Transition Metal Free Nucleophilic Benzylation of Nitroarenes. Umpolung of the Friedel Crafts Reaction

Article abstract of DOI:10.1002/adsc.201801715

Benzyl chloride and its derivatives are efficiently deprotonated with strong bases to form α-chlorocarbanions. These anions are long-lived enough to enter VNS reactions with nitroarenes or nitroheteroarenes to give a variety of unsymmetrical o- and p-nitrodiarylmethanes. Selectivity of the reaction can be controlled to some extent by changing metal counterions of the base. (Figure presented.).

Full text of DOI:10.1002/adsc.201801715

Title: Transition Metal Free Nucleophilic Benzylation of Nitroarenes.
Umpolung of the Friedel-Crafts Reaction
Authors: Kacper Kisiel, Jakub Brześkiewicz, Rafał Loska, and
Mieczysław Mąkosza
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10.1002/adsc.201801715
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Transition Metal Free Nucleophilic Benzylation of Nitroarenes.
Umpolung of the Friedel Crafts Reaction
Kacper Kisiel,a Jakub Brześkiewicz,a Rafał Loska,a,* and Mieczysław Mąkoszaa,*
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
[rafal.loska@icho.edu.pl; mieczyslaw.makosza@icho.edu.pl]
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. Benzyl chloride and its derivatives are efficiently Selectivity of the reaction can be controlled to some extent
deprotonated with strong bases to form -chlorocarbanions. by changing metal counterions of the base.
These anions are long-lived enough to enter VNS reactions
with nitroarenes or nitroheteroarenes to give a variety of
unsymmetrical o- and p-nitrodiarylmethanes.
Keywords: Aromatic substitution; Benzylation;
Nucleophilic substitution; Umpolung; VNS
this respect is vicarious nucleophilic substitution of
hydrogen (VNS), that involves addition of -
chlorocarbanions at positions ortho or para of
nitroarenes occupied by hydrogen to form anionic σH
adducts. Subsequent base-induced -elimination of
HCl from these adducts produces nitrobenzylic
carbanions that upon protonation give the substitution
products.[7]
Introduction
Diarylmethanes are rather simple molecules, but of
substantial interest as versatile intermediates in the
synthesis of pharmaceuticals, chemicals for
electronics and dyes, and compounds of peculiar
structure.[1] Synthesis of diarylmethanes, particularly
containing a variety of substituents on both aromatic
rings, is therefore of great interest. For instance, in
2018 more than 20 papers reporting various syntheses
of substituted diarylmethanes were published. In spite
of simplicity of their structure, practical synthesis of
substituted diarylmethanes is not a simple task. The
most obvious synthesis of diarylmethanes is the
Friedel-Crafts type reaction of benzyl halides or other
precursors of benzylic carbocations with arenes.
Although apparently simple, it is severely limited in
respect to substituents on both aromatic rings.[2]
Similarly, reactions of benzyl halides or sulfonates
with lithiated, magnesiated, etc. arenes cannot be
considered as a general method.[3] Presently, the most
often used way of synthesis of diarylmethanes is the
transition metal catalyzed coupling of benzylic
The VNS reaction is of general character in respect
to both reaction partners. Carbanions of -
chloronitriles, -chloroesters, -chloroalkyl sulfones,
haloforms, etc. react with nitroarenes and
nitroheteroarenes and also with electron-deficient
arenes that do not contain a nitro group, e.g. azines. It
should be stressed that VNS of hydrogen proceeds
faster than conventional SNAr of halogens, so VNS
proceeds efficiently in ortho- and para-
halonitrobenzenes.[7,8] The key features of VNS –
replacement of hydrogen in aromatic rings with
carbon substituents and the reaction stoichiometry –
are similar to the Friedel-Crafts reaction that proceeds
with opposite polarity. We can therefore consider
VNS to be in an umpolung relation to the Friedel-
Crafts reaction.[9] The VNS process has found many
practical applications and was used inter alia for
direct introduction of alkyl and diarylmethyl
substituents into nitroarenes. Recently, we reported
efficient -chlorobenzylation of nitroarenes via VNS
electrophiles:
benzyl
chlorides,
benzyl
trimethylammonium chlorides, benzylic esters, etc.,
with aryl boronic acids or aryl zinc chlorides.[4] Some
less general methods, such as replacement of
halogens in arenes by benzylic carbanions[5a-e] or
cycloaddition of difluoroalkenes to azine N-oxides[5f]
were also reported.
reaction
with
carbanions
of
benzylidene
dichlorides.[10]
Taking into account great interest in the synthesis
of substituted diarylmethanes and simplicity and wide
scope of VNS reactions, we decided to elaborate a
general method of synthesis of diarylmethanes via
VNS in nitroarenes by carbanions of substituted
benzyl chlorides. It has been already shown that p-
nitrobenzyl chloride enters VNS, but only with highly
electron-deficient m-dinitrobenzenes.[11] Also some
Nearly all of the mentioned reactions can in
general be considered as interaction of benzylic
electrophiles with aromatic nucleophiles. For many
years we have developed an alternative approach to
introduction of carbon substituents into aromatic
rings – nucleophilic substitution of hydrogen in
electron-deficient arenes.[6] Particularly valuable in
1
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10.1002/adsc.201801715
Advanced Synthesis & Catalysis
chloromethyl azines: pyridines and quinolines, react
with nitroarenes in the presence of strong bases
according to the VNS pathway to form nitroaryl
heteroarylmethanes.[12a] A multi-step procedure for
VNS-like methylation of nitroarenes has also been
reported.[12b] In our approach, we decided to use
benzyl chloride and its derivatives that form
carbanions much less stabilized than in the literature
cases mentioned above.
4-cyanobenzyl chloride 1c, 3-trifluoromethyl benzyl
chloride 1d, 3-nitrobenzyl chloride 1e and 4-(N,N-
diethylaminocarbonyl)benzyl chloride 1f is higher
than that of 1a, so they could be efficiently
deprotonated under the action of KHMDS. The VNS
reaction of these benzyl chlorides with a variety of
nitroarenes were therefore carried out under the
commonly used conditions: KHMDS, THF/DMF at
low temperature, for a relatively short time (15 min).
Such conditions were determined to be necessary,
because the starting -chlorobenzylic carbanions and
the nitrobenzylic carbanions of the products are rather
unstable species. The expected products of the
substitution - nitrodiarylmethanes - were obtained in
good to acceptable yields. The general scheme of the
reaction is shown in Scheme 2 and the results are
collected in Schemes 3 and 4. For appropriate
identification, the products are numbered by a
combination of the number of the nitroarene (2–16),
the letter corresponding to the benzyl chloride (a, b, c,
d, e, f) and, where necessary, a digit 2, 4 or 6
indicating the site of substitution in the nitroarene
ring.
Cl
H
Cl
Y
B-
B-
Z
Z
+
Y
-HCl
-
NO2
NO2
1a - f
2 - 16
H+
Y
Y
Z
Z
-O2N
O2N
As expected, substitution of hydrogen by
methylenic -chlorocarbanions of benzyl chlorides
proceeded at positions ortho and para to the nitro
group. Indeed, as it is shown in Scheme 3, in most
cases two isomeric VNS products – 2-(6-) or 4-
nitrodiarylmethanes were formed which usually could
be separated by chromatography or crystallization.
Only in the reactions with para-substituted
nitrobenzenes: 7, 8, 9, 12, 14 (entries 11, 12, 13, 21–
23, 25) the substitution occurred selectively at
position ortho to NO2. It should be stressed that even
the reactions of o- and p-halonitrobenzenes (3, 4, 7
and 8, Scheme 3) proceed exclusively as substitution
of hydrogen, with no traces of products of halogens
substitution (classical SNAr) detected. With meta-
substituted nitrobenzenes, products of benzylation at
the para and the less hindered ortho position were
formed in nearly equal amounts. Similarly, 3-
nitropyridine reacted mainly at its C-4 and C-6
positions. Only traces of benzylation between the
NO2 group and the other substituent or the ring
nitrogen atom were observed, with the exception of
10e and 6c. In the latter example, nucleophilic attack
occurred only at the positions ortho to the fluorine
atom, which are activated by its inductive effect.
Scheme 1. The concept of VNS benzylation of nitroarenes
Results and Discussion
First attempts of the VNS reaction between benzyl
chloride 1a and a few nitroarenes: nitrobenzene 2, 2-
nitroanisole 5 and 4-nitroanisole 9, carried out under
conditions commonly used for such reactions (t-
BuOK or KHMDS in THF/DMF at low temperature),
were not promising. The expected products of
substitution were formed in negligible yields (<10%)
and most of the starting materials were recovered
unchanged or decomposed. It appears that due to low
C–H acidity of the methylenic group of 1a its
deprotonation by the applied base-solvents system
was insufficient. After some experimentation we
found that the system LDA/HMPA exhibited
sufficiently strong basicity to assure deprotonation of
1a. Under these conditions carbanions of 1a are
generated and they add to nitroarenes to form H
adducts that are sufficiently long-lived to undergo
base induced -elimination of HCl. Subsequent
protonation of the nitrobenzylic carbanions gave
nitrodiarylmethanes – products of VNS reaction
(products 5a, 9a, 10a4, 10a6, 13a, Scheme 3). The
presence of HMPA in the system is necessary for
solvation of the Li+ cations so that aggregates of
lithium salts of carbanions are destroyed and
carbanions are in the form of loose ion pairs. It was
shown that only in such form carbanions add
efficiently to nitroaromatic rings.[13]
Cl
Y
Cond.
Z
Z
+
Y
A or B
NO2
O2N
+ ortho isomers
2 - 16 Y = H 1a
3-CF3 1d
2,4-Cl2 1b 3-NO2 1e
4-CN 1c 4-CONEt2 1f
Scheme 2. VNS Benzylation of nitroarenes. Conditions A:
1 (1.2 equiv.), LDA (4 equiv.), HMPA (8 equiv.),
THF/DMF, 78 C, 15 min. Conditions B: 1 (1.2 equiv.),
KHMDS (2.5 equiv.), THF/DMF, 78 C, 15 min
C–H acidity of the methylenic groups of benzyl
chlorides substituted in the ring with electron-
withdrawing groups: 2,4-dichlorobenzyl chloride 1b,
2
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10.1002/adsc.201801715
Advanced Synthesis & Catalysis
ortho-Z:
meta-Z:
para-Z:
NO2
NO2
NO2
7c 75%
Z = F
Z = Cl
Z = OMe
O2N
8e 55%
Z
O2N
F
9a 54% a)
Ar
Ar
Ar
Ar
Z = CF3 12b 32%
12e 60%
Ar
Z
F
Z = H 2b2, 2b4 75% (0.5:1)
2c2, 2c4 65% (1:0.8)
12f 49%
6c2, 6c4 61% (0.2:1)
Z
NO2
2d2, 2d4 35% (0.9:1)
2e2, 2e4 37% (1:0.8)
2f2, 2f4 54% (0.8:1)
NO2
NO2
MeO
O2N
CN
CN
Ph
Ar
Ar
Z = F 3c6, 3c4 45% (0.4:1)
Ar
3e6, 3e4 40% (0.3:1)
NC
4c6, 4c4 70% (0.6:1) b)
13a 41% a)
Z = Cl
OMe
10a2, 10a4, 10a6 43% (0:0.7:1) a), c)
10b2, 10b4, 10b6 70% (0:0.9:1)
10c2, 10c4, 10c6 77% (0:1:0.9)
10d2, 10d4, 10d6 80% (0:1:0.8)
10e2, 10e4, 10e6 74% (0.45:1.3:1.0)
O2N
5a 68% a)
Ph
MeO
NO2
NO2
Ar
O2N
NO2
Ar
11b 48%
11e 43%
14b2, 14b4 48% (0.6:1)
Ar
a)
Scheme 3. Results of benzylation of o-, m- and p-substituted nitroarenes and 1-nitronaphthalene. All reactions of 1a
performed using Conditions A (see Scheme 2). All other reactions performed using Conditions B. b) Reaction time 30 min.
c) Conditions A with LDA (2.4 equiv.), HMPA (4.8 equiv.)
A considerable number and diversity of the examples
collected in Scheme 3 and 4 demonstrates that the
reaction is of general character and of wide scope
with respect to substituents on both aromatic rings
and therefore it may serve as a versatile tool in
organic synthesis. It is thus of great interest to learn
what factors govern the orientation and control the
ratio of the isomers. In our early studies, it was
shown that orientation is governed by a complicated
interplay of steric and electronic effects.[6,7] Sterically
demanding methinic carbanions react preferentially at
positions para, although when these positions are
occupied, substitution can occur at positions ortho.
Orientation of VNS of methylenic carbanions is
controlled by the conditions, structure of the
nucleophile and the nature of the substituents in the
nitroaromatic ring. The VNS reaction proceeds via
two independent steps: reversible addition of -
chlorocarbanions to nitroarenes to form H adducts,
followed by base induced -elimination of HCl, thus
overall orientation of substitution is an interplay of
these processes. Orientation of the initial addition is
governed by the relation of electrophilicities of
various positions in the nitroaromatic rings. Under
conditions that disfavour dissociation, hence
equilibration of the addition (low temperature and
high concentration of strong base that ensures high
rate of -elimination), the substitution proceeds at the
most electron-deficient positions. We can consider
such orientation as kinetically controlled. Effect of
substituents on the electrophilicity of various
positions in nitroarenes was determined using VNS
with carbanion of chloromethyl phenyl sulfone as a
model nucleophile.[14] On the other hand, under
conditions that favour equilibration: higher
temperature and lower base activity, the orientation is
controlled by the relative rates of -elimination of
isomeric H adducts according to the Curtin-Hammett
principle. It is then thermodynamically controlled.
For instance, in the reaction of model carbanion of
chloromethyl phenyl sulfone the ratio of o-/p-
isomers under kinetic control is 3:1, whereas under
thermodynamic control only para isomer is
formed.[14]
Ar
NO2
Ar
NO2
NO2
Ar
N
N
N
15b2, 15b4, 15b6 62% (0:1:0.6)
15c2, 15c4, 15c6 62% (0:1:0.45)
15d2, 15d4, 15d6 91% (0.2:1:0.55)
15e2, 15e4, 15e6 71% (0:1:0.4)
Ar
NO2
Cl
NO2
Cl
16b4, 16b6 55% (1:1)
16e4, 16e6 47% (1:1)
Ar
N
N
Scheme 4. Benzylation of nitropyridines
3
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10.1002/adsc.201801715
Advanced Synthesis & Catalysis
The reactions of unstable carbanions of benzyl
77%, 70% and 50%. Reactions of 10 and 15 with
chloride 1b gave exclusively products of substitution
para to NO2 (Scheme 5), similarly to benzylation of
2-methoxynitrobenzene with 1a in the presence of
LDA and HMPA (product 5a in Scheme 3). These
results demonstrate that some control of
regioselectivity of benzylation is indeed possible.
It should be stressed that the process is of practical
value as it can be executed on gram scale. From 5
mmol of 3-fluoronitrobenzene we obtained 4-
cyanobenzylation products 6c2 and 6c4 in 74% total
yield and 0.2:1 ratio, which is even better than the
result at the standard 0.5 mmol scale (see Scheme 3).
The yields reported in Scheme 3 and 4 were obtained
in experiments according to one standard procedure,
without attempts of optimization of individual
examples, thus in many cases they can be probably
substantially improved. For example, performing the
reaction of 4 with 1c for 30 min instead of the
standard 15 min time period improved the yield from
42% to 70%. The scope of our benzylation protocol
can be probably extended on benzyl bromides, as a
single experiment with 2,4-dichlorobenzyl bromide
and nitroarene 10 gave the benzylation product in
similar yield and selectivity (75%, 10b4:10b6 0.8:1)
as with 1b.
chlorides 1a-f with nitroarenes have to be carried out
at low temperatures in the presence of excess of
strong base, so they probably proceed under kinetic
control. We could therefore expect that the
substitution
in
nitrobenzene
should
occur
preferentially at positions ortho, whereas orientation
in substituted nitrobenzenes should correlate with
electrophilicity of various positions of the ring
determined earlier.[14] As it is evident from the results
presented in Scheme 3, this is not the case. Moreover,
we cannot learn the orientation of the substitution
under thermodynamic control simply due to
instability of carbanions of 1a-e.
An interesting question is whether and how
substituents Y in the benzyl chloride ring affect the
orientation. Inspection of the ratio of isomeric
products of the reaction of nitrobenzene 2 with a
series of substituted benzyl chlorides 1b, 1c, 1d, 1e
and 1f carried out under the standard conditions
(Scheme 3) indicates that chlorobenzyl carbanions
with more electron-withdrawing groups in the ring
(4-CN, 3-CF3, 3-NO2, 4-CONEt2) give nearly equal
amounts of ortho and para substitution products,
whereas dichloro derivative 1b shows preference for
para substitution. This may be due to its sterical
demands (a chlorine atom ortho to the chloromethyl
group). A similar, but a less pronounced trend can be
observed with 3-cyanonitrobenzene 10. Some
irregularities are perhaps associated with moderate
yields of the products. In our opinion, orientation is
not substantially affected by the nature of substituents
Y.
We also attempted reactions with secondary benzyl
chlorides. Unfortunately, the reaction between 2-
chloronitrobenzene
and
1-chloro-1-(4’-
chlorophenyl)ethane was dominated by elimination of
HCl from the latter substrate.
Conclusion
NC
Ar
CN
-Chlorocarbanions generated via deprotonation of
benzyl chloride and a variety of its derivatives add to
nitroarenes at positions ortho and/or para to form
anionic H adducts that undergo base-induced -
elimination of HCl and subsequent protonation to
give substituted o- and p-nitrodiarylmethanes. The
reported method of nucleophilic benzylation is of
general character with respect to substituents in both
aromatic rings and the nature (homo- or heterocyclic)
of the ring of the electrophilic partner. It can be
viewed as a nucleophilic alternative to the classical
Friedel-Crafts benzylation applicable to electron-
deficient aromatic systems.
(i)
Ar
Cl
+
O2N
1b
O2N
10b6 (63%)
10
NO2
NO2
(i)
+
Ar
Cl
N
N
1b
15
Ar
15b6 (50%)
Scheme 5. Selective benzylation in the presence of lithium
base. (i): LiHMDS, HMPA, THF/Toluene, 78 C, 15 min.
Ar = 2,4-dichlorophenyl
Experimental Section
One might expect that the ratio of regioisomers could
be influenced by the reaction conditions, that is
solvent and the nature of base which affect the state
of the ion pairs of the carbanions. Earlier, we
observed a strong preference for substitution ortho to
the nitro group in reactions of carbanions of
PhSO2CH2Cl in t-BuOK/THF system.[15] Indeed, in
the reaction of 10 with 1c carried out in the presence
of KHMDS in DMF/THF, KHMDS in THF and
LiHMDS in THF/HMPA/toluene, the ratios of attack
ortho and para to the NO2 group were 1.1, 0.44 and
0.18, respectively, with the respective total yields of
General synthetic procedure for benzylation of
nitroarenes in the presence of LDA. 2M LDA solution in
THF (2 mmol, 1 mL) and anhydrous THF (1 mL) were
placed in a flame-dried Schlenk flask under Ar and cooled
to 78 C. Then HMPA (4 mmol, 0.73 mL) was added and
a solution of nitroarene (0.5 mmol) and 1a, 1b or 1d (0.6
mmol) in THF (1 mL) was added dropwise with vigorous
magnetic stirring. After 15 min 2M HCl(aq) (2 mL) was
added, followed by AcOEt (5 mL) and brine (5 mL). The
phases were separated, the organic phase was washed with
brine (3x10 mL), dried over anhydrous Na2SO4 and
evaporated. The products were purified by column
chromatography on silica gel using hexanes–AcOEt 10:1
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801715
Advanced Synthesis & Catalysis
or hexanes–AcOEt 5:1, unless specified otherwise in the
[4] a) P. Maity, D. M. Shacklady-McAtee, G. P. A. Yap, E.
R. Sirianni, M. P. Watson, J. Am. Chem. Soc. 2013, 135,
280-285; b) M. Micksch, M. Tenne, T. Strassner,
Organometallics 2014, 33, 3966-3976; c) P. L.
Türtscher, H. J. Davis, R. J. Phipps, Synthesis 2018,
793-802; d) V. Ramakrishna, M. J. Rani, N. D. Reddy,
Eur. J. Org. Chem. 2017, 7238-7255; e) B. R. P. Reddy,
S. Chowdhury, A. Auffrant, C. Gosmini, Adv. Synth.
Catal. 2018, 360, 3026-3029.
descriptions of particular compounds.
General synthetic procedure for benzylation of
nitroarenes the presence KHMDS. 1M KHMDS solution
in THF (1.25 mmol, 1.25 mL) was placed in a flame-dried
Schlenk flask under Ar and cooled to 78 C. A solution of
nitroarene (0.5 mmol) and 1b-f (0.6 mmol) in DMF (1 mL)
was added dropwise with vigorous magnetic stirring. After
15 min (or 30 min; see notes to Scheme 3) 2M HCl(aq) (2
mL) was added, followed by AcOEt (5 mL) and brine (5
mL). The work-up and purification of products as in the
above procedure with LDA.
[5] a) G. R. Newkome, Y. J. Joo, D. W. Ewans, S.
Pappalardo, F. R. Fronczek, J. Org. Chem. 1988, 53,
786-790; b) G. Wu, S. Xu, Y. Deng, C. Wu, X. Zhao,
W. Ji, Y. Zhang, J. Wang, Tetrahedron 2016, 72, 8022-
8030; c) M. Ueda, D. Nakakoji, Y. Kuwahara, K.
Nishimura, I. Ryu, Tetrahedron Lett. 2016, 57, 4142-
4144; d) D. Kong, P. J. Moon, W. Qian, R. J. Lundgren,
Chem. Comm. 2018, 6835-6838; e) P. J. Moon, A.
Fahandej‐ Sadi, W. Qian, R. J. Lundgren, Angew.
Chem. Int. Ed. 2018, 57, 4612-4616; f) M. Szpunar, R.
Loska, Eur. J. Org. Chem. 2015, 2133-2137.
Large scale preparation of 6c2/6c4 was performed
identically, multiplying all quantities by a factor of 10.
General synthetic procedure for benzylation of
nitroarenes in the presence of LiHMDS. 1M LiHMDS
solution in toluene (1.25 mmol, 1.25 mL) was placed in a
flame-dried Schlenk flask under Ar and cooled to 78 C.
Then HMPA (2.5 mmol, 0.44 ml) was added and a solution
of nitroarene (0.5 mmol) and 1b or 1c (0.6 mmol) in THF
(1 mL) was added dropwise with vigorous magnetic
stirring. After 15 min 2M HCl(aq) (2 mL) was added,
followed by AcOEt (5 mL) and brine (5 mL). The work-up
and purification of products as in the above procedure with
LDA.
[6] a) M. Mąkosza, Chem. Soc. Rev. 2010, 39, 2855-2868;
b) M. Mąkosza, Synthesis 2011, 2341-2356; c) M.
Mąkosza, K. Wojciechowski, Chem. Rev. 2004, 104,
2631-2666.
Acknowledgements
[7] a) J. Goliński, M. Mąkosza, Tetrahedron Lett. 1978, 19,
3495-3498; b) M. Mąkosza, J. Winiarski, Acc. Chem.
Res. 1987, 20, 282-289;
This work was supported by the National Science Centre, Poland
(grant UMO-2014/15/B/ST5/02180).
[8] a) K. Błaziak, W. Danikiewicz, M. Mąkosza, J. Am.
Chem. Soc. 2016, 138, 7276-7281; b) M. Mąkosza,
Synthesis 2017, 3247-3254.
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5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801715
Advanced Synthesis & Catalysis
FULL PAPER
Transition Metal Free Nucleophilic Benzylation of
Nitroarenes. Umpolung of the Friedel Crafts
Reaction
Z
1) B-
-HCl
Y
O2N
Cl
Cl
B-
Y
H
+
Z
2) H+
Adv. Synth. Catal. Year, Volume, Page – Page
Z
Y
-O2N
Y = H, 2,4-Cl2, 4-CN,
3-CF3, 3-NO2,
4-CONEt2
NO2
Kacper Kisiel, Jakub Brześkiewicz, Rafał Loska,*
and Mieczysław Mąkosza*
H adduct
+ ortho isomers
32 examples
6
This article is protected by copyright. All rights reserved.