Metal-free tandem Beckmann-electrophilic aromatic substitution cascade affording diaryl imines, ketones, amines, and quinazolines

Article abstract of DOI:10.1016/j.tetlet.2015.07.095

A cascade reaction sequence involving a Beckmann rearrangement on benzophenone oxime followed by an electrophilic aromatic substitution (EAS) on the intermediate nitrilium ion affords N-phenyl diaryl imines that may then be hydrolyzed to ketones, or reduced to the corresponding amines. Reaction with benzonitrile afforded 2,4-diphenylquinazoline through a Beckmann-Ritter-EAS cascade.

Full text of DOI:10.1016/j.tetlet.2015.07.095

Accepted Manuscript
Metal-Free Tandem Beckmann-Electrophilic Aromatic Substitution Cascade
Affording Diaryl Imines, Ketones, Amines and Quinazolines
Samuel R.S. Sarsah, Marlon R. Lutz Jr., Kailyn Chichi Liu, Daniel P. Becker
PII:
S0040-4039(15)01282-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.07.095
TETL 46585
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 July 2015
29 July 2015
30 July 2015
Please cite this article as: Sarsah, S.R.S., Lutz, M.R. Jr., Liu, K.C., Becker, D.P., Metal-Free Tandem Beckmann-
Electrophilic Aromatic Substitution Cascade Affording Diaryl Imines, Ketones, Amines and Quinazolines,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.07.095
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Metal-Free Tandem Beckmann-Electrophilic
Aromatic Substitution Cascade Affording
Diaryl Imines, Ketones, Amines and
Quinazolines
Leave this area blank for abstract info.
Samuel R.S. Sarsah, Marlon R. Lutz, Jr., Kailyn Chichi Bobb, and Daniel P. Becker*

Metal-Free Tandem Beckmann-Electrophilic
Aromatic Substitution Cascade Affording
Diaryl Imines, Ketones, Amines and
Quinazolines
Samuel R.S. Sarsah‡, Marlon R. Lutz§, Jr., Kailyn Chichi Liu, Daniel P. Becker*
Department of Chemistry, Loyola University Chicago, 1032 West Sheridan Road,
Chicago, IL 60660, dbecke3@luc.edu
‡Current Address: Research & Development, Star Thermoplastic Alloys and Rubbers
Inc., 2121 W 21st St, Broadview, IL 60155, ssarsah@luc.edu
§Current Address: Process Research and Development, Regis Technologies Inc., 8210
Austin Avenue, Morton Grove, IL 60053, mlutz@registech.com
Abstract
A cascade reaction sequence involving a Beckmann rearrangement on benzophenone
oxime followed by an electrophilic aromatic substitution (EAS) on the intermediate
nitrilium ion affords N-phenyl diaryl imines that may then be hydrolyzed to ketones, or
reduced to the corresponding amines. Reaction with benzonitrile afforded 2,4-
diphenylquinazoline through a Beckmann-Ritter-EAS cascade.
Cascade or domino reactions enable the assemblage of complex molecules through a
sequence of reactions where one reaction step prepares a reactive intermediate that is
immediately employed in a subsequent reaction.1 Examples of cascade reactions include
the tandem Aldol-Tishchenko reaction2,3 and the Banert cascade.4 The Beckmann
rearrangement5 is a synthetic workhorse that is still of current theoretical interest
regarding the concerted or stepwise nature of its mechanism.6 As part of our program to
investigate apex-modified derivatives7 of the bowl-shaped supramolecular scaffold
cyclotriveratrylene (CTV),8 we employed the Beckmann rearrangement to afford a ring
expansion via the oxime 19 derived from CTV to afford the corresponding 10-membered
CTV lactam 3, which depending upon the experimental conditions, was also
accompanied by the product of an intramolecular electrophilic addition reaction

affording an unexpected helical pentacycle 4 (Scheme 1).10 We realized that this by-
product must have arisen from a cascade process wherein the intermediate nitrilium ion 2
formed in the Beckmann reaction was intercepted by one of the electron-rich veratrole
rings of the macrocycle in a trans-annular process. We questioned whether this tandem
Beckmann-electrophilic aromatic addition reaction could be generalized to an
intermolecular variant with electrophilic aromatic substitution arising from the Beckmann
intermediate, and were encouraged by similar cascade processes. Schinzer previously
employed nucleophilic allylsilanes to intramolecularly trap the cationic Beckmann
rearrangement intermediate in the preparation of various heterocycles.11-13 Amidines
have been synthesized by trapping the Beckmann iminocarbocation intermediates derived
from oximes by Katritzky14 while Mukaiyama conveniently formed amidines and
enamines by trapping Beckmann carbocation intermediates with amines and resonance-
stabilized carbanion nucleophiles, respectively using trifluoromethanesulfonic anhydride
as the electrophilic initiator,15 but trapping of the cationic Beckmann rearrangement
intermediate by an intermolecular electrophilic aromatic addition has not been previously
reported to our knowledge. We describe herein the intermolecular tandem Beckmann-
electrophilic aromatic substitution cascade utilizing benzophenone oxime and a variety of
aromatic nucleophiles to afford the corresponding imines which could be isolated,
hydrolyzed, or reduced to the corresponding amines.
MeO
OMe
HO
N
SOCl2
CH2Cl2
MeO
MeO
OMe
OMe
OMe
OMe
MeO
MeO
N
MeO
OMe
2
1
H2O
MeO
MeO
OMe
OMe
O
H
N
N
MeO
MeO
OMe
OMe
MeO
OMe
3
OMe
4
MeO

Scheme 1: Intramolecular Tandem Beckman-Electrophilic Aromatic Addition from CTV
Oxime
In the original intramolecular case, the reaction is favored both by the very electron-rich
nature and close proximity (3.4-3.6Å)10 of the dimethoxy ring to the Beckmann nitrilium
intermediate. We therefore initially employed neat conditions and electron rich -
nucleophiles to probe the viability of the intermolecular variation, employing
benzophenone oxime as the Beckmann substrate. Initiating the Beckmann with thionyl
chloride did not afford the tandem product, as it led only to the formation of the simple
Beckmann product, benzanilide, as rapid attack of the chloride anion precluded attack by
the -nucleophile. Thus, an intermediate chloroimine presumably formed which was
hydrolyzed upon workup. Switching to trifluoromethanesulfonic anhydride to initiate the
Beckmann rearrangement15 in the absence of a nucleophilic leaving group allowed time
for the nitrilium ion to react with the -nucleophilic aromatic to give good to excellent
yields of the TB-EAS products (Table 1). In the first case with the -nucleophile
veratrole employed as solvent, a 95% isolated yield of the hydrolyzed ketone 6a was
obtained. We continued to explore the generality of the TB-EAS sequence employing
various electron rich and electron poor -nucleophiles, first under neat conditions,
followed by hydrolyzing the intermediate imine 7 directly to the ketone products (6). We
examined reducing the ratio of -nucleophile to two equivalents relative to benzophenone
oxime in 1,2-dichloroethane at reflux (Table 1). Once validated through isolation of the
ketone, the imines 7 were isolated, and the subsequent imines were reduced to the
corresponding ,N-arylbenzenemethanamines 8, as these molecules as a class are
important in pharmaceuticals16.

Scheme 2: Preparation of diarylketones 6 and amines 8 via imines 7
Table 1. TB-EAS Results with -Nucleophilesa
Ketone 6b
Amine 8
Yield
(%)
Imine 7c
Yield (%)
Entry
Ar
Yield
(% neat/soln)
95/91
-Nuc
a
veratrole
1,4-
3,4-dimethoxyphenyl
2,5-dimethoxyphenyl
58f
51d
b
dimethoxy-
benzene
97/72
56
57d
4-methoxyphenyl (plus
ortho)
2,5-dimethyl phenyl
4-methylphenyl (plus
ortho)
c
d
e
anisole
p-xylene
PhCH3
95/96
95/70
75/93
91f
90
66f
90e
63e
73e
4-chlorophenyl (plus
ortho)
f
PhCl
68/19
56f
45e
4-bromophenyl (plus
ortho)
g
h
PhBr
75/34
0g/0g
60f
39g
59e
PhCN
3-cyanophenyl
…
aBenzophenone oxime in 1,2-dichloroethane was treated with triflic anhydride under
reflux for 16-24h in the presence of 2 equivalents of -nucleophile with the exception for
b
PhCl and PhBr which used 4 eq and 8 eq, respectively. Hydrolytic workup with acid
c
afforded ketones 6; aqueous sodium bicarbonate quench afforded imines 7; dCrude
imines were treated with NaBH4 in MeOH or THF to form amines 8; eReflux with
lithium aluminum hydride in THF/2h followed by Fieser workup afforded amines 8;
g
fThe imine contained traces of ketone after workup; Reaction with benzonitrile gave the

imine even after acidic hydrolytic workup, along with 2,4-diphenylquinazoline (10 in
47% yield).
Encouraged by the success with neat veratrole, but wishing to avoid the inconvenience of
using neat -nucleophiles as solvent, we obtained a 91% yield of ketone 6a employing 2
equivalents of veratrole in 1,2-dichloroethane. In a separate experiment, veratrole
afforded a 58% yield of imine 7a after column chromatography, generally as a mixture of
E and Z isomers, and contaminated in most cases with some ketone 6a. The imines were
difficult to isolate as they suffered hydrolysis during purification, and were best reduced
directly. Direct reduction of the imine 7a after the TB-EAS sequence furnished a 51%
yield of ,N-arylbenzenemethanamine 8a (R=H). Ketone products 6a-g could also be
obtained by acid hydrolysis of the isolated imine, but as expected, the yields were lower
than the direct hydrolysis. Amine products (8a-g) were obtained by direct reduction of
the crude imines from the TB-EAS sequence without isolation. Employing p-
dimethoxybenzene gave a high yield of ketone 6b (97%) after hydrolysis but attempted
isolation of the imine was problematic due to very rapid hydrolysis even with an aqueous
bicarbonate workup. Direct reduction of the imine with sodium borohydride gave amine
8b in 57% yield. Neat anisole provided a 95% yield of ketone 6c (7:1 para:ortho) and
reaction with 2 equivalents of anisole in 1,2-dichloroethane at reflux gave a comparable
high isolated yield of ketone 6c (96%). A mild basic quench enabled isolation of imine
7c in 91% yield. Direct reduction of the imine to ,N-(4-methoxyphenyl)-
benzenemethanamine with sodium borohydride proceeded in 90% yield. The sigma
donor, p-xylene, furnished a 95% isolated yield of diaryl ketone 6d employing p-xylene
as the solvent, although the use of 2 equivalents of p-xylene resulted in a moderately
lower yield (70%). The imine 7d derived from p-xylene was isolated in 90% yield,
whereas reduction of imine 7d gave amine 8d in 63% yield. Performing the TB-EAS
reaction with toluene afforded a more modest yield under neat conditions (75%) but
surprisingly a higher yield (93%) when using 2 equivalents of toluene in 1,2-
dichloroethane. The imine 7e from toluene was isolated in 66% yield, and was reduced
to aryl amine 8e in 73% yield. The TB-EAS reactions with halobenzenes were more
sluggish and gave lower yields. Chlorobenzene and bromobenzene gave ketones 6f and

6g in moderate yields (68% and 75%, respectively), but yields were lower in solution,
despite employing 4 and 8 equivalents of the halobenzene, respectively (19% and 34%),
whereas the 4-chlorophenylimine 7f and 4-bromophenylimine 7g intermediates were
isolated in moderate yields (56% and 60%, respectively). Thus, the bromo and
chlorobenzene nucleophiles were considerably more concentration dependent and
relatively higher temperatures are needed to achieve moderate yields; reaction at 2M
concentration of nucleophile proved to be unsuccessful whereas reaction at 4M produced
low yields and 8M gave the yields shown. The amines 8f and 8g were isolated in 45 and
59% yield, respectively. Utilization of nitrobenzene as the π-nucleophile (not shown)
gave low yields of as-yet unidentified products and was not pursued.
Employing neat benzonitrile as the -nucleophile in the TB-EAS sequence did not give
the expected ketone 6h upon acidic hydrolysis, but rather imine 7h was isolated in 39%
yield, along with a 47% yield of 2,4-diphenylquinazoline 10a (Scheme 3), which arises
from a Ritter type reaction17-18 involving attack of the Beckmann nitrilium ion by
benzonitrile followed by an EAS reaction by the N-phenyl group on the resulting
nitrilium ion 9a/b, comprising a Beckmann-Ritter-EAS cascade sequence. Ritter
iminium ions have been trapped previously by intramolecular EAS to afford
dihydroisoquinolines,19 and Kofanov reported a similar cascade sequence starting with an
N-aryl amide to prepare 2,4-diarylquinazolines.20 The intermediate in this sequence
should be the same cation proposed by Meerwein in his early synthesis of quinazolines
where he treated the corresponding chloroiminium species with aluminum trichloride.21
When we employed benzonitrile in solution (8M in 1,2-dichloroethane) rather than in the
neat reaction, a much improved (88%) yield of 2,4-diphenylquinazoline 10a (R = Ph) was
obtained. On the other hand, employing acetonitrile as the solvent at 75°C afforded 2-
phenyl-4-methylquinazoline 10b (R = CH3) in 37% isolated yield, but acetonitrile as a
solution in 1,2-dichloroethane afforded 10b in only 13% yield). Thus, the Beckmann-
Ritter-EAS cascade affording quinazolines is higher yielding with the aryl nitrile versus
the aliphatic nitrile under the present conditions, but the generality with more substituted
derivatives in both categories remains to be explored.

Scheme 3: Preparation of quinazolines 10a (R = Ph) and 10b (R = CH3)
In summary, the intermolecular TB-EAS reaction commencing with benzophenone
oxime affords N,,-triarylimine derivatives which may be hydrolyzed to unsymmetrical
diarylketones or reduced to ,N-arylbenzenemethanamines. Reaction with benzonitrile
proceeded via a Beckmann-Ritter-EAS cascade sequence to afford 2,4-
diphenylquinazoline (10a) in very good (88%) yield. Current efforts are focused on
expanding the scope of the TB-EAS and Beckmann-Ritter-EAS cascade sequences,
particularly toward the synthesis of more highly substituted quinazolines under metal-free
conditions.
Acknowledgments
Loyola University Chicago is gratefully acknowledged for support of this research and
for a Mulcahy Scholarship for K.C.B under the auspices of LUROP (Loyola
Undergraduate Research Opportunities Program).
Supplementary data
Supplementary data associated with this article can be found in the online version.
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