Experimental and computational study of the 1,5-o → n carbamoyl snieckus-fries-type rearrangement

Article abstract of DOI:10.1021/acs.joc.0c01732

The reactions of o-lithiated O-aryl N,N-diethylcarbamates with different C-N multiple bond electrophiles have been thoroughly studied. A 1,5-O → N carbamoyl shift, a new variation of the anionic Fries-type rearrangement, takes place when nitriles, imines, or alkylcarbodiimides are employed. In these cases, the carbamoyl group plays a dual role as a directing group, building up a variety of functional groups through the 1,5-O → N carbamoyl migration. On the other hand, the use of iso(thio)cyanates and arylcarbodiimides led to non-rearranged o-functionalized Oarylcarbamates. This reactivity was further computationally explored, and the governing factor could be traced back to the relative basicity of the alternative products (migrated vs nonmigrated substrates). This exploration also provided interesting insights about the degree of complexation of the lithium cations onto these substrates. A new access to useful 2-hydroxybenzophenone derivatives has also been developed.

Full text of DOI:10.1021/acs.joc.0c01732

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Article
Experimental and Computational Study of the 1,5-
O#N Carbamoyl Snieckus-Fries-Type Rearrangement
Claudia Feberero, Carlos Sedano, Samuel Suarez-Pantiga, Carlos Silva López, and Roberto Sanz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01732 • Publication Date (Web): 08 Sep 2020
Downloaded from pubs.acs.org on September 8, 2020
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Experimental and Computational Study of the 1,5-
O→N Carbamoyl SnieckusFries-Type Rearrangement
†
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‡
Claudia Feberero, Carlos Sedano, Samuel Suárez-Pantiga, Carlos Silva López, * and Roberto
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Sanz†*
†Área de Química Orgánica, Departamento de Química, Facultad de Ciencias, Universidad de
Burgos, Pza. Misael Bañuelos s/n, 09001-Burgos (Spain)
‡Departamento de Química Orgánica and CITACA (Agri-Food Research and Transfer Cluster),
Universidade de Vigo, 36310-Vigo (Spain)
rsd@ubu.es
carlos.silva@uvigo.es
ABSTRACT:
The reactions of o-lithiated O-aryl N,N-diethylcarbamates with different CN multiple bond
electrophiles have been thoroughly studied. A 1,5-O→N carbamoyl shift, a new variation of the
anionic Fries-type rearrangement, takes place when nitriles, imines or alkylcarbodiimides are
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employed. In these cases, the carbamoyl group plays a dual role as directing group and building up a
variety of functional groups through the 1,5-O→N carbamoyl migration. On the other hand, the use of
iso(thio)cyanates and arylcarbodiimides led to non-rearranged o-functionalized O-arylcarbamates.
This reactivity was further computationally explored, and the governing factor could be traced back to
the relative basicity of the alternative products (migrated vs non-migrated substrates). This exploration
also provided interesting insight about the degree of complexation of the lithium cation onto these
substrates. A new access to useful 2-hydroxybenzophenone derivatives has also been developed.
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INTRODUCTION
The directed ortho-metalation (DoM) reaction is currently considered a useful tool for the synthesis
1
of regioselectively functionalized (hetero)aromatic compounds. The metalation of arenes bearing an
appropriate directing metalation group (DMG) with organolithiums or lithium amides, known as
2
ortho-lithiation, nicely complements the classical electrophilic aromatic substitution, as well as other
3
transition metalbased methodologies mainly related with CH activation reactions, for making
regiospecifically functionalized aromatic rings. Among oxygen-based DMGs employed for the
4
functionalization of phenols, O-aryl carbamates have been recognized arguably as one of the most
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powerful DMGs, and usefully leading to phenol derivatives, with many applications in the synthesis
7
of complex molecules. In addition, the carbamate group could undergo subsequent useful cross-
coupling reactions under transition metal-catalysis.8
On the other hand, the original Fries rearrangement, initially reported for the 1,3-O→C migration
9
of carbonyl groups in aromatic esters in the presence of Lewis acids, was cationic in nature. The
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anionic version of this process, also known as the SnieckusFries rearrangement, was pioneered by
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a
Snieckus in 1983. o-Lithiated O-aryl N,N-dialkylcarbamates are not stable in the face of an increase
of temperature evolving through an O→C 1,3-carbamoyl rearrangement that provides salicylamide
11
derivatives and a variety of useful synthetic transformations. The rate of this anionic ortho-Fries
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(
AoF) rearrangement mainly depends on the presence of additional functional groups on the aromatic
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ring and on the nature of the N-substituents.12 Typically for N,N-diethylcarbamates, upon slow
warming to room temperature from 78 °C, the intermediate lithiated species efficiently undergo the
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carbamoyl shift. Several different O→C carbamoyl transfer reactions have been reported (Scheme
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). Apart from the original 1,3-O→C shift, homologous versions, including the rearrangement of
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benzylic O-carbamates, and remote SnieckusFries rearrangements involving 1,4-O→C and 1,5-
or 1,6-O→C migrations, respectively, have been described and also employed as useful strategies for
the construction of complex molecules.17
In particular, the 1,5-O→C shift of the carbamoyl group to an ortho-enolate is a variant of the well-
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known Baker-Venkataraman rearrangement. In addition, regioselective 1,4- or 1,5-O→C shifts to an
o-alkenyl group have also been reported by Snieckus et al. depending on the substitution of the alkene
moiety.19 Furthermore, hetero-Fries rearrangements 1,3-X→C (X = N, C, S) are also known.20
However, the corresponding O→X (X ≠ C) carbamoyl migrations are much less developed and only
few examples of 1,5-O→O carbamoyl transfer reactions have been previously described.21
In the last years, we have been interested in the use of DoM reactions for the synthesis of
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functionalized heterocyclic compounds. In this field, we have recently reported a new pattern of the
AoF rearrangement consisting on a 1,5-O→N carbamoyl rearrangement that takes place in the
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reactions of o-lithiated O-arylcarbamates with nitriles. Herein, we wish to report a detailed study of
this reaction, both experimental and computational, as well as about the related processes of these
organolithium intermediates with a variety of unsaturated CN based electrophilic reagents.
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Scheme 1. Carbamoyl Rearrangements of Lithiated N,N-Diethylcarbamates
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RESULTS AND DISCUSSION
Reaction of o-lithiated O-aryl carbamates 2 with nitriles. Looking for a suitable method for the
preparation of 6-halo-2-hydroxybenzophenone derivatives, we found that the reaction of o-lithiated O-
arylcarbamates 2, readily generated by o-lithiation of N,N-diethylcarbamates 1, with (hetero)aromatic
nitriles gave rise to salicylidene urea derivatives 3 in high yields after hydrolysis with aqueous NH Cl
4
(
Scheme 2).23 Starting from O-3-fluorophenyl carbamate 1a, a wide variety of (hetero)aromatic
nitriles were shown to participate in this 1,5-O→N carbamoyl translocation, although nitriles bearing
-hydrogens, such as MeCN or c-C H CN, underwent competitive acid-base reaction leading to the
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hydrolysis of 2 and the recovery of the starting carbamate.24 Regarding the scope of the O-aryl
carbamate partner 1, we demonstrated that the rearrangement is quite general as carbamates bearing
no functional group, halogens, or methoxy substituents at different positions efficiently underwent the
translocation. In addition, the O-o-lithioarylcarbamate could also be generated by bromine-lithium
exchange instead of hydrogen abstraction as shown with O-(1-bromo-2-naphthyl) N,N-
diethylcarbamate 1k. Our mechanistic proposal for this new carbamoyl shift is shown in Scheme 2.
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Treatment of organolithium 2 with the nitrile would lead to N-lithiated intermediate I, which evolves
through an intramolecular 1,5-O→N carbamoyl rearrangement giving rise to lithium aryloxide II. The
subsequent hydrolysis releases the final salicylidene urea derivative 3 (Scheme 2).
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Scheme 2. Reactions of o-Lithiated N,N-Diethylcarbamates 2 with Nitriles. Synthesis of
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Salicylidene Urea Derivatives 3 and Mechanistic Proposal
Dimethylmalononitrile (DMMN) and related dinitriles are a particular type of cyano compounds
that have been described by Reeves and co-workers as useful transnitrilation reagents for the
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electrophilic cyanation of aryl Grignard or lithium compounds through a retro-Thorpe reaction. The
same authors have also described a tandem transnitrilation/S Ar reaction, which leads to 1,4-
N
difunctionalization of 4-fluorophenyl magnesium or lithium reagents, due to the generation of
isobutyronitrile anion and electronically activated p-fluorobenzonitrile after the transnitrilaton.
However 3-fluoro or 4-chloroaryl organometallics do not undergo the tandem process and 2-
fluorophenyl Grignard reagent failed to afford either cyanation or difunctionalization (Scheme 3, eq
1
).26
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Thus, we decided to study the reactivity of DMMN with o-lithiated carbamates 2. Surprisignly, we
obtained different products depending on the carbamate substitution pattern. For O-3-chlorophenyl
carbamates bearing an additional halogen substituent, such as 1j,l,m,n, their reaction with DMMN led
to the isolation of compounds 4 bearing two different cyano groups.22f Their formation could be
understood by an initial transnitrilation reaction that led to the carbamate IV through unstable
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intermediate III. Cyano-functionalized IV would undergo a S Ar reaction with the released
N
isobutyronitrile anion, likely favored by the additional electron-withdrawing effect of the second
halogen. Although with low to moderate yields, the overall process implies an interesting 2,3-
difunctionalization of the starting carbamate (Scheme 3, eq 2). Surprisingly, when we tried to extend
this reactivity to O-3-fluorophenyl carbamates 1a,o-r more favoured, a priori, to undergo the
subsequent S Ar reaction we did not obtain the same result. In theses cases DMMN behaves as the
N
(hetero)aromatic nitriles described in Table 1. Thus, the intermediate lithiated imine V, generated by
reaction of the corresponding o-lithiated carbamate 2 with DMMN, evolves through the 1,5-O→N
carbamoyl rearrangement leading to the cyano-functionalized urea derivatives 5 in high yields
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3
(
Scheme 3, eq 3). Moreover, with carbamates 1 that do not possess an halogen at the meta-position,
such as unfunctionalized 1b and p-substituted 1e,h,s,t, the reactions of their o-lithiated anions 2 with
DMMN afforded new enamide derivatives 6 in moderate to good yields after purification. For their
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formation we propose that the corresponding rearranged product 5 is initially generated, which upon
acid hydrolysis in the purification process by silica gel column chromatography leads to unstable
intermediate VI that easily releases CO giving rise to the isolated enamide 6 (Scheme 3, eq 4). The
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structure of 6b was further confirmed by X-ray analysis. These results show that, except for O-3-
chlorophenyl carbamates, the carbamoyl migration is faster than the competitive retro-Thorpe-type
process that release the isobutyronitrile anion leaving behind the cyano group.
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Scheme 3. Different Reactivity of o-Lithiated Carbamates 2 with Dimethylmalononitrile
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(DMMN). Synthesis of 4-6
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At this point, we wondered about the behaviour of other cyano-containing electrophilic reagents.
When we faced selected O-3-fluorophenyl and O-4-chlorophenyl carbamates, 1a and 1e, with
trimethysilyl cyanide (Me SiCN), o-silylated carbamates 7 were obtained in high yields (Scheme 4, eq
3
1
). This result showed that the cyanide behaves as a leaving group instead of being attacked by the
organolithium. This is not unexpected as it had been described the use of alkylsilyl cyanides as
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silylating reagents for accessing C-trimethylsilylated compounds from organometallics including
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organolithiums. In the same way, when the o-lithiated derivatives from the same starting materials
1a,e were treated with trichloroacetonitrile (Cl CCN), the chloro-functionalized carbamates 8 were
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isolated in high yields (Scheme 4, eq 2). In this case, an electrophilic chlorine atom is preferentially
attacked instead of the cyanide in Cl CCN, with the concurrent releasing of weak dichloroacetonitrile
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anion.30 Of course these TMS- or chloro-functionalized compounds could also be obtained by
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treatment of the intermediate organolithiums with TMSCl or “Cl ”-type electrophiles such as C Cl .
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Scheme 4. Reaction of Selected o-Lithiated Carbamates 2 with Me SiCN and Cl CCN
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Reaction of o-lithiated O-aryl carbamates 2 with imines. After having established the reactivity
of o-lithiated O-aryl carbamates 2 with nitriles, leading to the description of a new 1,5-O→N
carbamoyl rearrangement, we focused our attention on imines as electrophilic reagents. The presence
of a C=N functionality in these electrophiles suggests that they could behave in an analogous way as
nitriles undergoing the same type of carbamoyl shift. In a first experiment, unfunctionalized O-phenyl
carbamate 1b was o-lithiated and treated with commercially available N-benzylidene aniline. This
reaction affords, after acid hydrolysis, the phenol derivative 9ba in which the carbamoyl group was
shifted from the oxygen to the nitrogen atom (Table 1, entry 1). To test the scope of this process, a
selection of starting N,N-diethyl carbamates 1, possessing electron-rich as well as electron-
withdrawing groups, were treated with different aldimines that can also be functionalized with
halogens. In all cases the o-functionalized phenol derivatives 9 were obtained in high yields (entries
2
8
2
8). Their structure, further confirmed by X-ray analysis of 9ba, suggests that, after initial attack of
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the organolithium to the imine, the 1,5-O→N carbamoyl migration takes place efficiently. This result
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shows that the O→N migration does not require that the N atom to be bonded to a sp carbon to take
place.
Table 1. Reactions of O-Aryl N,N-Diethylcarbamates 1 with Imines. Synthesis of Derivatives 9
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entry
1
R
H
temp (ºC)
78
Ar1
Ph
Ph
Ph
Ar2
Ph
product yield (%)a
1b
2
3
4
5
6
7
8
1b
1c
1c
1c
1e
1e
1i
9ba
9ca
9cb
9cc
9ea
9ed
9ia
79
85
87
81
81
83
84
76
3-Cl
3-Cl
3-Cl
4-Cl
4-Cl
2-MeO
65
Ph
65
4-BrC H
6
4
65
4-MeC H
6
4
4-BrC H
6
4
70
Ph
Ph
70
4-MeC H 3-Cl-5-FC H
6 4 6 3
70
Ph
Ph
Ph
Ph
1q 3-F-4-Cl
65
9qa
a
b
Isolated yield of product based on starting material 1. Reaction time = 30 min.
Reaction of o-lithiated O-aryl carbamates 2 with iso(thio)cyanates. At this point we wondered
if other electrophilic reagents bearing the C=N fragment as reactive moiety would also undergo the
,5-O→N carbamoyl shift. In addition, if the rearrangement takes place an additional regiochemical
1
issue would arise as two heteroatoms (N,O and N,S) are present in the electrophile. We anticipated
that N would likely be the preferred nucleophilic center attending to the corresponding resonance
structures (computed charges obtained in preliminary calculations for these anions also assigned more
2
negative charge to the N than the O/S atoms). First, a variety of isocyanates (R N=C=O), including
aromatic ones and p-toluenesulfonyl isocyanate, were allowed to react with organolithium 2e, easily
generated by o-lithiation of carbamate 1e (Table 2, entries 16). In these cases, the O-(2-
carbamoylaryl) carbamates 10 were selectively obtained in high yields. Their structures show that no
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2
8
carbamoyl migration has taken place, as it was confirmed by X-ray crystallography of 10eb. In an
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
analogous way, a selection of o-lithiated carbamates 2 were treated with different isothiocyanates
2
(R N=C=S) as electrophilic counterparts (Table 2, entries 718). Again, the structure of the thioamide
derivatives obtained 11 reveal that no rearrangement of the N,N-diethylcarbamoyl group has occurred.
To confirm this, X-ray analysis of 11eb and 11ha was carried out.28 Apart from aromatic
isothiocyanates, an alkyl derivative like i-propylisothiocyanate could be used as electrophile giving
rise to the thioamide 11ef in high yield (entry 14). Thus, the reaction o-lithiated O-aryl carbamates 2
with both isocyanates and isothiocyanates afford the expected amide 10 and thioamide derivative 11,
respectively, with no carbamoyl transfer between the phenolic oxygen and any of the heteroatoms
from the electrophile. According to our preliminary simulations the isocyanate product was expected
to rearrange from a thermodynamic point of view. To discard that the migration did not occur only
due to kinetic issues we tried several experiments at higher temperature, but we never observed
migration. This apparent contradiction triggered a detailed computational work on the reaction
mechanism (see below).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2. Reactions of O-Aryl N,N-Diethylcarbamates 1 with Iso(thio)cyanates. Synthesis of
(thio)amide derivatives 10 and 11
R1
R2
product yield (%)a
entry
1
temp (ºC)
70
X
O
O
O
O
O
O
S
1
2
3
4
5
6
7b
1e
1e
1e
1e
1e
1e
1b
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
Ph
10ea
10eb
10ec
10ed
10ee
10ef
11ba
82
79
76
82
81
86
86
70
3-ClC H
6
4
70
3-BrC H
6 4
70
4-MeOC H
6
4
70
4-n-BuC H
6
4
70
SO p-Tol
2
78
Ph
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8
9
1
1
1
1
1c
1e
1e
1e
1e
1e
1e
1h
1i
3-Cl
4-Cl
65
70
70
70
70
70
70
70
70
78
65
S
S
S
S
S
S
S
S
S
S
S
2-FC H
11cb
11ea
11eb
11ec
11ed
11ee
11ef
11ha
11ia
11ka
11la
83
86
80
84
79
80
90
85
84
81
77
6
4
1
2
3
4
5
6
7
8
9
Ph
0
1
2
3
4-Cl
2-FC H
6
4
4-Cl
3-ClC H
6 4
4-Cl
4-BrC H
6 4
4-Cl
3,4-(MeO) C H
2 6 3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
14
4-Cl
i-Pr
Ph
1
5
4-MeO
2-MeO
16
Ph
1
7c
1k 3,4(CH)4
Ph
1
8
1l 3-Cl-4-FC H
Ph
6
3
a
b
c
Isolated yield of product based on starting carbamate 1. Reaction time = 30 min. O-(1-
bromo-2-naphthyl) N,N-diethylcarbamate 1k was used as starting material and the
corresponding intermediate o-lithiated carbamate 2k was generated by bromine-
lithium exchange with n-BuLi for 30 min.
Reactivity model via computational simulations. Once armed with a plethora of experimental
results we set out to rationalize the observations and, if possible, provide a model that could anticipate
the migratory behaviour of these substrates. Initially, two possible scenarios can be proposed for the
governing effects on the migratory ability of the o-lithiated N,N-diethyl O-arylcarbamates 2 upon
nucleophilic attack to the series of electrophiles explored experimentally: 1- some intermediates
rearrange and some do not because of kinetic control, or 2- the eventual migration depends only on the
relative stability of the anions involved in the process, hence thermodynamic control is operating. As a
corollary, the first scenario would involve a competition between the nucleophilic character of both
anions whereas the second cause would rely on their basicity. In order to provide in our simulations
with a chemical representation of the system as accurate as possible, while still maintaining
computational efficiency, we decided to keep structural truncations to the reacting substrates to a
minimum. Hence for the reaction with nitriles we employed benzonitrile, N-benzylideneaniline was
used to simulate the reaction with imines, and phenylisocyanate and phenylisothiocyanate were used
to simulate the reactions of substrates featuring the corresponding functional groups. The reaction
counterpart used was always N,N-dimethyl O-phenylcarbamate. This essentially means that the only
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truncation applied to the reaction with respect to the experimentally probed substrates is the
shortening of the ethyl to methyl groups at the amide fragment. This should have minimum impact on
the reaction profiles but restricts to some degree the conformational space of the already rather
flexible coupled product. The lithium counterion was taken into account explicitly and solvation
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(THF) was modelled implicitly via a continuum solvation model. A detailed description of the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
methodology can be found in the Supporting Information.
According to these simulations the benzonitrile and imine derived adducts (R, in Figure 1) have a
strong driving force toward migration (the final rearranged product P lie at 33 and 21 kcal mol1
with respect to the initial adduct R, which is compatible with the observed behaviour). However,
when considering the isocyanate and isothiocyanate derivatives some unexpected trends were
obtained. Our results, if we consider the thermodynamics of the reaction, indicate that the
isothiocyanate derivative should not migrate (as it is observed in the experiment), but the isocyanate
derivative shows a migrated product, P, which is 3.9 kcal mol1 more stable than the starting
compound R. This latter result suggests that isocyanate derivatives would migrate, but they never do
in our experiments. An extensive conformational search for a more stable isomer resulted in ca. 9
structures, none of which resulted more stable than the rearranged product. It seemed therefore clear
that the thermodynamic balance of this last reaction was such that did not fit with the observations.
Intriguingly, and despite being in contradiction with our experimental observations, these results do
bear some chemical logic since the pKa of these species in DMSO are: 23 for the amide, 17 for the
thioamide and 18 for the phenol. Hence, from this perspective, it can be expected that the phenolate is
released through nucleophilic attack by the amidate anion but not by the thioamidate one (it is worth
noting however that this pKa values are not measured in THF, and due to the last two substrates being
rather close in basicity, a solvent change could reverse the relative order). To address this
contradictory result, we explored the possibility of kinetic control governing the output of these
reactions. Our hypothesis being that perhaps this migration is not observed due to high barriers
hampering the reaction, despite the potential thermal stability of the rearranged product. We therefore
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computed the full profiles for the migration of these four types of substrates: nitrile, imide, isocyanate
and isothiocyanate. The results are summarized in Figure 1.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 1. a) Reaction scheme for the proposed 1,5-O→N carbamoyl rearrangement mechanism
starting from the migration adducts and considering the chair-like conformations of transition states

1
and intermediates. b) Relative Gibbs free energies (in kcal mol ) for the structures involved in the
migration illustrated on top. Solid lines represent conformational relations since both NEt equatorial
2
and axial intermediates are considered, only the lowest energy transition states are shown. Other
conformers explored for transition state structures and intermediates can be found in the SI
We are hereby only showing the lowest energy transition states and intermediates. These systems
have significant conformational freedom, and for instance, different transition states can be located in
which the NEt fragment of the carbamate is poised in pseudo-axial of pseudo-equatorial orientations.
2
Additionally, for some reacting systems, the adduct features alternative nucleophilic sites and in these
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Page 14 of 60
cases all the alternatives were explored as a benchmark to our calculations (i.e. to verify that in all
cases a non-observed reaction product is simulated as a non-competitive path in our simulations). An
illustrative example can be found in Figure 2 where the initial rearrangement for the isocyanate adduct
can be initiated via nucleophilic attack by the N or O site in two possible chair-like structures. These
and other alternative conformations for all the substrates included in this work along with energy data
can be found in the SI.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2. Isomeric possibilities for the rearrangement of the isocyanate complex including N and O
attacks onto the carbamoyl group. Initial transition state alternatives TSR-int (top), second transition
1
state alternatives TSint-P (bottom), activation free energies (in kcal mol ) relative to the initial adduct
R are reported with each structure.
It is interesting to note that, in all cases, the rate-limiting transition state is the nucleophilic attack,
and the subsequent release of the phenolate is almost barrierless, even in the case of the endergonic
reaction found for the isothiocyanate substrate. Actually, the four reactions feature a second barrier
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The Journal of Organic Chemistry

1
that is approximately only 1 kcal mol above the six-member ring intermediate. All the rate-limiting
barriers are surmountable at room temperature, and the results obtained for the kinetics of these
reactions therefore do not justify the unobserved rearrangement of the isocyanate derivative.
We therefore decided to look back into the chemical model used for these simulations. Due to the
minimal amount of simplifications that we applied when building our simulation model, there was not
much that could be added to it to make it more realistic. We considered including explicit solvent, but
this is a rather brute force approach for such an apparently simple governing effect (relative pKa
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
values are rather accurately computed with continuum solvent models). For this reason we focused
on what could have been added “in excess” to our model. In this regard we noticed that perhaps the
+
counterion effect was being overestimated since Li can be quite efficiently solvated in THF and may
not be chelating the substrate. In such a case this counterion effect would be screened by the
surrounding solvent. This scenario is actually quite appropriate for a continuum dielectric model.32
We therefore removed the explicit lithium cation and let the PCM model to mirror the negative charge
of the reacting molecule. After this minor modification to our model, we repeated the thermodynamic
simulations. Gratifyingly the four systems provided energetics according to the experimental
observations. The migrated products formed with benzonitrile and N-benzylideneaniline are more
1
stable than the non-migrated precursor by 36.1 and 15.1 kcal mol , respectively. On the contrary,

1
both iso(thio)cyanate derivatives feature endergonic migration steps (3.7 and 6.3 kcal mol ).
Actually, in these cases we also computed the possible, although unexpected, migrations due to an

1
initial S/O nucleophilic attack (with relative energies of 12.6 and 17.8 kcal mol for the isocyanate
and isothiocyanate derivatives, respectively). It does seem, therefore, that the governing factor of these
reactions is the relative basicity of the involved anions in the migrated vs. non migrated products.
Interestingly the fact that these latter results fit better with our observations provide some evidence
suggesting that the lithium cation under experimental conditions is only loosely bound to the organic
substrate, or perhaps even completely dissociated and stabilized by solvation with THF.
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Finally, we explored other potential candidates for which this migration could provide interesting
molecular scaffolds. Some substrates that, on paper or on preliminary simulations, seemed promising
did not furnish the desired product, mostly because they were excessively reactive and unstable, like
unsaturated nitrocompounds and allenoates. However, one derivative that also caught our attention
was the carbodiimide fragment. Initial exploratory work through computational simulations suggested
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
that aliphatic carbodiimides were good candidates to suffer nucleophillic attack by the o-lithiated
carbamate and undergo subsequent migration (the migrated product being ca. 16 kcal mol1 more
stable when using dimethyl carbodiimide). Surprisingly, when aromatic carbodiimides were
considered, most of the driving force for the migration vanished, and the reaction was anticipated to
be not far from equilibrium (the energy difference between migrated and non-migrated product lie

1
within only 2 kcal mol when diphenyl carbodiimide was simulated), so a question remained on what
would happen to this last kind of substrates under laboratory conditions. Another promising candidate
that was found during this exploratory work in the space of functional groups was N-sulfonylimines.
Our simulations yielded interesting results when compared with those obtained above for the imine
functional group. Unlike N-aryl imines, N-sulfonyl imines presented an energy balance that strongly
1
suggested non-migratory abilities: the non-migrated substrate was computed to be 3.5 kcal mol more
stable than the migrated alternative. The latter functional groups, carbodiimides (in their aliphatic and
aromatic form) and N-sulfonyl imines, can therefore serve as a litmus test for our calculations if these
reactions can be run in the laboratory.
Reaction of o-lithiated O-aryl carbamates 2 with carbodiimides. Inspired by the preliminary
computational results with carbodiimides we proceeded to study the behavior of selected o-lithiated
O-aryl carbamates 2 with this type of C=N based electrophilic reagents (Table 3). Carbodiimides have
been previously reported to react with organolithium reagents, however the focus was on the structure
3
3
of the amidinate complexes formed after treatment with different metallic salts. Initially, when we
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treated
the
o-lithiated
carbamates
1a,b
with
di(c)alkylcarbodiimides,
such
as
1
2
3
4
5
6
7
8
9
dicyclohexylcarbodiimide and di-i-propylcarbodiimide, o-hydroxy-N,N´-di(c)alkylbenzimidamide
derivatives 12 were selectively obtained (entries 1 and 2). Their structure, further confirmed with X-
ray analysis of 12bb,28 demonstrates that the carbamoyl transfer from O→N has occurred.
Gratifyingly, in excellent agreement with the predictions posed through our computational results, the
reaction of 2b with di-p-tolylcarbodiimide afforded the O-2-(N,N´-ditolylcarbamimidoyl)phenyl
carbamate 13bc instead of the corresponding derivative 12 (entry 3). This behavior in which the
success of the 1,5-O→N carbamoyl rearrangement seems to depend on the aryl or (c)alkyl nature of
the N-substituents of the carbodiimide was reproduced with different substituted starting carbamates 1
and the selected (c)alkyl or arylcarbodiimides. Thus, phenol derivatives 12 were obtained for
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(c)alkylcarbodiimides (entries 4,5,79) whereas non-rearranged carbamate 13ec was isolated when
using di-p-tolylcarbodiimide (entry 6). Its structure was again further confirmed by X-ray analysis.28
Table 3. Reactios of O-Aryl N,N-Diethylcarbamates 1 with Carbodiimides. Synthesis of
Derivatives 12 and 13
yield (%)a
temp
entry 1
R1
R2
product
(ºC)
1
2
13
1
1a 3-F
65
78
78
65
70
70
70
70
70
c-C H
aa
bb
bc
cb
ea
ec
79
88
–
–
6
11
2b 1b
3b 1b
H
H
i-Pr
–
p-Tol
i-Pr
81
–
4
5
6
7
8
9
1c 3-Cl
1e 4-Cl
1e 4-Cl
1h 4-MeO
1i 2-MeO
1u 2-Me
83
78
–
c-C H
–
6
11
p-Tol
88
–
i-Pr
i-Pr
i-Pr
hb
ib
76
78
77
–
ub
–
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a
b
Isolated yields referred to the starting carbamate 1. Reaction
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
time = 30 min.
These results show that amidinates having a higher degree of delocalization due to the presence of
aryl substituents favour the formation of carbamates 13, in which no rearrangement has taken place.
As predicted by our simulations and taking into account these findings, stabilized C=N electrophiles,
such as N-sulfonyl imines are expected to have no migratory abilities. This behaviour would contrast
with the results shown in Table 2 regarding reactions of o-lithiated O-aryl N,N-diethylcarbamates 2
with imines. To check this, N-benzylidene p-toluenesulfonamide was also explored as electrophile by
reaction with 2e, derived from O-4-chlorophenyl carbamate 1e. As anticipated, no carbamoyl
migration occurred and carbamate 14, whose structure was confirmed by X-ray analysis,28 was
obtained in high yields (Scheme 5).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
This latter result, together with the experiments performed on carbodiimides, strongly suggest that
the dissociated model eventually employed in our simulations is correct and it provides us with rather
powerful predictive power based on a simple energy balance between the migrated and non-migrated
substrates.
Scheme 5. Reaction of o-Lithiated Carbamate 2e with a N-sulfonyl Imine
Further transformations. Finally, we decided to prove the usefulness of benzylidene urea
derivatives 3 that were easily obtained from the reaction of o-lithiated carbamates 2 with
(
hetero)aromatic nitriles (see Scheme 1). We focused our attention in the development of procedures
that avoid the isolation of compounds 3 in pure form (Table 4). First, when a selection of crude ureas
3
were treated with NaBH the corresponding o-(-amidobenzyl)phenol derivatives 15 were obtained
4
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in good overall yields (entries 13). In addition, if the acid hydrolysis is carried out with mineral acid
1
2
(
HCl) instead of softer aqueous NH Cl, the lithium phenoxide intermediate [3]-Li is directly
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
transformed into o-hydroxybenzophenones 16 (entries 411). Due to the interest of these structural
motifs, which are included in several biologically active compounds and serve as useful synthetic
intermediates for the preparation of O-heterocycles like benzofurans, benzoxazoles, or coumarines,34
we synthesized a variety of these o-hydroxybenzophenone derivatives 16 further functionalized with
halogens, alkoxy or thioether groups in high overall yields. Interestingly, few general methods are
available for synthesizing 6-halo-2-hydroxybenzophenones such as 16aa and 16ad (entries 4 and 5).35
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Moreover, 2-hydroxybenzophenones bearing an o-fluorine substituent at the other aromatic ring, such
as 16ek, are easily transformed into xanthones under soft basic conditions.36
Having efficiently accessed to benzophenones 16, we also took advantage from the known
favorable effect of 2-hydroxyphenyl groups for ketimine formation of benzophenone derivatives,37
and applied it to the preparation of 2-(imino)benzyl phenol and 2-(-alkylamino)benzyl phenol
derivatives 17 (entries 12 and 13) and 18 (entries 14 and 15), respectively.
Table 4. Synthetic Applications of Urea Derivatives 3
entry carbamate
R
Ar
product yield (%)a
1
2
3
4
5
6
7
1a
1a
1g
1a
1a
1e
1e
3-F
3-F
2-Cl
3-F
3-F
4-Cl
4-Cl
4-ClC H
15aa
15af
15gk
16aa
16ad
16ej
77
76
80
85
83
88
83
6
4
2-BrC H
6
4
2-FC H
6
4
4-ClC H
6
4
4-MeSC H
6
4
4-EtOC H
6
4
2-FC H
16ek
6
4
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8
9
1
1f
1h
1i
4-F
4-ClC H
16fa
16ha
16ia
16ja
17ha
17ia
18ha
18ia
80
81
81
84
91
90
85
88
6
4
4
4
4
4
4
4
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4-MeO 4-ClC H
6
0
2-MeO 4-ClC H
6
11
1j
1h
1i
2-Cl
4-ClC H
6
1
2
4-MeO 4-ClC H
6
13
2-MeO 4-ClC H
6
1
4
1h
1i
4-MeO 4-ClC H
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
15
2-MeO 4-ClC H
6
aIsolated yields of products 15 and 16 referred to the starting
carbamate 1. Isolated yields of products 17 and 18 referred to
o-hydroxyketones 16.
CONCLUSIONS
In summary, we have reported a new type of the carbamoyl SnieckusFries rearrangement in
which the carbamoyl group migrates from oxygen to nitrogen (1,5-O→N). This type of reactivity is
observed in the reactions of o-lithioaryl N,N-diethylcarbamates with nitriles, imines, and
alkylcarbodiimides, whereas the corresponding electrophilic trappings with iso(thio)cyanates and
aromatic carbodiimides give rise to the non-rearranged o-functionalized O-arylcarbamates.
Particularly, dimethylmalononitrile, which has been described as an electrophilic cyano source,
presents different reactivity patterns depending on the carbamate moiety. A computational model is
provided that reveals how the relative basicity of the competing products is the governing factor in
this chemistry. Additionally, interesting implications on the non-direct participation of lithium in these
reactions have been derived from simulations with explicit and implicit counterion effects. It is also
worthy to note that the reactions of o-lithiated carbamates with nitriles led to new and interesting
salicylidene urea derivatives that have been further transformed into different highly functionalized
phenol derivatives, including the useful structural motifs 2-hydroxybenzophenones.
EXPERIMENTAL SECTION
General Methods. All reactions involving air sensitive compounds were carried out under a N2
atmosphere (99.99%). All glassware was oven-dried (120 °C), evacuated and purged with nitrogen.
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All common reagents and solvents were obtained from commercial suppliers and used without any
further purification. Solvents were dried by standard methods. Hexane and ethyl acetate were
purchased as extra pure grade reagents and used as received. TLC was performed on aluminum-
backed plates coated with silica gel 60 with F254 indicator; the chromatograms were visualized under
1
2
3
4
5
6
7
8
9
ultraviolet light and/or by staining with a Ce/Mo reagent and subsequent heating. R values are
f
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reported on silica gel. Flash column chromatography was carried out on silica gel 60, 230-240 mesh.
1
13
1
13
H and C NMR spectra were recorded on a Varian Mercury-Plus (300 MHz H; 75.4 MHz C) or
1
13
Bruker Avance (300 MHz H; 75.4 MHz C) spectrometers at room temperature. NMR splitting
pattern abbreviations are: s, singlet; bs, broad singlet; d, doublet; t, triplet; q, quartet; dd, doublet of
doublets; m, multiplet. Chemical shifts are reported in ppm using residual solvent peak as reference
1
13
1
13
(
CDCl : H δ = 7.26 ppm; C δ = 77.16 ppm; DMSO-d : H  = 2.50 ppm; C  = 39.50 ppm) and
3
6
1
3
the multiplicities of C signals were determined by DEPT experiments. High resolution mass spectra
(HRMS) were obtained on a Micromass Autospec spectrometer using EI at 70 eV or on an Agilent
6
545 Q-TOF mass spectrometer using electrospray ionization (ESI). Melting points were measured on
a Gallenkamp apparatus using open capillary tubes and are uncorrected. GC-MS and low-resolution
mass spectra (LRMS) measurements were recorded on an Agilent 6890N/5973 Network GC System,
equipped with a HP-5MS column. Single crystal X-ray diffraction analysis data collection was done
on a Bruker D8 Venture Dual source configuration diffractometer from Bruker using Photon III
detector or alternatively on a Bruker APEX-II CCD detector from Bruker. Microfocus IµS Cu/Mo X-
ray sources were used.
General Procedure for the Synthesis of O-Aryl-N,N-Diethylcarbamates 1. To a 50 mL flask,
NaOH (2 g, 50 mmol) was added to a solution of the corresponding phenol (20 mmol) in THF (10
mL) and the mixture was stirred at rt for 10 min. Then, diethylcarbamoyl chloride (2.54 mL, 20
mmol) was added, and the resulting mixture was stirred at rt for 24 h. H O (5 mL) was added to the
2
reaction mixture and most of the solvent was removed under reduced pressure. More water was added,
and the aqueous layer was extracted with Et O (3  20 mL), the combined organic layers were dried
2
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over anhydrous Na SO , and concentrated under reduced pressure. The obtained crude products 1
2
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
were used without further purification. Characterization and spectral data for 1a, 1c-f, 1h-r have been
previously reported in our previous works.22a,f,23 1g,u have been reported by Snieckus and co-
7f
38
workers. Finally, 1b,s,t have also been previously reported.
General Procedure for the Synthesis of Urea Derivatives 3. A solution of the corresponding
carbamate 1 (1 mmol, 1 equiv) in THF (2 mL) at –78 ºC under nitrogen, was treated with a solution of
s-BuLi (1.1 to 1.3 equiv, 1.4 M solution in cyclohexane) or LDA (1.1 equiv for 1d) or n-BuLi (1.1
equiv for 1k). The reaction mixture was allowed to reach to temp for 5 min, and stirred at this
temperature for 90 min (30 min for 1b,d,k) [temp = 78 ºC for 1b,d; temp = 70 ºC for 1e-i; temp =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0

65 ºC for 1a,c,j]. Then, the corresponding nitrile is added (same equivalents as the employed base)
and allowed to stir at temp for 60 min. The reaction mixture was allowed to warm to rt and stirred for
16 h. The resulting solution was quenched with saturated aqueous NH Cl. The aqueous phase was
4
extracted with EtOAc (3  10 mL) and the combined organic layers were dried over anhydrous
Na SO . The solvents were removed under reduced pressure and the residue was purified by silica gel
2
4
column chromatography, and recrystallization in some cases, affording the corresponding 1,1-diethyl-
-(2-hydroxyphenyl)(aryl)methylene ureas 3.Characterization and spectral data of 3 have been
3
previously reported in our previous communication.23
General Procedure for the Synthesis of Dicyano-Functionalized O-Aryl Carbamates
Derivatives 4 and Urea Derivatives 5 and 6. A solution of the corresponding O-aryl N,N-
diethylcarbamate 1 (1 mmol) in THF (2 mL) at –78 ºC under nitrogen, was treated with a solution of
s-BuLi (1.4 M solution in cyclohexane, 1.1 mmol for 1a,j-n,o-r or 1.21.3 mmol for 1b,e,h,s,t). The
reaction mixture was allowed to reach to temp for 5 min [temp = 78 ºC for 1b; temp = 70 ºC for
1
e,h,s,t; temp = 65 ºC for 1a,j-n,o-r], and stirred at this temperature for 90 min (30 min for 1b).
Then, dimethylmalononitrile (DMMN) (same amount as the employed base, 1.11.3 mmol) is added
and allowed to stir at temp for 60 min. The reaction mixture was allowed to warm to rt and stirred for
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6 h. The resulting solution was quenched with saturated aqueous NH Cl. The aqueous phase was
4
1
2
3
4
5
6
7
8
9
extracted with EtOAc (3  10 mL) and the combined organic layers were dried over anhydrous
Na SO . The solvents were removed under reduced pressure and the residue was purified by silica gel
2
4
column chromatography, and recrystallization in some cases, affording the corresponding 2-cyano-3-
2-cyanopropan-2-yl)phenyl N,N-diethylcarbamates 4, (E)-3-(2-cyano-1-(2-fluoro-6-hydroxyphenyl)-
2-methylpropylidene)-1,1-diethylurea derivatives or 1,1-diethyl-3-(1-(2-hydroxyphenyl)-2-
(
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
methylprop-1-en-1-yl)urea derivatives 6. Characterization and spectral data of compounds 422f and 523
have been previously reported.
1,1-Diethyl-3-(1-(2-hydroxyphenyl)-2-methylprop-1-en-1-yl)urea (6b). The reaction of O-phenyl
N,N-diethylcarbamate (1b) (193 mg, 1 mmol), s-BuLi (0.86 mL, 1.2 mmol) and DMMN (113 mg, 1.2
mmol), following the general procedure (purification by column chromatography in hexane/EtOAc =
4
:1), yielded 6b after recrystallization in CHCl /hexane (1:10), as a colorless solid (163 mg, 62%
3
1
yield): mp 109–111 ºC. H NMR (300 MHz, CDCl ): δ 9.39 (s, 1H), 7.22–7.16 (m, 1H), 6.97–6.91
3
(m, 2H), 6.83–6.78 (m, 1H), 5.48 (s, 1H), 3.30 (q, J = 7.2 Hz, 4H), 1.83 (s, 3H), 1.60 (s, 3H), 1.17 (t, J
1
3
1
=
7.2 Hz, 6H). C{ H} NMR (75.4 MHz, CDCl ): δ 157.9, 155.7, 137.0, 130.0, 129.3, 126.8, 124.5,
3
+
119.1, 117.0, 41.7, 20.8, 19.2, 13.8. LRMS (EI) m/z (%): 262 (M , 1), 189 (100), 174 (50), 145 (40),
+
1
32 (60). HRMS (ESI/Q-TOF) m/z: [M + H] calcd for C H N O , 263.1754; found, 263.1759.
1
5
23
2
2
3
-(1-(5-Chloro-2-hydroxyphenyl)-2-methylprop-1-en-1-yl)-1,1-diethylurea (6e). The reaction of O-
4-chlorophenyl N,N-diethylcarbamate (1e) (228 mg, 1 mmol), s-BuLi (0.93 mL, 1.3 mmol) and
DMMN (122 mg, 1.3 mmol), following the general procedure (purification by column
chromatography in hexane/EtOAc = 4:1), yielded 6e after recrystallization in CHCl /hexane (1:10), as
3
1
a yellow solid (178 mg, 60% yield): mp 130–132 ºC. H NMR (300 MHz, CDCl ): δ 9.62 (s, 1H),
3
7.14 (dd, J = 8.7, 2.5 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 5.51 (s, 1H), 3.32 (q,
13
1
J = 7.1 Hz, 4H), 1.83 (s, 3H), 1.61 (s, 3H), 1.19 (t, J = 7.1 Hz, 6H). C{ H} NMR (75.4 MHz,
CDCl ): δ 157.9, 154.5, 138.0, 129.5, 129.1, 128.2, 123.44, 123.42, 118.4, 41.7, 20.8, 19.2, 13.8.
3
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+
+
LRMS (EI) m/z (%): 298 (M +2, 1), 296 (M , 2), 251 (73), 233 (100), 205 (44). HRMS (ESI/Q-TOF)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
m/z: [M + H] calcd for C H ClN O , 297.1364; found, 297.1371.
1
5
22
2
2
1,1-Diethyl-3-(1-(2-hydroxy-5-methoxyphenyl)-2-methylprop-1-en-1-yl)urea (6h). The reaction of
O-4-methoxyphenyl N,N-diethylcarbamate (1h) (227 mg, 1 mmol), s-BuLi (0.93 mL, 1.3 mmol) and
DMMN (122 mg, 1.3 mmol), following the general procedure (purification by column
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
chromatography in hexane/EtOAc = 4:1), yielded 6h as a red oil (146 mg, 50% yield), R = 0.30
f
1
(
hexane/EtOAc, 5:1). H NMR (300 MHz, CDCl ): δ 6.83 (d, J = 8.8 Hz, 1H), 6.74 (dd, J = 8.8, 3.0
3
Hz, 1H), 6.51 (d, J = 3.0 Hz, 1H), 5.55 (s, 1H), 3.72 (s, 3H), 3.29 (q, J = 7.1 Hz, 4H), 1.81 (s, 3H),
1
3
1
1
.59 (s, 3H), 1.15 (t, J = 7.1 Hz, 6H), the OH signal does not appear. C{ H} NMR (75.4 MHz,
CDCl ): δ 157.8, 152.4, 149.5, 136.7, 127.2, 124.4, 117.4, 115.2, 114.4, 55.8, 41.6, 20.7, 19.2, 13.8.
3
+
+
LRMS (EI) m/z (%): 292 (M , 1), 219 (100), 161 (91). HRMS (ESI/Q-TOF) m/z: [M + H] calcd for
+
C H N O , 293.1860; found, 293.1865.
1
6
25
2
3
1,1-Diethyl-3-(1-(2-hydroxy-5-methylphenyl)-2-methylprop-1-en-1-yl)urea (6s). The reaction of O-
-methylphenyl N,N-diethylcarbamate (1s) (207 mg, 1 mmol), s-BuLi (0.93 mL, 1.3 mmol) and
DMMN (122 mg, 1.3 mmol), following the general procedure (purification by column
4
chromatography in hexane/EtOAc = 4:1), yielded 6s after recrystallization in CHCl /hexane (1:10), as
3
1
a colorless solid (180 mg, 65% yield): mp 120–122 ºC. H NMR (300 MHz, CDCl ): δ 9.19 (s, 1H),
3
6
.98 (dd, J = 8.2, 1.8 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 1.8 Hz, 1H), 5.54 (s, 1H), 3.29 (q,
1
3
1
J = 7.2 Hz, 4H), 2.24 (s, 3H), 1.82 (s, 3H), 1.59 (s, 3H), 1.16 (t, J = 7.2 Hz, 6H). C{ H} NMR (75.4
MHz, CDCl ): δ 157.8, 153.2, 136.4, 130.2, 129.7, 128.0, 126.5, 124.6, 116.6, 41.5, 20.7, 20.4, 19.1,
3
+
1
3.8. LRMS (EI) m/z (%): 276 (M , 1), 203 (100), 184 (44), 159 (55), 145 (82). HRMS (ESI/Q-TOF)
+
m/z: [M + H] calcd for C H N O , 277.1911; found, 277.1914.
1
6
25
2
2
1,1-Diethyl-3-(1-(4-hydroxy-[1,1'-biphenyl]-3-yl)-2-methylprop-1-en-1-yl)urea (6t). The reaction
of O-(1,1'-biphenyl)-4-yl N,N-diethylcarbamate (1t) (269 mg, 1 mmol), s-BuLi (0.93 mL, 1.3 mmol)
and DMMN (122 mg, 1.3 mmol), following the general procedure (purification by column
chromatography in hexane/EtOAc = 4:1), yielded 6t as a colorless solid (227 mg, 67% yield): mp
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38–140 ºC. H NMR (300 MHz, CDCl ) δ (ppm): 9.55 (s, 1H), 7.55–7.51 (m, 2H), 7.46–7.42 (m,
3
1
2
3
4
5
6
7
8
9
1
H), 7.41–7.36 (m, 2H), 7.30–7.24 (m, 1H), 7.21 (t, J = 2.9 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 5.49 (s,
1
3
1
1H), 3.30 (q, J = 7.1 Hz, 4H), 1.84 (s, 3H), 1.64 (s, 3H), 1.17 (t, J = 7.1, 6H). C{ H} NMR (75.4
MHz, CDCl ) δ (ppm): 157.9, 155.4, 140.8, 137.1, 132.0, 128.64, 128.58, 127.8, 127.0, 126.45,
3
+
1
26.36, 124.5, 117.3, 41.5, 20.8, 19.1, 13.7. LRMS (EI) m/z (%): 338 (M , 1), 265 (100), 207 (67).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
HRMS (ESI/Q-TOF) m/z: [M + H] calcd for C H N O , 339.2067; found, 339.2071.
21 27
2
2
General Procedure for the Synthesis of O-2-(Trimethylsilyl)aryl N,N-Diethyl Carbamates 7
and O-2-Chloroaryl N,N-Diethyl Carbamates 8. A solution of the corresponding carbamate 1 (1
mmol) in THF (2 mL) at –78 ºC under nitrogen, was treated with s-BuLi (1.4 M solution in
cyclohexane). The reaction mixture was allowed to reach to temp (temp = 65 ºC for 1a; temp = 70
ºC for 1e) for 5 min and stirred at this temperature for additional 90 min. Then, trimethylsilyl cyanide
(TMSCN) or trichloroacetonitrile (Cl CCN) is added and allowed to stir at temp for 60 min. The
3
reaction mixture was allowed to warm to rt and stirred for 16 h. The resulting solution was quenched
with saturated aqueous NH Cl. The aqueous phase was extracted with EtOAc (3  10 mL) and the
4
combined organic layers were dried over anhydrous Na SO . The solvents were removed under
2
4
reduced pressure and the residue was purified by silica gel column chromatography affording the O-2-
trimethylsilyl)aryl N,N-diethylcarbamate derivatives 7 or the O-2-chloroaryl N,N-diethylcarbamate
(
derivatives 8.
O-3-Fluoro-2-(trimethylsilyl)phenyl N,N-diethylcarbamate (7a). The reaction of O-3-fluorophenyl
N,N-diethylcarbamate (1a) (211 mg, 1 mmol), s-BuLi (0.78 mL, 1.1 mmol) and TMSCN (109 mg, 1.1
mmol), following the general procedure (purification by column chromatography in hexane/EtOAc =
1
10:1), yielded 7a as a yellowish liquid (230 mg, 81% yield), R = 0.32 (hexane/EtOAc, 5/1). H NMR
f
(300 MHz, CDCl ): δ 7.39–7.29 (m, 1H), 7.00–6.81 (m, 2H), 3.53–3.39 (m, 4H), 1.32–1.19 (m, 6H),
3
1
3
1
0
.40–0.35 (m, 9H). C{ H} NMR (75.4 MHz, CDCl ): δ 167.3 (d, J = 242.3 Hz), 156.8 (d, J = 14.6
3
Hz), 154.3, 131.1 (d, J = 10.5 Hz), 119.3 (d, J = 31.8 Hz), 118.5 (d, J = 3.3 Hz), 112.1 (d, J = 27.1
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+
Hz), 42.0, 41.7, 14.2, 13.3, 0.5 (d, J = 3.5 Hz). LRMS (EI) m/z (%): 283 (M , 1), 268 (55), 100 (100),
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
7
2 (30). HRMS (ESI/Q-TOF) m/z: [M + H] calcd for C H FNO Si, 284.1477; found, 284.1489.
1
4
23
2
O-4-Chloro-2-(trimethylsilyl)phenyl N,N-diethylcarbamate (7e). The reaction of O-4-chlorophenyl
N,N-diethylcarbamate (1e) (228 mg, 1 mmol), s-BuLi (0.93 mL, 1.3 mmol) and TMSCN (129 mg, 1.3
mmol), following the general procedure (purification by column chromatography in hexane/EtOAc =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
0:1), yielded 7e as a colorless solid (273 mg, 91% yield): mp 53–55 ºC. H NMR (300 MHz, CDCl ):
3
δ 7.40 (d, J = 2.6 Hz, 1H), 7.33 (dd, J = 8.6, 2.6 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 3.52–3.37 (m, 4H),
1
3
1
1
1
.29–1.19 (m, 6H), 0.32 (s, 9H). C{ H} NMR (75.4 MHz, CDCl ): δ 154.6, 154.0, 134.2, 134.1,
3
+
+
30.4, 130.1, 123.8, 41.6, 41.5, 14.1, 13.2, ‒1.1. LRMS (EI) m/z (%): 301 (M +2, 1), 299 (M , 3), 284
+
(59), 100 (100), 72 (69). HRMS (ESI/Q-TOF) m/z: [M + H] calcd for C H ClNO Si, 300.1181;
1
4
23
2
found, 300.1187.
O-2-Chloro-3-fluorophenyl N,N-diethylcarbamate (8a). The reaction of O-3-fluorophenyl N,N-
diethylcarbamate (1a) (211 mg, 1 mmol), s-BuLi (0.78 mL, 1.1 mmol) and Cl CCN (159 mg, 1.1
3
mmol), following the general procedure (purification by column chromatography in hexane/EtOAc =
1
1
0:1), yielded 8a as a yellowish liquid (226 mg, 92% yield), R = 0.21 (hexane/EtOAc, 5:1). H NMR
f
(
300 MHz, CDCl ): δ 7.30–7.21 (m, 1H), 7.14–7.01 (m, 2H), 3.55–3.38 (m, 4H), 1.35–1.22 (m, 6H).
3
1
3
1
C{ H} NMR (75.4 MHz, CDCl ): δ 158.9 (d, J = 249.1 Hz), 152.8, 149.2 (d, J = 2.2 Hz), 127.1 (d, J
3
=
9.1 Hz), 119.5 (d, J = 3.4 Hz), 115.6 (d, J = 18.9 Hz), 113.2 (d, J = 21.1 Hz), 42.6, 42.2, 14.1, 13.3.
+
+
LRMS (EI) m/z (%): 247 (M +2, 1), 245 (M , 3), 100 (100), 72 (42). HRMS (ESI/Q-TOF) m/z: [M +
+
H] calcd for C H ClFNO , 246.0692; found, 246.0696.
1
1
14
2
O-2,4-Dichlorophenyl N,N-diethylcarbamate (8e). The reaction of O-4-chlorophenyl N,N-
diethylcarbamate (1e) (228 mg, 1 mmol), s-BuLi (0.93 mL, 1.3 mmol) and Cl CCN (188 mg, 1.3
3
mmol), following the general procedure (purification by column chromatography in hexane/EtOAc =
1
1
0:1), yielded 8e as a yellowish liquid (233 mg, 89% yield), R = 0.20 (hexane/EtOAc, 5:1). H NMR
f
(
300 MHz, CDCl ): δ 7.43 (d, J = 2.3 Hz, 1H), 7.24 (dd, J = 8.7, 2.3 Hz, 1H), 7.17 (d, J = 8.7 Hz, 1H),
3
1
3
1
3
.50–3.38 (m, 4H), 1.32–1.19 (m, 6H). C{ H} NMR (75.4 MHz, CDCl ): δ 152.8, 146.5, 131.0,
3
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29.8, 128.1, 127.7, 125.1, 42.5, 42.1, 14.1, 13.3. LRMS (EI) m/z (%): 265 (M +4, 1), 263 (M +2, 3),
1
2
3
4
5
6
7
8
9
+
+
2
61 (M , 6), 100 (100), 72 (51). HRMS (ESI/Q-TOF) m/z: [M + H] calcd for C H Cl NO ,
11 14 2 2
262.0396; found, 262.0397.
General Procedure for the Synthesis of Urea Derivatives 9. A solution of the corresponding
carbamate 1 (1 mmol) in THF (2 mL) at –78 ºC under nitrogen, was treated with s-BuLi (1.4 M
solution in cyclohexane). The reaction mixture was allowed to reach to temp (see Table 1) for 5 min
and stirred at this temperature for additional 90 min (30 min for 1b). Then, the corresponding imine is
added and allowed to stir at temp for 60 min. The reaction mixture was allowed to warm to rt and
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
stirred for 16 h. The resulting solution was quenched with saturated aqueous NH Cl. The aqueous
4
phase was extracted with EtOAc (3  10 mL) and the combined organic layers were dried over
anhydrous Na SO . The solvents were removed under reduced pressure, the residue was purified by
2
4
silica gel column chromatography and further recrystallized in pentane/CH Cl (5:1), affording the
2
2
1,1-diethyl-3-((2-hydroxyphenyl)(phenyl)methyl)-3-phenylurea derivatives 9.
,1-Diethyl-3-((2-hydroxyphenyl)(phenyl)methyl)-3-phenylurea (9ba). The reaction of O-phenyl
1
N,N-diethylcarbamate (1b) (193 mg, 1 mmol), s-BuLi (0.86 mL, 1.2 mmol) and N-benzylideneaniline
(217 mg, 1.2 mmol), following the general procedure (purification by column chromatography in
hexane/MeOH/CH Cl = 10:2:1), yielded 9ba as a colorless solid (296 mg, 79% yield): mp 136–138
2
2
1
ºC. H NMR (300 MHz, CDCl ): δ 10.61 (s, 1H), 7.53 (d, J = 7.5 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H),
3
7.37–7.30 (m, 1H), 7.17–7.04 (m, 4H), 6.99–6.94 (m, 4H), 6.51–6.46 (m, 2H), 3.48–3.27 (m, 4H),
13
1
0
1
.94 (t, J = 6.9 Hz, 6H). C{ H} NMR (75.4 MHz, CDCl ): δ 163.6, 156.8, 143.6, 140.2, 131.6,
3
29.2, 129.0, 128.1, 127.8, 126.8, 126.2, 125.8, 123.4, 118.2, 117.6, 62.8, 42.2, 12.3. LRMS (EI) m/z
+
+
(
%): 374 (M , 1), 257 (100), 181 (36). HRMS (ESI/Q-TOF) m/z: [M + H] calcd for C H N O ,
24 27 2 2
375.2067; found, 375.2072.
1
-((2-Chloro-6-hydroxyphenyl)(phenyl)methyl)-3,3-diethyl-1-phenylurea (9ca). The reaction of O-
3
-chlorophenyl N,N-diethylcarbamate (1c) (228 mg, 1 mmol), s-BuLi (0.78 mL, 1.1 mmol) and N-
benzylideneaniline (199 mg, 1.1 mmol), following the general procedure (purification by column
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chromatography in hexane/EtOAc = 4:1), yielded 9ca as a colorless solid (348 mg, 85% yield): mp
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
49–151 ºC. H NMR (300 MHz, CDCl ): δ 11.82 (s, 1H), 7.38–7.24 (m, 9H), 7.13–7.03 (m, 3H),
3
6.86 (dd, J = 8.2, 1.2 Hz, 1H), 6.77 (dd, J = 8.2, 1.2 Hz, 1H), 3.33–3.13 (m, 4H), 0.84 (t, J = 7.1 Hz,
13
1
6
H). C{ H} NMR (75.4 MHz, CDCl ): δ 161.5, 158.3, 143.9, 137.4, 135.5, 129.8, 129.6, 128.6,
3
+
1
27.6, 127.5, 125.3, 124.6, 120.8, 120.3, 117.7, 64.2, 42.0, 12.3. LRMS (EI) m/z (%): 410 (M +2, 2),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+

408 (M , 6), 291 (100), 215 (52). HRMS (ESI/Q-TOF) m/z: [M ‒ H] calcd for C H ClN O ,
2
4
24
2
2
4
07.1532; found 407.1537.
-(4-Bromophenyl)-1-((2-chloro-6-hydroxyphenyl)(phenyl)methyl)-3,3-diethylurea (9cb). The
1
reaction of O-3-chlorophenyl N,N-diethylcarbamate (1c) (228 mg, 1 mmol), s-BuLi (0.78 mL, 1.1
mmol) and N-(4-bromophenyl)-1-phenylmethanimine (286 mg, 1.1 mmol), following the general
procedure (purification by column chromatography in hexane/EtOAc = 4:1), yielded 9cb as a
1
colorless solid (424 mg, 87% yield): mp 171–173 ºC. H NMR (300 MHz, CDCl ): δ 11.65 (s, 1H),
3
7.43–7.27 (m, 7H), 7.14–7.07 (m, 3H), 6.99 (s, 1H), 6.89–6.81 (m, 2H), 3.34–3.14 (m, 4H), 0.88 (t, J
1
=
7.1 Hz, 6H). 13C{ H} NMR (75.4 MHz, CDCl ): δ 160.9, 158.0, 142.9, 136.8, 135.3, 132.61,
3
1
32.59, 130.0, 128.6, 127.68, 127.66, 125.1, 120.3, 117.8, 117.7, 63.7, 41.9, 12.3. LRMS (EI) m/z
+
+
+
(%): 450 (M +4, 1), 488 (M +2, 1), 486 (M , 3), 415 (18), 215 (100). HRMS (ESI/Q-TOF) m/z: [M +
+
H] calcd for C H BrClN O , 487.0782; found, 487.0787.
2
4
25
2
2
1
-(4-Bromophenyl)-1-((2-chloro-6-hydroxyphenyl)(p-tolyl)methyl)-3,3-diethylurea (9cc). The
reaction of O-3-chlorophenyl N,N-diethylcarbamate (1c) (228 mg, 1 mmol), s-BuLi (0.78 mL, 1.1
mmol) and N-(4-methoxyphenyl)-1-(p-tolyl)methanimine (248 mg, 1.1 mmol), following the general
procedure (purification by column chromatography in hexane/MeOH/CH Cl = 10:2:1), yielded 9cc as
2
2
1
a colorless solid (406 mg, 81% yield): mp 175–177 ºC. H NMR (300 MHz, CDCl ): δ 11.57 (s, 1H),
3
7.38 (d, J = 8.8 Hz, 2H), 7.13–7.03 (m, 7H), 6.91 (s, 1H), 6.84–6.77 (m, 2H), 3.24–3.17 (m, 4H), 2.32
13
1
(
s, 3H), 0.87 (t, J = 7.1 Hz, 6H). C{ H} NMR (75.4 MHz, CDCl ): δ 161.0, 158.0, 143.0, 137.3,
3
1
35.3, 133.8, 132.6, 129.9, 129.4, 127.6, 125.1, 120.6, 120.4, 117.78, 117.75, 63.6, 41.9, 21.2, 12.3.
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+
LRMS (EI) m/z (%): 502 (M +2, 1), 500 (M , 3), 429 (17), 215 (100). HRMS (ESI/Q-TOF) m/z: [M +
1
2
3
4
5
6
7
8
9
+
H] calcd for C H BrClN O , 501.0939; found, 501.0934.
2
5
27
2
2
1-((5-Chloro-2-hydroxyphenyl)(phenyl)methyl)-3,3-diethyl-1-phenylurea (9ea). The reaction of O-
-chlorophenyl N,N-diethylcarbamate (1e) (228 mg, 1 mmol), s-BuLi (0.93 mL, 1.3 mmol) and N-
4
benzylideneaniline (236 mg, 1.3 mmol), following the general procedure (purification by column
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
chromatography in hexane/EtOAc = 4:1), yielded the product as a colorless solid (331 mg, 81%
1
yield): mp 151–153 ºC. H NMR (300 MHz, CDCl ): δ 10.75 (s, 1H), 7.51–7.36 (m, 5H), 7.21–7.10
3
(
m, 3H), 7.05–7.01 (m, 1H), 6.95 (d, J = 7.6 Hz, 2H), 6.87 (d, J = 9.1 Hz, 2H), 6.41 (s, 1H), 3.45–3.29
1
3
1
(
m, 4H), 0.93 (t, J = 6.8 Hz, 6H). C{ H} NMR (75.4 MHz, CDCl ): δ 163.6, 155.6, 143.2, 139.5,
3
131.0, 129.2, 129.1, 128.3, 127.8, 127.1, 126.1, 126.0, 125.3, 122.9, 119.0, 62.4, 42.3, 12.2. LRMS
+
+
+
(
EI) m/z (%): 410 (M +2, 1), 408 (M , 3), 208 (100). HRMS (ESI/Q-TOF) m/z: [M + H] calcd for
C H ClN O , 409.1677; found, 409.1681.
2
4
26
2
2
1-((5-Chloro-2-hydroxyphenyl)(p-tolyl)methyl)-1-(3-chloro-5-fluorophenyl)-3,3-diethylurea (9ed).
The reaction of O-4-chlorophenyl N,N-diethylcarbamate (1e) (228 mg, 1 mmol), s-BuLi (0.93 mL, 1.3
mmol) and N-(3-chloro-5-fluorophenyl)-1-(p-tolyl)methanimine (328 mg, 1.3 mmol), following the
general procedure (purification by column chromatography in hexane/MeOH/CH Cl = 10:2:1),
2
2
1
yielded 9ed as a colorless solid (395 mg, 83% yield): mp 150–152 ºC. H NMR (300 MHz, CDCl ): δ
3
1
0.67 (s, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.22–7.17 (m, 3H), 7.11 (dd, J = 8.7, 2.6 Hz, 1H), 7.04–6.94
(
m, 2H), 6.92 (d, J = 8.7 Hz, 1H), 6.66 (s, 1H), 6.46 (d, J = 2.6 Hz, 1H), 3.32 (q, J = 7.1 Hz, 4H), 2.39
1
3
1
(s, 3H), 0.89 (t, J = 7.1 Hz, 6H). C{ H} NMR (75.4 MHz, CDCl ): δ 163.0, 158.2 (d, J = 253.8 Hz),
3
1
55.8, 137.1, 135.3, 133.4 (d, J = 10.0 Hz), 130.6, 129.8 (d, J = 11.1 Hz), 129.60, 129.56, 129.2,
27.6, 125.2 (d, J = 3.5 Hz), 124.6, 123.2, 119.6, 117.4 (d, J = 24.0 Hz), 62.9, 42.4, 21.1, 12.4. LRMS
1
+
+
+
(EI) m/z (%): 476 (M +2, 1), 474 (M , 3), 254 (36), 100 (100). HRMS (ESI/Q-TOF) m/z: [M + H]
calcd for C H Cl FN O , 475.1350; found, 475.1352.
2
5
26
2
2
2
1
,1-Diethyl-3-((2-hydroxy-3-methoxyphenyl)(phenyl)methyl)-3-phenylurea (9ia). The reaction of
O-2-methoxyphenyl N,N-diethylcarbamate (1i) (223 mg, 1 mmol), s-BuLi (0.93 mL, 1.3 mmol) and
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