Nickel-Catalyzed C-Alkylation of Nitroalkanes with Unactivated Alkyl Iodides

Article abstract of DOI:10.1021/jacs.7b04312

Enabled by nickel catalysis, a mild and general catalytic method for C-alkylation of nitroalkanes with unactivated alkyl iodides is described. Compatible with primary, secondary, and tertiary alkyl iodides; and tolerant of a wide range of functional groups, this method allows rapid access to diverse nitroalkanes.

Full text of DOI:10.1021/jacs.7b04312

Communication
pubs.acs.org/JACS
Nickel-Catalyzed C‑Alkylation of Nitroalkanes with Unactivated Alkyl
Iodides
Sina Rezazadeh, Vijayarajan Devannah, and Donald A. Watson*
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
would enable this transformation. Herein, we report the nickel-
ABSTRACT: Enabled by nickel catalysis, a mild and
general catalytic method for C-alkylation of nitroalkanes
with unactivated alkyl iodides is described. Compatible
with primary, secondary, and tertiary alkyl iodides; and
tolerant of a wide range of functional groups, this method
allows rapid access to diverse nitroalkanes.
catalyzed nitroalkane alkylation. For the first time, this system
allows for the alkylation of nitroalkanes using primary,
secondary, and tertiary alkyl halides without the requirement
for stabilizing groups. The method allows for the preparation of
a diverse array of complex nitroalkanes using simple starting
materials.
Our initial investigation focused on the reaction of primary
alkyl iodide 1 and nitroalkane 2 (Table 1). Consistent with our
itroalkanes are one of the most versatile functional
N
groups in organic synthesis.1 Their use in C−C bond
formation, through conjugate addition, Henry reactions,
palladium-catalyzed arylation and allylation, and related
reactions, has been well established.1,2 In addition, the nitro
group can be readily converted into a range of other
functionalities, including amines, carbonyls, and alkanes.1
Despite this rich chemistry, however, C-alkylation of nitro-
alkanes with alkyl electrophiles has been historically challenging
due to competing O-alkylation and formation of carbonyl
byproducts.3 Early methods to overcome this inherent
reactivity and favor C-alkylation suffered from lack of
generality.4
Table 1. Discovery of the Catalyst System
a
entry
catalyst
solvent
additive yield of 3
b
1
2
3
4
5
6
7
8
20 mol % CuBr/4
Ni(COD)2/5
hexanes
dioxane
0%
7%
8%
0%
Ni(COD)2/6
dioxane
NiBr2·diglyme/6
NiBr2·diglyme/6
NiBr2·diglyme/7
NiBr2·diglyme/7
dioxane
dioxane
Et2Zn
Et2Zn
Et2Zn
59%
67%
74%
76%
In 2012, we reported a general method for benzylation of
dioxane
nitroalkanes using a simple copper catalyst (Figure 1).5 In
MTBE/dioxane
MTBE/dioxane
8
Et2Zn
a
b
1
Determined via H NMR against internal standard. 60 °C.
previous reports, we observed no C-alkylation product 3 when
the reaction was conducted in the presence of catalytic copper
bromide and diketimine ligands (entry 1), or in the absence of
catalyst. Other copper-based catalyst systems also failed to
provide product.7 Early in our first studies of nitroalkane
alkylation, we had noted that nickel catalysts, although less
reactive than the copper-based systems we investigated at that
time, did provide trace product in nitroalkane benzylation.5
Inspired by that result, and previous reports of nickel-catalyzed
reactions with unactivated alkyl halides,8 we investigated the
use of nickel catalysis in the present system. We were pleased to
find that the use of catalytic Ni(COD)2 with an appropriate
Figure 1. General method for nitroalkane alkylation.
subsequent studies, we have shown that this catalyst system is
also capable of alkylating nitroalkanes using α-bromocarbonyls
and α-bromonitriles.6 Although these reactions provided a
significant advance in nitroalkane synthesis compared to prior
art, they all required a radical stabilizing group adjacent to the
electrophilic center. Alkyl halides lacking such stabilization
failed to provide more than trace amounts of the desired
alkylated products.
Recognizing that a method capable of utilizing nonstabilized
alkyl electrophiles would greatly expand the scope and utility of
nitroalkane alkylation, we set out to identify catalysts that
Received: April 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b04312
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 1. Scope of Primary Alkyl Iodides
a
b
15 mol % 8, 30 mol % Et2Zn. 10 mol % 7 added.
ligand led to the first appreciable production of 3. For example,
with use of either tripyridyl ligand 5 (entry 2) or neocuproine
(6, entry 3), single digit yields of the product were observed.
Investigation of other nickel sources revealed that the
combination of NiBr2·diglyme and Et2Zn (as reductant) was
much more effective, providing 3 in 59% yield (entry 5).9
Further optimization revealed that the related ligand bath-
ocuproine (7) was optimally effective, as was a mixed solvent of
MTBE and dioxane (entries 6 and 7). Finally, the single-
component catalyst 8 (prepared from 7 and NiBr2·diglyme)
proved similarly effective and was selected for further study due
to ease of handling and reaction setup (entry 8).10
Scheme 2. Scope of Secondary and Tertiary Alkyl Iodides
As can be seen in Scheme 1, a broad range of primary alkyl
iodides, including those bearing a high degree of functionality,
are tolerated in the reaction. Particularly notable is the
reaction’s tolerance of steric hindrance (product 10 is derived
from a neopentyl iodide), common protecting groups (11, 16,
23), and aromatic halides (20−22). Biologically relevant
heterocycles (both aromatic and nonaromatic) are particularly
well tolerated (13−24). These include benzothiazoles,
benzofurans, piperidines, thiophenes, indoles, pyridines, and
pyrazoles, among others. Furthermore, alkyl chlorides and
bromides (13 and 14) were unaffected, allowing for
orthogonality with alkyl bis-electrophiles. Methyl iodide could
also be used, but gave low yields.7
We then turned our attention to more substituted alkyl
iodides (Scheme 2). A variety of cyclic and acyclic secondary
alkyl iodides were also well tolerated (25−32). As with the
primary substrates, the reaction also displayed outstanding
functional group tolerance. For example, aromatic (25, 28, 29),
heteroaromatic (32), and aliphatic heterocycles (31 and 32)
were all compatible.11 Unfortunately, little to no diastereose-
lectivity was observed with dissymmetric sec-alkyl iodide
substrates (25, 29).
a
15 mol % 8, 30 mol % Et2Zn.
access by other methods. Tert-butyl-, cyclohexylmethyl-, and
adamantyl-iodide all participated in the reaction without
incident.
A variety of functionalized nitroalkanes can also be used in
the reaction (Scheme 3). Although secondary and β-branched
nitroalkanes did not show satisfactory yields,7 various functional
groups on the nitroalkane proved to be compatible; including
alkenes (38), acetyl protected alcohols (41), esters (42), Boc-
protected amines (43), phthalimides (44), and nitriles (45).
We were very pleased to find that tertiary alkyl iodides can
also be utilized in the reaction (33−36). These substrates
provide very sterically encumbered nitroalkanes that are hard to
B
DOI: 10.1021/jacs.7b04312
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Journal of the American Chemical Society
Communication
Scheme 3. Scope of Nitroalkanes
Scheme 4. Mechanistic Probes
Scheme 5. Stereoconvergence of the Reaction
a
b
15 mol % 8, 30 mol % Et2Zn. 10 mol % 7 added.
Although nitroalkanes bearing unprotected ketone proved
unfruitful as substrates, protecting the ketone as an acetal
(39) allowed for good yields.
With some substrates bearing ill-positioned Lewis basic
groups (e.g., 18, 41, 44), poor reactivity was observed under
the standard reaction conditions. We attribute this to
competitive binding of the catalyst, possibly via chelation in a
reactive intermediate. Gratifyingly, however, we found adding
10 mol % of bathocuproine (7, in addition to catalyst 8) to the
reaction restores the reactivity.7
Scheme 6. Synthesis of Adapromine
Finally, the use of nitromethane was also examined. With
primary alkyl iodides, a mixture of mono- and dialkylated
products resulted.7 With secondary alkyl iodides, modest to
good levels of monoalkylation product were observed (see
Scheme 5 below, for an example).
Prior studies have shown that nickel-catalyzed cross-
couplings can proceed through diverse reaction mechanisms,
including one and two electron pathways.12,13 To gain insight
into the present alkylation reaction, several studies were
conducted. First, the addition of one equivalent of TEMPO
(a known radical scavenger)14 completely inhibits product
formation (Scheme 4, top). Second, the reaction involving
cyclopropylmethyl iodide (46) with nitroalkane 47 resulted in
ring-opening to provide product 48 in good yield (Scheme 4,
middle).15 Conversely, the reaction using 1-iodohex-5-ene
(49), resulted in 5-exo-trig ring-closure to give product 50
(Scheme 4, bottom).
reduction of the nitro group to the primary amine under Raney
nickel conditions provides the target compound in near
quantitative yield. This two-step sequence is highly competitive
with known routes to this pharmaceutical agent.17
In summary, enabled by the discovery of effective nickel
catalysis, we have developed the first general catalytic system
that achieves the C-alkylation of nitroalkanes with unactivated
alkyl halides. The reaction proceeds under mild conditions
using commercially available catalytic components and can be
applied to primary, secondary, and tertiary alkyl iodides.
Moreover, it shows exceptional functional group tolerance. The
simplicity of this reaction, combined with the rapid access to
complex nitroalkanes that it provides, should find wide use in
the preparation of nitrogen-containing molecules.
Third, we examined the stereospecificity of the alkylation
using each diastereostereoisomer of 51 (Scheme 5). Although
the yields in the reaction differed, both isomers led to the same
mixture of isomers of 52 in the reaction with nitromethane (as
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b04312.
■
S
1
determined by H and 19F NMR). Taken together, the results
presented in Schemes 4 and 5 strongly support a radical-based
mechanism of this transformation.16
Experimental procedures, crystallographic and spectral
data (PDF)
Data for C13H15FINO, compound cis-51 (CIF)
Data for C14H17FN2O3, compound cis-52 (CIF)
Data for C13H15FINO, compound trans-51 (CIF)
Data for C14H17FN2O3, compound trans-52 (CIF)
Finally, to demonstrate the synthetic value of this alkylation
reaction, the anti-viral drug adapromine (54) was prepared in
two steps from commercially available materials (Scheme 6).
First, alkylation of 1-nitropropane with 1-admantyl iodide
provides secondary nitroalkane 53 in good yield. Second,
C
DOI: 10.1021/jacs.7b04312
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
traces of alkene and hydrocarbon derived from elimination or
reduction of the alkyl iodide.
AUTHOR INFORMATION
■
Corresponding Author
*dawatson@udel.edu
(12) (a) Hu, X. Chem. Sci. 2011, 2, 1867−1886. (b) Biswas, S.; Weix,
D. J. J. Am. Chem. Soc. 2013, 135, 16192−16197. (c) Breitenfeld, J.;
Ruiz, J.; Wodrich, M. D.; Hu, X. J. Am. Chem. Soc. 2013, 135, 12004−
12012. (d) Schley, N. D.; Fu, G. C. J. Am. Chem. Soc. 2014, 136,
16588−16593. (e) Cornella, J.; Edwards, J. T.; Qin, T.; Kawamura, S.;
Wang, J.; Pan, C.-M.; Gianatassio, R.; Schmidt, M.; Eastgate, M. D.;
Baran, P. S. J. Am. Chem. Soc. 2016, 138, 2174−2177. (f) Mohadjer
Beromi, M.; Nova, A.; Balcells, D.; Brasacchio, A. M.; Brudvig, G. W.;
Guard, L. M.; Hazari, N.; Vinyard, D. J. J. Am. Chem. Soc. 2017, 139,
922−936.
(13) For related radical reactions involving palladium-catalysts, see:
(a) Bloome, K. S.; Alexanian, E. J. J. Am. Chem. Soc. 2010, 132,
12823−12825. (b) Monks, B. M.; Cook, S. P. Angew. Chem., Int. Ed.
2013, 52, 14214−14218. (c) Sargent, B. T.; Alexanian, E. J. J. Am.
Chem. Soc. 2016, 138, 7520−7523.
ORCID
Donald A. Watson: 0000-0003-4864-297X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The University of Delaware (UD), the University of Delaware
Research Foundation, the Research Corp. Cottrell Scholars
Program, and the NIH NIGMS (R01 GM102358) are
gratefully acknowledged for support. Dr. Glenn Yap (UD) is
acknowledged for assistant with X-ray crystallography. Data was
acquired at UD on instruments obtained with the assistance of
NSF and NIH funding (NSF CHE0421224, CHE0840401,
CHE1229234, CHE1048367; NIH S10 OD016267-01, S10
RR026962-01, P20GM104316, P30GM110758).
(14) (a) Beckwith, A. L. J.; Bowry, V. W.; Ingold, K. U. J. Am. Chem.
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(16) Secondary nitronate anions have been shown to undergo
reaction with free-radicals (see references 3c, 4f, and 4g for examples).
The fact that secondary nitroalkanes provide poor yield in this
alkylation may suggest that a complex mechanism is at play. Further
studies will be directed at elucidating the mechanistic details.
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(9) For additional optimization details, including the use of other
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(10) The reaction does not require light, see Supporting Information
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D
DOI: 10.1021/jacs.7b04312
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX