Synthesis of 2-Iminoindolines via samarium diiodide mediated reductive cyclization of carbodiimides

Article abstract of DOI:10.1246/cl.2012.44

A method of synthesizing 2-iminoindolines using samarium diiodide (SmI ₂) is reported. In the presence of tert-butyl alcohol, treatment of carbodiimides bearing α,β-unsaturated carbonyl moieties with a stoichiometric amount of SmI₂ afforded 2- iminoindolines in moderate to high yields. The products were isolated after Boc protection of the amidine moieties. This reaction proved to be applicable to lactams and acyclic/cyclic esters as substrates.

Full text of DOI:10.1246/cl.2012.44

doi:10.1246/cl.2012.44
44
Published on the web December 24, 2011
Synthesis of 2-Iminoindolines via Samarium Diiodide
Mediated Reductive Cyclization of Carbodiimides
Takayuki Ishida, Chihiro Tsukano, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501
(Received October 17, 2011; CL-111019; E-mail: takemoto@pharm.kyoto-u.ac.jp)
A method of synthesizing 2-iminoindolines using samarium
for the construction of amidines by reaction with a broad range
diiodide (SmI2) is reported. In the presence of tert-butyl alcohol,
treatment of carbodiimides bearing ¡,¢-unsaturated carbonyl
moieties with a stoichiometric amount of SmI2 afforded 2-
iminoindolines in moderate to high yields. The products were
isolated after Boc protection of the amidine moieties. This
reaction proved to be applicable to lactams and acyclic/cyclic
esters as substrates.
of organometallic species,11 but their applicability as radical
acceptors has been regarded as rather limited.12
Recently, Wood et al. reported a synthesis of oxindoles by
SmI2-promoted intramolecular cyclization of aryl isocyanates
possessing a cyclohexenone moiety, in the course of synthetic
studies of welwitindolinone A isonitrile.9g Inspired by their
results, we envisaged that the bond between a quaternary-carbon
center and an imine carbon in iminoindoline 1 could be
constructed by connecting different electron-withdrawing
groups, i.e., an ¡,¢-unsaturated carbonyl moiety and carbodi-
imide in 2 (Scheme 1). Radical or anionic species generated
from unsaturated carbonyl groups using SmI2 would attack the
central carbons of carbodiimides, or vice versa. Although the
syntheses of dihydroquinazoline 3 and 2-aminoquinoline 4 by
tandem nucleophilic addition and 6³ electrocyclic reaction of
analogous substrates have been reported, respectively,13,14 there
are no similar examples of cyclization to construct quaternary-
carbon centers. Thus, we started to seek mild conditions for the
desired cyclization.
Indole/indoline skeletons are one of the fundamental
structural units frequently observed in natural products and
pharmacologically active agents, so synthetic chemists continue
to develop novel and efficient methods for synthesizing these
privileged structures.1 Among the broad range of such structures,
2-iminoindolines and 2-aminoindoles2 are substructures found in
natural alkaloids such as flustramine C and perophoramidine
(Figure 1).3,4 Diverse methods for the synthesis of these classes
of compounds have been reported in the literature. Many of
the reported methods adopted tether-dependent condensation of
oxindole derivatives5a-5d or oxidative cyclization of indoles;5e
synthetic routes based on various strategies, including aza-
Pauson-Khand-type reactions,6a heteroannulation of N-alkynyl-
anilines,6b ring enlargement of aminoazirines,6c addition of
azides to indoles,6d oxidation of aminals,6e and amidination
of aryl halides,6f have been introduced. Mild and selective
synthetic methods for these substructures are still in high
demand. In this communication, we disclose SmI2-promoted
intramolecular reductive cyclizations of carbodiimides possess-
ing unsaturated carbonyl moieties, to provide 2-iminoindolines
bearing quaternary-carbon centers at the C3 position.
The use of SmI2 in synthetic chemistry has flourished since
Kagan and his co-workers introduced it as a powerful one-
electron reductant.7 Its versatility in the construction of carbon-
carbon bonds and its excellent functional group selectivity
enable formation of numerous structurally complex skeletons
found in natural products.8 There have been many studies of its
reductive homo-/heterocoupling reactions with electron-with-
drawing groups.9 To the best of our knowledge, however, no
similar reactions involving carbodiimides have been reported in
the literature.10 Carbodiimides are well-established as precursors
As a model substrate containing a partial perophoramidine
structure for investigation of the reaction, we synthesized lactam
derivative 5a.15 The results of optimization of the reaction
conditions are shown in Table 1. Substrate 5a was treated with
SmI2 in THF solution. No reaction occurred at ¹78 °C (Entry 1),
but the desired reaction proceeded at ambient temperature to
give the cyclized product 6a as a single product (Entry 2). The
use of additives improved the yields, and tert-butyl alcohol
proved to be a better additive than HMPA16 (Entries 3 and 4).
Other additives such as LiCl17a and NiI2
showed no
17b
significant effect on the reaction (Entries 5 and 6). Product 6a
was converted to the Boc derivative 7a as a single regioisomer in
excellent yield; the structure was unambiguously determined by
X-ray crystallography18 (Scheme 2).
Figure 1. Natural products containing 2-iminoindoline/
2-aminoindole skeletons.
Scheme 1. Synthetic strategy.
Chem. Lett. 2012, 41, 44-46
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45
Table 1. Optimization of reaction conditions
Table 2. Substrate scopes of reductive cyclization
Entrya
Temp
Additives
Yield/%
Entrya Substrate Substituent Product Yield/% (Ab/Bc)
1
2
3
4
5
6
¹78 °C
none
none
HMPAb
N.R.
55
78
83
68
1
2
3
4
5
6
7
8
9
5b
5c
5d
5e
5f
5g
5h
5i
3-MeO
4-Me
4-MeO
4-Cl
2¤-MeO
2¤-Cl
3¤-Me
4¤-MeO
4¤-F
7b
7c
7d
7e
7f
7g
7h
7i
75/®
87/®
73/®
62/®
42/66
45/86
65/86
46/74
54/87
rt
rt
rt
rt
rt
t-BuOHc
t-BuOHc + LiCld
e
t-BuOHc + NiI2
79
aSubstrate solutions were added to 0.1 M SmI2 solutions (2.4
equiv). b10 vol % in SmI2 solution. c2.2 equiv. d10 equiv.
e5 mol %.
5j
7j
aAll reactions were carried out on 0.100 mmol scale. bA
indicates yield from condition A: THF solution of substrate
and t-BuOH (2.2 equiv) were added to THF solution of SmI2
(2.4 equiv). cB indicates yield from condition B: THF solution
of SmI2 (2.1-2.2 equiv) were added to THF solution of
substrate and t-BuOH (10 equiv).
Scheme 2. Derivatization of 6a and X-ray structure of 7a.
Next, we investigated the scopes of the substrates for SmI2-
mediated reductive cyclizations (Table 2). Since some products
were unstable, the cyclization yields were evaluated after
treatment of the crude materials with Boc2O and DMAP.19 With
regard to the substituents on the tethering aromatic rings,
both electron-donating and chlorine functionalities, including
a conformationally restricting substituent at the 3-position of
the substrate, were tolerated, and products 7b-7e were obtained
in good to high yields (Entries 1-4). When substrates that
possessed substituents on the other aromatic ring of the
carbodiimides were examined, some unidentified by-products
were obtained by reductive cyclization, resulting in moderate
yields of the desired products (Entries 5-9). Interestingly, such
decreases in the product yields seemed to be general, and
independent of the properties of the substituents. Although it
made little difference in the model study using substrate 5a, a
combination of inverse addition and modification of the of SmI2,
and increased amounts of tert-butyl alcohol (Table 2, condi-
tion B), proved to be effective in achieving complete conversion
and obtaining the products in good to high yields. In the reaction
with substrate 5f, a small amount of product resulting from 6³
electrocyclic reaction was detected, presumably as a result of
Lewis acid promoted acceleration by a chelated Sm species.
We also applied the reductive cyclization to esters
(Scheme 3). The ¢,¢-disubstituted carbonyl moieties proved to
be essential, as shown by the fact that the reaction with the
corresponding ethyl cinnamate resulted in a complex mixture in
which dimerized or trimerized products were detected by mass
Scheme 3. Cyclization of acyclic/cyclic esters.
spectrometry. The acyclic substrate 5k and lactone 5l were
examined and in both cases, the optimal reaction conditions
(condition B in Table 2) gave the desired products in high
yields. It is known that addition of HMPA was essential for the
inter-/intramolecular homocoupling reactions of ¡,¢-unsaturat-
ed esters,9d but in our case, only tert-butyl alcohol was required
for these intramolecular reductive cyclization where one of ¡,¢-
unsaturated ester was replaced by a carbodiimide.
Scheme 4 shows a possible mechanism of reductive cy-
clization. First, the carbonyl oxygen of substrate 5m coordinates
to SmI2, and reduction of the unsaturated carbonyl group results
in a radical anionic species 8. This radical attacks the carbon in
the carbodiimide faster than the samarium enolate does, and
further reduction by the second SmI2 provides Sm amidinate 9.
As shown by the fact that the cyclized product was obtained in
the absence of tert-butyl alcohol (Table 1, Entry 2), dianion 9
can be generated without the assistance of any proton source.
Finally, protonation of 9 gave reductively cyclized iminoindo-
Chem. Lett. 2012, 41, 44-46
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46
7
a) J. L. Namy, P. Girard, H. B. Kagan, Nouv. J. Chim. 1977,
1, 5. For reviews of SmI2-mediated reactions, see: b) G. A.
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8
9
Scheme 4. Possible mechanism.
line 6m. It is still unclear whether the formation of carbon-
carbon bonds is promoted by chelation between a carbodiimide
moiety and SmI2 prior to cyclization. The reported instability
and difficulty in generation of nitrogen-centered radical species12
might suggest direct generation of the dianion 9 from the
chelated complex.
10 Dimerization of carbodiimide by samarocene was reported, see:
M. Deng, Y. Yao, Y. Zhang, Q. Shen, Chem. Commun. 2004,
2742.
11 A. Williams, I. T. Ibrahim, Chem. Rev. 1981, 81, 589.
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In summary, we have developed a synthetic method for
producing (spiro)-2-iminoindolines via SmI2-mediated reductive
cyclization of carbodiimides bearing unsaturated carbonyl
moieties such as lactams and acyclic/cyclic esters. This reaction
afforded various 2-iminoindolines in good to high yields. To the
best of our knowledge, this is the first example of a pinacol-type
coupling reaction, promoted by SmI2, using carbodiimide
functionalities.
13 T. Saito, K. Tsuda, Y. Saito, Tetrahedron Lett. 1996, 37, 209.
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15 Compound 5a was synthesized from 1-benzylpiperidine-2,4-
dione by four steps: 1) Tf2NPh, Et3N, CH2Cl2, rt, 97%; 2)
2-aminophenylboronic acid pinacol ester, [PdCl2(PPh3)2], Na2-
CO3, H2O, THF, reflux, 95%; 3) PhNCO, CH2Cl2, rt, 98%;
4) PPh3, CBr4, Et3N, CH2Cl2, rt, 94%.
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This work was supported in part by a Grant-in-Aid for
Scientific Research (B) and “Targeted Proteins Research
Program” from the Ministry of Education, Culture, Sports,
Science and Technology of Japan (Y.T.).
18 Crystallographic data reported in this manuscript have been
deposited with Cambridge Crystallographic Data Centre as
supplementary publication No. CCDC-847381. Copies of the
data can be obtained free of charge via http://www.ccdc.
cam.ac.uk/conts/retrieving.html (or from the Cambridge Crys-
tallographic Data Centre, 12, Union Road, Cambridge, CB2
1EZ, U. K.; fax +44 1223 336033; or deposit@ccdc.cam.
ac.uk).
19 General procedures of reductive cyclizations; to solutions of
samarium diiodide (0.1 M in THF, 2.4 mL) added a solution of
0.100 mmol carbodiimides and 21.0 ¯L t-BuOH in 2 mLTHF in
a dropwise manner (condition A) or to solutions of 0.100 mmol
carbodiimide and 95.6 ¯L t-BuOH in 2 mL THF, were added
solutions of samarium diiodide (0.1 M in THF, 2.1 mL) in
a dropwise manner (condition B). After 15 min, saturated
NH4Cl(aq) were added and organic solvents were removed.
The resultant aqueous solutions were extracted with AcOEt and
the organic layers were washed with saturated NH4Cl(aq), dried
over Na2SO4, concentrated under reduced pressure. To solu-
tions of 32.7 mg Boc2O in 1 mL CH2Cl2, were added solutions
of these crude materials in 2 mL CH2Cl2 at ambient temper-
ature. 12.2 mg DMAP was added and the reaction mixtures
were stirred for 5-20 h. The mixtures were evaporated and
directly subjected to silica gel column chromatography to give
iminoindolines.
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Chem. Lett. 2012, 41, 44-46
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