was
filtered and washed with chloroform, to give compound 4 in high
Supplementary data
yield (98%). Subsequent carbonyl nitrile formation involved the
2
Supplementary data relating to experimental procedures and
spectral data can be found in the online version.
2
2
addition of 2.5 eq. of SOCl to a stirred solution of 4 in DMF.
After two hours the reaction was quenched with water and
extracted with EtOAc, giving compound 1 in quantitative yield,
without the need for further purification (Scheme 1).
References
(
1)
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Following this success, the synthesis of brominated
compounds 2 and 3 was subsequently investigated (Table 1,
entries 1 and 2). Acylation and amide formation using 5-
bromoindole (entry 2) occurred in high yield, while the reaction
of 6-bromoindole (entry 1) generated α-oxoacetamide (11) in a
lower but still satisfactory yield. Dehydration of compounds 11
and 12 proceeded efficiently to deliver indoles 2 and 3 in higher
(2)
(3)
(4)
(5)
1
0,14,15
yields than those previously reported.
Further effects of ring
halogenation on this method were explored using three additional
halogenated indole analogues (entries 3 – 5). The presence of
chlorine at the indole C-6 position (entry 3) proved
inconsequential in the formation of compound 13, while reaction
with 5-fluoro-6-chloroindole (entry 4) resulted in a lower yield of
α-oxoacetamide (14). The proceeding dehydration step again
delivered carbonyl nitriles 5 and 6 in high yield. Interestingly, 7-
chloroindole (entry 5) significantly impeded the formation of 15,
reducing the overall yield of carbonyl nitrile 7. However, this
result was still pleasing since it had been demonstrated by Yeung
(6)
(7)
(8)
(9)
2
4
et al. that C-7 halogen displacement was possible in the
presence of a nucleophilic cyanide species, which is commonly
utilised in the previously described methods for carbonyl nitrile
formation.
(10)
(11)
Janosik, T.; Johnson, A.-L.; Bergman, J. Tetrahedron
2002, 58, 2813–2819.
Hogan, I. T.; Sainsbury, M. Tetrahedron 1984, 40, 681–
6
82.
Additional application of this method was demonstrated using
-methylindole (entry 6) whose corresponding carbonyl nitrile
8) was synthesized in high yield via 16, and 2-methyl indole
entry 7), where the synthesis of intermediate (17) lowered the
(
(
12)
13)
Tonsiengsom, F.; Miyake, F. Y.; Yakushijin, K.; Horne,
D. A. Synthesis 2006, 1, 49–54.
1
(
(
Miyake, F.; Hashimoto, M.; Tonsiengsom, S.;
Yakushijin, K.; Horne, D. A. Tetrahedron 2010, 66,
4
overall yield of 9.
888–4893.
Curiosity prompted further investigation as to whether this
method could be applied to additional related aromatic systems.
Acylation and amide formation of pyrrole (entry 8) and 1-methyl
pyrrole (entry 9) to generate the corresponding α-oxoacetamides
(14)
Veale, C. G. L.; Lobb, K. A.; Zoraghi, R.; Morrison, J.
P.; Reiner, N. E.; Andersen, R. J.; Davies-Coleman, M.
T. Tetrahedron 2014, 70, 7845–7853.
Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Org. Lett.
2002, 4, 941–943.
Yu, S.; You, X.; Liu, Y. Chem. Eur. J. 2012, 18, 13939–
13940.
Duplais, C.; Bures, F.; Sapountzis, I.; Korn, T. J.;
Cahiez, G.; Knochel, P. Angew. Chem. Int. Ed. 2004, 41,
2968–2970.
Murahashi, S.-I.; Naota, T.; Nakajima, N. Tetrahedron
Lett. 1985, 26, 925–928.
Denmark, S. E.; Chung, W. J. Org. Chem. 2006, 71,
4002–4005.
Denton, R. M.; An, J.; Lindovska, P.; Lewis, W.
Tetrahedron 2012, 68, 2899–2905.
(15)
(16)
(17)
1
8 and 19 was conducted under more dilute conditions, since this
reaction proved to be extremely vigorous. Carbonyl nitrile
formation of 20 and 21 mirrored all previous attempts and
occurred smoothly. Furan (entry 10) was found to be
significantly less reactive, and isolation of appreciable quantities
of α-oxoacetamide 22 proved challenging. Conducting this
reaction in the absence of solvent had little effect on improving
the yield of 22. Further exploration of this method was conducted
using chlorobenzene (entry 11) and methoxynaphthalene (entry
(18)
(19)
(20)
1
2), both of which remained unreacted after several hours,
suggesting that the initial acylation step is only possible on
electron rich ring systems.
(
(
(
21)
22)
23)
Yang, J.; Xiang, D.; Zhang, R.; Zhang, N.; Liang, Y.;
Dong, D. Org. Lett. 2015, 17, 809–811.
Siegl, W.; Ferris, F. C.; Mucci, P. A. J. Org. Chem.
In conclusion, a new procedure for the formation of variably
5
functionalised indolyl-3-carbonylnitriles has been developed.
2
The limiting step in this method is the acylation step, which was
significantly influenced by the electronic environment of the
respective ring systems, while the dehydrative nitrile formation
was seemingly unaffected. Importantly, in contrast to the two
previously described methods which proceed under reflux, this
method takes place at low temperature, rendering it appropriate
for starting materials with low boiling points. Additionally,
compounds 1 – 3 and 5 were produced in higher yields than
previously reported, without the requirement of toxic sources of
cyanide.
1
977, 42, 3442–3443.
Aubry, C.; Wilson, a J.; Emmerson, D.; Murphy, E.;
Chan, Y. Y.; Dickens, M. P.; García, M. D.; Jenkins, P.
R.; Mahale, S.; Chaudhuri, B. Bioorg. Med. Chem. 2009,
1
7, 6073–6084.
(
24)
Yeung, K.-S.; Qiu, Z.; Xue, Q.; Fang, H.; Yang, Z.;
Zadjura, L.; D’Arienzo, C. J.; Eggers, B. J.; Riccardi, K.;
Shi, P.-Y.; Gong, Y.-F.; Browning, M. R.; Gao, Q.;
Hansel, S.; Santone, K.; Lin, P.-F.; Meanwell, N. A.;
Kadow, J. F. Bioorg. Med. Chem. Lett. 2013, 23, 198–
2
02.

4
(
25)
General experimental procedure: Oxalyl chloride (1.5
equiv.) was added dropwise to a stirred solution of 14
(
200 mg, 1.18 mmol, 1 equiv.) in dry Et
2
O (3 mL) at 0
°
C under an atmosphere of argon gas. The mixture was
stirred for 1 h, resulting in a bright yellow precipitate,
after which time a concentrated aqueous solution of
4
NH Cl (2 g) and KOH (2 g) was added. The resultant
precipitate was filtered and washed with chloroform to
yield compound 21 (187.3 mg, 0.78 mmol, 66%) as a
white crystalline solid, without further need for
purification.
oxoacetamide (14). White crystalline solid (66% yield);
6-Chloro-5-fluoro-indolyl-3-α-
1
mp: decomp. 279 °C; H NMR (DMSO, 600 MHz) δ
1
3
7
2.38 (1H, s, NH-1), 8.79 (1H, s, H-2), 8.16 (1H, s, NH-
’), 8.03 (1H, d, J = 9.9 Hz, H-4), 7.81 (1H, s, NH-4’),
1
3
.74 (1H, d, J = 6.4 Hz, H-7); C NMR (DMSO, 150
, C-2’), 165.4 (q , C-1’), 153.9 (q , d,
F,C = 238 Hz, C-5), 140.4 (CH, C-2), 132.8 (q , C-7a),
25.6 (q , d, JF,C = 9.8 Hz, C-3a), 115.4 (q , d, JF,C = 20.9
Hz, C-6), 114.1 (CH, C-7), 112.2 (q , C-3), 107.5 (CH,
C-4) ppm; HRESMS m/z 241.0175 (calcd for
MHz) δ 182.9 (q
J
c
c
c
c
1
c
c
c
35
+
C
10
H
7
ClFN
dropwise to a stirred solution of 14 (100 mg, 0.42 mmol,
equiv) in dry DMF (1 mL) at 0 °C under an
2 2 2
O [M+H] 241.0180) SOCl was added
1
atmosphere of argon gas. After 2 h the reaction was
quenched with water and the organic fraction extracted
with EtOAc (3 x 5 mL). The organic phase was further
washed with water (2 x 10 mL) to ensure the removal of
DMF, dried on MgSO and filtered. The solvent was
4
removed under vacuum, yielding compound 6 as a white
crystalline solid (87.9 mg, 0.39 mmol, 94%). 6-Chloro-
5
crystalline solid (quantitative yield); mp: decomp. 300
-fluoro-indolyl-3-carbonylnitrile
(6).
White
1
°
C; H NMR (DMSO, 600 MHz) δ 12.09 (1H, s, NH-1),
.70 (1H, s, H-2), 7.84 (1H, d, J = 9.3 Hz, H-4), 7.77
8
1
3
(
1
(
1H, d, J = 6.3 Hz, H-7); C NMR (DMSO, 150 MHz) δ
58.6 (q , C-1’), 154.4 (q , d, JF,C = 240 Hz, C-5), 142.9
CH, C-2), 133.9 (q , C-7a), 123.5 (q , d, JF,C = 9.9 Hz,
C-3a), 116.9 (q , d, JF,C = 20.9 Hz, C-6), 115.9 (q , d, JF,C
3.8 Hz ,C-3), 114.9 (CH, C-7), 113.9 (q , C-1’), 107.4
CH, C-4) ppm; HRESMS m/z 220.9917 (calcd for
c
c
c
c
c
c
=
(
c
35
-
C
10 3 2
H ClFN O [M-H] 220.9918).