Intramolecular dehydrative coupling of tertiary amines and ketones promoted by KO-t-Bu/DMF: A new synthesis of indole derivatives

Article abstract of DOI:10.1021/ol402908m

A new synthesis of indole derivatives has been achieved through intramolecular dehydrative coupling of tertiary amines and ketones promoted by KO-t-Bu/DMF. The reaction probably proceeds via an α-amino alkyl radical pathway.

Full text of DOI:10.1021/ol402908m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Intramolecular Dehydrative Coupling of
Tertiary Amines and Ketones Promoted
by KO‑t‑Bu/DMF: A New Synthesis of
Indole Derivatives
Wen-tao Wei, Xue-jiao Dong, Shao-zhen Nie, Yan-yan Chen, Xue-jing Zhang, and
Ming Yan*
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, China
yanming@mail.sysu.edu.cn
Received October 9, 2013
ABSTRACT
A new synthesis of indole derivatives has been achieved through intramolecular dehydrative coupling of tertiary amines and ketones promoted by
KO-t-Bu/DMF. The reaction probably proceeds via an R-amino alkyl radical pathway.
Indole derivatives are abundant in natural products,
synthetic drugs, and materials.1 Their synthetic methods
have attracted great attention during the past 100 years.2,3
Although a number of successful methods have been
developed, new synthetic approaches are still desirable
considering the great structural diversity of indole deriva-
tives. In recent years, there has been increasing interest in
the direct functionalizations of R CꢀH bonds of amines.4
The generation of reactive R-amino radicals and conse-
quent reactions are highly efficient for the synthesis of R-
alkyl amines and nitrogen heterocycles.5 Rueping, Pandey,
and Reiser et al. reported the generation of R-amino
radicals via visible-light photoredox catalysis. The subse-
quent intramolecular conjugate addition to Michael ac-
ceptors gave indole derivatives in moderate yields.6
Recently, we found that KO-t-Bu/DMF promotes the
intramolecular cyclization of tertiary amines and alkenes.7
The exploration of the reaction mechanism suggested the
generation of R-amino alkyl radicals in this transforma-
tion. We speculate that nucleophilic R-amino alkyl radicals
(1) (a) Lalit, K.; Shashi, B.; Kamal, J. IJRPS 2012, 2, 23. (b) Biswal,
S.; Sethy, S.; Sahoo, U.; Kumar, H. K. S.; Banerjee, M. Asian J. Pharm.
Clin. Res. 2012, 5, 1. (c) Gul, W.; Hamann, M. T. Life Sci. 2005, 78, 442.
(d) Robinson, M. W.; Overmeyer, J. H.; Young, A. M.; Erhardt, P. W.;
Maltese, W. A. J. Med. Chem. 2012, 55, 1940.
(2) For the reviews of the synthesis of indoles, see: (a) Gribble, G. W.
J. Chem. Soc., Perkin Trans. 1 2000, 1045. (b) Humphrey, G. R.; Kuethe,
J. T. Chem. Rev. 2006, 106, 2875. (c) Song, J. J.; Reeves, J. T.; Gallou, F.;
Tan, Z.; Yee, N. K.; Senanayake, C. H. Chem. Soc. Rev. 2007, 36, 1120.
(d) Tirunahari, P. K.; Taber, D. F. Tetrahedron 2011, 67, 7195. (e)
Vicente, R. Org. Biomol. Chem. 2011, 9, 6469. (f) Inman, M.; Moody,
C. J. Chem. Sci. 2013, 4, 29. (g) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005,
105, 2873. (h) Platon, M.; Amardeil, R.; Djakovitch, L.; Hierso, J. C.
Chem. Soc. Rev. 2012, 41, 3929. (i) Nakamura, I.; Yamamoto, Y. Chem.
Rev. 2004, 104, 2127.
(3) For seleceted recent examples about the synthesis of indole
derivatives, see: (a) Flanagan, J. C. A.; Dornan, L. M.; McLaughlin,
M. G.; McCreanor, N. G.; Cook, M. J.; Muldoon, M. J. Green Chem.
2012, 14, 1281. (b) Shi, Z. Z.; Glorius, F. Angew. Chem., Int. Ed. 2012,
51, 9220. (c) Wei, Y.; Deb, I.; Yoshikai, N. J. Am. Chem. Soc. 2012,
134, 9098. (d) Zhan, F. X.; Liang, G. X. Angew. Chem., Int. Ed. 2013,
52, 1266. (e) Besandre, R.; Jaimes, M.; May, J. A. Org. Lett. 2013, 15,
1666.
(4) For the reviews of direct functionalizations of tertiary amines, see:
(a) Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069. (b) Mitchell, E. A.;
Peschiulli, A.; Lefevre, N.; Meerpoel, L.; Maes, B. U. W. Chem.;Eur. J.
2012, 18, 10092. (c) Shi, L.; Xia, W. J. Chem. Soc. Rev. 2012, 41, 7687.
(5) For reviews of R-aminoalkyl radicals in synthesis, see: (a)
Renaud, P.; Giraud, L. Synthesis 1996, 8, 913. (b) Cossy, J. In Radicals
in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
2001; Vol. 1, p 229. (c) Aurrecoechea, J. M.; Suero, R. ARKIVOC 2004,
xiv, 10.
(6) For recent examples of R-aminoalkyl radicals, see: (a) Zhu, A.;
Das, S. Q.; Bui, L.; Zhou, H. J.; Curran, D. P.; Rueping, M. J. Am.
Chem. Soc. 2013, 135, 1823. (b) Kohls, P.; Jadhav, D.; Pandey, G.;
Reiser, O. Org. Lett. 2012, 14, 672.
(7) Chen, Y. Y.; Zhang, X. J.; Yuan, H. M.; Wei, W. T.; Yan, M.
Chem. Commun. 2013, 49, 10974.
r
10.1021/ol402908m
XXXX American Chemical Society

are also reactive with carbonyl groups. Herein, we report
an intramolecular dehydrative coupling of tertiary amines
and ketones promoted by KO-t-Bu/DMF. The reac-
tion provides a new synthetic approach of 2-aryl indole
derivatives.
Table 2. Intramolecular Coupling of Tetrahydroisoquinoline
Derivatives 1aꢀja
Indolo[2,1-a]isoquinoline 2a and its analogues possess a
variety of interesting biological activities.8 The reaction of
2-(3,4-dihydroisoquinolin-2(1H)-yl)benzaldehyde in the
presence of a phosphazine base was reported to give
indolo[2,1-a]isoquinoline in low yield.8b The generation
of reactive R-aminoalkyl anion was proposed. Recently we
developed a synthesis of 2a via Ir-catalyzed dehydrative
coupling of 1-(2-(3,4-dihydroisoquinolin-2(1H)-yl)phenyl)-
ethanone 1a; however, the yield is unsatisfactory.9 Initially,
we examined the reaction of 1a in DMF with 3.0 equiv
of KO-t-Bu at 90 °C. To our delight, 2a was obtained in
good yield. Furthermore, a number of bases and reaction
solvents were examined and the results are summarized in
Table 1. NaO-t-Bu, LiO-t-Bu, and NaOMe also promoted
the reaction, but lower yields were obtained (Table 1,
entries 2ꢀ4). KOMe provided a similar yield in compar-
ison with KO-t-Bu (Table 1, entry 5). Other bases such as
KOH, NaOH, K2CO3, and NaH were also tested, but no
2a was obtained in substantial amounts. The reaction
solvent was also investigated. N,N-Dimethylacetamide
(DMA) and DMSO are also applicable, but lower yields
were observed (Table 1, entries 6 and 7). Other solvents
such as dioxin, toluene, ClCH2CH2Cl, CH3CN, THF,
t-BuOH, and glycol are incompatible with the reaction.
No product 2a could be obtained in these solvents.
Table 1. Intramolecular Dehydrative Coupling of 1aa
entry
base (equiv)
solvent
time (h)
yieldb (%)
1
KO-t-Bu (3.0)
NaO-t-Bu (3.0)
LiO-t-Bu (3.0)
NaOMe (3.0)
KOMe (3.0)
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
1
1
76
57
47
63
76
71
60
81
85
74
28
81
53
-
2
3
1
a Reaction conditions: 1aꢀj (0.2 mmol), KO-t-Bu (0.24 mmol), DMF
(2.0 mL), at 90 °C under an argon atmosphere, 3 h. b Isolated yields.
4
1
5
1
6
KO-t-Bu (3.0)
KO-t-Bu (3.0)
KO-t-Bu (1.5)
KO-t-Bu (1.2)
KO-t-Bu (1.0)
KO-t-Bu (0.5)
KO-t-Bu (1.2)
KO-t-Bu (1.2)
KO-t-Bu (1.2)
KO-t-Bu (1.2)
1
7
1
The effect of KO-t-Bu loading was also examined. The
bestyield was obtainedwith1.2 equiv of KO-t-Bu (Table1,
entries 8ꢀ11). The use of a substoichiometric amount
of KO-t-Bu led to a significant loss of the yield (Table 1,
entry 11). The reaction at 120 and 60 °C gave inferior yields
8
3
9
3
10
11
12c
13d
14e
15f
3
5
3
5
10
10
(8) For the synthesis and biological activity of indolo[2,1-R]iso-
20
€
quinolines, see: (a) Lotter, A. N. C.; Pathak, R.; Sello, T. S.; Fernandes,
M. A.; Otterlo, W. A. L. V.; Koning, C. B. D. Tetrahedron 2007, 63,
2263. (b) Kraus, G. A.; Gupta, V.; Kohut, M.; Singh, N. Bioorg. Med.
Chem. Lett. 2009, 19, 5539. (c) Mahoney, S. J.; Fillion, E. Chem.;Eur. J.
2012, 18, 68.
(9) Nie, S. Z.; Sun, X.; Wei, W. T.; Zhang, X. J.; Yan, M.; Xiao, J. L.
Org. Lett. 2013, 15, 2394.
a Reaction conditions: 1a (0.1 mmol), base, solvent (1 mL), at 90 °C
under an argon atmosphere. b GC yields. c Reaction was carried out at
120 °C. d Reaction was carried out at 60 °C. e Reaction was carried out
under an oxygen atmosphere. f TEMPO (0.12 mmol) was added.
B
Org. Lett., Vol. XX, No. XX, XXXX

(Table 1, entries 12 and 13). The aminoalkyl anion is the
proposed intermediate when sterically hindered phospha-
zine (super base) is used.8b However in the present reac-
tion, the basicity of KO-t-Bu is not enough to remove the
C1-proton. The control test indicated that the reaction is
inhibited by oxygen and radical scavenger TEMPO
(Table 1, entries 14 and 15). The results implicate a radical
reaction pathway.
Table 3. Intramolecular Coupling of Arylmethylamine-Derived
Substrates 1kꢀsa
With the optimal reaction conditions in hand, the reac-
tion was extended to a variety of tetrahydroisoquinoline
derivatives, and the results are summarized in Table 2.
2-Tetrahydroisoquinolinylpropiophenone 1b provided 2b
in a good yield (Table 2, entry 2). The reaction of 2-tetra-
hydroisoquinolinyl diphenyl ketone 1c gave 2c in a mod-
erate yield (Table 2, entry 3). Interestingly, a small amount
of benzophenone was also isolated in this case. This
compound is probably generated via the fragmentation
of the R-amino alkyl radical intermediate. Phenyl aryl
ketones 1d and 1e are also applicable. Products 2d and 2e
were obtained in moderate yields (Table 2, entries 4 and 5).
The substitutions at the N-phenyl of 1a with electron-
withdrawing groups or electron-donating groups are tol-
erated very well. Excellent yields were obtained for sub-
strates 1fꢀi (Table 2, entries 6ꢀ9). Tetrahydroisoquinoline
derivative 1j with 1,2-dimethoxy substitution also pro-
vided product 2j in good yield (Table 2, entry 10).
The reaction is not limited to tetrahydroisoquinoline
derivatives. Benzylamine-derived ketones were also ex-
amined, and the results are summarized in Table 3. The
N-substitutent was found to exert a strong effect on the
reaction. No expected product was obtained for secondary
amine (Table 3, entry 1).
When the N-substitutent is methyl, ethyl, phenyl, or
benzyl, respectively, the indole products were obtained in
good yields (Table 3, entries 2ꢀ5). 2-Naphthylmethylamine-,
4-bromobenzylamine-, and 3,4-dimethoxybenzylamine-
derived ketones 1pꢀr also gave products 2pꢀr in good
yields (Table 3, entries 6ꢀ8). Bis(4-methoxylbenzyl)amine-
derived substrate 1s provided the product 2s in moderate
yield (Table 3, entry 9).
Bis(4-trifluoromethyl-benzyl)amine-derived substrate
1t gave the product 2t in low yield, but 3-hydroxyindoline
2t0 was obtained in 50% yield (Scheme 1, eq 1). The com-
pound 2t0 could be transformed to 2t after treatment
with 4-toluenesulfonic acid.10 Interestingly, amide-derived
ketones 1u and 1v provided 3-methyleneindolines 3uꢀv in
good yields (Scheme 1, eq 2). The N-acyl group obviously
disfavors 1,2-dehydration of the alcohol intermediates;
instead, 3-exo-dehydration occurs exclusively.
a Reaction conditions: 1kꢀs (0.2 mmol), KO-t-Bu (0.24 mmol), DMF
(2.0 mL), at 90 °C under an argon atmosphere, 3 h. b Isolated yields.
and 4x were also isolated. In these cases, Cannizzaro
reaction competed with the coupling reaction and led to
the compounds 4wꢀx.11
Tetrahydroisoquinoline-derived benzaldehydes 1wꢀx
were also examined (Scheme 2). The expected products
2wꢀx were obtained in low yields. In addition, alcohols 4w
A tentative reaction mechanism is suggested in Scheme 3.7,12
The carbamoyl radical A is generated by the deprotona-
tion and subsequent single-electron transfer (SET) pro-
cess. The radical A abstracts C-1 hydrogen of 1a and the
resulting R-amino alkyl radical C adds to the carbonyl
group. The intermediate D abstracts a hydrogen from
DMF. 3-Hydroxyindoline intermediate E is formed as
(10) 2t0 could be converted slowly to 2t under the standard reaction
conditions.
(11) The reaction mixtures of 1wꢀx were carefully analyzed;
however, the expected carboxylic acid products from the Cannizzaro
reaction could not be found. We prepared 2-(3,4-dihydroisoquinolin-
2(1H)-yl)benzoic acid via the oxidation of 1w. This acid was found to
decompose under the reaction conditions.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 1. Intramolecular Coupling of Substrates 1tꢀv
Scheme 3. Tentative Reaction Mechanism
Scheme 2. Intramolecular Coupling of Substrates 1wꢀx
the primary product. In addition, the radical A is re-
generated. The final product 2a is generated after the
dehydration of E.
In conclusion, we have developed a new intramolecular
dehydrative coupling reaction of tertiary amines and
ketones. The reaction is efficiently promoted by the com-
bination of KO-t-Bu and DMF. A numberof 2-arylindoles
were prepared in good yields. A reaction mechanism
via an R-aminoalkyl radical intermediate is suggested.
The carbamoyl radical generated from DMF probably
works as the crucial initiator. The reaction provides a
practical synthesis of 2-arylindoles from N-arylmethyl-2-
aminophenyl ketones.
Acknowledgment. We thank the National Natural
Science Foundation of China (Nos. 20972195, 21172270)
and Guangdong Engineering Research Center of Chiral
Drugs for financial support of this study.
(12) The reactions with DMA and DMSO as the solvents (Table 1,
entries 6 and 7) are suggested to proceed via similar free-radical path-
ways. The deprotonation of DMSO and DMA provides the correspond-
ing R-carbonyl and R-sulfonyl carbon anions, which are further
transformed to R-carbonyl and R-sulfonyl radicals via the subsequent
single-electron transfer step. These radical intermediates initiate the
dehydrative coupling reaction. Sliwka and co-workers observed the
generation of radical intermediates in the basic DMF and DMSO
solution via EPR analysis; see: Øpstad, C. L.; MelØ, T. B.; Sliwka,
H. R.; Partali, V. Tertrahedron 2009, 65, 7616.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data of all new products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX