Catalyst-Free Reductive Coupling of Aromatic and Aliphatic Nitro Compounds with Organohalides

Article abstract of DOI:10.1002/anie.201814197

A rare reductive coupling of nitro compounds with organohalides has been realized. The reaction is initiated by a partial reduction of the nitro group to a nitrenoid intermediate. Therefore, not only aromatic but also aliphatic nitro compounds are efficiently transformed into monoalkylated amines, with organohalides as the alkylating agent. Given the innate reactivity of the nitrenoid, a catalyst is not required, resulting in a high tolerance for aryl halide substituents in both starting materials.

Full text of DOI:10.1002/anie.201814197

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Accepted Article
Title: Catalyst Free Reductive Coupling of Aromatic and Aliphatic Nitro
Compounds with Organohalides
Authors: Marian Rauser, Raphael Eckert, Max Gerbershagen, and
Meike Niggemann
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201814197
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10.1002/anie.201814197
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Catalyst Free Reductive Coupling of Aromatic and Aliphatic Nitro
Compounds with Organohalides
Marian Rauser,[a] Raphael Eckert,[a] Max Gerbershagen,[a] and Meike Niggemann*[a]
Abstract: A rare reductive coupling of nitro compounds with
organohalides has been realized. The reaction proceeds via a partial
reduction of the nitro group to a nitrenoid intermediate. Therefore, not
only aromatic but also aliphatic nitro compounds are efficiently
transformed into mono-alkylated amines, with organohalides as the
alkylating agent. On account of the nitrenoid’s innate reactivity, a
catalyst is not required, resulting in a high tolerance for aryl halide
substituents in both starting materials.
disclosed for such a transformation.[5] This is certainly due to the
fact, that methodologies engaging partially reduced nitro groups
remain scarce[6,7,8] and proceed mostly via nitroso intermedia-
tes.[6,7] Unfortunately, nitroso arenes easily dimerize, which sets
them up for a range of side reactions.[9] Aliphatic nitroso inter-
mediates are even more challenging, for they instantaneously
tautomerize to oximes, which forestalls further N-functionali-
zation.[10] Hence, many transformations engaging nitroso inter-
mediates rely on radical mediated processes,[6] including the only
reductive coupling of nitroarenes with organohalides (Scheme 1,
c).[5] This prevents overreduction and other side reactions, due to
the rapid recombination of the radical with the nitroso intermediate
I, which are formed concomitantly.
Cross-coupling reactions are an indispensable tool in organic
synthesis. Typically, they occur between an organohalide and an
organometallic reagent. The latter is prepared from a precursor,
mostly also an organohalide, in a preceding synthetic operation.[1]
Evidently, the reductive coupling of two stable and readily
available electrophiles is a more straightforward approach.[2] The
handling of hazardous, air- and moisture sensitive metal organic
reagents is avoided, and the step economy is improved. The in
situ Umpolung of one of the electrophiles is achieved via either
one of two strategies: (a) in situ metalation of the organohalide
prior to the cross coupling step (Scheme 1, a).[3] or (b) oxidative
addition of both electrophiles to the catalyst, which is turned over
by a stoichiometric reductant (e.g. Zn, Mn). The reduction may
occur at an intermediate stage of the catalytic cycle and/or
regenerate the catalyst at the end (Scheme 1, b).[2a,2e,4] Due to the
similar reactivity of the electrophiles, the obvious difficulty in these
reactions is the prevention of homocoupling. Therefore, each of
the electrophiles must be addressed selectively, in the presence
of the other, at different stages of the transformation. This may be
realized with electrophiles of significantly different redox
potentials and/or sterical properties and often calls for laborious
fine-tuning of the reductant/catalyst combination.
Even though the nitro moiety is electrophilic, due to the high
oxidation state of the N-atom, it remains inert to most reaction
conditions. Hence, unlike amines, whose nucleophilic character
often demands a late stage introduction or complex protection/
deprotection sequences, nitro groups do not require such
provisions. To release the nitro group’s electrophilicity, the
nitrogen’s reactivity may be customized by a partial reduction.
Given, that the reactivity profile of a nitro group is distinctly
different from an organohalide’s, each may easily be addressed
selectively, by a different chemical process. Consequently, these
two electrophiles make an ideal pair for a reductive cross coupling.
Even more so, as a reaction is realized, that not only allows for
the direct transformation of nitro compounds, but also gives rise
to mono-alkylated amines using organohalides, an alkylating
agent that is infamous for its disposition to bis-alkylate amines. It
is therefore surprising, that only a single protocol has ever been
Scheme 1: Reductive Coupling strategies.
To improve the applicability of partially reduced nitro compounds,
we recently developed a B2pin2 mediated protocol, which
proceeds via a more versatile intermediate, the nitrenoid II.[11] As
the erratic nitroso intermediate is bypassed, we reasoned that this
new partial reduction is ideally suited for a general reductive
coupling of both, aromatic and aliphatic nitro compounds with
organohalides. Furthermore, the innate reactivity of nitrenoid II is
sufficient to promote the electrophilic amination of the in situ
generated zinc organyl in the absence of a catalyst.
We started our investigation by treating benzyl bromide and nitro
benzene with Zn powder, in the presence of B2pin2 and NEt3 at
room temperature. Toluene was chosen as a solvent, for it has
proven best at suppressing an undesired direct reduction to
anilines in our previous work (Table 1, entry 1). Much to our
chagrin, no reaction occurred, also under reflux conditions (not
[a]
Dr. Marian Rauser, Raphael Eckert, Max Gerbershagen, Prof. Dr.
Meike Niggemann
Institute of Organic Chemistry, RWTH Aachen
Landoltweg 1, 52072 Aachen
E-mail: niggemann@oc.rwth-aachen.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201814197
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COMMUNICATION
shown). A survey of Zn powders/granules of different particle size
from different suppliers did not improve the results (not shown).
Even though proving beneficial in Hu’s protocol,[5] the addition of
TMSCl only promoted a background reaction to aniline, indicating
for the direct reduction of the nitro compound by the metal being
predominant (Table 1, entries 2 – 5). A pretreatment of the Zn
powder with catalytic amounts of TMSCl and 1,2-dibromoethane,
according to a protocol by Knochel,[12] gave the product in no more
than trace amounts, albeit with no background reactions (Table 1,
entry 6). The addition of 3.3 equiv of dried LiCl[13] improved overall
reactivity, with the selectivity remaining mediocre (Table 1, entry
7). Elevating the temperature to 50 °C proved unfavorable (Table
1, entry 8).
We began to explore the generality of the transformation starting
with a survey of different nitroarenes. A methyl group in the m-
and p-position does not affect the efficiency (3c, 88%; 3d, 81%),
whereas steric encumbrance imposed by an o-substitution slightly
diminishes the yield (3b, 57%). Electron rich nitroarenes bearing
an ether (3e, 85%) or silyl ether moiety (3f, 65%) readily react.
Even phenol 1g is transformed without any protection (3g, 61%).
Halogen substituted arenes are highly reactive in transition metal
catalyzed reductive couplings, and therefore typical starting
materials. Furthermore, they have been shown to readily insert
zinc metal in the presence of LiCl.[13f] However, in competition with
the formation of an alkyl zinc halide, the latter is expected to be
significantly faster. As the high reactivity of the nitrenoid
intermediate II ensures a rapid electrophilic amination and makes
a transition metal catalyst unnecessary, we anticipate the
transformation to tolerate halogen substituents, and thus provide
an orthogonal protocol. Indeed, fluorine (3h, 75%), chlorine (3i,
84%), bromine (3j, 80%) and iodine (3k, 71%) substituted nitro-
arenes give the desired products in good to excellent yields, with
no selectivity issues arising. As radical intermediates are also
prone to dehalogenation,[14] this also confirms the absence of
radical pathways. Electrophilic ester (3l, 87%) and nitril moieties
(3m, 82 %) are well tolerated. Heteroaromatic nitro compounds
such as pyridin 1n react readily (3n, 65%).
Next, we explored the scope of the organohalides. Electron rich
benzyl bromides (3o, 84%; 3p, 72%) react efficiently. Electron
poor benzyl halides are well known to form zinc organyls with
significantly reduced reaction rates.[13f] Nevertheless, the mono-
alkylated amine 3q is obtained with a moderate 56% yield,
alongside unreacted starting material. The halogen substituent in
the arene moiety is again well tolerated. The increased steric bulk
in branched, secondary benzyl bromides does not result in a loss
of efficiency (3t, 84%). The highly reactive allylhalides, gave the
mono-allylated amines in moderate yields of 63% (3r) and 55%
(3s), as their unbalanced reactivity[15] leads to various side
reactions. A double bond isomerization of cinnamyl bomide,
giving a branched product 3s’ was not observed. Simple primary
and secondary aliphatic halides give the desired amines in good
(3x, 78%; 3y, 81%) to excellent (3u, 93%; 3v, 91%; 3w, 92%)
yields. Intrigued by the broad applicability we also investigated
genuinely functionalized zinc organyls. As these tend to form with
lower reaction rates[16] the reaction temperature was slightly
increased. A variety of functionalities is tolerated. While ether
moieties led to slightly diminished yields (3ac, 71%; 3ad, 60%),
the direct coupling with nitro benzene proceeds with high
efficiency for acetyl and silyl protected alcohols (3z, 75%; 3ab,
85%). The results were excellent also for benzoyl esters and Boc-
protected amines. (3aa, >95%; 3ae, 90%). Providing access to an
interesting building block, an organohalide with an ester moiety
cyclized to the lactam 3af (76%). The in-situ insertion of zinc into
aryl halides was too slow for an efficient reductive coupling.
As already mentioned above we anticipate this new protocol to be
efficient also for aliphatic nitro compounds, as the nitroso
intermediate is bypassed. To probe this prediction, we chose
nitrophenyl ethane as a model compound, for it is a less volatile
alternative to simpler nitro alkanes. In addition, 2-nitropropane
and nitrocyclopentane were examined. To our delight both
primary and secondary nitro alkanes yield the desired
disubstituted amines in good to excellent yields with primary (3ag,
77%), secondary (3ah, 86%) and benzylic (3ai, 90%; 3aj, 92%)
halides as coupling partners.
Table 1. Optimization.
Metal
Additives
(equiv)
3a[h]
4a[h]
Entry[a]
Solvent
(equiv)
[%]
[%]
1
2
3
Zn (6)
Zn (6)
Zn (6)
NEt3 (2)
TMSCl (4), NEt3 (2)
TMSCl (4)
toluene
toluene
toluene
NMP
NMP
toluene
toluene
toluene
Et2O
DMF
THF
THF
THF
THF
THF
THF
THF
THF
THF
0
0
0
0
0
0
19
90
80
75
0
16
0
8
10
0
0
0
0
4
5
Zn (6)
Zn (6)
TMSCl (4), NEt3 (2)
TMSCl (4)
6
Zn (6)[b]
Zn (6)[b]
Zn (6)[b]
Zn (6)[b]
Zn (6)[b]
Zn (6)[b]
Zn (6)[b]
NEt3 (2)
trace
56
trace
83
78
87
93
92
41
83
50
0
7
LiCl (3.3), NEt3 (2)
LiCl (3.3), NEt3 (2)
LiCl (3.3), NEt3 (2)
LiCl (3.3), NEt3 (2)
LiCl (3.3), NEt3 (2)
LiCl (3.3)
8[c]
9
10
11
12
13
14
15[d]
16[e]
17
18[f]
19[g]
]
Zn (4)[b
Zn (3)[b]
Zn (4)[b]
Zn (4)[b]
-
LiCl (2.2)
LiCl (1.65)
LiCl (2.2)
LiCl (2.2)
LiCl (2.2)
LiCl (2.2)
LiCl (2.2)
0
0
0
0
Zn (4)[b]
Zn (4)[b]
0
0
0
[a] conditions: Metal (and LiCl) were dried in vacuo, then solvent (1 mL),
additives, BnBr (0.6 mmol, 3 equiv), nitrobenzene 1a (0.2 mmol) and B2pin2
(0.4 mmol, 2 equiv) were added and the reaction was stirred for 12 h at rt.
[b] Zinc powder was pretreated by addition of catalytic amounts of TMSCl
and dibromoethane. [c] 50 °C. [d] 2 equiv BnBr. [e] 1 equiv BnBr. [f] No
B2pin2. [g] No exclusion of air and moisture. [h] Isolated yield.
A survey of different solvents (exemplary results: Table 1, entries
9 – 11) identified polar solvents to increase not only the
conversion but also the selectivity drastically, when combined
with the pretreatment of the zinc powder and the beneficial
influence of LiCl. Among these, THF proved best (Table 1, entry
11). Unexpectedly, the omission of the NEt3 additive, which was
crucial for the suppression of aniline formation in our previous
work,[11b] further improved the result, allowing for the isolation of
3a in 93% yield (Table 1, entry 12). The amount of zinc was
reduced to 4 equiv with no loss in efficiency (Table 1, entry 13),
while less proved insufficient (Table 1, entry 14). With 2 equiv of
BnBr (instead of 3 equiv) the efficiency was slightly reduced
(Table 1, entry 15), while the conversion significantly drops with
only 1 equiv BnBr (Table 1, entry 16). No conversion was
observed in the absence of zinc (Table 1, entry 17) or B2Pin2
(Table 1, entry 18). The reaction ceases, when exposed to air
(Table 1, entry 19).
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10.1002/anie.201814197
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Table 2. Scope of the reductive coupling of nitro compounds with organohalides.
Conditions: Zn powder (4 equiv) and LiCl (2.2 equiv) were dried in vacuo, 1 mL THF was added, followed by a pretreatment with catalytic amounts of TMSCl
and dibromoethane. R1-X 2 (0.6 mmol, 3 equiv), nitro compound 1 (0.2 mmol), and B2pin2 (0.4 mmol, 2 equiv) were added and the reaction was stirred for 12 h
at rt. Aminoborane D was hydrolyzed by addition of water; [a] carried out at 50 °C; [b] reaction stirred for 1h at 50 °C before the addition of PhNO2 1a; [c] carried
out at 70 °C. Structures, compound numbers, and yields of isolated products after column chromatography are given.
Based on our previous work[11] and the successful transformation
of the aliphatic nitro compounds, which precludes the participation
of a nitroso intermediate, we propose the following mechanism
(Scheme 2): The reductive coupling reaction starts with the
formation of a zinc organyl XZnR1, via insertion of the activated
Zn in the carbon halogen bond in 2. Transfer of the organyl R1
analysis (see SI).[11] These investigations indeed confirm the
formation of a borate [B2pin2·R1]ˉ (A), the aminoborane D and an
increasing amount of pinBOˉ. A signal for the byproduct of the
first reduction step, the boronic ester R1Bpin, which remains after
the transfer of the nucleophilic boron moiety from [B2pin2·R1]ˉ (A)
was not observed throughout the reaction. This is not surprising,
from XZnR1 to B2pin2 generates an anionic adduct [B2pin2·R1]ˉ (A). as the residual concentration of the zinc organyl is expected to be
This initializes the two-step reduction sequence by addition of the
nucleophilic Bpin fragment in [B2pin2·R1]ˉ (A) to the nitro group’s
O-atom, generating a borylated dihydroxylamine anion B. Upon
reaction of B with more B2pin2, nitrenoid II is formed. Electrophilic
amination of a zinc organyl with this species, via an addition - 1,2
migration sequence gives aminoborane D. Finally, hydrolysis of D
yields the functionalized amine 3. To validate this mechanistic
proposal we studied the reaction via time resolved 11B{1H}-NMR
rather low in this reaction with the concentration of zinc salts
continuously raising. Hence, a rapid boron to zinc transmeta-
lation[17] is promoted, which feeds the boronic ester R1Bpin back
into the reaction sequence.[18] Confirming the participation of
borylated dihydroxylamine anion B and nitrenoid II in the partial
reduction of the nitro group, a stepwise reaction of 1a with a
preformed borate [B2pin2·R1]ˉ was also analyzed via time resolved
11B{1H}-NMR analysis (see SI).
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Scheme 2: Proposed mechanism.
In summary, we have developed a catalyst free reductive cross
coupling of nitro compounds with organohalides, which is
successful for both, aromatic and aliphatic nitro compounds.
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Keywords: nitro functionalization • reductive coupling • nitrenoid
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Marian Rauser, Raphael Eckert, Max
Gerbershagen, and Meike Niggemann*
Page No. – Page No.
Catalyst Free Reductive Coupling of
Aromatic and Aliphatic Nitro
Compounds with Organohalides
Nitro 2 Amine. Nitro compounds are directly coupled with (functionalized)
organohalides yielding mono-alkylated amines. As nitroso intermediates are
bypassed, not only aromatic but also aliphatic nitro compounds are efficiently
transformed. The nitrenoid’s innate reactivity makes a catalyst unnecessary.
Therefore, the reaction is orthogonal to traditional reductive couplings and aryl halide
substituents are well tolerated in both starting materials.
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