Synthesis of 1-arylcycloalkenamines by intramolecular arylation of lithiated ureas

Article abstract of DOI:10.1021/op500173q

The deprotonation of N′-arylurea derivatives of cyclohexenamines by alkyllithiums leads to migration of the N′-aryl substituent from N′ to the allylic position α to N via rearrangement of a urea-stabilised allyllithium intermediate. The product ureas may be solvolysed to reveal 1-arylcyclohexenamines.

Full text of DOI:10.1021/op500173q

Article
pubs.acs.org/OPRD
Synthesis of 1‑Arylcycloalkenamines by Intramolecular Arylation of
Lithiated Ureas
Michael B. Tait, Philipp A. Ottersbach, Daniel J. Tetlow, and Jonathan Clayden*
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
S
* Supporting Information
ABSTRACT: The deprotonation of N′-arylurea derivatives of cyclohexenamines by alkyllithiums leads to migration of the N′-
aryl substituent from N′ to the allylic position α to N via rearrangement of a urea-stabilised allyllithium intermediate. The
product ureas may be solvolysed to reveal 1-arylcyclohexenamines.
explore the utility of this reaction for the synthesis of
substituted cycloalkenylamines, we made the cyclohexenylureas
4 and cyclopentenylureas 5 by the method shown in Scheme 2.
INTRODUCTION
■
Amines carrying tertiary substituents are challenging synthetic
targets that have been made using a number of strategies, of
which rearrangements provide one important class.1 The
rearrangement, by aryl migration from N to C, of lithiated
derivatives of ureas,2,3 carbamates,4 and thiocarbamates5 has
provided a useful method for the synthesis of hindered amines,
alcohols, and thiols (Scheme 1). The reaction is formally an
Scheme 2. Synthesis of the urea starting materials
Scheme 1. Intramolecular arylation of ureas, carbamates, and
thiocarbamates
a
Yield over two steps from cyclopentene (volatile bromocyclopentene
b
not purified). 1-Naphthylurea.
The reported route10 to the HCl salt of amine 2 was less
convenient than the simple substitution of cyclohexenyl
bromide by methylamine.11 Bromocyclohexene and bromocy-
clopentene (made in situ by bromination of cyclopentene)
were treated with methanolic methylamine to provide cyclo-
hexenylamine 2 and cyclopentenylamine 3, respectively. An
alternative route involving hydroamination of cyclohexadiene12
(Scheme 3) gave the p-methoxyphenyl-substituted urea 4h.
The allylic amines were acylated in good yield either by direct
reaction with commercially available or easily made carbamoyl
chlorides or by condensation with isocyanates and N-
methylation to give cyclohexenylureas 4 or cyclopentenylureas
5, respectively.
intramolecular SNAr substitution.6 Unlike typical nucleophilic
aromatic substitutions, however, even electron-rich aryl rings
take part in the migration reaction, which has been used to
make a range of amine2 and amino acid7 derivatives.
Cycloalkyl- and cycloalkenylamines are common compo-
nents of biologically active compounds, especially within
neuroscience.8 Given the importance of functionalized amines
within medicinal chemistry, we have sought to make use of this
rearrangement for the synthesis of pharmaceutically active
compounds. For example, we showed that it could be used for
the asymmetric synthesis of clemastine.9 We now report its
applicability to the synthesis of cycloalkenylamines 1 bearing 1-
aryl substituents, whose structures are somewhat related to the
1-arylcyclohexylamine anaesthetic ketamine.
Special Issue: Organometallic Carbanions in Practical Organic
Synthesis
RESULTS AND DISCUSSION
■
N-Allyl-N′-arylureas, upon lithiation, undergo rearrangement
with migration of the aryl group to the position α to nitrogen
via a urea-substituted allyllithium intermediate.3 In order to
Received: May 29, 2014
Published: June 27, 2014
© 2014 American Chemical Society
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Table 1). These reactions could also be scaled up successfully
to 1 or 2 g of substrate without loss of yield. However, it was
crucial to the reaction to keep the temperature below −60 °C,
as above this temperature the intermediate allyllithium
appeared to be unstable. The best yields were obtained by
lithiation at −78 °C followed by addition of DMPU at −60 °C
or less. Rearrangements using LDA generally gave lower yields.
Rearrangement of 4g did not give a clean product under
these usual reaction conditions, but allowing air into the
reaction mixture gave an indication that this was due to the
unusual stability of a dearomatised intermediate along the
reaction pathway. Cyclohexenone 9, formed as a single
diastereoisomer in 15% yield, was presumably the result of air
oxidation of an intermediate organolithium 8. Dearomatised
intermediates have been proposed for this reaction before (and
a related cyclohexenone has been isolated),2a but there is no
evidence supporting dearomatised intermediates in rearrange-
ments of anything but 1-naphthyl groups.6
The rearranged ureas 6 could be converted in good yield to
the target 1-arylcylohexen-1-ylamines 7 by basic hydrolysis in a
microwave (Scheme 4 and Table 1).13 Alternatively, it was
possible to make use of the urea function to promote a
stereoselective functionalisation of the alkene by iodocyclisation
of 6d (Scheme 5) to yield 10. A similar cyclisation to form a
cyclic carbamate 12 took place from 11, the Boc derivative of
amine 7b.
Scheme 3. Synthesis of allylic urea 4h by amination of a
diene
We started with the cyclohexenylureas 4. Treatment of 4a or
4h with sec-BuLi gave only traces of rearranged compounds,
even in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone (DMPU), which usually accelerates rearrange-
ment.2a However, substituted rings migrated much more
efficiently than the Ph rings of 4a and 4h. Halo-substituted
4b−d gave rearranged ureas 6b−d in good yield (Scheme 4 and
Scheme 4. Rearrangements of cyclohexenylureas
Scheme 5. Transformations of the 1-arylcyclohexenylamine
products
Related rearrangements of cyclopentenylamines were also
possible, but in somewhat lower yields. Ureas 5a−c and 5f were
treated under conditions similar to those for 4 and gave
rearranged urea derivatives of 1-arylcyclopentenylamines in
poor to moderate yield (Scheme 6 and Table 2).
Table 1. Yields of the rearrangement and hydrolysis
reactions of six-membered-ring substrates
starting material
X
product 6, yield (%) product 7, yield (%)
4a
4h
4b
4c
4d
4e
4g
H
H
6a, 15
7a, 88
−
6h, trace
6b, 71
Scheme 6. Rearrangements of urea derivatives of
cyclopentenylamines
4-Cl
7b, 94
7c, 83
7d, 87
7e, 82
−
a
b
3-F
6c, 76, 72
3,5-diF
3-OMe
2,3-benzo
6d, 70, 65
6e, 34
c
9, 15
a
b
c
Carried out on a 1 g scale. Carried out on a 2 g scale. Quenching
with dry air.
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by TLC analysis. MeOH was added slowly, and the mixture was
allowed to warm to room temperature. NH4Cl (sat. soln.) was
added, and the mixture was extracted twice with Et2O. The
organic phases were combined, washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The crude
product was purified by flash column chromatography (PE/
EtOAc 4:1 + 1% NEt3) to give the α-arylated urea.
Table 2. Yields of the rearrangements of five-membered-ring
substrates
General Procedure 5: Solvolysis of Ureas under
Microwave Conditions. To the urea (1 equiv) was added a
1:1 (v/v) mixture of EtOH and 2 M NaOH solution (10
equiv). The resultant mixture was heated to 130 °C under
microwave irradiation for 2.5 h. After cooling, the mixture was
extracted twice with EtOAc, washed with brine, and dried over
MgSO4, and the solvent was removed under reduced pressure
to yield the amine without any further purification.
General Procedure 6: NIS-Promoted Cyclisation of
Carbamates. To a solution of the carbamate (1 equiv) in
CHCl3 (0.1 M) was added NIS (1.5 equiv). The mixture was
stirred overnight at room temperature. The solvent was
removed under reduced pressure, and the residue was dissolved
in EtOAc and washed four times with H2O. After the solution
was dried over MgSO4, the solvent was removed under reduced
pressure, and the crude cyclic carbamate was used without any
further purification unless otherwise stated.
starting material
X
product 13, yield (%)
5a
5b
5c
5f
H
13a, 30
13b, 18
13c, 28
13f, 4
4-Cl
3-F
4-OMe
In summary, 1-arylcyclohexenylamine derivatives may be
synthesized by aryl migration within organolithium derivatives
of allylic ureas. Further work is seeking to develop an
asymmetric version of these rearrangements.
EXPERIMENTAL SECTION
■
General Procedure 1: Urea Formation from Amines
and Isocyanates. To a solution of the amine (1 equiv) in
CH2Cl2 (0.2 M) were added NEt3 (1.5 equiv) and the aryl
isocyanate (1 equiv). The reaction mixture was stirred
overnight at room temperature. The solvent was removed
under reduced pressure, and the residue was dissolved in DMF
(0.2 M) and cooled to 0 °C. NaH (2 equiv) was added, and the
mixture was stirred for 30 min. MeI (2 equiv) was added
N-Methylcyclohex-2-en-1-amine (2).11 By the method of
Steinhardt and Vanderwal,11 3-bromo-1-cyclohexene (1.00 mL,
8.65 mmol) was added to a solution of methylamine (8 M in
MeOH, 10.8 mL, 86.49 mmol), and the mixture was stirred
overnight at room temperature. The reaction was quenched
with NaOH solution (0.7 M, 35 mL), and the mixture was
extracted with CH2Cl2 (3 × 10 mL), washed with brine (10
mL), and dried over MgSO4. The solvent was removed under
reduced pressure to yield the title compound 2 as a colourless
oil (0.840 g, 7.56 mmol, 87%), which was used without further
purification.
1
dropwise, and the reaction mixture was stirred until H NMR
analysis showed complete methylation. H2O was added
carefully, and the crude mixture was extracted three times
with Et2O, washed thoroughly with brine, and dried over
MgSO4. The solvent was removed under reduced pressure, and
the crude mixture was purified by flash column chromatography
(PE/EtOAc 9:1 + 1% NEt3) to yield the urea.
N-Methylcyclopent-2-en-1-amine (3).15 A mixture of cyclo-
pentene (13.25 mL, 150 mmol), NBS (6.674 g, 37.5 mmol),
and AIBN (0.246 g, 1.5 mmol) in CCl4 (25 mL) was heated at
reflux for 1 h. The reaction mixture was cooled to 0 °C and
filtered through a pad of diatomaceous earth to give a yellow
solution of 3-bromocyclopent-1-ene, which was used without
further purification. It was added to a solution of methylamine
(9.8 M in MeOH, 38.3 mL, 0.375 mol) dropwise at 0 °C, and
the mixture was stirred overnight at room temperature. The
reaction was quenched with NaOH solution (0.7 M, 150 mL),
and the mixture was extracted with CH2Cl2 (3 × 45 mL),
washed with brine (15 mL), and dried over MgSO4. The
solvent was removed under reduced pressure until about 10 mL
of a brown solution remained. This was purified by fractional
vacuum distillation to yield the title compound 3 as a colourless
General Procedure 2: Methylation of Ureas. To a
cooled solution of the urea (1 equiv) in DMF (0.2 M) at 0 °C
was added NaH (2 equiv), and the mixture was stirred for 1 h.
MeI (2 equiv) was added dropwise, and the reaction mixture
was stirred until 1H NMR spectroscopy showed complete
methylation. H2O was added carefully, and the crude mixture
was extracted three times with Et2O, washed thoroughly with
brine, and dried over MgSO4. The solvent was removed under
reduced pressure, and the crude mixture was purified by flash
column chromatography (PE/EtOAc 9:1 + 1% NEt3) to yield
the methylated urea.
General Procedure 3: Urea Formation from Carba-
moyl Chlorides. To a solution of the amine (1 equiv) and
NEt3 (1.3 equiv) in CH2Cl2 (0.2 M) were added the carbamoyl
chloride (1.1 equiv) and DMAP (0.05 equiv). The mixture was
stirred at room temperature overnight. The mixture was
quenched with NaHCO3 (sat. aq. soln.), extracted twice with
CH2Cl2, washed with brine, and dried over MgSO4, and the
solvent was removed under reduced pressure. The crude
mixture was purified by flash column chromatography (n-
pentane/EtOAc 5:1 to 1:1) to yield the urea.
1
liquid (0.823 g, 23% over two steps). H NMR (500 MHz,
CDCl3) δ 5.84−5.82 (1H, m, NCHCHCH), 5.78−5.76 (1H,
m, NCHCHCH), 3.72−3.69 (1H, m, NCH), 2.42−2.34
(1H, m, NCHCHH), 2.38 (3H, s, NMe), 2.26−2.20 (1H, m,
NCHCHH), 2.15−2.09 (1H, m, NCHCH2CHH), 1.53−1.46
(1H, m, NCHCH2CHH), 1.04 (1H, brs, NH); 13C NMR (125
MHz, CDCl3) δ 132.8, 132.6, 65.9, 33.9, 31.1, 30.2; MS (ES)
m/z 98 ([M + H]+).
1-(Cyclohex-2-en-1-yl)-1,3-dimethyl-3-phenylurea (4a).
Following general procedures 1 and 2, amine 2 (1.263 g,
11.36 mmol) in CH2Cl2 (57 mL) with NEt3 (2.38 mL, 17.04
mmol) and phenyl isocyanate (1.23 mL, 11.36 mmol) followed
by NaH (0.909 g, 22.72 mmol) and MeI (1.42 mL, 22.72
General Procedure 4: Rearrangement of Ureas Using
Alkyllithiums. To a cooled solution of the urea (1 equiv) in
THF (0.1 M) at −78 °C was added a solution of sec-
butyllithium (2.5 equiv) dropwise. The mixture was stirred for
2 h before the dropwise addition of DMPU (4:1 THF/
DMPU). The reaction mixture was stirred for a further 2 h or
until complete consumption of starting material as determined
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mmol) in DMF (57 mL) gave the title compound 4a as a pale-
yellow oil (1.912 g, 7.83 mmol, 70%) after flash column
chromatography. RF 0.44 (2:1 PE/EtOAc); H NMR (400
(0.640 g, 5.76 mmol) in CH2Cl2 (29 mL) with NEt3 (1.61 mL,
11.51 mmol) and 3,5-difluorophenyl isocyanate (0.82 mL, 5.76
mmol) followed by NaH (0.461 g, 11.52 mmol) and MeI (0.72
mL, 11.52 mmol) in DMF (29 mL) gave the title compound 4d
as a brown oil (1.252 g, 4.47 mmol, 78%) after flash column
1
MHz, CDCl3) δ 7.34−7.27 (2H, m, ArH), 7.12−7.06 (3H, m,
ArH), 5.83−5.75 (1H, m, NCHCHCH), 5.37−5.31 (1H, m,
NCHCHCH), 4.76−4.68 (1H, m, NCHCHCH), 3.19
(3H, s, NMe), 2.38 (3H, s, NMe), 1.96−1.89 (2H, m, CH
CHCH2), 1.78−1.68 (2H, m, NCHCHHCHH), 1.62−1.38
(2H, m, NCHCHHCHH); 13C NMR (100 MHz, CDCl3) δ
162.0 (CO), 147.1 (4° ArC), 130.9 (NCHCHCH), 129.3
(ArC), 128.6 (NCHCHCH), 124.2 (ArC), 123.9 (ArC),
53.5 (NCH), 39.8 (NMe), 31.1 (NMe), 26.0 NCHCH2), 24.5
(CHCHCH2), 21.4 (NCHCH2CH2); IR νmax (film)/cm−1
2928 (CCH), 1640 (CO), 1594 (CC); MS (ES) m/z
245 ([M + H]+); HRMS m/z calcd for C15H21N2O ([M +
H]+) 245.1649, found 245.1644.
1
chromatography. RF 0.39 (2:1 PE/EtOAc); H NMR (400
MHz, CDCl3) δ 6.62−6.43 (3H, m, ArH), 5.92−5.85 (1H, m,
NCHCHCH), 5.45−5.39 (1H, m, NCHCHCH), 4.79−
4.69 (1H, m, NCH), 3.19 (3H, s, NMe), 2.55 (3H, s, NMe),
2.03−1.94 (2H, m, CHCHCH2), 1.86−1.76 (2H, m,
NCHCHHCHH), 1.70−1.50 (2H, m, NCHCHHCHH); IR
νmax (film)/cm−1 2934 (CCH), 1614 (CO), 1593 (C
C); MS (ES) m/z 281 ([M + H]+); HRMS m/z calcd for
C15H19N2OF2 ([M + H]+) 281.1465, found 281.1467. Broad
signals in the 13C NMR spectrum prevented full analysis.
1-(Cyclohex-2-en-1-yl)-3-(3-methoxyphenyl)-1,3-dimethy-
lurea (4e). Following general procedures 1 and 2, amine 2
(0.571 g, 5.14 mmol) in CH2Cl2 (26 mL) with NEt3 (1.07 mL,
7.70 mmol) and 3-methoxyphenyl isocyanate (0.67 mL, 5.14
mmol) followed by NaH (0.411 g, 10.27 mmol) and MeI (0.64
mL, 10.27 mmol) in DMF (26 mL) gave the title compound 4e
as a yellow oil (0.729 g, 2.66 mmol, 52%) after flash column
1-(4-Chlorophenyl)-3-(cyclohex-2-en-1-yl)-1,3-dimethylur-
ea (4b). Following general procedures 1 and 2, amine 2 (0.840
g, 7.56 mmol) in CH2Cl2 (38 mL) with NEt3 (1.58 mL, 11.33
mmol) and 4-chlorophenyl isocyanate (1.160 g, 7.56 mmol)
followed by NaH (0.604 g, 15.11 mmol) and MeI (0.94 mL,
15.11 mmol) added in DMF (38 mL) gave the title compound
4b as a white solid (1.480 g, 5.31 mmol, 69%) after flash
column chromatography. MP 77−79 °C; RF 0.44 (2:1 PE/
1
chromatography. RF 0.32 (2:1 PE/EtOAc); H NMR (400
MHz, CDCl3) δ 7.22 (1H, t, J = 7.8, ArH), 6.73−6.62 (3H, m,
ArH), 5.85−5.78 (1H, m, NCHCHCH), 5.42−5.34 (1H, m,
NCHCHCH), 4.81−4.72 (1H, m, NCHCHCH), 3.79
(3H, s, OMe), 3.20 (3H, s, NMe), 2.42 (3H, s, NMe), 1.99−
1.92 (2H, m, CHCHCH2), 1.82−1.72 (2H, m,
NCHCHHCHH), 1.66−1.41 (2H, m, NCHCHHCHH); 13C
NMR (100 MHz, CDCl3) δ 161.9 (CO), 160.4 (4°
ArCOMe), 148.3 (4° ArC), 131.0 (NCHCHCH), 130.0
(ArC), 128.6 (NCHCHCH), 116.1 (ArC), 109.6 (ArC),
109.6 (ArC), 55.3 (OMe), 53.4 (NCH), 39.7 (NMe), 31.1
(NMe), 26.0 (NCHCH2), 24.5 (CHCHCH2), 21.5
(NCHCH2CH2); IR νmax (film)/cm−1 2929 (CCH), 1641
(CO), 1596 (CC); MS (ES) m/z 275 ([M + H]+);
HRMS m/z calcd for C16H23N2O2 ([M + H]+) 275.1755,
found 275.1749.
1
EtOAc); H NMR (500 MHz, CDCl3) δ 7.23−7.19 (2H, m,
ArH), 6.97−6.93 (2H, m, ArH), 5.78−5.73 (1H, m,
NCHCHCH), 5.30−5.25 (1H, m, NCHCHCH), 4.67−
4.60 (1H, m, NCHCHCH), 3.10 (3H, s, NMe), 2.34 (3H, s,
NMe), 1.92−1.86 (2H, m, CHCHCH2), 1.72−1.65 (2H, m,
NCHCHHCHH), 1.57−1.48 (1H, m, NCHCH2CHH), 1.44−
1.35 (1H, m, NCHCHHCH2); 13C NMR (125 MHz, CDCl3)
δ 161.7 (CO), 145.7 (4° ArC), 131.2 (NCHCHCH),
129.4 (ArC), 129.3 (4° ArC), 128.3 (NCHCHCH), 124.8
(ArC), 53.5 (NCH), 39.6 (NMe), 31.2 (NMe), 26.0
(NCHCH2), 24.5 (CHCHCH2), 21.4 (NCHCH2CH2); IR
νmax (film)/cm−1 2927 (CCH), 1642 (CO); MS (ES) m/z
301 ([M + Na]+); HRMS m/z calcd for C15H20N2O35Cl ([M +
H]+) 279.1259, found 279.1255.
1-(Cyclohex-2-en-1-yl)-3-(3-fluorophenyl)-1,3-dimethylur-
ea (4c). Following general procedures 1 and 2, amine 2 (0.690
g, 6.21 mmol) in CH2Cl2 (31 mL) with NEt3 (1.30 mL, 9.31
mmol) and 3-fluorophenyl isocyanate (0.70 mL, 6.21 mmol)
followed by NaH (0.496 g, 12.41 mmol) and MeI (0.77 mL,
12.41 mmol) in DMF (31 mL) gave the title compound 4c as a
yellow oil (1.320 g, 5.03 mmol, 81%) after flash column
1-(Cyclohex-2-en-1-yl)-1,3-dimethyl-3-(naphthalen-1-yl)-
urea (4g). Following general procedures 1 and 2, amine 2
(1.106 g, 9.95 mmol) in CH2Cl2 (50 mL) with NEt3 (2.08 mL,
14.92 mmol) and 1-naphthyl isocyanate (1.43 mL, 9.95 mmol)
followed by NaH (0.796 g, 19.90 mmol) and MeI (1.24 mL,
19.90 mmol) in DMF (50 mL) gave the title compound 4g as a
brown oil (2.476 g, 8.41 mmol, 85%) after flash column
1
chromatography. RF 0.41 (2:1 PE/EtOAc); H NMR (400
1
chromatography. RF 0.41 (2:1 PE/EtOAc); H NMR (400
MHz, CDCl3) δ 7.30−7.23 (1H, m, ArH), 6.89−6.75 (3H, m,
ArH), 5.88−5.81 (1H, m, NCHCHCH), 5.42−5.35 (1H, m,
NCHCHCH), 4.78−4.69 (1H, m, NCH), 3.21 (3H, s,
NMe), 2.47 (3H, s, NMe), 2.01−1.92 (2H, m, CHCHCH2),
1.84−1.72 (2H, m, NCHCHHCHH), 1.68−1.43 (2H, m,
NCHCHHCHH); 13C NMR (100 MHz, CDCl3) δ 163.4 (d, JF
= 244.7, ArCF), 161.5 (CO), 148.7 (d, JF = 9.7, 4° ArC),
131.3 (NCHCHCH), 130.4 (d, JF = 9.4, ArC), 128.3
(NCHCHCH), 118.5 (d, JF = 2.9, ArC), 110.6 (d, JF = 21.1,
ArC), 100.2 (d, JF = 23.3, ArC), 53.6 (NCH), 39.3 (NMe),
31.1 (NMe), 26.1 (NCHCH2), 24.6 (CHCHCH2), 21.5
(NCHCH2CH2); IR νmax (film)/cm−1 1659 (CO), 1606
(CC), 1587 (CC); MS (ES) m/z 263 ([M + H]+);
HRMS m/z calcd for C15H20N2OF ([M + H]+) 263.1560,
found 263.1568.
MHz, CDCl3) δ 8.07−8.01 (1H, m, ArH), 7.90−7.85 (1H, m,
ArH), 7.73 (1H, d, J = 8.3, ArH), 7.59−7.48 (2H, m, ArH),
7.41 (1H, dd, J = 8.3, 7.3, ArH), 7.23 (1H, dd, J = 7.6, 1.0,
ArH), 5.75−5.67 (1H, m, NCHCHCH), 5.27−5.20 (1H, m,
NCHCHCH), 4.76−4.69 (1H, m, NCH), 3.22 (3H, s,
NMe), 2.20 (3H, s, NMe), 1.89−1.81 (2H, m, CHCHCH2),
1.68−1.52 (2H, m, CHCHHCHH), 1.47−1.24 (2H, m,
CHCHHCHH); 13C NMR (100 MHz, CDCl3) δ 163.1
(CO), 143.5 (4° ArC), 134.7 (4° ArC), 130.7 (NCHCH
CH), 129.5 (4° ArC), 128.7 (NCHCHCH), 128.5 (ArC),
126.6 (ArC), 126.2 (ArC), 126.1 (ArC), 125.8 (ArC), 123.2
(ArC), 122.7 (ArC), 53.4 (NCH), 40.2 (NMe), 30.7 (NMe),
25.9 (NCHCH2), 24.4 (CHCHCH2), 21.3 (NCHCH2CH2);
IR νmax (film)/cm−1 2928 (CCH), 1639 (CO); MS (ES)
m/z 295 ([M + H]+); HRMS m/z calcd for C19H23N2O ([M +
H]+) 295.1805, found 295.1802.
1-(Cyclohex-2-en-1-yl)-3-(3,5-difluorophenyl)-1,3-dime-
thylurea (4d). Following general procedures 1 and 2, amine 2
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1-(Cyclohex-2-enyl)-1-(4-methoxyphenyl)-3-methyl-3-phe-
nylurea (4h). Following general procedures 1 and 2, N-
(cyclohex-2-enyl)-4-methoxyaniline12 (0.300 g, 1.48 mmol) in
CH2Cl2 (4 mL) with phenyl isocyanate (0.160 mL, 1.48 mmol)
followed by NaH (0.089 g, 3.69 mmol) and MeI (0.276 mL,
4.43 mmol) in DMF (4 mL) gave the title compound 4h as a
film (0.457 g, 1.36 mmol, 92%) after flash column
s, NMe), 2.42 (3H, s, NMe), 2.40−2.31 (1H, m, NCHCHH),
2.29−2.24 (1H, m, NCHCHH), 2.00−1.91 (1H, m,
NCH2CHH), 1.57−1.49 (1H, m, NCH2CHH); 13C NMR
(100 MHz, CDCl3) δ 163.3 (d, JF = 244.8), 161.4, 148.7 (d, JF
= 9.5), 134.7, 130.4 (d, JF = 9.5), 130.1, 118.7 (d, JF = 2.9),
110.7 (d, JF = 21.1), 110.4 (d, JF = 23.2), 63.5, 39.3, 31.6, 30.1,
26.3; MS (ES) m/z 271 ([M + Na]+); HRMS m/z calcd for
C14H17N2OFNa ([M + Na]+) 271.1223, found 271.1213.
1-(Cyclopent-2-en-1-yl)-3-(4-methoxyphenyl)-1,3-dime-
thylurea (5f). Following general procedure 3, amine 3 (0.194 g,
2.0 mmol) in CH2Cl2 (10 mL) with NEt3 (0.36 mL, 2.6 mmol),
N-methyl-N-(4-methoxyphenyl)carbamoyl chloride7a,14 (0.439
g, 2.2 mmol), and DMAP (0.012 g, 0.1 mmol) gave the title
compound 5f as a colourless oil (0.377 g, 1.4 mmol, 72%) after
1
chromatography. RF (2:1 PE/EtOAc) 0.26; H NMR (400
MHz, CDCl3) δ 7.06−7.01 (2H, m, ArH), 6.97−6.92 (1H, m,
ArH), 6.72−6.69 (2H, m, ArH), 6.52−6.45 (4H, m, H-ArH),
5.62−5.54 (2H, m, CHCH), 4.99−4.93 (1H, m, NCH), 3.69
(3H, s, OMe), 3.12 (3H, s, NMe), 1.98−1.79 (3H, m, Cy),
1.69−1.40 (3H, m, Cy); 13C NMR (100 MHz, CDCl3) δ 160.8
(CO), 156.3 (4° ArC), 145.2 (4° ArC), 133.3 (4° ArC),
129.3 (NCHCHCH), 128.9 (ArC), 128.4 (NCHCHCH),
127.6 (ArC), 125.1 (ArC), 123.8 (ArC), 112.1 (ArC), 54.3
(OMe), 53.9 (NCH), 38.7 (NMe), 26.8 (NCHCH2), 23.4
(CHCHCH2), 20.4 (NCHCH2CH2); IR νmax (film)/cm−1
1634 (CO), 1507 (CC); MS m/z (ES+) 337 ([M + H]+);
HRMS m/z calcd for C21H25N2O2 ([M + H]+) 337.1918,
found 337.1917.
1
flash column chromatography. H NMR (400 MHz, CDCl3) δ
7.01 (2H, d, J = 8.9, ArH), 6.85 (2H, d, J = 8.9, ArH), 5.86−
5.82 (1H, m, NCHCHCH), 5.40−5.36 (1H, m, NCHCH
CH), 5.18−5.13 (1H, m, NCH), 3.79 (3H, s, OMe), 3.14 (3H,
s, NMe), 2.35 (3H, s, NMe), 2.35−2.27 (1H, m, NCHCHH),
2.23−2.15 (1H, m, NCHCHH), 1.90−1.80 (1H, m,
NCH2CHH), 1.49−1.41 (1H, m, NCH2CHH); 13C NMR
(100 MHz, CDCl3) δ 162.4, 156.7, 140.5, 134.2, 130.6, 126.0,
114.6, 63.5, 55.4, 40.4, 31.6, 30.1, 26.2; MS (ES) m/z 261 ([M
+ H]+); HRMS m/z calcd for C15H20N2O2Na ([M + Na]+)
283.1422, found 283.1419.
1-(Cyclopent-2-en-1-yl)-1,3-dimethyl-3-phenylurea (5a).
Following general procedure 3, amine 3 (0.194 g, 2.0 mmol)
in CH2Cl2 (10 mL) with NEt3 (0.36 mL, 2.6 mmol), N-methyl-
N-phenylcarbamoyl chloride (0.373 g, 2.2 mmol), and DMAP
(0.012 g, 0.10 mmol) gave the title compound 5a as a
colourless oil (0.398 g, 1.7 mmol, 86%) after flash column
1,3-Dimethyl-1-(1,2,3,4-tetrahydro-[1,1′-biphenyl]-1-yl)-
urea (6a). Following general procedure 4, urea 4a (0.600 g,
2.46 mmol) in THF (25 mL) with s-BuLi (1.3 M, 4.72 mL, 6.14
mmol) and DMPU (6.25 mL) gave the title compound 6a as a
brown oil (0.087 g, 0.36 mmol, 15%) after flash column
1
chromatography. H NMR (500 MHz, CDCl3) δ 7.34−7.30
(2H, m, ArH), 7.12−7.07 (3H, m, ArH), 5.87−5.84 (1H, m,
NCHCHCH), 5.42−5.39 (1H, m, NCHCHCH), 5.19−
5.16 (1H, m, NCH), 3.21 (3H, s, NMe), 2.37 (3H, s, NMe),
2.37−2.29 (1H, m, NCHCHH), 2.24−2.17 (1H, m,
NCHCHH), 1.91−1.83 (1H, m, NCH2CHH), 1.51−1.45
(1H, m, NCH2CHH); 13C NMR (125 MHz, CDCl3) δ
162.0, 147.3, 134.3, 130.4, 129.4, 124.3, 124.1, 63.5, 39.8, 31.6,
30.1, 26.2; MS (ES) m/z 253 ([M + Na]+); HRMS m/z calcd
for C14H18N2ONa ([M + Na]+) 253.1317, found 253.1321.
1-(4-Chlorophenyl)-3-(cyclopent-2-en-1-yl)-1,3-dimethy-
lurea (5b). Following general procedure 3, amine 3 (0.097 g,
1.0 mmol) in CH2Cl2 (5 mL) with NEt3 (0.18 mL, 1.3 mmol),
N-(4-chlorophenyl)-N-methylcarbamoyl chloride7a,14 (0.224 g,
1.1 mmol), and DMAP (0.006 g, 0.05 mmol) gave the title
compound 5b as a colourless oil (0.222 g, 84%) after flash
1
chromatography. RF 0.21 (1:1 PE/EtOAc); H NMR (400
MHz, CDCl3) δ 7.43−7.39 (2H, m, ArH), 7.38−7.32 (2H, m,
ArH), 7.28−7.22 (1H, m, ArH), 5.95−5.87 (2H, m, CCH
CH), 4.28−4.19 (1H, brs, NH), 3.06 (3H, s, NMe), 2.59 (3H,
d, J = 4.6, NHMe), 2.46 (1H, ddd, J = 12.8, 9.3, 3.1, CCHH),
2.22 (1H, ddd, J = 13.0, 8.3, 3.0, CCHH), 2.15−2.01 (2H, m,
CHCHCH2), 1.78−1.58 (2H, m, CCH2CH2); 13C NMR
(100 MHz, CDCl3) δ 159.3 (CO), 146.7 (4° ArC), 131.9
(CCHCH), 129.3 (CCHCH), 128.8 (ArC), 127.0 (ArC),
126.2 (ArC), 62.4 (4° C), 33.2 (NMe), 32.9 (CCH2CH2), 27.5
(NHMe), 24.9 (CHCHCH2), 19.1 (CCH2CH2); IR νmax
(film)/cm−1 2932 (CCH), 1681 (CO); MS (ES) m/z 281
([M + H]+); HRMS m/z calcd for C15H19N2OF2 ([M + H]+)
281.1465, found 281.1470.
1
column chromatography. H NMR (400 MHz, CDCl3) δ 7.28
(2H, d, J = 8.8, ArH), 7.01 (2H, d, J = 8.8, ArH), 5.91−5.87
(1H, m, NCHCHCH), 5.44−5.42 (1H, m, NCHCHCH),
5.18−5.14 (1H, m, NCH), 3.18 (3H, s, NMe), 2.38 (3H, s,
NMe), 2.37−2.30 (1H, m, NCHCHH), 2.28−2.19 (1H, m,
NCHCHH), 1.98−1.89 (1H, m, NCH2CHH), 1.54−1.46 (1H,
m, NCH2CHH); 13C NMR (100 MHz, CDCl3) δ 161.6, 145.8,
134.7, 130.1, 129.5, 125.2, 125.1, 63.5, 39.6, 31.6, 30.2, 26.3;
MS (ES) m/z 265 ([M + H]+); HRMS m/z calcd for
C14H18N2OClNa ([M + Na]+) 287.0927, found 287.0917.
1-(Cyclopent-2-en-1-yl)-3-(3-fluorophenyl)-1,3-dimethy-
lurea (5c). Following general procedure 3, amine 3 (0.194 g,
2.0 mmol) in CH2Cl2 (10 mL) with NEt3 (0.36 mL, 2.6 mmol),
N-methyl-N-(3-fluorophenyl)carbamoyl chloride7a,14 (0.413 g,
2.2 mmol), and DMAP (0.012 g, 0.05 mmol) gave the title
compound 5c as a colourless oil (0.347 g, 1.4 mmol, 70%) after
1-(4′-Chloro-1,2,3,4-tetrahydro-[1,1′-biphenyl]-1-yl)-1,3-
dimethylurea (6b). Following general procedure 4, urea 4b
(0.125 g, 0.45 mmol) in THF (4.5 mL) with s-BuLi (1 M, 1.12
mL, 1.12 mmol) and DMPU (1.1 mL) gave the title compound
6b as a yellow oil (0.089 g, 0.32 mmol, 71%) after flash column
1
chromatography. RF 0.24 (2:1 PE/EtOAc); H NMR (500
MHz, CDCl3) δ 7.35−7.28 (4H, m, ArH), 5.93 (1H, dt, J =
10.1, 3.5, CCHCH), 5.88 (1H, dt, J = 10.1, 2.2, CCHCH),
4.27 (1H, q, J = 4.1, NH), 3.03 (3H, s, NMe), 2.65 (3H, d, J =
4.7, NHMe), 2.48 (1H, ddd, J = 12.9, 9.1, 3.2, CCHHCH2),
2.20−2.02 (3H, m, CCHHCH2CH2), 1.74−1.56 (2H, m,
CCH2CH2CH2); 13C NMR (125 MHz, CDCl3) δ 159.0 (C
O), 145.7 (4° ArC), 132.5 (4° ArC), 131.5 (CCHCH),
129.8 (CCHCH), 128.7 (ArC), 127.5 (ArC), 62.2 (4° C),
33.2 (NMe), 32.9 (CCH2), 27.5 (NHMe), 24.9 (CH
CHCH2), 19.0 (CCH2CH2); IR νmax (film)/cm−1 3376
(NH), 2929 (CCH), 2856 (CH), 1619 (CO); MS (ES)
m/z 301 ([M + Na]+); HRMS m/z calcd for C15H20N2O35Cl
([M + H]+) 279.1259, found 279.1260.
1
flash column chromatography. H NMR (400 MHz, CDCl3) δ
7.29−7.23 (1H, m, ArH), 6.85−6.83 (1H, m, ArH), 6.80−6.76
(2H, m, ArH), 5.91−5.88 (1H, m, NCHCHCH), 5.47−5.44
(1H, m, NCHCHCH), 5.20−5.15 (1H, m, NCH), 3.20 (3H,
1249
dx.doi.org/10.1021/op500173q | Org. Process Res. Dev. 2014, 18, 1245−1252

Organic Process Research & Development
Article
1-(3′-Fluoro-1,2,3,4-tetrahydro-[1,1′-biphenyl]-1-yl)-1,3-
dimethylurea (6c). Following general procedure 4, urea 4c
(0.050 g, 0.19 mmol) in THF (1.9 mL) with s-BuLi (1.3 M,
0.37 mL, 0.48 mmol) and DMPU (0.48 mL) gave the title
compound 6c as a pale-yellow oil (0.038 g, 0.15 mmol, 76%)
after flash column chromatography. RF 0.18 (1:1 PE/EtOAc);
1H NMR (400 MHz, CDCl3) δ 7.30 (1H, td, J = 8.0, 6.1, ArH),
7.17 (1H, brd, J = 8.0, ArH), 7.09 (1H, dt, J = 10.6, 2.2, ArC),
6.92 (1H, td, J = 8.3, 2.4, ArC), 5.96−5.85 (2H, m, CCH
CH), 4.27 (1H, m, NH), 3.04 (3H, s, NMe), 2.64 (3H, d, J =
4.6, NHMe), 2.49 (1H, ddd, J = 12.8, 9.0, 3.2, CCHHCH2),
2.21−2.02 (3H, m, CCHHCH2CH2), 1.76−1.57 (2H, m,
CCH2CH2CH2); 13C NMR (100 MHz, CDCl3) δ 163.1 (d, JF
= 244.3, ArCF), 159.0 (CO), 150.1 (d, JF = 6.2, 4° ArC),
131.5 (CCHCH), 130.0 (d, JF = 8.2, ArC), 129.9 (CCH
CH), 121.6 (d, JF = 2.9, ArC), 113.7 (d, JF = 21.1, ArC), 113.2
(d, JF = 22.4, ArC), 62.4 (d, JF = 1.7, 4° C), 33.2 (NMe), 33.0
(CCH2CH2), 27.5 (NHMe), 24.9 (CHCHCH2), 19.0
(CCH2CH2); IR νmax (film)/cm−1 3508 (NH), 2939 (C
CH), 1630 (CO); MS (ES) m/z 263 ([M + H]+); HRMS
m/z calcd for C15H20N2OF ([M + H]+) 263.1560, found
263.1568.
N-Methyl-1,2,3,4-tetrahydro-[1,1′-biphenyl]-1-amine (7a).
Following general procedure 5, urea 6a (0.233 g, 0.95 mmol) in
EtOH (2 mL) and 2 M NaOH solution (2 mL) gave the title
compound 7a as a pale-yellow oil (0.156 g, 0.83 mmol, 88%)
after workup. RF Flame (2:1 PE/EtOAc); 1H NMR (400 MHz,
CDCl3) δ 7.51−7.45 (2H, m, ArH), 7.37−7.31 (2H, m, ArH),
7.26−7.20 (1H, m, ArH), 6.04−5.93 (2H, m, CCHCH),
2.23 (3H, s, NMe), 2.10−2.02 (2H, m, CHCHCH2), 1.91−
1.77 (2H, m, CCH2CH2), 1.68−1.58 (1H, m, CCH2CHH),
1.50−1.40 (1H, m, CCH2CHH); 13C NMR (100 MHz,
CDCl3) δ 146.2 (4° ArC), 130.9 (CCHCH), 129.2
(CCHCH), 127.9 (ArC), 127.1 (ArC), 126.3 (ArC), 58.9
(4° C), 37.9 (CCH2CH2), 29.1 (NMe), 25.4 (CHCHCH2),
19.1 (CCH2CH2); IR νmax (film)/cm−1 3335 (NH), 2927 (C
CH), 1622 (CC); MS (ES) m/z 188 ([M + H]+); HRMS
m/z calcd for C13H18N ([M + H]+) 188.1434, found 188.1432.
4′-Chloro-N-methyl-1,2,3,4-tetrahydro-[1,1′-biphenyl]-1-
amine (7b). Following general procedure 5, urea 6b (0.850 g,
3.05 mmol) in EtOH (3 mL) and 2 M NaOH solution (3 mL)
gave the title compound 7b as a yellow oil (0.635 g, 2.87 mmol,
94%) after workup. RF Flame (2:1 PE/EtOAc); 1H NMR (500
MHz, CDCl3) δ 7.44−7.39 (2H, m, ArH), 7.32−7.28 (2H, m,
ArH), 6.02 (1H, dt, J = 10.4, 3.8, CCHCH), 5.95−5.89 (1H,
m, CCHCH), 2.22 (3H, s, NMe), 2.09−2.03 (2H, m,
CCHCHCH2), 1.85−1.79 (2H, m, CCH2), 1.66−1.58 (1H,
m, CCH2CHH), 1.45−1.35 (1H, m, CCH2CHH); 13C NMR
(125 MHz, CDCl3) δ 144.8 (4° ArC), 132.2 (4° ArC), 130.3
(CCHCH), 129.8 (CCHCH), 128.8 (ArC), 128.1 (ArC),
58.7 (4° C), 37.9 (CCH2), 29.0 (NMe), 25.3 (CCH2CH2CH2),
19.0 (CCH2CH2); IR νmax (film)/cm−1 2932 (CCH), 1764
(CC); MS (ES) m/z 222 ([M + H]+); HRMS m/z calcd for
C13H17N35Cl ([M + H]+) 222.1045, found 222.1042.
3′-Fluoro-N-methyl-1,2,3,4-tetrahydro-[1,1′-biphenyl]-1-
amine (7c). Following general procedure 5, urea 6c (0.275 g,
1.05 mmol) in EtOH (1 mL) and 2 M NaOH solution (1 mL)
gave the title compound 7c as a brown oil (0.179 g, 0.87 mmol,
83%) after workup. RF Flame (2:1 PE/EtOAc); 1H NMR (400
MHz, CDCl3) δ 7.32−7.18 (3H, m, ArH), 6.94−6.88 (1H, m,
ArH), 6.05−5.90 (2H, m, CCHCH), 2.23 (3H, s, NMe),
2.10−2.04 (2H, m, CCHCHCH2), 1.87−1.77 (2H, m,
CCH2), 1.68−1.58 (1H, m, CCH2CHH), 1.48−1.39 (1H, m,
CCH2CHH); 13C NMR (100 MHz, CDCl3) δ 162.9 (d, JF =
243.0, ArCF), 149.9 (d, JF = 6.2, 4° ArC), 130.5 (CCHCH),
129.6 (CCHCH), 129.2 (d, JF = 8.0, ArC), 122.8 (d, JF = 2.7,
ArC), 114.3 (d, JF = 21.9, ArC), 113.1 (d, JF = 21.1, ArC), 58.8
(d, JF = 1.7, 4° C), 37.9 (CCH2CH2), 29.1 (NMe), 25.3 (CH
CHCH2), 19.0 (CCH2CH2); IR νmax (film)/cm−1 2937 (C
CH), 1612 (CO), 1585 (CC); MS (ES) m/z 206 ([M +
H]+); HRMS m/z calcd for C13H17NF ([M + H]+) 206.1345,
found 206.1351.
1-(3′,5′-Difluoro-1,2,3,4-tetrahydro-[1,1′-biphenyl]-1-yl)-
1,3-dimethylurea (6d). Following general procedure 4, urea 4d
(1.152 g, 4.11 mmol) in THF (41.1 mL) with s-BuLi (1.3 M,
7.90 mL, 10.27 mmol) and DMPU (10.28 mL) gave the title
compound 6d as a brown oil (0.809 g, 2.89 mmol, 70%) after
1
flash column chromatography. RF 0.23 (1:1 PE/EtOAc); H
NMR (400 MHz, CDCl3) δ 6.90−6.84 (2H, m, ArH), 6.62
(1H, tt, J = 8.7, 2.3, ArH), 5.98−5.92 (1H, m, CCHCH),
5.87−5.82 (1H, m, CCHCH), 4.43−4.35 (1H, m, NH), 3.02
(3H, s, NMe), 2.67 (3H, d, J = 4.6, NHMe), 2.50 (2H, ddd, J =
12.5, 8.2, 3.6, CCH2), 2.13−2.05 (2H, m, CHCHCH2)
1.71−1.59 (2H, m, CCH2CH2); 13C NMR (100 MHz, CDCl3)
δ 163.1 (d, JF = 246.1, ArCF), 163.0 (d, JF = 245.9, ArCF),
158.7 (CO), 152.4, (t, JF = 7.8, 4° ArC), 131.0 (CCH
CH), 130.4 (CCHCH), 108.8, (d, JF = 25.7, ArC), 108.8 (d,
JF = 11.8, ArC), 101.8 (t, JF = 25.6, ArC), 62.6 (t, JF = 2.0, 4°
C), 33.1 (NMe), 33.1 (CCH2CH2), 27.4 (NHMe), 24.8
(CHCHCH2), 18.9 (CCH2CH2); IR νmax (film)/cm−1 2935
(CCH), 1642 (CO); MS (ES) m/z 281 ([M + H]+);
HRMS m/z calcd for C15H19N2OF2 ([M + H]+) 281.1465,
found 281.1470.
1-(3′-Methoxy-1,2,3,4-tetrahydro-[1,1′-biphenyl]-1-yl)-1,3-
dimethylurea (6e). Following general procedure 4, urea 4e
(0.080 g, 0.29 mmol) in THF (2.9 mL) with s-BuLi (1 M, 0.73
mL, 0.73 mmol) and DMPU (0.73 mL) gave the title
compound 6e as a colourless oil (0.027 g, 0.10 mmol, 34%)
after flash column chromatography. RF 0.17 (1:1 PE/EtOAc);
1H NMR (400 MHz, CDCl3) δ 7.20 (1H, t, J = 7.8, ArH),
6.95−6.85 (2H, m, ArH), 6.75−6.69 (1H, m, ArH), 5.86−5.77
(2H, m, CCHCHCH2), 4.22 (1H, q, J = 4.5, NH), 3.73 (3H,
s, OMe), 2.99 (3H, s, NMe), 2.52 (3H, d, J = 4.5, NHMe), 2.35
(1H, ddd, J = 12.9, 9.3, 3.3, CCHHCH2), 2.16−1.93 (3H, m,
CCHHCH2CH2), 1.68−1.50 (2H, m, CCH2CH2); 13C NMR
(100 MHz, CDCl3) δ 159.8 (CO), 159.3 (4° ArCOMe),
148.4 (4° ArC), 131.5 (CCHCH), 129.7 (ArC), 129.5
(CCHCH), 118.5 (ArC), 112.5 (ArC), 111.7 (ArC), 62.3
(4° C), 55.2 (OMe), 33.1 (NMe), 32.8 (CCH2CH2), 27.5
(NHMe), 24.8 (CHCHCH2), 19.0 (CCH2CH2); IR νmax
(film)/cm−1 3372 (NH), 2928 (CCH), 1623 (CO); MS
(ES) m/z 275 ([M + H]+); HRMS m/z calcd for C16H23N2O2
([M + H]+) 275.1755, found 275.1756.
3′,5′-Difluoro-N-methyl-1,2,3,4-tetrahydro-[1,1′-biphen-
yl]-1-amine (7d). Following general procedure 5, urea 6d
(0.200 g, 0.71 mmol) in EtOH (2 mL) and 2 M NaOH
solution (2 mL) gave the title compound 7d as a yellow oil
(0.139 g, 0.62 mmol, 87%) after workup. RF Flame (2:1 PE/
1
EtOAc); H NMR (400 MHz, CDCl3) δ 7.05−6.98 (2H, m,
ArH), 6.65 (1H, tt, J = 8.7, 2.4, ArH), 6.05−5.85 (2H, m,
CCHCH), 2.21 (3H, s, NMe), 2.09−2.03 (2H, m, CCH
CHCH2), 1.80−1.75 (2H, m, CCH2), 1.66−1.56 (1H, m,
CCH2CHH), 1.48−1.36 (1H, m, CCH2CHH); 13C NMR (100
MHz, CDCl3) δ 163.0 (d, JF = 245.3, ArCF), 162.9 (d, JF =
245.3, ArCF), 151.4 (t, JF = 7.7, 4° ArC), 130.2 (CCHCH),
129.9 (CCHCH), 110.2 (d, JF = 25.2, ArC), 110.2 (d, JF =
1250
dx.doi.org/10.1021/op500173q | Org. Process Res. Dev. 2014, 18, 1245−1252

Organic Process Research & Development
Article
11.9, ArC), 101.8 (t, JF = 25.6, ArC), 58.9 (4° C), 38.0
(CCH2CH2), 29.1 (NMe), 25.3 (CHCHCH2), 19.0
(CCH2CH2); IR νmax (film)/cm−1 2939 (CCH), 1621
(CC), 1594 (CC); MS (ES) m/z 224 ([M + H]+);
HRMS m/z calcd for C13H16NF2 ([M + H]+) 224.1251, found
224.1248.
(ES) m/z 429 ([M + Na]+); HRMS m/z calcd for
C15H18N2OF2I ([M + H]+) 407.0432, found 407.0432.
tert-Butyl N-(4′-Chloro-1,2,3,4-tetrahydro-[1,1′-biphenyl]-
1-yl)-N-methylcarbamate (11). To a solution of 4′-chloro-N-
methyl-1,2,3,4-tetrahydro-[1,1′-biphenyl]-1-amine (7b) (0.255
g, 1.15 mmol) in CH2Cl2 (12 mL) were added NEt3 (0.32 mL,
2.30 mmol) and di-tert-butyl dicarbonate (0.276 g, 1.27 mmol),
and the mixture was stirred overnight. The reaction was
quenched with brine, and the mixture was extracted with
CH2Cl2 and dried over MgSO4. The solvent was removed
under reduced pressure, and purification by flash column
chromatography (PE/EtOAc 4:1) yielded the title compound
11 as a pale-yellow oil (0.352 g, 1.09 mmol, 96%). RF 0.61 (2:1
3′-Methoxy-N-methyl-1,2,3,4-tetrahydro-[1,1′-biphenyl]-
1-amine (7e). Following general procedure 5, urea 6e (0.050 g,
0.18 mmol) in EtOH (1 mL) and 2 M NaOH solution (1 mL)
gave the title compound 7e as a colourless oil (0.036 g, 0.17
1
mmol, 82%) after workup. RF Flame (2:1 PE/EtOAc); H
NMR (500 MHz, CDCl3) δ 7.28−7.23 (1H, m, ArH), 7.09−
7.04 (2H, m, ArH), 6.80−6.77 (1H, m, ArH), 6.02 (1H, dt, J =
10.1, 3.8, CCHCHCH2), 5.97−5.93 (1H, m, CCH
CHCH2), 3.82 (3H, s, OMe), 2.25 (3H, s, NMe), 2.11−2.02
(2H, m, CCHCHCH2), 1.94−1.80 (2H, m, CCH2CH2),
1.67−1.59 (1H, m, CCH2CHH), 1.49−1.39 (1H, m,
CCH2CHH); 13C NMR (125 MHz, CDCl3) δ 159.5 (4°
ArCOMe), 147.5 (4° ArC), 130.2 (CCHCHCH2), 129.8
(CCHCHCH2), 128.9 (ArC), 119.7 (ArC), 113.2 (ArC),
111.7 (ArC), 59.2 (4° C), 55.2 (OMe), 37.6 (CCH2CH2), 29.0
(NMe), 25.3 (CCHCHCH2), 19.0 (CCH2CH2); IR νmax
(film)/cm−1 2932 (CCH), 1599 (CC); MS (ES) m/z 218
([M + H]+); HRMS m/z calcd for C14H20NO ([M + H]+)
218.1540, found 218.1546.
1
PE/EtOAc); H NMR (300 MHz, CDCl3) δ 7.31−7.15 (4H,
m, ArH), 5.94−5.80 (2H, m, CCHCH), 3.12 (3H, s, NMe),
2.41 (1H, ddd, J = 13.0, 9.2, 3.4, NCHH), 2.17−1.97 (3H, m,
CCHHCH2CH2), 1.74−1.50 (2H, m, CCH2CH2), 1.15 (9H, s,
C(CH3)3); 13C NMR (125 MHz, CDCl3) δ 155.6 (CO),
147.6 (4° ArC), 146.7 (4° ArC), 131.3 (CHCH), 129.5
(CHCH), 127.9 (ArC), 127.0 (ArC), 68.1 (4° C), 62.1 (4°
C), 33.8 (CCH2), 33.1 (NMe), 28.2 (C(CH3)3), 24.9
(CCH2CH2CH2), 18.9 (CCH2CH2); IR νmax (film)/cm−1
2933 (CCH), 1720 (CO), 1690 (CC); MS (ES) m/z
344 ([M + Na]+); HRMS m/z calcd for C18H24NO235ClNa
([M + Na]+) 344.1388, found 344.1373.
1,3-Dimethyl-3′H-spiro[cyclohex-2″-en-1″-yl]-4′H-spiro-
[imidazolidine-4,1′-naphthalene]-2,4′-dione (9). Compound
9 was obtained using a modification of general procedure 4. To
1-(cyclohex-2-en-1-yl)-1,3-dimethyl-3-(naphthalen-1-yl)urea
(4g) (0.113 g, 0.38 mmol) in THF (3.8 mL) at −78 °C was
added s-BuLi (1 M, 0.96 mL, 0.96 mmol) dropwise, and the
mixture was stirred for 2 h. DMPU (0.95 mL) was added, and
the mixture was stirred for 2 h. Compressed air was bubbled
through the mixture for 30 min. Purification by flash column
chromatography yielded the title compound 9 as a brown oil
(0.018 g, 0.06 mmol, 15%). RF 0.16 (1:1 PE/EtOAc); 1H NMR
(400 MHz, CDCl3) δ 8.18 (1H, dd, J = 7.6, 1.8, ArH), 7.60−
7.55 (1H, m, ArH), 7.53−7.48 (1H, m, ArH), 7.39 (1H, dd, J =
7.8, 1.5, ArH), 7.03 (1H, d, J = 10.3, CHCHCO), 6.54
(1H, d, J = 10.3, CHCHCO), 6.09 (1H, dt, J = 10.1, 3.8,
CCHCHCH2), 5.62 (1H, dt, J = 10.3, 2.0, CCHCHCH2),
2.78 (3H, s, NMe), 2.63 (3H, s, NMe), 1.98−1.76 (2H, m,
CHCHCH2), 1.40−1.08 (4H, m, CCH2CH2); 13C NMR
(100 MHz, CDCl3) δ 183.9 (CHCO), 160.8 (NMeCO),
150.7 (CCHCHCO), 140.0 (4° ArC), 134.2 (CCH
CH), 132.7 (4° ArC), 132.6 (ArC), 131.4 (CCHCHCO),
128.7 (ArC), 127.3 (ArC), 127.2 (ArC), 126.9 (CCHCH),
66.9 (4° C), 66.1 (4° C), 28.6 (CCH2), 27.7 (NMe), 27.0
(NMe), 24.2 (CHCHCH2), 18.7 (CCH2CH2); IR νmax
(film)/cm−1 1705 (CO), 1668 (CO); MS (ES) m/z
309 ([M + H]+); HRMS m/z calcd for C19H21N2O2 ([M +
H]+) 309.1598, found 309.1596.
3a-(3,5-Difluorophenyl)-7-iodo-1,3-dimethylhexahydro-
1H-benzo[d]imidazol-2(3H)-one (10). Following general
procedure 6, urea 6d (0.362 g, 1.29 mmol) in CHCl3 (13
mL) with NIS (0.436 g, 1.94 mmol) gave the title compound
10 as a dark-brown oil (0.450 g, 1.11 mmol, 86%) after workup.
1H NMR (400 MHz, CDCl3) δ 6.94−6.79 (3H, m, ArC), 4.72
(1H, d, J = 5.5, CHCHI), 4.30 (1H, dt, J = 4.9, 9.7, CHI), 3.13
(3H, s, NMe), 2.83 (3H, s, NMe), 2.41 (1H, ddd, J = 13.9, 9.1,
4.3, CHHCArN), 2.27−2.17 (1H, m, CHHCHI), 2.12−1.79
(3H, m, CHICHHCHHCHH), 1.72−1.61 (1H, m,
CHICH2CHH); IR νmax (film)/cm−1 1705 (CO); MS
3a-(4-Chlorophenyl)-7-iodo-3-methylhexahydrobenzo[d]-
oxazol-2(3H)-one (12). Following general procedure 6,
carbamate 11 (0.212 g, 0.66 mmol) in CHCl3 (7 mL) with
NIS (0.222 g, 0.99 mmol) gave the title compound 12 as a
1
dark-brown oil (0.230 g, 0.59 mmol, 89%) after workup. H
NMR (400 MHz, CDCl3) δ 7.42−7.37 (2H, m, ArH), 7.34−
7.29 (2H, m, ArH), 4.71 (1H, d, J = 4.8, CHCHI), 4.36 (1H,
dt, J = 7.0, 4.5, CHI), 2.66 (3H, s, NMe), 2.64−2.56 (1H, m,
CHHCArN), 2.26−2.16 (1H, m, CHHCHI), 2.11−1.83 (3H,
m, CHICHHCHHCHH), 1.73−1.62 (1H, m, CHICH2CHH);
13C NMR (100 MHz, CDCl3) δ 157.0 (CO), 139.1 (4°
ArC), 134.4 (4° ArC), 129.2 (ArC), 127.6 (ArC), 85.2
(CHCHI), 64.5 (4° C), 30.6 (CH2CHI), 28.4 (CH2CArN),
26.5 (NMe), 23.6 (CHI), 19.7 (CH2CH2CHI); IR νmax (film)/
cm−1 1704 (CO); MS (ES) m/z 391 ([M + H]+); HRMS
m/z calcd for C45H16NO235ClI ([M + H]+) 391.9914, found
391.9921.
1,3-Dimethyl-1-(1-phenylcyclopent-2-en-1-yl)urea (13a).
Following general procedure 4, urea 5a (0.380 g, 1.65 mmol)
in THF (16.5 mL) with s-BuLi (1.31 M, 3.14 mL, 4.13 mmol)
and DMPU (4.13 mL) gave the title compound 13a as a yellow
solid (0.115 g, 0.50 mmol, 30%) after flash column
1
chromatography. H NMR (500 MHz, CDCl3) δ 7.47−7.45
(2H, m, ArH), 7.36−7.32 (2H, m, ArH), 7.29−7.25 (1H, m,
ArH), 6.01−6.00 (1H, m, NCCHCH), 5.61−5.58 (1H, m,
NCCHCH), 4.43 (1H, brs, NH), 2.87−2.81 (1H, m,
NCCHH), 2.84 (3H, d, J = 4.6, NHMe), 2.72−2.65 (1H, m,
NCCHH), 2.70 (3H, s, NMe), 2.45−2.40 (1H, m,
NCCH2CHH), 1.78−1.71 (1H, m, NCCH2CHH); 13C NMR
(125 MHz, CDCl3) δ 158.8, 145.1, 128.4, 127.8, 125.9, 125.8,
61.6, 32.0, 28.8, 27.8; MS (ES) m/z 231 ([M + H]+); HRMS
m/z calcd for C14H18N2O ([M + H]+) 231.1492, found
231.1486.
1-(1-(4-Chlorophenyl)cyclopent-2-en-1-yl)-1,3-dimethylur-
ea (13b). Following general procedure 4, urea 5b (0.199 g, 0.75
mmol) in THF (7.5 mL) with s-BuLi (1.31 M, 1.44 mL, 1.88
mmol) and DMPU (1.88 mL) gave the title compound 13b as
a yellow solid (0.036 g, 0.14 mmol, 18%) after flash column
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Organic Process Research & Development
Article
chromatography. MP 143−145 °C; 1H NMR (400
MHz,CDCl3) δ 7.38 (2H, d, J = 8.6, ArH), 7.30 (2H, d, J =
8.6, ArH), 6.00−5.98 (1H, m, NCCHCH), 5.64−5.60 (1H,
m, NCCHCH), 4.38 (1H, brs, NH), 2.84 (3H, d, J = 4.6,
NHMe), 2.82−2.76 (1H, m, NCCHH), 2.70−2.63 (1H, m,
NCCHH), 2.69 (3H, s, NMe), 2.44−2.40 (1H, m,
NCCH2CHH), 1.79−1.70 (1H, m, NCCH2CHH); 13C NMR
(100 MHz, CDCl3) δ 157.8, 144.0, 134.1, 133.6, 128.6, 127.2,
126.6, 61.6, 32.0, 28.8, 27.7; MS (ES) m/z 265 ([M + H]+);
HRMS m/z calcd for C14H18N2OCl ([M + H]+) 265.1108,
found 265.1099.
many helpful discussions. J.C. is the recipient of a Royal Society
Wolfson Research Merit Award.
REFERENCES
■
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1-(1-(3-Fluorophenyl)cyclopent-2-en-1-yl)-1,3-dimethylur-
ea (13c). Following general procedure 4, urea 5c (0.323 g, 1.30
mmol) in THF (13 mL) with s-BuLi (1.31 M, 2.48 mL, 3.25
mmol) and DMPU (3.25 mL) gave the title compound 13c as a
brown oil (0.089 g, 0.36 mmol, 28%) after flash column
1
chromatography. H NMR (400 MHz, CDCl3) δ 7.34−7.31
(1H, m, ArH), 7.26−7.24 (1H, m, ArH), 7.17−7.13 (1H, m,
ArH), 7.01−6.96 (1H, m, ArH), 6.05−6.04 (1H, m, NCCH
CH), 5.68−5.64 (1H, m, NCCHCH), 4.49 (1H, brs, NH),
2.86 (3H, d, J = 4.6, NHMe), 2.84−2.79 (1H, m, NCCHH),
2.72 (3H, s, NMe), 2.70−2.64 (1H, m, NCCHH), 2.48−2.39
(1H, m, NCCH2CHH), 1.82−1.72 (1H, m, NCCH2CHH);
13C NMR (100 MHz, CDCl3) δ 162.9 (d, JF = 243.9), 158.7,
144.1 (d, JF = 2.3), 137.9 (d, JF = 7.4), 129.8 (d, JF = 8.5),
127.3, 121.5 (d, JF = 2.8), 114.5 (d, JF = 21.2), 112.7 (d, JF =
21.8), 61.4, 31.9, 28.8, 27.7, 27.7; MS (ES) m/z 271 ([M +
Na]+); HRMS m/z calcd for C14H17N2OFNa (M + Na+)
271.1223, found 271.1232.
1-(1-(4-Methoxyphenyl)cyclopent-2-en-1-yl)-1,3-dimethy-
lurea (13f). Following general procedure 4, urea 5f (0.349 g,
1.34 mmol) in THF (13.4 mL) with s-BuLi (1.31 M, 2.56 mL,
3.35 mmol) and DMPU (3.35 mL) gave the title compound
13f as a yellow oil (0.014 g, 0.14 mmol, 4%) after flash column
chromatography. 1H NMR (400 MHz, CDCl3) δ 7.40 (2H, d, J
= 8.8, ArH), 6.87 (2H, d, J = 8.8, ArH), 5.87−5.85 (1H, m,
NCCHCH), 5.59−5.54 (1H, m, NCCHCH), 4.41−4.39
(1H, m, NH), 3.82 (3H, s, OMe), 2.84 (3H, d, J = 4.6, NHMe),
2.83−2.77 (1H, m, NCCHH), 2.69 (3H, s, NMe), 2.68−2.61
(1H, m, NCCHH), 2.44−2.35 (1H, m, NCCH2CHH), 1.77−
1.69 (1H, m, NCCH2CHH); 13C NMR (100 MHz, CDCl3) δ
159.4, 158.8, 144.6, 128.5, 127.2, 123.7, 113.8, 61.7, 55.3, 32.1,
28.9, 27.9, 27.7; MS (ES) m/z 283 ([M + Na]+); HRMS m/z
calcd for 283.1422 C15H20N2O2Na (M + Na+), found 283.1410.
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̈
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: clayden@man.ac.uk. Fax: +44 161 275 4939.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by the EPSRC and AstraZeneca (CASE
Awards to M.B.T. and D.J.T.) and the Deutsche Forschungs-
gemeinschaft (fellowship to P.A.O.). We thank Sam Butter-
worth, Michael Waring, and David Clarke of AstraZeneca for
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dx.doi.org/10.1021/op500173q | Org. Process Res. Dev. 2014, 18, 1245−1252