Direct α-Imination of N-Acyl Pyrazoles with Nitrosoarenes

Article abstract of DOI:10.1021/acs.orglett.9b01913

Unprecedented α-imino N-acyl pyrazoles were efficiently and selectively prepared through the 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)-catalyzed reaction of nitrosoarenes with N-acyl pyrazoles via an N-nitroso aldol reaction/dehydration sequence. The α-imino acyl pyrazoles were demonstrated to be new versatile intermediates for practical one-pot syntheses of α-imino amides, dipeptide precursors, esters, and β-amino alcohols. The synthetic method competes with known protocols in terms of ready availability of the reagents and catalyst, mild and catalytic reaction conditions, gram-scale applicability, and scope of the α-imino acid derivatives achievable.

Full text of DOI:10.1021/acs.orglett.9b01913

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct α‑Imination of N‑Acyl Pyrazoles with Nitrosoarenes
Chiara Volpe,† Sara Meninno,† Giulia Mirra,† Jacob Overgaard,‡ Amedeo Capobianco,†
and Alessandra Lattanzi*,†
†
̀
Dipartimento di Chimica e Biologia, Universita di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy
‡Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus, Denmark
S
* Supporting Information
ABSTRACT: Unprecedented α-imino N-acyl pyrazoles were
efficiently and selectively prepared through the 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (TBD)-catalyzed reaction of
nitrosoarenes with N-acyl pyrazoles via an N-nitroso aldol
reaction/dehydration sequence. The α-imino acyl pyrazoles
were demonstrated to be new versatile intermediates for
practical one-pot syntheses of α-imino amides, dipeptide
precursors, esters, and β-amino alcohols. The synthetic method
competes with known protocols in terms of ready availability of
the reagents and catalyst, mild and catalytic reaction conditions, gram-scale applicability, and scope of the α-imino acid
derivatives achievable.
Scheme 1. Synthetic Routes to α-Imino Acid Derivatives
α-Imino acid derivatives are highly popular and versatile
compounds that are employed as starting materials in a variety
of transformations.1 In particular, α-keto imine esters and
amides are largely used in asymmetric synthesis of natural and
non-natural α-amino acids,2 Friedel−Crafts3 and Mannich-
type reactions,4 organometallic5 and Michael additions,6 and
cycloaddition/cyclization reactions.7 Most commonly, they are
prepared from α-keto acid derivatives followed by imination
(Scheme 1a).8 This method requires high temperatures, long
reaction times, and the absence of acid-labile groups in the
starting α-keto acid reagents, which are generally not readily
available compounds. Metal-catalyzed procedures provide
access to α-imino amides or esters in good yields, although
unusual reagents and relatively expensive metal catalysts
somewhat limit their synthetic utility (Scheme 1b,c).9 An
interesting oxidative decarboxylation approach to α-imino
esters was uncovered by Payette and Yamamoto, who reacted
2-substituted malonates with commercially available nitro-
sobenzene under strongly basic conditions at low temperature
(Scheme 1d).10 Mukaiyama reported that the reaction of
diethyl malonate with nitrosobenzene in absolute ethanol with
NaOH as the base afforded the α-iminomalonate product,
which proved to be sensitive to moisture.11 Despite a certain
number of synthetic methods to obtain α-imino acid
derivatives has been devised, strictly controlled or harsh
reaction conditions, particular reagents or precious metal
catalysts have to be employed.1 Therefore, a mild and versatile
approach providing access to a variety of α-imino acid
derivatives is lacking and would be highly desirable.
easily elaborated to afford common carbonyl compounds or
other derivatives.12 Inspired by the pivotal work of
Yamamoto10,13a,b and Mukaiyama11 on the reactivity of
nitrosobenzene in aldol-type reactions and prompted by our
interest in synthetic applications of carboxylic acid surro-
gates,14 we sought to develop a methodology for α-imination
N-Acyl pyrazoles have recently aroused interest in organic
synthesis, being comparatively more reactive as either a
Michael acceptor or enolate equivalent than the corresponding
esters or amides. They can be successfully employed as
alternative reagents under milder reaction conditions and then
Received: June 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01913
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of relatively α-acidic N-acyl pyrazoles. We speculated that N-
acyl pyrazoles treated with nitrosoarenes under basic
conditions would undergo a base-catalyzed N-nitroso aldol
reaction followed by dehydration to give unprecedented α-
imino N-acyl pyrazoles suitable for further functionalizations
(Scheme 1e). Indeed, herein we report a direct and selective α-
imination of N-acyl pyrazoles that proceeds at room temper-
ature, using a catalytic loading of a commercial base and readily
available compounds. Moreover, the α-imino N-acyl pyrazoles
serve as new versatile intermediates to access a range of
synthetically useful derivatives through convenient one-pot
transformations.
Scheme 2. Substrate Scope of N-Acyl Pyrazoles 1 with
Nitrosoarenes
a
At the outset of the study, N-acyl pyrazole 1A was reacted
with nitrosobenzene using a 20 mol % loading of different
bases in CDCl3 at room temperature (Table 1). To our
Table 1. Base-Catalyzed α-Imination of N-Acyl Pyrazole 1A
a
with Nitrosobenzene
b
c
entry
base
t (h)
yield (%)
dr
1
2
3
4
5
6
7
DABCO
Et3N
Cs2CO3
tBuOK
DBU
3
1
79
78
56
7
89
90
89
95/5
95/5
73/27
85/15
80/20
95/5
10
14
0.5
0.5
0.5
TBD
BEMP
72/28
a
Reaction conditions: 1A (0.1 mmol), 2a (0.12 mmol), and the base
b
(0.02 mmol) in CDCl3 (0.5 mL) under nitrogen. Yields of 3A were
determined by 1H NMR analysis using CH2Br2 as an internal
a
c
1
Reaction conditions: 0.2 mmol of 1, 0.24 mmol of 2, 0.02 mmol of
TBD, and 3 Å MS (45 mg) in anhydrous CH2Cl2 (1 mL). Yields of
isolated products after column chromatography are shown. Z/E ratios
standard. Determined by H NMR analysis.
1
were determined by H NMR analysis.
delight, 1,4-diazabicyclo[2.2.2]octane (DABCO) and triethyl-
amine afforded α-imino N-acyl pyrazole 3A in good yield with
a high diastereomeric ratio after a short time (entries 1 and 2).
The reaction was completely regioselective, showing only
unreacted 1A without traces of the α-aminooxy N-acyl
pyrazole.13a−c,15 Inorganic or organic oxygen-containing bases
proved to be much less effective and stereoselective (entries 3
and 4). Interestingly, stronger bases, such as 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (TBD), and 2-tert-butylimino-2-
diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine
(BEMP) rapidly provided compound 3A in high yield (entries
5−7). However, TBD proved to be superior, affording the
product in 90% yield with 95/5 dr (entry 6). A further
optimization study16 carried out using TBD allowed
identification of the best reaction conditions as 10 mol %
TBD and 3 Å molecular sieves in CH2Cl2 at room temperature
with the 3,5-dimethylpyrazol (DMP) group in the starting
reagent 1 (Scheme 2).
end of the reactions.17 Unsubstituted N-acyl pyrazole and
those bearing electron-withdrawing and halogen substituents at
different positions of the benzene ring, rapidly underwent
imination with excellent diastereoselectivity. Compounds 1,
bearing electron-donating groups, afforded moderate yields of
the products 3m and 3n (54−58%) and more pronounced
amounts (≤20%) of the corresponding nitrones 4m and 4n.
Interestingly, thiophenyl, N-unprotected 3-indolyl, and 2-
naphthyl groups in reagent 1 were also well-tolerated, with
products 3 being recovered in yields of 85%, 50%, and 80%,
respectively. Formation of the Z isomer was established by
single-crystal X-ray diffraction analysis of compounds 3c and
3q.16 For compound 3c, DFT computations predict an energy
difference of 3.4 kcal/mol between the most populated
conformer of the Z isomer and the most stable conformer of
the E product, thus showing that the thermodynamic product
was obtained. A variety of nitrosoarenes, bearing electron-
donating or -withdrawing groups, were then reacted with N-
acyl pyrazoles. Pleasingly, the expected products 3r−y were
isolated after short reaction times in good to high yields (70−
88%) with excellent Z/E ratios (≥96/4).
With suitable reaction conditions in hand, we explored the
generality of the procedure in terms of substrates. A range of
aryl and heteroaryl acetic acid-derived pyrazoles and nitro-
sobenzene were efficiently and rapidly converted into the
corresponding α-imino N-acyl pyrazoles 3a−q in good to high
yields (65−92%) with excellent Z/E ratios (≥97/3). Trace
amounts (<10%) of nitrones 4 were generally detected at the
With a view to extending the scope of substrates employable
in this reaction, we focused on more challenging β,γ-
unsaturated N-acyl pyrazoles 5 (Scheme 3). Ester derivatives
B
DOI: 10.1021/acs.orglett.9b01913
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Organic Letters
Letter
Scheme 3. Substrate Scope of N-Acyl Pyrazoles 5 with
Nitrosoarenes
Scheme 4. One-Pot Synthesis of α-Imino Amides, Dipeptide
Precursors, and Esters
a
a
a
Reaction conditions according to Scheme 2. Yields of isolated
products after column chromatography are shown.
of the products 6, namely, 1-azadienes, are often used in
cycloaddition and multicomponent reactions, leading to a
variety of nitrogen-based heterocycles and natural products as
well as reagents in 1,2- or 1,4-addition reactions.18 The general
approach for their preparation, illustrated in Scheme 1a, has
severe limitations due to side 1,4-addition by the amine to give
almost esclusively cyclic 3-amino-1,5-dihydro-2H-pyrrol-2-
ones.19 Palacios and co-workers illustrated an approach
based on aza-Wittig reaction of β,γ-unsaturated α-keto esters
and in situ-generated highly reactive phosphazenes. However,
esters of compounds 6 proved to be unstable and therefore
were used directly as crude mixture for further elaborations.20
(3E)-N-Acyl pyrazoles 5 bearing aryl substitutents at the γ-
position were treated under the previously optimized
conditions with different nitrosoarenes, affording the α-
imination products 6a, 6b, and 6d−g in moderate to good
isolated yields (55−76%) with moderate dr values after short
reaction times (Scheme 3).21 Some instability of compounds 6
was observed during silica gel chromatography, although
among the polar recovered mixture of compounds, we were
able to detect nitrones of type 4.22 To evaluate the α/γ-
regioselectivity, the crude reaction mixture of model
compound 6a was directly subjected to acid hydrolysis
a
Reaction conditions for the first step according to Schemes 2 and 3.
Toluene was used as the solvent for the first step. 20 mol % 4-
b
c
(dimethylamino)pyridine was added in the second step.
1
followed by H NMR analysis. The expected α- and γ-keto
acids were found to be in a 95/5 ratio, respectively, which
would be in agreement with the exclusive isolation of
compounds 6 being highly prevalent. DFT computations also
assign a larger stability to the (Z)-imine of 6a. However, the
energy difference between the most stable conformer of the Z
isomer and that of the E isomer is less pronounced (1.7 kcal/
mol), which would be in line with the observed moderate dr
values. The reaction proceeded on a compound bearing a
trisubstituted carbon−carbon double bond to give product 6c
in 62% yield. A γ-Alkyl-substituted compound reacted
sluggishly to give product 6h in 26% yield together with
30% of unreacted acyl pyrazole and other unidentified
byproducts. Aliphatic acyl pyrazoles were not effective reagents
under the current reaction conditions, likely because of the
difficulty of generating the corresponding enolates. To evaluate
the scalability and practicality of the process, a gram-scale
reaction of compound 1a (1.03 g) with nitrosobenzene was
performed, successfully leading to 3a in 87% isolated yield.
One-pot sequential procedures to obtain a variety of α-imino
amides, dipeptide precursors, and esters were developed,
attesting to the versatile nature of the α-imino N-acyl pyrazoles
as synthetic intermediates (Scheme 4).23 Interestingly, primary
and secondary amines and anilines can be employed in the
addition−elimination step to give secondary and tertiary α-
imino amides 7 in good to excellent yields. Less nucleophilic
anilines or sterically demanding secondary amines and anilines
reacted more effectively when the second step was carried out
at higher temperature in toluene, eventually with the addition
of DMAP as a cocatalyst. Notably, peptide coupling was
performed using α-amino acid ester salts, with the addition of
triethylamine without coupling agents. Product 8a and
optically active 8b were obtained in good yields, without any
racemization occurring.24 Compounds of type 8 are new
appealing precursors to employ in the synthesis of dipeptides
through asymmetric hydrogenation/reduction. The one-pot
reaction sequence was also effective when alcohols were added
as nucleophiles, leading to the isolation of α-imino esters 9 in
satisfactory yields.
Finally, a one-pot sequence was established to obtain β-
amino alcohols by treatment of crude intermediates 3 and 6
with NaBH4 or LiBH4 in THF as the solvent (Scheme 5). This
class of compounds are particularly attractive in the
pharmaceutical industry and are useful ligands in catalysis
and building blocks in total synthesis.25 The basic approach to
prepare β-amino alcohols of type 10 relies on ring opening of
styrene epoxides by anilines. Hence, control of the
C
DOI: 10.1021/acs.orglett.9b01913
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Organic Letters
Letter
then would react with nitrosoarene to form azoxyarene 12,
which was consistently found in similar amounts as nitrone 4.30
In conclusion, we have disclosed a protocol for the direct α-
imination of readily availalble N-acyl pyrazoles with nitro-
soarenes using catalytic amounts of a commercial base. Rapid
and effective formation of α-imino N-acyl pyrazoles occurs at
room temperature with complete regioselectivity and moderate
to excellent diastereoselectivity. We believe that this method
will be of great synthetic utility, as showcased by one-pot
transformations of α-imino N-acyl pyrazoles into a variety of α-
imino amides, esters, dipeptide precursors, and β-amino
alcohols. Further investigations on the application of this
system to other classes of carbonyl compounds are underway
in our laboratory.
Scheme 5. One-Pot Synthesis of β-Amino Alcohols
regioselectivity turns out to be a challenging issue to address,
and usually a mixture of regioisomeric β-amino alcohols is
observed.26 In contrast, the one-pot route illustrated in Scheme
5 enables the selective preparation of β-amino alcohols 10 in
good to excellent yields.27 NaBH4 can be conveniently used
with more reactive α-imino N-acyl pyrazoles such as 3a or the
more sensitive intermediate 6a. A limited number of
methodologies, often characterized by several steps, have
been reported for the preparation of 2-aryl glycinols, building
blocks involved in the synthesis of biologically active
compounds.28 The one-pot imination/reduction process,
followed by deprotection, provides an alternative strategy to
produce 2-aryl glycinols, as exemplified by the formation of 2-
aryl glycinol salt 11, which was obtained in 62% yield after
deprotection of 10e with trichloroisocyanuric acid (TCCA).
On the basis of the above results and previous
studies,10,13,14b,15 we propose the catalytic cycle set out in
Scheme 6. N-Acyl pyrazoles 1 and 5 are readily deprotonated
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01913.
Experimental procedures, characterization details, com-
putational details, and X-ray data for 3c and 3q (PDF)
Accession Codes
CCDC 1908966 and 1908967 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
e-mailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lattanzi@unisa.it.
ORCID
Scheme 6. Postulated Catalytic Cycle
Jacob Overgaard: 0000-0001-6492-7962
Amedeo Capobianco: 0000-0002-5157-9644
Alessandra Lattanzi: 0000-0003-1132-8610
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank MIUR, the University of Salerno, the Danish
National Research Foundation (DNRF-93) for financial
support and Dr. P. Iannece (University of Salerno) for
assistance with MS spectra.
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E
DOI: 10.1021/acs.orglett.9b01913
Org. Lett. XXXX, XXX, XXX−XXX