Regioselective oxidation of N-alkylpyrrolidines to pyrrolidin-5-ones by RuCl3/NaIO4

Article abstract of DOI:10.1016/j.tetlet.2003.12.072

RuCl₃/NaIO₄ under EtOAc/H₂O biphasic conditions, selectively oxidizes the Nα-endo-methylene group of pyrrolidine derivatives, without affecting the exo-methylene group adjacent to the N-heteroatom.

Full text of DOI:10.1016/j.tetlet.2003.12.072

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1403–1406
Regioselective oxidation of N-alkylpyrrolidines to pyrrolidin-5-ones
by RuCl3/NaIO4
q
Nagendra K. Sharma and Krishna N. Ganesh*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pashan Road, Pune 411008, India
Received 12 October 2003; revised 22 November 2003; accepted 11 December 2003
Abstract—RuCl3/NaIO4 under EtOAc/H2O biphasic conditions, selectively oxidizes the Na-endo-methylene group of pyrrolidine
derivatives, without affecting the exo-methylene group adjacent to the N-heteroatom.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Functionalized pyrrolidinone derivatives are key inter-
mediates for the synthesis of many biologically active
compounds.1 Pyroglutamic acids are known to intro-
duce unique structural constraints into peptide chains2
and derivatives functionalized at C4 have important
biological activities.3;4 Most reported methods to obtain
C4-functionalized pyroglutamates involve asymmetric
1,3-dipolar cycloadditions5 or N-alkylation using lith-
ium enolates derived from pyroglutamic esters.6 In a
recent report, C4-substituted N-Boc pyrrolidin-5-one
such as the exocyclic N-CH2 or CH2-NHBoc, which
yield the desired monomers for aepone-PNA synthesis.10
To test the efficiency of RuCl3/NaIO4, N-Boc-4-acetoxy
and 4-O-TBDMS proline methyl esters 1 were treated
with the reagent in two different biphasic solvent sys-
tems CCl4/CH3CN/H2O (1:1:1.5) and EtOAc/H2O (1:1)
(Scheme 1). The reaction gave the corresponding C5-one
products 2 in 70–75% yield. The structures of the com-
pounds were confirmed from the spectral data. Thus
RuCl3/NaIO4 is as efficient as RuO2/NaIO4 for oxida-
tion of the present substrates.
derivatives were synthesized from 4-(R)-hydroxy-L-
proline through oxidation of 4-substituted-N-Boc
proline7;8 using the versatile oxidizing agent RuO4 gen-
erated in situ from RuO2/NaIO4 in a biphasic solvent
system.9 Our intention was to prepare C4-functionalized
N-alkylated pyroglutamate derivatives 5 (Scheme 2) as
intermediates for the synthesis of modified peptide
nucleic acids (PNA). This can be achieved by N-alkyl-
ation of suitable pyroglutamates; however, the use of
strong bases in N-alkylation is accompanied by a facile
opening of the pyrrolidine ring. To overcome this, we
attempted a hitherto unknown direct oxidation of vari-
ous N-alkylated C4-substituted pyrrolidine derivatives 4
(Scheme 2) using the oxidizing agent RuCl3/NaIO4.
Herein we report the interesting results observed on
regioselective oxidation of the endocyclic Na-methylene
(C5), in preference to oxidation of other Na-methylenes
Various N-(Boc-aminoethyl)-4-(R/S)-substituted proline
methyl esters 4 (Scheme 2) prepared from 4-(R)-
hydroxyproline derivative 3 directly or via a Mitsunobu
reaction,11 at C4 were then subjected to oxidation using
RuCl3/NaIO4 in either CCl4/CH3CN/H2O (1:1:1.5) or
EtOAc/H2O (1:1) at room temperature and, as followed
by TLCanalysis, the starting materials disappeared with
the appearance of a major product during a 30 min to
1 h period. Isolation of the product after aqueous
X
X
4
5
1
RuCl3.xH2O
70-75%
O
N
COOCH3
N
COOCH3
O
O
O
O
Keywords: RuCl3/NaIO4; Oxidation; N-Alkyl pyrrolidinones.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2003.12.072
* Corresponding author. Tel./fax: +91-20-589-3153; e-mail: kng@ems.
ncl.res.in
2
1
a, X=OAc; b, X=OTBDMS
Scheme 1.
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.072

1404
HO
5
N. K. Sharma, K. N. Ganesh / Tetrahedron Letters 45 (2004) 1403–1406
Y
Y
4
X
O
X
(ii)
(i)
1
N
COOMe
COOMe
N
COOMe
N
NHBoc
5
NHBoc
4
NHBoc
3
Scheme 2. Reagents and conditions: (i) Ac2O, Py, rt, 5 h for 4b, 80%;
TBDMSCl, DMF, imidazole 6 h for 4c, 70%; Ph3P, DIAD, PhCOOH
for 4d, THF, 5 h, 80%; Ph3P, DIAD, methyl tosylate for 4e, THF, 8 h,
65%; Ph3P, DIAD, 4-nitrobenzoic acid for 4f, THF, 10 h, 70%; (ii)
NaIO4/RuCl3ÆxH2O, AcOEt/H2O, rt, 30 min to 1 h, yields 30–45%.
Details of a–f are given in the footnote of Table 1.
work-up and characterization indicated the structures to
be 5, with oxidation occurring at C5. The isolated yields
of the products were in the range 30–45% and the sol-
vent system EtOAc/H2O (1:1) gave the best yield (Table
1). There was no particular dependence of the yields on
the stereochemistry of the C4-substituents, with R and S
isomers behaving similarly. Among the different C4-
substituents OMs, OBz, OAc, TBDMS, OTs and
OPNB, the reaction gave the best yield with the 4-OMs
derivative. A comparable C5-one product was obtained
even with the proline substrate 4g lacking any C4-sub-
stituents.5 The reactions of N-alkyl substrates 4 were
also found to be faster than those of N-Boc analogues 1.
All products were characterized by appropriate spectral
data.
Figure 1. ORTEP diagram of the crystal structure15 of 5d.
Spectroscopic characterization. In the absence of any
crystallographic data, it is necessary to unambiguously
identify the site of oxidation and this was done using 1H
and 13CNMR data (Table 2). In view of the similar
chemical shifts of different Na-methylene protons, the
1
1H NMR was completely assigned using H–1H DQF
COSY. While assignment of H5 is straightforward due
to coupling with H4, assignment of bH0H00 were done via
the connectivity with NH followed by assignment of
aH0H00. The different carbons were assigned from the
1H–13CHETCOR experiment.
RuO4 generated in situ from RuCl3/NaIO4 is well
known to oxidize methylene groups a to N or O het-
eroatoms into carbonyl groups.12 In the case of tertiary
amines present as a part of polycyclic systems with
N-benzyl substitution, the first oxidation occurs at the
exocyclic benzylic methylene followed by the endocyclic
methylene.13 In the substrates used here (4a–4g), there
are three Na-methylene groups––endocyclic C5, exocy-
clic N-CH2 and NHBoc-CH2. Of the different possible
oxidation products including N-oxide formation, it was
found that the major products (5a–5g) obtained from a
regioselective oxidation of the endocyclic CH2 resulted
at C5 of the pyrrolidine ring to give the lactam deriva-
tives. The identity of the oxidation product was unam-
biguously confirmed by single crystal X-ray data for 5a10
and 5d (Fig. 1). The present approach is therefore con-
venient as it gave intermediates for transformation into
other C4-substituted pyrrolidin-5-ones, particularly the
aepone-PNA analogues.10
X
H'
X
H'
3
3
4
H
H
4
H
H
H
H
2
2
5
5
O
O
N
α
O
H'
H'
N
α
H
H'
H"
O
O
H'
H'
β
β
H"
H"
H"
O
N
O
N
H
H
O
O
5a, X= OSO2CH3
5b, X= OCOCH3
5g, X= H
4a, X= OSO2CH3
4b, X= OCOCH3
4g, X= H
Table 1. Reaction yields for RuCl3/NaIO4 oxidation of substrates 4a
Entry
Substrate
Product
EtOAc/H2O (% yield)
CH3CN/CCl4/H2O (1:1:1.5)
Time (min)
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
45
38
39
45
35
40
35
45
30
32
36
30
37
41
60
30
45
30
75
45
45
4g
5g
a For a–c, X ¼ H; d–f, Y ¼ H; a, Y ¼ OMs; b, Y ¼ OAc; c, Y ¼ OTBDMS; d, X ¼ OBz; e, X ¼ OTs; f, X ¼ OPNB; g, X ¼ H; Y ¼ H. For a typical
reaction procedure, see Ref. 14.

N. K. Sharma, K. N. Ganesh / Tetrahedron Letters 45 (2004) 1403–1406
1405
Table 2. Selected 1H and 13Cchemical shifts ( d ppm)a
Jawaharlal Nehru Centre for Advanced Scientific Re-
search, Bangalore. Special thanks are due to Dr. M. M.
Bhadbade and Mr. R. G. Gonnade for crystal data
and Dr. P. Rajamohan for NMR spectra.
Com-
pound
4a
5a
4b
5b
4g
5g
2.1
H40
5.2
5.3
5.3
5.4
1.8, 1.9
H5
2.8
3.4
––
––
2.6
3.5
––
––
2.4
3.1
––
––
H500
aH0
aH00
bH0
bH00
NH
C4
2.6
2.7
3.0
2.6
2.7
3.1
2.6
2.7
3.1
3.1
3.5
3.1
3.5
3.2
3.1
References and notes
3.1
3.1
3.1
3.2
3.1
3.1
3.7
4.8
3.7
4.9
3.4
4.9
1. (a) Najera, C.; Miguel, Y. Tetrahedron: Asymmetry 1999,
10, 2245–2303, and references cited therein; (b) Barco, A.;
Benetti, S.; Pollini, G. P.; Baraldi, P. G.; Guarneri, M.;
Gandolfi, C.; Ceserani, R.; Longiave, D. J. Med. Chem.
1981, 24, 625–628.
2. Bernardi, F.; Garavelli, M.; Scatizzi, M.; Tomasini, C.;
Trigari, V.; Crisma, M.; Formaggio, F.; Peggion, C.;
Toniolo, C. Chem. Eur. J. 2002, 8, 2516–2525.
5.1
5.2
5.2
79.0
58.4
53.5
39.0
75.6
169.8
42.0
37.4
73.0
58.6
53.2
39.0
69.6
171.2
42.9
37.5
23.3
53.4
54.8
39.0
23.0
172.4
42.1
38.2
C5
Ca
Cb
a All spectra were recorded at 500 MHz for 1H and 125 MHz for 13Cin
CDCl3.
3. Hon, Y.-S.; Chang, Y.-C.; Gong, M. I. Heterocycles 1990,
31, 191–195.
The oxidized products 5 exhibited characteristic simi-
1
4. (a) Dinsmore, A.; Doyle, P. M.; Steger, M.; Young, D. W.
J. Chem. Soc., Perkin Trans. 1 2002, 613–621; (b) Bourry,
A.; Pitard, F.; Rigo, B.; Sanz, G.; Camus, F.; Norberg, B.;
Durant, F.; Couturier, D. J. Heterocycl. Chem. 2002, 39,
109–114; (c) Goswami, L. N.; Srivastava, S.; Panday, S.
K.; Dikshit, D. K. Tetrahedron Lett. 2001, 42, 7891–7892;
(d) Tomasini, C.; Villa, M. Tetrahedron Lett. 2001, 42,
5211–5214; (e) Bragg, R. A.; Clayden, J.; Bladon, M.;
Ichihara, O. Tetrahedron Lett. 2001, 42, 3411–3414; (f)
Acevedo, C. M.; Kogut, E. F.; Lipton, M. A. Tetrahedron
2001, 57, 6353–6359; (g) Konas, D. W.; Coward, J. K.
J. Org. Chem. 2001, 66, 8831–8842.
larities in their H and 13CNMR data compared to the
reaction substrates 4 as seen from the selected data
shown in Table 2. In the 13CNMR, the signal around
68.0 ppm due to C5 in substrates 4 disappeared after
oxidation giving rise to a new signal at around
170.0 ppm characteristic of C@O. The C4-signal was
shifted upfield by 3.4 ppm in 5a–5b upon oxidation,
while that of Ca was shifted upfield by 10–12 ppm. In
contrast, the chemical shift of Cb was not affected much.
1
In the H NMR of 4, the multiplets arising from the
nonequivalent H50500 protons around 2.6 and 3.4 ppm
disappeared in product 5, while signals due to aH and
bH were retained with a downfield shift of ca. 0.3 ppm
perhaps due to anisotropic effects of the C5-carbonyl.
Interestingly, no significant changes were seen for H4,
except for a change of the multiplet to a triplet. The
spectral data shown in Table 2 are for 5a whose crystal
structure is known10 along with 5b and 5g whose crystal
structures are not available. All three compounds
showed similar patterns in NMR, strongly supporting
the regiospecificity of the reaction.
5. Merino, P.; Revuelta, J.; Tejero, T.; Chiacchio, U.;
Rescifina, A.; Piperno, A.; Romeo, G. Tetrahedron:
Asymmetry 2002, 13, 167–172.
6. (a) Ezquerra, J.; Pedregal, C.; Rubio, A.; Yruretagoyena,
B.; Escribano, A.; Ferrando, S. S. Tetrahedron 1993, 49,
8665–8678; (b) Ezquerra, J.; Pedregal, C.; Rubio, A.
J. Org. Chem. 1994, 59, 4327–4331; (c) Dikshit, D. K.;
Panday, S. K. J. Org. Chem. 1992, 57, 1920–1924.
7. Zhang, X.; Schmitt, A. C.; Jiang, W. Tetrahedron Lett.
2001, 42, 5335–5338.
8. Qiu, X. L.; Qing, F. L. J. Org. Chem. 2003, 68, 3614–3617.
9. Nakata, H. Tetrahedron 1963, 19, 1959–1963.
10. Sharma, N. K.; Ganesh, K. N. Chem. Commun. 2003, 19,
2484–2485.
11. (a) DꢀCosta, M.; Kumar, V. A.; Ganesh, K. N. Org. Lett.
1999, 1, 1513–1516; (b) Vidal, J. A. G.; Silverman, R. B.
Org. Lett. 2001, 3, 2481–2484.
In summary, we have observed that the endocyclic
methylene group at C5 of pyrrolidine derivatives is more
susceptible to oxidation with RuCl3/NaIO4 than the
other two exocyclic methylene groups a to heteroatom
N. These derivatives could be useful for synthesis of
N-alkylated pyrrolidinones and unnatural amino acids.
12. Sheehan, J. C.; Tulis, R. W. J. Org. Chem. 1974, 39, 2264–
2267.
13. Bettoni, G.; Carbonara, G.; Franchini, C.; Tortorella, V.
Tetrahedron 1981, 37, 4159–4164.
14. Typical general procedure: To a vigorously stirred solu-
tion of compound 4 (2.3 mmol) in AcOEt (20 mL), an
aqueous solution (20 mL) of NaIO4 (9.08 mmol) and
RuCl3ÆxH2O (catalytic amount, 0.02 mmol) was added.
After 30 min, the reaction was quenched by the addition of
isopropyl alcohol and stirred for another 20 min and then
the reaction mixture was concentrated in vacuo. The
residue was taken into ethyl acetate (20 mL) and washed
with water, the organic extract dried over Na2SO4 and
concentrated to dryness. The crude product was purified
by column chromatography to give 5 as a white foam.
Yield 30–45%.
Supplementary material
Experimental procedures, NMR (1H–1H COSY and
13C–1H HETCOR) and mass spectra of 5a, 5d, 5e and
5g are available in the supplementary material.
Acknowledgements
15. Single crystals of the compound 5d were obtained from a
mixture of CH2Cl2 and CH3OH and a good quality crystal
was selected using a Leica Polarizing Microscope. X-ray
intensity data were collected on a Bruker SMART APEX
N.K.S. thanks the UGC–CSIR, New Delhi, for a fel-
lowship. K.N.G. is an Honorary Professor of the

1406
N. K. Sharma, K. N. Ganesh / Tetrahedron Letters 45 (2004) 1403–1406
CCD diffractometer at room temperature. Crystal data:
ethyl)-4(S)-O-benzoyl-5-one-2(S)-proline methyl 5d. All
the data were corrected for Lorentzian, polarization and
absorption effects using Brukerꢀs SAINT and SADABS
programs. SHELX-97 (G. M. Sheldrick, SHELX-97
program for crystal structure solution and refinement,
University of Gottingen, Germany, 1997) was used for
structure solution and full matrix least squares refinement
on F 2. Hydrogen atoms were included in the refinement as
per the riding model.
C20H26N2O7, M ¼ 406:43, crystal dimensions 0.61 · 0.59 ·
0.14 mm, crystal system monoclinic, space group P21,
ꢀ
a ¼ 9:2779ð15Þ, b ¼ 8:9289ð14Þ, c ¼ 13:239ð2Þ A, b ¼
3
ꢀ3
,
ꢀ
96:512ð3Þꢁ, V ¼ 1089:7ð3Þ A , Z ¼ 2, Dc ¼ 1:239 g cm
lðMo-KaÞ ¼ 0:094 mmꢀ1
,
T ¼ 293ð2Þ K, F ð000Þ ¼ 432,
5493 reflections collected, 3634 unique [I > 2rðIÞ], S ¼
1.053, R value 0.0393, wR2 ¼ 0:1116 (all data R ¼ 0:0416,
wR2 ¼ 0:1135). CCDC no 221794: cis-1-(N-Boc-amino-