Regiospecific synthesis of 1,5,6,7-tetrahydro-4H-indol-4-ones via dehydroxylated [3+2] cyclization of β-hydroxy ketones with cyclic enaminones

Article abstract of DOI:10.1016/j.tetlet.2017.03.009

A new p-TsOH-promoted dehydroxylated [3+2] cyclization strategy has been established, allowing a flexible, practical and regiospecific approach to 23 examples of 1,5,6,7-tetrahydro-4H-indol-4-ones from low-cost and readily accessible β-hydroxy ketones and cyclic enaminones. Notably features of this work include broad functional group compatibility, mild reaction conditions and good reaction yields.

Full text of DOI:10.1016/j.tetlet.2017.03.009

Accepted Manuscript
Regiospecific synthesis of 1,5,6,7-tetrahydro-4H-indol-4-ones via dehydroxy-
lated [3+2] cyclization of β-hydroxy ketones with cyclic enaminones
Xin-Chan Lan, Ting-Ting Chen, Yan Zhao, Yu Wu, Jing Wang, Shu-Jiang Tu,
Bo Jiang, Wen-Juan Hao
PII:
S0040-4039(17)30295-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.009
TETL 48710
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 December 2016
28 February 2017
3 March 2017
Please cite this article as: Lan, X-C., Chen, T-T., Zhao, Y., Wu, Y., Wang, J., Tu, S-J., Jiang, B., Hao, W-J.,
Regiospecific synthesis of 1,5,6,7-tetrahydro-4H-indol-4-ones via dehydroxylated [3+2] cyclization of β-hydroxy
ketones with cyclic enaminones, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.03.009
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Tetrahedron Letters
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Regiospecific synthesis of 1,5,6,7-tetrahydro-4H-indol-4-ones via dehydroxylated
[3+2] cyclization of β-hydroxy ketones with cyclic enaminones
Xin-Chan Lan,a,1 Ting-Ting Chen,a,1 Yan Zhao,a,1 Yu Wu,a,1 Jing Wang,a,1 Shu-Jiang Tu,a Bo Jiang,*,a and
Wen-Juan Hao*,a
a School of Chemistry and Materials Science, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University,
Xuzhou, 221116, P. R. China, E-mail: jiangchem@jsnu.edu.cn; wjhao@jsnu.edu.cn; 1These authors contributed equally
ARTICLE INFO
ABSTRACT
A new p-TsOH-promoted dehydroxylated [3+2] cyclization strategy has been established,
allowing a flexible, practical and regiospecific approach to 23 examples of 1,5,6,7-tetrahydro-
4H-indol-4-ones from low-cost and readily accessible β-hydroxy ketones and cyclic
enaminones. Notably features of this work include broad functional group compatibility, mild
reaction conditions and good reaction yields.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
[3+2] Heterocyclization
Regiospecific synthesis
1,5,6,7-tetrahydro-4H-indol-4-ones
2016 Elsevier Ltd. All rights reserved.
Functional indoles, standing for a class of significant aza-
heterocycles, have been extensively applied in medical and
pharmaceutical chemistry and material science.1 Among them,
4,5,6,7-tetrahydro-1H-indoles have aroused long-standing
interest due to these molecules display a broad spectrum of
biological and pharmaceutical activities, including anti-
implantation, hypoglycemic, anti-inflammatory, and analgesic,2
potent neuroleptic3 (e.g. molindone), and antitumor.4 This
structural motif is also present in the family of Stemona alkaloids
including Tuberostemonine and Stenine5 and ergot alkaloids such
as Lysergic acid and Isolysergic acid.6 Besides, tetrahydroindoles
are also found to serve as valuable and potent intermediates for
constructing natural alkaloids7 such as goniomitine, arcyriacyanin
A, 6,7-secoagroclavine and chuangxinmycin as well as synthetic
drugs8 (pindolol) and highly functionalized indoles.9 Over the
past years, substantial efforts have been paid to develop various
methods for the synthesis of N-substituted and N-unsubstituted
tetrahydroindoles, most of which involved metal-catalyzed
cyclization strategies.10 However, some of those procedures often
requires multiple steps or harsh reaction conditions. Thus, the
exploration of a new, facile and rapid protocol for directly
on the development of various aza-heterocyclization cascades of
cyclic enaminones for the construction of multiple rings of
Scheme 1. Synthesis of 1,5,6,7-tetrahydro-4H-indol-4-ones
chemical and biomedical potentials.12 For instance, we have
reported several domino reaction of cyclic enaminones with
simple arylglyoxal monohydrate, allowing direct [3+2]
heterocyclization to access functionalized tetrahydroindoles.13 To
continue this project, we envisaged that under suitable catalytic
conditions, cyclic enaminones were subjected with the reaction
of β-hydroxy ketones14 with tertiary alcohol functionality, which
underwent [3+3] cyclization to give the expected spiro-
substituted hexahydrquinolines 3 due to the tertiary alcohol
functionality was easily substituted by suitable nucleophiles in
the presence of Brønsted acid or Lewis acid.15 Based on the
above analysis, the reaction of cyclic enaminones 2 with β-
hydroxy ketones with tertiary alcohol functionality 1 in HOAc
was conducted under microwave heating (MW) by using p-
toluenesulfonic acid (p-TsOH) as a promoter. Interestingly,
accessing
tetrahydroindole
skeleton
and
its
multifunctionalization, especially metal-free version, is still
highly favorable but fundamentally challenging.
Cyclic enaminones are competent reactants endowed with C,N-
nucleophilic sites, serving as versatile heterocyclic enamine (aza-
ene) feedstocks for many important targets in organic, medicinal,
and materials chemistry.11 In recent years, our group has focused

2
Tetrahedron Letters
instead of the expected hexahydrquinoline products 3 (Scheme
isolated in slightly higher yields than electron-withdrawing
substituents. Among them, challenging strong electron-
1a), this reaction occurred in a completely different direction,
a
affording the unexpected 1,5,6,7-tetrahydro-4H-indol-4-ones 4
withdrawing NO2 was well-suited for this present transformation,
regiospecifically converting into the corresponding products 4d
and 4i in 76% and 45% yields, respectively. Next, we turned our
attention to investigate the electronic properties of β-hydroxy
ketones (Ar) by conducting various N-aryl cyclic enaminones 2.
Different groups such as electron-withdrawing (Cl) and electron-
donating (Me and MeO) at the para position of the Ar ring were
proven to be suitable for this cyclization process, resulting in the
regiospecific formation of the desired products 4m-4v with yields
from 61% to 78% yields. Alternatively, N-alkyl enaminone
counterparts like cyclopropyl (2f) and benzyl (2j) proved to be
adaptable substrates in these transformations, enabling the
dehydroxylated [3+2] cyclization to furnish the corresponding
1,5,6,7-tetrahydro-4H-indol-4-ones 4f and 4t in 73% and 76%
yields, respectively. As an extension of the above study, 4,4-
dimethylsubstituted enaminone 2k was treated with β-hydroxy
ketone 1b to investigate the feasibility of this transformation.
Similar to the above, the reaction promoted by p-TsOH worked
well, enabling dehydroxylated [3+2] heterocyclization to
efficiently access the corresponding 1,5,6,7-tetrahydro-4H-indol-
4-one 4w in a high 86% yield. The structures of the resulting
1,5,6,7-tetrahydro-4H-indol-4-ones 4 were fully characterized by
their NMR, HRMS and IR spectra analyses. In the case of 4a, its
structure was further confirmed by single crystal X-ray
diffraction (Fig. 1).16
through
a dehydroxylated [3+2] heterocyclization cascade
(Scheme 1b). Herein, we reported this interesting observation.
Our study commenced with the reaction between the preformed
β-hydroxy ketone 1a and cyclic enaminone 2a in a 1:1 mole ratio
to search the optimal conditions. The results are summarized in
o
Table 1. The reaction proceeded in HOAc at 110 C, leading to
the desired product 4a albeit with a low yield of 31% (Table 1,
entry 1). Using 1.0 equiv of p-TsOH as a Brønsted acid promoter
in this reaction system afforded the expected product 4a in 82%
yield (entry 2). Subsequently, we investigated the solvent effect
for this transformation with use of various solvents such as 1,4-
dioxane, acetonitrile (CH3CN), ethanol (EtOH), and toluene. All
these attempted solvents were inferior to HOAc in terms of
reaction yields (entry 2 vs entries 3-6). Next, the amount of p-
TsOH required for this reaction was evaluated. Lowering the
loading of p-TsOH to 0.5 equivalent remarkably decreased the
yield of 4a (35%. entry 7). The similar inferior outcome was
observed when the use of 1.5 equivalents of p-TsOH was
selected as a Brønsted acid promoter (51%. entry 8). It was also
found that the reaction temperature affected the reaction
efficiency. The lower conversion was detected with reaction
temperature being at either 100 or 120 °C (entry 2 vs entries 9-
10).
Table 1. Optimization of reaction condition
O
O
O
4
R2
O
R2
O
OH
O
R2
R1
R2
R1
p
-TsOH
+
Ar
HOAc, 110 oC
MW
Ar
HN
R3
R1
N
R3
R1
O
1
2
Entry
Solvent
HOAc
p-TsOH (equiv)
T (oC)
110
Yield (%)a
--
1
2
3
4
31
82
17
16
O
O
O
O
O
O
1.0
1.0
1.0
1.0
O
O
O
HOAc
110
1,4-dioxane
CH3CN
110
Ph
4-BrPh
4-ClPh
N
N
N
110
R3
R3
R3
4a 4f
-
5
EtOH
110
110
110
110
100
120
22
44
35
51
34
53
4g 4l
-
4m 4o
-
, R3 = 4-BrPh (82%)
, R3 = 4-ClPh (79%)
, R3 = 4-IPh (70%)
, R3 = 4-BrPh (70%)
4a
4b
4c
4d
4e
3
4g
4h
4m
4n
1.0
0.5
1.5
1.0
1.0
, R = 4-O2NPh (61%)
6
Toluene
HOAc
HOAc
HOAc
HOAc
, R3 = 4-FPh (60%)
, R3 = 4-MePh (68%)
, R3 = 4-EtPh (70%)
7
3
4i
4j
, R = 4-O2NPh (45%)
4o
, R3 = 4-O2NPh (76%)
, R3 = 4-MePh (88%)
3
8
, R = 4-MePh (77%)
, R3 = 4-EtPh (74%)
4k
9
3
3
4f
, R = Cyclopropyl (73%)
4l
, R = 4-EtOPh (83%)
10
aIsolated yield based on 1a.
With the optimal reaction conditions for dehydroxylated [3+2]
heterocyclization in hand (Table 1, entry 2), we then set out to
evaluate the scope of these transformations by allowing a variety
of structurally diverse N-substituted cyclic enaminones 2 to react
with the preformed β-hydroxy ketone 1a and 1b. The results are
summarized in Scheme 2. As anticipated, substituents resided at
para-position on the phenyl ring (R3 = Ar) did not hamper the
reaction process. The variants of substituents (including bromo
2a, chloro 2b, iodo 2c, nitro 2d, methyl 2e, fluoro 2g, ethyl 2h,
and ethoxy 2i) can tolerate the conditions well. The results
revealed that the presence of electron-donating groups (methyl,
ethyl and ethoxy) seemed to improve the efficiency of the
reaction, as the corresponding products 4e and 4j-l could be
O
O
O
O
O
O
O
O
O
4-MePh
4-MeOPh
4-BrPh
N
N
N
R3
R3
-
4-BrPh
4w
4p 4t
-
4u 4v
(86%)
, R3 = 4-BrPh (65%)
, R3 = 4-ClPh (70%)
4p
, Ar2 = 4-EtPh (72%)
, Ar2 = 4-EtOPh (76%)
4u
4v
4q
4r
, R3 = 4-EtPh (73%)
3
4s
, R = 4-EtOPh (78%)
, R3 = Bn (76%)
4t
Scheme 2. Synthesis of 1,5,6,7-tetrahydro-4H-indol-4-ones 4
under MW.18
After our successful achievement with 1,5,6,7-tetrahydro-4H-
indol-4-ones 4 bearing multiple carbonyl moieties, we decided to

employ 4l as starting material to react with phenylhydrazine 5 to
investigate its synthetic utility. As expected, the [5 + 2]
cyclization reaction of 4l with 5 in refluxing methanol proceeded
smoothly, leading to the corresponding indeno[2',1':6,7][1,2]
diazepino[5,4,3-cd]indol-10(1H)-one 6 in 89% yield (Scheme 3).
the reaction scope and synthetic applications of this method
are underway. We believe this methodology may be of great
value to others seeking original synthetic fragments with
unique activities for medicinal and pharmaceutical research
Acknowledgments
We are grateful for financial support from the NSFC (No 21602087),
TAPP, PAPD of Jiangsu Higher Education Institutions, NSF of
Jiangsu Province (BK20151163, BK20160212), the Qing Lan
Project and NSF of Jiangsu Education Committee (15KJB150006),
and National Students’ Innovative Training Program (No.
201610320017). We thank Shuai Liu’s generous help.
Scheme 3. Synthetic utility of 1,5,6,7-tetrahydroindol-4-one 4l
Supplementary Material
On the basis of all the above results, a plausible mechanism for
this dehydroxylated [3+2] heterocyclization is proposed in
Scheme 4. Firstly, the protonation of hydroxyl group of substrate
1 in the presence of p-TsOH yields intermediate A. The
dehydration occurred prior to nucleophilic substitution step
Supplementary data (experimental details and spectroscopic
characterization of all compounds along with 1H NMR, IR and
mass spectra) associated with this article can be found, in the
online version, at doi:
because of strong steric hindrance of substrate
1 and
thermodynamic stability of dehydrated intermediate B with big
conjugated system. So, intermediate A undergoes dehydration
and Michael addition of enaminones 2,17 followed by
intramolecular nucleophilic addition of amino group to carbonyl
group, second dehydration and tautomerization to generate the
final products 4.
References and notes
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(3) Rubin, A. A.; Yen, H. C.; Pfeffer, M. Nature 1967, 216, 578.
(4) Martinez, R.; Clara-Sosa, A.; Ramirez Apan, M. T. Bioorg. Med. Chem.
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(5) (a) Wipf, P.; Spencer, S. R. J. Am. Chem. Soc. 2005, 127, 225; (b) Pilli,
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(9) (a) Hatanaka, N.; Watanabe, N.; Matsumoto, M. Heterocycles 1986, 24,
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(10) For recent reviews of indole synthesis, see. (a) Patil, S. A.; Patil, R.;
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G.; Goggiamani, A. Org. Biomol. Chem. 2011, 9, 641; (c) Taber, D. F.;
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Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875; (i)
Gribble, G. W. Pure Appl. Chem. 2003, 75, 1417; (j) Gribble, G. W. J.
Chem. Soc., Perkin Trans. 1 2000, 1045.
Scheme 4. The proposed mechanism
(11) (a) Chattopadhyay, A. K.; Hanessian, S. Chem. Commun. 2015, 51,
16450. (b) Chattopadhyay, A. K.; Hanessian, S. Chem. Commun. 2015,
51, 16437; (c) Jiang, B.; Li, Q.-Y.; Tu, S.-J.; Li, G. Org. Lett. 2012, 14,
5210; (d) Jiang, B.; Wang, X.; Li, M.-Y.; Wu, Q.; Ye, Q.; Xu, H.-W.;
Tu, S.-J. Org. Biomol. Chem. 2012, 10, 8533; (e) Xue, L. Y.; Jiang, B.;
Tu, M.-S.; Tu, S.-J. Tetrahedron Lett. 2012, 53, 6611; (f) Jiang, B.; Li,
Y.; Tu, M.-S.; Wang, S.-L.; Tu, S.-J.; Li, G. J. Org. Chem. 2012, 77,
7497.
(12) (a) Yang, Z.; Hao, W.-J.; Xu, H.-W.; Wang, S.-L.; Jiang, B.; Li, G.; Tu,
S.-J. J. Org. Chem. 2015, 80, 2781; (b) Jiang, B.; Liang, Y.-B.; Kong,
L.-F.; Tu, X.-J.; Hao, W.-J.; Ye, Q.; Tu, S.-J. RSC Adv. 2014, 4, 54480;
(c) Li, M.-Y.; Xu, H.-W.; Fan, W.; Ye, Q.; Wang, X.; Jiang, B.; Wang,
S.-L.; Tu, S.-J. Tetrahedron 2014, 70, 1004; (d) Zhao, F.-J.; Sun, M.-Y.;
Dang, Y.-J.; Meng, X.-Y.; Jiang, B.; Hao, W.-J.; Tu, S.-J. Tetrahedron
2014, 70, 9628; (e) Jiang, B.; Wang, X.; Xu, H.-W.; Tu, M.-S.; Tu, S.-
J.; Li, G. Org. Lett. 2013, 15, 1540.
Fig. 1. ORTEP drawing of compound 4a.
In summary, we have established a new, flexible and practical
[3+2] heterocyclization cascade between β-hydroxy ketones
with tertiary alcohol functionality and cyclic enaminones for
the regiospecific synthesis of a wide range of 1,5,6,7-
tetrahydro-4H-indol-4-ones through two C-O bond cleavage
under mild metal-free conditions. Significant features of this
work include operational simplicity, broad functional group
compatibility and good reaction yields. Further expansion of

4
Tetrahedron Letters
(13) (a) Fu, L.-P.; Shi, Q.-Q.; Shi, Y.; Jiang, B.; Tu, S.-J. ACS Comb. Sci.
2013, 15, 135; (b) Li, Y.; Li, Q.-Y.; Xu, H.-W.; Fan, W.; Jiang, B.;
Wang, S.-L.; Tu, S.-J. Tetrahedron 2013, 69, 2941; (c) Tu, X.-C.; Fan,
W.; Jiang, B.; Wang, S.-L.; Tu, S.-J. Tetrahedron 2013, 69, 6100; (d)
Jiang, B.; Yi, M.-S.; Shi, F.; Tu, S.-J.; Pindi, S.; McDowell, P.; Li, G.
Chem. Commun. 2012, 48, 808.
(14) The preparation of β-hydroxy ketones sees: (a) Carotti, A.; Casini, G.;
Gavuzzo, E.; Mazza, F. Heterocycles 1985, 23, 1659; (b) Kneubuehler,
S.; Thull, U.; Altomare, C.; Carta, V.; Gaillard, P.; Carrupt, P.-A.;
Carotti, A.; Testa, B. J. Med. Chem. 1995, 38, 3874.
(15) (a) Ghosh, S.; Kinthada, L. K.; Bhunia, S.; Bisai, A. Chem. Commun.
2012, 48, 10132; (b) Kinthada, L. K.; Ghosh, S.; Babu, K. N.; Sharique,
M.; Biswas, S.; Bisai, A. Org. Biomol. Chem. 2014, 12, 8152; (c) Babu,
K. N.; Kinthada, L. K.; Ghosh, S.; Bisai, A. Org. Biomol. Chem. 2015,
13, 10641; (d) Zhu, F.; Zhou, F.; Cao, Z.-Y.; Wang, C.; Zhang, Y.-X.;
Wang, C.-H.; Zhou, J. Synthesis 2012, 44, 3129; (e) Zhang, Y.; Wang,
S.-Y.; Xu, X.-P.; Jiang, R.; Ji, S.-J., Org. Biomol. Chem. 2013, 11,
1933; (f) Rad-Moghadam, K.; Sharifi-Kiasaraie, M.; Taheri-Amlashi,
H. Tetrahedron 2010, 66, 2316.
(16) Crystal data for 4a (CCDC 1523250): C31H24BrNO3, Mr = 538.42,
Monoclinic, space group P2(1)/c with a = 12.6974(11), b = 9.6815(8), c
= 23.1368(16), α = 90.00o, β = 116.345(4)°, γ = 90.00°, V = 2548.8(4)
Å3, Z = 4, Dc = 1.403 g/cm3, µ(MoKα) = 2.462 mm–1, F(000) = 1104,
the final R = 0.0872 and wR = 0.1351.
(17) Han, Y.; Sun, Y.; Sun, J.; Yan, C.-G. Tetrahedron 2012, 68, 8256.
(18) Typical procedure for the synthesis of 4a: 2-hydroxy-2-(2-oxo-2-
phenylethyl)-1H-indene-1,3(2H)-dione (1a, 1.0 mmol, 1.0 equiv.) and
3-((4-bromophenyl)amino)-5,5-dimethylcyclohex-2-enone (2a, 1.0
mmol, 1.0 equiv.) was introduced in a 10-mL Initiator reaction vial, p-
TsOH (1.0 mmol, 1.0 equiv), and HOAc (2.0 mL) were successively
added. Subsequently, the reaction vial was capped and then pre-stirred
for 20 s. The mixture was irradiated (Time: 20 min, Temperature: 110
oC; Absorption Level: High; Fixed Hold Time) until TLC (petroleum
ether: ethyl acetate 2:1) revealed that conversion of the starting material
was complete. The reaction mixture was cooled to room temperature.
Next, the system was neutralized by diluted base solution. The resulting
precipitate was collected by filtration and was purified by flash column
chromatography to afford the desired pure product 4a. White solid, mp
o
1
293-294 C; H NMR (400 MHz, DMSO-d6; δ, ppm) 7.93 (s, 4H), 7.63
(d, J = 7.6 Hz, 2H), 7.30-7.19 (m, 7H), 4.53 (s, 1H), 2.56 (s, 2H), 2.09
(s, 2H), 0.96 (s, 6H). 13C NMR (100 MHz, CDCl3; δ, ppm) 198.6, 193.7,
143.4, 142.1, 138.0, 136.1, 135.1, 132.4, 130.6, 129.4, 129.2, 128.5,
128.2, 123.0, 122.1, 116.9, 110.8, 53.8, 51.4, 37.0, 35.7, 28.7. IR (KBr,
-1
ν, cm ) 2924, 1714, 1647, 1490, 1463, 1007, 848. HRMS (APCI): m/z
calcd for C31H23BrNO3, 536.0861 [M-H]-, found: 536.0864.

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Regiospecific synthesis of 1,5,6,7-tetrahydro-
4H-indol-4-ones via dehydroxylated [3+2]
cyclization of β-hydroxy ketones and cyclic
enaminones
Xin-Chan Lan, Ting-Ting Chen, Yan Zhao, Yu Wu, Jing Wang, Shu-Jiang Tu, Bo Jiang, and Wen-Juan Hao

6
Tetrahedron Letters
1. A p-TsOH-promoted dehydroxylated [3+2] cyclization of
β-hydroxy ketones is established
2. The mechanism involves dehydration/ Michael addition /
cyclization-dehydration.
3. This method provides a new entry for regioselective
formation of 1,5,6,7-tetrahydro-4H-indol-4-ones.