Synthesis of nitrogen heterocycles via α-aminoalkyl radicals generated from α-silyl secondary amines under visible light irradiation

Article abstract of DOI:10.1039/c4cc03000a

We have succeeded in the visible light-mediated synthetic use of α-aminoalkyl radicals derived from α-silyl secondary amines toward addition to α,β-unsaturated carbonyl compounds. The resulting γ-aminocarbonyl compounds are converted into γ-lactams and pyrroles in a one-pot process. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03000a

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Synthesis of nitrogen heterocycles via
a-aminoalkyl radicals generated from a-silyl
secondary amines under visible light irradiation†
Cite this: Chem. Commun., 2014,
50, 8900
Received 23rd April 2014,
Accepted 12th June 2014
Kazunari Nakajima, Mai Kitagawa, Yuya Ashida, Yoshihiro Miyake*‡ and
Yoshiaki Nishibayashi*
DOI: 10.1039/c4cc03000a
www.rsc.org/chemcomm
We have succeeded in the visible light-mediated synthetic use of
a-aminoalkyl radicals derived from a-silyl secondary amines toward
addition to a,b-unsaturated carbonyl compounds. The resulting
c-aminocarbonyl compounds are converted into c-lactams and
pyrroles in a one-pot process.
Five-membered nitrogen heterocycles such as g-lactams and pyrroles
are found in various natural products and pharmaceuticals.1,2
Construction of these skeletons in a simple and efficient manner
is one of the most important topics in synthetic organic chemistry.
In this context, the development of a novel synthetic approach
for g-aminocarbonyl compounds composed of a secondary or
primary amine moiety plays a pivotal role because a rapid 5-exo-
cyclization between amine and carbonyl groups gives the corre-
sponding nitrogen heterocycles.1
Construction of g-aminocarbonyl skeletons by the addition
of a-aminoalkyl radicals derived from secondary amines
to a,b-unsaturated carbonyl compounds under the photoinduced
electron transfer conditions is a potentially useful strategy to
access the corresponding nitrogen heterocycles.3 However, in these
reaction systems, a large amount of N-alkylation products was
Scheme 1 Photoreactions of secondary amines via (a) aminyl radicals and
(b) a-aminoalkyl radicals.
Hence, we have envisaged the use of a-silylamines as substrates
usually observed due to the formation of aminyl radicals by because dissociation of the a-C–Si bond of the radical cations occurs
oxidation of secondary amines (Scheme 1a)4,5 or direct thermal readily, which is considered to be suitable for selective formation of
aza-Michael addition,6 where the desired g-aminocarbonyl com- a-aminoalkyl radicals over aminyl radicals (Scheme 1b).10,11 In fact,
pounds were obtained only in low yields.3 As a result, successful we have recently succeeded in the synthetic utilization of
examples for synthetic utilization of a-aminoalkyl radicals under a-aminoalkyl radicals generated from a-silyl tertiary amines in the
UV3,7 or visible light8,9 irradiation have been strictly limited to presence of visible light-photoredox catalysts.8,12 In the course of our
the use of tertiary amine derivatives. These results indicate that study, we have disclosed visible light-mediated synthetic utilization
the generation and utilization of a-aminoalkyl radicals derived of a-aminoalkyl radicals generated from a-silyl secondary amines
from secondary amines are quite difficult.
toward the addition to a,b-unsaturated carbonyl compounds, where
the produced g-aminocarbonyl compounds are converted into the
corresponding g-lactams and pyrroles in simple one-pot procedures.
The preliminary results are described here.
Initial investigations of one-pot synthesis of g-lactams were
conducted using N-(trimethylsilylmethyl)aniline (1a) and diethyl
benzylidenemalonate (2a) as substrates (Table 1). In the presence
of 1 mol% of [4a][BF4], the reaction of 1a with 1.2 equiv. of 2a
was carried out in N-methylpyrrolidone (NMP) under visible light
Institute of Engineering Innovation, School of Engineering, The University of Tokyo,
Yayoi, Bunkyo-ku, Tokyo, 113-8656, Japan. E-mail: ynishiba@sogo.t.u-tokyo.ac.jp
† Electronic supplementary information (ESI) available. CCDC 992086. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc03000a
‡ Present address: Department of Applied Chemistry, Graduate School of Engi-
neering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan.
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Table
1
Reactions of N-(trimethylsilylmethyl)aniline (1a) with diethyl
Table 2 Reactions of a-silyl secondary amines (1) with diethyl benzylidene-
malonate (2a)a
benzylidenemalonate (2a)a
Yield of 3b (%)
Trans/cisc
Entry
Photocatalyst
Solvent
Yield of 3ab (%)
Trans/cisc
Entry
a-Silylamine (1)
1
[4a][BF4]
[4a][BF4]
[4a][BF4]
[4a][BF4]
[4a][BF4]
[4a][BF4]
[4b][BF4]
[4c][BF4]
NMP
NMP
DMF
DMSO
EtOH
THF
NMP
NMP
NMP
89
34
83
73
31
6
74
77
86
420/1d
420/1
420/1
12/1
1
2
R1 = 4-CIC6H4, R2 = H (1b)
R1 = 4-FC6H4, R2 = H (1c)
R1 = 4-MeC6H4, R2 = H (1d)
R1 = 2-MeC6H4, R2 = H (1e)
R1 = 4-MeOC6H4, R2 = H (1f)
R1 = 1-Naphthyl, R2 = H (1g)
95 (3b)
85 (3c)
90 (3d)
66 (3e)
79 (3f)
75 (3g)
44 (3h)
62 (3i)
420/1
19/1
20/1
15/1
6/1
2e, f
3
3
4d
5e
6
4
5
6
7
8
9
14/1
420/1
420/1
420/1
420/1
9/1
7d,f
8
R1 = Bu, R2 = H (1h)
7/1
t
R1 = Ph, R2 = Me (1i)
6/1g
[Ru(bpy)3][BF4]2
a
All reactions of 1 (0.25 mmol) with 2a (0.30 mmol) were carried out in
the presence of [4a][BF4] (0.0025 mmol) in NMP (2.5 mL) under 14 W
white LED illumination at 25 1C for 18 h. Then, the resulting mixture
was treated with KOtBu (0.50 mmol) at room temperature for 4 h.
b
c
Isolated yield. The isomeric ratio was determined by 1H NMR of the
d
isolated products. Treatment with KOtBu was done at 100 1C for 17 h.
e
f
For 48 h of photoreaction. 1h (0.30 mmol) and 2a (0.25 mmol) were
g
used. The ratio of two major isomers.
a
All reactions of 1a (0.25 mmol) with 2a (0.30 mmol) were carried out in
the presence of a photocatalyst (0.0025 mmol) in solvent (2.5 mL) under
14 W white LED illumination at 25 1C for 18 h. Then, the resulting
mixture was treated with KOtBu (0.50 mmol) at room temperature for
(trimethylsilylmethyl)amine and an amide derivative N-(trimethyl-
silylmethyl)acetamide were used as substrates, no formation of the
corresponding products was observed.
4 h. Isolated yield. The isomeric ratio was determined by 1H NMR of
b
c
d
Reactions of N-(trimethylsilylmethyl)aniline (1a) with a vari-
ety of a,b-unsaturated esters (2) were examined (Table 3). Use of
a,b-unsaturated esters bearing various aromatic and alkyl
groups gave the corresponding products in high yields
(Table 3, entries 1–7). Introduction of a cyano group instead
of an ester group was successful to give 3q in 81% yield
(Table 3, entry 8). When ethyl acrylate (2j) was used, 3r was
obtained in 47% yield (Table 3, entry 9). Tetra-substituted
the crude products. The isomeric ratio of the isolated 3a is 14/1.
e
f
Without treatment with KOtBu. 3a0 is obtained in 58% yield.
illumination using a 14 W white LED at 25 1C for 18 h. After the
photoreaction, treatment of the resulting reaction mixture with
2 equiv. of KOtBu afforded N-phenyl-3-ethoxycarbonyl-4-phenyl-
2-pyrrolidone (3a) in 89% yield (Table 1, entry 1). In the absence
of base, uncyclized product (3a0) was obtained in 58% yield along
with 3a in 34% yield (Table 1, entry 2). These results indicate that
addition of base is important to obtain the g-lactam in a high
yield. When reactions were carried out in other polar solvents
such as N,N-dimethylformamide (DMF) and dimethylsulfoxide
(DMSO), 3a was obtained in lower yields (Table 1, entries 3 and 4).
Ethanol and tetrahydrofuran (THF) were not effective solvents in
this reaction system (Table 1, entries 5 and 6). Use of other
iridium complexes ([4b][BF4] and [4c][BF4]) and ruthenium(II)
tris(2,20-bipyridyl) complex ([Ru(bpy)3][BF4]2) as photocatalysts
gave 3a in slightly lower yields (Table 1, entries 7–9). Separately,
we confirmed that the photoreaction did not proceed at all in the
absence of photocatalysts or visible light illumination.
Next, we investigated reactions of various a-silylamines (1) with 2a
(Table 2). Use of a-silylamines bearing an electron-withdrawing or
donating group on the benzene ring afforded the corresponding
products in excellent yields (Table 2, entries 1–5). Introduction of a
naphthyl group instead of a phenyl ring was successful to give 3g in
75% yield (Table 2, entry 6). Dialkylamine derivative 1h was also
applicable to this reaction system to give the corresponding products
Table 3 Reactions of N-(trimethylsilylmethyl)aniline (1a) with a,b-unsaturated
esters (2a)a
Yield
Entry a,b-Unsaturated ester (2)
of 3b (%) Trans/cisc
1
2
3
4
5
6
R1 = 4-CIC6H4, R2 = H, R3 = CO2Et (2b)
R1 = 4-MeC6H4, R2 = H, R3 = CO2Et (2c)
79 (3j)
79 (3k)
420/1
20/1
420/1
20/1
14/1
19/1
11/1
8/1
R1 = 3-MeC6H4, R2 = H, R3 = CO2Et (2d) 62 (31)
R1 = 4-MeOC6H4, R2 = H, R3 = CO2Et (2e) 81 (3m)
R1 = 4-PhC6H4, R2 = H, R3 = CO2Et (2f)
61 (3n)
R1 = 2-Naphthyl, R2 = H, R3 = CO2Et (2g) 61 (3o)
7
R1
=
nPr, R2 = H, R3 = CO2Et (2h)
79 (3p)
81 (3q)
47 (3r)
77 (3s)
8d
9
R1 = Ph, R2 = H, R3 = CN (2i)
R1 = R2 = R3 = H (2j)
—
—
10
R1 = R2 = Me, R3 = CO2Et (2k)
a
All reactions of 1a (0.25 mmol) with 2 (0.30 mmol) were carried out in
in 44% yields (Table 2, entry 7). The use of an a-aminoethyl the presence of [4a][BF4] (0.0025 mmol) in NMP (2.5 mL) under 14 W
white LED illumination at 25 1C for 18 h. Then, the resulting mixture
radical generated from 1-(trimethylsilyl)ethyl amine (1i) gave
the corresponding tri-substituted g-lactam (3i) in 62% yield
was treated with KOtBu (0.50 mmol) at room temperature for 4 h.
b
c
Isolated yield. The isomeric ratio was determined by 1H NMR of the
d
(Table 2, entry 8). Unfortunately, when a primary amine derivative isolated products. Treatment with KOtBu was done at 100 1C for 17 h.
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alkene 2k was also applicable to give the corresponding g-lactam
(3s) in 77% yield (Table 3, entry 10).
The success in synthesis of g-lactams prompted us to
investigate other nitrogen heterocycles such as pyrroles. We
have designed a,b-unsaturated ketones as substrates for the
construction of a pyrrole ring. When the reaction of 1a with an
a,b-unsaturated ketone derivative (5) was examined under
similar reaction conditions to the g-lactam synthesis, dihydro-
pyrrole (6) was obtained in 64% yield (Scheme 2a). Encouraged
by this result, we have successfully developed one-pot synthesis
of pyrroles by oxidation of dihydropyrroles (Scheme 2b). After
photoreactions of a-silyl secondary amines (1a and 1i) with 5,
subsequent treatment of the resulting mixture with 2 equiv.
of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) at room
temperature for 30 min gave the corresponding tri- and tetra-
substituted pyrroles (7a and 7b) in high yields.
Scheme 3 Plausible reaction pathways.
cyclization of C (E = CO2Et) affords g-lactams, while oxidation of
dihydropyrroles (D) formed by dehydration condensation of C
(E = COCH3) gives pyrroles.
To obtain mechanistic insight, some additional experiments were
carried out. At first, the quantum yield of the reaction of 1a with 2a
was determined to be 0.13. The value is in the common range of the
photoredox reactions which proceed by a sequential redox process.8
Next, we monitored the photoreaction of 1a with 2a by GC-MS
because isolation of the primary products without an aqueous
work-up was not possible due to the high boiling point of NMP.
GC-MS analyses indicate that the reaction mixture includes
hexamethyldisiloxane and 3a0 (see Table 1 for the structure of
3a0). This result shows that the trimethylsilyl group was captured
by adventitious water8,10 and 3a0 is the primary product in the
reaction system. Separately, we carried out the reaction of 1a
with 2a in the presence of a small amount of water (NMP/H2O =
25/1), where 3a was obtained in 86% yield. This result indicates
that the additional water did not affect the yield of g-lactam.
Based on the experimental results, the reactions are considered
to proceed via a reaction pathway similar to the previously reported
sequential redox pathway, as shown in Scheme 3.8 At first, single
electron oxidation of a-silyl secondary amines 1 by a photo-excited
catalyst (*cat) occurs. Then, a-aminoalkyl radicals (A) are formed
along with generation of trimethylsilyl cations.10 The trimethylsilyl
cation is captured by adventitious water in the reaction system
to give hexamethyldisiloxane and protons. Addition of A to
a,b-unsaturated carbonyl compounds 2 affords the corresponding
radical intermediates (B). The reduction of B13 by a reduced catalyst
(catꢀ)14 and subsequent protonation give g-aminocarbonyl com-
pounds (C) as primary products. Subsequently, base-mediated
In summary, we have developed a novel reaction system for
generation and utilization of a-aminoalkyl radicals derived from
secondary amines. The a-aminoalkyl radicals were successfully
applied toward addition to a,b-unsaturated carbonyl compounds
and subsequent cyclization into nitrogen heterocycles such as
g-lactams and pyrroles. We believe that the method described
here provides a useful approach for syntheses of various nitrogen
heterocycles, which are useful in pharmacological science.
Further investigations on scope of substrates and mechanistic
details are now under way.
We thank the Funding Program for Next Generation World-
Leading Researchers (GR025) and Grants-in-Aid for Scientific
Research (Nos. 26288044, 26620075, 26105708, and 26870120)
from the Japan Society for the Promotion of Science (JSPS) and the
Ministry of Education, Culture, Sports, Science and Technology of
Japan (MEXT).
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