Metal-free decarboxylative acylation of isoquinolines using α-keto acids in water

Article abstract of DOI:10.1016/j.tetlet.2017.04.098

An efficient method for acylation of isoquinolines has been developed using α-ketoacids under metal- and additive-free conditions in water. The protocol involves C(sp²)–H functionalization of isoquinolines providing an easy access to C1-benzoylated isoquinolines, which constitute the core structure of a number of biological active compounds and serve as key intermediate in the synthesis of many alkaloids.

Full text of DOI:10.1016/j.tetlet.2017.04.098

Accepted Manuscript
Metal-Free Decarboxylative Acylation of Isoquinolines using α-Keto Acids in
Water
Narendra R. Chaubey, Krishna Nand Singh
PII:
S0040-4039(17)30560-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.098
TETL 48890
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 March 2017
27 April 2017
29 April 2017
Please cite this article as: Chaubey, N.R., Singh, K.N., Metal-Free Decarboxylative Acylation of Isoquinolines using
α-Keto Acids in Water, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.04.098
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Graphical Abstract
Metal-Free Decarboxylative Acylation of Isoquinolines
using α-Keto Acids in Water
Leave this area blank for abstract info.
Narendra R. Chaubey, Krishna Nand Singh*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Metal-Free Decarboxylative Acylation of Isoquinolines using α-Keto Acids in Water
Narendra R. Chaubey, Krishna Nand Singh∗
Department of Chemistry (Centre of Advanced Study), Institute of Science,
Banaras Hindu University, Varanasi – 221005, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient method for acylation of isoquinolines has been developed using α-ketoacids under metal-
and additive-free conditions in water. The protocol involves C(sp2)-H functionalization of
isoquinolines providing an easy access to C1-benzoylated isoquinolines, which constitute the core
structure of a number of biological active compounds and serve as key intermediate in the synthesis of
many alkaloids.
Received in revised form
Accepted
Available online
Keywords:
Acylation
2009 Elsevier Ltd. All rights reserved.
Benzoylation
Metal-Free
Isoquinolines
Radicals
Keto acids
C1-Substituted N-heterocycles constitute the core structure of many
biologically-active compounds and synthetic pharmaceuticals
containing antitussive, antipsychotic, antispasmodic, anxiolytic,
antibacterial, antifungal, and anticancer properties.1 Among them,
C1-benzyl and benzoyl substituted isoquinolines are particularly
important due to their bio-medical applications (Fig. 1), and also
serve as intermediates in the synthesis of many alkaloids.
Direct C-H functionalization has emerged as a potentially useful tool
for the synthesis of such vital molecules.2 Many reports concerning
the benzylation, benzoylation or acylation of N-heterocycles have
appeared in the last few years.3-8 Antonchick et al. have developed a
nice protocol for the benzoylation of isoquinolines using aldehydes
and PhI(OCOCF3)/TMSN3 in benzene.3 Prabhu et al. employed
TBAB/K2S2O8 combination with aldehydes in dichloroethane for the
acylation of isoquinolines and quinoxaline.4 Afterwards, Patel et al.
made use of methyl benzenes for benzoylation of such N-
heterocycles using AlCl3/TBHP via a Minisci-type reaction.5 In the
same year, Liu and co-workers carried out the benzylation and
benzoylation of isoquinolines using methyl arenes in the presence of
Y(OTf)3/DTBP and MnO2/TBHP/TFA blends respectively (Scheme
1).6
However, most of the previously reported methods for the
acylation of isoquinolines and similar N-heterocycles require either
the use of metals or oxidants with different additives or initiators.
Thus, there is adequate scope to bring about the reaction using
different reacting partners under mild and green conditions. As a part
of our ongoing programme on developing greener approaches for C-
H functionalization,9,10 and considering the biological significance of
C1-benzoyl substituted N-heterocycles, it was thought worthwhile to
explore the benzoylation of isoquinolines using keto acids as a
reacting partner in an environmentally benign way.
In order to optimize the reaction conditions, a model reaction
employing isoquinoline (1a) with phenylglyoxylic acid (2a) was
initially carried out using K2S2O8 as an oxidant and TFA as an
additive in acetonitrile at room temperature for 12 hours, but without
success to the desired benzoylated product 3a (Table 1, entry 1).
Fig. 1. Bio-active C1-benzyl/benzoyl-isoquinolines
———
∗ Corresponding author. Tel.: +91-5426702485; e-mail: knsingh@bhu.ac.in, knsinghbhu@yahoo.co.in

2
Tetrahedron
However, when the reaction temperature was raised to 100 °C
under similar conditions, we were happy to note the formation of C1-
Table 1. Optimization of reaction conditions
benzoyl isoquinoline (3a) in 56% yield (entry 2).
Entry
Oxidant
Additive Solvent t [h] Yield [%]a
1
2
3
4
5
6
7
8
K2S2O8 (3 eq.)
K2S2O8 (3 eq.)
K2S2O8 (3 eq.)
K2S2O8 (3 eq.)
TFA
TFA
TFA
CH3CN
CH3CN
DMSO
DMSO
DMSO
DMSO
12
12
12
12
12
6
N. R.b
56
68
70
N. R.
68
K2S2O8 (3 eq.)
K2S2O8 (3 eq.)
K2S2O8 (3 eq.)
6
6
trace
77
H2O
56c
74d
9
TBHP (3 eq.)
AIBN (3 eq.)
I2/TBHP
H2O
H2O
6
6
N. R.
N. R.
38
10
11
12
13
14
H2O
6
I2/TBHP
TBAI/TBHP
BMIM(BF)4
DMSO
H2O
H2O
12
12
6
35
30
N. R.
Reaction Conditions: 1a (0.5 mmol), 2a (1.25 mmol), oxidant (1.5
mmol), solvent (2 mL), 100 °C.
aYields refer to isolated product.
bReaction at room temperature.
cReaction at 80 °C.
dReaction at 120 °C.
When use was made of a heteroaromatic keto acid 2c, somewhat
lower product yield was observed (3c, 56%). Reaction of 2-
(naphthalene-2-yl)-2-oxoacetic acid (2g) under similar conditions
was also quite successful (3g, 77%). To check the behaviour of
aliphatic keto acid under standard conditions, the reaction of pyruvic
acid 2h with 1a was also undertaken, which afforded the product 3h
in 70% yield. Our next move was to study the scope of isoquinolines
and other N-heterocycles, which reacted smoothly under the
optimized reaction conditions. 4-Bromoisoquinoline (1b) gave rise to
the product 3i in 77% yield. Likewise, 4-phenyl isoquinoline (1c)
reacted smoothly with different keto acids providing fairly high yield
of the products 3j (74%), 3k (72%) and 3l (65%). Nitro group of the
5-nitroisoquinoline (1d) was well tolerated during the course of the
reaction, although with a relatively lower product yield (3m, 32%).
When the reaction was extended to quinoxaline (1e), it provided
mono acylated product 3n in 50% yield; whereas 4-picoline (1f)
gave rise to the mono acylated product 3o in 30% yield. In order to
study the behaviour of 1-substituted isoquinolines, the reaction of a
mono acylated compound 3h was carried out in the presence of
pyruvic acid 2h under the optimized conditions, but no further
acylation was observed in this case.
Scheme 1. Previous reports and our strategy
Interestingly, the functionalization of isoquinoline (1a) occurred
regioselectively at C1-position. When the solvent was changed to
DMSO, a reasonable increase in the yield of the product 3a was
observed (68%, entry 3). To ascertain the role of the additive, the
reaction was then carried out without the use of TFA, which
eventually yielded the product 3a in almost same yield (entry 4).
Nevertheless, no reaction was observed in DMSO without using the
oxidant and additive (entry 5). Also, only a trace of the product 3a
was formed when the reaction was carried out without using solvent
(entry 7). When the reaction time was reduced from 12 h to 6 h, just
a marginal decrease in the yield of the product was noticed (entry 6).
Taking into cognizance the intrinsic green credentials of water as
solvent, the reaction was subsequently carried out in water, which
delightedly led to the formation of the product in considerably high
yield (77%, entry 8). When K2S2O8 was changed to TBHP or AIBN
as oxidant, the desired product was not formed at all (entries 9 & 10).
The use of I2/TBHP and TBAI/TBHP combinations was also
helpless, as the product yields remained much poor (entries 11-13).
The application of an ionic liquid as catalyst in the reaction was also
futile (entry 14).
To look into the insights of the mechanism, a typical reaction of 1a
with 2a was carried out in the presence of 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO, 1 equiv), which completely
suppressed the formation of 3a, thereby revealing the involvement of
a radical pathway. Based on this observation, isolation of products
and existing knowledge,11 a plausible mechanism is outlined in Fig.
2.
In conclusion, an efficient method for acylation of isoquinolines
has been developed using α-ketoacids without using metal and
additive in water. The generality of the reaction is demonstrated by
using different keto acids and isoquinolines; and is extendable to
some other N-heterocycles. The methodology is endowed with an
easy isolation of products and avoids the formation of oxidation by-
products.
After establishing the optimized conditions, the scope and
versatility of the reaction was studied in detail using different
isoquinolines and keto acids. The outcome is summarized in Scheme
2. Arylglyoxylic acids containing para substituents like methyl,
chloro and methoxy underwent the reaction smoothly with
isoquinoline affording the products 3d, 3e and 3f in good yields.
Amusingly the reaction of sterically hindered mesitylglyoxylic acid
2b with isoquinoline gave rise to a fairly high yield (3b, 74%).

3
H); 13C NMR (125 MHz, CDCl3) δ 202.2, 154.1, 141.7, 138.9,
O
O
138.4, 137.0, 134.9, 130.3, 129.1, 128.5, 127.1, 126.4, 126.1, 124.1,
21.2, 19.7. HRMS: Calcd for C19H17NO (M+ + H) 276.1310; Found
276.1402.
R
K2S2O8
OH
R
N
N
Water, 100 oC, 6h
O
3a-3o
1a-1f
2a-2g
Isoquinolin-1-yl(thiophen-2yl)methanone (3c). Brown viscous oil;
IR (KBr) 3058, 2926, 2854, 1642, 1410, 1384, 1352, 1248, 776 cm-1;
1H NMR (500 MHz, CDCl3) 8.54 (d, J = 5.5 Hz, 1 H), 8.47 (d, J =
8.5 Hz, 1 H), 7.82 (m, 2 H), 7.74 (d, J = 6 Hz, 1 H), 7.66 (m, 2 H),
N
N
N
N
7.57 (m, 1 H), 7.07 (t, J = 5 Hz, 1 H); 13C NMR (125 MHz, CDCl )
3
O
O
O
O
186.1, 154.6, 142.6, 140.8, 136.9, 136.6, 136.1, 130.7, 128.6, 128.1,
127.1, 126.4, 126.2, 123.5. HRMS: Calcd for C14H9NOS (M+ + H)
240.0405; Found 240.0465.
S
3a
3c
3b
3d
74%
56%
77%
67%
Mesityl(4-phenylisoquinolin-1-yl)methanone (3k). Thick yellow
gum; IR (KBr) 2919, 1678, 1611, 1239, 846, 779 cm-1; 1H NMR (500
MHz, CDCl3) 9.05 (d, J = 8.5 Hz, 1 H), 8.42 (s, 1 H), 7.91 (d, J = 8
Hz, 1 H), 7.66 (m, 2 H), 7.43 (m, 5 H), 6.83 (s, 2 H), 2.24 (s, 3 H),
N
N
N
N
O
O
O
O
2.09 (s, 6 H); 13C NMR (125 MHz, CDCl ) 202.4, 153.4, 141.8,
3
Cl
OMe
139.1, 138.6, 136.9, 136.8, 135.5, 135.0, 130.6, 130.2, 129.1, 128.8,
128.7, 128.5, 126.8, 126.2, 125.6, 21.4, 20.0. HRMS: Calcd for
C25H21NO (M+ + H) 352.1623; Found 352.1723.
3f
3g
3h
3e
77%
59%
70%
74%
Br
Ph
Ph
Ph
Acknowledgement
We are thankful to SERB, New Delhi (File No. EMR /2016/000750)
for financial support, and UGC, New Delhi for D. S. Kothari Post-
Doctoral Fellowship to Dr. Narendra R. Chaubey.
N
N
N
N
S
O
O
O
O
3 i
3 j
3 k
3 l
65%
72%
References and notes
74%
77%
NO2
N
1. a) M. Shamma, J. L. Moniot, The Isoquinoline Alkaloids,
Chemistry and Pharmacology, Academic Press, New York and
London 1972; b) R. B. Herbert, in The Chemistry and Biology of
Isoquinoline Alkaloids, ed. J. D. Phillipson, M. F. Roberts, M. H.
Zenk, Springer Verlag, Berlin, Heidelberg, New York and Tokyo
1985; 213; c) L. Wu, H. Ling, L. Li, L. Jiang, M. He, J. Pharm.
Pharmacol. 2007; 59: 695; d) J. Kamei, Pulm. Pharmacol. 1996;
9: 349; e) C. Chen, Y.-F. Zhu, X. -J. Liu, Z. -X. Lu, Q. Xie, N.
Ling, J. Med. Chem. 2001; 44: 4001.
O
O
N
N
N
O
3m
32%
3o
3n
50%
30%
2. a) C. -J. Li Acc. Chem. Res. 2009; 42: 335; b) S. A. Girard, T.
Knauber, C.-J. Li Angew. Chem., Int. Ed. 2014; 53: 74; c) C. Liu,
H. Zang, W. Shi, A. Lei, Chem. Rev. 2011; 111: 1780; d) R.
Rohlmann, O. García Mancheno Synlett 2013; 6; e) E. Boess, D.
Sureshkumar, A. Sud, C. Wirtz, C. Faras, M. Klussmann J. Am.
Chem. Soc. 2011; 133: 8106; f) S. I. Murahashi, N. Komiya, H.
Terai, T. Nakae J. Am. Chem. Soc. 2003; 125: 15312; g) C. Guo, J.
Song, S. -W. Luo and L. -Z. Gong Angew. Chem. Int. Ed. 2010;
49: 5558; h) F. Benfatti, M. G. Capdevila, L. Zoli, E. Benedetto,
P. G. Cozzi, Chem. Commun. 2009; 5919. i) G. Zhang, Y. Zhang,
R. Wang Angew. Chem., Int. Ed. 2011; 50: 10429; j) J. Zhang, B.
Tiwari, C. Xing, X. Chen, Y. R. Chi, Angew. Chem., Int. Ed.
2012; 51: 3649. k) G. Zhang, Y. Ma, S. Wang, Y. Zhang, R.
Wang, J. Am. Chem. Soc. 2012; 134: 12334.
Reaction Conditions: N-Heterocycle 1 (0.5 mmol), keto acid 2 (1.25
mmol), K2S2O8 (1.5 mmol), H2O (2 mL), 100 °C, 6h. Yields refer to
isolated products after column chromatography.
Scheme 2. Scope of the reaction
O
S
O
S
heat
OSO2O
K
K
2
O
O
O
O K
O
O
NH
RCOCOO
O
O
R
OSO2O
CO2
OH
3. K. Matcha, A. P. Antonchick Angew. Chem. Int. Ed. 2013; 52:
2082.
R
O
4. Y. Siddaraju, M. Lamani, K. R. Prabhu J. Org. Chem. 2014; 79:
3856.
HSO4
5. W. Ali, A. Behera, S. Guin, B. K. Patel J. Org. Chem. 2015; 80:
5625.
OSO2O
Base
RCOCOO
N
6. M. Wan, H. Lou, L. Liu Chem. Commun. 2015; 51: 13953.
7. J. Chen, M. Wan, J. Hua, Y. Sun, Z. Lv, W. Li, L. Liu Org.
Biomol. Chem. 2015; 13: 11561.
NH
R
O
R
O
8. Y. Siddaraju, K. R. Prabhu Tetrahedron 2016; 72: 959.
9. R. Vanjari, T. Guntreddi, K. N. Singh Org. Lett. 2013; 15: 4908.
10. R. Vanjari, T. Guntreddi, S. Kumar, K. N. Singh Chem. Commun.
2015; 51: 366.
Fig. 2. Plausible reaction mechanism
Characterization data of new compounds:
11. J. K. Laha, K. V. Patel, K. S. Tummalpalli, N. Dayal Chem.
Commun. 2016; 52: 10245.
Isoquinolin-1-yl(mesityl)methanone (3b). Thick yellow gum, IR
1
(KBr) 3055, 2920, 2854, 1670, 1609, 1242, 913, 821, 756 cm-1; H
NMR (500 MHz, CDCl3) δ 9.03 (m, 1 H), 8.53 (d, J = 5.5 Hz, 1 H),
7.88 (m, 1 H), 7.74 (m, 3 H), 6.89 (s, 2 H), 2.31 (s, 3 H), 2.12 (s, 6

4
Tetrahedron
Highlights:
•
•
•
Our methodology is free from the use of
metals and additives.
Use of water as an environmentally benign
medium.
Our protocol avoids the formation of
oxidation by-products and is endowed with
an easy isolation of products.