Preparation of spiro[imidazolidine-4,3′-indolin]-2′-imines: Via copper(i)-catalyzed formal [2 + 2 + 1] cycloaddition of 3-diazoindolin-2-imines and triazines

Article abstract of DOI:10.1039/c9ob01767d

We report a facile and efficient synthesis of spiro[imidazolidine-4,3′-indolin]-2′-imines via a copper(i)-catalyzed cascade reaction of 3-diazoindolin-2-imines with 1,3,5-triazines. The reaction proceeds under very mild conditions and tolerates a variety of functional groups. The cascade process involves the formation of a copper-carbene intermediate and a formal [2 + 2 + 1] cycloaddition.

Full text of DOI:10.1039/c9ob01767d

Organic &
Biomolecular Chemistry
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PAPER
Preparation of spiro[imidazolidine-4,3’-indolin]-2’-
imines via copper(I)-catalyzed formal [2 + 2 + 1]
cycloaddition of 3-diazoindolin-2-imines and
triazines†
Cite this: Org. Biomol. Chem., 2019,
17, 8849
Yuxuan Zhou, Fanghui Ma, Ping Lu * and Yanguang Wang
*
Received 12th August 2019,
Accepted 21st September 2019
We report a facile and efficient synthesis of spiro[imidazolidine-4,3’-indolin]-2’-imines via a copper(I)-
catalyzed cascade reaction of 3-diazoindolin-2-imines with 1,3,5-triazines. The reaction proceeds under
very mild conditions and tolerates a variety of functional groups. The cascade process involves the for-
mation of a copper–carbene intermediate and a formal [2 + 2 + 1] cycloaddition.
DOI: 10.1039/c9ob01767d
rsc.li/obc
of formaldimines and have been used as effective amino-
Introduction
methylation reagents.8 One elegant example was reported by
Indole and its derivatives are prevalent structures for medic- Sun and co-workers for the gold-catalyzed formal [4 + 1] cyclo-
inal chemistry.1 Among them, many molecules with a spirocyc- addition of diazo esters with 1,3,5-triazines, which provided
lic framework at the 3-position of the indole ring exhibited a imidazolidines.9 In this transformation, 1,3,5-triazines acted
broad range of bioactivities (Fig. 1).2 For example, SAR-405838 as formal dipolar adducts. Inspired by these reports and in
and several other spiro[3H-indole-3-3′-pyrrolidin]-2(1H)-ones continuation with our ongoing interest in the 3-diazoindolin-
are clinical and preclinical inhibitors of mouse double minute 2-imine chemistry,4–6 we herein report a copper(I)-catalyzed
2 (MDM2) proto-oncogene, as they are chemically stable and cycloaddition of 1,3,5-triazines with 3-diazoindolin-2-imines,
orally active against MDM2–TP53 (tumor protein p53) interac- which resulted in the preparation of spiro[imidazolidine-4,3′-
tion.2a Additionally, spirooxindoles are common structural indolin]-2′-imines.
motifs and are often found in natural products. Hence, there
is an increasing interest in the development of novel
approaches to prepare architecturally challenging indole
derivatives with a spirocyclic framework such as spirooxindoles
both in organic synthesis and medicinal chemistry.3
In 2014, we reported two practical methods for the prepa-
ration of 3-diazoindolin-2-imines via
a copper-catalyzed
cascade reaction of o-ethynylanilines with sulfonyl azides4 and
a catalytic-free cascade 1,3-dipolar cycloaddition/dehydrogena-
tion of indoles with sulfonyl azides.5 Lately, we4–6 and several
other groups7 demonstrated that this unique class of diazo
compounds are valuable precursors of metal carbenes for the
construction of a series of heterocyclic compounds with the
indole ring system.
1,3,5-Triaryl-1,3,5-triazines show nucleophilic reactivity at
the nitrogen, but have also been employed as stable precursors
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China.
E-mail: pinglu@zju.edu.cn, orgwyg@zju.edu.cn
†Electronic supplementary information (ESI) available. CCDC 1820074. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9ob01767d
Fig. 1 Representatives of biologically active spirooxindoles.
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Organic & Biomolecular Chemistry
Results and discussion
To begin with, the reaction between 3-diazoindolin-2-imine 1a
and 1,3,5-tris(4-fluorophenyl)-1,3,5-triazine (2a) was carried
out in the presence of Cu(OTf)2 in 1,2-dichloroethane (DCE) at
room temperature under air. A [2 + 2 + 1] product 3a was iso-
lated in 56% yield (Table 1, entry 1) and its structure was con-
firmed by X-ray single-crystal analysis.10 By screening across
various Cu(I) and Cu(II) catalysts, Cu(OTf)·12C6H6 was found to
be optimal (Table 1, entries 2–5). No reaction occurred either
with Rh(II) or Ag(I) as the catalyst (Table 1, entries 6 and 7).
Using Cu(OTf)·12C6H6 as the catalyst, we further screened
several solvents including toluene, DCM, THF, and CH3CN.
Among these, DCE provided the highest yield (Table 1,
entries 8–11). Finally, either decreasing or increasing the reac-
tion temperature led to a slight decrease in the yield of 3a
(Table 1, entries 12–14).
With the optimized conditions in hand, we explored the
scope of the reaction with respect to variation of diazo com-
pounds and the triazine component (Scheme 1). Beginning
with the alternation of substituents on diazo compounds 1,
the R1 group at the 1 position on the indole ring could be
ethyl (1a), methyl (1b), isopropyl (1c), and benzyl (1d). The
corresponding products 3a–3d were obtained in 46–63%
yields. The substituent R2 on the indole ring could be 4-Br
(1e), 5-MeO (1f), 5-Me (1g), 5-Br (1h) and 7-Me (1i). Thus, the
corresponding products 3e–3i were isolated in 36–82% yields.
The R3 group on the diazo compounds could be any one
among phenyl (3j), p-chlorophenyl (3k), p-fluorophenyl (3l),
p-nitrophenyl (3m), and methyl (3n). In these cases, the yields
of the desired products ranged from 45% to 89%. Then, we
investigated the scope of 1,3,5-triaryl-1,3,5-triazines 2. 1,3,5-
Scheme 1 Substrate scope.
Triphenyl-1,3,5-triazine (2b), 1,3,5-tris(4-chlorophenyl)-1,3,5-
triazine (2c) and 1,3,5-tris(4-bromophenyl)-1,3,5-triazine (2d)
proceeded smoothly to give the corresponding products 3o–3q
in high yields (72–87%). In the cases where 1,3,5-tris(4-methoxy-
phenyl)-1,3,5-triazine (2e), 1,3,5-tris(2-chlorophenyl)-1,3,5-tri-
azine (2f) and 1,3,5-tris(2-bromophenyl)-1,3,5-triazine (2g) were
used, products 3r–3t were obtained in relatively lower yields
(41–62%). Finally, various 3-diazoindolin-2-imines and 1,3,5-
triaryl-1,3,5-triazines were subjected to this reaction and the
corresponding products 3u–3B were obtained in 45–73% yields.
To further understand the reaction mechanism, control experi-
ments were conducted (Scheme 2). The reaction of 1j (2 equiv.)
with 2b (1 equiv.) and 2e (1 equiv.) was carried out under stan-
dard conditions. In this case, the cross-cycloaddition products 3C
and 3D were isolated as a mixture with a ratio of 12 : 1 and charac-
terized by 1H and 13C NMR as well as HRMS analyses.
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
Solvent
Temp. (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
Cu(OTf)2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Toluene
DCM
THF
CH3CN
DCE
DCE
DCE
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
56
63
Cu(OTf)·1C6H6
Cu(OAc)22
CuCl
Cu(CH3CN)4PF6
Rh2(Oct)4
AgOTf
Trace
Trace
46
N.R
Trace
27
Cu(OTf)·12C6H6
Cu(OTf)·12C6H6
Cu(OTf)·12C6H6
Cu(OTf)·12C6H6
Cu(OTf)·12C6H6
Cu(OTf)·12C6H6
Cu(OTf)·12C6H6
Based on these results and the published studies,8,9,11 we
propose two plausible reaction mechanisms, as shown in
Scheme 3. First, the copper–carbene intermediate B is gener-
ated from diazo compound 1. In the next step, there are two
possible pathways to obtain product 3. In pathway a, the
nucleophilic addition of 1,3,5-triazine derived formaldimine A
to copper–carbene B generates ylide C, which releases Cu(I) to
9
62
10
11
12
13
14
N.R
N.R
52
55
50
50
75
a Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), catalyst
(0.01 mmol), solvent (2 mL), 12 h. b Isolated yields.
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zines as precursors of formaldimines. The reaction proceeded
under mild conditions and provided spiro products in moder-
ate to good yields. The cascade process involves the formation
of a copper–carbene intermediate and a formal [2 + 2 + 1]
cycloaddition.
Experimental section
Typical procedure for the synthesis of (Z)-N-(1′-ethyl-1,3-bis(4-
fluorophenyl)spiro[imidazolidine-4,3′-indolin]-2′-ylidene)-4-
methylbenzenesulfonamide (3a)
To an over-dried flask equipped with a magnetic stirrer were
added sequentially 1a (0.3 mmol), 2a (0.2 mmol), Cu
(OTf)·12C6H6 (0.01 mmol) and dry DCE (2 mL) under air. The
reaction mixture was stirred at room temperature for 12 h.
Upon completion, the solvent was evaporated under vacuum.
The residue was purified by column chromatography on silica
gel (petroleum ether/ethyl acetate = 5 : 1–3 : 1, v/v) to give
Scheme 2 Control experiments.
70 mg (63% yield) of pure 3a as
a white solid. M.
1
p. 195.0–196.0 °C; H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.9
Hz, 2H), 7.36 (t, J = 7.7, 1.2 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H),
7.08–6.97 (m, 6H), 6.73–6.61 (m, 4H), 6.00 (dd, J = 9.2, 4.0 Hz,
2H), 5.20 (s, 1H), 5.14 (s, 1H), 4.61 (d, J = 7.9 Hz, 1H), 4.13 (dq,
J = 14.2, 7.1 Hz, 1H), 3.91 (dq, J = 14.1, 7.0 Hz, 1H), 3.72 (d, J =
8.0 Hz, 1H), 2.30 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.9, 156.5 (d, JC–F = 235.7 Hz), 155.9 (d,
JC–F = 235.1 Hz), 142.5 (d, JC–F = 1.9 Hz), 142.0, 140.03, 139.99,
139.6 (d, JC–F = 1.9 Hz), 132.6, 129.6, 128.8, 125.9, 124.6, 123.2,
115.8 (d, JC–F = 22.3 Hz), 115.7, 115.5 (d, JC–F = 22.2 Hz), 114.4
(d, JC–F = 7.5 Hz), 112.8 (d, JC–F = 7.3 Hz), 109.6, 71.6, 68.9,
60.3, 37.6, 21.3, 11.6; IR (film): 3057, 2979, 2933, 1574, 1515,
1469, 1229, 1151, 1086 cm−1; HRMS (ESI-TOF) calcd for
C31H28F2N4NaO2S ([M + Na]+): 581.1793; found: 581.1797.
Conflicts of interest
There are no conflicts to declare.
Scheme 3 Proposed reaction mechanism.
Acknowledgements
form ylide D. Subsequent addition with another formaldimine
gives intermediate E. Finally, E undergoes an intramolecular
nucleophilic addition to furnish the final product 3. Although
the cross-cycloaddition products were isolated in our control
experiment, a direct reaction between triazine 2 and metal–
carbene intermediate B, as shown in pathway b, cannot be
exclusively excluded.
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No. 21632003
and 21772169). The authors would also like to thank Jiarui
Wang for reading and editing the manuscript.
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In conclusion, we demonstrated that spiro[imidazolidine-4,3′-
indolin]-2′-imines could be synthesized from 3-diazoindolin-2-
imines through a copper(I)-catalyzed reaction with 1,3,5-tria-
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