Sequential Reduction of Nitroalkanes Mediated by CS2 and Amidine/Guanidine Bases: A Controllable Nef Reaction

Article abstract of DOI:10.1021/acs.orglett.9b02987

In this letter, we describe a mild, functional group-tolerant reductive Nef reaction that utilizes CS₂ and an amidine or guanidine base to sequentially cleave N-O bonds. These conditions transform secondary nitroalkanes to ketones via an isolable oxime with minimal erosion at labile stereogenic carbons, show excellent compatibility with groups sensitive to oxidizing or reducing conditions, display good scalability, and are well-suited for generating useful 3-pyrrolidinone motifs from readily accessible 1,3-dipolar cycloaddition products.

Full text of DOI:10.1021/acs.orglett.9b02987

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Sequential Reduction of Nitroalkanes Mediated by CS2 and
Amidine/Guanidine Bases: A Controllable Nef Reaction
Minsoo Ju,† Weiyang Guan,†,§ Jennifer M. Schomaker,*,† and Kaid C. Harper*,‡
†Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States
‡Process Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States
S
* Supporting Information
ABSTRACT: In this letter, we describe a mild, functional
group-tolerant reductive Nef reaction that utilizes CS2 and an
amidine or guanidine base to sequentially cleave N−O bonds.
These conditions transform secondary nitroalkanes to ketones
via an isolable oxime with minimal erosion at labile
stereogenic carbons, show excellent compatibility with groups
sensitive to oxidizing or reducing conditions, display good
scalability, and are well-suited for generating useful 3-
pyrrolidinone motifs from readily accessible 1,3-dipolar
cycloaddition products.
he Nef reaction is a convenient method to convert readily
available primary and secondary nitroalkanes into the
complex substrates, especially those with labile stereocenters,
are still challenging. Despite these useful protocols, when a
Nef-type reaction became necessary for the development of a
medicinally relevant class of nitro-pyrrolidines (vide infra), we
found all of the above protocols to be either ineffective or not
robust enough to pursue for scale-up. Herein we report a mild,
functional group-tolerant reductive Nef reaction that uses CS2
and either an amidine or guanidine base to transform 2°
nitroalkanes to ketones with a minimal loss of stereochemical
information adjacent to the nitro group, even at very labile
stereogenic carbons.5 Other advantages include the lack of
stoichiometric metal reductants, compatibility with groups
sensitive to oxidizing or reducing conditions, scalability, and
excellent suitability for the late-stage functionalization of
complex molecules.
T
corresponding aldehydes and ketones.1 The classic Nef
reaction, reported in 1894, involves the basic treatment of a
nitroalkane precursor to form a nitronate intermediate, which
is then hydrolyzed to the carbonyl-containing product using a
strong acid.2 The harsh nature of these original conditions has
led to great interest in the development of modified protocols
with a broader scope and functional group compatibility
(Scheme 1). For example, oxidative Nef methods are a popular
Scheme 1. General Pathways for the Nef Reaction
Efforts to identify mild Nef chemistry were inspired by
bioactive 3-hydroxypyrrolidines (see Scheme 3, vide infra),
which exhibit a range of important antifungal,6 anticancer,7
antihypertensitive,8 and glucosidase inhibitory activities.9 More
recently, this class of compounds has received attention as
promising drug candidates for the treatment of cystic fibrosis.10
An efficient method to construct enantioenriched 3-hydroxy-
pyrrolidines involves 1,3-dipolar cycloadditions of azomethine
ylides (derived from glycine) and nitroalkenes, followed by the
Nef reaction and reduction of the resultant ketone. However,
efforts to transform nitro groups of heavily functionalized
pyrrolidines proved challenging under traditional Nef con-
ditions, particularly when several labile asymmetric centers
were present.4c,11 Prior to this work, the only successful
strategy for obtaining carbonyl-containing compounds from
the nitronate intermediate using reagents such as KMnO4,3a,b
H2O2,3c,d O3,3e and O2.3f In contrast, reductive protocols
typically proceed via a stepwise N−O bond cleavage to an
oxime, followed by a second reduction event and imine
hydrolysis. Within this latter class of Nef reactions, the TiCl3-
mediated McMurry protocol is quite popular,4a,b but other
reductants, including CrCl2,4c trimethylphosphine,4d,e and iron
powder,4f have been reported. Nonetheless, stereochemically
Received: August 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02987
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
conversion of these motifs was achieved using an excess
amount of an undesirable chromium(II) reductant.
The yield of ketone 3a can be maintained without dilution,
provided that the temperature and reaction progress are
carefully monitored (Figure 1) to prevent the rate of imine
To address this challenge, we took inspiration from old
reports from Oae12 and Barton13 describing the use of CS2 to
reductively cleave the N−O bond of amine oxides and
conjugated nitronates to furnish amines and α,β-unsaturated
aldoximes, respectively. Initial investigations focused on
treating a tert-butyl(dimethyl)silyl (TBS)-protected Henry
product 1a with CS2 and a nitrogenated base (Table 1).
Table 1. Optimization of CS2-Mediated Reductive Nef
a
Reaction
Figure 1. Reaction profile of CS2-mediated Nef reaction with 1a (0.1
mmol, 1 equiv) CS2 (6 equiv), DBU (1.5 equiv), Barton’s base (1.5
equiv), and 0.1 M CH3CN. Yields were determined by NMR using
mesitylene as an internal standard.
degradation from surpassing that of the conversion of oxime to
imine. The instability of the imine makes it difficult to quantify
in situ; thus samples were quenched with H2O to hydrolyze
the imine intermediate at each time point and the amount of
ketone determined. Figure 1 clearly indicates that a balance
between increasing temperatures to drive conversion and
minimizing the destabilization of the imine intermediate is
important to obtain ketone 3a in high yield.
a
Reactions were performed on a 0.1 mmol scale. Yields were
determined by NMR using mesitylene as an internal standard.
b
c
Reaction was stirred for 5 min at 0 °C. Reaction was stirred for 30
d
e
min at 0 °C. 1.5 equiv of each base was used. Reaction was run in
0.01 M CH3CN.
With optimized conditions in hand for the conversion of
nitroalkane 1a to the ketone 3a, the scope of the reductive Nef
reaction for 2° nitroalkanes was investigated (Scheme 2).
Reactions were conducted at room temperature (rt) (1 h) and
in 0.05 M CH3CN. A variety of TBS-protected Henry products
1a−d, containing electronically diverse aromatic rings, were
well-tolerated to yield the ketones in 61−71% yield. It is worth
noting that the aromatic NO2 group in 1c was not affected
Encouragingly, oxime 2a was noted using Et3N (entry 1),
albeit in low conversion. N,N-Diisopropylamine (DIPA) gave
no reaction (entry 2); however, the more basic 1,8-
diazabicyclo[5.4.0]-undeca-7-ene (DBU) resulted in a 53%
yield of 3a, along with 4% of 2a (entry 3). Decreasing the
temperature to 0 °C for 5 min gave a mixture of 2a and 3a
(entry 4) in good mass balance, suggesting that the poor mass
balance in entry 3 results from inefficient oxime-to-imine
conversion or competing imine hydrolysis to the ketone.
Interestingly, highly basic 2-t-butyl-1,1,3,3-methylguanidine
(Barton’s base (BB)) gave a 38% yield of 3a and 46% yield
of remaining 1a; only a trace amount of 2a was noted (entry
5). This result implied that the rate of the second reductive
N−O bond cleavage event is faster than the formation of the
oxime with this sterically hindered base. In contrast, 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (TBD) retarded the rate of the
second reduction to furnish a 75% yield of 2a with excellent
mass balance (entry 6). The selective reduction of nitroalkanes
to oximes, valuable building blocks for amides (via Beckmann
rearrangement)14 and heterocycles (via metal-mediated
cyclizations),15 is an attractive feature of this chemistry;
other methods employ stoichiometric, toxic metal salts (SnCl2,
TiCl3)16 or require carefully controlled hydrogenation.17 The
use of 1,1,3,3-tetramethylguanidine (TMG) as the base inhibits
the second reduction step (entry 7), similar to TBD. A
combination of DBU and BB improved the yield of 3a to 63%
(entry 8). Finally, we found that dilution (from 0.1 to 0.01 M
in CH3CN) minimized the degradation of the imine18 under
the reaction conditions (entry 9) to give the optimal
conversion of 1a to 3a in 76% yield.
a
Scheme 2. Scope of CS2-Mediated Nef Reaction
a
b
Reported yields are of isolated material on a 0.2 mmol scale. 17%
c
oxime and 16% 1f were detected by 1H NMR. Yield was determined
by NMR using mesitylene as an internal standard due to the volatility
of the product.
B
DOI: 10.1021/acs.orglett.9b02987
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Letter
under the reaction conditions. TMS-protected Henry product
1e furnished α-hydroxy ketone 3e in 76% yield after in situ
deprotection during acidic hydrolysis. Increased sterics in 1f
retarded the reaction, yielding 3f in 43% yield; the remainder
of the mass balance included oxime (17%) and 1f (16%). The
ability to tolerate amines was demonstrated by the presence of
a pyridine in 1g to furnish ketone 3g;19 a substrate bearing an
acidic N−H bond (aza-Henry product 1h) was also successful
in delivering α-amino ketone 3h. An alkene, which could be
sensitive to oxidative Nef conditions, was tolerated in 1l to give
3l in 69% yield. Low-molecular-weight nitroalkanes 1j,k and
functional groups traditionally sensitive to oxidative or
reductive conditions, including esters (1l), ketals (1m), and
alcohols (1n), gave the desired ketones 3j−n.
Scheme 4. Stereoretention in CS2-Mediated Nef Reaction
reaction conditions tolerate acidic, enolizable stereocenters
present in intermediates such as 4w.
The conversion of 1° nitroalkanes to aldehydes or carboxylic
acids is challenging, perhaps due to the lowered stability of the
nitronate intermediate.4e,21−23 Before embarking on efforts to
apply our conditions to 1° nitroalkanes, the mechanism of this
unusual transformation was explored. A base−CS2 adduct was
first considered as the species responsible for the initial N−O
bond cleavage. DBU has been reported to undergo
disproportionation with CS2 to generate a cyclic carbamic
carboxylic trithioanhydride and a [DBU−H]+SH− ionic pair
(Scheme 5A, top).24 However, the independent preparation of
We were pleased to find that applying our conditions to
stereochemically rich nitropyrrolidines 1o−v, generated by 1,3-
dipolar cycloaddition, resulted in the efficient production of 3-
pyrrolidinones 3o−v (Scheme 3), useful precursors to
a
Scheme 3. Nef Reactions on Nitropyrrolidines
Scheme 5. Mechanistic Evidence of CS2-Mediated Nef
Reaction
a
b
Reported yields are of isolated material on a 0.2 mmol scale.
mmol scale.
1
bioactive 3-hydroxy-pyrrolidines. When R3 = t-Bu, 3-
pyrrolidinones 3o−q were obtained in excellent 80−96%
yield due to the increased stability of the imine intermediate.
Furan and pyridine substituents were well-tolerated to furnish
3q and 3r in good yield. The removal of the t-Bu group
flanking the −NO2-bearing carbon did result in a lower 52%
yield of 3s, but improvements with 3t,u suggest that the steric
environment of the −NO2 affects the stability of the imine
intermediate. Thus further improvements in yields are
expected if imine decomposition is avoided (Figure 1). The
low yield of pyrrolidinone 3v is due to product instability.
Importantly, in every case where the pyrrolidinone bears
multiple epimerizable stereogenic centers, no formation of any
this adduct for use in the Nef reaction gave no oxime or
ketone, suggesting that the DBU−CS2 complex is not
responsible for the observed reactivity (Scheme 5A). However,
several clues as to the mechanism were obtained by the careful
monitoring of reaction progress using a variety of spectroscopic
techniques. Important observations areas follows: (1) Both
steric effects and base strength are critical, but the relative
importance of these factors differ for the first versus the second
reductive N−O cleavage steps, (2) SCO is a byproduct,
(3) oxime is observed even in the absence of H2O, and (4)
ketone is observed only in the presence of H2O. Moreover,
evidence of the intermediacy of the oxime was provided by
subjecting isolated oxime 2m to CS2-mediated conditions to
generate the ketone 3m upon hydrolysis (Scheme 5B). The
isolation of the stable imine intermediate 4u prior to hydrolysis
(Scheme 5C) further supports the hypothesis that the reaction
occurs via the sequential reductive cleavage of the N−O bonds.
Taken together, these observations led us to propose the
mechanism in Figure 2. DBU is both basic and unhindered
enough to deprotonate the acidic, sterically congested proton
of nitroalkane a to generate nitronate anion b and the
1
other diastereomer was observed by H NMR (>20:1 dr).
The preservation of stereochemical information at epimer-
izable stereocenters in acyclic nitroalkanes was also inves-
tigated (Scheme 4). A Cu-catalyzed asymmetric Henry
reaction gave a 70:30 enantiomeric ratio (er) of the syn
diastereomer; TBS protection furnished 1w.20 The treatment
of 1w under the standard condition (Scheme 2) confirmed the
stereoretention at the α carbon, highlighting that these mild
C
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Scheme 6. Reaction with Primary Nitroalkane 1x and 1,4,2-
Oxathiozole Synthesis
Figure 2. Proposed mechanism for CS2-mediated Nef reaction.
conjugate acid of DBU. The attack of the nitronate b on CS2
furnishes intermediate c; the elimination of dithiiranone d
cleaves the first N−O bond to deliver oxime anion e, which
protonates to furnish oxime f, the first key intermediate that
can be observed and isolated. Evidence of d was provided by
the headspace analysis of the reaction mixture, showing the
presence of SCO, a reported disproportionation product
resulting from the decomposition of dithiiranone.12,13,25
Depending on the base used in the first deprotonation,
reduction can be stopped at oxime f with good selectivity.
Bases bearing N−H bonds, such as TBD and TMG, enable the
deprotonation of a to furnish f; however, the further
deprotonation of f is disfavored, significantly slowing the rate
of the second reduction event (see Table 1) due to H-bonding
donor/acceptor interactions that stabilize the oxime−base
adduct.26 In contrast, the equilibrium with BB favors oxime
anion e, which attacks a second molecule of CS2 to furnish g.
The loss of d and the protonation of the imine anion yield h.
amounts of metal reductants. The chemistry is amenable to a
variety of sensitive functional groups and excels in retaining
stereochemical information at labile chiral centers. Evidence of
the reductive mechanism is provided by isolating products of
the first and second N−O reduction steps. This new method
provides convenient access to 3-pyrrolidinones from 1,3-
dipolar cycloaddition adducts, which can then be transformed
to biologically important 3-hydroxypyrrolidines.4c
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.9b02987.
Experimental procedures and spectroscopic data for all
new compounds (PDF)
We suspect the imine h is “protected” in situ by the reaction
27,28
AUTHOR INFORMATION
Corresponding Authors
with excess CS2
due to its stability toward hydrolysis to
■
give the desired ketone i.
The mechanism in Figure 2 has several important
implications for the further development of this reductive
Nef reaction. First, it suggests that the conversion of the
nitroalkane to oxime may be amenable to catalytic conditions if
off-cycle reactions between CS2 and DBU (Scheme 5A, top)
and BB (tetramethylthiourea was observed as a byproduct) can
be avoided. Second, the formation of byproduct d explains why
the initial efforts to transform 1° nitroalkanes into aldehydes
were unsuccessful. Oxime anion j (Scheme 6A) may react with
dithiiranone d to give k and extrude SCO. This species
rapidly rearranges to thiohydroxamic acid 5x, which was
isolated in 47% yield in the reaction of 1° nitroalkane 1x.
Bruice has reported that d can act as a sulfur transfer agent in
the reaction with electron-rich olefins.29 The observation of 5x
not only supports the existence of d but also can be harnessed
to synthesize unique S,N,O-containing heterocycles. A
sequential S-alkylation/oxidative cyclization developed by
Pierce30,31 enabled the efficient conversion of thiohydroxamic
acid 5x to 1,4,2-oxathiazole 6x in 43% yield over two steps
(Scheme 6B).
*E-mail: schomakerj@chem.wisc.edu (J.M.S.).
*E-mail: kaid.harper@abbvie.com (K.C.H.).
ORCID
Jennifer M. Schomaker: 0000-0003-1329-950X
Kaid C. Harper: 0000-0003-3894-4851
Present Address
§W.G.: Department of Chemistry and Chemical Biology,
Cornell University, Ithaca, NY 14853, USA.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The NMR facilities at UW-Madison are funded by the
National Science Foundation (NSF; CHE-9208463, CHE-
9629688) and National Institutes of Health (NIH; RR08389-
01). The Q-Exactive mass spectrometer was acquired with
funds from an NIH-S10 award through the National Institutes
of Health (NIH-1S10OD020022-1). We thank Steve Dough-
erty, Bradley Greiner, Jianguo Ji, and Jeff Kallemeyn for helpful
discussions and experimental support. AbbVie sponsored and
funded the study. AbbVie and the University of Wisconsin-
Madison contributed to the design and participated in the
In conclusion, this letter describes the development of a mild
and controllable Nef reaction that achieves the sequential
reduction of 2° nitroalkanes to generate ketoximes or ketones
using CS2 as the reducing agent while avoiding stoichiometric
D
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writing, reviewing, and approval of the final publication.
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