2-Phenyl-3-hydroxyimidazolidin-4-one: The regioselective synthesis, structure and enantiomerically enriched crystallization

Article abstract of DOI:10.1070/MC2003v013n03ABEH001790

The reaction of glycine hydroxamic acid with benzaldehyde regioselectively affords the title racemic cyclic hydroxamic acid, which crystallises as enantiomorphic crystals (space group P2₁2₁2₁) from a methanol solution.

Full text of DOI:10.1070/MC2003v013n03ABEH001790

,
2003, 13(3), 116–118
2
-Phenyl-3-hydroxyimidazolidin-4-one: the regioselective synthesis, structure
and enantiomerically enriched crystallization
a
b
c
Igor V. Vystorop,* Konstantin A. Lyssenko and Remir G. Kostyanovsky
a
Institute of Problems of Chemical Physics, Russian Academy of Sciences, 142432 Chernogolovka, Moscow Region,
Russian Federation. Fax: +7 096 514 3244; e-mail: vystorop@icp.ac.ru
b
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5085; e-mail: kostya@xray.ineos.ac.ru
c
N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 938 2156; e-mail: kost@center.chph.ras.ru
1
0.1070/MC2003v013n03ABEH001790
The reaction of glycine hydroxamic acid with benzaldehyde regioselectively affords the title racemic cyclic hydroxamic acid,
which crystallises as enantiomorphic crystals (space group P2 2 2 ) from a methanol solution.
1
1 1
We shown earlier1(a),(b) that reactions of glycine hydroxamic
acid (GlyHA) with aliphatic ketones proceed as regioselective
intramolecular N-aminoalkylation of the hydroxamic group
forms (Scheme 2). Secondly, according to the amplitude of
puckering (tm),1
(a),(b),3
the heterocycle of 5 in a crystal is
substantially more flattened (t = 7.3°), as compared with those
m
1
(a)
1(b)
(
CONHOH) leading to the formation of five-membered cyclic
of 1a (t = 31.4°)
and 1b (t = 33.7°).
This observation
m
m
hydroxamic acids (HAs) 1a–e. The condensation of GlyHA
is supported by the displacements of N(1), C(2), O(1) and O(2)
atoms from the N(3)C(4)C(5) plane equal to –0.006, 0.100,
0.189 and 0.026 Å, respectively.
1
(b)
with acetophenone similarly yields 1f. According to Charbonnel
and Barrans,2 the reactions of different α-amino HAs with
aliphatic and aromatic aldehydes result in the formation of
acyclic azomethins 2 or intramolecular (N)-O aminoalkylation
products, namely, six-membered cyclic hydroxamates 3. In
particular, the product of GlyHA reaction with benzaldehyde
in ethanol (reflux for 1 h) was assigned as azomethine 2a
5
The strong flattening of the heterocycle of in a crystal (Figure 1)
corresponds to a decrease of the twist value of the hydroxamic
† Procedure for the synthesis of 2-phenyl-3-hydroxyimidazolidin-
4-one 5. A suspension of GlyHA 4 (1.80 g, 20 mmol) and benzaldehyde
(2.55 g, 24 mmol) in 40 ml of absolute ethanol was refluxed for 1 h. The
hot reaction mixture was filtered and cooled to room temperature. The
precipitate was filtered off and the solution was evaporated to a small
volume. The resulting precipitate was filtered off, then combined with
that of earlier obtained and recrystallized from acetonitrile to yield 5 (2.42 g,
1
2
(
R = H, R = Ph; mp 144 °C, 55% yield) based on elemental
analysis data and positive test reaction with FeCl (in contrast
3
to one with hydroxamates 3) for the hydroxamic OH group,
additionally confirmed by a comparison of the IR spectra (KBr)
2
of 2a and its monoacylation product.
6
8%, mp 147–149 °C) as colourless crystals. Monocrystals of 5 (mp 150–
Because the structure of product 2a is questionable, taking
‡
151 °C) for X-ray diffraction analysis and optical activity measurements
1
(a),(b)
into account our previous results
(vide supra), this study
20
{
[a] +22.2° (c 0.68, MeOH), 8.2 mg} were grown from absolute methanol.
D
was devoted to reinvestigation of product of the reaction of
GlyHA with benzaldehyde.
18
Compound 4 (GlyHA) was prepared as described previously.
Characteristics and spectroscopic data. The NMR spectra were
recorded on Bruker WM-400 and Bruker AC-200 NMR spectrometers at
R1
400.13 (1H) and 50.32 (13C) MHz. The IR spectrum was obtained on a
OH
H
O
Specord-82M spectrometer. Optical rotation measurements were made
O
N
HN
H
on a Perkin–Elmer 341 polarimeter at the D line of sodium (2890 Å).
R1
R2
2
1
R CH=NCH(R )CONHOH
5, mp 147–149 °C (MeCN). 1H NMR (CD OD) d: 3.44 (d, 1H,
NH
3
N
H
2
2
O
CH H , J 16.1 Hz), 3.62 (d, 1H, CH H , J 16.1 Hz), 5.36 (s, 1H,
CHPh), 7.42 (m, 3H, Ph), 7.47 (m, 2H, Ph). C NMR ([ H ]DMSO) d:
6.66 (dd, CH , J 142.8 Hz, J 143.2 Hz), 77.55 (d, CHPh, J 154.1 Hz),
2
R2
A B A B
1
3
2
3
6
1
1
1
4
1
(
1
2
1
2
1
a R = R = Me
R = H, Alk, Ar
1
1
27.66 (dm, 2C , J 159.1 Hz), 128.60 (dm, 2C , J 160.2 Hz), 129.03
1
2
2
Ph
Ph
1
b,c R + R = (CH ) , (CH )
R = Alk, Ar
2
4
2
5
1
dm, p-C , J 160.9 Hz), 138.87 (m, i-CPh), 171.93 (m, C=O). IR (KBr,
v/cm ): 3220 (NH), 2908, 2864 (CH ), 2686 (br.), 2581 (br., OH), 1732
1
2
t
Ph
(
±)-1d,e,f R = Me, R = Et, Bu , Ph
–
1
2
†
(sh), 1698 (C=O), 1540, 1495, 1460, 1452, 1405, 1384, 1364, 1329,
Similarly to 1a–f, product 5 (Scheme 1) is a cyclic HA of
the imidazolidine series, as established by X-ray diffraction
1
284, 1272, 1234, 1208, 1088, 1072, 1050, 1020, 967, 933, 908, 861,
‡
1
804, 764, 705, 679, 612, 576, 470.
analysis and confirmed by the test reaction with FeCl and H,
C NMR data, which are consistent with published data for
3
‡
1
3
†
Crystallographic data for 5: at 298 K, the crystals of C9H10N2O2 are
orthorhombic, space group P2 2 2 , a = 5.734(1) Å, b = 8.987(2) Å, c =
1
(a),(b)
1 1 1
1
a–f.
3
–3
=
15.909(3) Å, V = 819.8(3) Å , Z = 4, M = 178.19, d = 1.444 g cm ,
calc
–
1
OH
m(MoKα) = 1.04 cm , F(000) = 376. Intensities of 1403 reflections
were measured with a Nonius CAD4 diffractometer at 298 K [l(MoKa) =
= 0.71072 Å, q/2q-scan mode, 2q < 60°], and 1392 independent reflec-
tions (Rint = 0.0094) were used in a further refinement. The structure was
solved by a direct method and refined by the full-matrix least-squares
O
jexo
H N
2
O
t1
N
t4
t0
Ph
+
PhCHO
t2
N t3
H
H
NHOH
2
technique against F in the anisotropic–isotropic approximation. Hydro-
gen atoms were located from the Fourier synthesis and refined in the
GlyHA 4
(±)-5
isotropic approximation. The refinement converged to wR = 0.0929 and
2
Scheme 1
GOF = 1.076 for all independent reflections [R = 0.0305 was calculated
1
against F for 1282 observed reflections with I > 2s(I)]. All calculations
were performed using SHELXTL PLUS 5.0 on IBM PC AT.
Atomic coordinates, bond lengths, bond angles and thermal param-
eters have been deposited at the Cambridge Crystallographic Data Centre
The characteristic features of the molecular structure of HA
in a crystal (Figure 1) were revealed by a comparison with its
5
1
(a)
1(b)
analogues 1a
phase angle of pseudorotation (P)
and 1b. Firstly, according to the calculated
1
(a),(b),3
the chiral N-type
(
CCDC). These data can be obtained free of charge via www.ccdc.cam.uk/
(
t2 > 0) conformation of heterocycle of (P,1R,2S,3S)-enantio-
conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336 033; or deposit@ccdc.cam.ac.uk).
Any request to the CCDC for data should quote the full literature citation
and CCDC reference number 214875. For details, see ‘Notice to Authors’,
Mendeleev Commun., Issue 1, 2003.
mer of 5 (Figure 1) is close (P = 52.1°) to the pure envelope
N
E (P = 54°) (Scheme 2) and only slightly differs from the
C(2)
N
1
(a)
1(b)
heterocycles of 1a (P = 44.0°)
and 1b (P = 43.8°)
in a
N
N
crystalline state, which are intermediate between the terminal
–
116 –

,
2003, 13(3), 116–118
H
N
Ha
N
H 5
1
O
H
H 4
C
N
H
H
3N
HO Ph
OH
2
H
O
Ph
N(1)
C(2)
T, PN = 36°
C(2)E, P = 54°
N
a
(P,1R,2S,3S)-5
c
0
Scheme 2 Some terminal forms of the heterocycle of 5.
fragment (j = 7.8°) in comparison with the molecules of 1a
exo
(a)
1(b)
(
jexo = 19.3°)1 and 1b (jexo = 17.9°) but retains the sign of
1
(a),(b)
this skew (jexo > 0) observed
meric form of heterocycle. Together with the simultaneous
for the P -type of enantio-
N
decrease of the opposite sign endocyclic dihedral angle (t =
0
1
(a)
=
–4.4°) of 5, as compared with its analogues 1a (t = –14.9°)
0
1
(b)
b
and 1b (t = –15.6°), this leads to the almost full planarity of
0
the amide N(3) atom [Σw N(3) = 358.6°; the height of its very
shallow pyramid is equal to 0.097 Å] in contrast to the expressed
non-planarity of N(3) atoms in the molecules of 1a (350.8°,
(a)
1(b)
0
.250 Å)1 and 1b (350.9°, 0.247 Å) in crystals. The planari-
zation of the amide group in 5 is accompanied by the enforcing
of the amide n –π*(C=O) conjugation that results in a change
N
in the N(3)–C(4), C(2)–N(3) and C(2)=O(4) bond lenghts
1
(a),(b)
(
Figure 1, cf. for 1a,b
), which are almost equal to the
averaged lengths of the corresponding bonds [1.335 Å (C –N),
sp2
Figure 2 Fragment of homochiral layers consisting of alternate antiparallel
translational columns in the crystal structure of 5. Hydrogen atoms without
H-bondings are omitted for clarity. H-bondings are shown by dashed lines.
The geometric parameters of H-bondings are as follows: H(1O)···N(1)
4
1
.455 Å (Csp
3
–N) and 1.232 Å (C=O)] of γ-lactams in a crystal-
line state. Moreover, the noticeable shortening of the C(2)–N(3)
bond (1.455 Å) in the molecule of 5 in comparison with the
1
1
.835 Å, O(1)···N(1) 2.726 Å, O(1)–H(1O)···N(1) 169.3°; H(1N)···O(2)
.977 Å, N(1)···O(2) 2.883 Å, N(1)–H(1N)···O(2) 165.0°; H(10)···O(2)
1
(a)
1(b)
molecules of 1a (1.484 Å) and 1b (1.474 Å) corresponds
to
diminution of the nN(1)–s*[C(2)–N(3)] interaction5
j[LPN(1)N(1)C(2)N(3)] = –128.5°}, as compared to 1a
a
2.352 Å, C(10)···O(2) 3.325 Å, N(1)–H(1N)···O(2) 149.1. [The symmetry
transformation used to generate the atoms N(1) (–x + 1, y + 1/2, –z + 1/2),
O(2) (x + 1, y, z) and O(2) (–x, –0.5 + y, –z)].
{
(
–152.5°)1 and 1b (–157°). The decrease of the piramidality
of the amine N(1) atom [Σw N(1) = 324.5°] of HA 5 is also
1(b)
(a)
1(b)
1
(a)
observed in comparison with HAs 1a (317.2°) and 1b (315°).
also formed between the molecules of 5 (Figure 2).
1
(a)
1(b)
‡
In all the three crystal structures of compounds 1a, 1b
The space group of 5 is chiral (P2 2 2 , Z = 4) to reveal the
1
1 1
6
and 5 (Figure 2), strong O(1)–H(10)···N(1) and weak N(1)–
H(1N)···O(2) intermolecular hydrogen bondings are formed.
enantiomorphic nature of crystals similarly to formally achiral
1
(a)
monocyclic HA 1a (P2 2 2 , Z = 4)
but as opposed to spiro
1
1 1
7
1(b)
Another hydrogen bonding of the C(10)–H(10)···O(2) type is
cyclic HA 1b (P2 /n, Z = 4).
1
Moreover, according to the polarimetric monitoring of the
optical activity of a monocrystal of a dextrorotatory enantiomer
H(1N)
H(52)
†
H(2)
of 5, the reaction rate of its racemization in methanol at 20 °C
is high (t1/2 » 1 h). Together with the chiral nature of crystals
C(5) N(1)
H(10)
C(2)
H(7)
of 5, this another ‘necessary’ condition of ‘spontaneous asym-
C(4) N(3)
O(2)
8(a)
metric synthesis’
enabled us to attempt the spontaneous
H(51)
O(1)
C(6)
C(7)
C(8)
enantiomerically enriched crystallization of 5 from a methanol
solution.
§
Really, in both of the trials, the precipitates were optically
C(11)
H(8)
active as a whole and 17% and 37% enantiomerically enriched.
Their optical yields correspond to the well-known dependence
on the duration of nucleation or crystal growth.8 The solids
obtained by quick evaporation of both mother liquors show the
absence of optical activity confirming that the above crystalli-
zations of 5 occurred under conditions of more rapid racemization
than crystal growth.
H(11)
,9
C(9)
C(10)
H(10)
H(9)
Figure 1 Molecular structure of hydroxamic acid 5 [the absolute con-
figuration is unknown and illustrated by (P,1R,2S,3S)-enantiomer].
Selected bond lengths (Å): O(1)–N(3) 1.381(2), N(1)–C(2) 1.479(2), N(1)–
C(5) 1.475(2), O(2)–C(4) 1.225(2), C(2)–N(3) 1.455(2), C(2)–C(6)
Note that the way in which the solutions of 5 for crystal-
§
lization have been performed, namely careful filtering followed
1
.512(2), N(3)–C(4) 1.335(2), C(4)–C(5) 1.503(2); selected bond and
§
dihedral angles (°): C(2)–N(1)–C(5) 108.7(1), N(1)–C(2)–N(3) 102.6(1),
N(1)–C(2)–C(6) 112.5(1), N(3)–C(2)–C(6) 113.4(1), O(1)–N(3)–C(2)
The crystallization of 5 was performed as follows: a hot solution of a
racemic modification of 5 in absolute methanol [400 mg/5 ml (trial a)
or 400 mg/10 ml (trial b)] was filtered through synthetic cotton wool
into a round-bottom flask. The filtrate was heated to boiling; the flask
was closed with a stopper and allowed to stand without stirring at room
temperature (18–20 °C) to give the crystals of 5 from the supersaturated
solution. The time during which the first crystals appeared [10 h (a) or 4
days (b)] was marked. After a time [7 h (a) or 3 days (b)], the precipitate
was filtered off, washed with a small volume of cold acetonitrile and
dried in vacuo at room temperature. The solid obtained [245 mg, 61.3%
conversion (a) or 170 mg, 42.5% (b)] was carefully ground and mixed
1
20.5(1), O(1)–N(3)–C(4) 122.1(1), C(2)–N(3)–C(4) 116.0(1), O(2)–C(4)–
N(3) 127.2(1), O(2)–C(4)–C(5) 126.5(1), N(3)–C(4)–C(5) 106.3(1), N(1)–
C(5)–C(4) 106.1(1), C(2)–C(6)–C(7) 117.9(1), C(2)–C(6)–C(11) 122.3(1);
H(10)–O(1)–N(3)–C(2) 74.0, H(10)–O(1)–N(3)–C(4) –120.3, H(1N)–
N(1)–C(2)–N(3) 109.8, C(5)–N(1)–C(2)–N(3) (t ) –6.6(1), C(5)–N(1)–
3
C(2)–C(6) 115.7(1), H(1N)–N(1)–C(5)–H(51) 132.3, H(1N)–N(1)–C(5)–
H(52) 8.3, C(2)–N(1)–C(5)–C(4) (t2) 4.5(1), N(1)–C(2)–N(3)–O(1)
1
73.6(1), N(1)–C(2)–N(3)–C(4) (t ) 7.0(1), C(6)–C(2)–N(3)–O(1) 51.9(1),
4
C(6)–C(2)–N(3)–C(4) –114.6(1), N(1)–C(2)–C(6)–C(7) 94.3(1), N(1)–
C(2)–C(6)–C(11) –82.0(2), N(3)–C(2)–C(6)–C(7) –149.8(1), N(3)–C(2)–
C(6)–C(11) 33.9(2), O(1)–N(3)–C(4)–O(2) (jexo) 7.8(2), O(1)–N(3)–C(4)–
C(5) –170.7(1), C(2)–N(3)–C(4)–O(2) 174.1(1), C(2)–N(3)–C(4)–C(5)
2
0
up. Then, it was studied polarimetrically {[a]D +3.8° (c 1.0, MeOH) or
[a]D –8.2° (c 1.0, MeOH), respectively}. The optical yield of the
2
0
(
–
t ) –4.4(2), O(2)–C(4)–C(5)–N(1) –178.8(1), N(3)–C(4)–C(5)–N(1) (t )
precipitate [17.1% (a) or 36.9% (b)] was calculated by comparing its
0
1
0.2(1), C(2)–C(6)–C(7)–C(8) –176.1(1), C(2)–C(6)–C(11)–C(10) 175.4(1).
specific rotation with that of the monocrystal.†
–
117 –

,
2003, 13(3), 116–118
by heating the solution to boiling prevents from inadvertent
seeding or crystalline dust. In addition, the opposite signs of the
optically active precipitates obtained show the random genera-
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1
(a) I. V. Vystorop, K. A. Lyssenko and R. G. Kostyanovsky, Mendeleev
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Voznesensky, V. P. Lodygina and R. G. Kostyanovsky, Mendeleev
Commun., 2002, 193.
§
tion of their handedness.
Owing to the enantiomeric enrichment of crystalline 5 pro-
§
263C, 824.
duced in unstirred crystallization, the human intervention to
2
3
4
J. Charbonnel and J. Barrans, Compt. Rend., 1966,
8
(b),9
10
C. Altona and M. Sundaralingam, J. Am. Chem. Soc., 1972, 94, 8205.
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or seeding,
may presumably substantially increase the optical purity of the
solid.
(
b) L. Nórskov-Lauritsen, H.-B. Bürgi, P. Hofmann and H. R. Schmidt,
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5
6
7
8
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1
1,12
10–12
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(crystallization-induced
)
asymmetric transformation. This process has frequently taken
1
0,11
( ) G. R. Desiraju,
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but was represented by rare cases
a
Acc. Chem. Res
of non-provoked crystallization of enantiomers.8
,12,13
In our
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its enantiomerically enriched crystallization occur without the
deterministic influence of any chiral agent. Therefore, this
9
(a) D. K. Kondepudi, R. J. Kaufman and N. Singh, Science, 1990, 250,
15
process is an example of an absolute asymmetric synthesis.
975; (b) D. K. Kondepudi, K. L. Bullock, J. A. Digits and P. D.
Taking into account the existence of several types16 of
chirality in the molecule of 5, namely, the N(1), C(2) and N(3)
asymmetric centres, the spiral chirality of the hydroxamic
fragment, and the handedness of heterocycle conformation,
compound 5 can theoretically exist as at least 16 diastereomeric
pairs of enantiomers. However, the spiral chirality of the
hydroxamic group and the configuration of the N(3) amide
atom are related to the heterocycle conformation chirality,
whose interconversion and the inversion of the configuration
of the N(1) centre proceed in solution much faster than the
epimerization of the C(2) centre. Thus, the possible presence of
several diastereomers of 5 in solution has no influence upon
kinetically controlled crystallization as pairs of (P,1R,2S,3S)-
and (M,1S,2R,3R)-enantiomers.
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65, 49.
1
2 E. L. Eliel, S. H. Wilen and L. N. Mander, Stereochemistry of Organic
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The enantiomeric enrichment during the spontaneous crys-
tallization of 5 under conditions of simultaneous racemization
in methanol can be best interpreted by the stereospecific auto-
catalysis model.8
1
1
6 R. S. Chan, C. K. Ingold and V. Prelog, Angew. Chem., Int. Ed. Engl.,
(a),14,15(a),17
1966, 5, 385.
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8 K. G. Cunningham, G. T. Newbold, F. S. Spring and J. Stark, J. Chem.
Soc., 1949, 2091.
1
(a),(b)
benzaldehyde similarly to that with ketones,
yields a
cyclic hydroxamic acid of the imidazolidine series rather than
2
an acyclic azomethine. It can be assumed that the regio-
1
selective N,N'-cyclocondensation is common to the reactions of
GlyHA with ketones and aldehydes.
Moreover, we expanded the range
8
,12,13
of racemic com-
pounds capable of chiral symmetry breaking by spontaneous
crystallization and present a further example of a heterogeneous
absolute asymmetric synthesis having an implication toward the
1
4,15,17
origin of homochirality in the biosphere.
This work was supported by the Russian Foundation for
Basic Research (grant nos. 03-03-32019 and 00-03-81187
BEL) and INTAS (grant no. 99-0157).
Received: 30th April 2003; Com. 03/2116
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