Facile synthesis and cleavage of imidazolidines in a novel protection strategy for the preparation of peptides containing a reduced amide bioisostere

Article abstract of DOI:10.1016/S0040-4039(02)02562-5

Unsymmetrical imidazolidines were obtained in 75-91% yield by treating monoalkoxycarbonyl vicinal diamines at room temperature with aqueous 37% formaldehyde in the presence of Montmorillonite KSF as a solid catalyst. The imidazolidines were shown to be useful intermediates in a novel protection strategy for the synthesis of peptide analogues containing a reduced glycine amide bioisostere. The imidazolidine intermediate was cleaved conveniently and efficiently by 50% TFA in methylene chloride.

Full text of DOI:10.1016/S0040-4039(02)02562-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 229–232
Facile synthesis and cleavage of imidazolidines in a novel
protection strategy for the preparation of peptides containing a
reduced amide bioisostere
Jun Zhao, Vatee Pattaropong, Yongying Jiang and Longqin Hu*
Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey,
160 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA
Received 18 October 2002; accepted 13 November 2002
Abstract—Unsymmetrical imidazolidines were obtained in 75–91% yield by treating monoalkoxycarbonyl vicinal diamines at
room temperature with aqueous 37% formaldehyde in the presence of Montmorillonite KSF as a solid catalyst. The imidazolidines
were shown to be useful intermediates in a novel protection strategy for the synthesis of peptide analogues containing a reduced
glycine amide bioisostere. The imidazolidine intermediate was cleaved conveniently and efficiently by 50% TFA in methylene
chloride. © 2002 Elsevier Science Ltd. All rights reserved.
Imidazolidine, a fully saturated imidazole heterocycle,
is an important intermediate and building block in the
construction of a variety of biologically active com-
pounds.1–3 Its vicinal diamine functionality is of great
interest in organic chemistry as a chiral auxiliary or a
metal ligand in catalytic asymmetric synthesis and in
medicinal chemistry as a component of various drugs.2
The hydrophobic nature of imidazolidines can be used
to increase the bioavailability of biologically active
precursors in the form of a prodrug.3
unsymmetrical imidazolidines.9–12 Kliegel and Franck-
enstein prepared unsymmetrical imidazolidines by con-
densation of aldehydes with vicinal diamines obtained
via a low-yielding SN2 reaction.9 Lambert and co-work-
ers reported the synthesis via two sequential reactions
of diethyl oxalate with 1 equiv. of two different primary
amines followed by reduction with LiAlH4 and conden-
sation with formaldehye.10 The overall yield of this
synthesis, however, was only about 25%. Perillo et al.
prepared 1-benzyl-N-arylimidazolidines via a three-step
process: condensation of haloalkylamides with primary
aromatic amine followed by reduction with borane in
refluxing THF and condensation with an aldehyde.11
Katritzky recently prepared imidazolidines by a Man-
nich reaction of diamines with benzotriazole and form-
aldehyde, followed by the nucleophilic substitution with
a C-nucleophile.12 Herein, we report a simple, efficient
method for the formation of unsymmetrical imidazo-
lidines using Montmorillonite KSF clay as a solid
catalyst and the application of using imidazolidine as a
protection strategy in the synthesis of peptide analogues
containing a reduced amide bioisostere.
A number of methods have been described in the
literature for the preparation of symmetrical imidazo-
lidines including condensation of vicinal diamines with
formaldehyde using a Dean–Stark apparatus or acti-
vated molecular sieves to remove water,4 treatment of
diamines with paraformaldehyde or benzaldehyde in
chloroform in the presence of anhydrous MgSO4 and
K2CO3,5 reduction of symmetrical cyclic urea with
LiAlH4,6 condensation of diamines with benzotriazole
and formaldehyde via a Mannich reaction followed by
substitution with a Grignard reagent,7 and condensa-
tion of acid-sensitive aldehydes containing furan and
pyrrole with diamino compounds in refluxing benzene.8
Despite the availability of these methods for the synthe-
sis of symmetrical imidazolidines, relatively few papers
have been published describing the preparation of
During our synthesis of peptides containing a reduced
glycine amide bioisostere using reductive alkylation of
monoalkoxycarbonyl diamine (1“2, Scheme 1), we
identified the formation of the unsymmetrical imidazo-
lidine 3 as a by-product in 5% yield. After evaluating
several literature procedures on the formation of imida-
zolidines,4,5,8 we tried to form imidazolidine 3 by con-
densation of 1 with aqueous 37% formaldehyde in the
* Corresponding author. Tel.: +1-732-445-5291; fax: +1-732-445-6312;
e-mail: LongHu@rci.rutgers.edu
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02562-5

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J. Zhao et al. / Tetrahedron Letters 44 (2003) 229–232
Table 1. Formation of unsymmetrical imidazolidines from
the presence of Montmorillonite KSF (400 mg per
mmole of the diamine).14,15 Table 1 lists the unsymmet-
rical imidazolidines synthesized from monoalkoxycar-
bonyl vicinal diamines, reaction times, and yields. The
reaction was complete between 1.5 and 4 h under our
mild conditions with yields between 75 and 91%.
monoalkoxycarbonyl vicinal diaminesa
Scheme 1. Reagents and conditions: (a) CH2O, NaBH(OAc)3;
(b) CH2O, Montmorillonite KSF.
Since imidazolidine ring is known to be unstable under
acidic conditions and easily reverts back to its corre-
sponding vicinal diamine, we envisioned that it might
be useful as an important intermediate in the temporary
protection of the secondary amine in vicinal diamines in
peptide synthesis. Here, Fmoc chemistry would be used
instead of Boc to achieve an orthogonal protection
scheme between the N-terminal amine protection and
imidazolidine.
Scheme 2 illustrates the use of imidazolidines as a
protection strategy during the synthesis of peptide ana-
logues containing a reduced glycine amide bioisostere.
Fmoc-glycine (4) was converted to its corresponding
aldehyde 6 through the Weinreb amide 5.16 Aldehyde 6
was then used to reductively alkylate isoleucine benzyl
ester in the presence of the reducing agent sodium
triacetoxyborohydride to give the vicinal diamine
Fmoc-Gly-c[CH2NH]-Ile-OBzl (7). Compound 7 was
absence of the reducing agent. Unfortunately, the yields
were always low (ꢀ50%). The importance of imidazo-
lidines in organic and medicinal chemistry in addition
to its potential application as a protection strategy
prompted us to develop a new set of conditions for the
efficient synthesis of unsymmetrical imidazolidines.
Recently, inorganic solids have gained popularity as
solid catalysts in a variety of organic transformations.
For example, solid clay has been shown to function as
a catalytically active agent, as a bifunctional or ‘inert’
support, and as a filler to give solid catalysts the
required physical properties.13 We decided to test the
feasibility of using Montmorillonite KSF as a solid
catalyst in the formation of unsymmetrical imidazolidi-
nes. It was found that monoalkoxycarbonyl vicinal
diamine 1 was converted easily to its corresponding
imidazolidine 3 in high yield (90%) at room tempera-
ture upon treatment with aqueous 37% formaldehyde in
Scheme 2. Reagents and conditions: (a) HOBt, EDC,
MeONHMe, 94%; (b) LiAlH4, anhydrous THF/DMF (5:1),
85%; (c) H–Ile–OBzl, Montmorillonite KSF, anhydrous THF;
then NaBH(OAc)3, 79%; (d) formaldehyde (37% aqueous
solution), Montmorillonite KSF, anhydrous THF, 75%; (e)
20% piperdine/CH2Cl2, 20 min; (f) Fmoc-Gly-OH, HATU,
DIEA, CH2Cl2/NMP (10:1), yield 63% (two steps from 8); (g)
50% TFA/CH2Cl2, 2 h, 100%.

J. Zhao et al. / Tetrahedron Letters 44 (2003) 229–232
231
Table 2. Peptide analogues containing a reduced amide
Also, excess piperidine must be removed completely,
otherwise it would affect the next coupling reaction.
Other reagents such as TBAF can also be used for the
selective deprotection of Fmoc in place of piperidine.19
As shown in Table 2, a number of peptide analogues
containing a reduced glycine amide bioisostere were
synthesized using the strategy outlined in Scheme 2 in
good overall isolated yields ranging from 56 to 68% for
the three steps of Fmoc deprotection, amino acid cou-
pling, and imidazolidine ring cleavage. Pmc was used as
a protecting group of side chain guanidinium group in
the synthesis of arginine-containing peptide analogues
(entries 2, 6, and 8). The acid treatment used to open
the imidazolidine ring also cleaved the Pmc protecting
group.
bioisostere synthesized in 3 steps from imidazolinesa
In conclusion, a simple, efficient method was developed
for the formation of unsymmetrical imidazolidines by
employing Montmorillonite KSF clay as a solid cata-
lyst. We have demonstrated that imidazolidines could
be used as an important intermediate in the synthesis of
peptide analogues containing a reduced glycine amide
bioisostere. Cleavage of the imidazolidine ring was
effected conveniently and efficiently using 50% TFA in
methylene chloride. The same strategy might also be
applied to the synthesis of peptide analogues containing
other reduced amides.20
Acknowledgements
We gratefully acknowledge the financial support of
grant GM 62752 from the National Institutes of
Health.
References
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mun. 1982, 282–283; (c) Stoit, A. R.; Pandit, U. K.
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treated with aqueous 37% formaldehyde in the presence
of Montmorillonite KSF as a catalyst to yield the
imidazolidine 8 in 75% yield.17 Selective removal of the
Fmoc protecting group with 20% piperidine in methyl-
ene chloride afforded imidazolidine 9 with a free sec-
ondary amine. After removing all solvents and excess
piperidine by a Speed Vac, compound 9 was coupled to
Fmoc-Gly-OH with HATU as the activating agent to
yield compound 10. After purification by flash column
chromatography, the imidazolidine ring was cleaved by
treatment with 50% TFA in methylene chloride to
produce the desired peptide analog Fmoc-Gly-Gly-
c[CH2NH]-Ile-OBzl (11) in quantitative yield.18
3. (a) Crank, G.; Harding, D. R. K.; Szinal, S. S. J. Med.
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imidazolidine 9 was not very stable and was subjected
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232
J. Zhao et al. / Tetrahedron Letters 44 (2003) 229–232
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17. (a) Gangjee, A.; Zhu, Y.; Queener, S. F.; Francom, P.;
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1
18. Spectroscopic data for compound 10: H NMR (CDCl3,
11. (a) Salerno, A.; Hedrera, M. E.; D’Accorso, N. B.; Alho,
M. M.; Perillo, I. A. J. Heterocyl. Chem. 2000, 37, 57–62;
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200 MHz) l ppm 0.90–1.00 (m, 6H), 1.24 (m, 2H), 1.84
(m, 1H), 3.06 (m, 1H), 3.20 (m, 1H), 3.57 (m, 3H), 3.90
(dd, 2H, J=4.4, 12.8 Hz), 4.12 (t, 1H), J=10.5 Hz), 4.36
(m, 2H), 4.44 (m, 2H), 5.18 (s, 2H),5.78 (br s, 1H), 7.38
(m, 9H), 7.64 (d, 2H, J=10.8 Hz), 7.79 (d, 2H, J=10.8
Hz). 13C NMR (CDCl3, 50 MHz) l ppm 11.0, 15.5, 25.9,
29.8, 35.3, 43.5, 47.3, 48.9, 64.4, 66.5, 67.3, 67.9, 120.0,
125.2, 127.2, 127.8, 128.6, 128.7, 128.8, 129.0, 129.8,
135.5, 141.4, 144.0, 156.3, 165.7, 171.3. LC-MS (ESI+)
m/z (relative intensity): 556.2 (M+H+, 100%), 578.2 (M+
Na+, 12%).
12. Katrizky, A. R.; Suzuki, K.; He, H.-Y. J. Org. Chem.
2002, 67, 3109–3114.
13. (a) Rajender, S. V. Tetrahedron 2002, 58, 1235–1255; (b)
Yadav, J. S.; Reddy, B. V. S.; Balanarsaiah, E.;
Raghavendra, S. Tetrahedron Lett. 2002, 43, 5105–5107.
14. Typical procedure for the formation of imidazolidines:
To a solution of substrate monoalkoxycarbonyl diamine
(1 mmol) in anhydrous THF (5 mL) was added at room
temperature Montmorillonite KSF (400 mg) followed by
aqueous 37% formaldehyde (3 mmol). The reaction mix-
ture was stirred at room temperature for 1 h or until the
starting material disappeared as monitored by TLC.
After filtration, the solvent was removed in vacuo and
residue was subjected to flash column chromatography to
afford the desired imidazolidine.
1
For compound 11: H NMR (CDCl3, 200 MHz) l ppm
0.90–1.00 (m, 6H), 1.28 (m, 2H), 2.07 (m, 1H, NH), 2.46
(m, 2H), 2.90 (m, 2H), 3.45 (m, 2H), 3.68 (m, 2H), 4.22
(t, 1H, J=10.5 Hz), 4.36 (m, 2H), 4.44 (m, 2H), 5.18 (s,
2H), 5.22 (br s, 2H, CONH), 7.28–7.37 (m, 9H), 7.64 (d,
2H, J=10.8 Hz), 7.79 (d, 2H, J=10.8 Hz). 13C NMR
(CDCl3, 50 MHz) l ppm 11.6, 14.1, 26.6, 29.8, 36.4, 36.7,
47.0, 49.9, 65.0, 67.8, 68.6, 120.1, 125.2, 127.2, 127.9,
128.9, 129.2, 141.4, 143.4, 156.3, 165.4, 176.2. LC–MS
(ESI+) m/z (relative intensity): 544.2 (M+H+, 100%),
566.2 (M+Na+, 20%).
15. Spectroscopic data for compound 1: 1H NMR (CDCl3,
200 MHz) l ppm 1.46 (s, 9H), 2.54 (br s, 1H), 2.62 (m,
2H), 3.20 (m, 2H), 3.48 (t, J=4.8 Hz, 1H), 3.68 (d, J=4.8
Hz, 2H), 3.73 (s, 3H), 4.54 (s, 2H), 5.01 (br s, 1H), 7.29
(m, 5H). 13C NMR (CDCl3, 50 MHz) l ppm 28.4, 40.3,
47.4, 60.9, 70.6, 73.2, 79.0, 127.6, 127.8, 128.4, 137.8,
141.4, 156.2, 173.2. LC–MS (ESI+) m/z (relative inten-
sity): 353.6 (M+H+ 100%), 705.7 (2M+H+, 24%);
For compound 3: 1H NMR (CDCl3, 200 MHz) l ppm
1.46 (s, 9H), 3.00 (m, 2H), 3.43 (m, 2H), 3.54 (m, 1H),
3.75 (s, 3H), 4.12 (m, 1H), 4.21 (m, 1H), 4.56 (s, 2H), 7.33
(m, 5H). 13C NMR (CDCl3, 50 MHz) l ppm 28.5, 43.8,
49.4, 52.0, 63.7, 65.1, 69.2, 73.4, 79.6, 127.8, 127.9, 128.5,
137.6, 153.4, 170.8. LC-MS (ESI+) m/z (relative inten-
sity): 365.4 (M+H+, 100%), 387.4 (M+Na+, 28%).
19. Greene, T. W.; Wuts, P. G. M. Protective Groups in
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20. Amino acids other than glycine have shown to undergo
successfully reductive alkylation in both solution and
solid phase. (a) Sasaki, Y.; Coy, D. H. Peptides 1987, 8,
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