α-Chlorobenzylation of Nitroarenes via Vicarious Nucleophilic Substitution with Benzylidene Dichloride: Umpolung of the Friedel-Crafts Reaction

Article abstract of DOI:10.1021/acs.joc.8b01091

Readily available α,α-dichlorotoluenes enter a vicarious nucleophilic substitution (VNS) reaction with electron-deficient arenes to give α-chlorobenzylated nitrobenzenes, as well as six- and five-membered heterocycles. Oxidation of the initially formed α-chlorobenzylic carbanions instead of protonation results in formation of diaryl ketones, providing a means for overall nucleophilic C-H benzoylation of electron-deficient aromatic rings. Alternatively, benzoylated nitroarenes can be obtained via the reaction of isolated α-chlorodiarylmethanes with sodium azide.

Full text of DOI:10.1021/acs.joc.8b01091

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Article
#-Chlorobenzylation of Nitroarenes via Vicarious Nucleophilic Substitution
with Benzylidene Dichloride. Umpolung of the Friedel-Crafts Reaction
Jakub Brze#kiewicz, Rafa# Loska, and Mieczyslaw Makosza
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01091 • Publication Date (Web): 15 Jun 2018
Downloaded from http://pubs.acs.org on June 15, 2018
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The Journal of Organic Chemistry
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α
-Chlorobenzylation of Nitroarenes via Vicarious Nucleophilic
Substitution with Benzylidene Dichloride. Umpolung of the Friedel-
Crafts Reaction
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Jakub Brześkiewicz, Rafał Loska* and Mieczysław Mąkosza*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01ꢀ224 Warsaw, Poland
Cl
Z
Cl
K
X
X
Cl
O2N
R
R
H+
R
H
+
O
Z
Z
[O]
X
O2N
O2N
X = CH, N
Z = H, F, Cl, Br, I, OMe, CN
ABSTRACT: Readily available α,αꢀdichlorotoluenes enter a vicarious nucleophilic substitution (VNS)
reaction with electronꢀdeficient arenes to give αꢀchlorobenzylated nitrobenzenes, as well as sixꢀ and
fiveꢀmembered heterocycles. Oxidation of the initially formed αꢀchlorobenzylic carbanions instead of
protonation results in formation of diaryl ketones, providing a means of overall nucleophilic C–Hꢀ
benzoylation of electronꢀdeficient aromatic rings. Alternatively, benzoylated nitroarenes can be obtained
via the reaction of isolated αꢀchlorodiarylmethanes with sodium azide.
Keywords: αꢀhalocarbanions, nitroarenes, vicarious nucleophilic substitution, hydrogen substitution,
chloroalkylation, benzoylation
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INTRODUCTION
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Vicarious Nucleophilic Substitution (VNS) is a versatile process for introduction of functionalized
carbon substituents into electronꢀdeficient aromatic rings (particularly nitroarenes), at positions
occupied by hydrogen atoms.1 The reaction proceeds via reversible addition of αꢀhalocarbanions (and
carbanions with other nucleofugal groups X) to nitroarenes and other electronꢀdeficient arenes to form
σH adducts, followed by baseꢀinduced βꢀelimination of HX to form nitrobenzylic carbanions of the
products. The final products are isolated upon protonation. It should be stressed that VNS of hydrogen
in oꢀand pꢀhalonitroarenes proceeds much faster than conventional SNAr substitution, which involves
much slower, but irreversible addition of nucleophiles at positions occupied by halogens. This is in
accord with the recently formulated general mechanism of substitution in electronꢀpoor aromatic
compounds.1cꢀe
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Particularly valuable are VNS reactions of nitroarenes with triꢀ and dihalocarbanions as they lead to
nitrobenzylic halides, potentially useful in further transformations. Treatment of chloroform or
bromoform with an excess of strong base at low temperature in the presence of nitroarenes resulted in
introduction of dihalomethyl groups in positions ortho and/or para to the nitro group.2 Hydrolysis of
these groups provides oꢀ or/and pꢀnitrobenzaldehydes. The VNS with haloforms can be therefore
considered as nucleophilic formylation of carboꢀ and heterocyclic nitroarenes.2 Even more valuable is
VNS with carbanions of alkyl dichloroacetates that produces esters of αꢀchloroꢀαꢀnitroaryl acetic
acids.3 Further reaction of ethyl αꢀchloroꢀαꢀnitroaryl acetates with sodium azide results in substitution
of chlorine with azide anion followed by spontaneous conversion of the azides into ethyl
nitrobenzoylformates. Acidic hydrolysis of tertꢀbutyl αꢀchloroꢀαꢀnitroarylacetates is followed by
instantaneous decarboxylation to form chloromethyl nitroarenes.3c,d VNS in electron deficient arenes
with tꢀbutyl dichloroacetate can therefore be considered as nucleophilic chloromethylation of
nitroarenes. Nitrobenzylic αꢀchlorocarbanions generated in a VNS reaction between nitroarenes and
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carbanions of alkyl dichloroacetates may also undergo oneꢀpot reactions with electrophiles, for example
addition to Michael acceptors with the formation of nitrophenyl cyclopropanes in a one pot process,4 or
to aromatic aldehydes giving oxiranes.5 A VNS reaction of carbanions proceeds also between 2ꢀ
dichloromethylimidazolines and nitroarenes to give αꢀchloronitrobenzylic carbanions, reacting in situ
with aromatic aldehydes with formation of oxiranes.6
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SCHEME 1 The Concept of α-Chlorobenzylation and Benzoylation of Electron-deficient Arenes
in a VNS Reaction with Dichlorotoluene Carbanions
Z
H
Cl
Cl
Cl
K
O
Cl
Z
N
O
+
R
1a- (R = H)
1b- (R = Cl)
1c- (R = OMe)
NO2
R
- HCl
2-17
Cl
Z
O
N
O
R
[O]
H+
O
Cl
Z
Z
O2N
R
O2N
R
Considering high value of αꢀchloronitrobenzylic carbanions as versatile active intermediates, we
were looking for a further extension of the scope of the VNS reaction. In this endeavor, we expected that
benzylidene dichlorides (α,αꢀdichlorotoluenes) 1 would be the proper choice as precursors of
dichlorocarbanions capable of entering VNS (Scheme 1).The VNS reaction between nitroarenes and
α,αꢀdichlorobenzyl carbanions would provide synthetically useful αꢀchlorobenzylated products
(nitrobenzhydryl chlorides). In fact, there is a lack of a general method for preparation of such
compounds with various substitution pattern. The simplest representative of this type of compounds – pꢀ
nitrobenzhydryl chloride – has been synthesized from pꢀnitrobenzophenone via ketone reduction and
OH to Cl exchange.7 Moreover, we envisioned that oxidation of the intermediate chlorobenzyl
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carbanions could provide a method of direct, nucleophilic benzoylation of electronꢀdeficient arenes.
Apart from the classical FriedelꢀCrafts acylation (applicable to electronꢀrich substrates),8 C–H
benzoylation of aromatic rings is currently possible using transitionꢀmetal catalyzed aromatic C–H
activation9 using arylpyruvates,10 aroyl chlorides and aromatic aldehydes11 as crossꢀcoupling partners. A
few reports of nucleophilic benzoylation of C–H positions in nitroarenes have been published. A
moderately efficient method has been reported by Katritzky who used αꢀalkoxyꢀαꢀbenzotriazolylꢀ
substituted carbanions in oxidative substitution of hydrogen, followed by hydrolysis.12 Very recently,
two protocols of oxidative nucleophilic benzoylation of nitrobenzene derivatives have been disclosed,
both employing arylacetic esters as nucleophile precursors.13,14 Another approach has been developed by
Suzuki and coꢀworkers, who achieved benzoylation of nitroarenes by nucleophilic substitution of ring
fluorine with the Breslow intermediates formed from aromatic aldehydes and Nꢀheterocyclic carbenes.15
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It should be mentioned that there is only one published report of VNS with carbanion of a benzyl
chloride derivative – the reaction between pꢀnitrobenzyl chloride and mꢀdinitrobenzene resulted in
introduction of a pꢀnitrobenzyl group into the dinitrobenzene ring.16 A similar reaction of chloromethylꢀ
substituted heterocycles has also been described that provides an efficient method of synthesis of
nitroaryl heteroaryl methanes.17
ꢀ
Similarly to deprotonation of chloroform, leading to a CCl3 carbanion that dissociates rapidly to
dichlorocarbene particularly under PTC conditions,18 but can be trapped by nitroarenes when generated
at low temperature,2 deprotonation of benzylidene dichloride 1a generates phenyl dichloromethyl
carbanion that dissociates rapidly to phenyl chlorocarbene.19 Lithiation of benzylidene dichloride via its
reaction with butyllithium at ꢀ100 °C results in formation of phenyldichloromethyl lithium which is
stable at such temperatures. This metaloorganic compound can be trapped by carbon dioxide or, upon
warming to ꢀ65 °C, it decomposes to phenyldichlorocarbene.20 An opposite process, involving addition
of chloride anion to phenyl chlorocarbene generated by thermolysis of phenyl chlorodiazirine, followed
by addition of the carbanion to an electrophile – acrylonitrile, has also been described.21 It was therefore
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of interest to examine whether α,αꢀdichlorocarbanion generated via deprotonation of readily available
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benzylidene dichloride can enter VNS reactions with nitroarenes.
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RESULTS AND DISCUSSION
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Carbanions of nitrobenzyl chlorides and nitrobenzylidene dichlorides (such as those produced in the
VNS reaction with chloroform) are very unstable entities. Therefore, deprotonation of benzylidene
dichloride 1a and the reaction between 1a- and nitroarenes should be carried out at low temperature.
Treatment of a mixture of 1a and nitrobenzene 2 in DMF/THF at ꢀ78 °C with potassium tertꢀbutoxide
resulted in coloration of the mixture, indicating formation of nitrobenzylic carbanions of the VNS
products. However, the yield of the expected pꢀnitrodiphenyl chloromethane (nitrobenzhydryl chloride)
2a obtained in preliminary experiments were moderate, perhaps due to insufficient basicity of tꢀBuOK.
Under similar conditions but using a stronger base, that is upon addition of a solution of 1a (0.6 mmol)
and nitrobenzene 2 (0.5 mmol) in DMF to a stirred solution of potassium bis(trimethylsilyl)amide
(KHMDS; 2.5 equiv. in THF cooled to ꢀ78 °C, followed by quenching of the mixture with aqueous HCl
after 15 min, the expected product 2a was obtained in much better yield of 61%. Increasing the excess
of base or of 1a with respect to nitroarene did not have any significant effect on the final yield. The
addition of the bulky methinic carbanion 1a- proceeded selectively at position para; the product of ortho
substitution was not detected.
Under these conditions: ꢀ78 °C, 2.5 equiv. of KHMDS, DMF/THF 1:1, 15 min, 1a reacted with
nitroarenes containing a variety of substituents in ortho and meta positions, giving the expected VNS
products 2a - 19a (Scheme 2). With nitrobenzene and its orthoꢀsubstituted derivatives, the reaction
proceeded selectively at position para to the nitro group due to the steric requirements of the bulky
methinic carbanion 1a-. mꢀSubstituted nitroarenes reacted with lower yields and lower ortho/para
selectivity, probably due to steric hindrance associated with addition of 1a- at the position ortho to the
substituent Z. The VNS reaction with carbanion of 1a proceeds also with some nitroheterocycles such as
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nitropyridines or a nitropyrrole derivative, or even azines without an activating nitro group - 1,4ꢀ
dichloropyridazine 18 or 2ꢀchloroquinoxaline 19.
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SCHEME 2 VNS Reaction of Electron-deficient Arenes with Dichlorotoluene Carbanion 1a- a
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2 - 19
1) KHMDS
- HMDS
- KCl
Z
H
Cl
Cl
K
Cl
Cl
Cl
Z
NO2
X = CH, N
KHMDS
Cl
Cl
O
X
N
O
DMF-THF
- 78 °C
X
2) HCl
O2N
1a-
1a
2a - 19a
Cl
Ph
Cl
Ph
2a Z = H (61%)
3a Z = F (75%)
4a Z = Cl (74%)
8a, 8a' Z = F (60%; 2.3:1)b
9a Z = Cl (23%)c
Z
Z
10a, 10a' Z = I (31%; 9.3:1)b
11a Z = OMe (50%)d
12a, 12a' Z = CN (26%; 25:1)b,c
Ph
Ph
5a, 5a' Z = Br (92%; 7.4:1)b
6a Z = OMe (86%)
Z
Z
NO2
NO2 Cl
NO2 Cl
NO2
8a - 12a
7a Z = CN (40%)b,c
2a - 7a
2a' - 7a'
8a' - 12a'
OMe
Cl
Ph
Cl
Ph
Cl
NO2
Cl
NO2
NO2
OMe
NO2
NO2
NO2
Cl
Ph
Ph
Ph
Cl
Ph
N
N
N
N
Cl
N
N
Cl
13a, 13a' (44%; 1:1)b
14a, 14a' (76%; 1:2.2)b
15a (74%)
16a (57%)
Cl
N
Cl
Me
N
Cl
N
N
Ph
O2N
17a (54%)
Ph
N
Ph
CO2Me
Cl
Cl
Cl
18a (66%)d
19a (61%)
a
Reaction conditions: nitroarene (1 equiv.) and 1a (1.2 equiv.) in DMF were added dropwise to KHMDS (2.5 equiv; 1M in THF)
cooled to ꢀ78 °C, stirred for 15 min, then quenched with 2M HCl. b Ratio of isomers resulting from attack at para and ortho position to the
nitro group. c Reaction time: 5 min. d Reaction time: 1 min.
In some cases, under the standard conditions we observed very low yields of the VNS reaction, or the
expected products were not obtained at all, particularly with substrates 7, 9, 11, 12, 3,6ꢀ
dichloropyridazine 18 and 2ꢀchloroquinoxaline 19. It was surprising because these nitroarene are highly
ꢀ
electrophilic and usually react satisfactorily in other VNS reactions, including those with CCl3
carbanions. As all starting materials were consumed in these cases, it appeared that the initially formed
αꢀchloronitrobenzylic carbanions were unstable even at low temperature. In order to verify this
supposition, the reactions of these nitroarenes were carried out in shorter time: 5 min or even 1 min. To
our satisfaction, the expected products could be obtained in acceptable yields and only minor quantities
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of nitroarenes were recovered unchanged. It should be stressed how fast these multistep reactions are
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being completed below ꢀ70 °C (within 1ꢀ5 min).
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Generally, nitroarenes exhibited very low propensity to react with 1a- (or carbanions derived from
other α,αꢀdihalotoluenes, see below) at the position ortho to the nitro group. Moreover, an attempt to
force ortho substitution in a reaction of 1a- with a substrate with blocked para position (pꢀ
chloronitrobenzene) led to recovery of substrate and formation of small amounts of a few products, one
of which was the expected products of VNS. Unfortunately, this compound turned out to be too unstable
for isolation in pure form, unlike ortho isomers obtained in some reactions in Scheme 2 (5a’, 8a’, 10a’).
On the other hand, in the case of some nitropyridines the reaction proceeded with low ortho/para
selectivity or even preferentially at the position vicinal to NO2 (14a, 14a’).
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Noteworthy, 1a- reacts with 2ꢀchloroquinoxaline 19 along the VNS pathway to give 19a. This reaction
takes a completely different course than the reactions of quinoxaline with carbanions of chloromethyl
aryl sulfones described in the literature that lead to annulated bis(aziridine)derivatives of quinoxaline.22
In those reactions, the intermediate anionic σH adducts undergo 1,3ꢀintramolecular substitution rather
than βꢀelimination. Apparently, the chlorine substituent in 19 contributes to negative charge
delocalization, promoting βꢀelimination to an αꢀchlorobenzyl carbanion, instead of nucleophilic
substitution with the negatively charged nitrogen atom of the heterocyclic ring.
ꢀ
Similarly to CCl3 carbanions, α,αꢀdichlorocarbanions formed from 1a may undergo fast dissociation
to phenyl chlorocarbene. The success of the VNS reaction with 1a- relies upon its generation in the
presence of electrophilic nitroarenes, so addition and formation of the σH adducts is faster than αꢀ
ꢀ
elimination. While studying VNS with CCl3 anions, we demonstrated that its fast and reversible
dissociation indeed proceeds in the solvent cage.2a Thus, dichloromethylation of moderately
electrophilic mononitroarenes by trichloromethyl carbanions proceeded satisfactorily at ꢀ70 °C in
THF/DMF but not in liquid ammonia that otherwise is an excellent solvent for VNS reactions with other
αꢀchlorocarbanions.1b,c It appears that dichlorocarbene generated by fast and reversible dissociation of
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ꢀ
CCl3 in the solvent cage is immediately quenched by ammonia solvent, whereas in THF/DMF the
carbanion can be trapped by nitroarene. This supposition was supported by the observation that very
active nitroarenes such as nitroquinolines are entering VNS with chloroform even in liquid ammonia.
On the other hand, we found that the reaction of 1a- in liquid ammonia proceeds efficiently even with
weakly electrophilic 2ꢀnitroanisole (75%). It demonstrates that spontaneous dissociation of 1- is
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ꢀ
considerably slower than that of CCl3 .
4ꢀChlorobenzylidene dichloride 1b, readily prepared from 4ꢀchlorobenzaldehyde,23 satisfactorily
enters the VNS reaction as demonstrated by formation of products 5b, 6b, 8b, 15b and 18b in high
yields (Scheme 3). Regioselectivity was usually higher than in similar reactions of 1a, for example mꢀ
fluoronitrobenzene underwent nearly exclusive attack para to the NO2 group (compare with 2.3:1
mixture of 8a and 8a’ in Scheme 2). In some cases (e.g. reactions of 6 and 8) we observed formation of
considerable amounts of 4ꢀchlorobenzoylꢀsubstituted nitroarenes. Only traces of similar ketones were
formed in the reactions of 1a.
On the other hand, similar reactions of 4ꢀmethoxybenzylidene dichloride 1c led to complex mixtures
containing unreacted nitroarenes and only traces of the expected VNS products. Such reaction course
may be associated with greater instability of 1c- anion. Changing the αꢀhalogen substituents, we found
that α,αꢀdibromotoluene 1d provided αꢀbromobenzylated nitroarenes in slightly lower yields (74% for
5d, 60% for 6d) compared to those observed with 1a under identical conditions (92% for 5a, 96% for
6a; see Scheme 2), probably due to greater steric hindrance and faster dissociation of the C–Br bond in
1d- (Scheme 3). On the other hand, reactions of 1d were more regioselective in favor of the para
substitution. α,αꢀDifluorotoluene failed to undergo deprotonation in the presence of KHMDS and in
consequence only the starting materials were recovered when its reaction with nitrobenzene was
attempted.
SCHEME 3 VNS Reactions of 4-Chlorobenzylidene Dichloride 1b and Benzylidene Dibromide 1d
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Cl
Cl
Z
X
KHMDS
1
Z
Cl
+
DMF-THF
- 78 °C
2
X
Cl
1b (ArCHCl2)
O2N
Cl
NO2
3
4
X = CH, N
5
6
7
Cl
Ar
Cl
Ar
OMe
N
Cl
Cl
F
NO2
N
8
9
Ar
Cl
Ar
N
Z
NO2
NO2
Cl
10
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14
15
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17
18
19
8b (37%)c
18b (75%)d
5b Z = Br (80%)
15b (87%)
6b Z = OMe (74%)b
Br
Z
KHMDS
Br
Ph
+
Z
DMF-THF
- 78 °C
Br
Ph
O2N
NO2
1d
5, 6
5d Z = Br (74%)
6d Z = OMe (60%)
a Reaction conditions: nitroarene (1 equiv.) and 1 (1.2 equiv.) in DMF were added dropwise to KHMDS (2.5 equiv; 1M in THF) cooled
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to ꢀ78 °C, then stirred for 15 min, then quenched with 2M HCl. b 4’ꢀChloroꢀ3ꢀmethoxyꢀ4ꢀnitrobenzophenone (6f) formed as side product in
13% yield. c 4ꢀChloroꢀ2’ꢀfluoroꢀ4’ꢀnitrobenzophenone (8f) formed as side product in 16% yield. d Reaction time: 1 min.
The VNS reactions described above were equally efficient when performed at a 10 times larger scale.
For example, 5 mmol of nitroarene 5 was converted into 5b in 82% yield, and pyridine 15 into 15a in
78% yield.
In some cases products of the VNS reactions of 1a and particularly 1b were accompanied by minor
amounts of nitrobenzophenones, such as 4ꢀnitrobenzophenone 2e in the reaction of nitrobenzene and 1a,
or ketones 6f and 8f in Scheme 3. Their formation can be probably attributed to nitroarene substrates
acting as oxidants, or traces of molecular oxygen present in the reaction mixture. Therefore, we
expected that a oneꢀpot benzoylation of nitroarenes could be achieved if the intermediate αꢀ
chloronitrobenzylic carbanions formed in the VNS process described above were subjected to direct
oxidation rather than protonation. In preliminary experiments, addition of a DMF solution of 1a and 2ꢀ
bromoꢀ or 2ꢀmethoxynitrobenzene to 1M KHMDS in THF at ꢀ78, followed after 15 min by bubbling
dried air (passed through a layer of solid KOH) through the reaction mixture until the characteristic
color of αꢀchlorobenzylic anions has disappeared (about 30 min), resulted in the formation of the
respective 4ꢀbenzoylation products in about 50% yield. After some experimentation, we found that the
reaction gives higher yields and proceeds much faster with oxygen instead of air. Further improvement
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can be obtained using 10 mol% of CuI as an additive. Under these optimized conditions,
nitrobenzophenone derivatives could be obtained in good or sometimes moderate yields, together with
varying amounts of unoxidized VNS products (Scheme 4).
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SCHEME 4 Benzoylation of Nitroarenes in a One-pot Procedure
Cl
Ar
O
Ar
O2
1a or 1b
KHMDS
CuI (10 mol%)
Z
Z
Z
DMF-THF
- 78 °C
-78 °C
NO2
N
O
O
NO2
Ar = Ph
2e, 2e' Z = H (78%; 4.2:1)a
3e Z = 3-F (55%)
5e, 5e' Z = 3-Br (73%; 5:1)a,b
6e Z = 3-OMe (79%)
8e Z = 2-F (36%)
11e Z = 2-OMe (30%)
Ar = 4-ClC6H4
2f, 2f' Z = H (74%; 10:1)a
a Ratio of regioisomers. b Air used instead of oxygen gas.
Unfortunately, the oneꢀpot protocol shown in Scheme 4 proved efficient only for simple nitrobenzene
derivatives, and failed altogether for benzoylation of heterocyclic substrates. Therefore, a twoꢀstep
benzoylation protocol has been established, based upon the reaction of sodium azide with αꢀ
chlorobenzylated products isolated after the VNS reaction. Spontaneous conversion of nitrobenzyl
azides into ketones was observed earlier.3a Nucleophilic substitution of chloride with azide, presumably
followed by a rearrangement to an imine and its hydrolysis, provides diaryl ketones in high (sometimes
quantitative) yields, as demonstrated by the examples in Scheme 5.
SCHEME 5 Transformation of the VNS Products into Diaryl Ketones
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Cl
O
1) NaN3/DMF
2) 2M HCl
Z
Z
1
2
X
X
O2N
R
O2N
R
3
4
5
6
O
O
O
MeO
O2N
Br
Ph
Ar
Ph
N
O2N
O2N
7
8
6e (89%)
5e Ar = Ph (73%)
5f Ar = 4-ClC6H4 (87%)
13e (98%)
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Cl
O
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O
MeO
O2N
15e (80%)
N
Ar
Ph
N
N
Cl
18e Ar = Ph (98%)
18f Ar = 4-ClC6H4 (63%)
Synthetic utility of the αꢀchlorobenzyl carbanions formed in VNS with α,αꢀdichlorotoluenes can be
also demonstrated by the reaction with a Michael acceptor, methyl acrylate, which gives a
diarylcyclopropane derivative in good yield and 4.5:1 ratio of diastereoisomers, after intramolecular
substitution of the remaining chlorine atom (Scheme 6). The configuration of the main diastereoisomer
has been determined to be Z in NOE NMR experiments. This example of the cyclopropane resembles a
similar, but somewhat less general cyclopropanation of enals with carbanions of dinitrobenzyl
chlorides.24
SCHEME 6 Formation of a Cyclopropane Derivative in a Tandem VNS-Michael Addition Process
Cl
1a
KHMDS
MeO
O2N
MeO
Ph
O
N
DMF-THF
- 78 °C
O
6
CO2Me
CO2Me
H
Ph
Cl
Ph
- Cl-
6g (77%;
Z:E 4.5:1)
CO2Me
MeO
MeO
NO2
NO2
CONCLUSIONS
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Carbanions of benzylidene dichloride and its analogues enter VNS reaction with a variety of
nitroarenes, nitroheteroarenes and even some azines to give products of substitution of the ring
hydrogen with αꢀchlorobenzyl substituents. This process, which can be considered a nucleophilic
analogue (umpolung) of the FriedelꢀCrafts reaction, is an efficient way of synthesis of substituted
benzhydryl chlorides – versatile intermediates in further synthetic transformations. The αꢀ
chlorocarbanions generated in the VNS process can be directly oxidized by oxygen to form respective
benzophenones. Alternatively, isolated αꢀchlorobenzyl nitroarenes can be converted into benzophenones
via reaction with sodium azide. The overall process is an example of nucleophilic benzoylation and can
be regarded as an umpolung of the FriedelꢀCrafts acylation.
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EXPERIMENTAL SECTION
General information. All 1H and 13C NMR spectra were recorded at 298 K in CDCl3 solutions with a
1
13
19
1
13
400 MHz (400, 100 and 376 MHz for H, C and F, respectively). The H and C NMR chemical
shifts are given relative to the TMS signal at 0.0 ppm and relative to CFCl3 for 19F spectra. Mass spectra
and HR MS measurements were obtained using a mass spectrometer equipped with an electrospray ion
source and qꢀTOF type mass analyzer (ES), or a magnetic sector mass spectrometer equipped with an
electron impact (EI) ion source and the EBE double focusing geometry mass analyzer. IR spectra were
obtained using a FTꢀIR spectrometer. Melting point temperatures were measured at a heating rate of 5
°C/min. Column chromatography was performed using silica gel 60 (0.040−0.063 mm). Thinꢀlayer
chromatography was performed on precoated silica gel plates and visualized under a UV lamp. Hexanes
for column chromatography were distilled before use. Dry DMF, α,αꢀdichlorotoluene and KHMDS (1M
in THF) were commercial and used as received. 4ꢀChloroꢀ and 4ꢀmethoxybenzylidene dichloride,23 as
well as α,αꢀdibromotoluene25 were obtained from the respective aldehydes following the literature
procedures.
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General synthetic procedure for α-chlorobenzylation. KHMDS solution in THF (1M, 1.25 mmol,
1
2
1.25 mL) was placed in a flameꢀdried Schlenk flask under Ar and cooled to ꢀ78 °C. A solution of
nitroarene (0.5 mmol) and 1a, 1b or 1d (0.6 mmol) in DMF (1.25 mL) was added dropwise with
vigorous magnetic stirring. After 15 min (or 5 min, or 1 min; see notes to Scheme 2 and 3) 2M HCl(aq) (1
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 or hexanes–DCM 5:1
as eluent, unless specified otherwise in the descriptions of particular compounds.
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4ꢀNitroꢀ1’ꢀphenylbenzyl chloride (2a). 76 mg (61%) yield; colorless oil; IR (DCM) νmax 3080, 2855,
1
1606, 1522, 1348, 1111, 837, 750, 701, 600 cmꢀ1; H NMR δ 6.17 (1H, s), 7.38 (5H, m), 7.60 (2H, d,
3
3JHH = 8.6 Hz), 8.19 (2H, d, JHH = 8.8 Hz); 13C NMR δ 62.7, 123.8, 127.7, 128.7, 128.7, 128.9, 139.7,
147.5, 147.9; MS (EI 70 eV, m/z, %) 247 (M+, 12), 212 (100), 165 (59), 153 (18), 77 (20); HR MS (EI+)
calcd for C13H10ClNO2 [M]+ 247.0400, found 247.0400. Elemental analysis calcd for C13H10ClNO2: C,
63.04; H, 4.07; Cl, 14.31; N, 5.66. Found: C, 63.11; H, 4.12; Cl, 14.13; N, 5.66.
3ꢀFluoroꢀ4ꢀnitroꢀ1’ꢀphenylbenzyl chloride (3a). 100 mg (75%) yield; pale yellow oil; IR (DCM) νmax
1
3063, 3033, 2928, 2866, 1613, 1529, 1454, 1428, 1350, 844, 733, 700 cmꢀ1; H NMR δ 6.10 (1H, s),
2
7.37 (7H, m), 8.03 (1H, t, 3J = 8.1 Hz); 13C NMR δ 62.0, 117.8 (d, JCF = 22.5 Hz), 123.7 (d, 3JCF = 4.1
2
Hz), 126.3 (d, 4JCF = 2.4 Hz), 127.6, 129.0, 129.1, 136.6 (m), 139.1, 149.6 (d, JCF = 7.6 Hz), 155.4 (d,
19
3
4
1JCF = 265.8 Hz); F NMR δ ꢀ116.01 (dd, JFH = 11.5 Hz, JHF = 7.5 Hz); MS (EI 70 eV, m/z, %) 265
(M+, 7), 230 (100), 183 (66), 171 (18); HR MS (EI+) calcd for C13H9FClNO2 [M]+ 265.0306, found
265.0311. Elemental analysis calcd for C13H9FClNO2: C, 58.77; H, 3.41; F, 7.15; Cl, 13.34; N, 5.27.
Found: C, 58.70; H, 3.44; F, 7.08; Cl, 13.30; N, 5.23.
3ꢀChloroꢀ4ꢀnitroꢀ1’ꢀphenylbenzyl chloride (4a). 105 mg (74%) yield; pale yellow oil; IR (DCM) νmax
3064, 3033, 2926, 2856, 1582, 1529, 1352, 1050, 840, 707 cmꢀ1; 1H NMR δ 6.09 (1H, s), 7.38 (5H, m),
3
4
4
3
7.45 (1H, dd, JHH = 8.4 Hz, JHH = 2.0 Hz), 7.62 (1H, d, JHH = 1.9 Hz), 7.85 (1H, d, JHH = 8.5 Hz);
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13C NMR δ 62.0, 125.8, 126.9, 127.4, 127.7, 129.0, 129.1, 131.1, 139.2, 146.9, 147.1; HR MS (ES+)
calcd for C13H10Cl2NO2 [M + H]+ 282.0089, found 282.0092. Elemental analysis calcd for
C13H9Cl2NO2: C, 55.34; H, 3.22; N, 4.96; Cl, 25.13. Found: C, 55.44; H, 3.34; N, 4.94; Cl, 24.39.
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3ꢀBromoꢀ4ꢀnitroꢀ1’ꢀphenylbenzyl chloride (5a). Chromatography with hexanes–DCM 2:1 as eluent;
132 mg (81%) yield; pale yellow oil; IR (DCM) νmax 3092, 3063, 3031, 2925, 2866, 1808, 1589, 1530,
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1
3
1351, 1216, 1039, 838, 703 cmꢀ1; H NMR δ 6.09 (1H, s), 7.38 (5H, m), 7.49 (1H, dd, JHH = 8.4 Hz,
4JHH = 1.5 Hz), 7.81 (2H, m); C NMR δ 61.9, 114.8, 125.8, 127.6, 127.7, 128.9, 129.1, 134.2, 139.2,
13
146.8, 149.0; MS (EI 70 eV, m/z, %) 325 (M+, 11), 290 (91), 181 (24), 165 (100), 153 (37), 115 (29);
HR MS (EI+) calcd for C13H9ClBrNO2 [M]+ 324.9505, found 324.9512. Elemental analysis calcd for
C13H9ClBrNO2: C, 47.81; H, 2.78; N, 4.29. Found: C, 48.04; H, 2.86; N, 4.33.
3ꢀBromoꢀ2ꢀnitroꢀ1’ꢀphenylbenzyl chloride (5a’). Chromatography with hexanes–DCM 2:1 as eluent;
1
13
18 mg (11%) yield; pale yellow oil; H NMR δ 6.13 (1H, s), 7.37 (6H, m), 7.63 (2H, m); C NMR δ
57.4, 113.2, 127.4, 128.8, 128.8, 129.0, 131.4, 133.5, 135.0, 138.4, 149.8; HR MS (ES−) calcd for
C13H8ClBrNO2 [MꢀH]ꢀ 323.9427, found 323.9424.
3ꢀMethoxyꢀ4ꢀnitroꢀ1’ꢀphenylbenzyl chloride (6a). 119 mg (86%) yield; pale yellow oil; IR (DCM)
ν
max 3062, 3031, 2945, 2847, 1609, 1520, 1455, 1416, 1353, 1285, 1168, 1094, 1027, 845, 728. cmꢀ1; 1H
NMR δ 3.93 (3H, s), 6.11 (1H, s), 7.03 (1H, dd, JHH = 8.4 Hz, 4JHH = 1.7, Hz), 7.19 (1H, d, JHH = 1.6
Hz), 7.37 (5H, m), 7.80 (1H, d, 3JHH = 8.4 Hz); 13C NMR δ 56.6, 63.0, 113.0, 119.6, 125.9, 127.7, 128.7,
128.9, 138.9, 139.7, 147.6, 153.0; HR MS (ES+) C14H12ClNO3Na [M + Na]+ calcd. 300.0403, found
300.0395.
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3ꢀCyanoꢀ4ꢀnitroꢀ1’ꢀphenylbenzyl chloride (7a). 42 mg (31%) yield; pale yellow oil; IR (DCM) νmax
3111, 3064, 2928, 2868, 2236, 1587, 1534, 1454, 1346, 1219, 844, 721 cmꢀ1; H NMR δ 6.16 (1H, s),
1
7.38 (5H, m), 7.85 (1H, dd, 3JHH = 8.7 Hz, 4JHH = 2.0 Hz), 7.94 (1H, d, 4JHH = 2.0 Hz), 8.30 (1H, d, 3JHH
13
= 8.7 Hz); C NMR δ 61.5, 108.4, 114.7, 125.9, 127.6, 129.3, 132.8, 134.7, 138.5, 147.6, 148.4; HR
MS (ES+) calcd for C14H9ClN2O2Na [M + Na]+ 295.0250, found 295.0244.
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2ꢀFluoroꢀ4ꢀnitroꢀ1’ꢀphenylbenzyl chloride (8a). 56 mg (42%) yield; pale yellow oil; IR (DCM) νmax
1
3087, 3033, 2962, 2871, 1532, 1490, 1453, 1424, 1354, 1236, 1072, 943, 884, 809, 741, 697 cmꢀ1; H
6
7
8
NMR δ 6.42 (1H, s), 7.29ꢀ7.45 (5H, m), 7.80 (dd, 3JHH = 8.5 Hz, 4JHF = 7.5 Hz), 7.92 (dd, 3JHF = 9.7 Hz,
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4
13
3
4JHH = 2.2 Hz), 8.06 (dd, JHH = 8.7 Hz, JHH = 1.8 Hz); C NMR δ 55.9 (d, JCF = 3.7 Hz), 111.5 (d,
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2JCF = 27.1 Hz), 119.6 (d, JCF = 3.7 Hz), 127.4, 128.8, 128.9, 130.2 (d, JCF = 2.9 Hz), 135.7 (d, JCF
=
13.2 Hz), 138.5, 148.4 (d, 3JCF = 8.8 Hz), 158.7 (d, 1JCF = 252.8 Hz); 19F NMR δ ꢀ112.12 (dd, 3JFH = 9.2
Hz, JFH = 7.8 Hz); MS (EI 70 eV, m/z, %) 265 (M+, 7), 230 (100), 183 (57), 171 (15); HR MS (EI+)
4
calcd for C13H9FClNO2 [M]+ 265.0306, found 265.0305. Elemental analysis calcd for C13H9FClNO2: C,
58.77; H, 3.41; F, 7.15; Cl, 13.34; N, 5.27. Found: C, 58.85; H, 3.46; F, 7.11; Cl, 13.35; N, 5.15.
4ꢀFluoroꢀ2ꢀnitroꢀ1’ꢀphenylbenzyl chloride (8a’). 24 mg (18%) yield; pale yellow oil; IR (DCM) νmax
3093, 3061, 1953, 1880, 1809, 1750, 1681, 1536, 1465, 1358, 1256, 952, 838, 806, 738, 698 cmꢀ1; H
1
NMR δ 6.70 (1H, s), 7.28ꢀ7.39 (4H, m), 7.46ꢀ7.53 (3H, m), 7.67 (1H, dm, J = 8.2 Hz); 13C NMR δ 53.4
(d, JCF = 2.9 Hz), 120.1 (d, JCF = 3.7 Hz), 121.3 (d, 2JCF = 22.7 Hz), 124.1 (d, 2JCF = 14.7 Hz), 126.8 (d,
3
1
JCF = 2.2 Hz), 128.1, 128.4, 130.4 (d, JCF = 9.5 Hz), 137.5, 149.6 (d, JCF = 4.4 Hz), 161.3 (d, JCF
=
258.2 Hz); 19F NMR δ ꢀ103.53 (m); MS (EI 70 eV, m/z, %) 230 (45), 213 (82), 183 (100), 199 (47), 105
(45), 77 (43).
2ꢀChloroꢀ4ꢀnitroꢀ1’ꢀphenylbenzyl chloride (9a). 32 mg (23%) yield; pale yellow oil; IR (DCM) νmax
3101, 3033, 2928, 2857, 1588, 1525, 1352, 1117, 894, 736, 696 cmꢀ1; 1H NMR δ 6.56 (1H, s), 7.38 (5H,
3
3
4
4
m), 7.88 (1H, d, JHH = 8.7 Hz), 8.16 (1H, dd, JHH = 8.7 Hz, JHH = 2.3 Hz), 8.26 (1H, d, JHH = 2.3
13
Hz); C NMR δ 59.1, 122.1, 124.9, 127.7, 128.8, 128.9, 130.7, 133.6, 138.3, 145.3, 147.7; MS (EI 70
eV, m/z, %) 281 (M+, 7), 246 (100), 199 (23), 165 (63); HR MS (EI+) calcd for C13H9Cl2NO2 [M]+
281.0010, found 280.9998.
2ꢀIodoꢀ4ꢀnitroꢀ1’ꢀphenylbenzyl chloride (10a). Chromatography with hexanes–Et2O 20:1 as eluent; 52
mg (28%) yield; pale yellow oil; IR (DCM) νmax 3092, 3029, 2925, 2856, 1523, 1347, 1114, 1031, 815,
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3
729, 696 cmꢀ1; 1H NMR δ 6.44 (1H, s), 7.38 (5H, m), 7.79 (1H, d, JHH = 8.7 Hz), 8.23 (1H, dd, JHH
=
1
2
3
4
5
6
7
8
9
3
13
8.7 Hz, 4JHH = 2.3 Hz), 8.69 (1H, d, JHH = 2.3 Hz); C NMR δ 66.1, 98.2, 123.5, 128.0, 128.8, 128.9,
130.2, 134.5, 138.4, 147.3, 149.9; MS (EI 70 eV, m/z, %) 373 (M+, 31), 338 (100), 210 (35), 165 (93),
152 (19); HR MS (EI+) calcd for C13H9ClINO2 [M]+ 372.9367, found 372.9362. Elemental analysis
calcd for C13H9ClINO2: C, 41.80; H, 2.43; N, 3.75. Found: C, 42.01; H, 2.52; N, 3.79.
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2ꢀMethoxyꢀ4ꢀnitroꢀ1’ꢀphenylbenzyl chloride (11a). Chromatography with toluene as eluent; 69 mg
(50%) yield; pale yellow oil; IR (DCM) νmax 3090, 3030, 2942, 2845, 1524, 1412, 1351, 1253, 1092,
1
1029, 802, 740 cmꢀ1; H NMR δ 3.93 (3H, s), 6.54 (1H, s), 7.26ꢀ7.37 (3H, m), 7.40 (2H, m), 7.73 (2H,
3
4
13
m), 7.86 (1H, dd, JHH = 8.5 Hz, JHH = 2.2 Hz); C NMR δ 56.3, 57.0, 105.8, 115.9, 127.6, 128.3,
128.6, 129.5, 136.6, 139.7, 146.5, 148.5, 156.2; MS (EI 70 eV, m/z, %) 277 (M+, 7), 242 (86), 165 (27),
152 (38), 91 (100); HR MS (EI+) calcd for C14H12ClNO3 [M]+ 277.0506, found 277.0513. Elemental
analysis calcd for C14H12ClNO3: C, 60.55; H, 4.36; Cl, 12.77; N, 5.04. Found: C, 60.84; H, 4.48; Cl,
12.69; N, 4.97.
2ꢀCyanoꢀ4ꢀnitroꢀ1’ꢀphenylbenzyl chloride (12a). 35 mg (26%) yield; pale yellow oil; IR (DCM) νmax
3085, 2930, 2233, 1764, 1616, 1532, 1454, 1355, 790, 740, 696 cmꢀ1; 1H NMR δ 6.52 (1H, s), 7.39 (5H,
3
3
4
4
m), 8.01 (1H, d, JHH = 8.7 Hz), 8.45 (1H, dd, JHH = 8.7 Hz, JHH = 2.3 Hz), 8.49 (1H, d, JHH = 2.4
13
Hz); C NMR δ 59.8, 112.8, 115.0, 127.6, 127.9, 128.0, 129.2, 129.3, 130.3, 137.7, 147.2, 150.7; MS
(EI 70 eV, m/z, %) 272 (M+, 17), 237 (100), 190 (68), 178 (18), 163 (19); HR MS (EI+) calcd for
C14H9ClN2O2 [M]+ 272.0353, found 272.0350.
4ꢀ(1’ꢀChlorobenzyl)ꢀ3ꢀnitropyridine (13a). 27 mg (22%) yield; pale yellow oil; IR (DCM) νmax 3460,
3065, 2928, 2866, 1956, 1886, 1699, 1601, 1578, 1525, 1452, 1353, 1185, 1115, 1017, 840, 758, 722,
1
3
697, 601 cmꢀ1; H NMR δ 6.22 (1H, s), 7.35 (3H, m), 7.46 (2H, m), 7.80 (1H, d, JHH = 8.7 Hz), 8.49
3
4
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13
(1H, dd, JHH = 8.7 Hz, JHH = 2.6 Hz), 9.36 (1H, d, JHH = 2.6 Hz); C NMR δ 63.5, 122.3, 127.7,
128.9, 128.9, 132.3, 138.5, 143.3, 144.6, 165.7; MS (EI 70 eV, m/z, %) 248 (M+, 8), 213 (100), 167 (81),
139 (23), 105 (43), 77 (24); HR MS (EI+) calcd for C12H9ClN2O2 [M]+ 248.0353, found 248.0348.
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2ꢀ(1’ꢀChlorobenzyl)ꢀ5ꢀnitropyridine (13a’). 27 mg (22%) yield; pale yellow oil; IR (DCM) νmax 3457,
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3063, 3033, 2868, 1599, 1529, 1453, 1405, 1351, 1210, 1053, 872, 822, 757, 697, 635, 589 cmꢀ1; H
NMR δ 6.95 (1H, s), 7.34 (5H, m), 7.90 (1H, 3JHH = 5.2 Hz), 8.87 (1H, 3JHH = 5.2 Hz), 9.16 (1H, s); 13C
NMR δ 57.3, 124.2, 127.9, 129.0, 129.1, 137.9, 143.6, 144.1, 146.0, 154.0; MS (EI 70 eV, m/z, %) 213
(60), 196 (100), 168 (87), 139 (87), 105 (97), 77 (87). Elemental analysis calcd for C12H9ClN2O2: C,
57.96; H, 3.65; Cl, 14.26; N, 11.27. Found: C, 57.99; H, 3.47; Cl, 14.32; N, 11.12.
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6ꢀ(1’ꢀChlorobenzyl)ꢀ2ꢀchloroꢀ3ꢀnitropyridine (14a) and 4ꢀ(1’ꢀchlorobenzyl)ꢀ2ꢀchloroꢀ3ꢀnitropyridine
(14a’). 108 mg (76%) yield; pale yellow oil; IR (DCM) νmax 3067, 3033, 2887, 1955, 1581, 1452, 1356,
1203, 1058, 852, 698, 604 cmꢀ1; 14a: 1H NMR δ 6.13 (1H, s), 7.36 (3H, m), 7.46 (2H, m), 7.70 (1H, d,
3
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3JHH = 8.3 Hz) 8.22 (1H, d, JHH = 8.3 Hz). C NMR δ 62.8, 121.3, 127.6, 129.0, 129.5, 135.4, 137.9,
142.7, 143.6, 163.7; 14a’: 1H NMR δ 6.13 (1H, s), 7.36 (5H, m), 7.65 (1H, d, 3JHH = 5.2 Hz), 8.53 (1H,
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d, JHH = 5.2 Hz); C NMR δ 56.3, 122.8, 127.5, 129.0, 129.2, 136.7, 142.4, 144.0, 144.3, 150.8; MS
(EI 70 eV, m/z, %) 282 (M+, 11), 247 (100), 201 (68), 166 (42), 139 (27); HR MS (EI+) calcd for
C12H8N2O2Cl2 [M]+ 281.9963, found 281.9966.
2ꢀ(1’ꢀChlorobenzyl)ꢀ4ꢀmethoxyꢀ5ꢀnitropyridine (15a). Chromatography with hexanes–AcOEt 2:1 as
eluent; 103 mg (74%) yield; pale yellow oil; IR (DCM) νmax 3063, 3031, 2949, 2863, 1601, 1522, 1355,
1289, 1019, 846, 740, 699 cmꢀ1; 1H NMR δ 4.04 (3H, s), 6.13 (1H, s), 7.35 (4H, m), 7.44 (2H, m), 8.92
(1H, s); 13C NMR δ 56.8, 63.8, 106.7, 127.7, 128.8, 128.9, 135.5, 138.7, 146.6, 159.8, 165.7; MS (EI 70
eV, m/z, %) 278 (M+, 7), 243 (100), 196 (54), 167 (52), 139 (22); HR MS (EI+) calcd for C13H11ClN2O3
[M]+ 278.0458, found 278.0450.
5ꢀ(1’ꢀChlorobenzyl)ꢀ3ꢀmethoxyꢀ2ꢀnitropyridine (16a). 79 mg (57%) yield; pale yellow oil; IR (DCM)
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νmax 3066, 2947, 1984, 1665, 1540, 1409, 1300, 1112, 1029, 965, 846, 723 cmꢀ1; H NMR δ 3.93 (3H,
s), 6.16 (1H, s), 7.38 (5H, m), 7.58 (1H, d, 4JHH = 1.7 Hz), 8.03 (1H, d, 4JHH = 1.8 Hz); 13C NMR δ 56.7,
60.2, 121.9, 127.6, 129.1, 129.1, 138.0, 138.8, 142.9, 147.7, 147.9; MS (EI 70 eV, m/z, %) 278 (M+, 27),
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243 (100), 202 (58), 167 (54), 127 (49), 77 (43); HR MS (EI+) calcd for C13H11ClN2O3 [M]+ 278.0458,
found 278.0456.
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Methyl 5ꢀ(1’ꢀchlorobenzyl)ꢀ1ꢀmethylꢀ4ꢀnitroꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (17a). 83 mg (54%) yield;
yellow oil; IR (DCM) νmax 3147, 2994, 2954, 1725, 1515, 1373, 1324, 1246, 1139, 1086, 870, 751 cmꢀ1;
1H NMR δ 3.71 (3H, s), 3.85 (3H, s), 7.36 (5H, m), 7.55 (1H, s), 7.69 (1H, d, JHH = 0.6 Hz); 13C NMR δ
35.5, 51.5, 52.0, 113.4, 123.2, 126.4, 128.4, 128.9, 133.6, 135.0, 135.9, 160.3; MS (EI 70 eV, m/z, %)
308 (M+, 24), 273 (87), 227 (52), 168 (100), 105 (71), 77 (56); HR MS (EI+) calcd for C14H13ClN2O4
[M]+ 308.0564, found 308.0568.
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4ꢀ(1’ꢀChlorobenzyl)ꢀ3,6ꢀdichloroꢀ1,2ꢀdiazine (18a). 90 mg (66%) yield; pale yellow oil; IR (DCM)
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νmax 3063, 2959, 2853, 1564, 1453, 1354, 1315, 1137, 1098, 735, 696, 542 cmꢀ1; H NMR δ 6.25 (1H,
13
s), 7.33 (2H, m), 7.39 (3H, m), 7.87 (1H, s); C NMR δ 58.1, 128.0, 128.8, 129.3, 129.6, 136.2, 142.2,
154.2, 156.7; HR MS (ES+) calcd for C11H8N2Cl3 [M + H]+ 272.9753, found 272.9745. Elemental
analysis calcd for C11H7Cl3N2: C, 48.30; H, 2.58; Cl, 38.88; N, 10.24. Found: C, 48.49; H, 2.68; Cl,
38.95; N, 10.10.
2ꢀChloroꢀ3ꢀ(1’ꢀchlorobenzyl)quinoxaline (19a). (61%) yield; pale yellow oil; IR (DCM) νmax 3064,
3032, 1561, 1483, 1453, 1256, 1181, 1121, 1041, 828, 764, 724, 695, 595 cmꢀ1; 1H NMR δ 6.73 (1H, s),
13
7.30ꢀ7.41 (3H, m), 7.63 (2H, m), 7.78 (2H, m), 8.00 (1H, m), 8.18 (1H, m); C NMR δ 59.6, 128.1,
128.6, 128.6, 128.8, 129.4, 130.6, 131.5, 137.5, 140.7, 141.5, 145.4, 151.4; MS (EI 70 eV, m/z, %) 288
(M+, 10), 253 (100), 218 (26), 190 (14), 125 (20), 116 (17), 102 (14), 89 (23); HR MS (EI+) calcd for
C15H10Cl2N2 [M]+ 288.0221, found 288.0220.
3ꢀBromoꢀ4ꢀnitrophenylꢀ(4ꢀchlorophenyl)chloromethane (5b). 144 mg (80%) yield; pale yellow oil that
solidified on standing, mp 43–45 °C; IR (DCM) νmax 3094, 3031, 1906, 1588, 1530, 1491, 1351, 1092,
3
1014, 810, 742 cmꢀ1; 1H NMR δ 6.05 (1H, s), 7.30 (2H, d, JHH = 8.7 Hz), 7.36 (2H, d, 3JHH = 8.5 Hz),
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7.47 (1H, dd, JHH = 8.4 Hz, JHH = 1.9 Hz), 7.77 (1H, d, JHH = 1.9 Hz), 7.82 (1H, d, JHH = 8.5 Hz);
13C NMR δ 61.1, 114.9, 125.9, 127.5, 129.0, 129.3, 134.2, 135.0, 137.7, 146.2, 149.1; MS (EI 70 eV,
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m/z, %) 359 (M+, 7), 326 (100), 280 (22), 243 (7), 199 (43), 163 (37), 152 (26), 139 (44); HR MS (EI+)
calcd for C13H8Cl2BrNO2 [M]+ 358.9115, found 358.9116. Elemental analysis calcd for
C13H8Cl2BrNO2: C, 43.25; H, 2.23; N, 3.88. Found: C, 43.21; H, 2.29; N, 3.88.
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4ꢀChlorophenylꢀ(3ꢀmethoxyꢀ4ꢀnitrophenyl)chloromethane (6b). 115 mg (74%) yield; pale yellow oil;
IR (DCM) νmax 2926, 2852, 1609, 1522, 1492, 1408, 1352, 1281, 1168, 1092, 1027, 846, 820, 752 cmꢀ1;
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1H NMR δ 3.95 (3H, s), 6.07 (1H, s), 7.01 (dd, JHH = 8.4 Hz, JHH = 1.4 Hz), 7.16 (d, JHH = 1.3 Hz),
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7.31 (d, JHH = 8.6 Hz), 7.35 (d, JHH = 8.6 Hz), 7.81 (d, JHH = 8.4 Hz); C NMR δ 56.6, 62.1, 112.9,
119.5, 126.0, 129.1, 129.1, 134.7, 138.3, 139.1, 146.9, 153.1; HR MS (ESꢀ) calcd for C14H10NO3Cl2 [M
ꢀ H]ꢀ 310.0038, found 310.0042.
4’ꢀChloroꢀ3ꢀmethoxyꢀ4ꢀnitrobenzophenone (6f). 20 mg (13%) yield; light yellow crystals; IR (DCM)
ν
max 3087, 2925, 2855, 1665, 1586, 1524, 1487, 1406, 1353, 1287, 1243, 1091, 1028, 983, 856, 747 cmꢀ
1; 1H NMR δ 3.15 (3H, s), 7.32 (1H, dd, 3JHH = 8.2 Hz, 4JHH = 1.5 Hz), 7.50 (3H, m), 7.76 (2H, dm, 3JHH
= 8.5 Hz), 7.87 (1H, d, 3JHH = 8.2 Hz); 13C NMR δ 56.8, 114.4, 121.6, 125.2, 129.0, 131.4, 134.7, 140.0,
141.9, 152.8, 193.5; MS (EI 70 eV, m/z, %) 291 (M+, 19), 244 (11), 180 (26), 139 (100), 119 (26), 111
(41), 75 (25); HR MS (EI+) calcd for C14H10ClNO4 [M]+ 291.0298, found 291.0303. Elemental analysis
calcd for C14H10ClNO4: C 57.65; H, 3.46; N, 4.80; Cl, 12.15. Found: C, 57.50; H, 3.70; N, 4.86; Cl,
12.07.
4ꢀChlorophenylꢀ(2ꢀfluoroꢀ4ꢀnitrophenyl)chloromethane (8b). 56 mg (37%) yield; pale yellow oil; IR
(DCM) νmax 3111, 3087, 2926, 1531, 1490, 1353, 1236, 1093, 1015, 811, 741 cmꢀ1; H NMR δ 6.37
1
(1H, s), 7.34 (4H, s), 7.78 (1H, dd, 3JHH = 8.4 Hz, 4JHF = 7.5 Hz), 7.93 (1H, dd, 3JHF = 9.6 Hz, 4JHH = 2.2
Hz), 8.08 (1H, dd, JHH = 8.6 Hz, 4JHH = 1.3 Hz); 13C NMR δ 55.2, 111.6 (d, 2JCF = 27.0 Hz), 119.7 (d,
3
4JCF = 3.7 Hz), 128.8, 129.1, 130.1 (d, JCF = 3.0 Hz), 134.9, 135.2 (d, 2JCF = 13.1 Hz), 137.1, 148.5 (d,
3
3JCF = 8.2 Hz), 158.6 (d, JCF = 253.3 Hz); F NMR δ ꢀ111.95 (dd, JFH = 9.6 Hz, JFH = 7.5 Hz); MS
(EI 70 eV, m/z, %) 299 (M+, 12), 264 (100), 218 (31), 183 (39); HR MS (EI+) calcd for C13H8FCl2NO2
[M]+ 298.9916, found 298.9922.
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4ꢀChloroꢀ2’ꢀfluoroꢀ4’ꢀnitrobenzophenone (8f). 22 mg (16%) yield; yellow crystals (heptane–DCM),
mp 99–101 °C; IR (DCM) νmax 3107, 2925, 2853, 1673, 1586, 1531, 1417, 1353, 1282, 1227, 1092,
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952, 912, 849, 810, 740, 613 cmꢀ1; H NMR δ 7.49 (2H, dm, JHH = 8.6 Hz), 7.71 (1H, dd, JHH = 8.4
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Hz, 4JHF = 6.6 Hz), 7.76 (2H, m), 8.06 (1H, dd, JHF = 9.0 Hz, 4JHH = 2.0 Hz), 8.17 (1H, dd, JHH = 8.4
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Hz, 4JHH = 2.0 Hz); 13C NMR δ 112.4 (d, 2JCF = 27.1 Hz), 119.6 (d, 3JCF = 3.7 Hz), 129.3, 131.1, 131.3
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(d, JCF = 3.3 Hz), 132.4 (d, JCF = 16.6 Hz), 134.5, 141.1, 150.2 (d, JCF = 8.5 Hz), 159.3 (d, JCF
=
19
256.5 Hz), 190.1; F NMR δ ꢀ107.01 (m); MS (EI 70 eV, m/z, %) 279 (M+, 53), 168 (30), 139 (100),
122 (25), 111 (46); HR MS (EI+) calcd for C13H7NO3FCl [M]+ 279.0098, found 279.0092.
4ꢀChlorophenylꢀ(4ꢀmethoxyꢀ5ꢀnitropyridꢀ2ꢀyl)chloromethane (15b). Chromatography with hexanes–
AcOEt 2:1 as eluent; 136 mg (87%) yield; pale yellow oil; IR (DCM) νmax 3104, 2949, 2863, 1602,
1
1523, 1491, 1354, 1288, 1092, 1017, 846, 791, 758 cmꢀ1; H NMR δ 4.05 (3H, s), 6.09 (1H, s), 7.33
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(3H, m), 7.38 (2H, d, JHH = 8.5 Hz), 8.91 (1H, s); C NMR δ 56.9, 62.9, 106.7, 129.1, 129.1, 134.8,
135.6, 137.3, 146.6, 159.8, 165.1; HR MS (ESꢀ) C13H9Cl2N2O3 [M ꢀ H]ꢀ 310.9990, found 310.9991.
4ꢀChlorophenylꢀ(3,6ꢀdichloroꢀ1,2ꢀpyridazinꢀ4ꢀyl)chloromethane (18b). 115 mg (75%) yield; pale
yellow oil; IR (DCM) νmax 3065, 2961, 1565, 1491, 1350, 1316, 1138, 1092, 1015, 829, 767, 543 cmꢀ1;
1H NMR δ 6.21 (1H, s), 7.27 (2H, dm, 3JHH = 8.6 Hz), 7.37 (2H, dm, 3JHH = 8.6 Hz), 7.87 (1H, d, JHH
=
0.6 Hz); 13C NMR δ 57.4, 128.7, 129.3, 129.6, 134.8, 135.7, 141.7, 154.1, 156.7; MS (EI 70 eV, m/z, %)
306 (M+, 33), 271 (100), 207 (27), 200 (17), 173 (29); HR MS (EI+) calcd for C11H6Cl4N2 [M]+
305.9285, found 305.9284. Elemental analysis calcd for C11H6Cl4N2: C, 42.90; H, 1.96; N, 9.10; Cl,
46.04. Found: C, 43.03; H, 1.75; N, 9.19; Cl, 46.16.
3ꢀBromoꢀ4ꢀnitroꢀ1’ꢀphenylbenzyl bromide (5d). Chromatography with hexanes–DCM 5:1 as eluent;
137 mg (74%) yield; yellow oil; IR (DCM) νmax 3089, 3063, 3030, 1955, 1909, 1804, 1588, 1529, 1351,
1
1196, 1158, 1039, 895, 838, 763, 700, 502 cmꢀ1; H NMR δ 6.20 (1H, s), 7.29ꢀ7.45 (5H, m), 7.53 (1H,
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dd, JHH = 8.5 Hz, JHH = 2.0 Hz), 7.81 (2H, m); C NMR δ 51.9, 114.7, 125.8, 128.3, 128.3, 128.9,
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129.1, 134.9, 139.1, 146.9, 148.9; MS (EI 70 eV, m/z, %) 290 (100), 165 (99), 153 (37), 115 (31).
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3ꢀMethoxyꢀ4ꢀnitroꢀ1’ꢀphenylbenzyl bromide (6d). 97 mg (60%) yield; pale yellow oil; IR (DCM) νmax
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3062, 3028, 2976, 2944, 1608, 1522, 1415, 1353, 1166, 1027, 845, 699 cmꢀ1; H NMR δ 3.93 (3H, s),
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6.24 (1H, s), 7.28ꢀ7.40 (3H, m), 7.42 (2H, m), 7.07 (1H, dd, 3JHH = 8.4 Hz, 4JHH = 1.8 Hz), 7.21 (1H, d,
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4JHH = 1.8 Hz), 7.80 (1H, d, JHH = 8.4 Hz); C NMR δ 53.4, 56.6, 113.9, 120.2, 125.9, 128.3, 128.7,
128.9, 138.9, 139.7, 147.6, 153.0; HR MS (ES+) calcd for C14H12BrNO3Na [M + Na]+ 343.9898, found
343.9895. Elemental analysis calcd for C14H12BrNO3: C, 52.20; H, 3.75; Br, 24.80; N, 4.35. Found: C,
52.24; H, 3.54; Br, 24.63; N, 4.60.
One-pot preparation of nitrobenzophenones. KHMDS solution in THF (1M, 1.25 mmol, 1.25 mL)
was placed in a flameꢀdried Schlenk flask under Ar and cooled to ꢀ78 °C. A solution of nitroarene (0.75
mmol) and 1a or 1b (0.6 mmol) in DMF (1.25 mL) was added dropwise with vigorous magnetic
stirring. After 15 min (or 5 min for preparation of 11e) CuI (0.06 mmol, 11.4 mg) was added and oxygen
(or, in the case of 5e/5e’, air dried by passing through a layer of powdered KOH) was bubbled through
the reaction mixture using a metal needle (0.8 mm in diameter) for 30 min (or 90 min for preparation of
5e/5e’ and 6e). After that period, 2M HCl(aq) (1 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 from 10:1 or hexanes–DCM–Et2O 20:4:1.
4ꢀNitrobenzophenone (2e). 86 mg (63%) yield; yellow crystals (heptane–DCM), mp 131–133 °C; IR
(DCM) νmax 3282, 3101, 3062, 1947, 1650, 1596, 1514, 1358, 1318, 872, 705, 692 cmꢀ1; H NMR δ
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7.52 (2H, t, 3JHH = 7.7 Hz), 7.64 (1H, t, 3JHH = 7.4 Hz), 7.8 (2H, d, 3JHH = 7.1 Hz), 7.92 (2H, d, 3JHH
=
8.8 Hz), 8.33 (2H, d, 3JHH = 8.8 Hz); 13C NMR δ 123.5, 128.7, 130.1, 130.7, 133.4, 136.3, 142.9, 149.8,
194.7; MS (EI 70 eV, m/z, %) 227 (M+, 40), 150 (21), 105 (100), 77 (65); HR MS (EI+) calcd for
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C13H9NO3 [M]+ 227.0582, found 227.0589. Elemental analysis calcd for C13H9NO3: C, 68.72; H, 3.99;
N, 6.16. Found: C, 68.94; H, 3.98; N, 6.12.
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2ꢀNitrobenzophenone (2e’). 20 mg (15%) yield; yellow oil that solidified on standing, mp 92–94 °C;
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IR (DCM) νmax 3064, 2924, 2854, 1675, 1529, 1448, 1348, 1280, 931, 853, 711, 633 cmꢀ1; H NMR δ
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7.45 (2H, t, JHH = 7.7 Hz), 7.50 (1H, d, JHH = 7.5 Hz, JHH = 1.3 Hz), 7.59 (1H, tm, JHH = 7.4 Hz),
7.68 (1H, m), 7.72 ꢀ 7.82 (3H, m), 8.24 (1H, dd, 3JHH = 8.2 Hz, 4JHH = 0.7 Hz); 13C NMR δ 124.5, 128.8,
128.9, 129.2, 130.5, 133.8, 134.1, 136.0, 136.3, 193.4; MS (EI 70 eV, m/z, %) 227 (M+, 14), 152 (27),
134 (69), 105 (100), 77 (66); HR MS (EI+) calcd for C13H9NO3 [M]+ 227.0582, found 227.0571.
Elemental analysis calcd for C13H9NO3: C, 68.72; H, 3.99; N, 6.16. Found: C, 68.84; H, 4.03; N, 6.09.
3ꢀFluoroꢀ4ꢀnitrobenzophenone (3e). 81 mg (55%) yield; pale yellow crystals (heptane–DCM), mp 84–
1
86 °C; IR (KBr) νmax 3112, 3058, 2869, 1817, 1665, 1597, 1526, 1358, 1280, 909, 869, 725 cmꢀ1; H
3
NMR δ 7.54 (2H, t, 3JHH = 7.7 Hz), 7.68 (3H, m), 7.79 (2H, m), 8.15 (1H, dd, JHH = 8.5 Hz, 4JHF = 7.2
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Hz); C NMR δ 119.6 (d, JCF = 22.0 Hz), 125.5 (d, JCF = 4.4 Hz), 126.2 (d, JCF = 2.9 Hz), 128.8,
2
1
19
130.0, 133.7, 135.7, 144.0 (d, JCF = 6.6 Hz), 155.1 (d, JCF = 267.2 Hz), 193.2; F NMR ꢀ116.10 (dd,
4
3JFH = 10.7 Hz, JFH = 7.4 Hz); MS (EI 70 eV, m/z, %) 245 (M+, 46), 168 (12), 122 (20), 105 (100), 94
(18), 77 (53); HR MS (EI+) calcd for C13H8FNO3 [M]+ 245.0488, found 245.0477.
3ꢀBromoꢀ4ꢀnitrobenzophenone (5e). 112 mg (61%) yield; pale yellow oil; IR (DCM) νmax 3087, 3027,
2864, 1664, 1574, 1532, 1447, 1360, 1277, 1038, 957, 853, 716, 672 cmꢀ1; 1H NMR δ 7.53 (2H, t, 3JHH
3
3
= 7.7 Hz), 7.66 (1H, m), 7.78 (2H, m), 7.82 (1H, dd, JHH = 8.3 Hz, 4JHH = 1.7 Hz), 7.90 (1H, d, JHH
=
8.3 Hz), 8.11 (1H, d, 4JHH = 1.6 Hz); 13C NMR δ 114.5, 125.3, 128.8, 129.4, 130.0, 133.7, 135.9, 136.0,
141.7, 151.7, 193.2; MS (EI 70 eV, m/z, %) 305 (M+, 27), 228 (8), 182 (5), 152 (8), 105 (100), 77 (51);
HR MS (EI+) calcd for C13H8BrNO3 [M]+ 304.9688, found 304.9689; Elemental analysis calcd for
C13H8BrNO3: C, 51.01; H, 2.63; Br, 26.10; N, 4.58. Found: C, 51.24; H, 2.53; Br, 26.04; N, 4.55.
3ꢀBromoꢀ2ꢀnitrobenzophenone (5e’). 22 mg (12%) yield; pale yellow oil; IR (DCM) νmax 3068, 2921,
1
2852, 1668, 1539, 1448, 1361, 1276, 955, 716, 649 cmꢀ1; H NMR δ 7.43ꢀ7.52 (4H, m), 7.64 (1H, m),
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7.79 (2H, m), 7.86 (1H, dd, 3JHH = 7.5 Hz, 4JHH = 1.9 Hz); 13C NMR δ 114.9, 128.7, 128.8, 130.1, 131.2,
134.2, 135.0, 135.2, 136.4, 149.8, 191.6; MS (EI 70 eV, m/z, %) 305 (M+, 6), 212 (27), 152 (24), 105
(100), 77 (73); HR MS (EI+) calcd for C13H8BrNO3 [M]+ 304.9688, found 304.9691.
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3ꢀMethoxyꢀ4ꢀnitrobenzophenone (6e). 122 mg (79%) yield; pale yellow crystals (heptane–DCM), mp
91–93 °C; IR (DCM) νmax 3061, 2925, 2853, 1983, 1737, 1663, 1603, 1524, 1406, 1027, 856, 722 cmꢀ1;
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1H NMR δ 4.01 (3H, s), 7.35 (1H, dd, 3JHH = 8.2 Hz, 4JHH = 1.5 Hz), 7.52 (3H, m), 7.65 (1H, tm, 3JHH
=
3
7.5 Hz), 7.80 (2H, m), 7.87 (1H, d, JHH = 8.2 Hz); 13C NMR δ 56.8, 114.5, 121.8, 125.1, 128.6, 130.1,
133.3, 136.4, 142.3, 152.7, 194.7; MS (EI 70 eV, m/z, %) 257 (M+, 63), 227 (5), 210 (6), 180 (21), 119
(18), 105 (100), 77 (60); HR MS (EI+) calcd for C14H11NO4 [M]+ 257.0688, found 257.0680. Elemental
analysis calcd for C14H11NO4 C, 65.37; H, 4.31; N, 5.44. Found: C, 65.10; H, 4.24; N, 5.46.
2ꢀFluoroꢀ4ꢀnitrobenzophenone (8e). 53 mg (36%) yield; pale yellow oil; IR (DCM) νmax 3107, 2925,
2855, 1673, 1531, 1417, 1355, 1284, 1226, 952, 812, 733 cmꢀ1; 1H NMR δ 7.51 (1H, t, 3JHH = 7.7 Hz),
3
3
4
3
7.66 (1H, t, JHH = 7.4 Hz), 7.71 (1H, dd, JHH = 8.3, JHF = 6.6 Hz), 7.82 (1H, d, JHH = 8.2 Hz), 8.05
(1H, dd, 3JHF = 9.0, 4JHH = 2.0 Hz), 8.16 (1H, dd, 3JHH = 8.4, 4JHH = 1.6 Hz); 13C NMR δ 112.3 (d, 2JCF =
3
4
2
27.0 Hz), 119.5 (d, JCF = 4.0 Hz), 128.8, 129.8, 131.3 (d, JCF = 3.6 Hz), 132.9 (d, JCF = 16.4 Hz),
3
1
19
134.4, 136.1, 150.1 (d, JCF = 7.7 Hz), 159.4 (d, JCF = 256.3 Hz), 191.3; F NMR δ ꢀ107.33 (m); MS
(EI 70 eV, m/z, %) 245 (M+, 52), 168 (21), 122 (22), 105 (100), 77 (55); HR MS (EI+) calcd for
C13H8FNO3 [M]+ 245.0488, found 245.0483. Elemental analysis calcd for C13H8FNO3: C, 63.68; H,
3.29; F, 7.75; N, 5.71. Found: C, 63.75; H, 3.44; F, 7.77; N, 5.51.
2ꢀMethoxyꢀ4ꢀnitrobenzophenone (11e). 46 mg (30%) yield; orange crystals (heptane–DCM), mp 131–
1
133 °C; IR (KBr) νmax 3105, 2980, 2944, 1924, 1680, 1593, 1516, 1248, 1016, 936, 801, 714 cmꢀ1; H
NMR δ 3.84 (3H, s), 7.47 (3H, m), 7.60 (1H, t, 3JHH = 7.4 Hz), 7.78 (2H, d, 3JHH = 7.4 Hz), 7.84 (1H, d,
3
4
13
4JHH = 1.9 Hz), 7.93 (1H, dd, JHH = 8.2 Hz, JHH = 2.0 Hz); C NMR δ 56.2, 106.5, 115.8, 128.6,
129.6, 129.7, 133.8, 134.9, 136.5, 150.0, 157.6, 194.4; MS (EI 70 eV, m/z, %) 257 (M+, 59), 240 (19),
180 (62), 166 (23), 134 (32), 105 (100), 77 (83); HR MS (EI+) calcd for C14H11NO4 [M]+ 257.0688,
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found 257.0680. Elemental analysis calcd for C14H11NO4: C, 65.37; H, 4.31; N, 5.44. Found: C, 65.36;
H, 4.27; N, 5.38.
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4ꢀChloroꢀ4’ꢀnitrobenzophenone (2f). 105 mg (67%) yield; light brown crystals (heptane–DCM), mp
98–100 °C; IR (KBr) νmax 3097, 3060, 1668, 1583, 1519, 1400, 1347, 1270, 1087, 1012, 928, 849, 737,
701 cmꢀ1; 1H NMR δ 7.48 (2H, dm, 3JHH = 8.6 Hz), 7.74 (2H, d, 3JHH = 8.6 Hz), 7.89 (2H, d, 3JHH = 8.8
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Hz), 8.32 (2H, d, JHH = 8.8 Hz); C NMR δ 123.6, 129.0, 130.6, 131.4, 134.6, 140.1, 142.5, 149.9,
193.5; MS (EI 70 eV, m/z, %) 261 (M+, 53), 226 (5), 180 (8), 150 (30), 139 (100), 111 (40); HR MS
(EI+) calcd for C13H8NO3Cl [M]+ 261.0193, found 261.0185. Elemental analysis calcd for C13H8ClNO3:
C, 59.67; H, 3.08; N, 5.35; Cl, 13.55. Found: C, 59.64; H, 3.15; N, 5.64; Cl, 13.59.
4ꢀChloroꢀ2’ꢀnitrobenzophenone (2f’). 11 mg (7%) yield; yellow crystalline powder; IR (DCM) νmax
3088, 2923, 2856, 1675, 1586, 1527, 1347, 1286, 1092, 930, 845, 745, 704 cmꢀ1; H NMR δ 7.43 (1H,
1
dm, 3JHH = 8.6 Hz), 7.48 (1H, dd, 3JHH = 7.5 Hz, 4JHH = 1.4 Hz), 7.70 (3H, m), 7.81 (1H, td, JHH = 7.5
3
Hz, 4JHH = 1.2 Hz), 8.25 (1H, dd, 3JHH = 8.2 Hz, 4JHH = 1.1 Hz); 13C NMR δ 124.6, 128.8, 129.2, 130.5,
130.7, 134.3, 134.4, 135.8, 140.4, 145.0, 192.2; MS (EI 70 eV, m/z, %) 261 (M+, 11), 152 (33), 139 (94),
134 (100), 111 (56), 104 (37), 75 (39); HR MS (EI+) calcd for C13H8ClNO3 [M]+ 261.0193, found
261.0198.
Preparation of nitrobenzophenones using sodium azide. αꢀChlorobenzylated arene (0.25 mmol)
was dissolved in DMF (1 mL) and sodium azide (0.5 mmol, 33 mg) was added in one portion. The
reaction mixture was stirred vigorously in open flask at rt. After substrate consumption (TLC control),
which required 30 min (13e, 15e, 18e, 18f), 3h (5e, 5f) or 24h (6e), 2M HCl(aq) (1 mL) was added and
stirring continued for another 30 min. Warning: At large reaction scale, potentially dangerous
amounts of toxic HN3 might be liberated at this point. The mixture was then separated between
AcOEt (5 mL) and brine (5 mL) and neutralized with saturated NaHCO3(aq). The organic phase was
washed with brine (3 x 5 mL), dried over Na2SO4 and concentrated. The products were purified by
column chromatography on silica gel using hexanes–DCM–Et2O 20:4:1 as eluent.
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3ꢀBromoꢀ4’ꢀchloroꢀ4ꢀnitrobenzophenone (5f). 74 mg (87%) yield; light yellow crystals (heptane–
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2
3
DCM), mp 129–131 °C; IR (KBr) νmax 3097, 3064, 3027, 2956, 1669, 1581, 1522, 1362, 1266, 1091,
4
5
6
7
8
9
3
958, 901, 851, 741 cmꢀ1; 1H NMR δ 7.52 (2H, dm, 3JHH = 8.8 Hz), 7.74 (2H, dm, JHH = 8.7 Hz), 7.80
3
4
3
4
13
(1H, dd, JHH = 8.3 Hz, JHH = 1.7 Hz), 7.91 (1H, d, JHH = 8.3 Hz), 8.09 (1H, d, JHH = 1.7 Hz); C
NMR δ 114.7, 125.4, 129.2, 129.2, 131.4, 134.1, 135.9, 140.4, 141.2, 151.8, 192.0; MS (EI 70 eV, m/z,
%) 339 (M+, 24), 304 (2), 258 (2), 228 (8), 198 (3), 139 (100), 111 (44), 75 (45); HR MS (EI+) calcd for
C13H7ClBrNO3 [M]+ 338.9298, found 338.9297; Elemental analysis calcd for C13H7ClBrNO3 C, 45.85;
H, 2.07; N, 4.11. Found: C, 45.62; H, 2.08; N, 4.18.
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2ꢀBenzoylꢀ5ꢀnitropyridine (13e). 56 mg (98%) yield; light yellow crystals (heptane–DCM), mp 83–85
°C; IR (KBr) νmax 3062, 2862, 1983, 1876, 1827, 1674, 1597, 1518, 1446, 1358, 1318, 1273, 1246,
1166, 1016, 932, 854, 724, 697 cmꢀ1; 1H NMR δ 7.50 (2H, t, 3JHH = 7.7 Hz), 7.64 (1H, t, 3JHH = 7.4 Hz),
3
3
3
4
8.06 (1H, d, JHH = 7.2 Hz), 8.19 (1H, d, JHH = 8.6 Hz), 8.65 (1H, dd, JHH = 8.6 Hz, JHH = 2.5 Hz),
4
13
9.49 (1H, d, JHH = 2.4 Hz); C NMR δ 125.0, 128.4, 131.0, 132.3, 133.8, 135.1, 143.9, 145.0, 159.2,
191.6; HR MS (ES+) calcd for C12H8N2O3Na [M + Na]+ 251.0433, found 251.0423; Elemental analysis
calcd for C12H8N2O3 C, 63.16; H, 3.53; N, 12.28. Found: C, 63.22; H, 3.34; N, 12.31.
2ꢀBenzoylꢀ4ꢀmethoxyꢀ5ꢀnitropyridine (15e). 52 mg (80%) yield; light yellow crystals (heptane–DCM),
mp 144–146 °C; IR (KBr) νmax 3093, 3022, 2949, 2864, 1924, 1661, 1594, 1520, 1484, 1393, 1361,
1284, 1148, 1017, 977, 859, 824, 742, 715, 694, 613 cmꢀ1; H NMR δ 4.13 (3H, s), 7.50 (2H, m), 7.63
1
13
(1H, m), 7.77 (1H, s), 8.08 (2H, m), 9.03 (1H, s); C NMR δ 57.2, 109.5, 128.4, 131.1, 133.7, 135.2,
137.5, 145.6, 159.4, 159.7, 191.7; MS (EI 70 eV, m/z, %) 258 (M+, 35), 230 (24), 200 (30), 154 (13),
105 (100), 77 (90); HR MS (EI+) calcd for C13H10N2O4 [M]+ 258.0641, found 258.0638; Elemental
analysis calcd for C13H10N2O4 C, 60.47; H, 3.90; N, 10.85. Found: C, 60.41; H, 4.05; N, 10.68.
4ꢀBenzoylꢀ3,6ꢀdichloroꢀ1,2ꢀdiazine (18e). 62 mg (98%) yield; light yellow crystals (heptaneꢀDCM),
mp >180 °C (decomp.); IR (DCM) νmax 3060, 2925, 2853, 1678, 1595, 1450, 1326, 1258, 1141, 968,
822, 800, 713, 560 cmꢀ1; H NMR δ 7.50 (1H, s), 7.55 (2H, t, JHH = 7.8 Hz), 7.72 (1H, m), 7.77 (2H,
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13
m); C NMR δ 127.7, 129.3, 130.0, 134.0, 135.4, 140.0, 151.7, 156.2, 189.0; MS (EI 70 eV, m/z, %)
252 (M+, 21), 105 (100), 77 (55); HR MS (EI+) calcd for C11H6Cl2N2O [M]+ 251.9857, found 251.9861.
Elemental analysis calcd for C11H6Cl2N2O: C, 52.20; H, 2.39; N, 11.07; Cl, 28.02. Found: C, 52.25; H,
2.52; N, 10.92; Cl, 27.22.
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4ꢀ(4’ꢀChlorobenzoyl)ꢀ3,6ꢀdichloroꢀ1,2ꢀdiazine (18f). 45 mg (63%) yield; colorless crystals (heptane–
DCM), mp 97–98 °C; IR (KBr) νmax 3042, 1919, 1674, 1587, 1401, 1323, 1254, 1142, 1089, 965, 907,
842, 824, 750, 566 cmꢀ1; 1H NMR δ 7.50 (1H, s), 7.52 (2H, m), 7.72 (2H, dm, 3JHH = 8.6 Hz); 13C NMR
δ 127.8, 129.8, 131.2, 132.4, 139.5, 142.4, 151.5, 156.3, 187.9; MS (EI 70 eV, m/z, %) 286 (M+, 24),
139 (100), 111 (43), 75 (28); HR MS (EI+) calcd for C11H5Cl3N2O 285.9467, found 285.9478;
Elemental analysis calcd for C11H5Cl3N2O C, 45.95; H, 1.75; Cl, 36.99; N, 9.74. Found: C, 46.00; H,
1.96; Cl, 37.05; N, 9.67.
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Preparation of cyclopropane 6g. The general synthetic procedure for αꢀchlorobenzylation described
above was followed, but instead of quenching the reaction with 2M HCl(aq), methyl acrylate (1.5 mmol,
129 mg, 135 ꢀL) was added, the cooling bath was removed and the reaction mixture was stirred for
another 1.5h. 2M HCl(aq) (1 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. Column chromatography on silica gel using hexanes–AcOEt 5:1 gave 94 mg (57%) of cisꢀ
6g and 32 mg (20%) of 1:0.4 trans:cis mixture. Cyclopropane cisꢀ6g: bright yellow crystals (heptane–
DCM), mp 91–92 °C; IR (DCM) νmax 3024, 2950, 2850, 1733, 1606, 1519, 1439, 1348, 1242, 1173,
1
3
2
1092, 1023, 843, 757, 700 cmꢀ1; H NMR δ 1.68 (1H, dd, JHH = 8.2 Hz, JHH = 5.0 Hz), 2.17 (1H, dd,
3JHH = 5.8 Hz, 2JHH = 5.1 Hz), 2.62 (1H, dd, 3JHH = 8.2 Hz, 5.9 Hz), 3.56 (3H, s), 3.92 (3H, s), 7.00 (1H,
3
4
4
3
dd, JHH = 8.4 Hz, JHH = 1.7 Hz), 7.04 (1H, d, JHH = 1.6 Hz), 7.26 (5H, m), 7.80 (1H, d, JHH = 8.4
13
Hz); C NMR δ 20.5, 28.9, 39.9, 52.1, 56.5, 114.7, 121.6, 126.0, 127.3, 127.6, 128.8, 138.2, 143.0,
147.8, 153.1, 170.7; HR MS (ES+) calcd for C18H17NO5Na [M + Na]+ 350.1004, found 350.0998;
Elemental analysis calcd for C18H17NO5 C, 66.05; H, 5.23; N, 4.28. Found: C, 65.94; H, 5.22; N, 4.29.
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2
transꢀ6g: H NMR δ 1.63 (1H, dd, JHH = 8.3 Hz, JHH = 5.1 Hz), 2.24 (1H, dd, JHH = 5.9, JHH = 5.3
1
2
3
3
Hz), 2.58 (1H, dd, JHH = 8.3 Hz, 6.1 Hz), 3.48 (3H, s), 3.86 (3H, s), 6.89 (2H, m), 7.31 (5H, m), 7.76
4
5
3
13
(1H, d, JHH = 8.3 Hz); C NMR δ 20.5, 29.3, 39.5, 51.9, 56.4, 113.0, 119.0, 126.0, 127.7, 128.7,
6
7
8
129.6, 138.6, 151.9, 153.1, 170.2.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information available: copies of 1H, 13C and 19F NMR spectra for all new compounds.
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: rafal.loska@icho.edu.pl
*Eꢀmail: mieczyslaw.makosza@icho.edu.pl
ACKNOWLEDGMENT
This work was supported by the National Science Centre, Poland (grant UMOꢀ
2014/15/B/ST5/02180).
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