Scalable, One-Pot, Microwave-Accelerated Tandem Synthesis of Unsymmetrical Urea Derivatives

Article abstract of DOI:10.1021/acs.joc.6b02521

We report a facile, microwave-accelerated, one-pot tandem synthesis of unsymmetrical ureas via a Curtius rearrangement. In this method, one-pot microwave irradiation of commercially available (hetero)aromatic acids and amines in the presence of diphenylphosphoryl azide enabled extremely rapid (1-5 min) construction of an array of unsymmetrical ureas in good to excellent yields. We demonstrate the utility of our method in the efficient, gram-scale synthesis of key biologically active compounds targeting the cannabinoid 1 and α7 nicotinic acetylcholine receptors.

Full text of DOI:10.1021/acs.joc.6b02521

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Article
Scalable, one-pot, microwave-accelerated tandem
synthesis of unsymmetrical urea derivatives
Abhijit R Kulkarni, Sumanta Garai, and Ganesh A Thakur
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02521 • Publication Date (Web): 14 Dec 2016
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Scalable, one-pot, microwave-accelerated tandem synthesis of unsymmetrical
urea derivatives
‡
‡
Abhijit R. Kulkarni , Sumanta Garai , Ganesh A. Thakur*
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Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern
University, 140 The Fenway, 360 Huntington Avenue, Boston, Massachusetts, 02115, United
States.
* g.thakur@neu.edu
ABSTRACT
We report a facile, microwave-accelerated, one-pot tandem synthesis of unsymmetrical ureas via
Curtius rearrangement. In this method, one-pot microwave irradiation of commercially available
(hetero)aromatic acids and amines in presence of diphenylphosphorylazide enabled extremely
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rapid (1-5 mins) construction of an array of unsymmetrical ureas in good to excellent yields. We
demonstrate the utility of our method in efficient, gram-scale synthesis of key biologically active
compounds targeting the cannabinoid 1 and α7 nicotinic acetylcholine receptors.
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INTRODUCTIONꢀ
Considerable attention has been devoted to the synthesis of the urea scaffold as it is an important
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motif in many biologically active natural products, pharmaceuticals, agrochemicals (e.g.
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Cumyluron as herbicide), material science and as organocatalysts. A large number of
biologically
Fig. 1. Diverse biologically active compounds with urea backbone
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important compounds like PKI-587, a potent kinase inhibitor as anti- cancer agent; Lisuride
maleate, an anti-Parkinson’s agent working through agonism at the dopamine D2 and D4
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receptors ; and PFI-1, a bromodomain-containing protein 4 inhibitor as an anti-cancer agent ,
have a urea skeleton (Fig. 1). Recent literature reports have cited use of the urea scaffold as lead
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molecules in the G-protein coupled receptor (GPCR) superfamily, such as SB 265610, a potent
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CXCR2 chemokine receptor inhibitors that obstructs HIV replication (Fig. 1); cannabinoid 1
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(
CB1) receptor negative allosteric modulators (NAMs) like PSNCBAM-1 (6), to treat obesity
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and addiction ; as well as in the ligand-gated ion channel (LGIC) receptor system as positive
allosteric modulators (PAMs) of the α7 nicotinic acetylcholine receptor (nAChR) like PNU-
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20596 (9), to treat neurological disorders like pain and Alzheimer’s disease . As these urea
analogs have shown (pre)clinical utility in treating several medical conditions, rapid construction
of novel libraries of a variety of urea derivatives still holds great demand. As a consequence, the
development of an efficient method for the synthesis of urea scaffold is an important area of
synthetic research.
Conventional approaches for urea synthesis involve the addition of an appropriate amine to
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isocyanates, which are moisture-sensitive, or the reaction of amines with triphosgene.
Alternative methods to synthesize unsymmetrical ureas include: (a) step-wise addition of amines
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to carbonyldiimidazole; (b) zirconium(IV)-catalyzed exchange process from dialkyl carbonates
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and carbamates; (c) direct carbonylation of primary amines using carbon monoxide; (d)
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transition-metal-catalyzed reactions and other miscellaneous urea formations reaction.
Carbamoyl chlorides and isocyanates have limited commercial availability, whereas phosgene
and triphosgene are toxic and moisture sensitive, thereby setting limitations to such approaches.
Isocyanates/acyl azides are unstable and therefore various methods have been developed to allow
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16b
their in situ generation from carbamates,
carbamic acids,
hydroxamic acids,
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acetoacetanilides. Such processes not only eliminate the need for isolation of potentially
unstable isocyanates, but also decrease the amount of chemical waste generated. Urea derivatives
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have also been obtained with sequential addition of amine to the isocyanate formed in situ,
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however with longer reaction time and in moderate yields. In most of the above reported urea
syntheses, multiple steps are required to obtain the desired urea and thus, a one-pot process that
allows the direct conversion of carboxylic acids into urea is desirable.
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Our laboratory is actively engaged in the synthesis of urea derivatives as biologically important
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compounds, especially, the allosteric modulators of the CB1 and the α7 nAChR. To expedite
the lead optimization process of identification of ‘druggable candidates’, there is a need for the
development of an efficient process for the synthesis of urea. Several methods that are accessible
for the synthesis of urea scaffold are plagued with severe drawbacks including the number of
steps for the synthesis, high reaction time, moderate yields, limited substrate scope, and use of
toxic, unstable, explosive (phosgene, inorganic azides) and bio-hazardous metallic reagents. In
this letter, we describe the one-pot, super-accelerated synthesis of urea which is facile and
versatile on gram scale.
RESULT AND DISCUSSION
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Although one-pot synthesis of carbamates and isocyanates is reported,
to the best of our
knowledge, there is no report on a one-pot tandem (one-step, non-sequential) synthesis of
unsymmetrical ureas using an acid and an amine. Initially we attempted a one-pot urea formation
reaction under conventional reflux conditions (Scheme 1) using 4-chlorobenzoic acid (1; 1.0
eq.), aniline (2; 1.0 eq.), triethylamine (TEA, 3.0 eq.) and diphenylphosphorylazide (DPPA; 1.2
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eq.) as a source of azide in toluene which reached completion in 3 h in good yield (70 %). With
this unprecedented observation, we wanted to optimize reaction conditions to improve yield and
reduce the reaction time. It has been well demonstrated that microwave-assisted synthesis is an
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important tool in organic and medicinal chemistry for enhancing the rate of reactions, improving
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reaction yields, and reducing thermal degradation byproducts.
Scheme 1. General scheme for one-pot urea formation
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ꢀ
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In our preliminary investigation, all the above reaction ingredients were added to a microwave
vial and irradiated at 100 °C, for 15 minutes. The desired urea was obtained in 55 % yield with
some amine unreacted (Table 1, entry 1). This yield was lower than that of the prototype
conventional reflux reaction. As this urea formation is a series of three tandem reactions in one-
pot: (a) acid to acid azide; (b) acid azide to isocyanate; and (c) isothiocyanate to urea; we
observed that if the aromatic acid and amine are reacted with equal stoichiometry, some
unconsumed amine remains in the reactions, reducing the overall yield. It was observed that with
the increase in the amount of acid, the amount of unreacted amine reduced and the yield
increased. Thus, 1.5 eq. of acid was found to be necessary for the highest yield (95 %) and any
further increase in the quantity of acid did not lead to any increase in yield (Table 1, entries 1-4)
and was used for the further optimization. Interestingly, we observed that gradually decreasing
the reaction time from 15 min to 1 min did not show any noticeable decrease in the yield (Table
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, entries 5-7). We also examined the temperature of microwave irradiation which indicated that
gradually decreasing the temperature of the microwave irradiation from 100 °C to 25 °C (rt)
increased the amount of unreacted starting materials (Table 1, entries 8-9) suggesting that 100 °C
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temperature is crucial for the complete consumption of acid. The next step in this optimization
protocol was to attempt a variety of aprotic
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Table 1. Optimization of urea formation under microwave irradiation
Isolated yield
Entry
Time (min) Temp (°C)
Solvent
Acid:
Amine
1.0:1.
1.2:1
1.5:1
2.0:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
(%)
a
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10
5
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100
100
100
100
100
100
25
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
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82
95
90
93
92
95
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b
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72
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91
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100
100
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1
DMSO
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solvents to form the reaction mixture. When high boiling and very polar solvent like dimethyl
sulfoxide (DMSO), and low boiling solvent like tetrahydrofuran (THF) were used, good
conversion to urea was observed but the yield was lower when compared to toluene as solvent
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(
entries 3, 10-11).
After establishing the optimum reaction conditions (Table 1, entry 7), we turned our attention
towards exploring various aromatic acids to examine the scope of the method (Table 2). We
evaluated the electronic requirement of this reaction, and relatively electronically neutral, rich
and deficient aromatic carboxylic acids yielded corresponding ureas in good to excellent yields
(88%
Table 2. Scope of (hetero)aromatic acids for the synthesis of urea
a = 17% aniline recovered; b = 85% conversion
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9%) in a short time (1 min) (2a-2h). This indicates that the rate and yield of the reaction was not
much influenced by the electronic properties of the substituents on the aromatic acid. Also, the
reaction proceeded with similar efficiency for o, m and p-chloro substitution on benzoic acid
(2d-2f). The reaction with relatively sterically hindered acid as well as polycyclic aromatic acid
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also occurred smoothly in short time (2h, 2i). More importantly a wide range of heterocyclic
acids with a thiophene, indole and isoquinoline core furnished the corresponding ureas in good
yields (45-55%) in relatively short time (1-3 min) (2j-2l). It is noteworthy that the triazole
moiety, which introduces one more amine to compete in the urea formation, was compatible for
this method (2m). Impressively, majority of the product was isolated with analytical purity by
filtration post workup when washed with cold dichloromethane, and the remaining minor
fraction was isolated by silica gel column chromatography. This method is not effective for
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phenyl acetic acid in which case we isolated only amide compound.
To further explore the scope of this reaction, a wide range of amines (Table 3) were used with 4-
chlorobenzoic acid under optimized reaction condition. Electron rich as well as deficient amines
demonstrated equal efficiency for the urea formation reaction (3a, 3b). Urea synthesis also
occurred smoothly and in short time with naphthalene amine in good yield (3c). It is worth
noting that several heterocyclic amines like pyridine, triazole, thiazole and 5-benzotriazole (3f-
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i) as well as aliphatic/alicyclic amines (3d, 3e) worked well with our method to yield
corresponding urea derivatives in moderate to excellent yields (68-95%) in a short time (1-5
min). The urea formation reaction was found to be effective with the presence of an array of
different functional groups such as amide and sulfonamide (3j-3k). Interestingly, when we
attempted this reaction with secondary amines it observed that in addition to the ureas, some
quantity of amides were formed and their proportion depended on the nucleophilicity of the
amine. However, amide formation with such secondary amines could be completely avoided by
sequential addition of amine to the microwaved mixture of acid, TEA and DPPA followed by
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microwave exposure for a minute. The simplicity and mildness of this method makes it a
versatile and useful transformation with potential for large scale applications up to gram scales.
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Table 3. Scope of (hetero)aromatic amines for the synthesis of urea
Having determined the effect of electronic and steric nature of the substituents on yield and time
of reaction through a variety of (hetero)aromatic and polycyclic acids and amines, this study
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revealed the versatility of this synthetic approach and diverse ureas could be obtained in
excellent to good yields without the need for purification and in short duration of time. Based on
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previous literature report, we have postulated a plausible mechanism for the one-pot,
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microwave-assisted unsymmetrical urea formation (Scheme 2).
Scheme 2. Plausible mechanism for the “one-pot” urea formation reaction.
Our next focus was on expanding the utility of our one-pot methodology in rapid and concise
synthesis of biologically important molecules. In receptor pharmacology and medicinal
chemistry, allosterism is a recent concept that is attracting significant attention due to several
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therapeutic advantages it provides over the orthosteric site targeting.
As a drug discovery
lab with an interest in capitalizing the medical benefits of allosteric modulators of the CB1
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receptor as well as the α7 nAChR, we chose two distinct receptor ligands PSNCBAM-1 and
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PNU-120596 targeting these receptor allosteric sites, respectively. PSNCBAM-1 has shown to
have hypophagic effects in rodent models and is a promising strategy for treating obesity and
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addiction through the CB1 receptor. Under our optimized conditions, the reaction between 4-
chlorobenzoic acid (4) and the tricyclic amine (5) led to the synthesis of PSNCBAM-1 (6) in
excellent yield (75 %). This was superior to the earlier reports in terms of reaction time and
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yield. PNU-120596 and other Type II PAMs of the α7 nAChR have been proven to be
neuroprotective in an in vivo model and hold the promise in the treatment of neuropathic pain
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and Alzheimer’s disease. Reaction between 5-chloro-2, 4-dimethoxy aniline (7) and 5-
methylisoxazol acid (8) under our optimized conditions led to the construction of PNU-120596
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(
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antagonist of the GIRK receptor in good yield from corresponding acid (10) and amine (11)
using this methodology in 2 min (Scheme 2).
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Scheme 3. Gram-scale synthesis of PSNCBAM-1, PNU-120596 and ML297
CONCLUSION
We have developed a convenient, efficient and one-pot route for the super-accelerated synthesis
of wide array unsymmetrical ureas through Curtius rearrangement in excellent yields using
readily available aromatic acids and amines. This novel protocol allows the synthesis of a variety
of biologically important ureas on gram-scale and in a short duration of time, and will prove to
be valuable in the iterative design of structural analogs to rapidly construct compound libraries.
EXPERIMENTAL SECTION
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All commercial chemicals and solvents were purchased from standard commercial sources as
reagent grade and unless otherwise specified were used without further purification. Biotage
Initiator microwave system was used for the synthesis of a few of the intermediates of the final
covalent probes. Reaction progress was monitored by thin-layer chromatography (TLC) using
commercially prepared silica gel 60 F254 glass plates. Compounds were visualized under
ultraviolet (UV) light or by staining with iodine, phosphomolybdic acid,or p-anisaldehyde
reagent. Flash column chromatography was carried out on an auto-flash purification unit using
pre-packed columns from Reveleris, Biotage and Luknova. Solvents used include hexanes, ethyl
acetate, acetone, methanol and dichloromethane. Characterization of compounds and their purity
were established by a combination of HPLC, TLC, mass spectrometry and NMR analyses. NMR
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spectra were recorded in DMSO-d6, chloroform-d or methanol-d4, on NMR spectrometer ( H
13
NMR at 500 MHz and C NMR at 125 MHz). Chemical shifts were recorded in parts per
million (δ) relative to tetramethylsilane (TMS; 0.00 ppm) or solvent peaks as the internal
reference. Multiplicities are indicated as br (broadened), s (singlet), d (doublet), t (triplet), q
(quartet), quin (quintet), sept (septet) or m (multiplet). Coupling constants (J) are reported in
hertz (Hz). All test compounds were greater than 95% pure as determined by LC/MS analysis
performed with dual-wavelength UV−visible detector and Quadrupole mass spectrometer
(electrospray ionization). HRMS was done on a MALDI-TOF-MS in a negative ion mode with a
delay time of 150 ns. Each sample well was surveyed to find a “sweet spot”, and then, 400 laser
pulses were averaged to generate a spectrum. MS/MS was performed with a medium pressure of
air and a mass resolution window of 400 with the metastable-ion suppressor on.
General Procedure: To a microwave vial was added a suspension of the carboxylic acid, the
amine, diphenyl phosphorylazide (DPPA) and triethyl amine (TEA) in anh. toluene and the
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reaction was irradiated in a Biotage Microwave Synthesizer for 1 – 5 min at 100 °C (surface
sensor). The reaction mixture was poured in water and extracted with dichloromethane/ethyl
acetate (3 x 50 mL). The combined organic layer was washed with water (20 ml), brine (20 ml),
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dried over Na SO and evaporated under vacuum. The crude residue was purified by silica gel
column chromatography (EtOAc:Hexane) to yield the desired urea. Refer to individual
compounds for details.
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,3-diphenylurea (2a) : Compound was synthesized according to the general procedure using
benzoic acid (393 mg, 3.22 mmol), aniline (200 mg, 2.14 mmol), DPPA (707 mg, 2.58 mmol)
1
and TEA (648 mg, 6.42 mmol) to give a white solid; H NMR (500 MHz, DMSO-d6) δ (s, 2H),
7
.45 (dd, J = 9.0 Hz, 1.0 Hz, 4H), 7.28 (dd, J = 8.5 Hz, 7.5 Hz, 4H), 6.97 (tt, J = 7.5 Hz, 1.0 Hz,
+
2H); MS-ESI (m/z): 213 [M+H] .
3
4
1-(4-methylphenyl)-3-phenylurea (2b) : Compound was synthesized according to the general
procedure using 4-methylbenzoic acid (345 mg, 3.22 mmol), aniline (200 mg, 2.14 mmol),
DPPA (485 mg, 2.56 mmol) and TEA (445 mg, 6.42 mmol) to give a white solid to give a white
1
solid; H NMR (500 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.50 (s, 1H), 7.42 (d, J = 8.0 Hz, 2H),
7
.31 (d, J = 8.5 Hz, 2H), 7.25 (t, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.94 (t, J = 7.5 Hz,
+
1H), 2.23 (s, 3H); MS-ESI (m/z): 227 [M+H]
3
4
1-(4-methoxyphenyl)-3-phenylurea (2c) : Compound was synthesized according to the
general procedure using 4-methoxybenzoic acid (490 mg, 3.22 mmol), aniline (200 mg, 2.14
1
mmol), DPPA (707 mg, 2.56 mmol) and TEA (648 mg, 6.42 mmol) to give a white solid.; H
NMR (500 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.45 (s, 1H), 7.43 (dd, J = 8.5 Hz, 1.0 Hz, 2H), 7.35
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(
d, J = 9.0 Hz, 2H), 7.26 (dd, J = 8.5 Hz, 7.5 Hz, 2H), 6.95 (tt, J = 7.5 Hz, 1.0 Hz, 1H), 6.87 (d, J
+
=
9.0 Hz, 2H), 3.71 (s, 3H); MS-ESI (m/z): 243 [M+H] .
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1-(4-chlorophenyl)-3-phenylurea (2d) : Compound was synthesized according to the general
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procedure using 4-chlorobenzoic acid (502 mg, 3.21 mmol), aniline (200 mg, 2.14 mmol), DPPA
1
(
706 mg, 2.56 mmol) and TEA (6.48 mg, 6.42 mmol) to give a white solid.; H NMR (500 MHz,
DMSO-d6) δ 8.80 (s, 1H), 8.69 (s, 1H), 7.48 (d, J = 9.0 Hz, 2H), 7.44 (dd, J = 8.5 Hz, 1.0 Hz,
2
H), 7.32 (d, J = 9.0 Hz, 2H), 7.28 (dd, J = 8.5 Hz, 7.5 Hz, 2H), 6.97 (tt, J = 7.5 Hz, 1.0 Hz, 1H)
+
; MS-ESI (m/z): 247 [M+H] .
3
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1-(3-chlorophenyl)-3-phenylurea (2e) : Compound was synthesized according to the general
procedure using 3-chlorobenzoic acid (502 mg, 3.21 mmol), aniline (200 mg, 2.14 mmol), DPPA
1
(
706 mg, 2.56 mmol) and TEA (6.48 mg, 6.42 mmol) to give a white solid.; H NMR (500 MHz,
DMSO-d6) δ 8.92 (s, 1H), 8.78 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.45 (dd, J = 7.0 Hz, 1.5 Hz,
+
2
H), 7.31 – 7.26 (m, 4H), 7.03 – 6.96 (m, 2H); MS-ESI (m/z): 247 [M+H] .
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-(2-chlorophenyl)-3-phenylurea (2f) : Compound was synthesized according to the general
procedure using 2-chlorobenzoic acid (502 mg, 3.21 mmol), aniline (200 mg, 2.14 mmol), DPPA
1
(
706 mg, 2.56 mmol) and TEA (6.48 mg, 6.42 mmol) to give a white solid.; H NMR (500 MHz,
DMSO-d6) δ 9.42 (s, 1H), 8.32 (s, 1H), 8.17 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 7.47 (dd, J = 8.5 Hz,
1
.0 Hz, 1H), 7.46 (dd, J = 8.0 Hz, 1.5 Hz, 1H), 7.33 – 7.27 (m, 3H), 7.06 – 7.01 (m, 1H), 6.99 (tt,
+
J = 7.0 Hz, 1.0 Hz, 1H); MS-ESI (m/z): 247 [M+H] .
3
4
1
-(4-nitrophenyl)-3-phenylurea (2g) : Compound was synthesized according to the general
procedure using 4-nitrobenzoic acid (538 mg, 3.22 mmol), aniline (200 mg, 2.14 mmol), DPPA
1
(
707 mg, 2.64 mmol) and TEA (648 mg, 6.42 mmol) to give a white solid.; H NMR (500 MHz,
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DMSO-d6) δ 9.45 (s, 1H), 8.32 (s, 1H), 8.20 (d, J = 9.5 Hz, 2H), 7.70 (d, J = 9.5 Hz, 2H), 7.48
(dd, J = 7.5 Hz, 1.0 Hz, 2H), 7.31 (td, J = 7.5 Hz, 1.5 Hz, 2H), 7.02 (tt, J = 7.5 Hz, 1.0 Hz, 1H);
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MS-ESI (m/z): 258 [M+H] .
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-mesityl-3-phenylurea (2h) : Compound was synthesized according to the general procedure
using 2,4,6-trimethylbenzoic acid (528 mg, 3.22 mmol), aniline (200 mg, 2.14 mmol), DPPA
1
(
707 mg, 2.58 mmol) and TEA (648 mg, 6.42 mmol) to give a white solid.; H NMR (500 MHz,
DMSO-d6) δ 8.66 (s, 1H), 7.60 (s, 1H), 7.44 (dd, J = 8.5 Hz, 1.0 Hz, 2H), 7.24 (t, J = 8.0 Hz,
2H), 6.92 (tt, J = 9.0 Hz, 1.0 Hz, 1H), 6.88 (s, 2H), 2.23 (s, 3H), 2.16 (s, 6H); MS-ESI (m/z): 255
+
[
M+H] .
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-(naphthalen-2-yl)-3-phenylurea (2i) : Compound was synthesized according to the general
procedure using 2-naphthalinic acid (469 mg, 2.99 mmol), aniline (200 mg, 2.14 mmol), DPPA
1
(
659 mg, 2.58 mmol) and TEA (605 mg, 6.42 mmol) to give a white solid.; H NMR (500 MHz,
DMSO-d6) δ 8.94 (s, 1H), 8.91 (s, 1H), 8.10 (s, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 8.5
Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.49 (dd, J = 8.5 Hz, 2.0 Hz, 1H),
+
7
.45 (t, J = 7.5 Hz, 1H), 7.40 – 7.30 (m, 3H); MS-ESI (m/z): 263 [M+H] .
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-(isoquinolin-3-yl)-3-phenylurea (2j) : Compound was synthesized according to the general
procedure using isoquinolinic acid (340 mg, 2.17 mmol), aniline (200 mg, 2.14 mmol), DPPA
0
1
(
497 mg, 2.58 mmol) and TEA (439 mg, 6.42 mmol) to give a white solid; mp 227-231 C; H
1
NMR (500 MHz, DMSO-d6) H NMR (500 MHz, DMSO-d6) δ 12.60 (s, 1H), 9.95 (s, 1H), 8.70
(d, J=8.5 Hz, 1H), 8.22 (d, J=6.0 Hz, 1H),7.94 (d, J=8.0 Hz, 1H), 7.82-7.79 (m, 1H), 7.68-7.67
13
(
m, 1H), 7.49 (d, J=5.5 Hz, 1H), 7.38-7.35 (m, 2H), 7.08 (t, J=7.5 Hz, 1H); C NMR (125 MHz,
DMSO d6): δ 152.54, 151.44, 139.85, 138.75, 138.33, 131.14, 128.93, 127.36, 127.10, 123.92,
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23.82, 119.58, 118.33, 115.48; MS-ESI (m/z): 264 [M+H] ; HRMS m/z [M + H] calcd for
16 13 3
C H N O 264.1131, found 264.1124.
1-(5-chlorothiophen-2-yl)-3-phenylurea (2k): Compound was synthesized according to the
general procedure using 5-chlorothiophene carboxylic acid (522 mg, 3.22 mmol), aniline (200
mg, 2.14 mmol), DPPA (707 mg, 2.56 mmol) and TEA (648 mg, 6.42 mmol) to give a white
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solid; mp 174-177 C; H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.82 (s, 1H), 7.44 (d, J =
8
.0 Hz, 2H), 7.29 (t, J = 8.0 Hz, 2H), 7.00 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 4.5 Hz, 1H), 6.37 (d, J
1
3
= 4.5 Hz, 1H); C NMR (125 MHz, DMSO d6): δ 151.7, 139.1, 139.0, 128.0, 123.3, 122.4,
+
1
2
18.6, 118.0, 107.4; MS-ESI (m/z): 253 [M+H] ; HRMS m/z [M + H]+ calcd for C11
H
9
ClN
2
OS
53.0197, found 253.0201.
1
-(1H-indol-2-yl)-3-phenylurea (2l): Compound was synthesized according to the general
procedure using 5-chloroindole carboxylic acid (630 mg, 3.22 mmol), aniline (200 mg, 2.14
mmol), DPPA (707 mg, 2.56 mmol) and TEA (648 mg, 6.42 mmol) to give an off-white solid;
0
1
mp 185-188 C; H NMR (500 MHz, DMSO-d6) δ 11.96 (s, 1H), 9.26 (s, 1H), 8.91 (s, 1H), 7.50
(
d, J = 7.5 Hz, 2H), 7.35-7.29 (m, 4H), 7.00 (t, J = 7.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.01 (s,
1
3
1
H); C NMR (DMSO d6, 125 MHz): 151.8, 139.2, 137.5, 131.2, 129.1, 128.9, 123.6, 122.2,
+
118.6, 118.4, 117.0, 112.2; MS-ESI (m/z): 286 [M+H] ; HRMS m/z [M + H]+ calcd for
15 3
C H12ClN O 286.0742, found 286.0727.
1
-(1H-benzo[d][1,2,3]triazol-5-yl)-3-phenylurea (2m): Compound was synthesized according
to the general procedure using 1H-benzo[d][1,2,3]triazol carboxylic acid (525 mg, 3.22 mmol),
aniline (200 mg, 2.14 mmol), DPPA (707 mg, 2.56 mmol) and TEA (648 mg, 6.42 mmol) to give
0
1
a white solid; mp 348-352 C; H NMR (500 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.75 (s, 1H), 8.16
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(
s, 1H), 7.90 (s, 1H), 7.48 (d, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.18 (s, 1H), 6.99 (t, J =
1
3
7
.5 Hz, 1H) C NMR (125 MHz, DMSO-d6): δ 152.72, 139.56, 128.86, 122.07, 118.42; MS-ESI
+
(m/z): 254 [M+H] ; HRMS m/z [M + H]+ calcd for C13
H
11
N
5
O 254.1036, found 254.1046.
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-(4-chlorophenyl)-3-(p-tolyl)urea (3a) : Compound was synthesized according to the general
procedure using 4-chlorobenzoic acid (438 mg, 2.80 mmol), p-toluidine (200 mg, 1.87 mmol),
1
DPPA (615 mg, 2.24 mmol) and TEA (566 mg, 5.60 mmol) to give a white solid; H NMR (500
MHz, DMSO-d6) δ 8.79 (s, 1H), 8.62 (s, 1H), 7.48 (d, J = 9.0 Hz, 2H), 7.36 – 7.29 (m, 4H), 7.09
+
(d, J = 8.5 Hz, 2H), 2.25 (s, 3H); MS-ESI (m/z): 261 [M+H] .
4
1
1-(4-chlorophenyl)-3-(4-methoxyphenyl)urea (3b) : Compound was synthesized according to
the general procedure using 4-chlorobenzoic acid (381 mg, 2.44 mmol), 4-methoxyaniline (200
mg, 1.63 mmol), DPPA (537 mg, 1.95 mmol) and TEA (492 mg, 4.88 mmol) to give a white
1
solid; H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.54 (s, 1H), 7.47 (d, J = 9.0 Hz, 2H), 7.35
(d, J = 9.0 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 3.71 (s, 3H); MS-ESI
+
(m/z): 277 [M+H] .
4
2
1-(4-chlorophenyl)-3-(naphthalen-2-yl)urea (3c) : Compound was synthesized according to
the general procedure using 4-chlorobenzoic acid (345 mg, 2.20 mmol), 2-naphthylamine (200
mg, 1.47 mmol), DPPA (485 mg, 1.76 mmol) and TEA (445 mg, 4.41 mmol) to give a white
1
solid. H NMR (500 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.91 (s, 1H), 8.10 (s, 1H), 7.84 (d, J = 9.0
Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.49 (dd, J =
+
8.5 Hz, 2.0 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.40 – 7.30 (m, 3H); MS-ESI (m/z): 297 [M+H] .
4
3
1-(4-chlorophenyl)-3-cyclohexylurea (3d) : Compound was synthesized according to the
general procedure using 4-chlorobenzoic acid (473 mg, 3.02 mmol), cyclohexylamine (200 mg,
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.02 mmol), DPPA (666 mg, 2.42 mmol) and TEA (610 mg, 6.05 mmol) to give a white solid;
1
H NMR (500 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz,
2
H), 6.15 (d, J = 7.5 Hz, 1H), 3.51 – 3.38 (m, 1H), 1.83 – 1.74 (m, 2H), 1.69 – 1.59 (m, 2H),
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60
+
1
.56 – 1.47 (m, 1H), 1.35 – 1.24 (m, 2H), 1.20 – 1.09 (m, 3H); MS-ESI (m/z): 253 [M+H] .
4
4
1
-(tert-butyl)-3-(4-chlorophenyl)urea (3e) : Compound was synthesized according to the
general procedure using 4-chlorobenzoic acid (473 mg, 3.02 mmol), tert-butyl amine (200 mg,
2
.02 mmol), DPPA (666 mg, 2.42 mmol) and TEA (610 mg, 6.05 mmol) to give a white solid.
1
H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.37 (d, J = 9.0 Hz, 2H), 7.23 (d, J = 9.0 Hz,
+
2
H), 6.00 (s, 1H), 1.28 (s, 9H); MS-ESI (m/z): 227 [M+H] .
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-(4-chlorophenyl)-3-(pyridin-2-yl)urea (3f) : Compound was synthesized according to the
general procedure using 4-chlorobenzoic acid (499 mg, 3.19 mmol), 2-aminopyridine (200 mg,
2
.12 mmol), DPPA (700 mg, 2.54 mmol) and TEA (642 mg, 6.36 mmol) to give a white solid;
1
H NMR (500 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.51 (s, 1H), 8.28 (ddd, J = 5.5 Hz, 2.0 Hz, 1.0
Hz, 1H), 7.75 (tdd, J = 7.0 Hz, 2.0 Hz, 1.0 Hz, 1H), 7.57 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 8.5 Hz,
1
H), 7.36 (d, J = 9.5 Hz, 2H), 7.01 (ddd, J = 7.5 Hz, 5.0 Hz, 1.0 Hz, 1H); MS-ESI (m/z): 248
+
[M+H] .
1
-(4-chlorophenyl)-3-(thiazol-5-yl)urea (3g): Compound was synthesized according to the
general procedure using 4-chlorobenzoic acid (469 mg, 2.99 mmol), thiazol-5-amine (200 mg,
.77 mmol), DPPA (659 mg, 2.39 mmol) and TEA (605 mg, 5.99 mmol) to give a white solid;
1
0
1
mp 250-254 C; H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.10 (s, 1H), 7.53 (d, J = 9.0
1
3
Hz, 2H), 7.39 (d, J = 3.5 Hz, 1H), 7.37 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 4.0 Hz, 1H); C NMR
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(
125 MHz, DMSO d6): δ 159.7, 151.9, 137.8, 136.8, 128.8, 126.3, 120.2, 112.4; MS-ESI (m/z):
+
2
54 [M+H] ; HRMS m/z [M + H]+ calcd for C10
H
8
ClN
3
OS 254.0149, found 254.0152.
1-(4-chlorophenyl)-3-(1H-1,2,3-triazol-4-yl)urea (3h): Compound was synthesized according
to the general procedure using 4-chlorobenzoic acid (558 mg, 3.56 mmol), 1H-1,2,3-triazol-4-
amine (200 mg, 2.38 mmol), DPPA (768 mg, 2.86 mmol) and TEA (721 mg, 7.14 mmol) to give
0
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9
0
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8
9
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9
0
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7
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9
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a white solid; mp 319-322 C; H NMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.73 (d, J = 9.0
13
Hz, 2H), 7.67 (s, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.35 (s, 2H); C NMR (125 MHz, DMSO d6): δ
+
157.0, 150.1, 149.0, 136.3, 128.5, 128.1, 122.6; MS-ESI (m/z): 238 [M+H] ; HRMS m/z [M +
9 8 5
H]+ calcd for C H ClN O 238.0490, found 238.0482.
1
-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-chlorophenyl)urea (3i): Compound was synthesized
according to the general procedure using 4-chlorobenzoic acid (350 mg, 2.24 mmol), 1H-
benzo[d][1,2,3]triazol-5-amine (200 mg, 1.49 mmol), DPPA (489 mg, 1.78 mmol) and TEA (448
0
1
mg, 4.40 mmol) to give a white solid; mp 340-343 C; H NMR (500 MHz, DMSO-d6) δ 9.07 (s,
1H), 8.93 (s, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.51 (d, J = 9.0 Hz, 1H),
13
7
1
.35 (d, J = 8.5 Hz, 1H), 7.29 – 7.15 (m, 1H); C NMR (125 MHz, DMSO-d6): δ 152.6, 138.6,
+
28.7, 125.6, 119.9; MS-ESI (m/z): 288 [M+H] ; HRMS m/z [M + H]+ calcd for C13
H
10ClN
5
O
2
88.0647, found 288.0660.
4-(3-(4-chlorophenyl)ureido)benzenesulfonamide (3j): Compound was synthesized according
to the general procedure using 4-chlorobenzoic acid (272 mg, 1.74 mmol), sulfanilamide (200
mg, 1.16 mmol), DPPA (383 mg, 1.39 mmol) and TEA (352 mg, 3.48 mmol) to give a white
0
1
solid; mp 244-247 C; H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.94 (s, 1H), 7.73 (d, J =
8
.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.21 (s,
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H); C NMR (125 MHz, DMSO-d6): 152.2, 142.7, 137.0, 128.7, 126.8, 125.8, 120.0, 117.6;
+
MS-ESI (m/z): 326 [M+H] ; HRMS m/z [M + H]+ calcd for C13
H
12ClN
3
O
3
S 326.0361, found
3
26.0360.
-(3-(4-chlorophenyl)ureido)benzamide (3k): Compound was synthesized according to the
10
11
12
13
14
15
16
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general procedure using 4-chlorobenzoic acid (345 mg, 2.20 mmol), 4-aminobenzamide (200
mg, 1.47 mmol), DPPA (485 mg, 1.76 mmol) and TEA (445 mg, 4.41 mmol) to give a white
0
1
solid; mp 288-291 C; H NMR (500 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.96 (s, 1H), 7.83 (d, J =
1
3
9.0 Hz, 3H), 7.51 (t, J = 9.0 Hz, 4H), 7.33 (d, J = 8.5 Hz, 2H), 7.21 (s, 1H); C NMR (125 MHz,
DMSO-d6): 167.7, 152.3, 142.4, 138.5, 128.7, 128.6, 127.5, 125.7, 119.9, 117.2; MS-ESI (m/z):
+
2
90 [M+H] ; HRMS m/z [M + H]+ calcd for C14
H12ClN
3
O
2
290.0691, found 290.0681.
1
0
1
-(4-chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea(6) : Compound was
synthesized according to the general procedure using 4-chlorobenzoic acid (1.24 g, 7.35 mmol),
3
-(6-(pyrrolidin-1-yl)pyridin-2-yl)aniline (1 g, 4.90 mmol), DPPA (1.87 g, 7.99 mmol) and TEA
1
(
1.80 g, 15.99 mmol) to give a white solid. H NMR (500 MHz, DMSO-d6) δ 8.82 (d, J = 12.00
Hz, 2H), 8.08 (s, 1H), 7.43−7.71 (m, 5H), 7.23−7.40 (m, 3H), 7.06 (d, J = 7.5 Hz, 1H), 6.42 (d, J
+
=
8.5 Hz, 1H), 3.48 (br s, 4H), 1.97 (br s, 4H); MS-ESI (m/z): 393 [M+H] .
1
4
1
-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea(9) :
Compound
was
synthesized according to the general procedure using 4-methyloxazole carboxylic acid (934 mg,
7
.35 mmol), 5-chloro-2,4-dimethoxyaniline (920 mg, 4.90 mmol), DPPA (2.20 g, 7.99 mmol)
1
and TEA (1.60 g, 15.99 mmol) to give a white solid. H NMR (500 MHz, DMSO-d6) δ 9.90 (s,
1
H), 8.60 (s, 1H), 8.11 (s, 1H), 6.87 (s, 1H), 6.48 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 2.35 (s, 3H);
+
MS-ESI (m/z): 312 [M+H] .
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32
1
-(3,4-difluorophenyl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea(12) : Compound was
synthesized according to the general procedure using 3,4-difluorobenzoic acid (1.368 gm, 8.66
mmol), 3-methyl-1-phenyl-1H-pyrazol-5-amine (1 gm, 5.78 mmol), DPPA (1.908 gm, 6.92
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
mmol) and TEA (2.60 g, 26.0 mmol) to give a white solid. H NMR (500 MHz, DMSO-d6) δ
9.48 (s, 1H), 8.80 (s, 1H), 7.92-7.90 (m, 1H), 7.88-7.80 (m, 4H), 7.73-7.69 (m, 1H), 7.63 (q, J =
+
1
0.0 Hz, 1H), 7.38-7.36 (m, 1H), 6.58 (s, 1H), 2.19 (s, 3H). MS-ESI (m/z): 331 [M+H] .
ASSOCIATED CONTENT
Supporting Information
1
The Supporting Information is available free of charge on the ACS Publications website. H and
1
3
C spectra and characterization of all new compounds is included.
AUTHOR CONTRIBUTIONS
‡
These authors contributed equally.
ACKNOWLEDGMENT
This work was supported by National Institutes of Health Grants DA027113 and EY024717 to
G.A.T. The authors are thankful to Drs. Giese and Kulkarni for their help with HRMS.
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