N,N′-diarylureas: A new family of atropisomers exhibiting highly diastereoselective reactivity

Article abstract of DOI:10.1021/jo702706c

(Chemical Equation Presented) 2,6-Disubstituted N-aryl ureas rotate slowly about their Ar-N bonds and can exist as separable atropisomers. They also react remarkably diastereoselectively, with the urea axis controlling new stereogenic centers with high fidelity in a variety of nucleophilic and electrophilic addition reactions. The sense of diastereoselectivity in lateral lithiation-electrophilic quench reactions is electrophile-dependent and appears to be the result of stereospecific reaction with one of two interconvertible diastereoisomeric organolithiums.

Full text of DOI:10.1021/jo702706c

N,N′-Diarylureas: A New Family of Atropisomers Exhibiting Highly
Diastereoselective Reactivity
Jonathan Clayden,*,† Hazel Turner,† Madeleine Helliwell,† and Elizabeth Moir‡
School of Chemistry, UniVersity of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom, and
Organon Research Laboratories Limited, Newhouse, Lanarkshire ML1 5SH, United Kingdom
clayden@man.ac.uk
ReceiVed December 20, 2007
2,6-Disubstituted N-aryl ureas rotate slowly about their ArsN bonds and can exist as separable
atropisomers. They also react remarkably diastereoselectively, with the urea axis controlling new
stereogenic centers with high fidelity in a variety of nucleophilic and electrophilic addition reactions.
The sense of diastereoselectivity in lateral lithiationselectrophilic quench reactions is electrophile-
dependent and appears to be the result of stereospecific reaction with one of two interconvertible
diastereoisomeric organolithiums.
Introduction
their lateral lithiation-electrophilic quench,4 exhibit remarkably
high levels of stereoselectivity. These observations open up the
possibility that aromatic ureas might provide a useful chiral
scaffold for the development of new ligands or catalysts.5
Several classes of compounds other than the well-known
biaryls1 exhibit atropisomerism (stereochemistry due to slow
bond rotation).2 To date, these have been principally benzamides
and anilides and their derivatives.3 In this paper, we report for
the first time that atropisomerism is displayed by simple aromatic
ureas, and we show that several of their reactions, including
Results and Discussion
We have previously shown that N-methylated N,N′-diaryl-
ureas 1 may be functionalized regioselectively via ortholithiation
to give dianions 2.6 When 2 was quenched at -78 °C with an
aldehyde as the electrophile, two separable isomeric products
3 were formed (Scheme 1 and Table 1, entries 1-3).7 These
† University of Manchester.
‡ Organon Research Laboratories Ltd.
(1) Adams, R.; Yuan, H. C. Chem. ReV. 1933, 12, 261. Bott, G.; Field, L. D.;
Sternhell, S. J. Am. Chem. Soc. 1980, 102, 5618.
(2) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley:
New York, 1994. Betson, M. S.; Clayden, J.; Worrall, C. P.; Peace, S. Angew.
Chem., Int. Ed. 2006, 45, 5803.
(4) Clayden, J.; Dufour, J. Tetrahedron Lett. 2006, 47, 6945.
(5) For recent examples of non-biaryl atropisomers as chiral ligands, see:
Mino, T.; Tanaka, Y.; Yabusaki, T.; Okumura, D.; Sakamoto, M.; Fujita, T.
Tetrahedron: Asymmetry 2003, 14, 2503. Mino, T.; Tanaka, Y.; Hattori, Y.;
Yabusaki, T.; Saotome, H.; Sakamoto, M.; Fujita, T. J. Org. Chem. 2006, 71,
7346. Clayden, J.; Lai, L. W.; Helliwell, M. Tetrahedron: Asymmetry 2001, 12,
695. Dai, W.-M.; Yeing, K. K. Y.; Liu, J.-T.; Zhang, Y.; Williams, I. D. Org.
Lett. 2002, 4, 1615. Smith, M. D.; Shimizu, K. D. Tetrahedron Lett. 2001, 42,
7185.
(3) Ahmed, A.; Bragg, R. A.; Clayden, J.; Lai, L. W.; McCarthy, C.; Pink,
J. H.; Westlund, N.; Yasin, S. A. Tetrahedron 1998, 54, 13277. Clayden, J.
Angew. Chem., Int. Ed. 1997, 36, 949. Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi,
A.; Taguchi, T. J. Org. Chem. 1998, 63, 2634. Kitagawa, O.; Yoshikawa, M.;
Tanabe, H.; Morita, T.; Takahashi, M.; Dobashi, Y.; Taguchi, T. J. Am. Chem.
Soc. 2006, 128, 12923. Brandes, S.; Bella, M.; Kjaersgaard, A.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2006, 45, 1147. Petit, M.; Geib, S. J.; Curran, D. P.
Tetrahedron 2004, 60, 7543. Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C.
J. Am. Chem. Soc. 1994, 116, 3131. Clayden, J. Tetrahedron 2004, 60, 4335
and references cited therein. Clayden, J.; Mitjans, D.; Youssef, L. H. J. Am.
Chem. Soc. 2002, 124, 5266. Bennett, D. J.; Blake, A. J.; Cooke, P. A.; Godfrey,
C. R. A.; Pickering, P. L.; Simpkins, N. S.; Walker, M. D.; Wilson, C.
Tetrahedron 2004, 60, 4491. Zhang, Y.; Wang, Y.; Dai, W.-M. J. Org. Chem.
2006, 71, 2445.
(6) Clayden, J.; Turner, H.; Pickworth, M.; Adler, T. Org. Lett. 2005, 7,
3147.
(7) For comparable reactions of lithiated benzamides and naphthamides, see:
Bowles, P.; Clayden, J.; Helliwell, M.; McCarthy, C.; Tomkinson, M.; Westlund,
N. J. Chem. Soc., Perkin Trans. 1 1997, 2607. Clayden, J.; Stimson, C. C.;
Keenan, M. Synlett 2005, 1716.
10.1021/jo702706c CCC: $40.75
Published on Web 04/10/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4415–4423 4415

Clayden et al.
SCHEME 1. Addition of Ortholithiated Ureas to Aldehydes
FIGURE 1. X-ray crystal structures of (a) syn-3d and (b) anti-3c.
FIGURE 2. Stereoselectivity of (a) addition and (b) reduction.
rotation about the more hindered Ar-N bond possibly as high
9
TABLE 1. Atroposelective Formation of Alcohols 3
as 130 kJ mol-1
.
entry
R1 ) t-Bu and R2 )
Me
Et
3b
89
i-Pr
3c
69
Ph
3d 3e
76 95
Mea
The diastereoselectivities of the addition reactions are re-
markably high, and resubjecting the products to the conditions
of the reaction by treatment with 2 equiv of BuLi showed that
the origin of the selectivity was kinetically determined in the
C-C bond forming step. We propose a transition state structure
approximated in Figure 2a to explain the syn selectivity of these
reactions. Aggregation of the lithiated amide in solution means
that the approach of the aldehyde takes place syn to the urea
methyl group: steric hindrance between R2 and the methyl group
controls the relative diastereofacial selectivity.
Reduction of the ketones 4 with either sodium borohydride
or superhydride gave the same pairs of atropisomers, again in
favor of the syn diastereoisomer but with poorer diastereose-
lectivity (Table 1, entries 4 and 5).10 The syn stereochemistry
results from nucleophilic attack on the less hindered face of
ketones 4 in the conformation shown in Figure 2b. Atropisomers
3 were finally also made by the addition of excess organome-
tallic nucleophiles to the aldehyde 5, but only PhMgBr gave a
high selectivity.10
These results clearly show that unsymmetrical 2,6-disubsti-
tuted arylureas have the potential to exhibit atropisomerism and
thus reveal a new class of stereogenic axes,11 which also possess
a powerful lithiation directing ability.4,6 Lateral lithiation
(lithiation at a benzylic position ortho to a directing group)12 is
well-known for amides13,14 and anilides14,15 but only recently
has been reported for ureas.4 It was possible to generate
atropisomeric ureas by using lateral lithiation to desymmetrize
the 2,6-diethyl urea 6. Treatment of 6 with 2.5 equiv of s-BuLi
product 3
yield from 1 (-90 °C) (%) 79
Ratio syn/anti-3
3a
1
2
3
4
5
6
from 1 (-90 °C)
from 1 (-78 °C)
from 4 (NaBH4)b
from 4 (LiBHEt3)c
from 5
99:1
97:3 98:2 70:30
84:16 83:17 97:3 63:37 80:20
55:45 65:35 79:21 77:23
51:49 56:44 62:38 92:8
80:20d
50:50f
78:22g
92:8e
7
after heating
62:38h
a R1 ) i-Pr. b Yields quantitative. c Yields 80-100%. d MeLi (88%).
e PhMgBr (63%). f MeMgBr (44%). g From syn-3a: ratio reached after
18 h, 110 °C, toluene. h From syn-3e: equilibrium ratio determined after
48 h, 70 °C, THF.
products were shown to be pairs of atropisomeric diastereo-
isomers of 3a-e by NMR and by oxidation of each (or of the
product mixture) to a single ketone 4a-d. X-ray crystallography
proved the syn stereochemistry for the major isomer of 3d and
the anti stereochemistry for the minor diastereoisomer of 3c
(Figure 1a,b),8 and we assumed the syn stereochemistry for the
other major isomers, all of which were the less polar of each
pair. As shown in Table 1, the stereoselectivity was significantly
higher when the addition reactions were carried out at -90 °C
(entries 2 and 3 in Table 1).
To establish the stability of the atropisomers syn- and anti-3
with respect to epimerization by rotation about the stereogenic
Ar-N bond, syn-3e was dissolved in THF and heated at 70 °C.
Epimerization eventually gave an equilibrium mixture of
62:38 (Table 1, entry 7). Eyring analysis returned barriers of
111 kJ mol-1 (syn-3e) and 114 kJ mol-1 (anti-3e) for the
interconversion of the diastereoisomers at this temperature.
Likewise, syn-3a was heated to 110 °C for 18 h. Conversion to
anti-3a reached 22% after this time, suggesting a barrier to
(9) Decomposition prevented longer epimerization times, but this ratio does
not appear to represent the equilibrated ratio of diastereoisomers. A barrier of
130 kJ mol-1 would give a half-life of 18 h at 110 °C for epimerization to an
equilibrium mixture of atropisomers.
(10) For comparable reactions of lithiated benzamides and naphthamides,
see: Clayden, J.; Westlund, N.; Beddoes, R. L.; Helliwell, M. J. Chem. Soc.,
Perkin Trans. 1 2000, 1351.
(11) We have previously established that ureas bearing a single 2-substituent
rotate slowly on the NMR timescale. Atropisomerism appears to arise only in
2,6-disubstituted ureas. Adler, T.; Bonjoch, J.; Clayden, J.; Font-Bardf´ıa, M.;
Pickworth, M.; Solans, X.; Sole´, D.; Vallverdu´, L. Org. Biomol. Chem. 2005, 3,
3173.
(8) For all four atropisomeric ureas whose X-ray crystal structures are reported
in this paper, the angle between the aryl ring and the average plane of the urea
is 90 ( 10°. The X-ray crystallographic data for anti-3c, syn-3d, 10e (major
diastereoisomer), and 12 can be found in CCDC 629964, 629965, 629966, and
629967, respectively. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
(12) Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon: Oxford,
2002. Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1.
(13) Court, J. J.; Hlasta, D. J. Tetrahedron Lett. 1996, 37, 1335.
(14) Thayumanavan, S.; Basu, A.; Beak, P. J. Am. Chem. Soc. 1997, 119,
8209.
(15) Basu, A.; Beak, P. J. Am. Chem. Soc. 1996, 118, 1575.
4416 J. Org. Chem. Vol. 73, No. 12, 2008

N,N′-Diarylureas: New Family of Atropisomers
TABLE 2. Formation of Atropisomers 9 and 10
entry
E+ (E) )
9: yield from 6 (%)
9a, 81
ratio anti-9:/syn-9
>98:2
10: yield from 7 (%)
ratio anti-10/syn-10
1
2
3
4
EtI (Et)
10a, 73
85a
>98:2
<2:98a
>98:2b
>98:2
59b
9b, 65
>98:2b
>98:2
61b
Me3SiCl
(Me3Si)
Me2PhSiCl
(Me2PhSi)
Bu3SnBr
(Bu3Sn)
10b, 62
5
10c, 62
10d, 65
>98c:2
6
7
8
9
9d, 88
90:10
59:41d
90:10b
(14:21)e
(65f)
>98:2
72b
>98:2d
MeCHO
(Me(OH)CH)
PhCHO
(Ph(OH)CH)
Acetone
(Me2(OH)C)
PhCHdNMe
(Ph(NHMe)CH)
Ac2O
9e, 74
9f, 87
9g, 90
9 h, 78
10e, 81
10f, 80
(12:7)e
(40:41g)
<2
10
11
12
13
<2
(69:31)h
<2:98
(77:23)h
<2:98
10 g, 100
10 h, 74
10i, 55
<2
(68:32)
<2:98
<2:98
(MeCO)
a By lithiation and methylation of 11. b By tinslithium exchange (from anti-9d or 10d for entry 3; from a mixture of syn- + anti-9d for entry 8).
c Stereospecific oxidation yields anti-3a. d After being heated at 110 °C in toluene for 26 h. e Ratios determined by isolating four diastereoisomers:
oxidation to a common ketone showed that bracketed pairs differ in stereochemistry at the hydroxyl-bearing center. f Inseparable mixture of two
diastereoisomers. g Stereochemistry proved by X-ray crystal structure. h Ratio determined by NMR: only two isomers observed, both giving the same
ketone on oxidation.
gave organolithium(s) 8, which were quenched with electro-
philes to yield the atropisomeric products 9 shown in Table 2.
Similar results were obtained by treating 2-t-butyl urea 7 with
s-BuLi and electrophiles to yield atropisomers 10.
Alkylation, silylation, addition to a ketone, and acylation
proceeded with excellent diastereoselectivity (Table 2, entries
1, 4, 5, 11, and 13) - in these cases, the minor diastereoisomer
was undetectable by NMR.16 To confirm the existence of a
diastereoisomeric compound, and to prove that the stereoselec-
tivity is the result of kinetic control, 11 was made by alkylation
of 1 and methylated, yielding the other diastereoisomer of 10,
FIGURE 3. X-ray crystal structure of (a) 12 and (b) 10e (major
again with >98:2 diastereoselectivity (entry 2 in Table 2). A
slightly lower diastereoselectivity was observed upon stanny-
lation (entry 6 in Table 2), and reaction with aldehydes gave
mixtures of diastereoisomers at one (entry 10 in Table 2) or
both (entry 9 in Table 2) of the new stereogenic centers. The
reaction with an imine (entry 12 in Table 2) was fully
diastereoselective when R was t-Bu but gave a mixture of
diastereoisomers when R was Et.
diastereoisomer). The t-butyl group is disordered.
SCHEME 2. Atroposelective Lateral Lithiations of Ureas
The stereochemistry of the products could not be determined
in every case, but a combination of X-ray crystallography,
stereospecific interconversion, and analogy allowed confidence
in most assignments. For 9a, a second lithiation and quench
with EtI gave the crystalline symmetrical product 12 (Scheme
2) whose X-ray crystal structure (Figure 3a)8 indicates the anti
stereochemistry for the alkylation products 9a and 10a. Anti
stereochemistry was assigned to silane 10c (and, by analogy,
9b and 10b) by stereospecific oxidation17 to the alcohol anti-
3a (Scheme 2). By contrast, the stereochemistry at the new C-C
bond in both major diastereoisomers of 10e (formed by the
addition to MeCHO) is syn: both oxidize to the ketone 10i
(16) For comparable reactions of lithiated benzamides and naphthamides,
see: Clayden, J.; Pink, J. H.; Westlund, N.; Frampton, C. S. J. Chem. Soc., Perkin
Trans. 1 2002, 901.
produced on acetylation of 8 (entry 13 in Table 2), and the X-ray
crystal structure of the major diastereoisomer of 10e is shown
in Figure 3b.8 We assume syn stereochemistry for the
major products of all CdO and CdN additions (entries 9-13
in Table 2).
(17) Tamao, K.; Nakajo, E.; Ito, Y. J. Org. Chem. 1987, 52, 4412. Shintani,
R.; Okamoto, K.; Hayashi, T. Org. Lett. 2005, 7, 4757. Fleming, I.; Henning,
R.; Parker, D. C.; Plaut, H. E.; Sanderson, P. E. J. J. Chem. Soc., Perkin Trans.
1 1995, 317. Fleming, I.; Barbero, A.; Walter, D. Chem. ReV. 1997, 97, 2063.
Jones, G.; Landais, Y. Tetrahedron 1996, 52, 7599.
J. Org. Chem. Vol. 73, No. 12, 2008 4417

Clayden et al.
SCHEME 3. Mechanistic Pathways in Diastereoselective
LithiationsQuench Reactions of Laterally Lithiated Ureas
philes) or invertive (for alkylating and silylating agents)
electrophilic substitution. Further investigation of the finer
mechanistic details of this reaction is in progress.
In summary, we found that 2,6-disubstituted aryl ureas exhibit
atropisomerism and can be made diastereoselectively by reac-
tions of their lithio derivatives, governed by the stereogenic
Ar-N axis. We are currently working on ways to synthesize
members of this new class of atropisomers in enantiomerically
pure forms.
Experimental Procedures
General experimental details are provided in the Supporting
Information.
1-(2-Isopropylphenyl)-1-methyl-3-phenylurea (1, R1 ) i-Pr).
1-(2-Isopropylphenyl)-3-phenylurea11 (1.00 g, 3.94 mmol) was
dissolved in THF (50 mL) and treated with NaH (0.189 g, 4.72
mmol) and MeI (0.37 mL, 0.838 g, 5.906 mmol) to give a colorless
oil purified by flash chromatography to afford the product in 72%
yield (0.760 g, 2.84 mmol) as a white solid, mp 68-69 °C; Rf (3:
1, petrol/EtOAc) 0.40; IR νmax(CHCl3)/cm-1 1654.6 (CdO); δH
(300 MHz; CDCl3) 1.24 (d, J ) 6.9 Hz, 3H, CH(CH3)2), 1.27 (J )
6.9 Hz, 3H, CH(CH3)2), 3.21 (qn, J ) 6.9 Hz, 1H, CH(CH3)2),
3.31 (s, 3H, NCH3), 6.00 (bs, 1H, NH), 7.01 (tt, J ) 6.8, 1.7 Hz,
1H, Ar-H), 7.23-7.27 (m, 3H, Ar-H), 7.29 (dd, J ) 8.0, 1.3 Hz,
2H, Ar-H), 7.33 (td, J ) 7.8, 1.7 Hz, 1H, Ar-H), 7.45 (dd, J ) 7.9,
1.3 Hz, 1H, Ar-H), 7.49 (td, J ) 7.9, 1.7 Hz, 1H, Ar-H); δC (75
MHz; CDCl3) 24.2 (CH(CH3)2), 24.6 (CH(CH3)2), 28.1 (CH(CH3)2),
37.5 (NCH3), 119.6, 123.3, 128.2, 128.2, 129.1, 129.2 129.8, 139.2,
139.8, 148.1, 155.2 (CdO); m/z (CI) 269 (100%, M + H+); HRMS
found [M + H]+ 269.1652. C17H20N2O requires M + H 269.1648.
1-(2-t-Butyl-6-(1-hydroxyethyl)phenyl)-1-methyl-3-phenyl-
Stereoselective lateral lithiation may proceed by stereoselec-
tive metalation (a) under kinetic control (to give a configura-
tionally stable lithio intermediate), (b) under thermodynamic
control (to give a configurationally unstable lithio intermediate
that equilibrates to a preferred stereochemistry) followed by
stereospecific electrophilic quench, or (c) with stereoselectivity
controlled solely by the electrophilic quench step. The three
mechanisms are known from Beak’s investigations of enanti-
oselective RLi·(s)-sparteine chemistry18 but have diastereo-
selective equivalents.19 A few simple experiments established
that the reactions of these ureas are probably not of type (a)
because the organolithium intermediate 8 appears to be con-
figurationally unstable (at least at -40 °C). First, thermal
epimerization of the stannanes 9d converted the 90:10 product
ratio to one of 59:41 (Table 2, entry 7: under the same
conditions, the diastereoisomeric ratio of 10d did not change).
Treatment of this mixture with n-BuLi at -40 °C generated a
new organolithium 8 (Scheme 3), which was quenched with
Bu3SnBr to yield 9d (entry 8 in Table 2) with the same 90:10
ratio of products formed in the first reaction, or quenched with
EtI to yield 9a again with >98:2 diastereoselectivity. These
results suggest that the organolithiums 8 in Schemes 2 and 3
are, despite their different origins, the same, probably because
the lithium-bearing stereogenic center is configurationally
unstable, as in related lithiated anilides under certain condi-
tions.14
urea (3a). 1-(2-t-Butylphenyl)-1-methyl-3-phenylurea 1 (R1
)
t-Bu)6 (0.200 g, 0.71 mmol) in anhydrous THF (20 mL) was cooled
to -78 °C, and a solution of s-BuLi (1.1 M solution in cyclohexane,
1.6 mL, 1.78 mmol, 2.5 equiv) was added dropwise under N2. The
resulting reaction mixture was stirred for 15 min at this temperature
to afford a yellow solution. Excess acetaldehyde (0.5 mL) was
added, and the mixture was stirred for a further 2 h. The reaction
mixture was diluted with diethyl ether (5 mL), and saturated
ammonium chloride solution (5 mL) was added. The reaction
mixture was left to warm to room temperature. The aqueous layer
was extracted with diethyl ether (3 × 10 mL). The organic layers
were dried over MgSO4 and concentrated under reduced pressure
to give a residue that was purified by flash column chromatography
to yield the title compound in 79% yield (0.184 g, 0.56 mmol) as
a separable mixture of diastereoisomers. Major diastereoisomer,
white solid, mp 164 °C; Rf (1:3 EtOAc/petrol) 0.11; IR νmax(CHCl3)/
cm-1 3410 (OH), 1651.8 (CdO); δH (300 MHz; CDCl3) 1.46 (s,
9H, C(CH3)3), 1.54 (d, J ) 6.4 Hz, 3H, CHOHCH3), 2.24 (bs, 1H,
OH), 3.20 (s, 3H, NCH3), 5.02 (q, J ) 6.4 Hz, 1H, CHOH), 6.15
(s, 1H, NH), 7.02 (dd, J ) 8.6, 4.5 Hz, 1H, Ar-H), 7.25 (d, J ) 4.5
Hz, 4H, Ar-H), 7.48 (t, J ) 7.6 Hz, 1H, Ar-H), 7.61 (td, J ) 8.6,
1.7, 2H, Ar-H); δC (75 MHz; CDCl3) 25.7 (CH3), 32.4 (C(CH3)3),
36.8 (C(CH3)3), 39.4 (NCH3), 64.8 (CHOH), 120.3, 123.6, 126.6,
129.1, 129.2, 137.2, 138.9, 146.3, 148.7, 156.0 (CdO); m/z (CI)
327; HRMS found [M + H]+ 327.2064. C20H26N2O2 requires M
+ H 327.2067. Minor diastereoisomer, white solid, mp 164 °C; Rf
(1:3 EtOAc/petrol) 0.05; IR νmax(CHCl3)/cm-1 3415.7 (OH), 1660.0
(CdO); δH (300 MHz; CDCl3) 1.47 (s, 9H, C(CH3)3), 1.80 (bs,
1H, OH), 3.33 (s, 3H, NCH3), 5.04 (q, J ) 6.4 Hz, 1H, CHOHCH3),
5.88 (bs, 1H, NH), 7.01-7.08 (m, 1H, Ar-H), 7.24-7.31 (m, 4H,
Ar-H), 7.50 (t, J ) 7.6 Hz, 1H, Ar-H), 7.62 (td, J ) 7.6, 1.6 Hz,
2H, Ar-H); δC (75 MHz; CDCl3) 25.5 (CH3), 32.6 (C(CH3)3), 36.9
(C(CH3)3), 39.2 (NCH3), 65.2 (CHOH), 119.9, 123.6, 126.7, 129.3,
129.7, 130.2, 137.0, 138.7, 146.3, 148.7, 155.6 (CdO); m/z (CI)
327 (100%, M+); HRMS found M+ 327.2067 requires C20H27N2O2
327.2067.
A difference in stereochemistry between the products of, on
the one hand, alkylation and silylation and on the other hand
addition to CdO groups is precedented for stereochemically
defined benzylic organolithiums, many of which have been
reported to react with alkylating and silylating agents with
inversion but with carbonyl compounds with retention.19,20 We
therefore propose that the stereochemistry of 9 and 10 arises
from rapid equilibration of 8, once formed, to a thermodynami-
cally more favorable diastereoisomeric configuration syn-8
(Scheme 3) followed by retentive (for CdO and CdN electro-
(18) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S.
Acc. Chem. Res. 1996, 29, 552.
(19) Clayden, J.; Helliwell, M.; Pink, J. H.; Westlund, N. J. Am. Chem. Soc.
2001, 123, 12449.
(20) Gawley, R. E. Tetrahedron Lett. 1999, 40, 4297. Norsikian, S.; Marek,
I.; Klein, S.; Poisson, J.-F.; Normant, J.-F. Chem.sEur. J. 1999, 5, 2055.
Carstens, A.; Hoppe, D. Tetrahedron 1994, 50, 6097. Derwing, C.; Hoppe, D.
Synthesis 1996, 149. Derwing, C.; Frank, H.; Hoppe, D. Eur. J. Org. Chem.
1999, 3519. Hammerschmidt, F.; Hanninger, A. Chem. Ber. 1995, 128, 1069.
Hammerschmidt, F.; Hanninger, A.; Vo¨llenkle, H. Chem.sEur. J. 1997, 3, 1728.
Hammerschmidt, F.; Hanninger, A.; Simov, B. P.; Vo¨llenkle, H.; Werner, A.
Eur. J. Org. Chem. 1999, 3511. Faibish, N. C.; Park, Y. S.; Lee, S.; Beak, P.
J. Am. Chem. Soc. 1997, 119, 11561. For a summary, see: Clayden, J.
Organolithiums: SelectiVity for Synthesis; Pergamon: Oxford, 2002; pp 246-
256.
4418 J. Org. Chem. Vol. 73, No. 12, 2008

N,N′-Diarylureas: New Family of Atropisomers
1-(2-t-Butyl-6-(1-hydroxypropyl)phenyl)-1-methyl-3-phenyl-
urea (3b). In the same way, 1-(2-t-Butylphenyl)-1-methyl-3-
phenylurea 1 (R1 ) t-Bu)6 (0.200 g, 0.71 mmol), s-BuLi (1.1 M
solution in cyclohexane, 1.6 mL, 1.78 mmol, 2.5 equiv), and excess
propionaldehyde (0.5 mL) were mixed. The title compound was
obtained in 89% yield (0.215 g, 0.63 mmol) as a separable mixture
of diastereoisomers. Major diastereoisomer, white solid, mp 134
°C; Rf (1:3 EtOAc/petrol) 0.20; IR νmax(CHCl3)/cm-1 3411.2 (OH),
1654.3 (CdO); δH (300 MHz; CDCl3) 1.05 (t, J ) 7.4 Hz, 3H,
CH2CH3), 1.48 (s, 9H, C(CH3)3), 1.75-1.95 (m, 2H, CH2CH3),
2.40-2.53 (bm, 1H, OH), 3.22 (s, 3H, NCH3), 4.70 (dd, J ) 8.1,
5.1 Hz, 1H, CHOH), 6.21 (s, 1H, NH), 7.04 (dt, J ) 5.5, 2.9 Hz,
1H, Ar-H), 7.28 (dd, J ) 4.9, 1.6 Hz, 4H, Ar-H), 7.50 (t, J ) 7.8
Hz, 1H, Ar-H), 7.58 (dd, J ) 7.8, 1.8, 1H, Ar-H), 7.63, (dd, J )
7.8, 1.8 Hz, 1H, Ar-H); δC (75 MHz; CDCl3) 11.2 (CH3), 31.9
(CH2CH3), 32.3 (C(CH3)3), 36.7 (C(CH3), 39.9 (NCH3), 70.3
(CHOH), 120.2, 123.5, 126.7, 129.1, 129.3, 129.9, 137.6, 138.8,
145.1, 148.7, 155.9 (CdO); m/z (CI) 341; HRMS found [M + H]+
341.2223. C20H28N2O2 requires M + H 341.2225. Minor diaste-
reoisomer, white solid, mp 134 °C; Rf (1:3 EtOAc/petrol) 0.07; IR
white solid, mp 190-191 °C; Rf (1:4 EtOAc/petrol) 0.21; IR
max(CHCl3)/cm-1 3447 (OH), 1732.49 (CdO); δH (300 MHz;
ν
CDCl3) 1.44 (s, 9H, C(CH3)3), 2.97 (s, 3H, NCH3), 3.54 (d, J )
4.4 Hz, 1H, OH), 5.88 (d, J ) 4.4 Hz, 1H CHCOH), 6.46 (s, 1H,
NH), 6.96 (t, J ) 7.3 Hz, 1H, Ar-H), 7.14 (t, J ) 7.3 Hz, 2H,
Ar-H), 7.22 (d, J ) 7.4 Hz, 1H, Ar-H), 7.30-7.40 (m, 8H, Ar-H)
7.60 (dd, J ) 7.6, 2.2 Hz, 1H, Ar-H); δC (75 MHz; CDCl3) 32.4
(C(CH3)), 36.77 (C(CH3), 39.3 (NCH3), 70.8 (CHOH), 120.0, 123.3,
127.2, 128.0, 128.5, 128.8, 129.1, 129.6, 129.8, 138.2, 139.0, 143.7,
144.1, 148.7, 155.8 (CdO); m/z (CI) 389; HRMS found M + H +
389.2227. C25H28N2O2 requires M + H 389.2224. EA Found C,
77.4; H, 7.4; N, 7.2. C25H28N2O2 requires C, 77.3; H, 7.3; N, 7.2.
Minor diastereoisomer; mp 191-192 °C; Rf (1:4 EtOAc/petrol)
0.07; δH (300 MHz; CDCl3) 1.45 (s, 9H, C(CH3)3), 2.21 (s, 1H,
OH), 3.42 (s, 3H, NCH3), 5.88 (bs, 1H, NH), 6.00 (s, 1H, CHOH),
6.94-6.99 (m, 3H, Ar-H), 7.12 (t, J ) 7.3 Hz, 1H, Ar-H), 7.16 (d,
J ) 7.3 Hz, 2H, Ar-H), 7.22 (t, J ) 7.6 Hz, 2H, Ar-H), 7.39 (d, J
) 7.2 Hz, 2H, Ar-H), 7.47 (t, J ) 7.9 Hz, 1H, Ar-H), 7.62 (dd, J
) 8.2, 1.5 Hz, 1H, Ar-H), 7.66 (dd, J ) 7.7, 1.5 Hz, 1H, Ar-H);
δC (75 MHz; CDCl3) 32.6 (C(CH3)3), 37.1 (C(CH3)3), 39.0 (NCH3),
72.0 (CHOH), 119.5, 123.2, 126.9, 127.0, 127.9, 128.3, 128.9,
129.9, 130.2, 137.4, 138.6, 143.2, 144.3, 149.2, 155.2 (CdO); m/z
(CI) 389 (100%, M+); HRMS found M + H+ 389.2226,
C25H28N2O2 requires M + H 389.2224.
1-(2-(1-Hydroxyethyl)-6-isopropylphenyl)-1-methyl-3-phenyl-
urea (3e). General procedure 1 was followed employing 1-(2-
isopropylphenyl)-1-methyl-3-phenylurea 1 (R1 ) i-Pr)4 (0.100 g,
0.37 mmol), s-BuLi (1.2 M solution in cyclohexane, 1.10 mL, 0.93
mmol, 2.5 equiv), and excess freshly distilled acetaldehyde (1 mL).
The title compound was obtained in 95% yield (0.108 g, 0.35 mmol)
as a separable mixture of diastereoisomers. Major diastereoisomer,
mp 135-137 °C; Rf (1:3 EtOAc/petrol) 0.22; IR νmax(CHCl3)/cm-1
3412.1 (OH), 1649.9 (CdO); δH (300 MHz; CDCl3) 1.20 (d, J )
6.8 Hz, 3H, CH(CH3)2), 1.28 (d, J ) 6.8 Hz, 3H, CH(CH3)2), 1.53
(d, J ) 6.4 Hz, 3H, CHOHCH3), 2.66 (bs, 1H, OH), 3.10 (q, J )
6.8 Hz, 1H, CH(CH3)2), 3.18 (s, 3H, NCH3), 5.05 (q, J ) 6.4 Hz,
1H, CHOH), 6.35 (s, 1H, NH), 6.97-7.03 (m, 1H, Ar-H), 7.24 (d,
J ) 4.3 Hz, 4H, Ar-H), 7.40 (dd, J ) 7.6, 1.8 Hz, 1H, Ar-H), 7.50
(t, J ) 7.6 Hz, 1H, Ar-H), 7.56 (dd, J ) 7.6, 1.8 Hz, 1H, Ar-H);
δC (75 MHz; CDCl3) 24.6, 24.7, 24.8, 28.3 (CH(CH3)2), 38.3
(NCH3), 65.2 (CHOH), 120.2, 123.4, 125.3, 127.4, 129.2, 130.1,
136.9, 139.2, 144.0, 148.2, 156.0 (CdO); m/z (CI) 313; HRMS
found M + H+ 313.1909. C19H25N2O2 requires M + H 313.1911.
Minor diastereoisomer, white solid, mp 135-138 °C; Rf (1:3
EtOAc/petrol) 0.09; IR νmax(CHCl3)/cm-1 3412.7 (OH), 1649.0
(CdO); δH (300 MHz; CDCl3) 1.25 (d, J ) 6.8 Hz, 3H, CH(CH3)2),
1.27 (d, J ) 6.8 Hz, 3H, CH(CH3)2), 1.50 (d, J ) 6.4 Hz, 3H,
CHOHCH3), 1.78 (bs, 1H, OH), 3.13 (q, J ) 6.8 Hz, 1H,
CH(CH3)2), 3.31 (s, 3H, NCH3), 5.11 (q, J ) 6.4 Hz, 1H, CHOH),
5.92 (s, 1H, NH), 7.00-7.04 (m, 1H, Ar-H), 7.22-7.28 (m, 4H,
Ar-H), 7.42 (dd, J ) 7.7, 1.7 Hz, 1H, Ar-H), 7.52 (t, J ) 7.6 Hz,
1H, Ar-H), 7.61 (dd, J ) 7.7, 1.6 Hz, 1H, Ar-H); δC (75 MHz;
CDCl3) 24.4, 25.1, 25.5, 28.2 (CH(CH3)2), 37.1 (NCH3), 65.8
(CHOH), 119.9, 123.6, 125.5, 127.5, 129.3, 130.5, 136.0, 138.8,
144.8, 148.2, 155.3 (CdO); m/z (CI) 313; HRMS found M + H+
313.1908. C19H25N2O2 requires M + H 313.1911.
ν
max(CHCl3)/cm-1 3412.0 (OH), 1651.7 (CdO); δH (300 MHz;
CDCl3) 0.94 (t, J ) 7.1 Hz, 3H, CH2CH3), 1.47 (s, 9H, C(CH3)3),
1.82 (dq, J ) 19.7, 7.3 Hz, 2H, CH2CH3), 2.39 (bs, 1H, OH), 3.33
(s, 3H, NCH3), 4.72 (dd, J ) 7.7, 5.5 Hz, 1H, CHOH), 5.88 (s,
1H, NH), 7.04 (td, J ) 6.3, 2.1 Hz, 1H, Ar-H), 7.26 (d, J ) 7.1
Hz, 4H, Ar-H), 7.50 (t, J ) 7.8 Hz, 1H, Ar-H), 7.58 (dd, J ) 7.8,
1.8, 1H, Ar-H), 7.63, (dd, J ) 7.8, 1.8 Hz, 1H, Ar-H); δC (75 MHz;
CDCl3) 11.1 (CH3), 31.4 (CH2CH3), 32.5 (C(CH3)3), 36.9 (C(CH3)3),
39.2 (NCH3), 70.4 (CHOH), 119.7, 123.5, 126.7, 129.2, 129.7,
129.9, 137.6, 138.6, 144.7, 148.8, 155.6 (CdO); m/z (CI) 341
(100%, M+); HRMS found [M + H]+ 341.2223. C20H28N2O2
requires M + H 341.2215.
1-(2-t-Butyl-6-(1-hydroxy-2-methylpropyl)phenyl)-1--3-phe-
nylurea (3c). In the same way, 1-(2-t-Butylphenyl)-1-methyl-3-
phenylurea 1 (R1 ) t-Bu)6 (0.200 g, 0.71 mmol), s-BuLi (1.1 M
solution in cyclohexane, 1.6 mL, 1.78 mmol, 2.5 equiv), and excess
isobutyraldehyde (0.5 mL) were mixed. The title compound was
obtained in 69% yield (0.173 g, 0.49 mmol) as a separable mixture
of diastereoisomers. Major diastereoisomer, white solid, mp 162
°C; Rf (1:3 EtOAc/petrol) 0.23; IR νmax(CHCl3)/cm-1 3401.9 (OH),
1650.5 (CdO); δH (300 MHz; CDCl3) 0.80 (d, J ) 6.8 Hz, 3H,
CH3), 1.19 (d, J ) 6.8 Hz, 3H, CH3),1.48 (s, 9H, C(CH3)3),
2.15-2.25 (m, 1H, CH(CH3)2), 3.23 (s, 3H, NCH3), 4.37 (d, J )
9.0 Hz, 1H, CHOH), 6.24 (s, 1H, NH), 7.00-7.06 (m, 1H, Ar-H),
7.22-7.28 (m, 4H, Ar-H), 7.50 (t, J ) 7.7 Hz, 1H, Ar-H), 7.54
(dd, J ) 7.7, 1.9 Hz, 1H, Ar-H), 7.64 (dd, J ) 7.7, 1.9 Hz, 1H,
Ar-H); δC (75 MHz; CDCl3) 19.6 (CH3), 32.5 (C(CH3)3), 34.6
(CH(CH3)2), 36.9 (C(CH3)3), 40.4 (NCH3), 74.8 (CHOH), 120.2,
123.5, 126.8, 129.2, 129.5, 130.0, 138.5, 139.0, 144.3, 149.0, 156.1
(CdO); m/z (CI) 355; HRMS found M+ 355.2381. C22H31N2O2
requires 355.2380. Minor diastereoisomer, white solid, mp 162 °C;
Rf (1:3 EtOAc/petrol) 0.07; IR νmax(CHCl3)/cm-1 3418.4 (OH),
1661.0 (CdO); δH (300 MHz; CDCl3) 0.76 (d, J ) 6.8 Hz, 3H,
CH3), 1.16 (d, J ) 6.8 Hz, 3H, CH3),1.48 (s, 9H, C(CH3)3),
2.15-2.25 (m, 1H, CH(CH3)2), 3.37 (s, 3H, NCH3), 4.40 (d, J )
8.9 Hz, 1H, CHOH), 5.86 (s, 1H, NH), 7.01-7.06 (m, 1H, Ar-H),
7.25-7.28 (m, 4H, Ar-H), 7.50-7.56 (m, 2H, Ar-H), 7.64 (dd, J
) 7.5, 2.1 Hz, 1H, Ar-H); δC (75 MHz; CDCl3) 19.6 (CH3), 32.6
(C(CH3)3), 34.1 (CH(CH3)2), 36.9 (C(CH3)3), 39.4 (NCH3), 75.0
(CHOH), 119.3, 123.4, 126.7, 129.3, 130.1, 130.2, 138.5, 139.0,
143.9, 149.0, 156.2 (CdO); m/z (CI) 355 (100%, M+); HRMS
found M + H+ 355.2384 C22H31N2O2 requires M + H 355.2380.
1-(2-t-Butyl-6-(hydroxy(phenyl)methyl)phenyl)-1-methyl-3-
phenylurea (3d). In the same way, 1-(2-t-butylphenyl)-1-methyl-
3-phenylurea 1 (R1 ) t-Bu)6 (0.100 g, 0.35 mmol), s-BuLi (1.3 M
solution in cyclohexane, 0.68 mL, 0.89 mmol, 2.5 equiv), and
benzaldehyde (0.09 mL, 0.89 mmol, 2.5 equiv) were mixed. The
title compound was obtained in 83% yield (0.113 g, 0.29 mmol)
as a separable mixture of diastereoisomers. Major diastereoisomer,
1-(2-t-Butyl-6-acetylphenyl)-1-methyl-3-phenylurea (4a). Gen-
eral procedure 2 was followed employing 3a (0.100 g, 0.31 mmol)
dissolved in 3 mL of acetone and 0.3 mL of Jones’ reagent (prepared
by dissolving CrO3 (2.5 g) in 20% sulfuric acid). The orange
mixture was stirred until completion as judged by TLC. The reaction
mixture was poured into a saturated NaHCO3 (50 mL) solution
and extracted with EtOAc (4 × 20 mL). The combined organic
extracts were dried over MgSO4 and concentrated under reduced
pressure to afford the ketone 4a in 100% yield (0.100 g, 0.31 mmol),
mp 110 °C; Rf (1:3 EtOAc/petrol) 0.23; IR νmax(CHCl3)/cm-1
1697.5 (CdO), 1669.9 (CdO),; δH (300 MHz; CDCl3) 1.48 (s,
9H, C(CH3)3), 2.55 (s, 3H, COCH3), 3.18 (s, 3H, NCH3), 6.00 (s,
1H, NH), 6.99-7.05 (m, 1H, Ar-H), 7.25-7.30 (m, 4H, Ar-H),
J. Org. Chem. Vol. 73, No. 12, 2008 4419

Clayden et al.
7.48-7.51 (m, 2H, Ar-H), 7.79 (dd, J ) 5.8, 3.9 Hz, 1H, Ar-H);
δC (75 MHz; CDCl3) 30.7 (CH3), 32.3 (C(CH3)3), 37.0 (C(CH3)3),
39.2 (NCH3), 120.0, 123.4, 127.4, 129.1, 129.2, 132.7, 136.9, 138.9,
142.0, 150.2, 155.4 (CdO), 201.8 (CdO); m/z (CI) 325; HRMS
found M + H+ 325.1911. C20H24N2O2 requires M + H 325.1911.
1-(2-t-Butyl-6-propionylphenyl)-1-methyl-3-phenylurea (4b).
In the same way, 3b (0.100 g, 0.29 mmol) was dissolved in 3 mL
of acetone and 0.3 mL of Jones’ reagent to afford the ketone in
93% yield (0.093 g, 0.28 mmol), mp 104 °C; Rf (1:3 EtOAc/petrol)
0.28; IR νmax(CHCl3)/cm-1 1681 (CdO), 1671 (CdO); δH (300
MHz; CDCl3) 1.17 (t, J ) 7.2 Hz, 3H, CH2CH3), 1.47 (s, 9H,
C(CH3)3), 2.80-2.92 (m, 2H, CH2CH3), 3.16 (s, 3H, NCH3), 5.99
(s, 1H, NH), 6.90-7.03 (m, 1H, Ar-H), 7.20-7.80 (m, 4H, Ar-H),
7.40 (d, J ) 7.4 Hz, 1H, Ar-H), 7.48 (t, J ) 7.8, 1H, Ar-H), 7.76,
(dd, J ) 7.8, 1.8 Hz, 1H, Ar-H); δC (75 MHz; CDCl3) 8.4
(CH3CH3), 32.3 (C(CH3)3), 36.4 (CH2CH3), 37.0 (C(CH3), 39.3
(NCH3), 119.9, 123.3, 126.9, 129.0, 129.2, 132.3, 136.7, 139.0,
142.4, 150.1, 155.5 (CdO), 205.1 (CdO); m/z (CI) 339; HRMS
found M + H+ 339.2071. C21H26N2O2 requires M + H 339.2067.
1-(2-t-Butyl-6-(isobutyryl)phenyl)-1-methyl-3-phenylurea (4c).
In the same way, 3c (0.100 g, 0.28 mmol) was dissolved in 3 mL
of acetone and 0.3 mL of Jones’ reagent to afford the ketone in
100% yield (0.100 g, 0.28 mmol), mp 88 °C; Rf (1:3 EtOAc/petrol)
0.35; IR νmax(CHCl3)/cm-1 1693.1 (CdO), 1687 (CdO); δH (300
MHz; CDCl3) 1.19 (d, J ) 6.8 Hz, 3H, CH3), 1.20 (d, J ) 6.8 Hz,
3H, CH3), 1.47 (s, 9H, C(CH3)3), 3.15 (s, 3H, NCH3), 3.22 (sept,
J ) 6.8 Hz, 1H, CH(CH3)2), 5.99 (s, 1H, NH), 7.01 (tt, J ) 6.7,
1.9 Hz, 1H, Ar-H), 7.22-7.30 (m, 4H, Ar-H), 7.44 (dd, J ) 7.6,
2.1 Hz, 1H, Ar-H), 7.49 (t, J ) 7.6 Hz, 1H, Ar-H), 7.77 (dd, J )
7.7, 2.1 Hz, 1H, Ar-H); δC (75 MHz; CDCl3) 18.6 (CH3), 19.7
(CH3), 32.3 (C(CH3)3), 34.6 (CH(CH3)2), 39.2 (NCH3), 40.1
(C(CH3)3), 119.8, 123.2, 127.2, 129.1, 132.5, 137.1, 139.0, 141.5,
150.3, 155.5 (CdO), 208.4 (CdO); m/z (CI) 353; HRMS found M
+ H+ 353.2223. C22H28N2O2 requires M + H 353.22224.
1-(2-t-Butyl-6-benzoylphenyl)-1-methyl-3-phenylurea (4d). In
the same way, 3d (0.100 g, 0.26 mmol) was dissolved in 3 mL of
acetone and 0.3 mL of Jones’ reagent to afford the ketone in 100%
yield (0.100 g, 0.26 mmol), mp 148 °C; Rf (1:3 EtOAc/petrol) 0.26;
IR νmax(CHCl3)/cm-1 1669.3 (CdO), 1622.6 (CdO); δH (300 MHz;
CDCl3) 1.50 (s, 9H, C(CH3)3), 3.01 (s, 3H, NCH3), 6.18 (s, 1H,
NH), 6.97-7.05 (m, 1H, Ar-H), 7.20-7.24 (m, 4H, Ar-H), 7.32
(dd, J ) 7.4, 1.4 Hz, 1H, Ar-H), 7.42 (t, J ) 7.8 Hz, 2H, Ar-H),
7.51 (t, J ) 7.6 Hz, 1H, Ar-H), 7.57 (t, J ) 7.6 Hz, 1H, Ar-H),
7.80-7.87 (m, 3H, Ar-H); δC (75 MHz; CDCl3) 32.2 (C(CH3)),
36.9 (C(CH3), 39.2 (NCH3), 120.0, 123.1, 127.5, 128.5, 128.8,
128.9, 130.4, 131.8, 134.0, 136.8, 137.7, 139.0, 141.4, 150.3, 155.5
(CdO), 196.3 (CdO); m/z (CI) 387; HRMS found M + H+
387.2077. C25H26N2O2 requires M + H 387.2067.
and dried under high vacuum to afford 1-(2,6-diethylphenyl)-3-
phenylurea in 88% yield (4.708 g, 17.5 mmol) as a white powder;
mp 235 °C; Rf (1:3 EtOAc/petrol) 0.19; IR νmax(CHCl3)/cm-1
1635.7 (CdO); δH (300 MHz; CDCl3) 1.16 (t, J ) 7.6 Hz, 6H,
CH2CH3), 2.62 (q, J ) 7.6 Hz, 4H, CH2CH3), 6.95 (tt, J ) 7.3, 1.0
Hz, 1H, Ar-H), 7.10-7.20 (m, 3H, Ar-H), 7.27 (t, J ) 7.5 Hz, 2H,
Ar-H), 7.48 (dd, J ) 7.5, 1.2 Hz, 2H, Ar-H), 7.69 (bs, 1H, NH),
8.77 (bs, 1H, NH); δC (75 MHz; CDCl3) 15.4 (CH2CH3), 25.2
(CH2CH3), 118.5, 122.0, 126.7, 127.5, 129.4, 134.7, 141.1, 142.7,
154.6 (CdO); m/z (CI) 269 (100%, M + H+); HRMS found M +
H+ 269.1648. C17H20N2O requires M + H 269.1648.
1-(2,6-Diethylphenyl)-3-phenylurea (1.00 g, 5.94 mmol) was
treated with NaH (0.285 g, 7.13 mmol) and MeI (0.50 mL, 1.26 g,
8.90 mmol) in 50 mL of anhydrous THF to give a colorless oil
purified by flash chromatography to afford the title compound in
72% yield (0.783 g, 4.28 mmol) as a white solid; mp 86 °C; Rf
(1:3 EtOAc/petrol) 0.41; IR νmax(CHCl3)/cm-1 1679.9 (CdO); δH
(300 MHz; CDCl3) 1.29 (t, J ) 7.5 Hz, 6H, CH2CH3), 2.67 (q, J
) 7.5 Hz, 4H, CH2CH3), 3.27 (s, 3H, NCH3), 6.01 (bs, 1H, NH),
6.99-7.05 (m, 1H, Ar-H), 7.25-7.31 (m, 6H, Ar-H), 7.46 (dd, J
) 8.5, 6.7 Hz, 1H, Ar-H); δC (75 MHz; CDCl3) 15.0 (CH2CH3),
24.1 (CH2CH3), 36.1 (NCH3), 119.6, 123.1, 127.8, 129.1, 129.5,
138.3, 139.1, 143.2, 155.0 (CdO); m/z (CI) 283 (100%, M + H+);
HRMS found M + H+ 283.1802. C18H22N2O requires M + H
283.1805.
1-(2-t-Butyl-6-ethylphenyl)-1-methyl-3-phenylurea (7). By the
method used for 3a-e, 1-(2-t-butylphenyl)-1-methyl-3-phenylurea
1 (R1 ) t-Bu)6 (0.600 g, 2.13 mmol), s-BuLi (1.2 M solution in
cyclohexane, 3.90 mL, 4.68 mmol, 2.2 equiv), and ethyl iodide
(0.20 mL, 2.55 mmol, 2.5 equiv) gave the title compound in 60%
yield (396 mg, 1.28 mmol). mp 126-128 °C; Rf (1:3 EtOAc/petrol)
0.45; IR νmax(CHCl3)/cm-1 2964.7 (NH), 1664.7 (CdO); δH (300
MHz; CDCl3) 1.29 (t, J ) 7.6 Hz, 3H, CH2CH3), 1.46 (s, 9H,
C(CH3)3), 2.63 (q, J ) 7.6 Hz, 2H, CH2CH3), 3.26 (s, 3H, NCH3),
6.00 (bs, 1H, NH), 6.99-7.05 (m, 1H, Ar-H), 7.26-7.30 (m, 4H,
Ar-H), 7.32 (dd, J ) 8.8, 1.7 Hz, 1H, Ar-H), 7.40 (t, J ) 7.6 Hz,
1H, Ar-H), 7.50 (dd, J ) 7.9, 1.8 Hz, 1H, Ar-H); δC (75 MHz;
CDCl3) 15.1 (CH2CH3), 23.7 (CH2CH3), 32.5 (C(CH3)3), 36.8
(C(CH3)3), 38.6 (NCH3), 119.7, 123.3, 127.7, 128.4, 129.2, 129.4,
138.4, 139.1, 144.7, 148.9, 155.7 (CdO); m/z (CI) 311 (100%, M
+ H+); HRMS found M + H+ 311.2124. C20H26N2O requires M
+ H 311.2118.
1-(2-Ethyl-6-isopropylphenyl)-1-methyl-3-phenylurea (9a). In
the same way, 1-(2,6-diethylphenyl)-1-methyl-3-phenylurea 6 (0.100
g, 0.355 mmol), s-BuLi (1.2 M solution in cyclohexane, 1.04 mL,
0.89 mmol, 2.5 equiv), and ethyl iodide (0.07 mL, 0.89 mmol, 2.5
equiv) gave the title compound in 81% yield (0.085 g, 2.87 mmol),
mp 79-80 °C; Rf (1:3 EtOAc/petrol) 0.52; IR νmax(CHCl3)/cm-1
1681.8 (CdO); δH (300 MHz; CDCl3) 0.88 (t, J ) 7.4 Hz, 3H,
CHCH2CH3), 1.20 (d, J ) 7.0 Hz, 3H, CHCH3), 1.28 (t, J ) 7.0
Hz, 3H, CH2CH3), 1.65 (qn, J ) 7.4 Hz, 2H, CHCH2CH3), 2.67
(q, J ) 7.6 Hz, 2H, CH2CH3) 2.88 (sp, J ) 7.6 Hz, 1H,
CH2CHCH3), 3.26 (s, 3H, NCH3), 5.99 (bs, 1H, NH), 6.98-7.04
(m, 1H, Ar-H), 7.25-7.30 (m, 6H, Ar-H), 7.45 (t, J ) 7.3 Hz, 1H,
Ar-H); δC (75 MHz; CDCl3) 12.9 (CHCH2CH3), 14.9 (CH2CH3),
22.6 (CHCH3), 24.3 (CH2CH3), 31.5 (CHCH2CH3), 35.4 (CHCH3),
36.7 (NCH3), 119.6, 123.1, 125.6, 127.6, 129.1, 129.7, 138.1, 139.1,
143.0, 147.3, 155.1 (CdO); m/z (CI) 311 (100%, M + H+); HRMS
found M + H+ 311.2117. C20H26N2O requires M + H 311.2118.
1-(2-Ethyl-6-(1-(trimethylsilyl)ethyl)phenyl)-1-methyl-3-phe-
nylurea (9b). In the same way, 1-(2,6-diethylphenyl)-1-methyl-3-
phenylurea 6 (0.200 g, 0.71 mmol), s-BuLi (1.1 M solution in
cyclohexane, 1.60 mL, 1.78 mmol, 2.5 equiv), and chlorotrimeth-
ylsilane (0.23 mL, 0.193 g, 1.78 mmol) gave the title compound
obtained in 65% yield (0.165 g, 0.46 mmol), mp 64 °C; Rf (1:6
EtOAc/petrol) 0.19; IR νmax(CHCl3)/cm-1 1675.4 (CdO); δH (300
MHz; CDCl3) 0.04 (s, 9H, Si(CH3)3), 1.27 (t, J ) 7.6 Hz, 3H,
CH2CH3), 1.32 (d, J ) 7.5 Hz, 3H, CHCH3), 2.37 (q, J ) 7.5 Hz,
1H, CHCH3), 2.65 (q, J ) 7.6 Hz, 2H, CH2CH3), 3.23 (s, 3H,
1-(2-t-Butyl-6-formylphenyl)-1-methyl-3-phenylurea (5). By
the method used for 3a-e, 1-(2-t-butylphenyl)-1-methyl-3-pheny-
lurea 1 (R1 ) t-Bu)6 (0.100 g, 0.35 mmol), s-BuLi (0.68 mL, 0.88
mmol), and DMF (0.1 mL) gave a crude product that was purified
by flash chromatography to yield the aldehyde as a white solid in
66% yield (0.071 g, 0.23 mmol), mp 128 °C; IR νmax(CHCl3)/cm-1
1685 (CHdO); δH (300 MHz; CDCl3) 1.52 (s, 9H, C(CH3)3), 3.37
(s, 3H, NCH3), 5.88 (bs, 1H, NH), 7.03-7.10 (m, 1H, Ar-H),
7.23-7.26 (m, 4H, Ar-H), 7.61 (t, J ) 7.6 Hz, 1H, Ar-H), 7.98
(dd, J ) 7.6, 1.8 Hz, 2H, Ar-H), 10.18 (s, 1H, CHO); δC (75 MHz;
CDCl3) 32.2 (C(CH3)3), 36.9 (C(CH3)3), 40.4 (NCH3), 120.2, 123.9,
129.1, 129.5, 130.0, 136.3 (ArC-H), 135.5, 135.3, 138.4, 150.1,
155.2 (NCdO), 190.2 (CdO); m/z (CI) 311 (100%, M + H+);
HRMS found M + H+ 311.1755. C19H22N2O2 requires M + H
311.1754. EA Found C, 73.3; H, 7.1; N, 8.9. C19H22N2O2 requires
C, 73.5; H, 7.1; N, 9.0.
1-(2,6-Diethylphenyl)-1-methyl-3-phenylurea (6). 2,6-Diethyl
aniline (3.32 mL, 20.0 mmol, 1 equiv) was added to a solution of
phenyl isocyanate (2.17 mL, 20.0 mmol, 1 equiv) in anhydrous
CH2Cl2 at room temperature, and the solution was stirred for 3 h.
The white precipitate was filtered and washed with cold CH2Cl2
4420 J. Org. Chem. Vol. 73, No. 12, 2008

N,N′-Diarylureas: New Family of Atropisomers
NCH3), 6.03 (bs, 1H, NH), 7.01 (tt, J ) 6.2, 2.4 Hz, 1H, Ar-H),
7.18 (dd, J ) 7.8, 2.2 Hz, 2H, Ar-H), 7.26-7.30 (m, 4H, Ar-H),
7.36 (t, J ) 7.7 Hz, 1H, Ar-H); δC (75 MHz; CDCl3) -2.1
(Si(CH3)3), 14.9 (CH2CH3), 17.9 (CHCH3), 23.1 (CHCH3), 24.6
(CH2CH3), 36.8 (NCH3), 119.5, 123.1, 126.4, 126.9, 129.1, 129.3,
139.1, 146.6, 155.0 (CdO); m/z (CI) 355 (100%, M + H+); HRMS
found M + H+ 355.2200. C21H30SiN2O requires M + H 355.2200.
1-(2-(1-(Tributylstannyl)ethyl)-6-ethylphenyl)-1-methyl-3-
phenylurea (9d). In the same way, 1-(2,6-diethylphenyl)-1-methyl-
3-phenylurea 6 (0.210 g, 0.74 mmol), s-BuLi (1.2 M solution in
cyclohexane, 1.55 mL, 1.87 mmol, 2.5 equiv), and Bu3SnBr (0.5
mL, 1.87 mmol, 2.5 equiv) gave a colorless oil purified by column
chromatography to afford the title compound as an inseparable
mixture of diastereoisomers in 88% yield (0.370 g, 0.65 mmol); Rf
(1:9 EtOAc/petrol) 0.28; IR νmax(CHCl3)/cm-1 1686.2 (CdO); δH
(300 MHz; CDCl3) 0.89 (t, J ) 7.2 Hz, 9H, CH2CH2CH2CH3),
0.96 (t, J ) 7.5 Hz, 3H, CH2CH3), 1.21-1.44 (m, 18H, CH2 × 9),
1.56 (d, J ) 7.6 Hz, 3H, CHCH3), 2.63 (q, J ) 7.6 Hz, 2H,
CH2CH3), 2.78 (q, J ) 7.6 Hz, 1H, CHCH3), 3.21 (s, 3H,
NCH3major), 3.24 (s, 3H, NCH3minor), 6.03 (bs, 1H, NHminor), 6.08
(bs, 1H, NHmajor), 6.98-7.03 (m, 1H, Ar-H), 7.09 (d, J ) 7.5 Hz,
Ar-H), 7.17 (d, J ) 8.0 Hz, Ar-H), 7.25-7.35 (m, 5H, Ar-H); δC
(75 MHz, CDCl3) 9.7 (CH2CH2CH2CH3), 13.9 (SnCH2), 15.0, 20.2,
21.2, 24.5, 27.7, 29.3, 35.8 (NCH3), 119.5, 123.0, 125.4, 126.8,
129.0, 129.4 (Ar-C), 135.9, 138.2, 143.2, 148.9, 155.1 (CdO); m/z
(ES+) 597 (60%, M + Na+); HRMS found MNa+ 595.2681.
C30H48N2OSn requires M + Na 595.2681.
1-(2-Ethyl-6-(3-hydroxybutan-2-yl)phenyl)-1-methyl-3-phenyl-
urea (9e). In the same way, 1-(2,6-diethylphenyl)-1-methyl-3-
phenylurea 6 (0.150 g, 0.53 mmol), s-BuLi (1.1 M solution in
cyclohexane, 1.20 mL, 1.33 mmol, 2.5 equiv), and excess freshly
distilled acetaldehyde (1 mL) gave the title compound in 64% yield
(0.110 g, 0.34 mmol) as a separable mixture of diastereoisomers.
Diastereoisomer A Rf (1:3 EtOAc/petrol) 0.25; IR νmax(CHCl3)/
cm-1 1656.5 (CdO); δH (300 MHz; CDCl3) 1.24 (t, J ) 7.6 Hz,
3H, CH2CH3), 1.26 (d, J ) 7.0 Hz, 3H, CH3), 1.39 (d, J ) 6.1 Hz,
3H, CH3), 1.63 (bs, 1H, OH), 2.63 (q, J ) 7.6 Hz, 2H, CH2CH3),
3.05 (dd, J ) 79.0, 7.0 Hz, 1H, CHCH3), 3.21 (s, 3H, NCH3), 3.98
(dd, J ) 9.0, 6.1 Hz, CHOHCH3), 6.96 (tt, J ) 7.1, 1.4 Hz, 1H,
Ar-H), 7.02 (bs, 1H, NH), 7.19-7.31 (m, 6H, Ar-H), 7.41 (t, J )
7.6 Hz, 1H, Ar-H); δC (75 MHz; CDCl3) 14.7 (CH2CH3), 19.6
(CH3), 22.7 (CH3), 24.2 (CH2CH3), 36.8 (NCH3), 41.9 (CHCH3),
73.8 (CHOH), 119.3, 122.5, 124.8, 127.7, 128.9, 129.3, 139.8,
139.9, 143.4, 144.6, 156.1 (CdO); m/z (CI) 297 (100%, M + H+);
HRMS found M+ 297.1966. C20H26N2O requires 297.1972. Dias-
tereoisomer B Rf (1:3 EtOAc/petrol) 0.17; IR νmax(CHCl3)/cm-1
1662.5 (CdO); δH (300 MHz; CDCl3) 1.14 (d, J ) 6.4 Hz, 3H,
CHCH3), 1.26 (t, J ) 7.6 Hz, 3H, CH2CH3), 1.32 (d, J ) 7.0 Hz,
3H, CHCH3), 2.19 (bs, 1H, OH), 2.63 (q, J ) 7.6 Hz, 2H, CH2CH3),
3.02 (qn, J ) 7.0 Hz, 1H, CHCH3), 3.16 (s, 3H, NCH3), 4.01 (qn,
J ) 6.4 Hz, CHOHCH3), 6.33 (bs, 1H, NH), 6.97-7.02 (m, 1H,
Ar-H), 7.22-7.29 (m, 6H, Ar-H), 7.40 (t, J ) 7.6 Hz, 1H, Ar-H);
δC (75 MHz; CDCl3) 14.8 (CH2CH3), 18.8 (CH3), 21.8 (CH3), 24.2
(CH2CH3), 36.8 (NCH3), 41.1 (CHCH3), 72.2 (CHOH), 119.5,
123.1, 125.4, 126.8, 128.0, 129.1, 138.9, 139.3, 143.3, 144.3, 155.6
(CdO); m/z (CI) 297 (100%, M + H+); HRMS found M+ 297.1966.
C20H26N2O requires 297.1972. Diastereoisomers C and D (insepa-
rable) Rf (1:3 EtOAc/petrol) 0.06; IR νmax(CHCl3)/cm-1 1662.8
(CdO); δH (300 MHz; CDCl3) 1.13 (d, J ) 6.3 Hz, 3H, CH3),
1.17 (d, J ) 7.0 Hz, 3H, CH3), 1.27 (t, J ) 7.6 Hz, 3H, CH2CH3),
1.28 (t, J ) 7.6 Hz, 3H, CH2CH3), 1.30 (d, J ) 6.2 Hz, 3H, CH3),
1.33 (d, J ) 6.1 Hz, 3H, CH3), 1.70 (bs, 1H, OH), 2.66 (q, J ) 7.6
Hz, 2H, CH2CH3), 2.67 (q, J ) 7.6 Hz, 2H, CH2CH3), 2.94 (qn, J
) 6.8 Hz, 1H, CHCH3), 2.95 (qn, J ) 7.0 Hz, 1H, CHCH3), 3.26
(s, 3H, NCH3), 3.30 (s, 3H, NCH3), 3.86-3.98 (m, 1H, CHOHCH3),
5.95 (bs, 1H, NH), 6.98-7.05 (m, 1H, Ar-H), 7.23-7.45 (m, 7H,
Ar-H); δC (75 MHz; CDCl3) 14.6, 15.0 (CH2CH3), 18.2, 19.7 (CH3),
21.4, 22.7 (CH3), 24.4, 24.5 (CH2CH3), 36.8, 37.1 (NCH3), 41.4,
42.3 (CHCH3), 72.2, 72.8 (CHOH), 119.8, 123.4, 123.4, 125.9,
126.5, 128.3, 128.5, 129.8, 130.0, 138.2, 139.0, 139.1, 139.2, 143.4,
143.6, 144.6, 145.2, 155.2, 155.3 (CdO); m/z (CI) 297 (100%, M
+ H+); HRMS found M+ 297.1966. C20H26N2O requires 297.1972.
1-(2-Ethyl-6-(1-hydroxy-1-phenylpropan-2-yl)phenyl)-1-meth-
yl-3-phenylurea (9f). In the same way, 1-(2,6-diethylphenyl)-1-
methyl-3-phenylurea 6 (0.150 g, 0.53 mmol), s-BuLi (1.1 M solution
in cyclohexane, 1.20 mL, 1.33 mmol, 2.5 equiv), and excess freshly
distilled benzaldehyde (1 mL) gave the title compound in 87% yield
(0.178 g, 0.46 mmol) as an inseparable mixture of diastereoisomers,
mp 178-188 °C; Rf (1:3 EtOAc/petrol) 0.18; IR νmax(CHCl3)/cm-1
3414.1 (OH), 1664.2(CdO); δH (300 MHz; CDCl3) 0.98 (d, J )
6.8 Hz, 3H, CH2CH3), 1.16 (t, J ) 7.6 Hz, 3H, CHCH3 minor),
1.25 (t, J ) 7.6 Hz, 3H, CHCH3 major), 2.48-2.57 (m, 1H,
CHCHCH3),2.64 (q, J ) 7.6 Hz, 2H, CH2CH3), 2.71 (s, 3H, NCH3
minor), 3.27 (s, 3H, NCH3 major), 4.70 (d, J ) 9.2 Hz, CHOH
major), 4.81 (d, J ) 6.8 Hz, CHOH minor), 5.85 (bs, 1H, NH
minor), 5.91 (bs, 1H, NH major), 6.92-6.97 (m, 1H, Ar-H),
7.18-7.47 (m, 12H, Ar-H); δC (75 MHz; CDCl3) 14.6, 15.3, 17.2,
19.6, 24.0, 35.9 (NCH3 minor), 36.1 (NCH3 major), 41.4 (CHCH3),
41.6 (CHCH3), 77.6 (CHOH), 79.9 (CHOH), 119.3, 122.9, 122.9,
125.6, 127.0, 127.1, 127.4, 128.1, 128.1, 128.2, 128.6, 128.8, 129.0,
129.6, 138.0, 138.7, 138.7, 138.8, 142.7, 143.0, 143.2, 143.4, 143.7,
143.9, 154.7 (CdO minor), 155.0 (CdO major); m/z (CI) 389
(100%, M + H+); HRMS found M + H+ 389.2218. C25H28N2O2
requires M + H 389.2224.
1-(2-Ethyl-6-(3-hydroxy-3-methylbutan-2-yl)phenyl)-1-meth-
yl-3-phenylurea (9g). In the same way, 1-(2,6-diethylphenyl)-1-
methyl-3-phenylurea 6 (0.100 g, 0.355 mmol), s-BuLi (1.2 M
solution in cyclohexane, 0.75 mL, 0.426 mmol, 2.5 equiv), and
excess freshly distilled acetone (0.5 mL) gave the title compound
in 90% yield (0.105 g, 0.32 mmol), mp 182-188 °C; Rf (1:3 EtOAc/
petrol) 0.58; IR νmax(CHCl3)/cm-1 3414.5 (OH), 1658.7 (CdO);
δH (300 MHz; CDCl3) 1.25 (t, J ) 7.6 Hz, 3H, CH2CH3), 1.31 (d,
J ) 3.9 Hz, 3H, CHCH3), 1.35 (s, 6H, COH(CH3)2), 2.61 (q, J )
7.6 Hz, 2H, CH2CH3), 3.14 (s, 3H, NCH3), 3.20 (q, J ) 3.9 Hz,
1H, CHCH3), 6.94-7.02 (m, 1H, Ar-H), 7.22 (d, J ) 4.3 Hz, 4H,
Ar-H), 7.30 (dd, J ) 7.6, 1.5 Hz, 1H, Ar-H), 7.38 (t, J ) 7.7 Hz,
1H, Ar-H), 7.52 (dd, J ) 7.8, 1.6 Hz, 1H, Ar-H); δC (75 MHz;
CDCl3) 13.8 (CHCH3), 17.2 (CH2CH3), 23.7 (CH2CH3) 25.4
(COHCH3), 29.5 (COHCH3), 36.3 (NCH3), 43.6 (CHCH3), 73.1
(COH(CH3)2), 119.7, 122.6, 126.9, 127.5, 128.3, 128.5, 139.5,
139.7, 142.3, 143.7, 157.5 (CdO); m/z (CI) 341 (100%, M + H+);
HRMS found M + H+ 341.2226. C21H28N2O2 requires M + H
341.2224.
1-(2-Ethyl-6-(1-(methylamino)-1-phenylpropan-2-yl)phenyl)-
1-methyl-3-phenylurea (9h). In the same way, 1-(2,6-diethylphe-
nyl)-1-methyl-3-phenylurea 6 (0.150 g, 0.53 mmol), s-BuLi (1.1
M solution in cyclohexane, 1.20 mL, 1.33 mmol, 2.5 equiv), and
excess N-benzylidenemethylamine (0.2 mL) gave the title compound
in 78% yield (0.166 g, 0.41 mmol) as a separable mixture of
diastereoisomers. Minor diastereoisomer, pale yellow oil; Rf (1:3
EtOAc/petrol) 0.15; IR νmax(CHCl3)/ cm-1 3413.8 (NH), 1674.8
(CdO); δH (300 MHz; CDCl3) 1.03 (d, J ) 8 Hz, 3H, CHCH3),
1.23 (t, J ) 7.6 Hz, 3H, CH2CH3), 2.00 (s, 3H, NHCH3), 2.63 (q,
J ) 7.6 Hz, 2H, CH2CH3), 3.15 (s, 3H, NCH3), 3.32-3.36 (m,
1H, CHCHCH3), 3.54 (d, J ) 10 Hz, 1H, CHCHCH3), 6.91-6.95
(m, 1H, Ar-H), 7.18-7.41 (m, 12H, Ar-H and NH), 8.16 (bs, 1H,
NH); δC (75 MHz; CDCl3) 14.8, 20.3, 24.2, 35.2, 37.2, 41.6, 72.7,
119.6, 122.6, 124.7, 127.9, 128.0, 128.4, 129.1, 129.1, 129.4, 140.6,
141.0, 142.5, 143.7, 144.5, 156.8 (CdO); m/z (CI) 402 (100%, M
+ H+) HRMS found M + H+ 402.2541. C26H31N3O requires M +
H 402.2540. Major diastereoisomer, pale yellow oil; Rf (1:3 EtOAc/
petrol) 0.10; IR νmax(CHCl3)/cm-1 3413.4 (NH), 1675.8 (CdO);
δH (300 MHz; CDCl3) 1.18 (t, J ) 7.6 Hz, 3H, CH2CH3), 1.30 (d,
J ) 7.2 Hz, 3H, CHCH3), 2.16 (s, 3H, NHCH3), 2.50-2.57 (q, J
) 7.6 Hz, 2H, CH2CH3), 3.19 (s, 3H, NCH3), 3.37-3.43 (m, 1H,
CHCHCH3), 3.77 (d, J ) 6 Hz, 1H, CHCHCH3), 6.36 (bs, 1H,
NH), 6.88-6.95 (m, 2H, Ar-H), 7.03-7.22 (m, 12H, Ar-H and
NH); δC (75 MHz; CDCl3) 14.7, 19.2, 24.0, 35.3, 37.0, 40.1, 70.5,
J. Org. Chem. Vol. 73, No. 12, 2008 4421

Clayden et al.
119.4, 122.8, 127.5, 127.7, 127.9, 128.4, 128.5, 129.0, 139.6, 139.7,
141.4, 143.0, 143.4, 156.1 (CdO); m/z (CI) 402 (100%, M + H+).
HRMS found M + H+ 402.2540. C26H31N3O requires M + H
402.2540.
Ar-H), 7.44 (dd, J ) 8.0, 1.7 Hz, 1H, Ar-H); δC (75 MHz; CDCl3)
-4.2 (SiCH3), -3.3 (SiCH3), 18.2 (CH3CHSi), 23.0 (CH3CHSi),
32.3 (C(CH3)3), 36.1 (C(CH3)3), 38.9 (NCH3), 119.6, 123.2, 126.3,
127.8, 128.0, 129.1, 129.5, 133.3, 134.4, 137.4 (4°Ar-C), 137.5
(4°Ar-C), 138.8 (4°Ar-C), 147.6 (4°Ar-C), 149.2 (4°Ar-C), 155.7
(CdO); m/z (CI) 445 (100%, M + H+); HRMS found M + H
445.2660 C28H36N2OSi requires M + H 445.2670.
1-(2-t-Butyl-6-(1-(tributylstannyl)ethyl)phenyl)-1-methyl-3-
phenylurea (10d). In the same way, 1-(2-t-butyl-6-ethylphenyl)-
1-methyl-3-phenylurea 7 (0.250 g, 1.08 mmol), s-BuLi (1.2 M
solution in cyclohexane, 2.24 mL, 2.69 mmol, 2.5 equiv), and
tributyltin bromide (0.73 mL, 2.5 equiv) gave the title compound
as a colorless oil in 65% yield (0.351 g, 0.70 mmol); Rf (1:8 EtOAc/
petrol) 0.50; IR νmax(CHCl3)/cm-1 1685.2 (CdO); δH (300 MHz;
CDCl3) 0.83-0.92 (m, 15H, Sn(CH2CH2CH2CH3)3), 1.25-1.38 (m,
12H, Sn(CH2CH2CH2CH3)3), 1.44 (s, 9H, C(CH3)3), 1.55 (d, J )
9.0 Hz, 3H, CH3CH), 2.68 (q, J ) 9.0 Hz, 1H, CH3CH), 3.20 (s,
3H, NCH3), 6.06 (s, 1H, NH), 7.00-7.04 (m, 1H, Ar-H), 7.20-7.33
(m, 7H, Ar-H); δC (75 MHz; CDCl3) 9.8, 13.9, 20.4, 21.4, 27.7,
29.2, 32.3 (C(CH3)3), 36.6 (C(CH3)3), 38.2 (NCH3), 119.7, 123.1,
125.0, 127.6, 129.0, 129.2, 135.9, 138.9, 149.0, 150.5, 156.0
(CdO); m/z (CI) 601; HRMS found M + H+ 601.3174.
C32H52N2OSn requires M + H 601.3174.
1-(2-t-Butyl-6-(3-hydroxybutan-2-yl)phenyl)-1-methyl-3-phe-
nylurea (10e). In the same way, 1-(2-t-butyl-6-ethylphenyl)-1-
methyl-3-phenylurea 7 (0.100 g, 0.32 mmol), s-BuLi (1.1 M solution
in cyclohexane, 0.70 mL, 0.806 mmol, 2.5 equiv), and excess
freshly distilled acetaldehyde (1 mL) gave the title compound in
94% yield (0.106 g, 0.30 mmol) as a separable mixture of
diastereoisomers. Diastereoisomer A Rf (1:3 EtOAc/petrol) 0.12,
mp 138-142 °C; IR νmax(CHCl3)/cm-1 3413.5 (OH), 1660.0
(CdO); δH (300 MHz; CDCl3) 1.14 (d, J ) 6.9 Hz, 3H,
CHOHCH3), 1.33 (d, J ) 6.1 Hz, 3H, CHCH3), 1.45 (s, 9H,
C(CH3)3), 1.63 (bs, 1H, OH), 2.84 (dq, J ) 9.0, 6.9 Hz, 1H,
CHCH3), 3.28 (s, 3H, NCH3), 3.92 (dq, J ) 9.0, 6.1 Hz, 1H,
CHOHCH3), 5.91 (bs, 1H, NH), 6.99 (tt, J ) 6.5, 2.0 Hz, 1H, Ar-
H), 7.21-7.26 (m, 4H, Ar-H), 7.36 (dd, J ) 7.7, 1.6 Hz, 1H, Ar-
H), 7.44 (t, J ) 7.9 Hz, 1H, Ar-H), 7.54 (dd, J ) 8.1, 1.6 Hz, 1H,
Ar-H); δC (75 MHz; CDCl3) 19.8 (CHCH3), 21.6 (CHOHCH3),
32.4 (C(CH3)3), 36.8 (C(CH3)3), 39.6 (NCH3), 41.9 (CHCH3), 73.0
(CHOH), 119.6, 123.3, 126.3, 128.3, 129.1, 129.8, 138.8, 139.1,
146.1, 149.2, 155.7 (CdO); m/z (CI) 355 (100%, M + H+).
Diastereoisomer B Rf (1:3 EtOAc/petrol) 0.12, mp 142-148 °C;
IR νmax(CHCl3)/cm-1 3411.5 (OH), 1651.0 (CdO); δH (300 MHz;
CDCl3) 1.25 (d, J ) 6.9 Hz, 3H, CHOHCH3), 1.37 (d, J ) 6.1 Hz,
3H, CHCH3), 1.44 (s, 9H, C(CH3)3), 1.63 (bs, 1H, OH), 2.89 (dq,
J ) 9.6, 6.9 Hz, 1H, CHCH3), 3.24 (s, 3H, NCH3), 4.02 (dq, J )
9.6, 6.1 Hz, 1H, CHOHCH3), 6.82 (bs, 1H, NH), 6.98 (tt, J ) 7.2,
1.3 Hz, 1H, Ar-H), 7.20-7.35 (m, 4H, Ar-H), 7.43 (t, J ) 7.6 Hz,
2H, Ar-H), 7.51 (dd, J ) 7.9, 1.7 Hz, 1H, Ar-H; δC (75 MHz;
CDCl3) 20.4 (CHCH3), 22.6 (CHOHCH3), 32.4 (C(CH3)3), 36.8
(C(CH3)3), 39.2 (NCH3), 42.0 (CHCH3), 73.5 (CHOH), 119.4,
122.6, 125.6, 127.9, 128.9, 129.3, 139.1, 139.6, 146.0, 149.1, 156.0
(CdO); m/z (CI) 355 (100%, M + H+). Diastereoisomer C Rf (1:3
EtOAc/petrol) 0.04, mp 143-146 °C; IR νmax(CHCl3)/cm-1 3418.3
(OH), 1658.3 (CdO); δH (300 MHz; CDCl3) 1.10 (d, J ) 6.3 Hz,
3H, CHOHCH3), 1.35 (d, J ) 6.9 Hz, 3H, CHCH3), 1.46 (s, 9H,
C(CH3)3), 1.65 (bs, 1H, OH), 2.83 (qn, J ) 6.8 Hz, 1H, CHCH3),
3.24 (s, 3H, NCH3), 3.97 (qn, J ) 6.3 Hz, 1H, CHOHCH3), 6.00
(bs, 1H, NH), 6.98-7.06 (m, 1H, Ar-H), 7.25-7.26 (m, 4H, Ar-
H), 7.36-7.44 (m, 2H, Ar-H), 7.55 (dd, J ) 7.6, 2.2 Hz, 1H, Ar-
H); δC (75 MHz; CDCl3) 18.9 (CHCH3), 22.9 (CHOHCH3), 32.3
(C(CH3)3), 32.5 (C(CH3)3), 39.0 (NCH3), 40.9 (CHCH3), 72.8
(CHOH), 119.2, 123.2, 127.2, 128.2, 129.1, 130.0 137.7, 138.7,
146.8, 148.9, 155.4 (CdO); m/z (CI) 355 (100%, M + H+).
Diastereoisomer D Rf (1:3 EtOAc/petrol) 0.02, mp 120-135 °C;
IR νmax(CHCl3)/cm-1 3416.6 (OH), 1661.2 (CdO); δH (300 MHz;
CDCl3) 1.20 (d, J ) 6.3 Hz, 3H, CHOHCH3), 1.28 (d, J ) 6.9 Hz,
3H, CHCH3), 1.46 (s, 9H, C(CH3)3), 1.70 (bs, 1H, OH), 2.85 (qn,
1-(2-t-Butyl-6-s-butylphenyl)-1-methyl-3-phenylurea (10a). In
the same way, 1-(2-t-butyl-6-ethylphenyl)-1-methyl-3-phenylurea
7 (0.080 g, 0.28 mmol), s-BuLi (1.2 M solution in cyclohexane,
0.58 mL, 0.71 mmol, 2.5 equiv), and excess ethyl iodide (0.5 mL)
gave the title compound as a white solid in 73% yield (0.064 g,
0.21 mmol) as a single diastereoisomer, mp 102 °C; Rf (1:3 EtOAc/
petrol) 0.50; IR νmax(CHCl3)/cm-1 1681.6 (CdO); δH (300 MHz;
CDCl3) 0.93 (t, J ) 7.6 Hz, 3H, CH2CH3), 1.19 (d, J ) 6.7 Hz,
3H, CHCH3), 1.47 (s, 9H, C(CH3)3), 1.63 (quintet, J ) 7.3 Hz,
2H, CH2CH3), 2.76 (sextet, J ) 7.0 Hz, 1H CHCH3), 3.24 (s, 3H,
NCH3), 6.00 (bs, 1H, NH), 6.99-7.04 (m, 1H, Ar-H), 7.25-7.31
(m, 5H, Ar-H), 7.40 (t, J ) 7.9 Hz, 1H, Ar-H), 7.49 (dd, J ) 7.9,
1.8 Hz, 1H, Ar-H); δC (75 MHz; CDCl3) 12.9 (CH3CH2), 22.2
(CH3CH2), 32.1 (CHCH3), 32.4 (C(CH3)3, 35.0 (CHCH3), 36.7
(C(CH3)3, 39.3 (NCH3), 119.6, 123.2, 126.5, 127.4, 129.1, 129.6,
137.8, 138.9, 148.6, 149.1, 155.8 (CdO); m/z (CI) 339 (100%, M
+ H+); HRMS found M + H+ 339.2430. C22H30N2O requires M
+ H 339.2431.
1-(2-t-Butyl-6-s-butylphenyl)-1-methyl-3-phenylurea (10a). In
the same way, 1-(2-t-butyl-6-propylphenyl)-1-methyl-3-phenylurea
11 (0.070 g, 0.22 mmol), s-BuLi (1.2 M solution in cyclohexane,
0.44 mL, 0.54 mmol, 2.5 equiv), and methyl iodide (0.03 mL, 2.5
equiv) gave the title compound as a white solid in 85% yield (0.063
g, 0.19 mmol) as a single diastereoisomer, mp 102-104 °C; Rf
(1:3 EtOAc/petrol) 0.50; IR νmax(CHCl3)/cm-1 1681.0 (CdO); δH
(300 MHz; CDCl3) 0.80 (t, J ) 7.3 Hz, 3H, CH2CH3), 1.22 (d, J
) 6.7 Hz, 3H, CHCH3), 1.43 (s, 9H, (C(CH3)3), 1.62 (quintet, J )
7.6 Hz, 2H, CHCH2CH3), 2.79 (q, J ) 7.0 Hz, 1H, CHCH3), 3.23
(s, 3H, NCH3), 5.96 (bs, 1H, NH), 6.98-7.03 (m, 1H, Ar-H),
7.24-7.29 (m, 5H, Ar-H), 7.41 (t, J ) 7.9 Hz, 1H, Ar-H), 7.48
(dd, J ) 8.2, 1.5 Hz, 1H, Ar-H); δC (75 MHz; CDCl3) 13.1
(CH3CH2), 23.5 (CH3CH2), 31.2 (CHCH3), 32.5 (C(CH3)3, 35.2
(CHCH3), 36.8 (C(CH3)3, 39.2 (NCH3), 119.3, 123.1, 126.3, 127.5,
129.1, 129.5, 137.9, 138.9, 148.7, 148.9, 155.6 (CdO); m/z (CI)
339 (100%, M + H+); HRMS found M + H+ 339.2435. C22H30N2O
requires M + H 339.2431.
1-(2-t-Butyl-6-(1(trimethylsilyl)ethyl)phenyl)-1-methyl-3-phe-
nylurea (10b). In the same way, 1-(2-t-butyl-6-ethylphenyl)-1-
methyl-3-phenylurea 7 (0.100 g, 0.35 mmol), s-BuLi (1.2 M solution
in cyclohexane, 0.74 mL, 0.89 mmol, 2.5 equiv), and chlorotrim-
ethylsilane (0.11 mL, 2.5 equiv) gave the title compound as a pale
yellow oil in 62% yield (0.083 g, 0.22 mmol) as a single
diastereoisomer; Rf (1:3 EtOAc/petrol) 0.55; IR νmax(CHCl3)/cm-1
1681.7 (CdO); δH (300 MHz; CDCl3) 0.06 (s, 9H, Si(CH3)3), 1.31
(d, J ) 7.3 Hz, 3H, CHCH3), 1.45 (s, 9H, (C(CH3)3), 2.26 (q, J )
7.3 Hz, 1H, CHCH3), 3.20 (s, 3H, NCH3), 6.02 (bs, 1H, NH),
6.98-7.04 (m, 1H, Ar-H), 7.19-7.30 (m, 5H, Ar-H), 7.35 (t, J )
7.9 Hz, 1H, Ar-H), 7.41 (dd, J ) 8.2, 1.5 Hz, 1H, Ar-H); δC (75
MHz; CDCl3) -1.93 (Si(CH3)3, 18.2 (CH3CH), 22.7 (CH3CH), 32.4
(C(CH3)3, 36.7 (C(CH3)3, 39.6 (NCH3), 119.6, 123.2 126.2, 127.6,
129.1, 129.2, 137.5, 138.9, 148.3, 149.0, 155.8 (CdO); m/z (CI)
383 (100%, M + H+); HRMS found M + H+ 383.2509.
C23H34N2OSi requires M + H 383.2513.
1-(2-t-Butyl-6-(1-dimethyl(phenyl)silyl)ethyl)phenyl)-1-meth-
yl-3-phenylurea (10c). In the same way, 1-(2-t-butyl-6-ethylphe-
nyl)-1-methyl-3-phenylurea 7 (0.200 g, 0.65 mmol), s-BuLi (2.1
M solution in cyclohexane, 0.77 mL, 1.61 mmol, 2.5 equiv), and
chloro(dimethyl)phenylsilane (0.27 mL, 2.5 equiv) gave the title
compound as a pale yellow oil in 62% yield (0.083 g, 0.22 mmol)
as a single diastereoisomer; Rf (1:3 EtOAc/petrol) 0.47; IR
ν
max(CHCl3)/cm-1 1678.3 (CdO), 1247.4 (Si-C); δH (300 MHz;
CDCl3) 0.34 (s, 3H, SiCH3), 0.43 (s, 3H, SiCH3), 1.40 (s, 9H, tBu),
2.43 (q, J ) 7.4 Hz, 1H, SiCHCH3), 2.83 (s, 3H, NCH3), 5.95 (bs,
1H, NH), 6.98-7.03 (m, 1H, Ar-H), 7.20 (dd, J ) 7.6, 1.7 Hz,
1H, Ar-H), 7.24 (d, J ) 4.5 Hz, 4H, Ar-H), 7.30-7.39 (m, 7H,
4422 J. Org. Chem. Vol. 73, No. 12, 2008

N,N′-Diarylureas: New Family of Atropisomers
J ) 6.9 Hz, 1H, CHCH3), 3.25 (s, 3H, NCH3), 3.94 (qn, J ) 6.3
Hz, 1H, CHOHCH3), 5.94 (bs, 1H, NH), 7.00-7.06 (m, 1H, Ar-
H), 7.26 (d, J ) 4.2 Hz, 4H, Ar-H), 7.38-7.45 (m, 2H, Ar-H),
7.54 (dd, J ) 7.3, 2.4 Hz, 1H, Ar-H); δC (75 MHz; CDCl3) 17.3
(CHCH3), 22.5 (CHOHCH3), 32.4 (C(CH3)3), 36.8 (C(CH3)3), 39.8
(NCH3), 40.4 (CHCH3), 72.1 (CHOH), 119.7, 123.4, 127.3, 128.0,
129.1, 129.6, 137.9, 138.7, 146.7, 149.1, 155.6 (CdO); m/z (CI)
355 (100%, M + H+); HRMS found M + H+ 355.2386.
C22H30N2O2 requires M + H 355.2380.
1-(2-t-Butyl-6-(1-hydroxy-1-phenylpropan-2yl)phenyl)-1-methyl-
3-phenylurea (10f). In the same way, 1-(2-t-butyl-6-ethylphenyl)-
1-methyl-3-phenylurea 7 (0.200 g, 0.62 mmol), s-BuLi (1.2 M
solution in cyclohexane, 1.30 mL, 1.54 mmol, 2.5 equiv), and excess
benzaldehyde (0.3 mL) gave the title compound as a colorless oil
in 94% yield (0.243 g, 0.58 mmol) as an inseparable mixture of
diastereoisomers; Rf (1:3 EtOAc/petrol) 0.19; IR νmax(CHCl3)/cm-1
3415.5 (OH), 1664.9 (CdO); δH (300 MHz; CDCl3) 0.98 (d, J )
6.9 Hz, 3H, CHCH3major), 1.30 (d, J ) 6.9 Hz, 3H, CHCH3minor),
1.40 (s, 9H, C(CH3)3minor), 1.49 (s, 9H, C(CH3)3major), 1.88 (bs, 1H,
OH), 2.15 (bs, 1H, OH), 2.84 (s, 3H, NCH3minor), 3.16-3.29 (m, 2
× 1H, CHOHCHCH3), 3.40 (s, 3H, NCH3major), 4.75 (d, J ) 9.6
Hz, 1H, CH3CHOHmajor), 4.93 (d, J ) 6.1 Hz, 1H, CH3CHOHminor),
5.87 (bs, 1H, NHminor), 5.93 (bs, 1H, NHmajor), 6.96-7.03 (m, 1H,
Ar-H), 7.22-7.30 (m, 5H, 7.35-7.65, Ar-H); δC (75 MHz; CDCl3)
20.0 (CH3CH), 32.4 (C(CH3)3, 36.9 (C(CH3)3, 39.3 (NCH3), 41.4
(CHCH3), 80.5 (CHOH), 119.6, 123.2 126.3, 127.4, 128.3, 128.5,
128.9, 129.1, 129.7, 138.7, 139.0, 142.8, 145.8, 149.2, 155.6
(CdO); m/z (CI) 417 (100%, M + H+); HRMS found M + H+
417.2536. C27H32N2O2 requires M + H 417.2537.
(CI) 430 (100%, M + H+); HRMS found M + H 430.2853
C28H35N3O requires M + H 430.2853.
1-(2-t-Butyl-6-(3-oxobutan-2-yl)phenyl)-1-methyl-3-phenyl-
urea (10i). In the same way, 1-(2-t-butyl-6-ethylphenyl)-1-methyl-
3-phenylurea 7 (0.100 g, 0.32 mmol), s-BuLi (1.3 M solution in
cyclohexane, 0.62 mL, 0.806 mmol, 2.5 equiv), and excess acetic
anhydride (0.2 mL) gave the title compound as a white solid in
55% yield (0.062 g, 0.18 mmol) as a single diastereoisomer, mp
160-163 °C; Rf (1:3 EtOAc/petrol) 0.31; IR νmax(CHCl3)/cm-1
1712.5 (CdO), 1675.9 (CdO); δH (300 MHz; CDCl3) 1.36 (s, 9H,
C(CH3)3), 1.40 (d, J ) 6.9 Hz, 3H, CHCH3), 1.97 (s, 3H,
CdOCH3), 3.16 (s, 3H, NCH3), 3.83 (q, J ) 6.9 Hz, 1H, CHCH3),
5.90 (bs, 1H, NH), 6.90-7.93 (m, 1H, Ar-H), 7.10 (dd, J ) 7.6,
1.3 Hz, 1H, Ar-H), 7.13-7.17 (m, 4H, Ar-H), 7.33 (t, J ) 7.9 Hz,
1H, Ar-H), 7.48 (dd, J ) 8.2, 1.6 Hz, 1H, Ar-H); δC (75 MHz;
CDCl3) 19.1 (CHCH3), 29.1 (C(CH3)3), 32.1 (C(CH3)3), 36.6
(NCH3), 38.8 (CHCH3), 47.1 (CdOCH3), 119.1, 123.1, 127.9,
128.8, 128.9, 129.4, 137.7, 138.3, 141.1, 148.9, 155.2 (CdO), 208.8
(CdO); m/z (CI) 353 (100%, M + H+). HRMS found M + H+
353.2224. C22H28N2O2 requires M + H 353.2224.
1-(2-t-Butyl-6-propylphenyl)-1-methyl-3-phenylurea (11). In
the same way, 1-(2-t-butylphenyl)-1-methyl-3-phenylurea 1 (R1 )
t-Bu)6 (0.400 g, 1.42 mmol), s-BuLi (1.2 M solution in cyclohexane,
2.98 mL, 3.54 mmol, 2.5 equiv), and n-propyl iodide (0.35 mL,
2.5 equiv) gave the title compound as a white solid in 68% yield
(0.310 g, 0.96 mmol), mp 98 °C; Rf (1:6 EtOAc/petrol) 0.19; IR
ν
max(CHCl3)/cm-1 1680.9 (CdO); δH (300 MHz; CDCl3) 1.02 (t,
J ) 7.3 Hz, 3H, CH2CH3), 1.46 (s, 9H, C(CH3)3), 1.64-1.76 (m,
2H, CH2CH2CH3), 2.48 (dd, J ) 8.2, 7.9 Hz, 2H, CH2CH2CH3),
3.25 (s, 3H, NCH3), 5.98 (bs, 1H, NH), 6.99-7.03 (m, 1H, Ar-H),
7.26-7.32 (m, 5H, Ar-H), 7.38 (t, J ) 7.6 Hz, 1H, Ar-H), 7.50
(dd, J ) 7.9, 1.8 Hz, 1H, Ar-H); δC (75 MHz; CDCl3) 14.7
(CH3CH2CH2), 23.9 (CH3CH2), 32.4 (C(CH3)3, 32.7 (CH3CH2CH2),
36.7 (C(CH3)3, 38.6 (NCH3), 119.6, 123.2, 127.6, 128.8, 129.1,
129.2, 138.5, 139.0, 143.3, 148.9, 155.6 (CdO); m/z (CI) 326
(100%, M + H+); HRMS found M + H+ 325.2277. C21H28N2O
requires M + H 325.2274.
1-(2-t-Butyl-6-(3-hydroxy-3-methylbutan-2-yl)phenyl)-1-methyl-
3-phenylurea (10g). In the same way, 1-(2-t-butyl-6-ethylphenyl)-
1-methyl-3-phenylurea 7 (0.100 g, 0.32 mmol), s-BuLi (1.3 M
solution in cyclohexane, 0.62 mL, 0.806 mmol, 2.5 equiv), and
excess freshly distilled acetone (1 mL) gave the title compound as
a white solid in 100% yield (0.117 g, 0.32 mmol) as a single
diastereoisomer, mp 156-160 °C; Rf (1:3 EtOAc/petrol) 0.19; IR
ν
max(CHCl3)/cm-1 3416.0 (OH), 1659.2 (CdO); δH (300 MHz;
1-(2,6-Di-s-butylphenyl)-1-methyl-3-phenylurea (12). In the
same way, 1-(2,6-diethylphenyl)-1-methyl-3-phenylurea 6 (0.150
g, 0.53 mmol), s-BuLi (0.8 M solution in cyclohexane, 1.70 mL,
1.33 mmol, 2.5 equiv), and ethyl iodide (0.05 mL, 0.62 mmol, 1.2
equiv) gave the title compound in 83% yield (0.162 g, 0.44 mmol),
mp 82-83 °C; Rf (1:3 EtOAc/petrol) 0.58; IR νmax(CHCl3)/cm-1
1683.6 (CdO); δH (300 MHz; CDCl3) 0.90 (t, J ) 7.4 Hz, 6H,
CH2CH3), 1.20 (d, J ) 6.8 Hz, 6H, CHCH3), 1.66 (qn, J ) 7.4 Hz,
4H, CHCH2CH3), 2.88 (sp, J ) 7.0 Hz, 2H, CH2CHCH3), 3.24 (s,
3H, NCH3), 5.97 (bs, 1H, NH), 6.98-7.04 (m, 1H, Ar-H),
7.25-7.30 (m, 6H, Ar-H), 7.45 (t, J ) 7.4 Hz, 1H, Ar-H); δC (75
MHz; CDCl3), 13.0 (CH2CH3), 22.7 (CHCH3), 31.4 (CH2CH3), 35.6
(NCH3), 37.3 (CHCH3), 119.5, 123.1, 125.5, 129.1, 129.9, 137.8,
139.0, 147.1, 155.3 (CdO); m/z (CI) 339 (100%, M + H+); HRMS
found M+ 338.2356. C22H30N2O requires 338.2358.
CDCl3) 1.21 (s, 3H, CH3), 1.35 (d, J ) 7.3 Hz, 3H, CHCH3), 1.39
(s, 3H, CH3), 1.44 (s, 9H, C(CH3)3), 1.73 (bs, 1H, OH), 3.02 (q, J
) 7.1 Hz, 1H, CHCH3), 3.21 (s, 3H, NCH3), 6.59 (bs, 1H, NH),
6.98 (tt, J ) 7.1, 1.2 Hz, 1H, Ar-H), 7.20-7.31 (m, 4H, Ar-H),
7.38 (t, J ) 7.9 Hz, 1H, Ar-H), 7.70 (dd, J ) 8.2, 1.5 Hz, 1H,
Ar-H); δC (75 MHz; CDCl3) 19.2 (CHCH3), 28.5 (CH3), 30.7 (CH3),
32.6 (C(CH3)3), 37.0 (C(CH3)3), 39.1 (NCH3), 43.0 (CHCH3), 74.1
(CHOH), 119.1, 122.8, 127.5, 128.3, 129.0, 138.5, 139.2, 146.0,
148.7, 155.6 CdO; m/z (CI) 369 (100%, M + H+); HRMS found
M + H+ 369.2536. C23H32N2O2 requires M + H 369.2537.
1-(2-t-Butyl-6-(1-(methylamino)-1-phenylpropan-2-yl)phenyl)-
1-methyl-3-phenylurea (10h). In the same way, 1-(2-t-butyl-6-
ethylphenyl)-1-methyl-3-phenylurea 7 (0.100 g, 0.32 mmol), s-BuLi
(1.3 M solution in cyclohexane, 0.62 mL, 0.806 mmol, 2.5 equiv),
and excess N-benzylidenemethylamine (0.2 mL) gave the title
compound as a white solid in 74% yield (0.318 g, 0.32 mmol) as
a single diastereoisomer, mp 91-99 °C; Rf (1:0 EtOAc/petrol) 0.43;
IR νmax(CHCl3)/cm-1 3417.4 (NHRMe), 1679.7 (CdO); δH (300
MHz; CDCl3) 0.92 (d, J ) 6.8 Hz, 3H, CHCH3), 1.48 (s, 9H, tBu),
2.05 (s, 3H, NHCH3), 3.05-3.15 (m, 1H, CHCHCH3), 3.47 (s, 3H,
NCH3), 3.59 (d, J ) 9.9 Hz, 1H, CHCHCH3), 5.88 (bs, 1H, NH),
6.92-6.98 (m, 1H, Ar-H), 7.19 (d, J ) 4.3 Hz, 4H, Ar-H),
7.28-7.49 (m, 7H, Ar-H), 7.58 (dd, J ) 7.2, 2.4 Hz, 1H, Ar-H);
δC (75 MHz; CDCl3) 21.2 (CHCH3), 32.7 (C(CH3), 35.5, 37.1, 39.9
(NCH3), 41.0, 72.9, 119.8, 123.4, 126.3, 127.9, 128.6, 128.8, 128.9,
129.2, 130.1, 138.9, 139.1, 142.5, 146.5, 149.5, 155.6 (CdO); m/z
Acknowledgment. We thank EPSRC and Organon for
support of this work.
Supporting Information Available: CIF files of X-ray
crystal structures of anti-3c, syn-3d, 10, and 12. General
1
experimental data. Copies of H and 13C NMR spectra for all
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO702706C
J. Org. Chem. Vol. 73, No. 12, 2008 4423