Copper-Catalyzed Alkylation of Nitroalkanes with α-Bromonitriles: Synthesis of β-Cyanonitroalkanes

Article abstract of DOI:10.1021/acs.orglett.6b00093

Copper catalysis now enables the efficient C-alkylation of nitroalkanes with α-bromonitriles. Using a simple and inexpensive catalyst, this process provides access to β-cyanonitroalkanes. The method is highly tolerant of various functional groups and substitution patterns. These functionally dense products serve as orthogonally masked 1,3-diamines, which can be revealed selectively for access to differentially substituted diamines. These products can also be exploited for the formation of complex cyanoalkenes and 5-aminoisoxazoles.

Full text of DOI:10.1021/acs.orglett.6b00093

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Alkylation of Nitroalkanes with α‑Bromonitriles:
Synthesis of β‑Cyanonitroalkanes
Kirk W. Shimkin, Peter G. Gildner, and Donald A. Watson*
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: Copper catalysis now enables the efficient C-alkylation
of nitroalkanes with α-bromonitriles. Using a simple and inexpensive
catalyst, this process provides access to β-cyanonitroalkanes. The
method is highly tolerant of various functional groups and substitu-
tion patterns. These functionally dense products serve as orthogonally
masked 1,3-diamines, which can be revealed selectively for access to differentially substituted diamines. These products can also be
exploited for the formation of complex cyanoalkenes and 5-aminoisoxazoles.
β-Cyanonitroalkanes are highly appealing and synthetically
valuable building blocks, particularly because of their potential
to serve as orthogonally masked diamines.1 Several prior entries
into β-cyanonitroalkanes have been reported, but all are limited
with respect to generality (Scheme 1A−C). In 1984, Kornblum
found wide use in catalytic reactions,6,7 their use to alkylate
nitroalkanes has not been well developed. The noncatalyzed
addition of nitronate anions to these reagents was studied
by Ros in 1988.8 Although α-bromoisobutyronitrile could be
used to alkylate simple, unfunctionalized nitronate anions in
modest yields (36−70%), only a single example of another
α-bromonitrile was reported. In this latter case, the product was
formed in only 16% yield, along with significant amounts of
elimination products (56%). No examples of α-bromonitriles
bearing α hydrogens were reported, drawing into question the
generality of the procedure.
Scheme 1. Synthesis of β-Cyanonitroalkanes
In general, nitroalkanes are highly versatile synthetic inter-
mediates, particularly as precursors to nitrogen containing
molecules. The nitro group serves as a diverse functional handle
that can undergo myriad reactions including oxidation, reduc-
tion to amines, arylation, allylation, additions to aldehydes, and
conjugate additions.9 However, simple C-alkylation of nitro-
alkanes using alkyl electrophiles has been challenging, as non-
catalyzed alkylation reactions are dominated by O-alkylation.10
This challenge might inform on the difficulties observed in the
Ros study.
Recently, however, our group has developed inexpensive
copper catalysts that allow the C-alkylation of nitroalkanes using
simple alkyl halides.11 In previous studies, we have shown that
benzylic, heterobenzylic, and α-bromocarbonyls can serve as the
electrophiles in these reactions.11 Preliminary evidence suggests
that these reactions proceed via stabilized radical intermediates.
As nitrile groups can also serve as potential radical stabilizing
groups, we reasoned that copper catalysis of the alkylation of
nitroalkanes with α-bromonitriles might be possible. If so, this
system would provide straightforward access to β-cyanonitroal-
kanes. In this paper, we now report that a wide range of
β-cyanonitroalkanes can be accessed using this strategy.
We set out to develop a general, robust, and functional group
tolerant route to β-cyanonitroalkanes. Based upon our
reported that nitronates could be alkylated using α-nitronitriles
under photolytic conditions.2 However, only fully substituted
α-nitronitriles could be utilized as electrophiles, which signifi-
cantly limits the accessible substitution patterns. Moreover, only
simple alkyl substrates were examined, providing little evidence
of functional group compatibility. β-Cyanonitroalkanes have also
been accessed via the conjugate addition of cyanide to simple
nitroalkenes.3 However, these reactions require the use of toxic
cyanide reagents (or equivalents), and β-cyanonitroalkanes
bearing full substitution at the nitro center are not accessible
via this method.4
An alternative route for the preparation of β-cyanonitroalkanes
would be alkylation of nitroalkanes with α-bromonitriles. This
is attractive as α-bromonitriles are stable, readily available
compounds that can be prepared on a multigram scale from
aldehydes or alkyl nitriles.5 Although these reagents have recently
Received: January 11, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b00093
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Letter
mechanistic hypothesis for copper-catalyzed nitroalkane alkyla-
tion, we began by examining the alkylation of 1-nitropropane
with 1-bromocyclohexanecarbonitrile (1). Gratifyingly, using
our previously identified catalytic system for the alkylation of
nitronates with benzyl halides (20 mol % CuBr, 25 mol % ligand
2, 1.2 equiv NaOtBu),11a the desired β -cyanonitroalkane was
formed smoothly in excellent yield (Scheme 2). The reaction
Scheme 4. Scope of the Alkylation Reaction with Respect to
α-Bromonitriles
Scheme 2. Identification of Catalyst Conditions
proceeds at room temperature and uses an inexpensive, easily
accessed catalyst. No product is formed in the absence of catalyst.
Further investigations revealed that the scope of this
transformation is broad (Schemes 3 and 4). A variety of primary
Scheme 3. Scope of the Alkylation Reaction with Respect to
Nitroalkane
amines (11), esters (17), Weinreb amides (18), ethers (20), and
ketones (25, 26) proved compatible with the reaction. Product
11 is particularly notable due to its potential use as a latent
triamine. Aryl bromides were also tolerated without incident
(19), providing a convenient handle for further functionalization.
Acyclic, fully substituted bromonitriles (22), as well as hetero-
cycles (23, 24) were tolerated under the reaction conditions.
The scalability of the reaction was also demonstrated, as product
21 could be synthesized on a 4 g scale without incident.
Although the diastereoselectivity of the reaction is moderate,
it should be noted that in almost all cases diastereomers were
easily separated by standard column chromatography. It appears
that the observed diastereomeric ratio is kinetic in origin. For
example, the alkylation reaction produces compound 21 as a
59:41 mixture of diastereomers. Analysis of aliquots (NMR)
shows that this ratio of products is constant over the course
of the reaction. However, subjecting isolated samples of each
diastereomer to mild base (sodium propylnitronate) results in
equilibration to a ∼40:60 diastereomeric mixture with an opposite
sense of diastereomeric enrichment.12
Bromoacetonitrile proved to be a particularly recalcitrant
electrophile in the alkylation reaction, providing only trace
amounts of product under our optimized conditions. We assume
this is due to the difficulty in formation of the putative primary
radical intermediate. However, a survey of reaction conditions
revealed that a weaker base, sodium trimethylsilanolate, in
conjunction with the use of the nitroalkane as the limiting reagent
provided cyanomethylated products (27, 28) in moderate yield
(Scheme 5). Notably, these products, as well as many outlined in
Schemes 3 and 4, are not accessible via the aforementioned
nitroalkanes were subjected to the reaction using 1-bromocyclo-
hexanecarbonitrile as an alkylating reagent. Nitroalkanes bearing
alkenes, amides, esters, acetates, and aryl ethers were all alkylated
in good to excellent yields (4−8). Nitromethane was alkylated
smoothly, although an excess of the nucleophile was required (9).
2-Nitropropane participated in the alkylation reaction to provide
product 10 bearing two contiguous quaternary centers in
moderate yield. This reaction demonstrates the ability of the
alkylation protocol to form highly congested carbon−carbon
bonds and potentially access sterically congested diamines. It is
notable that formation of product 8 (as well as products 16, 24,
and 28 discussed below) utilizes a nitroalkane prepared from
benzylation of simple nitroalkanes using our previously developed
procedure.11a This serves to demonstrate how copper-catalyzed
nitroalkane alkylation can be exploited to generate complexity
from simple, inexpensive starting materials.
A number of functionalized α-bromonitriles were also
examined in the alkylation reaction. While fully substituted
α-bromonitriles often underwent smooth coupling at room
temperature, secondary bromides required slightly elevated tem-
perature (50 °C) to avoid significant production of protode-
brominated starting materials. While hexanes is the solvent of
choice for nonpolar substrates, dichloromethane is often superior
to improve solubility in the case of more polar substrates. Basic
B
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Scheme 5. Alkylation of Nitroalkanes with Bromoacetonitrile
Scheme 7. Synthesis of 5-Aminoisoxazoles
photolytic or conjugate addition methods, highlighting the com-
plementarity of this work to existing methods.
With convenient access to β-cyanonitroalkanes in hand,
we sought to investigate the reactivity of these functionally rich
compounds. Exposure of the β-cyanonitroalkanes to DBU resulted
in rapid formation of the corresponding cyanoalkenes in excellent
yield (Scheme 6). In the case of compound 31, high selectivity for
the Z product was observed (as determined by NOE analysis).
Scheme 8. Synthesis of Bispiperidine Core of GlyT1
Inhibitor 43
Scheme 6. Synthesis of Cyanoalkenes
Isolation of the β-cyanonitroalkane was not required to achieve
this elimination reaction. After simply filtering the salts formed in
the alkylation reaction, DBU could be added to the crude reaction
mixture, providing convenient access to the cyanoalkene (eq 1).
functionalized 1,3-diamines. To illustrate this, we targeted the
synthesis of bispiperidine 42 (Scheme 8). This motif serves the
core for a series of amides 43 that have recently been shown
to be nanomolar inhibitors of glycine transporter 1 (GlyT1).16
This enzyme regulates glycine concentrations in the brain and
has been implicated in the treatment of schizophrenia and other
cognitive disorders.17
Nitroalkane 40 was accessed smoothly on a 2 g scale via our
alkylation strategy. Ozonolysis using a reductive workup provided
an intermediate aminoaldehyde. Sequential reductive amination
and reduction of the nitrile provided amine 42,18 which is the
reported intermediate for the synthesis of amides 43.16
β-Cyanonitroalkanes can also be utilized in the synthesis
of nitrogen-rich heterocycles. 5-Aminoisoxazoles have been
accessed via the spontaneous cyclization of α-cyanooximes, but
access to the oxime intermediates often requires harsh or highly
toxic conditions.13,14 We envisioned that controlled reduction
of the nitro group of our products to the oxime would allow
interception of this pathway in a convergent and mild fashion.
Carreira has reported a streamlined process for the conversion of
nitroalkanes to oximes using benzyl bromide in the presence
of tetrabutylammonium iodide.10,15 After optimization, we found
that treatment of the β-cyanonitroalkanes under similar condi-
tions resulted in formation of α-cyanooximes, which undergo
spontaneous cyclization to form 5-aminoisoxazoles.
To investigate the mechanism of the alkylation reaction,
several experiments were performed. First, when the reaction
was run in the presence of 1 equiv of TEMPO, a known
radical scavenger, no alkylation product (15) was formed (eq 2).
Using this method, several such heterocycles were prepared in
good yield (Scheme 7). β-Cyanonitroalkanes bearing ketones
(36), aryl ethers (38), arenes (35), and heteroarenes (37, 38) all
cyclized smoothly, allowing a highly convergent entry into these
interesting products. Importantly, β-cyanonitroalkanes may be
used as a mixture of diastereomers, rendering the stereoselectivity
of the nitroalkane alkylation reaction inconsequential for the
preparation of 5-aminoisoxazoles.
β-Cyanonitroalkanes are exceptionally versatile in their ability
to be used as latent diamines. The presence of the orthogonal
nitrile and nitro groups allows simple chemoselective functional
group interconversions, allowing easy access to differentially
Instead, only remaining starting material and 44 (the adduct
of TEMPO with the starting material) were observed. This
adduct likely results from the radical recombination of TEMPO
with a transient α-cyano radical.19 Additionally, no alkylation was
observed when the reaction was run in the presence of galvinoxyl
free radical, also a known radical scavenger. These results are
C
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Letter
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Scheme 9. Fragmentation/Alkylation of the
Cyclopropylcarbinyl Radical Resulting from Substrate 45
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In conclusion, we have demonstrated a facile and con-
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α-bromonitriles. The synthesis is mild and tolerant of a variety
of functional groups and substitution patterns and may be
performed on the benchtop utilizing standard anaerobic
technique. The densely functionalized products obtained
therein may be utilized in the synthesis of various synthetically
valuable targets including cyanoalkenes, 1,3-diamines, and
5- aminoisoxazoles.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00093.
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(17) (a) Harvey, R. J.; Yee, B. K. Nat. Rev. Drug Discovery 2013, 12, 866.
(b) Mohler, H.; Boison, D.; Singer, P.; Feldon, J.; Pauly-Evers, M.; Yee,
̈
B. K. Biochem. Pharmacol. 2011, 81, 1065.
*E-mail: dawatson@udel.edu.
Notes
(18) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849.
(19) (a) Beckwith, A. L. J.; Bowry, V. W.; Ingold, K. U. J. Am. Chem. Soc.
1992, 114, 4983. (b) Bowry, V. W.; Ingold, K. U. J. Am. Chem. Soc. 1992,
114, 4992.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(20) (a) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317.
(b) Newcomb, M. Tetrahedron 1993, 49, 1151.
The University of Delaware, the University of Delaware Research
Foundation, the Research Corp. Cottrell Scholars Program, and
the NIH NIGMS (R01 GM102358) are gratefully acknowledged
for support. K.W.S. thanks the University of Delaware for a
graduate fellowship. Benjamin L. Prather (University of
Delaware) is acknowledged for help with starting material
synthesis. Data were acquired at UD on instruments obtained
with the assistance of NSF and NIS funding (NSF CHE0421224
and CHE1229234; NIH P20 GM104316, P30 GM110758, S10
RR02692, and S10 OD016267).
(21) (a) Newcomb, M.; Johnson, C. C.; Manek, M. B.; Varick, T. R. J.
Am. Chem. Soc. 1992, 114, 10915. (b) Martin-Esker, A. A.; Johnson, C.
C.; Horner, J. H.; Newcomb, M. J. Am. Chem. Soc. 1994, 116, 9174.
(22) Ros and co-workers also suggest a radical mechanism in their
study. See ref 8.
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