Visible light catalyzed Mannich reaction between: Tert -amines and silyl diazoenolates

Article abstract of DOI:10.1039/c7ob01756a

The present work documents the α-C-H functionalization of tertiary amines via the visible light catalyzed Mannich reaction with silyl diazoenolates. The reaction takes place at room temperature with an organic dye, Rose Bengal, as a photocatalyst and oxygen as the oxidant. The resulting multifunctional products bearing an α-diazo-β-keto group undergo Rh-carbenoid mediated cyclization, affording stable ammonium ylides in high yields.

Full text of DOI:10.1039/c7ob01756a

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Visible light catalyzed Mannich reaction between
tert-amines and silyl diazoenolates†
Cite this: DOI: 10.1039/c7ob01756a
Mukund M. D. Pramanik,a,b Savita B. Nagode,a,b Ruchir Kantc and
a,b
Namrata Rastogi
*
The present work documents the α-C–H functionalization of tertiary amines via the visible light catalyzed
Mannich reaction with silyl diazoenolates. The reaction takes place at room temperature with an organic
dye, Rose Bengal, as a photocatalyst and oxygen as the oxidant. The resulting multifunctional products
bearing an α-diazo-β-keto group undergo Rh-carbenoid mediated cyclization, affording stable
ammonium ylides in high yields.
Received 17th July 2017,
Accepted 15th August 2017
DOI: 10.1039/c7ob01756a
rsc.li/obc
conditions10 and iminium ion formation under anaerobic con-
Introduction
ditions.11 Recently, visible light mediated α-CH functional-
The α-functionalization of tertiary amines by activation of ization of tertiary amines without any photocatalyst12 or under
sp3 C–H bonds adjacent to nitrogen is a powerful strategy for sequence/dual catalysis has helped in the development of
the synthesis of functionalized amines.1 Out of various novel transformations of tertiary amines.13 Furthermore, suc-
methods known for the α-C–H activation of tertiary amines, cessful adoption of VLPC reactions in continuous flow micro-
the most widely used one is the oxidation of the amine into a reactors has introduced an automated approach to the
reactive iminium intermediate which is then trapped by a suit- method.14 With such progress in terms of catalysts, oxidants
able carbon or heteroatom nucleophile. Although the oxidative and reaction conditions, the search for hitherto unknown
activation of tertiary amines is predominantly carried out nucleophiles has become even more vigorous.
under transition metal mediated conditions,2 several elegant
Diazo compounds have been extensively utilized as nucleo-
metal-free protocols have been reported in recent times.3 philes owing to the nucleophilicity of their α-carbon.15 Despite
Lately, the application of visible light photoredox catalysis this, there are only two reports for α-CH functionalization of
(VLPC) has gained popularity over traditional metal-catalysis tertiary amines with α-diazocarbonyl compounds.16 Notably,
as a greener and more sustainable alternative.4 In 2010, the nucleophilicity values “N” for the diazocarbonyl com-
Stephenson and co-workers reported the oxidative coupling of pounds employed in these reactions were well within the pre-
tertiary amines with nitroalkanes as nucleophiles under visible dicted range (for example, N = 4.91 for ethyl diazoacetate)15a
light catalysis.5 Since then, visible light photoredox catalysis for the reaction with iminium ions (electrophilicity value
has been regularly utilized for the oxidative functionalization E = −5 to −10)17 according to Mayr’s rule of thumb for suit-
of tertiary amines with various nucleophiles employing able nucleophile–electrophile combinations.18 Also, there are
organic dyes,6 Ru/Ir complexes,7 or inorganic semiconductor plenty of reports employing silyl enol derivatives for the oxi-
photocatalysts.8 Usually, these reactions proceed via iminium dative functionalization of tertiary amines.13a,19 However, to
ions with oxygen as an oxidant; but, in the absence of oxygen, the best of our knowledge, diazoenolates have not been used
the α-amino radical gives addition products with suitable as nucleophiles for oxidative coupling with tertiary amines.
radical trapping agents.9 However, there are examples of
We here report, for the first time, the use of silyl diazoeno-
reactions following
a
radical mechanism under aerobic lates as nucleophiles for the α-CH functionalization of tertiary
amines under VLPC conditions (Scheme 1).
aMedicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
Lucknow 226031, India. E-mail: namrata.rastogi@cdri.res.in
bAcademy of Scientific and Innovative Research, New Delhi, India
cMolecular & Structural Biology Division, CSIR-Central Drug Research Institute,
Lucknow 226031, India
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of all new compounds. CCDC 1539489. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c7ob01756a
Results and discussion
We started our investigation with N-phenyltetrahydroisoquino-
line 1a, ethyl 3-((tert-butyldimethylsilyl)oxy)-2-diazobut-3-
enolate 2 and Rose Bengal (2 mol%) as the photocatalyst in
DMF (entry 1; Table 1).
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that visible light, photocatalyst as well as oxygen were necess-
ary for the reaction.
After establishing the optimized conditions for the reaction,
we set out to examine the scope of tertiary amines 1 in the
reaction (Table 2). It is evident from Table 2 that substrates
bearing electron-withdrawing groups such as chloro, bromo,
nitro as well as electron-releasing groups such as methyl,
butyl, and methoxy in the N-aryl ring react smoothly with dia-
zoenolate 2 and provide the corresponding products 3a–h in
good yields (54%–82%). However, it is to be noted that the
reaction in the case of substrates possessing electron-
withdrawing substituents on the N-aryl ring 1f–h was sluggish,
taking up to 12 h for completion. Furthermore, the introduc-
tion of electron-releasing methoxy groups into the phenyl ring
of THIQ did not cause much difference in terms of reaction
yields (52%–63%) but the reaction time significantly increased
in the case of substrates 1i–m. On the other hand, introducing
an electron-withdrawing bromo group into the phenyl ring of
THIQ resulted in low product yield (35%) in 3 h whereas a
complex mixture formed upon continuing the reaction for a
longer time. The reaction worked smoothly with N-aryl pyrroli-
dine 1o too albeit in low yield but it was disappointing that
the desired product could not be isolated with aliphatic
tertiary amine 1p even with high catalyst loading.
Scheme 1 α-CH
α-diazocarbonyl compounds.
functionalization
of
tertiary
amines
with
Table 1 Optimization of reaction conditionsa
Photocatalyst
(mol%)
Solvent
(2 mL)
Entry
2 (eq.)
3a b (%)
3a′ b (%)
1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
2.0
2.5
3.0
2.5
2.5
2.5
Rose Bengal (2)
Eosin Y (2)
DMF
DMF
DMF
48
45
40
40
52
60
69
70
65
55
72
78
78
0
0c
10
16
0
2
3d
4
[Ru(bpy)3Cl2] (2)
Rose Bengal (2)
Rose Bengal (2)
Rose Bengal (2)
Rose Bengal (1)
Rose Bengal (0.5)
Rose Bengal (0.3)
Rose Bengal (0.5)
Rose Bengal (0.5)
Rose Bengal (0.5)
Rose Bengal (0.5)
—
CH2Cl2
MeCN
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
5
6
7
8
0
0
0
0
0
0
0
0
Mechanistically, the reaction can be depicted as a Mannich
reaction of in situ generated iminium ions with a diazoenolate
nucleophile (Scheme 2).20
9
10
11
12
13
14
15e
16f
0
Table 2 Scope of tert-amines 1 in the coupling reactiona
<10
<10
0
Rose Bengal (0.5)
Rose Bengal (0.5)
0
0
a Unless otherwise noted, all reactions were performed at 0.5 mmol of
1a scale under green light irradiation for 4 h except for entries 11–13
(3 h). b Isolated yields. c 12% when reaction was carried out with
oxygen balloon. d Blue light irradiation. e Reaction without visible light.
f Under nitrogen.
Upon irradiation of the reaction mixture with green light
(530 nm) for 4 h at room temperature, the ethyl 2-diazo-3-oxo-
4-(2 phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)butanoate 3a was
isolated in 48% yield (entry 1). Upon changing the photo-
catalyst to Eosin Y or [Ru(bpy)3Cl2], a slight reduction in yield
was noted and the oxidized product 3a′ was isolated as a side-
product (entries 2 and 3). Therefore, Rose Bengal was selected
as the preferred photocatalyst for further optimization. Solvent
optimization led to the selection of MeOH20b (60%) over other
solvents tested, for e.g., CH2Cl2 (40%) and MeCN (52%)
(entries 4–6). Further changing the catalyst loading (entries
6–9) and the amount of diazoenolate 2 (entries 8, 10–13)
revealed that 0.5 mol% of Rose Bengal and 2.5 equivalents
of 2 were the best conditions in terms of reaction yield
and economy (entry 12). Additionally, control experiments
conducted in the absence of photocatalyst or visible light or
under inert atmosphere (entries 14–16) substantiated the fact
a Reaction conditions: 1 (0.5 mmol), 2 (1.25 mmol), Rose Bengal
(0.5 mol%), MeOH (2 mL), green light at rt in open air. b With 5 mol%
Rose Bengal.
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Table 3 Scope of substituted THIQ’s 3 in the ylide formationa
a Reaction conditions: 3 (0.05 mmol), Rh2(OAc)4 (1.0 mol%), CH2Cl2
(1 mL) at room temperature under inert atmosphere.
Scheme 2 Plausible reaction mechanism.
Initially, the photocatalyst excited by visible light RB*
undergoes reductive quenching by single electron transfer
(SET) from tertiary amine 1. This process generates tertiary
amine radical cation A and the reduced photocatalyst. The
oxygen present in the air oxidizes back the reduced photo-
catalyst and forms the superoxide radical anion. This radical
anion removes a hydrogen atom from the radical cation A,
leading to the formation of iminium ion B and the peroxide
anion. The peroxide anion undergoes protonation in the
solvent to form hydrogen peroxide and nucleophilic attack of
diazoenolate on the iminium ion B followed by the elimin-
ation of the t-BuMe2Si+ yields the desired Mannich type
product 3.
Furthermore, in an attempt to establish the synthetic poten-
tial of β-oxo-α-diazocarboxylate products 3, we decided to
investigate their behaviour in metal carbenoid-mediated reac-
tions.15e,21 Upon treating compound 3b with 1 mol% of
Rh2(OAc)4 in dichloromethane at room temperature, a gummy
solid was obtained which upon recrystallization provided a
colorless solid. The structure of this solid on the basis of
spectroscopic and single crystal X-ray analysis was established
to be the ammonium ylide 4a (Scheme 3).22
It is well known in the literature that metal carbenoids
derived from diazocarbonyl compounds form transient
ammonium ylides with amines which undergo intramolecular
rearrangement(s) or trapping with suitable dipolarophiles to
afford stable scaffolds. However, to the best of our knowledge,
there are only handful of reports documenting the isolation of
stable ammonium ylides.23 The reaction works smoothly with
other substrates as well affording the ylide products in high
yields (Table 3).
Scheme 4 Mechanism of ammonium ylide 4 formation.
The reaction proceeds via the rhodium carbenoid A which
interacts with the lone pair of electrons on nitrogen. The
resulting rhodium-ylide B dissociates to provide the resonance
stabilized ammonium ylide 4 (Scheme 4). It is noteworthy that
the aryl group on the nitrogen did not undergo 1,2-migration
in the reaction.23b
Conclusions
In summary, we developed the first Mannich reaction between
tertiary amines and diazoenolates under visible light photo-
redox catalysis. The resulting α-diazo-β-oxo-carboxylate pro-
ducts undergo rhodium carbenoid mediated intramolecular
ylide formation with amine. Further exploration of the method
to expand the scope of tertiary amines as well as silyl diazoeno-
lates is currently underway in our laboratory.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
MMDP and SBN thank CSIR, New Delhi and UGC, New Delhi,
respectively, for the Ph.D. fellowships. We thank SAIF division
of CSIR-CDRI for the analytical support. We also thank
Dr Tejender S. Thakur of Molecular and Structural Biology
Division, CSIR-Central Drug Research Institute for supervising
the X-ray data collection and structure determination of 4a.
CDRI Communication No. 9546.
Scheme 3 Rh-Carbenoid mediated ammonium ylide 4a formation.
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