Silver-catalyzed nucleophilic substitution of aminals with ethyl diazoacetate: a new pathway to β-amino-α-diazoesters

Article abstract of DOI:10.1039/c6ob02136k

A novel silver-catalyzed nucleophilic substitution of aminals with ethyl diazoacetate producing β-amino-α-diazoesters has been developed. A series of aminals with different amino moieties and substituents were successfully incorporated in this reaction, which delivered a wide range of β-amino-α-diazocarbonyl compounds in the presence of a lower catalyst loading in 2 hours.

Full text of DOI:10.1039/c6ob02136k

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Silver-Catalyzed Nucleophilic Substitution of Aminals with Ethyl
Diazoacetate: A New Entry to -Amino- -Diazoesters
Jiawen Li,a,c Guiping Qin a,c and Hanmin Huang*a,b
β
α
Received 00th January 20xx,
Accepted 00th January 20xx
A novel silver-catalyzed nucleophilic substitution of aminals with ethyl diazoacetate producing
β-amino-α-diazoesters has
DOI: 10.1039/x0xx00000x
been developed. A series of aminals with different amino moieties and substituents were successfully incorporated in this
www.rsc.org/
reaction, which delivered a wide range of
in 2 hours.
β-amino-α-diazocarbonyl compounds in the presence of lower catalyst-loading
nucleophilic addition of ethyl diazoacetate to activated imines,
bearing strong electron-withdrawing groups (N-SO2R, N-COAr,
N-Boc, N-Cbz, et. al) at the nitrogen atom, has been emerged
Introduction
α
-Diazocarbonyl compounds are significant starting materials
as a powerful method for the synthesis of
β-amino-α-
and have been widely applied in transition-metal-catalyzed X-H
(X = N, O, S, B, Si, et al) insertion,1 and coupling reactions
owing to their unusual properties and versatile reactivities.2-3
As a result, considerable efforts have been devoted to
discovering simple and efficient approaches for the
construction of such molecules.4 The traditional strategies for
diazocarbonyl compounds with the retention of the diazo
functionality (Scheme 2, (1)).9 However, these elegant
methods are limited to activated imines only, which
significantly reduced the appeal of these methods. Although
other significant routes to β-amino-α-diazo compounds were
also reported, such as nucleophilic addition of diazo
compounds to enamines (2),10a iminium salts,10b imines10c and
oxidative coupling of tertiary amines (3)10d with diazo
compounds, this protocol we disclosed here provided a new
the synthesis of α-Diazocarbonyl compounds could be realized
via primary amine diazotization, decomposition of hydrazones
and diazo transfer reaction (Scheme 1).5-7 However, such
reactions could not be utilized for synthesis of
diazoesters, which not only are the most important precursors
for the synthesis of -substituted
-amino acids,3a,b,f but also
are attractive building blocks for chemical synthesis.8 Over the
β-amino-α-
and efficient way to prepare β-amino-α-diazo compounds
employing easily prepared aminals and commercial available
α
β
diazoacetate.
Scheme 2. Ag-catalyzed nucleophilic substitution of aminals
with ethyl diazoacetate
Scheme 1. Strategies for preparation of
α
-diazocarbonyl
compounds
Previous work
O
N
R1
NHR3
EWG
EWG
N2
COOR
HN
R1
N
Cat.
R2
COOR
(1)
R1
H
(b) dehydrogenation
N2
EWG = SO2R, Boc, Cbz, COAr, NHCOAr
O
O
O
R
R
NR3
2
(c)
diazo transfer
(a)
N2
N2
NH2
N2
NR3
R1
R1
R1
2
diazotization
R1
H
(2)
(3)
R2
COOEt
R2
R2
R2
R1 R2
COOEt
past several years, the base-mediated or Lewis acid-catalyzed
N2
Cat.
N
N
R
LED
Ar
Ar
R
N2
This work
NR'2
NR'2
N2
[Ag]
COOEt
R1
R1
NR'2
COOEt
N2
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Aminals have long been recognized as surrogates of imines When AgBF4 was introduced into the reaction system, the
and widely used as electrophiles in metal-catalyzed reaction proceeded well to give 3a in 74% isolated yield while
nucleophilic substitution/addition reactions.11 The C-N bond in other silver salts didn’t give better results (entries 7-9). To
these molecules is easily cleaved under mild conditions to maximize the efficiency of this reaction, a variety of organic
generate an iminium ion together with a basic amino anion. solvents were screened. As a result, THF proved to be the best
Inspired by this unique feature and on the basis of our work solvent. If the solvent was switched to DCM, CH3CN, anisole,
about aminals,12 we envisaged that aminal might be used as a toluene or DMF, the yields of 3a were reduced (entries 10-14).
surrogate of imine to react with diazoacetate for furnishing the Finally, control experiment demonstrated that the desired
β
-amino-α-diazoester, in which one amino moiety contained in product 3a was not formed at all in the absence of a catalyst
the aminal could act as the inner base to abstract a proton to (entry 15). Trace amount of ethyl 3-morpholino-3-
complete the transformation. Herein, we report a Ag-catalyzed phenylacrylate was detected when Ag(I) was employed as the
nucleophilic substitution reaction of aminals with ethyl catalyst. It might be stemmed from the reaction of 3a which
diazoacetate that provides an alternative access to
diazoesters.
Table 1. Optimization of the reaction conditions a
β
-amino-
α-
can undergo the corresponding Bamford–Stevens-Shapiro
reaction in the presence of Ag(I).13
Table 2. Substrate scope of aminals a
R2
R2
R2
R1
R2
N
N2
N
AgBF4
R2
COOEt
R1
N
H
COOEt
THF, 100 oC, 2 h
R2
N2
1
2a
3
COOEt
COOEt
N
N
N
N
COOEt
COOEt
N2
N2
entry
1
[M]
solvent
yield 3a (%)
N2
N2
b
3b, 85%b
3c,
3d,
3e,
77%
81%
77%
Sc(OTf)3
Al(OTf)3
Zn(OTf)2
Cu(OTf)2
Cu(TFA)2
Ag(TFA)
Ag(OTf)
AgClO4
AgBF4
THF
trace
trace
trace
0
O
O
O
2
THF
N
N
3
N
N
THF
COOEt
COOEt
COOEt
COOEt
4
N2
THF
N2
N2
N2
5
THF
0
3f, 74%
3g, 87%
3h, 79%
3i, 82%
O
6
THF
47
65
66
74
49
51
62
68
37
0
O
O
O
7
N
THF
N
N
N
COOEt
8
COOEt
COOEt
COOEt
THF
N2
N2
N2
9
N2
THF
Cl
Cl
Cl
3j, 46%
3k, 58%
3l, 62%
3m, 77%
10
11
12
13
14
15
AgBF4
toluene
CH3CN
anisole
DCM
DMF
THF
O
N
O
O
NBn2
AgBF4
N
COOEt
N
AgBF4
COOEt
COOEt
COOEt
N2
AgBF4
N2
N
N2
O
N2
3n,
3o,
3p,
3q,
78%
82%
40%
13%
AgBF4
aReaction conditions:
1
(0.5 mmol), 2a (114.0 mg, 1.0 mmol),
-
AgBF4 (5.0 mol %), THF (1.5 mL) at 100 oC for 2 h, isolated yield.
bAgBF4 (1.0 mol %), 2a (68.4 mg, 0.6 mmol).
With the optimized reaction conditions identified, the scope
aReaction conditions: 1a (131.0 mg, 0.5 mmol), 2a (114.0 mg,
o
1.0 mmol), [M] (5.0 mol%), solvent (1.5 mL) at 100 C for 2 h,
isolated yield.
of various aminals
1 were explored with ethyl diazoacetate 2a
at 100 oC by using AgBF4 as the catalyst. As illustrated in Table
2, aminals synthesized from both paraformaldehyde and
aromatic aldehydes with a diverse set of substituents, such as
Results and discussion
At the outset of our studies, we explored the viability of the
process with 4,4'-(phenylmethylene)dimorpholine 1a and ethyl
diazoacetate 2a as the model substrates. The reaction was
methyl (3g-3i), chloride (3j-3l) on the phenyl ring, were well
tolerated to give the desired products with good yields.
Generally, aminals bearing electron-donating groups on the
phenyl ring give higher yields than those with electron-
withdrawing groups, as shown for products 3g-3l. Besides,
reactions with aminals bearing electron-withdrawing groups (-
Cl) underwent smoothly, giving the corresponding products up
o
performed at 100 C in THF for 2 h. First, several typical Lewis
acids, such as Sc(OTf)3, Al(OTf)3, Zn(OTf)2, Cu(TFA)2 and
Cu(OTf)2 were found to be ineffective catalysts for the desired
reaction (Table 1, entries 1-5). When Sc(OTf)3, Al(OTf)3 or
Zn(OTf)2 was employed as a catalyst, the starting materials
were remained giving trace amount of the desired product
(detected by TLC). If Cu(TFA)2 or Cu(OTf)2 was introduced into
the reaction system, 2a was decomposed completely providing
the dimerization product of 2a (detected by GC-MS analysis).
To our delight, the corresponding product ethyl 2-diazo-3-
morpholino-3-phenylpropanoate 3a was obtained in 47% yield
when Ag(TFA) was employed as the catalyst (entry 6). Inspired
by this result, we then investigated a series of silver salts.
to 62% yield
(3j-3l). In addition, aminals derived from
naphthaldehydes were also compatible with this
transformation, generating the corresponding products (3m
and 3n) in 77% and 82% yield, respectively. After the
exploration of the reaction scope of aminals above, we turned
our attention to more challenging substrates derived from
furaldehyde and pyridylaldehyde. The furaldehyde derived
aminal 1o was tolerable in the present reaction to give the
desired product 3o in 40% isolated yield. However, under the
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present reaction conditions, only 13% yield of 3p was observed
when 4-pyridylaldehyde derived aminal was employed as a
Notes and references
1
For selected reviews on transition-metal-catalyzed X-H
insertion, see: (a) H. M. L. Davies and R. E. J. Beckwith,
Chem. Rev., 2003, 103, 2861. (b) H. M. L. Davies and J.
R. Manning, Nature, 2008, 451, 417. (c) M. P. Doyle, R.
coupling
partner.
N,N,N',N'-tetrabenzyl-1-
phenylmethanediamine 1q proceeds current reaction giving
the desired product 3q in 78% yield. The solid state structures
of 3g and 3j were confirmed by single-crystal X-ray analysis
(Figure 1).14
Duffy, M. Ratnikov and L. Zhou, Chem. Rev., 2010, 110
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Figure 1. X-ray structures of 3g and 3j.
2
For selected examples on transition-metal-catalyzed
coupling
reaction
involving
α-diazocarbonyl
compounds, see: (a) Q. Xiao, Y. Zhang and J. Wang, Acc.
Chem. Res., 2013, 46, 236. (b) Y. Xia, Y. Zhang and J.
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On the basis of the results we obtained here and literature
reports,9,10,11 a plausible reaction pathway for the present C-C
bond formation reaction was proposed as shown in Scheme 3.
First, the electrophilicity of the aminal would be enhanced by
the AgBF4 via coordination, which was then nucleophilic
attacked by ethyl diazoacetate to give the desired product. It is
likely that the one amino moiety in the aminal serves as an
inner base to abstract the proton to deliver the desired
product with the formation of a new C-C bond.
3
For selected examples involving α-diazocarbonyl
compounds, see: (a) T. Ye and M. A. McKervey, Chem.
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N. Slattery, A. R. Maguire and M. A. McKervey, Chem.
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Scheme 3. Proposed reaction pathway
4
5
6
For recent review on synthesis of diazo compounds,
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3
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In summary, we have developed a novel silver-catalyzed direct
implanting of ethyl diazoacetate into aminals to produce
diverse donor-acceptor diazo-compounds through nucleophilic
,
For enantioselective acid-catalyzed nucleophilic
addition of diazo-compounds to activated imines, see:
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substitution reaction. Various
β-amino-α-diazoacetates with
different amino moieties were efficiently constructed by
cleavage of C-N bond of aminals under mild and neutral
reaction conditions. This strategy not only enlarges the
application of ethyl diazoacetate in organic synthesis, but also
provides an alternative synthetic method to prepare
-diazoacetates. The practical advantage of the present
protocol is that it could transform the simple available starting
materials (ethyl diazoacetate and aminals) into complex
amino- -diazoacetates. Further investigations to apply this
β-amino-
α
2011,
Org. Lett., 2012, 14
3
, 642. (f) H. Zhang, X. Wen, L. Gan and Y. Peng,
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α
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This research was supported by the CAS Interdisciplinary
Innovation Team, the National Natural Science Foundation of
China (21133011 and 21672199).
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14 CCDC 1502480 (3g) and 1502481 (3j) contain the
supplementary crystallographic data for this paper.
This data can be obtained free of charge from The
Cambridge
www.ccdc.cam.ac.uk/data_request/cif.
Crystallographic
Data
Centre
via
TOC
A novel silver-catalyzed nucleophilic substitution of
aminals with ethyl diazoacetate producing -amino-α-
β
diazoesters has been developed. A series of aminals
with different amino moieties and substituents were
successfully incorporated in this reaction.
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