A diversity-oriented synthesis of caroverine derivatives via TEMPO-promoted aerobic oxidative C-N bond formation

Article abstract of DOI:10.1016/j.tetlet.2014.03.061

A concise method has been developed for the synthesis of caroverine and its derivatives. The quinoxalinone scaffold of these compounds was constructed via the tandem nitrosation/aerobic oxidative CN bond formation reaction of N-(2-chloroethyl)-2-cyano-N-phenylacetamide, followed by sequential Grignard, Finkelstein and nucleophilic substitutions reactions to give several different derivatives. Herein, we describe the development of this strategy in terms of the optimization of each step as well as the effect of different additives on the individual reactions.

Full text of DOI:10.1016/j.tetlet.2014.03.061

Accepted Manuscript
A diversity-oriented synthesis of caroverine derivatives via TEMPO-promoted
aerobic oxidative C–N bond formation
Yusuke Kobayashi, Yusuke Suzuki, Tokutaro Ogata, Tetsutaro Kimachi,
Yoshiji Takemoto
PII:
S0040-4039(14)00470-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.03.061
TETL 44383
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
1 February 2014
9 March 2014
13 March 2014
Please cite this article as: Kobayashi, Y., Suzuki, Y., Ogata, T., Kimachi, T., Takemoto, Y., A diversity-oriented
synthesis of caroverine derivatives via TEMPO-promoted aerobic oxidative C–N bond formation, Tetrahedron
Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.03.061
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A diversity-oriented synthesis of caroverine derivatives via TEMPO-promoted aerobic oxidative C‒N
bond formation
Yusuke Kobayashi,1 Yusuke Suzuki,1Tokutaro Ogata,2Tetsutaro Kimachi,2,* and Yoshiji Takemoto1,*
1Graduate School and Faculty of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachicho, Sakyo-ku,
Kyoto 606-8501, Japan
2
School of Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 KoshienKyu-bancho, Nishinomiya, Hyogo
663-8179, Japan
*Corresponding author. Tel: +81-75-753-4528; Fax: +81-75-753-4569. Email:tkimachi@mukogawa-u.ac.jp;
takemoto@pharm.kyoto-u.ac.jp
Abstract: A concise method has been developed for the synthesis of caroverine and its derivatives. The quinoxalinone
scaffold of these compounds was constructed via the tandem nitrosation/aerobic oxidative C‒N bond formation reaction of
N-(2-chloroethyl)-2-cyano-N-phenylacetamide, followed by sequential Grignard, Finkelstein and nucleophilic substitutions
reactions to give several different derivatives. Herein, we describe the development of this strategy in terms of the
optimization of each step as well as the effect of different additives on the individual reactions.
Keywords: quinoxaline, organocatalyst, heterocycles, nitroxyl radical

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Carbon‒nitrogen bond forming reactions are one the most fundamental transformations in organic synthesis.1 During the
last few decades, there has been an increase in the number of reports pertaining to the development of direct C‒H
functionalization/C‒N bond forming methodologies, with particular emphasis on atom economy.2 Oxidative transformations
of this type have also recently been elaborated to include metal-free reactions,3 as well as reactions involving inexpensive
oxidants such as molecular oxygen,4 where they have been used to provide efficient approaches to a variety of interesting
nitrogen-containing heterocycles.2‒4 As part of our previous study,5,6 we reported the tandem nitrosation/aerobic oxidative
C‒N bond formation reaction of cyanoacetanilides 1, to give the corresponding quinoxalinones 2,5 which were successfully
applied to the synthesis of biologically important compounds, such as ataquimast7 and opaviralne.8 It was envisaged that
this method could also be applied to the diversity-oriented synthesis (DOS)9 of caroverine and its derivatives (Scheme 1).
Caroverine itself is a spasmolytic and inner-ear-protective agent, as well as a potent antioxidant.10 Aminoalkyl moieties can
be found in wide range of pharmaceutical agents, where they generally make a significant contribution to the
pharmacological activity.11 For this reason, we designed a new strategy for the DOS of caroverine derivatives 3 involving
the introduction of a variety of different amino groups to the halide 2 with the aim of establishing a detailed
structure-activity relationship (SAR). It was envisaged that the CN group of 2 could be substituted with organometallic
reagents,5 enabling further derivatization. Furthermore, the late stage introduction of the polar amino group would avoid any
difficulties associated with the preparation and isolation of compounds 1 and 2. Herein, we report the development of a
DOS strategy for the construction of 3 using the tandem nitrosation/aerobic oxidative C‒N bond forming reaction of
cyanoacetanilides 1 as the key step, with 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) being used to promote the
oxidative C‒N bond-forming step.

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Scheme 1. Strategy for the synthesis of caroverine derivatives
Scheme 2. Preparation of cyanoacetanilide 1
First, we attempted to establish a method for the synthesis of the cyanoacetanilide bearing a halide as a leaving group
(Scheme 2). The treatment of the commercially available N-hydroxyethylaniline (4) with SOCl2 gave the corresponding
chloride 5, which was subjected to an amidation reaction with 2-cyanoacetyl chloride to give the chloro-substituted anilide
1a in good yield (70% in 2 steps).6 With the anilide in hand, we proceeded to investigate the tandem nitrosation/aerobic
oxidative C‒N bond forming reaction of 1a (Table 1). Unfortunately, the use of five equivalents of NaNO2 and H2SO4 in
MeCN gave the desired product 2 in a low yield of 20% (Table 1, entry 1). We hypothesized that the low yield of 2 occurred

4
as a consequence of the oxidation step (vide infra), with it not being possible for the substrate to interact efficiently with the
oxidant (gaseous NO2). Given that NO2 and nitroxyl radicals have been used previously for the oxidation of alcohols,12 we
conducted the reaction in the presence of TEMPO (10 mol%) and found that the chemical yield was significantly improved
to 87% (Table 1, entry 2). However, our efforts to reduce the amount of NaNO2 and H2SO4 were unsuccessful (Table 1,
entries 3 and 4). The optimized condition shown in entry 2 was successfully applied to the gram-scale (4.9 g) synthesis of 2
in 77% yield (Table 1, entry 5).
Table 1. Tandem nitrosation/aerobic oxidative C‒N bond formation of 1a
Entry
Conditions
TEMPO (equiv)
Yielda (%)
1
NaNO2 (5.0 equiv), H2SO4 (5.0 equiv)
NaNO2 (5.0 equiv), H2SO4 (5.0 equiv)
NaNO2 (3.0 equiv), H2SO4 (3.0 equiv)
NaNO2 (2.0 equiv), H2SO4 (2.0 equiv)
NaNO2 (5.0 equiv), H2SO4 (5.0 equiv)
‒
20
87
65
43
77
2
0.1
0.1
0.1
0.1
3
4
5b
aIsolated yield.
bThe reaction was performed on 25 mmol scale.
Scheme 3. A plausible promoting effect of TEMPO

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A plausible mechanism to account for the promoting effect of TEMPO is shown in Scheme 3. According to this mechanism,
the active methylene of 1 would be nitrosated and isomerized to give oxime-type intermediate A, which would be oxidized
to give the N-oxonitrenium intermediate B.5 It was envisaged that the NO2 generated in situ would behave as the oxidant
under the original reaction conditions,5 although this system was found to be inefficient when 1a was used as the substrate.
In contrast, TEMPO and/or its oxidized form C would interact more effectively with intermediate A to afford B, and the
resulting reduced form D would be immediately oxidized by NO2 to afford C.12,13 Finally, the cyclization of B would give
the desired product 2.
Scheme 4. Substitution of CN group utilizing Grignard reagents
With a robust method for the preparation of 2 in hand, we proceeded to investigate the substitution of the CN group with a
variety of different carbon nucleophiles (Scheme 4). As expected, several commercially available Grignard reagents reacted
with 2 to afford the corresponding quinoxalinone-N-oxides 6 bearing different substituents at the C2 position in yields of
53‒72%. Subsequent reductive cleavage of the N-oxides 6 with Na2S2O414 gave the chlorides 7,15 which were converted to
the corresponding iodides in high yields (77‒84%) using a Finkelstein Reaction.16 These compounds were now ready for the

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final substitution reaction to give the target compounds.
Table 2. Introduction of various amino groups
N
N
R
O
N
N
R
O
H
N
9
N
N
R
O
R2 R3
additive
CH2Cl2
N
OH
10
I
R2 R3
8
3
Entry
8 (R)
9 (R2, R3)
9A (Et, Et)
9A
Additive
3 (Yield, %)a
3aA (0)b
1
8a (CH2-4-MeOC6H4)
‒
2
8a
TBSCl (1.0 equiv)
TBSCl (1.0 equiv)
TBSCl (1.0 equiv)
TBSCl (1.0 equiv)
TBSCl (1.0 equiv)
TBSCl (1.0 equiv)
TBSCl (1.0 equiv)
3aA (90)
3aB (quant.)
3aC (93)
3aD (57)
3bA (70)
3cA (78)
3
8a
9B (-CH2CH2CH2CH2-)
4
8a
9C (-CH2CH2CH2CH2CH2-)
5
8a
9D (-CH2CH2OCH2CH2-)
6
8b (Et)
8c (n-C12H25)
8d (Ph)
9A
9A
9A
7
8
3dA (82)
aIsolated yield.
b 10 was obtained in 68% yield.
To complete this work, we investigated the nucleophilic substitution of the alkyl iodide in compound 8 with a range of
secondary amines (Table 2). Disappointingly, the use of diethylamine (9A) as the nucleophilic amine did not afford any of
the desired product 3aA, with the undesired alcohol 10 being isolated instead in 68% yield (Table 2, entry 1). This product
was most likely formed via the intramolecular substitution of the alkyl iodide moiety of 8a with the oxygen atom of the
amide moiety followed by hydration. When the reaction was conducted in the presence tert-butyldimethylchlorosilane
(TBSCl),17 the desired product 3aA was formed in 90% yield (Table 2, entry 2). This amination protocol was also
successfully applied to a range of different secondary amines, including prrolidinyl-, piperidinyl, and morpholinyl amines,
with the corresponding products 3aB‒aD being formed in good to excellent yields (Table 2, entries 3‒5). To expand the
scope of this transformation even further, it was also applied to the synthesis of the caroverine derivatives 3bA and 3cA,

7
bearing different R groups, which were synthesized from 8b‒d in 70‒82% yields (Table 2, entries 6‒8).
In conclusion, we have demonstrated that the tandem nitrosation/aerobic oxidative C‒N bond forming reaction of 1a can be
used to provide facile access to caroverine derivatives. We have also shown that TEMPO can be used an effective catalyst to
promote the oxidative C‒N bond forming step, and that TBSCl could be used to inhibit the hydrolysis of the alkyl iodide
moiety during the final nucleophilic substitution step. We believe that these finding could be useful for the synthesis of other
quinoxalinone derivatives, as well as the development of the related C‒N bond forming reactions, which we are currently
investigating in our laboratory.
References and notes
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2008, 47, 6338.
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W. C. P.; Munday, R. H.; Brasche, G.; Zheng, N.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7603.
3. For a recent review, see: Samanta, R.; Matcha, K.; Antonchick, A. P. Eur. J. Org. Chem. 2013, 5769.
4. For selected recent reviews, see: (a) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062.
(b) Wertz, S.; Studer, A. Green Chem. 2013, 15, 3116. (c) Chiba, S. Bull. Chem. Soc. Jpn. 2013, 86, 1400.
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6. For our previous work using cyanoacetanilides, see: (a) Kobayashi,Y.; Harayama, T. Org. Lett. 2009, 11, 1603. (b)

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Kobayashi, Y.; Harayama, T. Tetrahedron Lett. 2009, 50, 6665. (c) Kobayashi, Y.; Katagiri, K.; Azumaya, I.; Harayama, T. J.
Org. Chem. 2010, 75, 2741. (d) Kobayashi, Y.; Nakatani, T.; Tanaka, R.; Okada, M.; Torii, E.; Harayama, T.; Kimachi, T.
Tetrahedron 2011, 67, 3457. (e) Kobayashi,Y. YakugakuZasshi 2011, 131, 1037.
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Retroviruses 2000, 16, 517. (c) Cass, L. M.; Moore, K. H. P.; Dallow, N. S.; Jones, A. E.; Sisson, J. R.; Prince,W. T. J. Clin.
Pharmacol. 2001, 41, 528.
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(b) Nohl, H.; Bieberschulte, W.; Dietrich, B.; Udilova, N.; Kozlov, A.V. BioFactors 2003, 19, 79.
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133, 6497.
13. This reaction was performed under in an open flask, because the reaction was unsuccessful when it was conducted in the
presence of a catalytic amount of NaNO2, even under an oxygen atmosphere. This difference in the outcome was attributed
to the gradual release of NOx from of the open flask. Details of the experimental process are provided in the Supplementary

9
Data section. The reaction promoting effect of TEMPO using several different substrates has also been described in the
Supplementary Data section.
14. Note that a fresh Na2S2O4 should be used for the reduction reaction. The use of an old bottle of this material led to a
significant decrease of in the chemical yield of the reaction.
15. Very little product was obtained when chloride 7 was subjected to the nucleophilic substitution reaction with secondary
amines 9.
16. Landini, D.; Albanese, D.; Mottadelli, S.; Penso, M. J. Chem. Soc., PerkinTrans. 1, 1992, 2309.
17. TBSCl was selected as the additive because the use of TMSNEt2 as a nucleophile in the substitution reaction gave 3aA
in 87% yield.

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A diversity-oriented synthesis of caroverine
derivatives via TEMPO-promoted aerobic
oxidative C‒N bond formation
Yusuke Kobayashi, Yusuke Suzuki, Tokutaro Ogata, Tetsutaro Kimachi, and Yoshiji Takemoto