A catalyst-free N-H insertion/Mannich-type reaction cascade of α-nitrodiazoesters

Article abstract of DOI:10.1016/j.tetlet.2013.05.131

A catalyst-free N-H insertion/Mannich-type reaction cascade of α-nitrodiazoesters with anilines has been developed to afford a variety of α-amino-α-aryl esters in 60-83% yields and under mild reaction conditions (23 or 40 C).

Full text of DOI:10.1016/j.tetlet.2013.05.131

Accepted Manuscript
A catalyst-free N-H insertion/Mannich-type reaction cascade of α-nitrodia‐
zoesters
Ting Yang, Hao Zhuang, Xichen Lin, Zhong Zhong, Jia-Ning Xiang, John D.
Elliott, Lianghui Liu, Feng Ren
PII:
S0040-4039(13)00922-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.131
TETL 43031
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
6 April 2013
14 May 2013
20 May 2013
Please cite this article as: Yang, T., Zhuang, H., Lin, X., Zhong, Z., Xiang, J-N., Elliott, J.D., Liu, L., Ren, F., A
catalyst-free N-H insertion/Mannich-type reaction cascade of α-nitrodiazoesters, Tetrahedron Letters (2013), doi:
http://dx.doi.org/10.1016/j.tetlet.2013.05.131
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A catalyst-free N-H insertion/Mannich-type
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reaction cascade of ꢀ-nitrodiazoesters
Ting Yanga, Hao Zhuangb, Xichen Lina, Zhong Zhonga, Jia-Ning Xianga, John D. Elliotta, Lianghui Liuc, and
Feng Rena,

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A catalyst-free N-H insertion/Mannich-type reaction cascade of ꢀ-nitrodiazoesters
Ting Yanga, Hao Zhuangb, Xichen Lina, Zhong Zhonga, Jia-Ning Xianga, John D. Elliotta, Lianghui Liuc
∗
and Feng Rena,
aResearch and Development, GlaxoSmithKline Pharmaceuticals, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, China
bSchool of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China
cCollege of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A catalyst-free N-H insertion/Mannich-type reaction cascade of ꢀ-nitrodiazoesters with anilines
has been developed to afford a variety of ꢀ-amino-ꢀ-aryl esters in 60–83% yields and under mild
reaction conditions (23°C or 40°C).
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Catalyst-free reaction
N-H insertion
Mannich-type reaction
ꢀ-Nitrodiazo ester
ꢀ-Amino-ꢀ-aryl ester
Carbene
Metal-catalyzed N-H insertions of carbenes have enabled a
number of transformations to form C-C, C-N and C-O bonds.1 It
has been proved as a powerful strategy to construct many
important pharmaceutical compounds as well as natural products
during the past twenty years. Enantioselective versions of this
reaction were developed using chiral ligands, and high
enantioselectivities were achieved.2 In addition, organocatalysis
has attracted more attentions due to its advantages to avoid the
expensive metals from the reaction systems and to allow
reactions to occur under much milder conditions in an
environmentally friendly manner.3 More recently, the Mattson
carbenes from ꢀ-nitrodiazoesters, followed by N-H
insertion/Mannich-type reaction cascade to afford ꢀ-amino-ꢀ-aryl
esters in high yields under mild reaction conditions.
Scheme 1. Mattson’s N-H insertion reaction and the catalyst 1
The discovery was initiated in order to find novel
organocatalysts by mimicking the biological active molecules,
and the same approach has led to several successful cases in
literature.8 Recently, we discovered that aminopyrimidinones
demonstrated similar biological activities as ureas in certain
circumstances.9 Inspired by this finding, we decided to evaluate
the feasibility to use aminopyrimidinones as the alternative
organocatalysts as ureas in synthetic organic chemistry.10
Our investigation began with the studies of N-H bond
insertion of the ꢀ-nitrodiazoester 3a into aniline 4a, where
aminopyrimidinone catalyst 2 was used to replace the reported
urea catalyst 1 (Table 1).4 To our delight, the reaction worked
smoothly in the presence of the aminopyrimidinone catalyst 2 in
toluene and a reasonable yield of the desired product was
obtained, even at lower temperature (23 °C) than that reported by
group developed
a
N-H insertion reaction using the
difluoroboronate urea (1, Scheme 1) as the organocatalyst to
afford ꢀ-amino-ꢀ-aryl esters from the ꢀ-nitrodiazoester and
anilines in toluene. In this reaction cascade, a N-H insertion into
carbene followed by Mannich-type nucleophilic addition was
proposed.4,5 The enhanced acidity of the difluoroboronate urea
catalyst (1) proved to be critical to activate the ꢀ-nitrodiazoester
for the carbene generation.4 In general, there was very limited
investigation to generate carbenes or carbenoids from ꢀ-
nitrodiazoester, and catalysts were required in all reported cases
in order to achieve reasonable yields of products.6,7 Herein, for
the first time, we report a catalyst-free system to generate the
———
∗Corresponding author. Tel.: +86-186-1674-3377; fax: +86-021-6159-0730; e-mail: feng.q.ren@gsk.com

2
Tetrahedron
the Mattson group (40 °C) (entry 1). A survey of solvent effect
aniline (entry 2). When the aniline with an electron-withdrawing
substitute such as F was used as the substrate, a high yield (69%)
of desired product could still be achieved at a slightly elevated
temperature (40 °C) and a longer reaction time (entry 3). Similar
yield was obtained for 3-chloro aniline (70%) at the similar
reaction condition (entry 4). For the di-substituted aniline, 3-
fluoro-5-methyl aniline, a moderate yield (60%) was obtained
despite a prolonged reaction time at 40 °C (entry 5). In addition
to the ethyl ꢀ-nitrodiazo ester, the methyl ester was tolerated in
the reaction and comparable yields were obtained (entries 6–10).
on the reaction (entries 2–4) revealed that methanol was the most
optimal solvent for this transformation, providing a 74% yield
after stirring at 23 °C for 36 hours. To evaluate the efficiency of
catalyst 2, a control experiment was carried out in methanol. To
our surprise, an even higher yield (95%) was obtained without
catalyst 2 (entry 5). The reaction was repeated for several times
and similarly high yields (> 90%) were always obtained. To the
best of our knowledge, this is the first time the catalyst-free N-H
insertion into the carbene generated from the ꢀ-nitro-ꢀ-diazo
ester resulted in a high yield at room temperature. Even for the
more extensively studied ꢀ-aryl/carbonyl-ꢀ-diazo esters, the
reported catalyst-free N-H insertion protocols either provided
low yield (30-40%)11 or only proceeded at elevated temperature
(reflux in PhCF3).12 Encouraged by this result, we set out to
further evaluate the effect of solvents. When DMF or acetonitrile
were used as the reaction solvents, much decreased yields were
resulted (entries 6–7). In addition, only trace amounts of product
were obtained when the reactions were carried out in
dichloromethane or ethyl acetate (entries 8–9). The results
suggested that protic solvents such as methanol inclined to
provide good yield of the desired product. This is probably due to
the ability of methanol to form hydrogen bonds with the nitro
group of 3a to facilitate the carbene formation for N-H insertion
and to accelerate the loss of the nitro group to generate the
iminium intermediate for the subsequent Mannich-type reaction
to produce the desired product. Reducing the amount of aniline
4a from 10 equivalents to 5 equivalents resulted in a slight
decrease in the yield (84%, entry 10). Further reduction of the
aniline amount to two equivalents only afforded 23% yield (entry
11).
Table 2. Substrate scope for catalyst free N-H insertion/Mannich-type
reaction cascade of ꢀ-nitrodiazo esters
entrya R1
aniline 4
product 5
condition
yieldb(%)
23°C
1.5 d
1
2
Et
Et
83
23°C
1 d
72
69
40°C
7 d
3
4
Et
Et
40°C
5 d
Table 1. Reaction condition optimization on the N-H insertion/Mannich-
type reaction cascade of ꢀ-nitrodiazoester 3a with aniline 4a
70
60
40°C
4.5 d
5
Et
entrya
catalyst
2
aniline
10 eq.
10 eq.
10 eq.
10 eq.
10 eq.
10 eq.
10 eq.
10 eq.
10 eq.
5 eq.
solvent
Toluene
DMF
yieldb(%)
1
2
51
35
33
74
95
20
20
7
23°C
1.5 d
2
6
7
Me
Me
74
71
3
2
CH3CN
MeOH
MeOH
DMF
4
2
23°C
1 d
5
none
none
none
none
none
none
none
6
7
CH3CN
DCM
40°C
7 d
8
8
9
Me
Me
79
67
9
EtOAc
MeOH
MeOH
6
10
11
84
23
40°C
5 d
2 eq.
a) The reaction was carried out using ꢀ-nitrodiazoester 3a (30 mg), catalyst (20 mol%), aniline 4a in solvent (0.2 mL) at RT
for 36 hours. b) yield was measured by HNMR using mesitylene as an internal standard.
With the optimized reaction condition in hands, we then
investigated the substrate scope of this catalyst-free N-H
insertion/Mannich-type reaction. As shown in table 2, the N-H
insertion of 2-nitrodiazo esters with meta-substituted anilines
processed smoothly to afford desired product ꢀ-amino-ꢀ-aryl
esters in good yields (60–83%). Meta-substituted anilines bearing
a variety of functional groups with different electronic/steric
properties were tolerated in the reaction. N-H insertion of 3-
methyl aniline provided comparable yield (72%) as that of
40°C
4.5 d
10
Me
74
a) The reaction was carried out using ꢀ-nitrodiazo esters (100 mg), substituted anilines (10 eq) in MeOH (0.2 mL); b)
Isolated yield.
The proposed reaction pathway begins from the N-H insertion
of the aniline to the ꢀ-nitrodiazo ester 3, giving rise to the ꢀ-
amino-ꢀ-nitro ester intermediate I (Scheme 2). The nitro group is

3
then extruded from I to generate the iminium intermediate II.
Mannich-type addition of the nucleophile, herein the second
equivalent of aniline at the para-position, to II affords the
desired product 5. The N-H insertion step is sensitive to steric
hindrance of the aniline. When ortho-substituted anilines were
used, the formation of desired products was not observed and
only aniline starting materials were recovered. The regio-
selectivity of the Mannich-type nucleophilic addition of anilines
to the iminium intermediate II is somewhat surprising. Only the
para-position of the second equivalent aniline could react to form
the product 5, and the ortho-addition product 6 was not observed
in all cases. The regio-chemistry of the products (5a–5j) was
confirmed by 2D-NMR and NOE studies (supporting
information). The para-substituted anilines failed to afford any
desired product 5 because the Mannich-type reaction was
blocked by the para-substitutions. The reactions were either
messy or some undesired side-products were formed. Further
mechanistic studies were ongoing to understand the regio-
selectivity of the desired products 5 and also the reaction
pathways towards the side-products from the para-substituted
anilines.
References and notes
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(f) Slattery, C. N.; Ford, A.; Maguire, A. R. Tetrahedron 2010,
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4. So, S. S.; Mattson, A. E. J. Am. Chem. Soc. 2012, 134, 8798.
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Scheme 2. Proposed N-H insertion/Mannich-type reaction cascade
In summary, for the first time,
a catalyst-free N-H
insertion/Mannich-type cascade reaction of ꢀ-nitrodiazoesters
with anilines has been developed to afford a variety of ꢀ-amino-
ꢀ-aryl esters in good yields and under mild reaction conditions
(23°C or 40°C). The protic solvent, methanol, was proved to be
critical for the reaction to provide high yields of products. The
reaction cascade worked well with meta-substituted anilines as
substrates. Further investigations are ongoing to expand the
substrate scope to sterically hindered ortho-substituted anilines.
In addition, a three component coupling reaction based on the
methodology is being developed to further extend its utility.
8.
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Acknowledgments
9. Results will be published elsewhere.
We thank Mr. Morris Sui for NMR analysis and Dr. Ruina
Gao for HRMS analysis. We are grateful for the financial support
of the Forum for Innovative Research and Scientific Talents
Award, GlaxoSmithKline.
10. A similar structure was used as organocatalysis: Suez, G.;
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12. Hansen, S. R.; Spangler, J. E.; Hansen, J. H.; Davies, H. M. L.
Org. Lett. 2012, 14, 4626.
Supplementary Material
Supplementary data (detailed experimental for all compounds
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including procedures, H NMRs, 13C NMRs, HRMSs and nOe
characterizations) associated with this article can be found, in the
online version, at XXXXXX.