Nickel-Catalyzed Reductive Amidation of Unactivated Alkyl Bromides

Article abstract of DOI:10.1002/anie.201605162

A user-friendly, nickel-catalyzed reductive amidation of unactivated primary, secondary, and tertiary alkyl bromides with isocyanates is described. This catalytic strategy offers an efficient synthesis of a wide range of aliphatic amides under mild conditions and with an excellent chemoselectivity profile while avoiding the use of stoichiometric and sensitive organometallic reagents.

Full text of DOI:10.1002/anie.201605162

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201605162
German Edition: DOI: 10.1002/ange.201605162
Reductive Coupling Very Important Paper
Nickel-Catalyzed Reductive Amidation of Unactivated Alkyl
Bromides
Eloisa Serrano and Ruben Martin*
Abstract: A user-friendly, nickel-catalyzed reductive amida-
tion of unactivated primary, secondary, and tertiary alkyl
bromides with isocyanates is described. This catalytic strategy
offers an efficient synthesis of a wide range of aliphatic amides
under mild conditions and with an excellent chemoselectivity
profile while avoiding the use of stoichiometric and sensitive
organometallic reagents.
A
lthough unactivated alkyl halides are inherently disposed
towards destructive b-hydride elimination and homodimeri-
zation pathways, these molecules have successfully been
employed in a myriad of metal-catalyzed cross-coupling
reactions.[1] At present, the vast majority of these processes
are based on stoichiometric, well-defined, and in many
instances, air-sensitive organometallic species. Challenged
by these drawbacks, recent years have witnessed the develop-
ment of cross-electrophile coupling processes,[2] becoming
powerful and practical synthetic alternatives to classical cross-
coupling reactions, achieving an otherwise similar molecular
complexity under milder reaction conditions while avoiding
the need for organometallic reagents.
À
Scheme 1. Amide synthesis through C C bond formation using isocya-
nates. 1o =primary; 2o =secondary; 3o =tertiary.
Despite the advances realized, the palette of electrophilic
partners in cross-electrophile processes remains rather lim-
ited when compared with classical nucleophile/electrophile
regimes. It comes as a surprise that isocyanates, privileged
synthons in industrial settings,[3] have been virtually unex-
plored in cross-electrophile events with organic (pseudo)ha-
lides.[4,5] This is likely due to the strong binding properties of
isocyanates to low-valent transition-metal complexes, leading
to unproductive dimerization or trimerization pathways.[6] At
present, cross-electrophile coupling reactions with isocya-
nates as coupling partners remain confined to substrates that
rapidly undergo oxidative addition, such as aryl or benzyl
halides lacking b-hydrogen atoms, thus preventing undesired
pathways (Scheme 1, path a).[7] Ideally, this field of expertise
should include the use of unactivated alkyl halides possessing
b-hydrogen atoms,[1] thus resulting in a new synthetic route
for rapidly preparing aliphatic amides, ubiquitous motifs in
pharmaceuticals, agrochemicals, peptides, and polymers.[8]
Indeed, a close look into the literature data indicates that
À
there is a paucity of highly chemoselective catalytic C C
bond-forming processes[9] with improved flexibility, practical-
ity, and generality that would give access to primary,
secondary, or even tertiary amides at will, including hindered
substrate combinations, while avoiding the handling of carbon
monoxide (CO) at high pressures[10] or well-defined and
stoichiometric organometallic species,[11] among others
(Scheme 1, path b).[12]
As part of our interest in reductive coupling reactions,[13]
we questioned whether a unified catalytic umpolung strategy
through the in situ generation of carbogenic nucleophiles (II)
from unactivated alkyl halides (I) and their coupling with
isocyanates would constitute a generic platform for preparing
aliphatic amides (III; Scheme 1, bottom). However, at the
outset of our investigations it was unclear whether it would be
possible to balance the high reactivity of isocyanates and the
commonly observed parasitic b-hydride elimination or homo-
dimerization pathways when using unactivated alkyl halides.
Herein, we describe the successful realization of this concept,
providing access to primary, secondary, and even tertiary alkyl
amides by exploiting a previously unrecognized opportunity
through sequential cross-coupling reactions of three different
electrophiles.
[*] E. Serrano, Prof. R. Martin
Institute of Chemical Research of Catalonia (ICIQ)
The Barcelona Institute of Science and Technology
Av. Paꢀsos Catalans 16, 43007 Tarragona (Spain)
E-mail: rmartinromo@iciq.es
Prof. R. Martin
Catalan Institution for Research and Advanced Studies (ICREA)
Passeig Lluꢀs Companys 23, 08010 Barcelona (Spain)
We began our investigations by studying the reaction of
1a with isocyanate 2a (Scheme 2). The choice of 2a was not
arbitrary, as primary amides can be prepared by simple
deprotection of the tert-butyl group.[14] After judicious
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201605162.
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Scheme 2. Optimization of the Ni-catalyzed reductive amidation of 1a
with 2a. [a] Reaction conditions: 1a (0.50 mmol), 2a (0.75 mmol),
NiBr2 (3 mol%), ligand (4.5 mol%), Mn (0.75 mmol), DMF (1 mL) at
RT, 16 h. [b] GC yield using n-decane as the internal standard. [c] Yield
of isolated product. 1a-I=1-iodo-4-phenylbutane; 1a-OTs=4-phenyl-
butyl-4-methylbenzenesulfonate.
evaluation of the reaction parameters,[15] we found that
a
combination of inexpensive NiBr2 (3 mol%), L2
(4.5 mol%),[16] and Mn as the reducing agent in DMF at RT,
delivered 3a, which was isolated in 86% yield. Importantly,
only traces of b-hydride elimination and homodimerization
products were detected in the crude mixtures. Notably, ligand
optimization revealed a crucial influence of the substitution
pattern on the aromatic ring, with bipyridine ligands lacking
ortho substituents (entry 2) or structurally similar phenan-
throline ligands L4 and L5 providing inferior results (entries 4
and 5).[17,18] Strikingly, the utilization of L3 had a deleterious
impact on yield when using 2a as substrate (entry 3),[19]
revealing an interesting effect of the substituents located at
the ortho position. As shown in entries 6–12, the use of other
solvents, precatalysts, reducing agents, or 1a-I/1a-OTs ana-
logues resulted in diminished yields of 3a,[20] thus showing the
subtleties of our procedure. As expected, control experiments
revealed that all of the reaction parameters were critical for
success.[15]
Scheme 3. Scope of alkyl bromides and isocyanates. Reaction condi-
tions: as for Scheme 2, entry 1; Yields of isolated products, average of
at least two independent runs. [a] 1a (4.69 mmol). [b] NiBr2
(10 mol%), L2 (15 mol%). [c] [(TMEDA)Ni(o-tolyl)Cl] (15 mol%), L2
(30 mol%). [d] NiBr2 (10 mol%), L3 (20 mol%), RNCO (0.5 mmol).
[e] NiBr2 (5 mol%), L2 (7.5 mol%). TMEDA=tetramethylethylenedi-
amine; cy=cyclohexyl; TBDPS=tert-butyldiphenylsilyl.
Encouraged by these results, we turned our attention to
study the preparative scope of our Ni-catalyzed reductive
amidation of unactivated alkyl bromides with isocyanates
(Scheme 3). As shown for 3a–3 f, the procedure allowed for
the coupling of either aromatic or aliphatic isocyanates with
equal ease. Intriguingly, a procedure employing L3 was
particularly efficient when dealing with aromatic isocya-
nates.[21,22] At present, we do not have any rational explan-
ation for this behavior. Particularly illustrative was the
chemoselectivity profile of the procedure, as substrates
containing silyl ethers (3k), acetals (3l), esters (3h, 3o, 3q),
amides (3p), nitriles (3r), heterocycles (3q), or chlorides (3j,
3n) could all be perfectly accommodated. As shown for 3h
and 3n, aryl pivalates and chlorides, substrates commonly
employed in Ni-catalyzed cross-electrophile couplings, do not
compete with the efficacy of this method. Boronic esters (3m)
were tolerated as well, leaving an additional handle for
further functionalization. Although in lower yields, we found
that terminal epoxides could also participate in the targeted
reaction (3s). Importantly, the reaction could be easily scaled
up, obtaining 3a in similar yields. On the basis of these results,
we wondered whether our procedure could accommodate
unactivated secondary or tertiary alkyl halides. Despite the
higher statistical propensity for b-hydride elimination path-
À
ways and increased steric hindrance around the C Br bond,
a host of cyclic and acyclic secondary alkyl bromides could be
equally accommodated under otherwise identical reaction
conditions (3t–3x). A noteworthy observation concerns the
preferential formation of 3x from exo-1x, reinforcing the idea
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that radical species might come into play.[23] The successful
preparation of 3y showcases the generality of our approach as
unactivated tertiary alkyl halides have rarely been employed
in metal-catalyzed cross-electrophile coupling reactions.[24,25]
A close survey of the literature data reveals that a unified
metal-catalyzed strategy for accessing primary, secondary,
and tertiary amides remains elusive. In a final venture to
unlock the full potential of our procedure, we sought to
intercept the in situ generated IV upon subsequent addition
of a proper electrophile, thus accessing tertiary aliphatic
amides in a one-pot fashion (Scheme 4, top left). Although
Scheme 5. Preliminary mechanistic studies.
catalytically competent as reaction intermediates, delivering
3d in slightly lower yield to that observed in Scheme 3 (57%
yield).[30] More importantly, we found that 3d could be
obtained regardless of whether Mn was present or not with
stoichiometric amounts of 7. As expected, 8 delivers 3d with
similar yields to those shown for 7. Although we cannot
rigorously rule out other conceivable pathways,[31] we propose
a mechanistic scenario involving alkyl–NiI species generated
by comproportionation of in situ generated alkyl–NiII inter-
mediates and Ni0(L)2, followed by insertion of the isocyanate
motif, and a final SET mediated by Mn.[32,33]
In summary, we have described the first Ni-catalyzed
reductive amidation of unactivated alkyl halides with iso-
cyanates for accessing primary, secondary, or even tertiary
amides through iterative techniques. The reaction proceeds
under mild conditions, thus minimizing unproductive b-
hydride elimination or dimerization/trimerization events,
while accommodating a wide range of substrates with an
excellent chemoselectivity profile. Further investigations on
the mechanism and the elaboration of an asymmetric version
of the reaction are currently being pursued in our laborato-
ries.
À
Scheme 4. Sequential C C bond-forming scenarios.
counterintuitive at first sight, the preparation of 4a–4d
demonstrates the feasibility of this approach, constituting
a formal cross-coupling reaction of three different electro-
philes. On the other hand, primary amides could easily be
obtained by deprotection of the tert-butyl group with Sc-
(OTf)3 (4e).[26] Importantly, such a design principle allowed us
to rapidly convert 1a into 4 f, thus constituting a powerful
alternative platform for handling flammable and toxic
MeNCO in amidation technologies (Scheme 4, bottom).[27]
Taken together, the results in Scheme 3 and Scheme 4
demonstrate the prospective impact of our catalytic amida-
tion procedure for accessing a wide variety of amides from
simple starting materials in a straightforward manner.
Acknowledgements
Although a comprehensive mechanistic study should
await further investigations, deuterium labelling experiments
were performed to study the stereochemical course of the
reaction (Scheme 5, top). Interestingly, we found a statistical
mixture of diastereoisomers in 6 when exposing 5 to our
optimized reaction conditions, suggesting the intermediacy of
single-electron-transfer (SET) processes.[23] In line with this
notion, a complete racemization was detected when using
(R)-(3-bromo-butyl)benzene (97% ee) as substrate. We then
turned our attention to study the reactivity of the putative
Ni0(L3)2 (7) and NiBr2(L3) (8) species (Scheme 5,
bottom).[28,29] These compounds were easily prepared from
either Ni(COD)2 or NiBr2 and were characterized by X-ray
crystallography.[15] As expected, both 7 and 8 were found to be
We thank ICIQ, the European Research Council (ERC-
277883), MINECO (CTQ2015-65496-R and Severo Ochoa
Excellence Accreditation 2014–2018, SEV-2013-0319),
FEDER, and the Cellex Foundation for support. Johnson
Matthey, Umicore, and Nippon Chemical Industrial are
acknowledged for a gift of metal and ligand sources. E.S.
thanks MINECO for a FPI fellowship. We sincerely thank E.
Escudero and E. Martin for all X-ray data.
Keywords: cross-coupling · nickel · reductive coupling ·
synthetic methods
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[30] b-hydride elimination, reduction, homodimerization, and the
formation of N-acylureas account for the mass balance.
[31] At present, we cannot rule out a significant contribution dealing
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[32] For selected comproportionation events en route to NiI species,
see: a) J. Cornella, E. Gómez-Bengoa, R. Martin, J. Am. Chem.
Received: May 26, 2016
Published online: && &&, &&&&
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Communications
Reductive Coupling
E. Serrano, R. Martin*
&&&& — &&&&
Nickel-Catalyzed Reductive Amidation of
Unactivated Alkyl Bromides
Mild and selective: A versatile Ni-cata-
lyzed reductive amidation of unactivated
primary, secondary, and tertiary alkyl
bromides with isocyanates gives access
to a wide range of aliphatic amides. The
reaction proceeds under mild conditions,
has excellent chemoselectivity, and
avoids the use of stoichiometric and
sensitive organometallic reagents.
6
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