Unusual reactivity of nitronates with an aryl alkyl carbonate: Synthesis of α-amino esters

Article abstract of DOI:10.1021/ol5028199

The monoanions of nitroalkanes are ambident nucleophiles that react with carbonate electrophiles through the oxygen atom. Products arising from reactivity at the carbon atom will yield α-nitro esters, which are precursors for α-amino esters. We demonstrate this in the reactions of nitroalkanes with benzyl phenyl carbonate and DABCO where α-nitro esters are obtained instead of nitrile oxides. The products are readily reduced to α-amino esters. This pathway could be a safe alternative to the Strecker reaction.

Full text of DOI:10.1021/ol5028199

Letter
pubs.acs.org/OrgLett
Unusual Reactivity of Nitronates with an Aryl Alkyl Carbonate:
Synthesis of α‑Amino Esters
Golipalli Ramana Reddy, Debopreeti Mukherjee, Arjun Kumar Chittoory, and Sridhar Rajaram*
†
†,§
†
,‡
†
‡
New Chemistry Unit and International Centre for Materials Science, Jawaharlal Nehru Centre for Advanced Scientific Research,
Bangalore 560064, India
*
S Supporting Information
ABSTRACT: The monoanions of nitroalkanes are ambident nucleo-
philes that react with carbonate electrophiles through the oxygen atom.
Products arising from reactivity at the carbon atom will yield α-nitro
esters, which are precursors for α-amino esters. We demonstrate this in
the reactions of nitroalkanes with benzyl phenyl carbonate and DABCO
where α-nitro esters are obtained instead of nitrile oxides. The products
are readily reduced to α-amino esters. This pathway could be a safe
alternative to the Strecker reaction.
roteinogenic and non-proteinogenic α-amino acids have
(Scheme 1). This provides an operationally simple alternative
to the use of toxic cyanide for the synthesis of α-amino acids.
1
P
found utility in various fields such as catalysis, medicinal
2
3
chemistry, and materials science. Among the various methods
4
5
for the synthesis of α-amino acids, the Strecker reaction has
Scheme 1. Synthesis of α-Amino Esters Using Carbonates
one of the broadest substrate scopes. In this reaction, an imine
(
electrophile) is treated with cyanide (nucleophile) to obtain α-
amino nitriles. The cyanide moiety is hydrolyzed to yield the
carboxyl group of the amino acid. A major drawback of this
approach is the toxicity of cyanide. This has led to alternative
6
approaches wherein cyanide is generated in situ. In order to
completely avoid the use of cyanide, several groups have looked
7
,8
at alternative one-carbon synthons. Among these, carbon
9
dioxide is a convenient one-carbon synthon. However, mostly
high pressures of CO are required, and the substrate scope is
2
1
0,11
limited.
In this context, the synthesis of α-nitro esters represents a
convenient and easily scalable alternative to the Strecker
reaction. The Seebach group has shown that dialkyl
carbonates can react with dianions of nitroalkanes to give α-
1
2
Our initial studies were guided by the proposed mechanism
shown in Scheme 2. We began our studies with benzyl phenyl
carbonate as our one-carbon synthon. In this carbonate, the
phenoxy moiety is a good leaving group that can be selectively
expelled upon attack of a nucleophile. The benzyloxy moiety
cannot be expelled in this manner, and this ensures that the
carbonyl group in the product will not be susceptible to
nucleophilic attack. We posited that nucleophilic activation of
benzyl phenyl carbonate by 1,4-diazabicylco[2.2.2]octane
1
2j,k
nitro esters.
The nitro esters can be readily reduced to give
1
3
α-amino esters. Formation of dianion is required to force
reactivity through the carbon atom of the ambident nitronate
anion. Indeed, the monoanion preferentially reacts through the
oxygen atom with electrophiles such as choloroformates,
carbonates, and isocyanates to yield nitrile oxides. The
dianions are generated by using 2 equiv of a strong base at low
temperatures. Additionally, in certain cases like β-phenyl
14
(
DABCO) would result in the generation of a phenoxide
12j−l
anion. Phenol, the conjugate acid of this anion, has a higher pK
nitroethane the second deprotonation is not regioselective.
a
15
than nitroalkanes (Scheme 2). Therefore, the phenoxide
anion will deprotonate a nitroalkane to generate a nitronate
anion. The monoanion can then react with the activated
carbonate either through the oxygen atom or through the
carbon atom. Reaction through the oxygen atom would result
in the formation of a nitrono carbonate. However, attack of
As a result, inseparable mixtures of the product nitroesters are
obtained. The above limitations can be overcome if the reaction
can be carried with the monoanion of nitroalkanes. This would
then represent a safe and scalable alternative to the Strecker
reaction. Herein, we detail an approach where we overturn the
preferred reactivity pattern of nitronate anions by using a
nucleophile. In the process, we generate α-nitro esters under
mildly basic conditions. The nitro group can be reduced readily
to obtain the corresponding α-amino esters in good yields
Received: September 24, 2014
Published: November 5, 2014
©
2014 American Chemical Society
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Organic Letters
Letter
Scheme 2. Initial Mechanistic Hypothesis
substrates (Table 1). One of the highest yields was obtained
when the reaction was performed under solvent-free conditions
(
entry 7, Table 1). From the initially hypothesized mechanism,
it appeared that addition of a small amount of DMSO might
speed up the reaction as it is known to stabilize cations. Indeed,
addition of 3 equiv of DMSO reduced the reaction time to half
with a nominal increase in yield (entry 8, Table 1). Further, we
were able to reduce the amount of DABCO to 2 equiv.
Using this procedure, we evaluated the substrate scope of this
reaction (Table 2). The steric size and substitution pattern on
a
Table 2. Substrate Scope
DABCO on the nitronocarbonate was expected to regenerate
the nitronate anion. On the other hand, reaction through the
carbon atom would lead to formation of an α-nitro ester. The
carbonyl group in this compound is unlikely to be attacked by
DABCO due to its lower electrophilicity. On the basis of pKa
values, DABCO is expected to deprotonate the product
1
(
confirmed by H NMR studies, vide infra). This should
ensure that reaction through the carbon atom is irreversible.
To test the feasibility of this approach, a mixture of 2-
phenylnitroethane, benzyl phenyl carbonate, and DABCO was
refluxed in THF for 20 h. We obtained the α-nitro ester in 49%
1
yield after chromatographic purification (Table 1, entry 1). H
a
Table 1. Solvent Screen
b
entry
solvent
temp (°C)
time (h)
% yield
1
2
3
4
5
6
7
8
tetrahydrofuran
acetonitrile
66
50
60
60
50
70
60
60
20
64
59
67
64
2.5
12
5
49
58
64
59
58
52
76
77
ethyl acetate
isopropyl acetate
chlorobenzene
c
DMSO
d
neat
d,e
DMSO
a
Conditions: carbonate (2.0 equiv), DABCO (4.0 equiv), ∼ 0.66 M of
b
c
3
a. Yield of product after column chromatography. ∼0.33 M of 3a.
d
e
Carbonate (3.0 equiv), DABCO (2.0 equiv). DMSO (3.0 equiv).
NMR studies indicated that DABCO does not deprotonate the
nitroalkanes (see Supporting Information). When benzyl p-
nitrophenyl carbonate and benzyl pentafluorophenyl carbonate
were used, the nitroalkane remained unreacted. This is possibly
due to the lower basicity of the corresponding phenoxides.
Using this as our standard reaction, we set out to identify the
most suitable nucleophile. We performed reactions with various
nucleophiles, and the percent conversion of 2-phenylnitro-
ethane was monitored by gas chromatography (GC) using an
internal standard. While pyridine, DMAP, and imidazole
appeared to be competent nucleophiles, DABCO gave the
highest conversions (see Supporting Information). We then
attempted optimization of the solvent system using the same
a
All yields are average of two runs. Conditions: 3a−i (1.0 equiv), 1
b
(3.0 equiv), DABCO (2.0 equiv), 60 °C. 3.5 equiv of 1 was used.
c
Reaction was run at 45 °C with 3.5 equiv of 1.
the aryl ring had minimal impact on the yields (Table 2, 4a, 4b,
4c, 4d). To understand whether a nucleophilic aromatic system
will result in acylation of the aromatic ring, we chose substrates
with a dimethoxy aryl group and a thiophene-yl group. The
corresponding products 4e and 4f were obtained in 64% and
75% yield, respectively. We were unable to detect any acylation
of the aromatic ring. When an indole derivative was used as a
substrate, the indole nitrogen had to be protected. In the
5
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dx.doi.org/10.1021/ol5028199 | Org. Lett. 2014, 16, 5874−5877

Organic Letters
Letter
absence of a protecting group, the indole nitrogen reacts with
the activated carbonate in a competing side reaction resulting in
react with softer π-electrophiles. The reported reactivity of
nitronate anions with carbonates and similar electrophiles is
1
6
14
lower yields. A pyridine ring was also tolerated, and the
corresponding pyridyl nitro ester was synthesized in moderate
yields. In this case, the reaction did not proceed in the absence
of DABCO (see Supporting Information). Pyridylalanines have
contrary to what is expected based on the HSAB concept. In
these reactions, the harder oxygen atom of the nitronate anion
reacts with the soft π-electrophile leading to the formation of a
nitronocarbonate that undergoes an elimination to yield nitrile
oxides. In contrast to the reported reactions of nitronate anions
with carbonates, we observe formation of α-nitro esters. Mayr
and co-workers have shown that the reactivity of nitronate
anions with various electrophiles can be explained on the basis
17
found extensive use in medicinal chemistry. Homophenyla-
lanine is an amino acid residue found in the inhibitor of
18
angiotensin converting enzyme. The corresponding α-nitro
ester was synthesized using this method, albeit in low yields (4i,
Table 2). All of the α-nitro esters were readily reduced to the
corresponding α-amino esters in good yields using zinc and
23
of the reversibility of attack through the oxygen atom. Based
on this, we believe that in our reaction the attack through
oxygen atom is kinetically favored and reversible. The
reversibility is engendered by the presence of DABCO, which
converts the kinetically favored nitrono carbonate back to an
activated carbonate and a nitronate anion. Teramura and co-
workers have shown that nitroalkanes react with ethyl
chloroformate in the presence of triethylamine, a non-
13a
acetic acid (Table 3). To test the scalability of the α-nitro
a
Table 3. Reduction of α-Nitro Esters to α-Amino Esters
14b
nucleophilic base, to give nitrile oxides.
This proceeds
through the formation of a nitronocarbonate. In our case, we
use a nucleophilic base that can potentially regenerate the
nitronate anion from the nitronocarbonate. To further
understand the irreversible nature of the α-nitro ester formation
entry
substrate
product
% yield
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
88
84
85
84
82
85
88
77
83
1
we performed an H NMR study. This indicated that DABCO
deprotonates the product nitro ester (see Supporting
Information). This potentially makes the ester carbonyl inert
to DABCO attack, therefore making this reaction irreversible.
In conclusion, we have developed a safe and scalable
alternative to the Strecker reaction. We have utilized an easy-to-
handle carbonate as a carboxyl equivalent. A reaction was
performed on a gram scale without the need for extensive
purification of the carbonate. The product α-nitro esters have
been reduced readily to the corresponding α-amino esters.
Using this procedure, β-aryl-α-amino esters can be accessed
readily under mild conditions. This is in contrast to the
procedures that utilize dianions of nitroalkane. The formation
of α-nitro esters is mechanistically intriguing, as previous
reports indicate that similar reactions give rise to nitrile oxides.
Further research in our laboratory will focus on delineating the
mechanism of this reaction.
b
4g
5g
5h
5i
4h
4i
a
Conditions: (i) Zn dust (6.0 equiv), AcOH; (ii) 4 M HCI in dioxane
1.6 equiv), toluene. 4.8 equiv of HCl was used; isolated as the
dihydrochloride salt.
b
(
ester formation, we decided to synthesize 4a on a 1 g scale.
With practicality in mind, we avoided column purification of
benzyl phenyl carbonate required for this reaction. Instead, we
purified it by distillation. This material contained approximately
9
% by mass of dibenzyl carbonate as an impurity. We used this
carbonate in our large-scale reaction and obtained 4a in ∼85%
yield and ∼93% purity after a simple workup. Further
purification of the product by chromatography resulted in
isolation of ∼1.2 g (73%) of the product (Scheme 3).
ASSOCIATED CONTENT
■
*
S
Supporting Information
Scheme 3. Gram-Scale Synthesis of α-Nitro Ester
Synthetic procedures and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*
E-mail: rajaram@jncasr.ac.in.
The reactivity pattern of nitronate anion in this reaction is
1
4
different from what has been reported previously. Nitronate
anions are ambident nucleophiles that can react through either
the carbon atom or the oxygen atom. In the case of alkyl
halides, the dominant pathway is reaction through the oxygen
Present Address
§Department of Chemistry, University of Pennsylvania,
Philadelphia, PA.
1
9,20
atom with the exception of 4-nitrobenzyl chloride.
Notes
Reactivity through carbon has been accomplished under radical
The authors declare no competing financial interest.
2
1
conditions. In the case of aldehydes and imines, the nitronate
2
2
anion reacts through the carbon atom. The apparent
dichotomy in reactivity has been explained using the hard
and soft acids and bases (HSAB) concept. In this explanation,
the softer carbon center of the nitronate anion is expected to
ACKNOWLEDGMENTS
■
We thank JNCASR and DST for funding. G.R.R. and A.K.C.
thank CSIR, India, for Senior Research Fellowships.
5
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Letter
6
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