Synthesis of imidazolidin-2-one-4-carboxylate and of (tetrahydro)pyrimidin- 2-one-5-carboxylate via an efficient modification of the Hofmann rearrangement

Article abstract of DOI:10.1039/b801909f

A mild and efficient methodology for the rearrangement of protected asparagine and protected glutamine is reported; good results are obtained with a wide selection of protecting groups. The Royal Society of Chemistry.

Full text of DOI:10.1039/b801909f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of imidazolidin-2-one-4-carboxylate and of
(tetrahydro)pyrimidin-2-one-5-carboxylate via an efficient
modification of the Hofmann rearrangement†
Gaetano Angelici,a Simone Contaldi,a Sarah Lynn Greenb and Claudia Tomasini*a
Received 1st February 2008, Accepted 5th March 2008
First published as an Advance Article on the web 7th April 2008
DOI: 10.1039/b801909f
A mild and efficient methodology for the rearrangement of protected asparagine and protected
glutamine is reported; good results are obtained with a wide selection of protecting groups.
The Hofmann rearrangement is a well-known reaction that easily
allows the transformation of primary amides into amines,1 utiliz-
ing bromine in aqueous basic conditions. Several methods have
been described, employing different reagents that are generally
able to deliver a positive halogen.2 However, the classical method
for converting a primary carboxamide into an amine using an
alkaline solution of bromine can be unsatisfactory and unreliable.3
Several reagents have also been reported, such as Pb(OAc)4,4
benzyltrimethylammonium tribromide in aqueous NaOH,5 and
NBS with Hg(OAc)2 or AgOAc in DMF6 and more recently some
solid supported reagents.7 Analytical and synthetic usefulness have
also been demonstrated in peptide sequencing8 and retro-inverso
peptide synthesis.9
In our approach, imidazolidin-2-one-4-carboxylates and (tetra-
hydro)pyrimidin-2-one-5-carboxylates can be easily obtained in a
short time and under very mild conditions starting from protected
asparagine or glutamine respectively; this method proved to be
quite general because it can be applied to both amino acids in the
presence of several protecting groups (Scheme 1). PhI(OAc)2 was
the source of iodine(III), as it is cheap and can be easily stored.
In the recent years, iodine(III) reagents10 have been used to
perform the same conversions under acidic conditions. The io-
dine(III) reagents normally employed are PhI(OCOCF3)2,11 PhIO–
HCO2H12 and PhI(OTs)OH,13 which lead to high yields of the
corresponding ammonium salts. Moreover by reacting primary
amides with iodine(III) compounds in methanol under basic
conditions, the corresponding methyl carbamates are obtained,14
as methanol behaves both as a solvent and a reagent to trap the
intermediate isocyanate.
Scheme 1 General method for the rearrangement of compounds 1a–f.
While our continued interest lies in the synthesis and application
of proline analogues,15 we want to describe herein a method
for the rearrangement of protected asparagine and glutamine to
imidazolidin-2-one-4-carboxylate and to (tetrahydro)pyrimidin-
2-one-5-carboxylate respectively. This reaction has already been
reported using NaOCl–NaOH16 and, more recently, Br2–NaOH.17
The reaction times in both cases are quite long and only N-
carbobenzoxy-L-asparagine can be used as starting material, as
N-tert-butoxy-L-asparagine does not afford the desired product,
only by-products. Moreover the authors claim that the reaction is
particularly troublesome, as impurities or incomplete conversion
make crystallization of the desired product difficult;17b of partic-
ular importance is the addition of bromine, the amount added
proving to be crucial in order to achieve good reaction yields.
Furthermore bromine is toxic and its use should be avoided.
THF is the solvent of choice for this reaction. The reaction
was also tested in acetonitrile and dichloromethane, but in these
solvents the yield was reduced. The choice of the base was crucial
too; the use of DBU was needed for the formation of 5-membered
rings 2a–d, while better results were obtained with diisopropy-
lethylamine for the formation of the 6-membered rings 2e–f. If
DBU is employed for this reaction, the mixture suddenly becomes
brownish and a poor yield of the cyclic product is obtained.
In a typical reaction, to a mixture of base (for details see
Table 1) and reagent 1a–f in THF, PhI(OAc)2 was added in one
portion. The mixture was stirred for 15 minutes at 0 ◦C, then
a few drops (<0.5 mL) of water were added and the mixture
was allowed to stir for an additional 30 minutes. The mixture
was concentrated and THF was replaced with ethyl acetate. The
product was washed with water and the organic layer was dried
and concentrated. Some compounds were obtained pure after
crystallization from cyclohexane, while for others, purification by
flash chromatography was required.
aDipartimento di Chimica “G. Ciamician” - Alma Mater Studiorum,
Universita` di Bologna, Via Selmi 2, 40126 Bologna, Italy. E-mail: claudia.
tomasini@unibo.it; Fax: +39-0512099456; Tel: +39-0512099596
No by-products are present in the reaction mixture. However
if the mixture is allowed to stir for longer reaction times, the
yield drops and several by-products are obtained, probably due to
bSchool of Chemistry, Trinity College Dublin, Dublin 2, Ireland
† CCDC reference number 676653. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b801909f
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Table 1 Chemical yields for the rearrangement of compounds 1a–f
of water after 15 minutes enhances the chemical yield, probably
because this favours the formation of isocyanates 4.
The structure of 2a was confirmed by an X-ray diffraction study
(Fig. 2). As this sample was obtained by cyclization of Cbz-D-Asn-
OMe, (R)-2a was actually analyzed, after crystallization from ethyl
acetate.
Entry
Product
n
Base (equiv.)
Yield (%)
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
1
1
1
1
2
2
DBU (2)
DBU (2)
DBU (2)
DBU (2)
Et(i-Pr)2N (3)
Et(i-Pr)2N (3)
87
76
69
55
79
85
partial hydrolysis of the heterocycle. The reaction was successfully
made on amounts up to 0.500 g of 1a–f and can be easily performed
on a multigram scale.
The reaction affords the desired compounds in good to high
yield, independent of the nature of the protecting group on
the amino moiety. Indeed, L-asparagine was protected with
carbamates (entries 1 and 2) or with amides (entries 3 and 4) and in
each case the desired compound was obtained in a high yield. The
reaction was repeated with some samples of protected Cbz-D-Asn-
OMe and of Boc-D-Asn-OBn, and the same results were obtained.
Remarkably, the dipeptide Ac-L-Ala-L-Asn-OBn was successfully
cyclized, thus showing that this method may be employed also
for the formation of 2-oxaimidazolidinone-4-carboxylate starting
from asparagine moieties belonging to polypeptide chains.
Protected L-glutamine was cyclized under the same reaction
conditions: both protecting groups (Cbz, entry 5 and Boc, entry
6) proved to be compatible with this synthetic method, so that
(tetrahydro)pyrimidin-2-one-5-carboxylate has been obtained in
good yield.
Fig. 2 Molecular structure of (R)-2a.
The molecular structure of (R)-2a shows that the imidazolidin-
2-one ring is almost planar, as has been found in analogous
3
compounds,16c and the sp carbon (C(4)) is 0.09 A out of the
˚
plane defined by the five-membered ring. With respect to this
plane, the amido-ester group is slightly twisted [8.1(1)◦], while the
methyl ester group makes a dihedral angle of 73.1(2)◦ with the
oxoimidazolidine ring (Fig. 3).
The Boc and Cbz protecting groups can be easily removed
following the usual protocol (TFA in dichloromethane and H2
on Pd/C in methanol respectively).
The most likely reaction mechanism follows a path similar to
the classical Hofmann rearrangement.11c,13a,14a,18 The first step is the
formation of the intermediate 3 (Fig. 1), that easily evolves into the
corresponding isocyanate 4. Then 4 is trapped by the nitrogen of
the carbamate (or amide) unit, thus forming a thermodynamically
driven five or six-membered ring. The introduction of a few drops
Fig. 3 View of (R)-2a perpendicular to the oxoimidazolidine ring,
showing the almost coplanar endocyclic (C2O2) and exocyclic (C3O3)
carbonyls and the orientations of the side-arms.
The methyl ester chain and the benzyl chain lie on opposite sides
of the oxoimidazolidine ring; while the two planes defined by the
ester group and the phenyl ring are twisted of 12.0◦. The absolute
configuration of the stereogenic centre at C(4) is R.
Conclusions
By means of this modification of the Hofmann rearrangement,
protected asparagine and glutamine are easily transformed into
imidazolidin-2-one-4-carboxylate and (tetrahydro)-pyrimidin-2-
one-5-carboxylate, respectively, in good yield. The reagents are
cheap and easily available, the reaction is general, environmentally
friendly and the reaction times are very short. The structure of the
cyclization product has been confirmed by X-ray diffraction.
Fig. 1 Reaction pathway for the formation of 2-oxaimidazolidinone (n =
1) or of 2-(tetrahydro)pyrimidinone (n = 2).
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9H, t-Bu), 3.38 (dd, 1H, J = 3.6, 9.6 Hz, CHH-Asn), 3.73 (dd,
1H, J = 9.6, 10.2 Hz, CHH-Asn), 4.72 (dd, 1H, J = 3.6, 10.2 Hz,
CHa-Asn), 5.24 (AB, 2H, J = 12.0 Hz OCH2Ph), 6.91 (bs, 1H,
NH), 7.35–7.50 (m, 5H, Ph); 13C NMR (CDCl3,75 MHz): d 28.1,
40.6, 56.3, 67.8, 83.4, 128.8, 128.9, 135.2, 149.7, 156.5, 170.2. Anal.
Calcd. for C16H20N2O5: C, 59.99; H, 6.29; N, 8.74. Found: C, 60.04;
H, 6.31; N, 8.78%.
Experimental
General notes
Routine NMR spectra were recorded with spectrometers at 300 or
200 MHz (1H NMR) and at 75 or 50 MHz (13C NMR). Chemical
shifts are reported in d values relative to the solvent peak of CHCl3,
set at 7.27 ppm. Measurements were carried out in CDCl3 and
proton signals were assigned by COSY spectra.
Infrared spectra were recorded with an FT-IR spectrometer.
High quality infrared spectra (64 scans) were obtained at 2 cm−1
resolution using a 1 mm NaCl solution cell. All spectra were
obtained in 3 mM solutions in dry CH2Cl2 at 297 K. All
compounds were dried in vacuo and all the sample preparations
were performed in a nitrogen atmosphere.
Benzyl 3-acetyl-imidazolidin-2-one-4(S)-carboxylate (2c)
Mp = 187 ◦C; [a]D −12.0 (c 0.1, CH2Cl2); IR (CH2Cl2, 1 mM): m =
3406, 1755, 1710 cm−1; 1H NMR (CDCl3, 200 MHz): d 2.56 (s, 3H,
CH3), 3.41 (dd, 1H, J = 4.0, 9.6 Hz, CHH-Asn), 3.77 (dd, 1H, J =
9.6, 10.2 Hz, CHH-Asn), 4.91 (dd, 1H, J = 4.0, 10.2 Hz, CHa-
Asn), 5.15 (bs, 1H, NH), 5.24 (s, 2H, OCH2Ph), 7.28–7.38 (m, 5H,
Ph); 13C NMR (CDCl3, 50 MHz): d 27.0, 40.1, 55.0, 67.8, 128.4,
128.7, 128.8, 137.6, 151.1, 169.4. Anal. Calcd. for C13H14N2O4: C,
59.54; H, 5.38; N, 10.68. Found: C, 59.58; H, 5.42; N, 10.69%.
Melting points were determined in open capillaries and are
uncorrected.
Cbz-L-Asn-OH, Boc-L-Asn-OH, Ac-L-Asn-OH, Cbz-L-Gln-
OH, Boc-L-Gln-OH were purchased. The benzyl esters were
prepared by reaction of the acid with benzyl bromide and TEA
in acetone, the methyl esters were prepared by reaction of the
acid with SOCl2–MeOH at −15 ◦C. Ac-L-Asn-L-Ala-OBn was
prepared by coupling of Ac-L-Asn-OH and L-Ala-OBn in the
presence of HBTU and TEA in acetonitrile.
Benzyl 3-L-alanyl-imidazolidin-2-one-4(S)-carboxylate (2d)
◦
Mp = 192 C; [a]D −31.0 (c 0.1, CH2Cl2); IR (Nujol): m = 3423,
1763, 1739, 1700, 1682 cm−1; 1H NMR (CDCl3, 300 MHz): d 1.48
(d, 3H, J = 7.2 Hz, CH3-Ala), 2.58 (s, 3H, CH3-Ac), 3.61 (dd,
1H, J = 9.6, 11.2 Hz, CHH-Asn), 3.84 (dd, 1H, J = 3.6, 11.2 Hz,
CHH-Asn), 4.60 (q, 1H, J = 7.2 Hz, CHa-Ala), 4.86 (dd, 1H, J =
3.6, 9.6 Hz, CHa-Asn), 4.98 (bs, 1H, NH), 5.19 (m, 2H, OCH2Ph),
6.98 (dq, 1H, J = 7.2, 7.2 Hz, NH), 7.37 (m, 5H, Ph); 13C NMR
(CDCl3,75 MHz): d 27.2, 39.4, 48.2, 56.2, 67.6, 128.5, 128.6, 128.9,
135.5, 156.2, 168.4, 172.6, 176.6. Anal. Calcd. for C16H19N3O5: C,
57.65; H, 5.75; N, 12.61. Found: C, 57.70; H, 5.78; N, 12.68%.
General method for the synthesis of imidazolidin-2-ones-
4-carboxylates 2a–d
To a stirred solution of DBU (2 equiv., 0.9 mmol, 135 ll) in
THF (20 mL) was added solid 1a–d (1 equiv., 0.35 mmol). Upon
dissolution, the flask contents were cooled to 0 ◦C in ice, then
PhI(OAc)2 (2 equiv., 0.7 mmol) was added in one portion to the
cooled solution and the reaction was left to proceed, stirring at
General method for the synthesis of (tetrahydro)pyrimidin-2-one-
5-carboxylate 2e–f
◦
0 C for 15 min, after which time a few drops (<1 mL) of H2O
were added and the mixture was stirred for additional 30 min.
The reaction mixture was gently concentrated; the resulting
yellow oily liquid was dissolved in ethyl acetate and washed with
H2O, dried over Na2SO4, filtered, concentrated and dried under
vacuum to obtain the crude imidazolidinone. Recrystallization
from cyclohexane or silica gel chromatography afforded the pure
final product as a solid.
To a stirred solution of DIEA (3 equiv., 1.02 mmol, 175 ll) in
THF (20 mL) was added solid 1e–f (1 equiv., 0.35 mmol). Upon
dissolution, the flask contents were cooled to 0 ◦C in ice, then
PhI(OAc)2 (2 equiv., 0.68 mmol) was added in one portion to the
cooled solution and the reaction was left to proceed, stirring at
◦
0 C for 15 min, after which time a few drops (<1 mL) of H2O
were added and the mixture was stirred for additional 30 min. The
reaction mixture was gently concentrated, the resulting yellow
oily liquid was dissolved in ethyl acetate and washed with H2O,
dried over Na2SO4, filtered, concentrated and dried under vacuum
to obtain the crude pyrimidinone. Purification by flash column
chromatography (80 : 20 then 40 : 60 cyclohexane : ethyl acetate
as eluent) afforded the pure final product as a solid.
Methyl 3-benzyloxycarbonyl-imidazolidin-2-one-4(R)-carboxylate
(2a)
Mp = 192 ◦C; [a]D +42.0 (c 0.1, CH2Cl2); IR (CH2Cl2, 1 mM): m =
3450, 1805, 1759, 1698 cm−1; 1H NMR (CDCl3, 300 MHz): d 3.45
(dd, 1H, J = 3.6, 9.9 Hz, CHH-Asn), 3.72 (s, 3H, CH3), 3.76 (dd,
1H, J = 9.9, 10.2 Hz, CHH-Asn), 4.82 (dd, 1H, J = 3.6, 10.2 Hz,
CHa Asn), 5.30 (AB, 2H, J = 12.3 Hz OCH2Ph), 5.96 (bs, 1H,
NH), 7.35–7.44 (m, 5H, Ph); 13C NMR (CDCl3, 75 MHz): d 40.8,
53.3, 56.1, 68.5, 128.6, 128.7, 128.9, 135.4, 137.7, 151.4, 155.2,
170.5. Anal. Calcd. for C13H14N2O5: C, 56.11; H, 5.07; N, 10.07.
Found: C, 56.08; H, 5.04; N, 10.00%.
Methyl 3-benzyloxycarbonyl-(tetrahydro)pyrimidin-2-one-5(S)-
carboxylate (2e)
Mp = 183 ◦C; [a]D −18.0 (c 0.1, CH2Cl2); IR (CH2Cl2, 1 mM): m =
3421, 1745, 1706, 1671 cm−1; 1H NMR (DMSO-d6, 300 MHz): d
1.62–1.91 (m, 2H, CH2-Glu), 2.95–3.11 (m, 2H, CH2-Glu), 3.65 (s,
3H, OCH3), 4.04–4.13 (m, 1H, CHa-Glu), 5.04 (s, 2H, OCH2Ph),
5.97 (t, 1H, J = 6.0 Hz, NH), 7.30–7.40 (m, 5H, Ph); 13C NMR
(CDCl3, 75 MHz): d 33.8, 36.6, 51.7, 52.9, 67.5, 128.4, 128.6, 128.9,
136.3, 156.9, 158.2, 173.2. Anal. Calcd. for C14H16N2O5: C, 57.53;
H, 5.52; N, 9.58. Found: C, 57.56; H, 5.55; N, 9.60%.
Benzyl 3-tert-butyloxycarbonyl-imidazolidin-2-one-4-(R)-
carboxylate (2b)
◦
Mp = 181 C; [a]D +28.0 (c 0.1, CH2Cl2); IR (Nujol): m = 3291,
1
1801, 1767, 1741 cm−1; H NMR (CDCl3, 300 MHz): d 1.41 (s,
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Benzyl 3-tert-butyloxycarbonyl-(tetrahydro)pyrimidin-2-one-5(S)-
carboxylate (2f)
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Mp = 172 ◦C; [a]D −26.0 (c 0.1, CH2Cl2); IR (CH2Cl2, 3 mM): m =
1
3430, 1745, 1714, 1671 cm−1; H NMR (DMSO-d6, 300 MHz):
d 1.37 (s, 9H, t-Bu), 1.61–1.82 (m, 2H, CH2-Glu), 2.93–3.08 (m,
2H, CH2-Glu), 3.96–4.03 (m, 1H, CHa-Glu), 5.11 (AB, 2H, J =
12.6 Hz, OCH2Ph), 5.92 (t, 1H, J = 5.7 Hz, NH), 7.30–7.38 (m,
5H, Ph); 13C NMR (CDCl3, 75 MHz): d 28.6, 33.7, 36.5, 51.5, 67.4,
80.3, 128.5, 128.7, 128.9, 135.6, 156.2, 158.4, 172.9. Anal. Calcd.
for C17H2N2O5: C, 61.07; H, 6.63; N, 8.38. Found: C, 61.04; H,
6.60; N, 8.34%.
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X-Ray crystallography
Single crystals of methyl 3-benzyloxycarbonyl-2-oxaimidazoli-
dinone-4(R)-carboxylate (2a) grew as yellow-colourless prisms
from ethyl acetate by slow evaporation.
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The X-ray intensity data were measured on a Bruker Apex
II CCD area detector diffractometer. Cell dimensions and the
orientation matrix were initially determined from a least-squares
refinement on reflections measured in three sets of 20 exposures,
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all data. For th◦e crystal, a full sphere of reciprocal space was
scanned by 0.3 x steps. The software SMART19 was used for
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of lattice parameters. The collected frames were then processed for
integration by the SAINT program,19 and an empirical absorption
correction was applied using SADABS.20 The structure was solved
by direct methods (SIR 97)21 and subsequent Fourier syntheses
and refined by full-matrix least-squares on F2 (SHELXTL),22
using anisotropic thermal parameters for all non-hydrogen atoms.
Two independent molecules were found in the asymmetric unit.
All hydrogen atoms were added in calculated positions, included
in the final stage of refinement with isotropic thermal parameters,
U(H) = 1.2Ueq(C) [U(H) = 1.5Ueq(C-Me)], and allowed to ride
on their carrier carbons.
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Crystal data for 2a. [C13H14N2O5], M= 278.26, monoclinic,
˚
˚
˚
space group P21, a = 9.624(1) A, b = 7.956(1) A, c = 9.809(1)
3
˚
A, b = 118.093(1), U = 662.68 A , Z = 2, l = 0.08, theta range
for data collection 1.29–24.10◦, a total of 2950 reflections were
measured, and 2499 of them have I > 2r(I).
Acknowledgements
We thank Ministero dell LꢀUniversita` e della Ricerca Scientifica
(PRIN 2006 “Sintesi, attivita` biologica e applicazioni diagnostiche
di ligandi delle integrine a-v-b-3, a-4-b-1 e a-4-b-7”) and University
of Bologna (Funds for selected topics) for financial support.
19 SMART & SAINT Software Reference Manuals, version 5.051 (Win-
dows NT Version), Bruker Analytical X-ray Instruments Inc., Madison,
WI, 1998.
Notes and references
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20 G. M. Sheldrick, SADABS, Program for empirical absorption correction,
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2 (a) G. M. Loudon and M. E. Parham, Tetrahedron Lett., 1978, 437;
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Pallai and M. Goodman, J. Chem. Soc., Chem. Commun., 1982, 280;
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21 A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, A. G. G.
Moliterni, M. C. Burla, G. Polidori, M. Camalli and D. Siliqi, Acta
Crystallogr., Sect. A, 1996, 52, C79.
22 G. M. Sheldrick, SHELXTLplus (Windows NT Version) Structure De-
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1852 | Org. Biomol. Chem., 2008, 6, 1849–1852
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The Royal Society of Chemistry 2008
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