General regioselective synthesis and crystal structure of racemic 5-substituted 2,2-dimethyl-3-hydroxyimidazolidin-4-ones

Article abstract of DOI:10.1016/j.mencom.2010.03.014

The cyclocondensation of racemic valine, leucine and β-phenylalanine hydroxamic acids with acetone regioselectively affords corresponding cyclic hydroxamic acids; the crystal structure of the 5-isobutyl derivative was determined by X-ray diffraction analy

Full text of DOI:10.1016/j.mencom.2010.03.014

Mendeleev
Communications
Mendeleev Commun., 2010, 20, 106–108
General regioselective synthesis and crystal structure of racemic
5-substituted 2,2-dimethyl-3-hydroxyimidazolidin-4-ones
Igor V. Vystorop,*a Yulia V. Nelyubina,b Vladimir N. Voznesensky,c Wen-Hua Sun,d
Vera P. Lodygina,a Konstantin A. Lyssenkob and Remir G. Kostyanovskyc
a Institute of Problems of Chemical Physics, Russian Academy of Sciences, 142432 Chernogolovka,
Moscow Region, Russian Federation. Fax: +7 496 514 3244; e-mail: vystorop@icp.ac.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 495 135 5085; e-mail: unelya@xrlab.ineos.ac.ru
c N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 495 938 2156; e-mail: kost@center.chph.ras.ru
d Key Laboratory of Engineering Plastics, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190,
P. R. China. Fax: +86 10 6261 8239; e-mail: whsun@iccas.ac.cn
DOI: 10.1016/j.mencom.2010.03.014
The cyclocondensation of racemic valine, leucine and β-phenylalanine hydroxamic acids with acetone regioselectively affords
corresponding cyclic hydroxamic acids; the crystal structure of the 5-isobutyl derivative was determined by X-ray diffraction
analysis and compared with that of its 5-methyl homologue.
Hydroxamic acids [HAs, RC(O)N(R')OH] possess important
pharmacological properties,1 function as NO donors2 and good
bioligands for vital metals3 (siderophores, metalloenzyme inhi-
bitors, etc.).
As for the mode of cyclocondensation regioselectivity (N,N'
or N,O) for reactions of sterically hindered α-amino HAs with
aliphatic ketones, here we studied the reactions of DL-ValHA (8),
DL-LeuHA (9) and DL-PheHA (10) with acetone, as its sym-
metry avoids the formation of diastereomeric products. In addi-
tion, we compared acids 2a (R1 = R2 = Me)5 and 47 earlier
characterized by an X-ray method.
It is known that reactions of the simplest α-amino hydroxamic
acid (glycine hydroxamic acid, GlyHA) with aliphatic or aromatic
aldehydes (EtOH, Δ, 2–4 h)4 and ketones (MeOH, Δ, 1 h)5,6
form 3-hydroxyimidazolidin-4-one derivatives 1 (yield, 70–90%)4
and 2 (27–57%),5,6 respectively. Cyclic hydroxamic acids (CHAs)
could also be formed in the reactions of β- and α-methyl sub-
stituted derivatives of GlyHA, namely, sarcosine hydroxamic
acid (SarHA) with aldehydes (EtOH, 2–4 h, 3, 70–90%)4 and
DL-α-alanine hydroxamic acid (DL-AlaHA) with acetone (Δ,
3 h, 4, 83%),7 respectively. Extensively, the analogous regio-
selective N,N'-cyclocondensation also occurred in the reactions
of β-AlaHA with aldehydes and ketones (MeOH, Δ, 3–6 h, 5,
26–74%).8
On the other hand, products obtained by the reactions of bulky
substituted α-amino HAs [e.g., DL-leucine HA (DL-LeuHA) and
DL-β-phenylalanine HA (DL-PheHA)] with aldehydes (benzene +
EtOH, Δ, 1 h) are assigned to six-membered cyclic hydroxa-
mate structures 6 and 7 (10–45%)9 that implies regioselective
N,O-cyclocondensation.
The reactions of bulky α-amino HAs 8–10 with acetone gave
the corresponding 5-substituted derivatives of 2,2-dimethyl-
3-hydroxyimidazolidin-4-one 11–13 (Scheme 1),† i.e., as in
the reactions of ordinary α-amino HAs with aldehydes and
ketones,4–7 the regioselective N,N'-cyclocondensation occurs.
The reactions (Scheme 1) are self-catalytic and proceed under
mild conditions (with an excess of ketone) leading to moderate
product yields (55–67%).† Furthermore, the addition of a small
amount of MeOH (1–2 ml), to increase the solubility of reactive
zwitterionic form of reactants 8–10, shortened the reaction time
to 0.5–1 h. However, the addition of MeOH caused lower yields
of 11–13 in the range of 15–25% owing to the formation of an
oligomeric by-product. The most plausible mechanism for this
reaction was discussed earlier.6
All compounds were characterized by IR and NMR spectra†
(cf. data for 1–44–7) and elemental analysis. The broad bands
observed at 2850–2550 cm–1 in the IR spectra (KBr), likewise the
OH
OH
OH
O
O
O
j0
1
downfield resonance signals of H NMR spectra (dC ~9.5 ppm,
N
2
N
N
[2H6]DMSO) and the test reactions with ferric chloride con-
firm the presence of the exocyclic OH group in 11–13. It
follows that for reactions considered the formation of type 6
4
5
t4
t1
3
1
R1
R2
H
Me
t0
N
H
Me
t
N
H
N
t2
R
3 Me
Me
†
Reactants 8–10 were synthesized according to known procedures.13
( )-1 R1 = H,
( )-3 R = H, Alk, Ar
( )-4
R2 = Alk, Ar
General procedure for the synthesis of 11–13. Suspension of 5 mmol
of 8 (or 9, 10) and 30 cm3 (0.4 mol) of dry acetone was weakly refluxed
until the reagent was dissolved (1–2 h) followed by filtration and solvent
evaporation in a vacuum. The residue was extracted by hot benzene [or
cold CH2Cl2 (12), hot dioxane (13)] and filtered. The filtrate was dried in
a vacuum and recrystallized from an appropriate solvent to give a white
solid of 11 (or 12, 13). Products are soluble in cold MeOH, DMSO or
hot acetone, MeCN, benzene and CHCl3.
( )-2 R1, R2 = Alk, Ph
O
O
R1
HN
NH
O
N
NH
R2
HO
R1
H
R2
5 R1 = H, Alk, Ar
R2 = Alk, Ar
6 R1 = CH2CHMe2, R2 = Ar
7 R1 = CH2Ph, R2 = Alk, Ar
For characteristics of compounds 11–13, see Online Supplementary
Materials.
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© 2010 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2010, 20, 106–108
The crystal structures of CHAs 2a, 4 and 12 exhibit the
OH
O
O
same pattern of intermolecular hydrogen bonding, namely,
strong O–H···Nsp3 and weak Nsp3–H···O=C bonds are formed
(Figures 2 and 3). Moreover, in racemic crystals of 4 and 12,
the weak [N(1)–H(1N)···O(2)=C(4)] hydrogen bond connects
homochiral molecules into infinite chains, but the strong bond
[O(1)–H(1O)···N(1)] couples molecules of opposite handedness.
The packing arrangement of the independent molecules in
12, however, differs from that in 4. Checking them in detail, the
alternate non-equivalent molecules in a crystal of 12 are con-
nected into heterochiral layer together through, as mentioned above,
N
R
Me
Me
+
NHOH
O
R
N
NH2
H
8 R = Pri (DL-ValHA)
9 R = Bui (DL-LeuHA)
10 R = Bn (DL-PheHA)
( )-11 R = Pri
( )-12 R = Bui
( )-13 R = Bn
Scheme 1
and 7 hydroxamates by concurrent N,O-cyclocondensation did
not occur.
the weak homochiral N–H···O=C hydrogen bond –A(S)–B(S)
–
Moreover, the spectral evidences are not enough to confirm
the formation of the corresponding azomethine form but rather
the cyclic structure of products 11–13, namely: (i) the chemical
shifts of the C(2) atom (dC ~75 ppm) in the 13C NMR spectra
of 11–13 do not correspond to trigonal carbon of azomethine
form (dC ~125 ppm)8 but to the tetrahedral carbon of the cyclic
form,4–7 (ii) the presence of the NH group of cyclic structure
is confirmed by IR (νNH ~3250 cm–1) and 1H NMR spectra
(δNH, ~2.8 ppm, [2H6]DMSO).
and –A(R)–B(R)– and the strong heterochiral O–H···Nsp3 one
–A(S)–B(R)– and –A(R)–B(S)– (Figure 2). However, the inde-
pendent molecules in a crystal of 4 separately form alternate
heterochiral layers (sublattices) by the weak homochiral
(–A(S)–A(S)– and –A(R)–A(R)– or –B(S)–B(S)– and –B(R)–B(R)–)
and the strong heterochiral –A(S)–A(R)– (Figure 3) or –B(S)–B(R)
–
hydrogen bonds.
At the same time, the independent molecules in crystals of 4
and 12 are similarly arranged by both types of intermolecular
The 13C NMR spectra of acids 11–13 (dC=O 169–172 ppm,
CD3OD), similarly to 1–4,5–7 do not show the presence of
hydroxynitrone tautomer.10
O(2AC)
O(1AC)
B2(R)
A2(R)
O(2BA)
The structure of CHA 12 was confirmed by X-ray diffraction
analysis (Figure 1).‡
N(1AC)
N(1BA)
A2(S)
N(1BA)
The comparison of crystal structures of homologues 2a, 4
and 12 shows that acids ( )-4 [mp 163–164 °C (acetone); space
group P21/c, Z(Z') = 8(2)]7 and ( )-12 [mp 132–133 °C (acetone);
C2/c, Z(Z') = 16(2)]‡ form racemic crystals whose asymmetric
units contain two crystallographically independent molecules
(A and B), possessing similar geometric parameters (Figure 1),
but parent achiral acid 2a [mp 177–178 °C (acetone)] crystallizes
as a conglomerate [P212121, Z(Z') = 4(1)].5
O(1C)
N(1C)
O(1A)
O(2A)
N(1AB)
O(2C)
B0(R)
B2(S)
O(2AB)
O(1AB)
O(2)
N(1A)
O(1)
N(1)
O(1B)
A0(R)
N(1B)
N(1AA)
O(2B)
C(11)
A1(S)
C(10)
C(9)
B1(S)
O(1AA)
H(8B)
O(2AA)
H(9A)
C(8)
H(8A)
H(5A)
Figure 2 Fragment of the crystal structure of 12. Hydrogen atoms that do
not form H-bonds are omitted for clarify. The H-bonds are shown by
dashed lines. The geometric parameters of H-bonds are as follows:
O(1A)–H(1OA) 0.96 Å, H(1OA)···N(1C) 1.81 Å, O(1A)···N(1C) 2.764(2) Å,
O(1A)–H(1OA)···N(1C) 173°; O(1)–H(1O) 0.94 Å, H(1O)···N(1AA) 1.82 Å,
O(1)···N(1AA) 2.767(2) Å, O(1)–H(1O)···N(1AA) 178°; N(1A)–H(1NA)
0.97 Å, H(1NA)···O(2) 2.31 Å, N(1A)···O(2) 3.251(2) Å, N(1A)–H(1NA)···O(2)
166°; N(1)–H(1N) 0.99 Å, H(1N)···O(2BB) 2.30 Å, N(1)···O(2BB) 3.264(2) Å,
N(1)–H(1N)···O(2BB) 167°. The symmetry transformation used to generate the
atoms from the basic ones: –x, –y + 1, –z + 1 for N(1C); –x + 0.5, –y + 0.5,
–z + 1 for N(1AA); x, y + 1, z for O(2); x + 0.5, y – 0.5, z for O(2BB).
C(5)
O(2)
N(1)
C(2)
C(4)
N(3)
C(7)
H(1O)
C(6)
O(1)
Figure 1 General view of 12 with some hydrogen atoms omitted for
clarity [is illustrated by (1R,5R)-enantiomer].
‡
Crystallographic data. Crystals of 12 (C9H18N2O2, M = 186.25) are
monoclinic, space group C2/c at 153 K: a = 14.8213(4), b = 14.8271(4)
and c = 19.4308(5) Å, b = 96.957(1)°, V = 4238.6(2) Å3, Z = 16 (Z' = 2),
dcalc = 1.167 g cm–3, m(MoKα) = 0.83 cm–1, F(000) = 1632. Intensities
of 19658 reflections were measured with a Bruker P4 diffractometer
[l(MoKα) = 0.71072 Å, w-scans, 2q < 56°] and 5087 independent reflec-
tions (Rint = 0.0247) were used in the further refinement. The structure
was solved by a direct method and refined by the full-matrix least-
squares technique against F2 in the anisotropic-isotropic approximation.
The hydrogen atoms of OH and NH groups were found in difference
Fourier synthesis. The H(C) atom positions were calculated. All hydrogen
atoms were refined in an isotropic approximation in a riding model. For
12 the refinement converged to wR2 = 0.1516 and GOF = 1.001 for all
independent reflections [R1 = 0.0474 was calculated against F for 3204
observed reflections with I > 2s(I)]. All calculations were performed using
SHELXTL PLUS 5.0 program.
A1(S)
N(1A)
A0(R)
O(1)
O(2B)
O(2)
O(1B)
N(1AA)
A3(R)
A2(S)
Figure 3 Fragment of the crystal packing of 4 showing the H-bonds
within the A sublattice. The geometric parameters of the H-bonds are as
follows: O(1)–H(1O) 0.94 Å, H(1O)···N(1A) 1.77 Å, O(1)···N(1A) 2.712(3) Å,
O(1)–H(1O)···N(1A) 173°; N(1A)–H(1NA) 0.93 Å, H(1NA)···O(2B) 2.26 Å,
N(1A)···O(2B) 3.145(3) Å, N(1A)–H(1NA)···O(2B) 159°. The symmetry
transformation used to generate the atoms from the basic ones: x, –y + 0.5,
z + 0.5 for N(1A); –x + 1, –y + 1, –z + 1 for O(2).
CCDC 766522 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2010.
– 107 –

Mendeleev Commun., 2010, 20, 106–108
1
hydrogen bonds into cyclic heterochiral tetramers of two species,
namely, as 14-membered [–H(1N)···O=C–N–O–H···N(1)–]2 and
20-membered [–H(1N)···O=C–C(5)–N(1)···H(1O)–N(3)–C(2)–
N(1)–H(1N)–]2 rings (Figure 2). However, both kinds of tetra-
mers in a crystal of 12 are formed as –A(R)–B(R)–A(S)–B(S)–
(Figure 2), but those of acid 4 as –A(R)–A(S)–A(S)–A(R)– (Figure 3)
or –B(R)–B(S)–B(S)–B(R)– associates. Moreover, the correspond-
ing tetramers of 4 and 12 adopt the similar forms.
The increase of the molecule size is accompanied by the
weakening of both hydrogen bonds [O(1)···N(1) 2.68 Å and
N(1)···O(2) 3.04 Å (2a)5, (4) (Figure 3), (12) (Figure 2)].
Accordingly, the stretching frequencies of the characteristic O–
H and N–H bonds in the IR spectra of these homologues tend to
increase {2a [3214 cm–1 (νNH); 2719, 2631, 2533 cm–1 (νOH)]5, 4
[3240 cm–1 (νNH); 2735, 2583 cm–1 (νOH)],7 and 12 [3251 cm–1
(νNH); 2821, 2730 cm–1 (νOH)]}.
According to the H NMR spectra, the dominant conforma-
tion of the molecule of 12 in solution is consistent with that in a
crystal (Figure 1). In particular, the vicinal coupling constant of
H(1N) and H(4) protons (3J = 8.0 Hz, [2H6]DMSO) corresponds
to their trans orientation in crystal [jH(1N)–N(1)–C(5)–H(5A) = 149.4°
(A0), 148.7° (B0)]. Moreover, a sequence of the mutual orien-
tations for each of the methylene protons H(8A) and H(8B)
with protons H(5A) and H(9A) [namely, trans–cis orien-
tation for H(8A): jH(5A)–C(5)–C(8)–H(8A) = 176° (A0), 176.4° (B0);
j
H(8A)–C(8)–C(9)–H(9A) = –65.6° (A0), –65.3° (B0) and cis–trans
orientation for H(8B): jH(5A)–C(5)–C(8)–H(8B) = –68.5° (A0), –68.2°
(B0); jH(8B)–C(8)–C(9)–H(9A) = –178.9° (A0), 179.4° (B0)] (Figure 1)
agrees with a sequence of small and large vicinal couplings
constants in the 1H NMR spectrum of 12 in CDCl3 (or in
[2H6]acetone): JH(8A),H(5) 10.0 (or 10.1) Hz, JH(8A),H(9) 5.2
(5.2) Hz, 3JH(8B),H(5) 3.9 (4.0) Hz, 3JH(8B),H(9) 9.1 (9.0) Hz.
In summary, according to the results of X-ray analysis, IR
and NMR spectroscopy, acids 11–13, similarly to 1–4,5–7 exist in
crystal and in solution as a strongly predominant hydroxyamide
tautomer. Taking into account published data,5–7 we concluded
that the regioselective N,N'-cyclocondensation is the general
tendency for reactions of neutral aliphatic and aromatic α-amino
HAs with aliphatic ketones.
3
3
The H(1N) hydrogen atom is pseudo-axial [jH(1N)–N(1)–C(2)–N(3)
=
= 82.3° (2a);5 80.1° (A0) and –81.3° (B0) (4);7 88.7° (A0)
and 85.1° (B0) (12) (Figure 1)]. It follows that (i) the (1R) or
(1S) absolute configuration of asymmetric amine N(1) atom in
homologues 2a, 4 and 12 is related to the corresponding enantio-
meric N- (t2 > 0) or S-type (t2 < 0)5,11 form of imidazolidine
ring, (ii) the basic independent homochiral molecules (A0 and
B0) in crystal of 12 can be presented as (1R,5R) (Figures 1, 2)
or (1S,5S) as compared to those of opposite handedness for 4
[(1R,5R) (Figure 3) and (1S,5S)].
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2010.03.014.
According to calculated puckering parameters (pseudorota-
tion angle P and amplitude of puckering tm),5,11 the form of
N-type heterocycle of (1R,5R)-enantiomer 12 [PN = 48.5°,
tm = 30.9°, t1 = –2.8° (A0); PN = 49.4°, tm = 31.3°, t1 = –2.3°
(B0)] is close to an ideal envelope C(2)E (PN = 54°, t1 = 0, |t0| = t2,
|t3| = t4 = tm) (quod vide5). On the other hand, the ring of
References
1
2
3
(a) C. J. Marmion, D. Griffith and K. B. Nolan, Eur. J. Inorg. Chem.,
2004, 3003; (b) M. J. Miller, Chem. Rev., 1989, 89, 1563.
C. J. Marmion, T. Murphy, J. R. Docherty and K. B. Nolan, Chem.
Commun., 2000, 1153.
(a) R. Codd, Coord. Chem. Rev., 2008, 252, 1387; (b) B. Kurzak,
H. Kozlowski and E. Farkas, Coord. Chem. Rev., 1992, 114, 169;
(c) B. Chatterjee, Coord. Chem. Rev., 1978, 26, 281.
(a) R. E. Harmon, V. L. Rizzo and S. K. Gupta, J. Heterocycl. Chem.,
1970, 7, 439; (b) I. V. Vystorop, K. A. Lyssenko and R. G. Kostyanovsky,
Mendeleev Commun., 2003, 116.
I. V. Vystorop, K. A. Lyssenko and R. G. Kostyanovsky, Mendeleev
Commun., 2002, 85.
I. V. Vystorop, K. A. Lyssenko, V. N. Voznesensky, V. P. Lodygina and
R. G. Kostyanovsky, Mendeleev Commun., 2002, 193.
I. V. Vystorop, Z. G. Aliev, N. Yu. Andreeva, L. O. Atovmyan and
B. S. Fedorov, Izv. Akad. Nauk, Ser. Khim., 2000, 180 (Russ. Chem.
Bull., Int. Ed., 2000, 49, 182).
(1R,5R)-4 [PN = 39.5°, tm = 35.5° (A0); PN = 42.3°, tm = 34.7°
N(1)
(B0)] is almost half-chair
T (PN = 36°, t0 = t1 < 0, t2 = t4 > 0,
C(2)
t3 < 0) and more puckered than that of 12. Note that the ring of
parent molecule 2a for (1R)-enantiomer (PN = 44.4°, tm = 31.4°)
4
N(1)
is intermediate between ideal C(2)E and
T forms5 and more
C(2)
flattened as compared to that of 4, but similar to 12.
5
6
7
This analysis allowed us to conclude that methyl and isobutyl
groups at the C(5) atom have an opposite effect upon change of
ring skeleton as compared to that of 2a. Nevertheless, the rings
in 2a, 4 and 12 adopt a quite narrow range of forms.
The form (P) and puckering (tm) of 4 and 12 rings are related
to their values of a mean ring torsion angle [tmid
=
t /5 = 22.9°
Σ
i
8
9
O. A. Luk’yanov and P. B. Gordeev, Izv. Akad. Nauk, Ser. Khim., 1998,
691 (Russ. Chem. Bull., 1998, 47, 669).
J. Charbonnel and J. Barrans, Compt. Rend., 1966, 263C, 824.
(A), 22.3° (B) (4); 19.5° (A), 19.6° (B) (12)] and a mean ring
bond angle [tmid
(A), 106.1° (B) (12)].
=
w
i
endo/5 = 105.6° (A), 105.8° (B) (4); 106.2°
Σ
10 G. I. Shchukin, I. A. Grigor’ev and L. B. Volodarskii, Khim. Geterotsikl.
Soedin., 1990, 478 [Chem. Heterocycl. Compd. (Engl. Transl.), 1990,
26, 409].
Conformational changes of ring (from half-chair in 4 to enve-
lope in 12) also agree well with the higher tendency to non-pla-
exo
narity of the exocyclic hydroxamic moiety [j
=
11 (a) C. Mathe and C. Perigand, Eur. J. Org. Chem., 2008, 1489; (b) I. V.
O(1)–N(3)–C(4)–O(2)
Vystorop, A. Rauk, C. Jaime, I. Dinares and R. G. Kostyanovsky, Khim.
Geterotsikl. Soedin., 1995, 1479 [Chem. Heterocycl. Compd. (Engl.
Transl.), 1995, 31, 1280].
18.6° (A0), –20.5° (B0) (4); 20.4° (A0), 21° (B0) (12)] and its
conjugated amide bond torsion angle [t0 C(2)–N(3)–C(4)–C(5) = –13.7°
(A0), 15.2° (B0) (4); –16.5° (A0), –17.1° (B0) (12) (Figure 1)].
Accordingly, the more pronounced pyramidalization of the amide
12 T. Ohwada, H. Hirao and A. Ogawa, J. Org. Chem., 2004, 69, 7486.
13 (a) K. G. Cunningham, G. T. Newbold, F. S. Spring and J. Stark, J. Chem.
Soc., 1949, 2091; (b) Th. Wieland and H. Fritz, Ber., 1953, 86, 1186.
N(3) atom in 12 [ wN(3) = 348.7° (A), 347.8° (B)] as compared
Σ
to that for 4 [ wN(3) = 351.2° (A), 349.5° (B)] is observed, cor-
Σ
responding to decrease in the p-character of the lone electron
pair (LP)12 of the atom N(3). On the other hand, the decrease in
pyramidality degree for the amine N(1) atom in 12 [ w
=
Σ
N(1)
= 323.6° (A), 322.3° (B)] (Figure 1) as compared to that for 4
[319.8° (A), 321° (B)] corresponds to increase in the p-char-
acter of pseudo-e-LPN(1) in 12. As result, the mutual trans
orientation of LPN(1) and LPN(3) in 12 [jLP
=
N(1)N(1)···N(3)LPN(3)
= 155.4° (A0), 154.5° (B0)] increases with respect to that of 4
[150.7° (A0), –151.7° (B0)].
Received: 12th October 2009; Com. 09/3400
– 108 –