Synthesis of reduction-sensitive 1,1-diarylhydrazines from 1,1-diarylamines

Article abstract of DOI:10.1139/cjc-2014-0132

1-(2-Nitrophenyl)-1-phenylamine and methyl 4-((2-nitrophenyl)amino)benzoate have been transformed into their corresponding urea derivatives through the action of chlorosulfonyl isocyanate. The initial sulfimidate product from the former reaction has sufficient stability so that it can be isolated and characterized as its disodium salt, and this, as well as three other subsequent products, have been characterized by X-ray diffraction. The corresponding intermediary urea was converted into its hydrazine derivative via a Hofmann rearrangement under oxidative conditions. Density functional theory has been used to examine the nature of the intermediates and transition states for the Hofmann rearrangement. There is little theoretical indication for a cyclic aziridinonium intermediate and the transition state between the urea and the isocyanate corresponds to a reactant-like rotation of the planar singlet nitrene before migration and formation of the new N-N bond.

Full text of DOI:10.1139/cjc-2014-0132

904
ARTICLE
Synthesis of reduction-sensitive 1,1-diarylhydrazines from
1,1-diarylamines
Cheryl D. Bain, Julia M. Bayne, D. Scott Bohle, Ian S. Butler, and Joël Poisson
Abstract: 1-(2-Nitrophenyl)-1-phenylamine and methyl 4-((2-nitrophenyl)amino)benzoate have been transformed into their cor-
responding urea derivatives through the action of chlorosulfonyl isocyanate. The initial sulfimidate product from the former
reaction has sufficient stability so that it can be isolated and characterized as its disodium salt, and this, as well as three other
subsequent products, have been characterized by X-ray diffraction. The corresponding intermediary urea was converted into its
hydrazine derivative via a Hofmann rearrangement under oxidative conditions. Density functional theory has been used to
examine the nature of the intermediates and transition states for the Hofmann rearrangement. There is little theoretical
indication for a cyclic aziridinonium intermediate and the transition state between the urea and the isocyanate corresponds to
a reactant-like rotation of the planar singlet nitrene before migration and formation of the new N−N bond.
Key words: hydrazines, Hofmann rearrangement, sulfimate salt.
Résumé : La 1-(2-nitrophényle)-1-phénylamine et la 4-((2-nitrophényle)amino)benzoate de méthyle ont été transformé par leur
réaction avec l’isocyanate de chlorosulfonyle en leurs urées correspondantes. Dans le premier cas, le produit initial de cette
réaction, un sulfimidé, démontre une stabilité qui permet son isolement comme sel de sodium. Celui-ci ainsi que trois produits
ultérieurs ont été caractérisés par diffraction de rayons X. L’urée de 1-(2-nitrophényle)-1-phénylamine a été transformé en
hydrazine par réarrangement de Hofmann sous conditions oxydatives. La théorie de la fonctionnelle de la densité a été utilisé
afin d’examiner les intermédiaires et les états de transition de ce réarrangement. Les calculs indiquent qu’un intermédiaire
aziridononium cyclique est peu probable et que l’état de transition qui mène de l’urée a` l’isocyanate et finalement a` l’hydrazine
correspond a` une rotation de la nitrène planaire de forme singulet avant sa migration et la formation d’une nouvelle liaison
entre les deux atomes d’azote.
Mots-clés : hydrazines, Hofmann réarrangement, sel sulfimate.
Scheme 1. Amination by the reductive nitration sequence of
1,1-diarylamines.
Introduction
Although 1,1-diarylhydrazines have proven useful in medicinal
chemistry1 and in the catalysis of hydrohydrazination reactions,2,3
their syntheses4 often require a two-step nitrosation/reduction
of a diaryl amine (Scheme 1). Many possible amines, for example
those containing nitro or carboxyl substituents, are not com-
patible with these reductive conditions and the intermediary ni-
trosamines are often potent carcinogens. In addition to these
limitations, 1,1-diarylamines often cannot be transformed to hydra-
zines by this method due to the cleavage of the weak N–NO2 bonds in
the product under reducing conditions.5 One method for circum-
venting these obstacles is to use copper6–8 or patented palladium
1,1-diarylhydrazines via the Hofmann rearrangement of suitable
complexes for the amination of diarylamines;9 however, the li-
gand selection process to obtain useful results is often cumber-
some and somewhat unpredictable.
urea derivatives. Among the structurally characterized interme-
diates is the dianionic sulfimidate of the urea, [R=RNC(O)NSO3]2−
,
with R = Ph and R= = 2-C6H4NO2. This novel disodium salt is suffi-
ciently stable for isolation and characterization by X-ray diffrac-
tion. To understand the unusual stability and reactivity of these
species, density functional theory is used to theoretically charac-
terize these intermediates and to determine the key intermedi-
ates and transition states in their Hofmann rearrangements.
A rather less-developed method for the synthesis of A is via a
mild base-catalyzed Hofmann rearrangement10 of 1,1-diarylureas.
This methodology offers selectivity and moderate to good yields
and utilizes inexpensive and commercially available materials.
However, the sole preliminary report on this reaction only suc-
ceeded in isolating derivatives of the initial hydrazine and inferred
the presence and intermediacy of the parent hydrazines. We re-
port here the production of novel redox-sensitive 1,1-diarylureas
and the first complete structural characterization of the key spe-
cies in the stepwise conversion of diarylamines to substituted
Results and discussion
The substituted ureas were produced by the action of chlorosulfo-
nyl isocyanate, OCNSO2Cl, on 1,1- diarylamines (Scheme 2). While
1-(2-nitrophenyl)-1-phenylamine is commercially available, the
Received 17 March 2014. Accepted 3 July 2014.
C.D. Bain, J.M. Bayne, D.S. Bohle, I.S. Butler, and J. Poisson. Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, QC
H3A 0B8, Canada.
Corresponding author: D. Scott Bohle (e-mail: scott.bohle@mcgill.ca).
Can. J. Chem. 92: 904–912 (2014) dx.doi.org/10.1139/cjc-2014-0132
Published at www.nrcresearchpress.com/cjc on 8 July 2014.

Bain et al.
905
Scheme 2. Synthetic route to 1,1-diarylureas.
Fig. 1. ORTEP representation of the solid structure of the dianion in
sodium 1-(2-nitrophenyl)-1-phenylcarbamoylsulfimidate
pentahydrate (1). Key metric parameters: N(1)−C(13) 1.411(2) Å,
C(13)−N(3) 1.344(2) Å, N(3)–S(1) 1.598(1) Å, N(1)–C(1) 1.430(2) Å, N(1)–C(7)
1.420(2) Å, N(3)–S(1) 1.598(1) Å, and C(7)–N(1)–C(13)–N(3) 171.4(1)°.
bis(2-nitrophenyl)amine and methyl 4-((2-nitrophenyl)amino)benzoate
analogues were synthesized using the methods of Ren11 and
Tietze,12 respectively. The latter compound has a high melting
point (145–146 °C), suggesting strong crystalline packing. Coupled
with this observation is the fact that despite varying reaction
temperatures and reaction times, the bis(2-nitrophenyl)amine
failed to react with chlorosulfonyl isocyanate. A trend operating
here is that there is diminished availability of the nitrogen lone
pair, which is necessary for this reaction to occur. Hence, by in-
creasing the number and strength of electron-withdrawing groups
on the flanking phenyl rings, it is easy to reduce the nucleophilic-
ity of the diphenylamine to the point of no reaction.
It was expected, based on literature precedent,13–15 that follow-
ing the reaction of such amines with chlorosulfonyl isocyanate,
and subsequent hydrolysis, the reactions would furnish the de-
sired urea derivatives directly (Scheme 2). In the two examples
reported here, the desired urea can be generated reliably if an
extraction with aqueous dilute hydrochloric acid is performed. In
the presence of excess sodium bicarbonate, the desired urea was
formed only as a small by-product in the case of 1-(2-nitrophenyl)-
1-phenylamine with the main product being the frequently pro-
posed intermediate 1-(2-nitrophenyl)-1-phenylcarbamoylsulfimidate
(1), which crystallized as a disodium pentahydrate. An ORTEP repre-
sentation of the structure of the dianion is shown in Fig. 1, with
images of the salt and its hydration sphere being shown in the sup-
porting information (Fig. S1) (see “Supplementary material” section).
A comparison of the sulfimidate, urea, and hydrazine for the
1-(2-nitrophenyl)-1-phenylamine-derived products also reveals bond
angles as well as a near planar geometry at N(1) (Table 1), consistent
with partial sp(2) hybridization and delocalization of its lone pair.
The C(13)–N(3)–S(1) bond angle of 118.1(1)° indicates an sp(2) hybrid-
ization about N(3). Such an arrangement results in an increased
S−N bond order, N(3)–S(1) = 1.598(1) Å, which helps stabilize the
sulfimidate. The increased Lewis basicity of the sulfoxyl oxygens
enhances the ability to coordinate sodium leading to unusually
robust and isolable salts.
The isolation of this intermediate is unexpected, since the sul-
fonyl chlorides generated upon reaction with chlorosulfonyl iso-
cyanate are typically unstable and undergo decomposition in
aqueous media to give the desired substituted ureas. There are
only a few reports of the isolation of these types of products16–18
and only a single remotely related structure has been described.19
Terminal sulfimic acid moieties and their carbamoylsulfimidate
derivatives similar to 1 do not seem to have been reported. In the
cases where sulfimides have been isolated, they are engineered
such that the sulfur atom is annealed into a relatively inert or-
ganic ring20 or is part of a tosylate group,21–23 which abates their
inherent instability. Although the urea carbamoyl sulfimidate
framework in 1 is unusual, the related carbamoyl sulfinate esters
−O3SNHC(O)OR include the natural product saxitoxin and allied
neurotoxins isolated from dinoflagellates.24,25
Table 1. Comparison of geometry around N(1) in 1-(2-nitrophenyl)-1-
phenyl derivatives.
Parameter
Sulfimidate (1)
Urea (2a)
Hydrazine (3)
Out-of-plane distance
of N(1) (Å)a
0.0031
0.0184
0.1158
C(7)−N(1)−C(1) (°)
C(7)−N(1)−C(13) (°)
C(13)−N(1)−C(1) (°)
C(7)−N(1)−N(3) (°)
C(1)−N(1)−N(3) (°)
Sum of angles around
N(1) (°)
117.4(1)
120.5(1)
122.1(1)
117.8(1)
118.7(1)
123.4(1)
123.7(1)
na
na
113.7(1)
120.6(1)
358.0(1)
360.0(1)
359.9(1)
aSeparation of N(1) from the plane defined by the three carbons to which it is
bound.
1,1-substituted urea quantitatively. The acid addition could be made
following the isolation of the sulfimidate or as an additive to the
mother liquor. Analysis of the urea by single-crystal X-ray diffrac-
tion (Fig. 2) shows that it crystallizes in the centro-symmetric
space group P−1 with a planar 1,1=-diarylurea.
The addition of acid at room temperature in a final acid workup
step leads to sulfimidate decomposition to give the corresponding
To illustrate the compatibility of this urea formation with
amines containing other functional groups sensitive to reduction,
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Can. J. Chem. Vol. 92, 2014
Fig. 2. (a) ORTEP representations of the solid-state structures of (a) 1-(2-nitrophenyl)-1-phenylurea (2a) and (b) methyl 4-(1-(2-
nitrophenyl)ureido)benzoate (2b). Key metric parameters for 2a: N(1)–C(13) 1.387(1) Å, C(13)–N(3) 1.342(2) Å, N(1)–C(1) 1.438(1) Å, N(1)–C(7)
1.426(1) Å, and C(7)–N(1)–C(13)–N(3) 169.9(1)°. Key metric parameters for 2b: N(2)–C(7) 1.394(2) Å, C(7)–N(3) 1.332(2) Å, N(2)–C(6) 1.438(2) Å,
N(2)–C(8) 1.421(2) Å, and C(6)–N(2)–C(7)–N(3) –11.2(2)°.
Scheme 3. Reaction sequence in the hypochlorite-promoted Hofmann rearrangement of ureas.
NO2
HN
NO2
NH2
NO2
Cl
NH2
N
O
N
O
N
OCl-
-OH-
H2O
-CO2, -HCl
R
R
R
3
2
the synthesis of the analogous urea derivative starting from
methyl 4-((2-nitrophenyl)amino)benzoate was also demonstrated
following a similar procedure (Fig. 2b). This second derivative also
crystallizes in the space group P−1 and has a coplanar diarylamine
and urea groups with very small out-of-plane geometries for the
diarylamine nitrogen N(1) Table 1. Hydrogen bonding organizes
efficient packing in 2a and 2b with there being extensive inter-
molecular hydrogen bonds between adjacent urea carbonyls and
amino groups.
zation as was reported previously.10 The crystals of 3 were of out-
standing quality for single-crystal X-ray diffraction and sufficiently
high-resolution data were collected to allow for the location of all
hydrogen atoms, including those of the terminal nitrogen, being
located in the penultimate electron density maps. These hydrogens
were included in the final refinement, which led to the geometry
shown in Fig. 3. Thus, it is possible to have a meaningful interpre-
tation of the terminal amino group geometry in 3, which orients
the dipoles of the amine and nitro groups.
To obtain a hydrazine, a modified Hofmann rearrangement
was performed (Scheme 3). Extensive kinetics by Judd26 of the
hypohalite-promoted Hofmann rearrangement indicates that the
reaction is first order in hypochlorite and urea. Since the stoichi-
ometric amounts of hypochlorite have been shown to be of con-
sequence in producing the desired hydrazine and commercially
available sodium hypochlorite is variable in its composition, de-
grading over time, the more stable solid calcium salt, Ca(OCl)2,
was used. As such, the stoichiometry of hypochlorite used could
be more tightly controlled so as to minimize the degradation of
the desired hydrazine product. Although the crude yields ob-
tained were comparable with those of the prior report,7 this mod-
ified preparation allowed the isolation of the desired hydrazine 3
(Scheme 3) in crystalline form (Fig. 3) without requiring derivati-
This geometry is not compatible with an intramolecular hydrogen
bond, although there are numerous intermolecular hydrogen-
bonding interactions. Even though hydrazine conformational
dynamics are surprisingly complicated,27–29 this crystalline con-
formation is noteworthy by the absence of an intramolecular hy-
drogen bond.
The comparison of this hydrazine with its urea and its sulfimi-
date shows global delocalization of the N(1) lone pair electrons
into their aromatic systems (Table 1). In addition, delocalization is
seen in the sulfimidate and carbonyl groups, resulting in near
planar geometry at N(3) in the sulfimidate and the urea. Despite a
slightly larger distortion of N(1) out of its plane in the hydrazine,
the N–N bond length, angular geometry, and planar positioning
Published by NRC Research Press

Bain et al.
907
Fig. 3. ORTEP plot of the solid-state structure of 1-(2-nitrophenyl)-1-
phenylhydrazine (3). Key metric parameters: N(1)–N(3) 4.416(3) Å,
N(1)–C(1) 1.413(2) Å, N(1)–C(7) 1.401(2) Å, C(2)–C(1)–N(1)–N(3) –163.5(1)°,
and C(8)–C(7)–N(1)–N(3) –134.1(1)°.
Scheme 5. Proposed nitrene intermediate and transition state in
the Hofmann reaggrangement.
Scheme 4. Reaction mechanism for formation of hydrazines from
ureas (R = alkyl or aryl). All structures shown in square brackets are
proposed species.
O
R2N
OCl-
NH2
A
-OH-
O
H
N
are also consistent with sp2 hybridization. All of these observa-
tions are consistent with those made by Carrillo,30 supporting the
assertion that the ␲NN interactions lead to minor bonding effects,
in diarylhydrazines as the nitrogen lone pair is strongly conju-
gated with the ␲-system of the aromatic rings.
R2N
B
Cl
The generalization of the hypochlorite-promoted urea decar-
boxylations to include diarylhydrazines, and the stability of some
of the key intermediates, has important implications for the
Hofmann rearrangement. Mechanistically, the Hofmann rearrange-
ment is often discussed along with the Curtius, Wolff, Schmidt,
and Lossen reactions, which share a common substituent nitrogen
bond forming step, and an initial isocyanate product, but which
are distinguished in the approach to generating the leaving group
at the nitrogen.31–34 Key characteristics of these rearrangements
are the retention of the stereointegrity of the R= group of the
amides, R=C(O)NH2,35 the lack of scrambling of its isotopically
labelled the R= and NH2 fragments,33,36–38 their overall first-order
kinetics,31,39–41 and the interception of the isocyanate intermedi-
ate with methanol.42 Although the mechanistic discussion of the
Hofmann rearrangement was extensive in the heyday of physical
organic chemistry, and based on a variety of sound experimental
studies,31,36,43 more recent density functional theoretical ap-
proaches34,44,45 have largely concerned the Curtius rearrangement.
In outline, the Hofmann rearrangement shown in Schemes 4 and 5 is
a variant of the Shestakov reaction,46 with the key step in all of
O
C
R2N
N
R
R
C O
N
N
D
+H2O
-CO2
R2N NH2
E
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Can. J. Chem. Vol. 92, 2014
Fig. 4. Optimized structures for the intermediates for the Hofmann rearrangement of 1,1-diphenylurea. The urea anions with Z and
E chloride geometries are show in I and II, respectively, and III depicts the optimized transition state between the singlet nitrene in IV and
the isocyanate product. VI shows the isocyanate. Note the coplanarity of the NC(O)N unit and the compact O–C–N bond angle in the nitrene IV
as compared with the more expanded orthogonal orientation for the transition state in III. The singlet and triplet nitrenes are shown in IV
and V, respectively.
Table 2. Theoretical results for the Hofmann intermediates and tran-
these reactions being the formation of the new N−N bond. Given
sition states (G).
the poor nucleophilicity of the diarylamine groups used here, we
Relative
energy
CNCN
torsion
angle (°)c
sought to clarify some of these mechanistic questions with den-
sity functional theory.47 In prior publications, we have found that
B3LYP/6-311++G** is an excellent combination of method and model
for the ground-state geometries and vibrational modes or electron-
rich nitrogen species with multiple lone pairs such as these.48,49
Here, the inclusion of diffuse functions is an important factor.50,51
This is the case for these urea starting materials and hydrazine
products, which have theoretically calculated ground-state struc-
tures and vibrational modes (supplementary information S28–
S31) that match well the expected intensities and positions of the
experimental data.
To theoretically screen the possible intermediates, simple diphe-
nylamino systems were initially employed in these calculations,
with the ground and transition states located therein being used
to aid in the location of those for the 2-fluoro and 2-nitro deriva-
tives. Chlorination of A to give B followed by its deprotonation
would lead to F as either Z or E N-chloroanions (Fig. 4). N-haloamides
such F are strong acids that are known to form well-characterized
but unstable sodium salts.52 Theoretically, either conformation
corresponds to a local minimum with the Z being more stable by
approximately 6 kcal/mol in the gas phase. Although the NC(O)NCl
atoms are all coplanar, this plane is almost orthogonal to that de-
fined by the diphenylamine. From Scheme 5, the chlorinated anions
would either lose chloride to go to a singlet nitrene intermediate, C,
Ph2NC(O)N, by heterolysis of the weak N–Cl bond. In analogy to
carbenes, nitrene intermediates such as C form either stable sin-
glet or triplet states, both of which correspond to local minima
with the triplet state being ϳ8.48 kcal/mol more stable (Table 2).
As shown in Fig. 4, these intermediates are predicted to have
completely planar NC(O)N groups that in their ground states are
coplanar with the diarylamine, which is also planar. The singlet
nitrene has an unusual geometry for the modified urea group
Structure RR=N
Absolute
and species
energy (au)a
(kcal/mol)b
Diphenylamine
Singlet nitrene
Transition state
Isocyanate
Triplet nitrene
2-Nitrophenylphenyl
Singlet nitrene
Transition state
Isocyanate
Triplet nitrene
2-Fluorophenylphenyl
Singlet nitrene
Transition state
Isocyanate
−686.39252451
−686.1829586
−686.46054470
−686.4060394
0
−0.83
129.61
−8.87
+6.88
−42.7
−8.48
−175.08
−890.944689
−890.7314099
−891.0124295
−890.960301
0
178.72
129.65
−44.08
−177.78
+7.80
−42.5
−9.80
−785.6488335
−785.441599
−785.716939
−785.6617371
0
−179.74
−115.06
−41.88
+10.53
−42.7
−8.10
Triplet nitrene
−171.50
aAll calculations performed with restricted B3LYP density functionals and
6-311++G** basis sets except for the triplet nitrenes where unrestricted methods
were employed. All ground-state energies are zero-point corrected.
bRelative energies from singlet nitrenes for ground states include zero-point
energy; the relative energies for the transitions states are for the electronic
components only.
cTorsion angle is from the ipso carbon of one of the two aryl rings to the diaryl
nitrogen and then to the carbonyl carbon and the terminal (nitrene) nitrogen.
with angles for the terminal nitrogen of 89.61° and 140.09° for
O−C−N and N−C−N, respectively. Both C–N bond lengths are short
with C−N to the terminal nitrogen being 1.27575 Å, which is
0.0722 Å shorter than to the diphenylamine. Significantly, in
these ground states, the migration to give the new N−N bond is
not well poised for a Hofmann rearrangement.
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Bain et al.
909
Fig. 5. Density functional theory results for the isomerization of
the singlet nitrene from Ph(2-O2NC6H4)N(CO)N, with a reaction
coordinate step (IRC) of approximately −10, to the corresponding
isocyanate with an IRC of appoximately 15. In the top panel, the
transition state with an IRC = 0 is shown to separate the two
minima and in the bottom panel, the C–N bond that breaks (solid
circles) is contrasted with the N–N bond that forms (open circles). At
an IRC of approximately 7, the two bond lengths are equal or the
C−N−N ring is an isosceles triangle. Note that in the top panel, the
nitro group is not shown in the structures.
Scheme 6. Related mechanisms for the Hofmann rearrangement
(R = aryl).
farther uphill. While solvation is expected to have some influence
on these energetics, when these calculations are transferred to a
polar aqueous media by using an Onsager model for the reaction
field for the optimized structures, the only notable difference
from the gas-phase data in Table 2 is a slight stabilization of the
singlet nitrene intermediate (Table S1). Thus, the key feature of
the profiles in Fig. 5 and for the diphenyl and the fluorine analogs
is that the only instance for the presence of a R2NC(O)N cyclic
species is in the transition state structure G. It is not an interme-
diate.
Earlier researchers have proposed that the Hofmann rearrange-
ment for disubstituted hydrazines goes through a cyclic aziridion-
one type intermediate, H, in Scheme 6.33 Here, a proposed species
such as H was described as “undoubtedly of high energy” but
“should exist as a discrete entity, occupying a small minimum on
the potential energy profile.” Related cations are thought to be
formed53 in the reactions for 1,2-dialkylureas. Density functional
theory predicts that intermediates such as H would not lead to a
protonated isocyanate D. The prediction of a high-energy minor
local minimum has not been borne out with density functional
theory calculations where the aziridones consistently appear only
as transition states. Indeed, species such as H are likely to have basic
nitrogen, and their generation and protonation consistently led
to net aromatic ring addition to give N-arylbenzimidazolone I
following ring addition and deprotonation. It is significant that
N-arylbenzimidazolones have not been seen as products in our
reactions. Thus, for the diarylureas used in our studies, the pres-
ence of cyclic aziridionone intermediates is unlikely.
The transition states for the Hofmann rearrangement were lo-
cated and then demonstrated to connect the singlet nitrene inter-
mediate C to the isocyanate D by reaction pathway following
intrinsic reaction coordinate (IRC) calculations. The nitrene side
of these potential energy surfaces corresponds to a rotational con-
former of the nitrene arising from rotation of the C(O)N group out
of the plane of the diaryl amine. As shown in Fig. 5, rotation of the
nitrene around the Ph2N–C(O)N bond so that it is orthogonal leads
to a state only 6.88 kcal/mol below the actual transition state,
which is reactant-like in geometry with a significantly lengthened
Ph2N–C bond of 1. 44992 Å. The gas-phase energy change for the
rearrangement is −42.7 kcal/mol, and hydrolysis to the product
hydrazine would render the rearrangement irreversible.
These values are only slightly smaller than those found for the
2-nitro derivative shown in Fig. 5. The transition states in these
transformations are reactant-like as can be seen in Fig. 5 (bottom)
where at the transition state, with a reaction following step IRC =
0, the N–C bonds are only marginally lengthened. Given the mag-
nitude of the energy change alone in Fig. 5, this reaction is irre-
versible, and to go back to the urea precursor would be even
Conclusions
We report here the first isolation of a functionalized 1,1-
diarylhydrazine in its basic form produced via a Hofmann rear-
rangement. Generation of the required precursors to the hydrazine
involves a rare intermediate sulfimidate species, which can be
isolated in aqueous medium with enhanced ionic strength and
subsequently decomposed by inhibiting its hydrogen-bonding
ability. This decomposition leads the corresponding urea, which
can be transformed using an easily controlled Hofmann rear-
rangement employing Ca(OCl)2 into the corresponding hydra-
zine, which bears potentially useful reactivity in its unsubstituted
form that has yet to be explored. Density functional theory sug-
gests that the rearrangement involves a single nitrene species
where the transition state for N−N bond formation is reached by
rotation of the C(O)N fragment out of the plane of the diarylamine
fragment. The methodology communicated here is suitable for
forming ureas from amines, which contain reduction-sensitive
functionalities such as methyl esters and nitro groups.
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Can. J. Chem. Vol. 92, 2014
1-(2-Nitrophenyl)-1-phenylhydrazine (3)
Experimental section
To 100 mL of distilled water was added 1-(2-nitrophenyl)-1-
phenylurea (0.69 g, 2.6 mmol) and the solution was cooled in ice for
30 min. Calcium hypochlorite (0.2648 g, 0.65 equiv.) was added
along with sodium hydroxide (0.5369 g, 5 equiv.). The suspension
was placed in an oil bath and refluxed for 1 h. The resulting red
solution was cooled and extracted (3 × 75 mL) with ethyl acetate to
remove the amine by-product. The aqueous phase was then acid-
ified, neutralized with sodium bicarbonate, and extracted (3 ×
50 mL) with dichloromethane. The organic washings were com-
bined, washed with saturated sodium chloride (3 × 50 mL), dried
over magnesium sulfate, and evaporated to yield a crude hydra-
zine in 0.498 g (80%) yield as a red oil. This red oil was then heated
under vacuum at 140 °C for 12 h and the residue combined with
ethanol, which, upon refrigeration, furnished the red crystalline
product in 0.243 g (55%) yield; mp 85.3–87.0 °C. 1H NMR (300 MHz,
DMSO-d) ␦ (ppm): 5.16 (s, 2H), 6.86 (t, 1H, J = 7.50 Hz), 7.03 (d, 2H, J =
8.7 Hz), 7.52 (m, 2H), 7.79 (d, 1H, J = 6.60 Hz). 13C NMR (300 MHz,
DMSO-d) ␦ (ppm): 116.6, 121.2, 123.7, 125.7, 125.8, 129.3, 133.7, 142.3,
143.7, 148.7. IR (KBr, cm−1): 476 (w), 510 (s), 613 (w), 658 (w), 697 (s),
748 (vs), 764 (s), 781 (m), 849 (s), 880 (s), 949 (s), 1037 (w), 1163 (w),
1191 (vw), 1247 (m), 1299 (m), 1367 (s), 1442 (m), 1488 (vs), 1518 (vs),
1590 (vs), 1621 (s), 3343 (w). HRMS calcd. for C12H11N3O2Na:
252.0743; found: 252.0756. Elemental anal. calcd. for C12H11N3O2:
C 62.87, H 4.84, N 18.33; found: C 62.94, H 4.80, N 18.52.
General methods
Benzene was dried over potassium/benzophenone and toluene
was dried over molecular sieves and stored under nitrogen before
use. All other reagents were obtained from commercial sources
and used as received. Melting points were recorded with a mi-
1
cromelting apparatus and were calibration corrected. H and
13C NMR spectra were recorded on a 300 MHz spectrometer. High-
resolution mass spectroscopy was measured by electrospray tech-
niques with a time of flight detector (ESI/TOF).
Sodium 1-(2-nitrophenyl)-1-phenylcarbamoylsulfimidate
pentahydrate (1)
A 500 mL three-necked flask equipped with a reflux condenser
and purged with nitrogen was charged with benzene (70 mL).
Solid 1-(2-nitrophenyl)-1-phenylamine (6.43 g, 30 mmol) was added
and the dark red solution was cooled in an ice bath for 30 min.
Chlorosulfonyl isocyanate (2.61 mL, 1 equiv.) was then added over
a period of 20 min. The mixture was left to stir cold for 30 min and
then warmed to room temperature and stirred for an additional
2 h. The resulting solid green intermediate was collected by filtra-
tion and dissolved in acetonitrile (300 mL). An aqueous solution of
sodium bicarbonate (200 mL, 5% w/w) was added and the mixture
was allowed to stir at room temperature for 4 h. Distilled water
was added to dissolve the precipitate produced and the biphasic
solution was left to crystallize at 4 °C. The resulting yellow crystals
were collected in 8.52 g (60%) yield; mp 180–182 °C. 1H NMR
(300 MHz, D2O) ␦ (ppm): 7.03 (t, 2H, J = 8.10 Hz), 7.15 (m, 5H), 7.35 (t,
1H, J = 7.3 Hz), 7.76 (dd, 1H, J = 9 Hz). 13C NMR (300 MHz, D2O) ␦
(ppm): 124.9, 125.6, 125.8, 127.6, 128.8, 130.2, 133.9, 138.2, 143.5,
145.7, 161.2. IR (KBr, cm−1): 507 (w), 599 (w), 643 (w), 699 (w), 776 (w),
848 (w), 858 (w), 1018 (vs), 1116 (m), 1146 (m), 1237 (vw), 1277 (w),
1307 (m), 1362 (s), 1394 (w), 1496 (w), 1530 (vs), 1603 (vs), 1660 (vw),
3501(br, vs), 3584 (m). Elemental anal. calcd. for C13H20N3Na2O11S:
C 33.13%, H 4.06%, N 8.91%, S 6.80%; found: C 33.22%, H 4.12%,
N 8.80%, S 6.51%.
Methyl 4-((2-nitrophenyl)amino)benzoate (4)
To a 250 mL three-necked flask equipped with a reflux con-
denser and flushed with nitrogen was added 2-nitroaniline
(2.000 g, 14.47 mmol), cesium carbonate (9.429 g, 2 equiv.), methyl
4-bromobenzoate (4.667 g, 1.5 equiv.), tris(dibenzylideneacetone)-
dipalladium(0) (0.416 g, 5 mol%), 2,2=-bis(diphenylphosphino)-1,1=-
binaphthyl (0.676 g, 7.5 mol%), and 50 mL of freshly dried toluene.
The contents were heated to 110 °C for 20 h. The mixture was then
cooled, filtered through a pad of celite, and the filtrate reduced to
small volume. The crude product was obtained by column chro-
matography on silica gel with dichloromethane as eluent and
rinsed with ethanol to furnish the pure product in 3.522 g (89%)
1
yield; mp 145–146 °C. H NMR (300 MHz, CDCl3) ␦ (ppm): 3.92 (s,
1-(2-Nitrophenyl)-1-phenylurea (2a)
3H), 6.90 (dt, 1H, J = 8.40 Hz), 7.30 (d, 2H, J = 8.70 Hz), 7.45 (d, 2H),
8.04 (d, 2H, J = 8.70), 8.21 (d, 1H, J = 8.70 Hz), 9.48 (s, 1H). 13C NMR
(300 MHz, CDCl3) ␦ (ppm): 52.1, 117.0, 119.2, 121.2, 125.8, 126.8, 131.3,
131.4, 131.5, 134.8, 135.6, 140.6, 143.6, 166.4. IR (KBr, cm−1): 736 (s),
764 (m), 1076 (w), 1106 (m), 1119 (w), 1149 (m), 1166 (m), 1175 (m),
1194 (vw), 1219 (sh), 1232 (m), 1268 (s), 1285 (s), 1308 (w), 1354 (m),
1403 (vw), 1428 (m), 1446 (vw), 1499 (m), 1515 (vs), 1574 (m), 1587 (m),
1604 (s), 1619 (w), 1724 (vs), 2958 (vw), 3067 (vw), 3326 (m). HRMS
calcd. for C14H12N2O4Na: 295.0689; found: 295.0684. Elemental
anal. calcd. for C14H12N2O4: C 61.76, H 4.44, N 10.29; found: C 61.62,
H 4.38, N 10.38.
A 500 mL three-necked flask equipped with a reflux condenser
and purged with nitrogen was charged with benzene (70 mL).
1-(2-Nitrophenyl)-1-phenylamine (12.85 g, 60 mmol) was added and
dissolved. The dark red solution was cooled in an ice bath and
chlorosulfonyl isocyanate (6.5 mL, 1.2 equiv.) was added over a
period of 20 min. The mixture was left to stir cold for 30 min and
then warmed to room temperature and stirred for an additional
2 h. The resulting solid green intermediate was collected by filtra-
tion and dissolved in acetonitrile (300 mL). An aqueous solution of
sodium bicarbonate (200 mL, 5% w/w) was added and the mixture
was allowed to stir at room temperature for 4 h. The resulting
mixture was evaporated under reduced pressure to remove the
volatile solvent. The crude product that resulted was stirred in
200 mL of benzene for 4 h and the insoluble portion was collected
and dissolved in 150 mL of ethyl acetate. The mixture was ex-
tracted three times with a 5% v/v solution of hydrochloric acid. The
organic phase was then washed three times with saturated so-
dium chloride (60 mL), dried over magnesium sulfate, and evap-
orated to give the crude urea. Recrystallization from ethanol
yielded the yellow−green crystalline product in 10.925 g (71%)
yield; mp 186–186.6 °C. 1H NMR (300 MHz, DMSO-d) ␦ (ppm): 6.23 (s
br, 2H), 7.14 (d, 1H, J = 8.10 Hz), 7.26–7.44 (m, 6H), 7.92 (dd, 1H, J =
8.40 Hz). 13C NMR (300 MHz, DMSO-d) ␦ (ppm): 125.2, 126.8, 127.4,
128.2, 130.1, 130.2, 134.2, 137.1, 142.4, 146.6, 156.3. IR (KBr, cm−1):
704 (m), 1146 (w), 1345 (m), 1392 (m), 1486 (w), 1523 (vs), 1594 (s),
1679 (vs), 3200 (w), 3293 (vw), 3351 (vw), 3478 (m). Elemental anal.
calcd. for C13H11N3O3: C 60.70, H 4.31, N 16.33; found: C 60.44,
H 4.28, N 16.21.
Methyl 4-(1-(2-nitrophenyl)ureido)benzoate (2b)
A 500 mL three-necked flask equipped with a reflux condenser
and purged with nitrogen was charged with benzene (70 mL).
Methyl 4-((2-nitrophenyl)amino)benzoate (1.20 g, 4.4 mmol) was
added and dissolved. The orange solution was cooled in an ice
bath and chlorosulfonyl isocyanate (0.46 mL, 1.2 equiv.) was added
over a period of 20 min. The mixture was left to stir cold for 30 min
and then warmed to room temperature and stirred for an addi-
tional 2 h. The resulting solid yellow−orange intermediate was
collected by filtration and dissolved in acetonitrile (300 mL). An
aqueous solution of sodium bicarbonate (200 mL, 5% w/w) was
added and the mixture was allowed to stir at room temperature
for 4 h. The resulting mixture was evaporated under reduced
pressure to remove the volatile solvent. The crude product that
resulted was stirred in 200 mL of benzene for 4 h and the insoluble
portion was collected and dissolved in 150 mL of ethyl acetate. The
mixture was extracted three times with a 5% v/v aqueous solution
Published by NRC Research Press

Bain et al.
911
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of hydrochloric acid. The organic phase was then washed three
times with saturated sodium chloride (60 mL), dried over magne-
sium sulfate, and evaporated to give the crude urea. Recrystalliza-
tion from ethanol gave the pale yellow crystalline product in
1
0.602 g (44%) yield; mp 219–220 °C. H NMR (300 MHz, DMSO-d)
␦ (ppm): 3.82 (s, 3H), 6.50 (s, br, 2H), 7.24 (d, 1H, J = 6.60 Hz), 7.33 (d,
2H, 8.70 Hz), 7.48 (t, 1H, J = 7.80 Hz), 7.66 (t, 1H, J = 7.80 Hz), 7.93 (t,
2H, 8.70 Hz), 8.00 (d, 1H, 9.00 Hz). 13C NMR (300 MHz, DMSO-d)
␦ (ppm): 52.6, 125.7, 126.8, 126.9, 128.0, 130.8, 131.1, 134.8, 136.4, 146.7,
146.9, 155.7, 166.2. IR (KBr, cm−1): 704 (s), 745 (m), 774 (m), 783 (s),
829 (vw), 849 (s), 1016 (w), 1027 (vw), 1054 (vw), 1110 (m), 1117 (s), 1171 (w),
1194 (w), 1281 (s), 1305 (m), 1358 (m), 1392 (s), 1436 (m), 1448 (w),
1509 (m), 1528 (vs), 1581 (w), 1601 (s), 1621 (m), 1693 (vs), 1726 (vs),
2953 (w), 3168 (s), 3307 (w), 3403 (vs). HRMS calcd. for C15H13N3O5Na:
338.0747; found: 338.0751. HRMS calcd. for KC15H13N3O5: 354.0487;
found: 354.0490. Elemental anal. calcd. for C15H13N3O5: C 57.04,
H 4.16, N 13.33; found: C 57.08, H 3.91, N 13.30.
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The X-ray diffraction data were measured with graphite mono-
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Theoretical methods
All of the calculations described above were performed using
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Supplementary material
Supplementary material is available with the article through
the journal Web site at http://nrcresearchpress.com/doi/suppl/
10.1139/cjc-2014-0132. Copies of all 1-D 1H and 13C NMR spectra and
crystallographic information (CIF) files for all new compounds sre
provided. In addition, ab initio theoretically calculated ground
states and vibrational frequencies are included.
Note added in proof
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Acknowledgements
This research was supported by NSERC discovery grants to
D.S.B. and I.S.B. The authors are grateful to Dr. Alexander Wahba
and Nadim Saade for mass spectrometry analysis.
ja00947a024.
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