Key words
amides - ureas - hypervalent iodine - Hofmann rearrangement - isocyanates
Due to their interesting physicochemical and biological properties, urea-containing
molecules are increasingly used in various research fields such as medicinal chemistry,[1] agrochemistry[2] and petrochemistry.[3] In particular, the extensive utilization of such moieties in drug discovery as bioisosteres
of peptide bonds arises from their structural, biological and electronic similarities.[4]
This key structural motif (Figure [1]) can be found in natural products such as the amino acid citrulline (1) and allantoin (2), in marketed drugs such as cetrorelix (a decapeptide for in vitro fertilization)[5] and degarelix (treatment of prostate cancer),[6] and in several molecules with different biological activities such as anticancer
(3, a checkpoint kinase inhibitor),[7] anti-obesity (4),[8] antiviral (5)[9] and antibacterial (6).[10] In addition, primary ureas are not only useful in medicinal chemistry but can also
be employed as versatile building blocks for further transformations.[11]
Figure 1 Biologically active compounds containing a primary urea moiety
Since the first synthesis of urea from ammonium cyanate by Wöhler in 1828, historically
considered as the birth of organic chemistry,[12] researchers have developed a myriad of synthetic methods in order to prepare them.
One of the most common method implies the reaction between ammonia and isocyanates,
albeit with safety concerns.[13] Consequently, isocyanates are usually formed in situ thanks to Hofmann, Curtius
or Lossen rearrangements,[14] respectively from primary carboxamides, acyl azides and bis-acylated hydroxylamines.
Interestingly, hypervalent iodine species appeared to be suitable oxidizing reagents
for the Hofmann rearrangement, since they are mild, powerful, and are able to react
with amide substrates without added base. Under various conditions, amines,[15] carbamates[16] and symmetric 1,3-disubstituted ureas[17] can be prepared (Scheme [1]).
Herein, we report a straightforward synthesis of primary alkyl- and arylureas (Scheme
[1]) by addition of ammonia to in situ generated isocyanates, proceeding via the Hofmann
rearrangement of primary amides induced by phenyliodine diacetate (PIDA).
Scheme 1 Reactions of carboxamides with hypervalent iodine species
Numerous methods have been developed for the synthesis of primary ureas (Scheme [2]) using different precursors. Examples include carboxylic acids,[18] phenyl carbamate,[19] anilines in the presence of urea,[20] aryl chlorides by Pd-catalyzed cross-couplings with benzylurea followed by in situ
hydrogenolysis,[21] arylcyanamides by hydration reactions (with or without HCO2H),[22] amines by nucleophilic addition to potassium isocyanate,[23] nitriles via the Tiemann rearrangement,[24] or arenes by CH amination.[25]
Scheme 2 Literature methods for the preparation of primary ureas
Originally, the unexpected formation of an N-substituted urea was observed during
the investigation of the one-pot synthesis of 3H-diazirines from α-amino acids,[26] using PIDA and a methanolic solution of ammonia. Under these conditions, l-glutamine afforded a crystalline compound 7, X-ray analysis of which[27] revealed that the amide moiety was converted into the corresponding primary urea
(Scheme [3]).
Scheme 3 Formation of diazirine 7 (from l-glutamine) and its X-ray crystal structure (packing with H-bonding)
Since the formation of methyl carbamate 8
[19] was not observed, despite the presence of methanol in the reaction medium,[28] we assumed that the isocyanate intermediate, formed in situ via a Hofmann-like rearrangement,[29] was trapped by ammonia which is more nucleophilic (Scheme [4]).
Scheme 4 Proposed mechanism
Table 1 Optimization of the Reaction Conditions for the Formation of 9a
 
|
|
Entry
|
PIDA (equiv)
|
NH3 (equiv)
|
Temp
|
Isolated yield (%)
|
|
1
|
1
|
5.0
|
rt
|
47
|
|
2
|
1
|
5.0
|
0 °C to rt
|
51
|
|
3
|
2
|
5.0
|
0 °C to rt
|
70
|
|
4
|
3
|
5.0
|
0 °C to rt
|
50
|
|
5
|
2
|
10.0
|
0 °C to rt
|
80
|
|
6
|
2
|
15.0
|
0 °C to rt
|
85
|
|
7
|
2
|
17.5
|
0 °C to rt
|
>99
|
Based on this encouraging result, optimization of the reaction conditions was carried
out using 4-methoxybenzamide as a model substrate (Table [1]). Using the same amounts of methanolic ammonia and PIDA, the reaction performed
at 0 °C afforded the desired urea 9a in a better yield than at room temperature (entries 1 and 2). Increasing the amount
of PIDA to 2 equivalents improved the yield of the reaction, however, higher amounts
were not beneficial (entries 3 and 4). Finally, 17.5 equivalents of methanolic ammonia
were required to obtain the urea in a quantitative yield (entries 5–7).
With optimized conditions in hand (conditions A), different alkyl-, aryl- and heteroaryl-amides
were converted into the corresponding primary ureas 9a–r (Scheme [5]).
Scheme 5 Scope of the reaction. a An additional amount of PIDA/NH3 was added and the reaction time was extended to 48 h.
Reactions with aromatic amides bearing electron-donating (9a–c,n) or deactivating groups (9f,o) afforded the corresponding ureas in good to excellent yields, as well as pyridyl-
(9h), phenyl- (9i) and benzylureas (9m). Although aliphatic amides were fully converted into the expected ureas (9k,l), the loss of small amounts of the products during purification was observed due
to their volatility and consequently impacted their isolated yields. Furthermore,
the reaction time was extended to 48 hours to achieve the synthesis of compounds 9g, 9j and 9p in high yields. On the other hand, the presence of an electron-withdrawing group
on the aromatic amide seemed to lower the reaction yield of this transformation since
4-cyanophenylurea 9d was obtained in only 16% yield and 4-nitrophenylurea 9e could not be prepared using this procedure.[30] However, it was possible to increase the electrophilicity of PIDA by using a highly
polar and strong hydrogen-bond donating solvent, such as 2,2,2-trifluoroethanol (TFE).[31] Moreover, we reasoned that using a slow ammonia release source, such as ammonium
carbamate (AC), would improve the yield as we had already shown in the sulfoximination
reaction of sulfides.[32] Hence, it was found that performing the reaction using conditions B (Scheme [5]) allowed the synthesis of compounds 9d and 9e in 95% and 98% yields, respectively. In contrast, a substrate with an aromatic ring
bearing a 4-OH group failed to give the desired urea 9q,[33] whereas that with a 2-OH group gave the cyclic carbamate 9r isolated in quantitative yield. However, 2-furamide did not react under both sets
of conditions.
In conclusion, an easy, mild and affordable method to convert primary carboxamides
into N-substituted ureas has been developed by utilizing a PIDA-induced Hofmann rearrangement
followed by addition of ammonia. The reactivity of the hypervalent reagent was increased
by using TFE as the solvent and AC as the ammonia source, allowing the synthesis of
aromatic ureas bearing electron-withdrawing groups. This reaction allows access to
a wide range of alkyl-, aryl- and heteroarylureas which could potentially possess
interesting biological activities.
Column chromatography was performed on Merck silica gel (230–400 mesh). Thin-layer
chromatography was performed using Merck pre-coated, aluminium-backed silica gel plates.
Melting points were determined using a Gallen-Kamp melting point apparatus. IR spectra
were recorded on a PerkinElmer ATR-spectrum one spectrometer. 1H NMR spectra were recorded at 500 MHz or 600 MHz and 13C NMR spectra were recorded at 125 MHz or 150 MHz on Bruker Avance III 500 and Avance
600 Neo spectrometers. High-resolution mass spectrometry (HRMS) was performed using
a Xevo G2-XS QTof Waters mass spectrometer equipped with an electrospray ion source
(ESI) operated in positive ion mode.
N-Substituted Ureas; General Procedure A
N-Substituted Ureas; General Procedure A
(Diacetoxyiodo)benzene (1.0 mmol, 2.0 equiv) was added in one portion to a stirred
solution of the amide (0.5 mmol, 1.0 equiv) in NH3/MeOH (7 M, 1.25 mL, 17.5 equiv) at 0 °C under argon. After 30 min at 0 °C, the reaction
mixture was allowed to reach room temperature and was left to stir for 90 min. After
completion (monitored by TLC and 1H NMR), the reaction mixture was concentrated under reduced pressure and the crude
product was purified by flash chromatography on silica gel.
N-Substituted Ureas; General procedure B
N-Substituted Ureas; General procedure B
(Diacetoxyiodo)benzene (1.0 mmol, 2.0 equiv) was added in one portion to a stirred
solution of the amide (0.5 mmol, 1.0 equiv) and ammonium carbamate (AC) (0.75 mmol,
1.5 equiv) in trifluoroethanol (1.25 mL) at 0 °C under argon. After 30 min at 0 °C,
the reaction mixture was allowed to reach room temperature and was left to stir for
9 h. Additional amounts of PIDA and AC (1.0 equiv each) were added at rt and the reaction
mixture was stirred for 12 h at rt. After concentration of the reaction mixture under
reduced pressure, the crude product was purified by flash chromatography on silica
gel.
1-(4-Methoxyphenyl)urea (9a)
1-(4-Methoxyphenyl)urea (9a)
Prepared according to General Procedure A using 4-methoxybenzamide (75.6 mg, 0.5
mmol) and purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95:5) to afford urea 9a (83.1 mg, 99%) as a brown solid.
Mp 163 °C; Rf
= 0.2 (CH2Cl2/MeOH, 95:5).
IR (ATR): 3469, 3301, 1643, 1542, 1215, 1037, 822, 561 cm–1.
1H NMR (600 MHz, DMSO-d
6): δ = 8.30 (s, 1 H, NH), 7.28 (d, J = 9.0 Hz, 2 H, CHAr
), 6.80 (d, J = 9.0 Hz, 2 H, CHAr
), 5.71 (s, 2 H, NH2
), 3.68 (s, 3 H, OCH3
).
13C NMR (150 MHz, DMSO-d
6): δ = 156.2 (CO), 153.9 (CAr), 133.7 (CAr), 119.4 (CAr), 113.8 (CAr), 55.1 (OCH3).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C8H11N2O2: 167.0821; found: 167.0821.
1-(2-Ethoxyphenyl)urea (9b)
1-(2-Ethoxyphenyl)urea (9b)
Prepared according to General Procedure A using 2-ethoxybenzamide (82.6 mg, 0.5 mmol)
and purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95:5) to afford urea 9b (90.1 mg, 99%) as a brown solid.
Mp 115 °C; Rf
= 0.3 (CH2Cl2/MeOH, 95:5).
IR (ATR): 3484, 3328, 3198, 1661, 1525, 1450, 1249, 1045, 746 cm–1.
1H NMR (600 MHz, DMSO-d
6): δ = 8.07 (dd, J = 7.8, 1.8 Hz, 1 H, CHAr
), 7.75 (s, 1 H, NH), 6.93 (dd, J = 7.8, 1.8 Hz, 1 H, CHAr
), 6.79–6.85 (m, 2 H, CHAr
), 6.24 (br s, 2 H, NH2
), 4.08 (q, J = 7.0 Hz, 2 H, OCH2
CH3), 1.38 (t, J = 7.0 Hz, 3 H, OCH2CH3
).
13C NMR (150 MHz, DMSO-d
6): δ = 156.0 (CO), 146.5 (CAr), 129.7 (CAr), 121.0 (CAr), 120.4 (CAr), 118.3 (CAr), 111.6 (CAr), 63.8 (OCH2CH3), 14.7 (OCH2
CH3).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C9H13N2O2: 181.0977; found: 181.0977.
1-(p-Tolyl)urea (9c)
Prepared according to General Procedure A using p-toluamide (67.6 mg, 0.5 mmol) and purified by flash chromatography on silica gel
(CH2Cl2/MeOH, 95:5) to afford urea 9c (71.3 mg, 95%) as a white solid.
Mp 180 °C; Rf
= 0.4 (CH2Cl2/MeOH, 95:5).
IR (ATR): 3422, 3306, 1650, 1589, 1546, 1354, 811, 550, 501 cm–1.
1H NMR (500 MHz, DMSO-d
6): δ = 8.37 (s, 1 H, NH), 7.26 (d, J = 8.1 Hz, 2 H, CHAr
), 7.01 (d, J = 8.1 Hz, 2 H, CHAr
), 5.75 (s, 2 H, NH2
), 2.20 (s, 3 H, CH3
).
13C NMR (125 MHz, DMSO-d
6): δ = 156.0 (CO), 138.0 (CAr), 129.7 (CAr), 129.0 (CAr), 117.8 (CAr), 20.3 (CH3).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C8H11N2O: 151.0871; found: 151.0873.
1-(4-Cyanophenyl)urea (9d)
1-(4-Cyanophenyl)urea (9d)
Prepared according to General Procedure B using 4-cyanobenzamide (73.1 mg, 0.5 mmol)
and purified by flash chromatography on silica gel (CH2Cl2/EtOH, 97:3) to afford urea 9d (76.5 mg, 95%) as a white solid.
Mp 220 °C; Rf
= 0.2 (CH2Cl2/EtOH, 97:3).
IR (ATR): 3484, 3379, 2219, 1678, 1587, 1538, 1361, 835, 510 cm–1.
1H NMR (500 MHz, DMSO-d
6): δ = 9.07 (s, 1 H, NH), 7.65 (d, J = 8.5 Hz, 2 H, CHAr
), 7.57 (d, J = 8.5 Hz, 2 H, CHAr
), 6.12 (s, 2 H, NH2
).
13C NMR (125 MHz, DMSO-d
6): δ = 155.5 (CO), 145.1 (CAr), 133.1 (CAr), 119.5 (CN), 117.5 (CAr), 102.4 (CAr).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C8H8N3O: 162.0667; found: 162.0667.
1-(4-Nitrophenyl)urea (9e)
1-(4-Nitrophenyl)urea (9e)
Prepared according to General Procedure B using 4-nitrobenzamide (83.1 mg, 0.5 mmol)
and purified by flash chromatography on silica gel (CH2Cl2/EtOH, 97:3) to afford urea 9e (88.7 mg, 98%) as a white solid.
Mp 225 °C; Rf
= 0.1 (CH2Cl2/EtOH, 97:3).
IR (ATR): 3486, 3378, 1687, 1547, 1483, 1316, 1095, 854, 692 cm–1.
1H NMR (500 MHz, DMSO-d
6): δ = 9.31 (br s, 1 H, NH), 8.13 (d, J = 9.1 Hz, 2 H, CHAr
), 7.63 (d, J = 9.1 Hz, 2 H, CHAr
), 6.22 (br s, 2 H, NH2
).
13C NMR (125 MHz, DMSO-d
6): δ = 155.3 (CO), 147.3 (CAr), 140.4 (CAr), 125.1 (CAr), 116.9 (CAr).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C7H8N3O3: 182.0566; found: 182.0567.
1-(4-Bromophenyl)urea (9f)
1-(4-Bromophenyl)urea (9f)
Prepared according to General Procedure A using 4-bromobenzamide (100.0 mg, 0.5 mmol)
and purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95:5) to afford urea 9f (78.0 mg, 73%) as a white solid.
Mp 226 °C; Rf
= 0.3 (CH2Cl2/MeOH, 95:5).
IR (ATR): 3417, 3306, 3213, 1651, 1582, 1544, 1486, 1353, 815, 586 cm–1.
1H NMR (500 MHz, DMSO-d
6): δ = 8.67 (s, 1 H, NH), 7.37 (s, 4 H, CHAr
), 5.91 (s, 2 H, NH2
).
13C NMR (125 MHz, DMSO-d
6): δ = 155.8 (CO), 140.0 (CAr), 131.3 (CAr), 119.6 (CAr), 112.3 (CAr).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C7H8N2OBr: 214.9820; found: 214.9832.
1-(4-Chlorophenyl)urea (9g)
1-(4-Chlorophenyl)urea (9g)
Prepared according to General Procedure A using 4-chlorobenzamide (77.8 mg, 0.5 mmol).
Additional amounts of PIDA (0.25 mmol) and NH3 in MeOH (7 M, 0.3 mL) were added after 16 h and the mixture was left stirring for
an additional 24 h. The mixture was concentrated under reduced pressure and the residue
was purified by flash chromatography on silica gel (CH2Cl2/EtOH, 95:5) to afford urea 9g (76.8 mg, 90%) as a white solid.
Mp 209 °C; Rf
= 0.3 (CH2Cl2/MeOH, 95:5).
IR (ATR): 3419, 3311, 1651, 1545, 1490, 1090, 820, 585, 489 cm–1.
1H NMR (500 MHz, DMSO-d
6): δ = 8.66 (s, 1 H, NH), 7.42 (d, J = 8.5 Hz, 2 H, CHAr
), 7.24 (d, J = 8.5 Hz, 2 H, CHAr
), 5.90 (s, 2 H, NH2
).
13C NMR (125 MHz, DMSO-d
6): δ = 155.8 (CO), 139.6 (CAr), 128.4 (CAr), 124.5 (CAr), 119.2 (CAr).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C7H8N2OCl: 171.0325; found: 171.0328.
1-(Pyridin-3-yl)urea (9h)
1-(Pyridin-3-yl)urea (9h)
Prepared according to General Procedure A using nicotinamide (66.2 mg, 0.5 mmol) and
purified by flash chromatography on silica gel (CH2Cl2/MeOH, 90:10 + a few drops of NH3) to afford urea 9h (68.6 mg, 99%) as a yellow solid.
Mp 199 °C; Rf
= 0.3 (CH2Cl2/MeOH, 90:10 + a few drops of NH3).
IR (ATR): 3374, 3198, 1672, 1550, 1485, 1356, 1302, 571 cm–1.
1H NMR (600 MHz, DMSO-d
6): δ = 8.73 (s, 1 H, NH), 8.51 (d, J = 2.4 Hz, 1 H, CHAr
), 8.10 (dd, J = 4.6, 1.4 Hz, 1 H, CHAr
), 7.89 (ddd, J = 8.3, 2.6, 1.5 Hz, 1 H, CHAr
), 2.23 (ddd, J = 8.3, 4.6, 0.5 Hz, 1 H, CHAr
), 6.01 (br s, 2 H, NH2
).
13C NMR (150 MHz, DMSO-d
6): δ = 156.0 (CO), 142.1 (CAr), 139.6 (CAr), 137.2 (CAr), 124.5 (CAr), 123.5 (CAr).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C6H8N3O: 138.0667; found: 138.0670.
1-Phenylurea (9i)
Prepared according to General Procedure A using benzamide (60.6 mg, 0.5 mmol) and
purified by flash chromatography on silica gel (CH2Cl2/EtOH, 97:3) to afford urea 9i (67.8 mg, >99%) as a beige solid.
Mp 149 °C; Rf
= 0.2 (CH2Cl2/EtOH, 97:3).
IR (ATR): 3420, 3311, 3214, 1651, 1590, 1548, 1353, 750, 694, 584 cm–1.
1H NMR (500 MHz, DMSO-d
6): δ = 8.49 (s, 1 H, NH), 7.38 (d, J = 7.7 Hz, 2 H, CHAr
), 7.20 (t, J = 7.7 Hz, 2 H, CHAr
), 6.88 (t, J = 7.7 Hz, 1 H, CHAr
), 5.82 (s, 2 H, NH2
).
13C NMR (125 MHz, DMSO-d
6): δ = 156.0 (CO), 140.6 (CAr), 128.6 (CAr), 121.0 (CAr), 117.7 (CAr).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C7H9N2O: 137.0715; found: 137.0713.
1-Cyclohexylurea (9j)
Prepared according to General Procedure A using cyclohexanecarboxamide (63.6 mg, 0.5
mmol). Additional amounts of PIDA (0.15 mmol) and NH3 in MeOH (7 M, 0.18 mL) were added after 16 h and the mixture was left stirring for
an additional 24 h. The mixture was concentrated under reduced pressure and the residue
was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95:5) to afford urea 9j (55.0 mg, 77%) as a white solid.
Mp 195 °C; Rf
= 0.2 (CH2Cl2/MeOH, 95:5).
IR (ATR): 3328, 3196, 2928, 2852, 1649, 1544, 1351, 1157, 609 cm–1.
1H NMR (500 MHz, DMSO-d
6): δ = 8.81 (d, J = 8.0 Hz, 1 H, NH), 5.28 (br s, 2 H, NH2
), 3.26–3.32 (m, 1 H, CH), 1.71–1.73 (m, 2 H, CH
2
), 1.61–1.64 (m, 2 H, CH
2
), 1.50–1.52 (m, 1 H, CH), 1.20–1.28 (m, 2 H, CH2
), 1.10–1.20 (m, 1 H, CHH), 1.01–1.10 (m, 2 H, CH).
13C NMR (125 MHz, DMSO-d
6): δ = 157.9 (CO), 47.6 (CAr), 33.3 (CAr), 25.3 (CAr), 24.5 (CAr).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C7H15N2O: 143.1184; found: 143.1185.
1-Butylurea (9k)
Prepared according to General Procedure A using valeramide (50.6 mg; 0.5 mmol) and
purified by flash chromatography on silica gel (CH2Cl2/EtOH, 9:1) to afford urea 9k (47.5 mg, 82%) as colorless needles.
Mp 98 °C; Rf
= 0.3 (CH2Cl2/EtOH, 90:10).
IR (ATR): 3411, 3348, 3208, 2968, 2932, 1554, 1339, 1157, 533 cm–1.
1H NMR (500 MHz, DMSO-d
6): δ = 5.87 (s, 1 H, NH), 5.34 (s, 2 H, NH2
), 2.93 (q, J = 6.5 Hz, 2 H, NHCH2
CH2), 1.23–1.34 (m, 4 H, H3CCH
2
CH2
CH2), 0.86 (t, J = 7.2 Hz, 3 H, CH3
).
13C NMR (125 MHz, DMSO-d
6): δ = 158.7 (CO), 38.8 (CH2), 32.1 (CH2), 19.5 (CH2), 13.7 (CH3).
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C7H12N2ONa: 139.0847; found: 139.0844.
1-Ethylurea (9l)
Prepared according to General Procedure A using propionamide (73.1 mg, 1.0 mmol) and
purified by flash chromatography on silica gel (CH2Cl2/EtOH, 9:1) to afford urea 9l (74.3 mg, 84%) as colorless needles.
Mp 83 °C; Rf
= 0.2 (CH2Cl2/EtOH, 90:10).
IR (ATR): 3350, 3207, 2931, 1548, 1340, 1157, 536 cm–1.
1H NMR (500 MHz, DMSO-d
6): δ = 5.86 (s, 1 H, NH), 5.36 (s, 2 H, NH2
), 2.96 (quin, J = 7.0 Hz, 2 H, CH2
), 0.96 (t, J = 7.2 Hz, 3 H, CH3
).
13C NMR (125 MHz, DMSO-d
6): δ = 158.6 (CO), 34.0 (CH2), 15.7 (CH3).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C3H9N2O: 89.0715; found: 89.0713.
1-Benzylurea (9m)
Prepared according to General Procedure A using 2-phenylacetamide (67.6 mg, 0.5 mmol)
and purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95:5) to afford urea 9m (75.1 mg, 86%) as a white solid.
Mp 150 °C; Rf
= 0.3 (CH2Cl2/MeOH, 95:5).
IR (ATR): 3428, 3328, 1647, 1598, 1557, 695, 583, 546 cm–1.
1H NMR (500 MHz, DMSO-d
6): δ = 7.20–7.32 (m, 5 H, CHAr
), 6.40 (t, J = 6.0 Hz, 1 H, NH), 5.52 (br s, 2 H, NH2
), 4.17 (d, J = 6.0 Hz, 2 H, CH2
).
13C NMR (125 MHz, DMSO-d
6): δ = 158.7 (CO), 140.9 (CAr), 128.2 (CAr), 127.0 (CAr), 126.5 (CAr), 42.8 (CH2).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C8H11N2O: 151.0871; found: 151.0870.
1-(3-Ethoxyphenyl)urea (9n)
1-(3-Ethoxyphenyl)urea (9n)
Prepared according to General Procedure A using 3-ethoxybenzamide (82.6 mg, 0.5 mmol)
and purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95:5) to afford urea 9n (90.0 mg, 99%) as a brown solid.
Mp 112 °C; Rf
= 0.3 (CH2Cl2/MeOH, 95:5).
IR (ATR): 3434, 3307, 3208, 1652, 1531, 1191, 1044, 766, 593 cm–1.
1H NMR (500 MHz, DMSO-d
6): δ = 8.48 (s, 1 H, NH), 7.06–7.12 (m, 2 H, CHAr
), 6.83 (d, J = 8.0 Hz, 1 H, CHAr
), 6.44 (d, J = 8.0 Hz, 1 H, CHAr
), 5.82 (s, 2 H, NH2
), 3.94 (q, J = 6.8 Hz, 2 H, CH2
), 1.30 (t, J = 6.8 Hz, 3 H, CH3
).
13C NMR (125 MHz, DMSO-d
6): δ = 158.9 (CO), 155.9 (CAr), 141.8 (CAr), 129.3 (CAr), 110.0 (CAr), 106.9 (CAr), 104.0 (CAr), 62.7 (CH2), 14.7 (CH3).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C9H13N2O2: 181.0977; found: 181.0977.
1-(2-Bromophenyl)urea (9o)
1-(2-Bromophenyl)urea (9o)
Prepared according to General Procedure A using 2-bromobenzamide (100.0 mg, 0.5 mmol)
and purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95:5) to afford urea 9o (107.5 mg, 99%) as an off-white solid.
Mp 206 °C; Rf
= 0.3 (CH2Cl2/MeOH, 95:5).
IR (ATR): 3419, 3287, 3196, 1651, 1516, 1474, 1354, 755, 539 cm–1.
1H NMR (500 MHz, DMSO-d
6): δ = 8.00 (d, J = 8.2 Hz, 1 H, CHAr
), 7.85 (s, 1 H, NH), 7.54 (d, J = 7.8 Hz, 1 H, CHAr
), 7.26 (t, J = 7.8 Hz, 1 H, CHAr
), 7.89 (t, J = 7.8 Hz, 1 H, CHAr
), 6.40 (s, 2 H, NH2
).
13C NMR (125 MHz, DMSO-d
6): δ = 155.6 (CO), 137.9 (CAr), 132.3 (CAr), 127.9 (CAr), 123.3 (CAr), 121.9 (CAr), 112.4 (CAr).
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C7H8N2OBrNa: 236.9639; found: 236.9640.
1-(3-Chlorophenyl)urea (9p)
1-(3-Chlorophenyl)urea (9p)
Prepared according to General Procedure A using 3-chlorobenzamide (77.8 mg, 0.5 mmol).
Additional amounts of PIDA (0.5 mmol) and NH3 in MeOH (7 M, 0.60 mL) were added after 4 h and the mixture was left to stir for
an additional 24 h. The mixture was concentrated under reduced pressure and the residue
was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95:5) to afford urea 9p (76.2 mg, 89%) as a pale brown solid.
Mp 143 °C; Rf
= 0.2 (CH2Cl2/MeOH, 95:5).
1H NMR (500 MHz, DMSO-d
6): δ = 8.73 (s, 1 H, NH), 7.69 (t, J = 2.0 Hz, 1 H, CHAr
), 7.22 (t, J = 8.2 Hz, 1 H, CHAr
), 7.16 (ddd, J = 8.2, 1.9, 1.0 Hz, 1 H, CHAr
), 6.92 (ddd, J = 7.8, 2.0, 1.0 Hz, 1 H, CHAr
), 5.96 (s, 2 H, NH2
).
13C NMR (125 MHz, DMSO-d
6): δ = 155.8 (CO), 142.2 (CAr), 133.1 (CAr), 130.2 (CAr), 120.6 (CAr), 117.0 (CAr), 116.0 (CAr).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C7H8N2OCl: 171.0325; found: 171.0325.
2(3H)-Benzoxazolone (9r)
Prepared according to General Procedure A using salicylamide (68.6 mg, 0.5 mmol) and
purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95:5) to afford urea 9r (67 mg, 99%) as a brown solid.
Mp 140 °C; Rf
= 0.4 (CH2Cl2/MeOH, 95:5).
IR (ATR): 3201, 1732, 1478, 1253, 937, 686 cm–1.
1H NMR (500 MHz, DMSO-d
6): δ = 11.6 (s, 1 H, NH), 7.27 (d, J = 8.0 Hz, 1 H, CHAr
), 7.12–7.16 (m, 1 H, CHAr
), 7.06–7.09 (m, 2 H, CHAr
).
13C NMR (125 MHz, DMSO-d
6): δ = 154.4 (CO), 143.3 (CAr), 130.4 (CAr), 123.8 (CAr), 121.8 (CAr), 109.8 (CAr), 109.5 (CAr).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C7H6NO2: 136.0399; found: 136.0401.
