1,5-O → N Carbamoyl Snieckus-Fries-Type Rearrangement

Article abstract of DOI:10.1021/acs.orglett.8b00782

The reaction of o-lithiated O-aryl N,N-diethylcarbamates with (hetero)aromatic nitriles gives rise to functionalized salicylidene urea derivatives in high yields through a new 1,5-O → N carbamoyl migration. This Snieckus-Fries-type rearrangement nicely complements previously known O → C and O → O related shifts. In addition, when dimethylmalononitrile is used as the electrophilic partner, the carbamoyl shift is preferred over the expected transnitrilation reaction.

Full text of DOI:10.1021/acs.orglett.8b00782

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
1,5‑O → N Carbamoyl Snieckus−Fries-Type Rearrangement
Claudia Feberero, Samuel Suarez-Pantiga, Zaida Cabello, and Roberto Sanz*
́
́
Area de Química Organ
́
ica, Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Pza. Misael Banuelos s/n, 09001
̃
Burgos, Spain
S
* Supporting Information
ABSTRACT: The reaction of o-lithiated O-aryl N,N-diethylcarba-
mates with (hetero)aromatic nitriles gives rise to functionalized
salicylidene urea derivatives in high yields through a new 1,5-O → N
carbamoyl migration. This Snieckus−Fries-type rearrangement
nicely complements previously known O → C and O → O related
shifts. In addition, when dimethylmalononitrile is used as the
electrophilic partner, the carbamoyl shift is preferred over the
expected transnitrilation reaction.
Scheme 1. Rearrangements of Lithiated O-Aryl N,N-
Diethylcarbamates
rom the pioneering work of Gilman and Wittig, the
Fdirected ortho metalation (DoM) reaction has become an
essential tool for organic synthesis in the context of accessing
regioselectively functionalized aromatic compounds.1 In this
field, O-aryl carbamates are one of the most powerful and useful
directed metallating groups (DMG), as very low temperatures
are needed for their lithiation, and in addition, deprotection to
the corresponding phenol derivatives is easily achieved after the
corresponding functionalization.2 The o-lithioaryl N,N-dialkyl-
carbamate intermediates are not stable upon an increase of the
temperature evolving through the anionic version of the Fries
rearrangement, also known as the Snieckus−Fries rearrange-
ment.3 It consists of a O → C 1,3-carbamoyl shift that affords
salicylamide derivatives and has led to the development of a
variety of synthetic applications.4 The ease of this carbamoyl
translocation depends on the substituents both on the nitrogen
atom and on the aromatic ring, but for the most used N,N-
diethylcarbamates it typically takes place when the temperature
is raised from −78 °C to room temperature following the o-
lithiation.5 Through the years, different O → C carbamoyl
transfer reactions have been described, mainly by Snieckus and
co-workers, including the homologous anionic ortho-Fries,6 the
remote anionic Fries,7 the 1,2-Wittig vs 1,5-O → C,8 and the
anionic O → Cα/β-vinyl carbamoyl translocations,9 as well as
the carbamoyl version of the Baker−Venkataraman rearrange-
ment.10 Whereas the anionic N-Fries rearrangement involving
N-carbamoyl N → C translocations are also known,11 much
less developed are the corresponding O → heteroatom
carbamoyl transfer processes, and to the best of our knowledge,
a few examples of 1,5-O → O rearrangements have been
described (Scheme 1).12
In the past few years, we have been interested in the o-
lithiation of O-3-halo and O-3,n-dihalophenyl N,N-diethylcar-
bamates and the study of the reactivity of the corresponding o-
lithiated species.14 In this context, and due to the relevance of
2-hydroxybenzophenones as motifs that are present in different
biologically active compounds,15 we were interested in
preparing 6-halo-2-hydroxybenzophenone derivatives. Toward
this goal, we tested the reaction of organolithium intermediate
2a, easily generated from O-3-fluorophenyl carbamate 1a, with
4-chlorobenzonitrile. After acidic hydrolysis, we obtained
directly 2-hydroxybenzophenone 3a in high yield, instead of
Following our interest in the development of synthetic
methodologies based on the application of DoM reactions,13
herein, we report a new 1,5-O → N carbamoyl migration, a
Snieckus−Fries-type rearrangement, that gives access to new
and interesting urea derivatives from the reaction of o-lithiated
carbamates with nitriles.
Received: March 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00782
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the expected carbamate 3′a (Scheme 2). Considering this
In the same way, benzonitriles bearing electron-donating
groups can also be used as the electrophilic partners (entries
3 and 4). Heteroaromatic nitriles were also tested, and whereas
4-cyanopyridine efficiently afforded urea 4ah (entry 8), when 2-
furonitrile was employed, a competitive acid−base process
likely lowered the yield of 4ai (entry 9). Finally, aliphatic
nitriles, such as cyclopropyl cyanide (entry 10) or allyl cyanide,
were investigated leading to the recovery of starting carbamate,
probably due to a competitive proton abstraction.
unexpected result, we carried out the hydrolysis with aqueous
Scheme 2. Preliminary Results
Having established the variety of nitriles that can be used for
the carbamoyl transfer, we then studied the scope of the
reaction with regard to the aryl carbamate moiety. We treated a
variety of o-lithiated halo- and methoxy-functionalized O-aryl
N,N-diethylcarbamates 1b−j with a selection of aromatic
nitriles as electrophilic reagents. Gratifyingly, we found that
both types of substituents on the aryl moiety of the starting
carbamate are compatible with the rearrangement, as the
expected benzylidine urea derivatives 4 were obtained in all
cases with high yields (Table 2). Interestingly, we found that
Table 2. Reactions of O-Aryl N,N-Diethylcarbamates 1 with
Selected Nitriles
NH4Cl, and surprisingly, the N,N-diethyl urea derivative 4aa
was selectively obtained in good yield. To account for its
formation, we propose that after the initial attack of the o-
lithiated species 2a to the cyano group an intermediate N-
lithiated imine A is generated. This evolves through an
intramolecular 1,5-O → N carbamoyl translocation affording
phenoxide B, which leads to the final urea derivative 4aa upon
hydrolysis (Scheme 2).
Choosing carbamate 1a as a model, we evaluated the scope
of this new 1,5-O → N carbamoyl translocation with regard to
the nitrile moiety. As shown in Table 1, a variety of
(hetero)aromatic nitriles efficiently participate in this process,
giving rise to benzylidene ureas 4 in good to high yields.
Electron-withdrawing groups such as halogens were well
tolerated, regardless of their position (entries 1, 2, 6, and 7).
a
entry
1
R1
temp (°C)
R2
product yield (%)
1
2
3
1b
1b
1c
1d
1d
1e
1e
1f
H
H
−78
−78
−65
−78
−78
−70
−70
−65
−70
−70
−70
−70
−70
−65
4-ClC6H4
4-EtOC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-ClC6H4
2-FC6H4
4ba
4bj
4ca
4da
4dc
4ea
4ek
4fa
4ga
4ha
4hk
4ia
72
71
79
75
80
82
86
81
87
83
85
83
74
79
3-Cl
b
4
b
3-Br
5
3-Br
6
4-Cl
7
4-Cl
8
4-F
4-ClC6H4
4-ClC6H4
4-ClC6H4
2-FC6H4
9
1g
1h
1h
1i
2-Cl
10
11
12
13
14
4-MeO
4-MeO
2-MeO
2-MeO
3,4-Cl2
Table 1. Reaction of Carbamate 1a with Nitriles to
Synthesize Urea Derivatives 4
4-ClC6H4
4-EtOC6H4
4-ClC6H4
1i
4ij
1j
4ja
a
b
Yield of isolated product referred to starting carbamate 1. LDA was
used instead of s-BuLi.
with all the carbamates 1 we could use s-BuLi as the metallating
reagent, except for 3-bromophenyl carbamate 1d in which LDA
was employed, without any other additive by careful control
and adjustment of the reaction temperature. In this way, highly
interesting benzylidene ureas 4 bearing halogen and alkoxy
substituents, apart from the free hydroxyl group, have been
easily and efficiently accessed from simple O-aryl N,N-
diethylcarbamates 1.16
O-Naphth-2-yl carbamates 1k,l also provide facile entry to
diarylmethylene urea derivatives 4ka and 4la (Scheme 3).
However, in order to achieve regioselective lithiations, two
independent routes were followed. The O-naphth-2-yl
carbamate 1k could be regioselectively lithiated at C-3 with
LiTMP,17 as described by Snieckus and co-workers. On the
other hand, to reach C-1 selective lithiation, O-(1-bromo-2-
naphth-2-yl) carbamate 1l was used. In both cases, the desired
a
entry
R
product
yield (%)
1
2
4-ClC6H4
4-FC6H4
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
e
75
90
82
88
88
77
71
85
3
4-MeOC6H4
4-MeSC6H4
Ph
4
5
6
2-BrC6H4
3,5-Cl2C6H3
7
b
8
4-(C5H4N)
c
d
9
2-(C4H3O)
42
10
c-C3H5
a
b
Yield of isolated product referred to starting carbamate 1a. 4-
Cyanopyridine was used. 2-Furonitrile was used. Ca. 40% of starting
carbamate was recovered. Starting carbamate 1a was recovered.
c
d
e
B
DOI: 10.1021/acs.orglett.8b00782
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Selective Synthesis of Ureas 4ka and 4la from O-
Naphth-2-yl N,N-Diethylcarbamates 1k and 1l
Table 3. Reaction of Carbamates 1 with DMMN to
Synthesize Cyano-Functionalized Urea Derivatives 5
a
entry
carbamate
X
product
yield (%)
1
2
3
4
5
1a
H
5a
5b
5c
5d
5e
84
74
75
78
71
1m
1n
1o
1p
4-F
2-F
4-Cl
3-Cl
1,5-O → N carbamoyl migration efficiently took place, leading
to the corresponding (hydroxynaphthalenyl)methylene urea
4ka and 4la in high yields (Scheme 3).
a
Yield of isolated product referred to starting carbamate 1.
On the other hand, Reeves and co-workers had reported the
electrophilic cyanation of aryl Grignard or lithium reagents by
transnitrilation with dimethylmalononitrile (DMMN).18 More
recently, they have also developed the 1,4-difunctionalization of
the corresponding 4-fluoromagnesium or -lithium reagents via a
subsequent SNAr reaction with the isobutyronitrile anion
expelled from the initial transnitrilation (Scheme 4).18b In
atoms, a tertiary cyano group, and a free hydroxyl group on the
salicylidene urea moiety.
To further show the potential usefulness of the benzylidene
urea derivatives 4, we carried out two different in situ
transformations. As initially established in Scheme 2, acidic
hydrolysis of the reaction of o-lithiated carbamates 2 with
selected nitriles afforded o-hydroxybenzophenones 3 in high
yields (Scheme 5). Interestingly, if prior to the hydrolysis the
Scheme 4. Reaction of Aryllithiums with DMMN18 and
Proposal for o-Lithiated O-Arylcarbamates 2
Scheme 5. Further Transformations of Ureas 4
our previous report,14 we described a few examples of the 2,3-
difunctionalization of O-(3-chlorophenyl) carbamates, such as
1j, which led to dicyano-functionalized O-arylcarbamates
derived from a transnitrilation−SNAr reaction, although in
low to moderate yields. At this point, we decided to react a
variety of O-(3-fluorophenyl) carbamates 1a,m−p with
DMMN with the aim of studying which of the two competitive
processes, sequential transnitrilation−SNAr reaction (via a) vs
the 1,5-O → N carbamoyl rearrangement (via b), would be
favored (Scheme 4).
With all of the assayed O-3-fluorophenyl N,N-diethylcarba-
mates 1a,m−p, bearing one or two fluorine atoms or one
fluorine and one chlorine atoms (Table 3), we isolated cyano-
functionalized urea derivatives 5 in high yields, which keep the
original halide substituents in their structures. Interestingly, the
obtained results indicate that the carbamoyl migration (via b in
Scheme 4) is faster than the competitive retro-Thorpe-type
reaction (via a). It is interesting to note that compounds 5 are
highly functionalized substrates bearing one or two halogen
crude lithium phenoxide intermediate is treated with an excess
of organolithium reagents, such as hex-1-ynyllithium or
methyllithium, the new benzo[1,3]oxazin-2-ones 6 are
obtained, bearing a quaternary center at C-4. Their formation
could be understood by a tandem nucleophilic addition of the
organolithium to the CN bond of the benzylidene urea,
followed by the attack of the lithium phenoxide to the carbonyl
group of the urea (Scheme 5).19
In summary, we have reported a new O → N carbamoyl
rearrangement that takes place in the reaction of o-lithiated
carbamates with nitriles. It provides a general regioselective
entry into sterically encumbered and highly functionalized
salicylidene urea derivatives. In addition to aromatic nitriles,
dimethyl malononitrile is also able to participate in this
carbamoyl transfer, avoiding the previously reported retro-
C
DOI: 10.1021/acs.orglett.8b00782
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00782.
Full experimental procedures, characterization data, and
copies of NMR spectra (PDF)
(12) Chauder, B. A.; Kalinin, A. V.; Taylor, N. J.; Snieckus, V. Angew.
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AUTHOR INFORMATION
■
́ ́
(13) (a) Sanz, R.; Castroviejo, M. P.; Fernandez, Y.; Fananas, F. J. J.
̃
Corresponding Author
*E-mail: rsd@ubu.es.
ORCID
Org. Chem. 2005, 70, 6548−6551. (b) Sanz, R.; Castroviejo, M. P.;
Guilarte, V.; Perez, A.; Fananas, F. J. J. Org. Chem. 2007, 72, 5113−
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Biomol. Chem. 2010, 8, 3860−3864. (e) Guilarte, V.; Castroviejo, M.
Samuel Suarez-Pantiga: 0000-0002-4249-7807
́
P.; García-García, P.; Fernan
́
dez-Rodríguez, M. A.; Sanz, R. J. Org.
Roberto Sanz: 0000-0003-2830-0892
Chem. 2011, 76, 3416−3437.
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5519−5528.
Notes
The authors declare no competing financial interest.
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(b) Cascioferro, S.; Raimondi, M. V.; Cusimano, M. G.; Raffa, D.;
Maggio, B.; Daidone, G.; Schillaci, D. Molecules 2015, 20, 21658−
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properties, see: (a) Kaya, I.; Bilici, A. J. Appl. Polym. Sci. 2007, 105,
1356−1365. (b) Al-Obaidi, O. H. J. Appl. Chem. 2012, 1, 352−359.
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ACKNOWLEDGMENTS
We are grateful to the Junta de Castilla y Leon
(BU076U16) and Ministerio de Economia y Competitividad
(MINECO) and FEDER (CTQ2016-48937-C2-1-P) for
■
́
and FEDER
́
́
financial support. S.S.-P. thanks Junta de Castilla y Leon and
FEDER for a postdoctoral contract. C.F. thanks Universidad de
Burgos for a predoctoral contract.
(18) (a) Reeves, J. T.; Malapit, C. A.; Buono, F. G.; Sidhu, K. P.;
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afford either the cyanation product or the difunctionalized one.
(19) It is interesting to note that the cyclization of the phenoxide
onto the urea happens only after nucleophilic attack on the CN
bond and not before, likely due to the (E)-configuration of the CN
bond in benzylidene ureas 4.
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DOI: 10.1021/acs.orglett.8b00782
Org. Lett. XXXX, XXX, XXX−XXX