Full text of DOI:10.1070/MC2003v013n06ABEH001749

, 2003, 13(6), 275–276
Configurationally stable axially chiral N,N'-dialkyl-2,2'-biphenylene-N,N'-ureas
Alexander I. Roshchin and Remir G. Kostyanovsky*
N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 938 2156; e-mail: kost@chph.ras.ru
10.1070/MC2003v013n06ABEH001749
The configurational stability of compounds 1–4 has been confirmed by NMR spectroscopy and chiral chromatography (analytical
separation of enantiomers 1 and 2); the antiaromatic (4n) destabilisation of the planar transition state of enantiomerisation is
discussed.
2,2'-Disubstituted and 2,2',6,6'-tetrasubstituted biaryls are clas-
sical stereochemical objects.1 Of particular interest are bridging
biaryls with a fragment linking the 2- and 2'-positions. For
2 RX
example, dibenzodiazocine A (Scheme 1) was obtained in an
DMSO, KOH
80–100%
optically active form;2 it undergoes racemisation only on heat-
HN
NH
N
N
ing to 268 °C, which is accompanied by decomposition (the
racemisation barrier is about 36 kcal mol–1).2(c),(d) Such a high
configurational stability of compound A can be explained by
the anti-aromatic (4n) destabilisation of the planar transition
state of racemisation, similarly to its carbon analogue B (the
racemisation barrier is 30 kcal mol–1 at 100 °C).3 The high
configurational stability is also observed in compound C (the
racemisation barrier is about 27 kcal mol–1)4 and nitrogen ana-
logues, viz., dianthranilides D obtained in optically active forms,
which exist in the boat chiral conformation (X-ray diffraction
analysis).5 Although biaryls containing a saturated three- or
four-carbon 2–2' bridge have limited configurational stability
(the barriers are 12.3 and 23.2 kcal mol–1, respectively),2(a),(c),3
the enantiomerisation of diphenimide E occurs quickly even on
the NMR time scale (the calculated barrier is 3.8 kcal mol–1).6
This can be explained by the absence of the anti-aromatic
destabilisation of a planar transition state in E. If it is the case,
this destabilisation should exist for compounds F, G and H. In
R
R
O
I
O
1 R(X) = PhCH2(Br)
2 R(X) = Me2CHCH2(I)
3
4
R(X) = CH2=CHCH2(Br)
R(X) = (S)-Et(Me)CHCH2(Br)
Scheme 2
fact, compounds F and G have been obtained in optically active
forms2(d),7 (Scheme 1). However, the configurational stability
of these compounds, their 6,6'-unsubstituted analogues and com-
pound H8 has not been studied.
In this work, we studied N,N'-dialkyl-2,2'-biphenylene-N,N'-
ureas (dibenzodihydro-1,3-diazepin-2-ones) 1–4. Initial com-
pound I was obtained by a reaction of 2,2'-diaminobiphenyl
with urea.2(d),9 Unlike other ureas,10 compound I did not give
N-derivatives in reactions with either formaldehydes or amino-
methylating reagents, namely, (Me2N)2CH2 or bis(1-morpho-
lino)methane. However, compound I can be readily alkylated
by an alkyl halide taken in an excess in DMSO in the presence
of KOH (Scheme 2).†
HOOC
COOH
The NMR spectra of compounds 1–4† suggest that the chiral
cyclic system is stable on the time scale of this method. The
CH2N protons display diastereotopicity, which is maintained at
90 °C for compound 1 (in this case, ∆n in C5D5N increases
from 226 Hz at 20 °C to 233 Hz at 90 °C). For compound 2,
neither exchange broadening of lines nor their coalescence
occurs on heating to 110 °C; conversely, a considerable increase
in ∆n is observed for CH2N. Methyl groups in compound 2
N
N
Ph
Ph
Ph
N
Ph
A2
B3
X
H
COOH
1
are also diastereotopic: in the H NMR spectrum, ∆n = 64 Hz
Br
at 20 °C; it decreases to 48 Hz at 110 °C. In the 13C NMR
spectrum at 90 °C, ∆n = 15.8 Hz (at 75 MHz) for the carbon
atoms of methyl groups.
According to NMR data, compound 4 obtained from an
optically active alkyl halide is a 1:1 mixture of diastereomers
(Figure 1), which cannot be separated by TLC or by crystal-
lisation from ethanol or hexane.
N
COOH
H
X
C4
D5
X = O, S
The HPLC separation of compounds I, 1 and 2 on a
Chiralcel OD column was studied. Compound I gives one peak;
derivative 2 gives a split peak, whereas compound 1 gives two
peaks resolved at about half-height; the retention times are
10.77 and 11.46 min (Figure 2).
N
NH
HN
NH
N
O
O
Ph
O
H
E6
F2( ),7
G2( ),7
d
d
HN
NH
O
4.1 4.0 3.9 3.8 3.7 3.6 3.5 3.4 3.3 3.2 3.1
H8
d/ppm
Figure 1 1H NMR spectrum of CH2N protons in compound 4.
Scheme 1
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, 2003, 13(6), 275–276
This study was supported by the Russian Foundation for
Basic Research (grant nos. 03-03-32019 and 03-03-04010),
INTAS (grant no. 99-00157) and the Russian Academy of
Sciences.
1.3
1.2
10.77
11.46
References
1
E. L. Eliel, S. H. Wilen and L. N. Mander, Stereochemistry of Organic
Compounds, Wiley-Interscience, New York, 1994, p. 1143.
(a) F. Bell, J. Chem. Soc., 1952, 1527; (b) K. Mislow, M. A. W. Glass,
R. O. Brien, P. Putkin, D. H. Steinberg, J. Weiss and C. Djerassi, J.
Am. Chem. Soc., 1962, 84, 1455; (c) D. M. Hall and J. M. Insole,
J. Chem. Soc., 1964, 2326; (d) J. M. Insole, J. Chem. Soc. (C), 1971,
1712; (e) N. L. Allinger, W. Szkeybalo and M. A. DaRooge, J. Org.
Chem., 1963, 28, 3007.
2
0
10
t/min
Figure 2 Chromatogram of compound 1.
3
(a) K. Müllen, W. Heinz, F.-G. Klärner, W. R. Roth, I. Kindermann,
O. Adamczak, M. Wette and J. Lex, Chem. Ber., 1990, 123, 2349; (b)
P. Rashidi-Rajobar and J. Sandström, Tetrahedron Lett., 1987, 28,
1537.
Thus, as expected, the test compounds are configurationally
stable axially chiral systems.
4
5
K. Mislow and H. D. Perlmutter, J. Am. Chem. Soc., 1962, 84, 3591.
T. Olszewska, T. Polonski and M. Gdaniec, Book of Abstracts of the
7th International Conference on Circular Dichroism, August 25–29,
1999, Mierki, Poland, p. 93.
We are grateful to O. R. Malyshev (N. D. Zelinsky Institute
of Organic Chemistry, Russian Academy of Sciences) for
performing chromatographic experiments.
6
7
8
9
M. Kwit, U. Rychlewska and J. Gawronski, New J. Chem., 2002, 26,
1714.
S. Sako, Mem. Coll. Eng. Kyushu Imp. Univ., 1932, 6, 263 (Chem.
Abstr., 1932, 26, 3246).
A. Reisinger, R. Koch and C. Wentrup, J. Chem. Soc., Perkin Trans. 1,
1998, 2247.
(a) S. von Niementowski, Chem. Ber., 1901, 34, 3330; (b) W. Ried and
W. Storbeck, Chem. Ber., 1962, 95, 459.
†
1H NMR spectra were recorded on a Bruker WM-400 spectrometer
(400.13 MHz); 13C NMR spectra were measured on a Bruker AM-300
spectrometer (75.47 MHz) for compound 3 or on a Bruker AC-200
instrument (50.32 MHz) for compound 5. HPLC was carried out using a
Chiralcel OD column (4.6×250 mm); 10% PriOH in hexane was an
eluent (flow rate of 1 ml min–1); UV detection at 254 nm was performed.
For I: a solution of 2,2'-diaminobiphenyl (0.77 g, 4.18 mmol) and
urea (0.50 g, 8.4 mmol) in 3 ml of AcOH was refluxed for 3 h, diluted
with 10 ml of propan-2-ol and cooled. The residue (bright colourless
thin plates) was filtered off and dried in vacuo. Yield 0.63 g (72%),
mp 319 °C (subl.), (lit.: mp 311–313 °C,6 328–330 °C4); after crystallisa-
tion from BuOH, mp 318–320 °C. 1H NMR ([2H6]DMSO) d: 7.08 (d, 2H,
H-6, 3J 8.0 Hz), 7.14 (t, 2H, H-5, 3J 7.4 Hz), 7.29 (t, 2H, H-4, 3J 7.6 Hz),
7.44 (d, 2H, H-3, 3J 7.6 Hz), 8.77 (br. s, 2H, HN).
10 A. A. Bakibaev, A. Yu. Yagovkin and S. N. Vostretsov, Usp. Khim.,
1998, 67, 333 (Russ. Chem. Rev., 1998, 67, 295).
Alkylation of I, general procedure. DMSO (2 ml) and an alkyl halide
(2.0 mmol) were added to a mixture of compound I (105 mg, 0.5 mmol)
and crushed KOH (140 mg, ~2.0 mmol). The reaction mixture was stirred
for 12 h. Water was added (20 ml); the amorphous precipitate was filtered
off and dried in vacuo.
1
For 1: yield 70% (cryst. from EtOH), mp 144 °C. H NMR of CH2N
protons (CDCl3, 20 °C) d: 4.93 (m, 4H, 2CH2N, AB spectrum, ∆n
2
1
200 Hz, J –15.2 Hz). H NMR of CH2N protons ([2H6]DMSO, 80 °C)
d: 4.90 (m, 4H, 2CH2N, AB spectrum, ∆n 148 Hz, 2J –15.5 Hz). 1H NMR
of CH2N protons (C5D5N, 20 °C) d: 5.01 (m, 4H, 2CH2N, AB spectrum,
1
∆n 226 Hz, 2J –15.3 Hz). H NMR of CH2N protons (C5D5N, 90 °C) d:
5.03 (m, 4H, 2CH2N, AB spectrum, ∆n 233 Hz, 2J –15.2 Hz).
1
For 2: yield 85%, mp 119 °C (EtOH). H NMR ([2H6]DMSO, 20 °C)
d: 0.38 (d, 6H, A-2Me, 3J 6.6 Hz), 0.54 (d, 6H, B-2Me, 3J 6.6 Hz), 1.46
2
(m, 2H, 2CH), 3.45 (m, 4H, 2CH2N, ABX spectrum, ∆n 148 Hz, JAB
3
3
3
–13.4 Hz, JAX 6.1 Hz, JBX 8.3 Hz), 7.27 (t, 2H, H-5, J 7.4 Hz), 7.33
3
3
(d, 2H, H-6, J 7.9 Hz), 7.41 (t, 2H, H-4, J 6.9 Hz), 7.53 (d, 2H, H-3,
3J 6.7 Hz). 1H NMR of the alkyl fragment ([2H6]DMSO, 110 °C) d:
3
3
0.43 (d, 6H, 2A-Me, J 6.6 Hz), 0.55 (d, 6H, 2B-Me, J 6.6 Hz), 1.49
2
(m, 2H, 2CH), 3.50 (m, 4H, 2CH2N, ABX spectrum, ∆n 196 Hz, JAB
–13.4 Hz, 3JAX 6.1 Hz, 3JBX 8.3 Hz). 13C{1H} NMR ([2H6]DMSO, 90 °C)
d: 19.26 (A-Me), 19.47 (B-Me), 26.51 (CH), 54.86 (CH2), 121.47,
124.87, 127.81, 128.30 (C-3-6), 134.05 (C-1), 143.90 (C-2), 164.45 (CO).
For 3: yield 98%, mp 170–175 °C. 1H NMR (CDCl3) d: 4.35 (m, 4H,
2
3
2CH2N, ABX spectrum, ∆n 152 Hz, JAB –15.9 Hz, JAX 5.9 Hz,
3JBX 5.1 Hz), 4.98–5.05 (m, 4H, 2H2C=), 5.67 (m, 2H, 2-CH=), 7.21–
7.28 (m, 4H, H-5 and H-6), 7.38 (t, 2H, H-4, 3J 8 Hz), 7.50 (d, 2H, H-3,
3J 8 Hz).
For 4: yield 89%, mp 96–99 °C (aq. MeOH). 1H NMR (CDCl3) d: 1:1
diastereomer mixture, arbitrary assignment, diastereomer A: 0.41 (d, 6H,
2MeCH, 3J 6.6 Hz), 0.61 (t, 6H, 2MeCH2, 3J 7.4 Hz), 0.77, 0.91 (m, 4H,
2CH2Me), 1.39 (m, 2H, 2CH), 3.57 (m, 4H, 2CH2N, ABX spectrum,
∆n 360 Hz, 2JAB –13.2 Hz, 3JAX3 = 3JBX = 7.4 Hz), 7.19–7.27 (m, 4H, H-
3
6 and H-5), 7.37 (t, 2H, H-4, J 7.5 Hz), 7.49 (d, 2H, H-3, J 7.6 Hz);
diastereomer B: 0.53 (d, 6H, 2MeCH, 3J 6.6 Hz), 0.68 (t, 6H, 2MeCH2,
3J 7.4 Hz), 1.00, 1.12 (m, 4H, CH2Me), 1.46 (m, 2H, 2CH), 3.59 (m,
2
3
4H, 2CH2N, ABX spectrum, ∆n 128 Hz, JAB –13.2 Hz, JAX 5.5 Hz,
3JBX 8.8 Hz), H-3-6 is identical to that of diastereomer A. 13C{1H} NMR
(CDCl3) d: 10.71, 11.00 (MeCH2), 16.52, 16.77 (MeCH), 26.49, 27.01
(CH2Me), 32.69, 33.02 (CH), 53.35, 54.06 (CH2N), 121.58, 121.72,
124.94, 127.99, 128.13, 128.22 (C-3-6), 134.39, 134.53 (C-1), 143.67,
144.53 (C-2), 166.17 (CO).
Received: 7th April 2003; Com. 03/2075
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