An efficient synthesis of cyclic urethanes from Boc-protected amino acids through a metal triflate-catalyzed intramolecular diazocarbonyl insertion reaction

Article abstract of DOI:10.1016/j.tetlet.2006.08.111

A simple and efficient synthesis of cyclic urethanes and related oxazinanones 1a-l from diazoketones 3a-l is described. The transformation involves generation of carbenes by activation of diazo groups using metal triflates in intramolecular diazocarbonyl insertion reactions in high overall yields.

Full text of DOI:10.1016/j.tetlet.2006.08.111

Tetrahedron Letters 47 (2006) 7969–7972
An efficient synthesis of cyclic urethanes from Boc-protected
amino acids through a metal triflate-catalyzed intramolecular
diazocarbonyl insertion reaction
Jae-Chul Junga and Mitchell A. Averya,b,c,
*
aDepartment of Medicinal Chemistry, School of Pharmacy, University of Mississippi, PO Box 1848,
University, MS 38677-1848, USA
bDepartment of Chemistry, University of Mississippi, PO Box 1848, University, MS 38677-1848, USA
cNational Center for Natural Products Research, University of Mississippi, PO Box 1848, University, MS 38677-1848, USA
Received 15 June 2006; revised 28 August 2006; accepted 29 August 2006
Available online 25 September 2006
Abstract—A simple and efficient synthesis of cyclic urethanes and related oxazinanones 1a–l from diazoketones 3a–l is described.
The transformation involves generation of carbenes by activation of diazo groups using metal triflates in intramolecular diazocar-
bonyl insertion reactions in high overall yields.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
bene insertion reaction. The Kubota group9 reported
the preparation of cyclic urethanes from amino alcohols
and carbon dioxide using phosphorus (II) reagents and
haloalkanes in high yield. The Pansare group10 demon-
strated that scandium triflate catalyzed diazocarbonyl
insertions from intramolecular reactions of carbenoids
with a carboxycarbonyl N-protecting group, followed
by debenzylation in 61% yield. The Arai group11 devel-
oped a route to cyclic urethanes and related oxazina-
nones using direct reaction of urea with diamines,
amino alcohols, or amino phenols at 150 °C in the
absence of a catalyst.
Cyclic urethanes and related oxazinanones are impor-
tant classes of compounds in organic, pharmaceutical,
medical, agrochemical, and polymer chemistry,1 which
possess biologically significant properties such as
anticonvulsants,2 antibacterials,3 antiepileptics,4 and
enzyme inhibitors.5 They are also useful chemical
intermediates for many industrial products such as fine
chemicals, cosmetics, and pesticides.6 A variety of routes
for the synthesis of cyclic urethanes have been reported
in the literature.7 Most of these methods are based on
the reactions of diamines or amino alcohols with several
different reagents, that is, phosgene dialkyl carbonates
or a mixture of carbon monoxide and oxygen through
oxidative carbonylation. The generation of cyclic ure-
thanes from aliphatic or aromatic amino alcohols are
limited due to low yields, longer reaction times, stringent
conditions, and use of expensive reagents. Recently, the
Hanessian group8 performed the generation of four-
membered ketone ring as a major product and five-
membered ketone ring, a six-membered oxazinanone
as two side products through rhodium-catalyzed car-
In the context of our medicinal chemistry program
dealing with the development of new antimalarials, we
required 1,3-oxazinane-2,5-diones and several amino
ketones as important intermediates for the generation
of novel cysteine protease inhibitors. We wish to report
herein the synthesis of cyclic urethanes and related oxaz-
inanones via metal triflate [M(OTf)3] catalyzed intra-
molecular diazocarbonyl insertion reactions.
2. Results and discussion
Keywords: Cyclic urethanes; 1,3-Oxazinane-2,5-diones; Diazoketones;
Indium triflate.
Although a number of methods have been developed for
the generation of urethanes and azetidinones through
carbene insertion into the N–H bond of diazoketones,10
*
Corresponding author. Tel.: +1 662 915 5879; fax: +1 662 915
5638; e-mail: mavery@olemiss.edu
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.08.111

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J.-C. Jung, M. A. Avery / Tetrahedron Letters 47 (2006) 7969–7972
Table 1. Synthesis of various 4-substituted-1,3-oxazinane-2,5-diones
(1a–l)a via In(OTf)3 catalyzed N–H insertion reaction of functionalized
diazoketones (3a–l)
practically all of the previous studies on Lewis acid or
metal-mediated diazoketone insertion reactions involv-
ing heteroatom participation were restricted to the intra-
molecular mode. Recently, Hanessian and co-workers
reported an intramolecular version, which offers an
alternative to most methods for the synthesis of 4–6-
membered ketones by addition of the carbonyl oxygen
atom of the Boc protecting group.8 To explore the scope
and generality of this latter method, we investigated a
series of N-Boc protected amino acids 2a–l with different
substituted moieties. The diazoketones 3a–l were pre-
pared from amino acids 2a–l by reacting with freshly
prepared diazomethane12 in the presence of N-methyl-
morpholinepolystyrene and isobutyl chloroformate in
excellent yields. Intramolecular N–H insertion of
diazoketones 3a–l was achieved by treatment with a
catalytic amount of indium triflate to generate 4-
substituted-1,3-oxazinane-2,5-diones 1a–l in high yields
(Scheme 1).13 Most intramolecular ring cyclization reac-
tions using indium triflate were completed in high yield.
We found that N–H insertion of diazoketones 3a–l
containing aliphatic groups, aromatic groups, and
heterocyclic groups readily generated 4-substituted 1,3-
oxazinane-2,5-diones (1a–l, Table 1).
Entry
R
Yield (%)b
Product
1
2
3
4
5
6
7
8
9
H
Me
Et
n-Bu
c-Propyl
c-Hexyl
Ph
3,4-Difluorophenyl
Bn
CH2–Bn
3-Methylbenzothienyl
N-BOM-imidazolylc
95
98
96
96
95
97
93
94
96
98
93
90
1a
1b
1c
1d
1e
1f
1g
1h
1i
10
11
12
1j
1k
1l
a The reaction was carried out using diazoketones (1.0 mmol) and
indium triflate (0.03 equiv) in dichloromethane at 0 °C to rt for
30 min.
b Isolated yield.
c N-Benzyloxymethyl (BOM)-imidazolyl.
Table 2. Intramolecular diazocarbonyl insertion reaction of 3j using
various catalysts
We investigated the catalytic activity of several activa-
tors such as Sc(OTf)3, In(OTf)3, Cu(OTf)2, Sn(OTf)2,
La(OTf)3, Yb(OTf)3, Mg(OTf)2, Hg(OTf)2, and
Bi(OTf)3. Diazoketone 3j was treated with a catalytic
amount of metal triflate as an initial study (Table 2).
Excellent results were obtained with diazoketone 3j in
the presence of 3 mol% of indium triflate in dry dichlo-
romethane at 0 °C for 30 min (Table 2, entry 2). Practi-
cally, most of the other metal triflates showed a similar
effect for the reaction while they suffered from draw-
backs such as longer reaction times (Table 2, entry 1
and entries 3–9).
Entry
Activator
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
Sc(OTf)3
In(OTf)3
Cu(OTf)2
Sn(OTf)2
La(OTf)3
Yb(OTf)3
Mg(OTf)2
Hg(OTf)2
Bi(OTf)3
8
0.5
5
91
98
95
93
91
96
92
90
91
4
10
10
16
16
16
a Isolated yield.
primary alcohol 4 was generated as the single product
(Table 3, entries 11–14). This fact implied that diazo-
ketone 3j can be activated preferentially under acidic
media to generate the carbene, followed by removal of
the N-Boc group, while under basic media, the unacti-
vated diazogroup of 3j was readily replaced by different
nucleophiles leading to substituted N-Boc ketones 4–7 in
low yields and with slow reaction rates.
Our initial endeavors focused on the preparation of N-
Boc ketones 4–7 as key fragments of cysteine protease
inhibitors. We have performed the substitution reaction
of diazoketone 3j with several nucleophiles that is,
hydroxide, halides, and acetates to generate N-Boc
ketones 4–7 under mild reaction conditions (Table 3).
The acylation reactions were tentatively examined in
the presence of several acids such as sulfuric acid, hydro-
chloric acid, hydrobromic acid, peracetic acid, per-
chloric acid, periodic acid, and various bases (lithium
hydroxide, sodium hydroxide, potassium hydroxide,
and magnesium bromide). Interestingly, when the di-
azoketone 3j was reacted under acidic conditions, the
cyclic urethane 1j was isolated (Table 3, entries 1–7),
however when 3j was treated with bases in THF/H2O,
In conclusion, we have reported that a catalytic amount
of metal triflate efficiently catalyzes the intramolecular
diazocarbonyl insertion reaction of activated diazo-
ketones 3a–l to generate cyclic urethanes and related
six-membered oxazinanones 1a–l in high yields. It was
found that the cyclic urethanes were readily generated
O
N
O
O
O
O
O
Cl
H
O
,
In(OTf)3
H
N
N2
N
HN
Boc
OH
Boc
CH2N2/THF, -20 oC, 2 h.
CH2Cl2,
0 oC to rt,
30 min.
O
R
R
R
2a-l
3a-l
1a-l
Scheme 1.

J.-C. Jung, M. A. Avery / Tetrahedron Letters 47 (2006) 7969–7972
Table 3. Diazoketone 3j under various conditions
7971
O
O
O
O
NH
N2
X
O
+
HN
HN
Boc
Boc
3j
4 X=OH
5 X=Cl
6 X=Br
7 X=OAc
1j
Entry
Reaction conditions
Solvent
Temperature (°C)
Time (h)
Product
Yield (%)a
(10 + 80)
(15 + 60 + 20)
5b
1
2
3
0.25 M-H2SO4
1.0 M-HCl (aq)
MeCO3H
HClO4
THF/H2O
CH2Cl2
CH2Cl2
rt
rt
rt
rt
36
12
8
(4 + 1j)
(4 + 5 + 1j)
1j
4
CH2Cl2
1
1j
93
5
5
6
7
8
9
10
11
12
13
14
15
HClO4
HClO4
HIO4
HIO4
H2O/AcOH
HCl/AcOH
HBr/AcOH
LiOH
LiOH, H2O2
NaOH
CH2Cl2
THF/H2O
CH2Cl2
THF/H2O
CH2Cl2
THF/Et2O
THF/Et2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
Et2O/CH2Cl2
ꢀ78 to rt
2
12
2
12
2
0.2
0.2
24
16
24
24
1
(4 + 1j)
(4 + 1j)
1j
(10 + 85)
(15 + 80)
90
(12 + 85)
(5 + 30)
95
rt
rt
rt
rt
0
(4 + 1j)
(4 + 7)
5
0
6
93
rt
rt
rt
rt
rt
4
5b
4
5b
4
33
KOH
MgBr2, MeNO2
4
30
—
c
—
a Isolated yield.
b Based on recovered starting material.
c No reaction.
7. (a) Puschin, N. A.; Mitic, R. V. Justus Leibigs Ann. Chem.
1937, 532, 300–301; (b) Li, P.; Xu, J. C. Tetrahedron 2000,
56, 9949–9955; (c) Yoshida, T.; Kambe, N.; Murai, S.;
Sonoda, N. Tetrahedron Lett. 1986, 27, 3037–3040; (d)
Tominaga, K.-I.; Sasaki, Y. Synlett 2002, 2, 307–309; (e)
Kim, Y. J.; Varma, R. S. Tetrahedron Lett. 2004, 45, 7205–
7208; (f) Egli, M.; Dreiding, A. S. Helv. Chim. Acta 1986,
69, 1442–1460; (g) Porzi, G.; Sandri, S. Tetrahedron:
Asymmetry 1996, 7, 189–196.
in acidic media, and indium triflate was the most
effective catalyst for generation of cyclic urethanes and
related six-membered oxazinanones among all the tested
metal triflates.
Acknowledgment
This work has been supported by the University of
Mississippi.
8. Hanessian, S.; Fu, J.-M. Can. J. Chem. 2001, 79, 1812–
1826.
9. Kubota, Y.; Kodaka, M.; Tomohiro, T.; Okuno, H. J.
Chem. Soc., Perkin Trans. 1 1993, 5–6.
References and notes
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13. General procedure for the preparation of 4-substituted-
1,3-oxazinane-2,5-diones 1a–l. To a stirred suspension of
N-Boc amino alcohols 2a–2l (2.0 mmol) in dry THF
(10 mL) was slowly added N-methylmorpholinepoly-
styrene (0.5 g, 200–400 mesh) at ꢀ20 °C, followed by
addition of isobutyl chloroformate (2.4 mmol). The mix-
ture was stirred at ꢀ20 °C for 2 h and filtered. The resin
was washed with anhydrous THF (2 mL). The filtrate was
re-cooled to ꢀ20 °C under an argon atmosphere, and
freshly prepared diazomethane12 was added dropwise at
the same temperature. The resulting reaction mixture was
stirred for 1 h and then gradually warmed to room
temperature. After elimination of excess diazomethane
under argon gas, the organic phase was concentrated
under reduced pressure to give diazoketone 3a–l, which

7972
J.-C. Jung, M. A. Avery / Tetrahedron Letters 47 (2006) 7969–7972
was diluted with dry dichloromethane (10 mL) and treated
with indium triflate (0.03 M equiv) at 0 °C. The mixture
was warmed to room temperature for 30 min. The
resulting reaction mixture was diluted with dichlorometh-
ane (10 mL/mmol). The organic layer was washed with
satd aqueous NH4Cl solution (10 mL) and brine (10 mL),
dried over anhydrous MgSO4, and concentrated under
reduced pressure. The residue was purified by flash column
chromatography (silica gel, 20–30% ethyl acetate/hexanes)
to give 4-substituted 1,3-oxazinane-2,5-diones 1a–l.
Selected data: 1j: white crystals, mp 122–123 °C. Rf = 0.2
25
(30% ethyl acetate in hexanes); ½aꢁD ꢀ34.04 (c 0.3, CHCl3);
IR (neat, NaCl) 3252, 3029, 2919, 1728, 1681, 1453, 1271,
1
1081, 878 cmꢀ1; H NMR (CDCl3, 500 MHz) d 7.36–7.20
(m, 6H), 4.60 (dd, J = 17.5, 17.5 Hz, 2H), 3.89 (t,
J = 7.0 Hz, 1H), 2.81 (t, J = 7.5 Hz, 2H), 2.27–2.17 (m,
1H), 2.16–2.06 (m, 1H); 13C NMR (CDCl3, 125 MHz) d
202.3, 155.3, 139.5, 128.6, 128.5, 126.5, 71.9, 58.7, 33.9,
31.1; HRMS calcd for C12H14NO3: 220.0974 [M+H]+,
found: 220.1017.