Synthesis of oxazolidinones initiated by regio- and diastereo-controlled crotylation of α-dicarbonyl compounds

Article abstract of DOI:10.1039/c000197j

A one-pot synthesis of oxazolidinones was initiated via the allylation of α-dicarbonyl compounds, accompanying regio- and diastereo-controlled carbon-carbon bond formation on the side chains of the oxazolidinones.

Full text of DOI:10.1039/c000197j

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Synthesis of oxazolidinones initiated by regio- and diastereo-controlled
crotylation of a-dicarbonyl compounds†
Ikuya Shibata,*a Ryota Kojima,a Shinji Tsunoi,a Takashi Nozaki,b Tomonari Watanabe,b Atsushi Ninomiya,c
Makoto Yasudac and Akio Babac
Received 14th January 2010, Accepted 9th March 2010
First published as an Advance Article on the web 16th March 2010
DOI: 10.1039/c000197j
A one-pot synthesis of oxazolidinones was initiated via the
allylation of a-dicarbonyl compounds, accompanying regio-
and diastereo-controlled carbon–carbon bond formation on
the side chains of the oxazolidinones.
Oxazolidinones1 are important heterocyclic compounds that are
useful as intermediates in organic synthesis and as biologically
active compounds.2 Allylation of the oxazolidinone ring is im-
portant not only for the introduction of a 3-C unit but also
for the introduction of alkene functionality. As an example,
oxazolidinones with an allylic group at the 5-position of the
ring are used as an NK1-antagonist3 or as a precursor for an
HIV-1 protease inhibitor.4 Although the allylation of carbonyl
compounds by allyl tin reagents is a well-known method of
carbon–carbon bond formation,5 the resulting tin alkoxides are
rarely used for further transformation; most frequently the tin–
oxygen bonds are hydrolysed to homoallylic alcohols. However,
Sn–O and Sn–N bonds bear high nucleophilicity. In some cases,
their nucleophilicity is higher than that of the corresponding
free alcohols and amines.6 In the present study, we performed
a one-pot synthesis of oxazolidinones initiated by the addition of
allylic tin reagents to a-dicarbonyl compounds, 1. The reactions
involved both regio- and diastereocontrolled, carbon–carbon
bond formation in the side chains of oxazolidinones.7,8
Scheme 1 Synthesis of oxazolidinones from allylation of 1a.
b-elimination of tin hydroxide afforded products 3 in a one-pot
procedure.12
Using a-ketoester 1b in place of diketone 1a also afforded
cyclization. Elimination of tin methoxide from III occurred to
give 1,3-oxazolidine-2,4-dione 4a–c (Scheme 2)
Scheme 1 shows the reaction using 2,3-butanedione (1a).
After the allylation of 1a, the resulting mixture reacted with an
isocyanate, and subsequent heating afforded 5-methyl-5-allyl-4-
methylene-2-oxazolidinones 3a–3c.9 As a reaction course, the al-
lylation was promoted by allyliododi-n-butyltin 2 generated in situ
by the redistribution of allyltri-n-butyltin and Bu2SnI2.10 Although
allylic tri-n-butyltins bear low reactivities toward carbonyl groups,
allylic iododi-n-butyltin 210 worked well with no addition of a
Lewis acid.
Scheme 2 Synthesis of heterocycles from the allylation of a-ketoester
(1b).
Next, we applied crotyltin reagents in the initial carbon–carbon
bond formation. Crotylmetalation of the carbonyl functionality
incurred regio- and diastereoselectivities. A halogen substituent
on the tin center was easily introduced by the redistribution of
crotyltri-n-butyltin with n-Bu2SnI2.13 Initially, crotyltri-n-butyltin,
n-Bu2SnI2, and 1a were combined at rt for 4 h. The subsequent
= =
addition of RN C O at rt, followed by heating, gave 2-oxa-
Next, the generated tin–oxygen bond of I spontaneously
reacted with an isocyanate.11 The resulting tin–nitrogen bond
of II successively added to the remaining carbonyl moiety and
zolidinones 5a–d‡, which included Z-crotyl substituents on the
oxazolidinone rings (Table 1).
As shown in Scheme 3, it is assumed that the Z-crotyl
substituents in 5 were derived from the in situ-generated iododi-n-
butyl(1-methylallyl)tin A, which was added to the carbonyl group
of 1a at the terminal g¢-carbon of A. This (Z)-preference of
allylated products was derived from the steric congestion between
aResearch Center for Environmental Preservation, Osaka University, 2-4
Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: shibata@epc.osaka-
u.ac.jp; Fax: (+81) -6-6879-8978; Tel: (+81) -6-6879-8975
bAsahi Kasei Chemicals Coorporation, Kandajinbocho, Chiyodaku, Tokyo
101-8101, Japan
cGraduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita,
Osaka 565-0871, Japan
† Electronic supplementary information (ESI) available: Synthetic proce-
dures and experimental data for the products. CCDC reference numbers
729634–729638. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c000197j
Scheme 3 Reaction route to 5.
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Table 1 Synthesis of 5a
Thus, regio-controlled carbon–carbon bond formation was
established in the side chain of the oxazolidinone rings. A similar
change in regio-selectivity by the order of the addition of tin
reagents also was found in the reaction using a-ketoester 1b
(Scheme 5). The reaction of crotyltri-n-butyltin, n-Bu2SnHal2, and
a-ketoester 1b in a single portion afforded a-adduct 7, whereas the
preheating of two tin reagents afforded g-adduct 8.
Entrya
R
Product
Yield (%)
1
2
3
4
Ts
Ph
5a
5b
5c
5d
66
69
66
40
p-MeOC6H4
p-IC6H4
a The reaction was carried out on 1a 1 mmol, crotylSnBu3 1 mmol, Bu2SnI2
=
=
1 mmol, RN
C O 3 mmol scale.
Table 2 Synthesis of 6
Scheme 5 Change of regio-selectivity using a-ketoester (1b).
In the formation of g-adduct 8, the threo isomer was obtained
predominantly (95% ds), which is the reverse of the diastereo-
selectivity in the formation of 6 (Table 2). The change of diastereo-
selectivity between the two g-adducts 6 and 8 can be explained
in terms of chelate formation of the tin center with dicarbonyl
substrate 1a or 1b (Scheme 6). In the erythro-forming reaction
of 1a with the in situ-generated (Z)-crotyltin B, an acetyl group
occupied the equatorial position in a six-membered chair as in
a transition state (V), whereas in the threo-forming reaction of
1b, the reaction proceeded through a bicyclic chelation transition
state (VI). Thus, the coordinating ability of carbonyl groups in
dicarbonyl substrates 1 determined the diastereo-selectivity.
Entrya
R
Product
Yield (%)
dr
1
2
3
4
5
Ts
6a
6a
6b
6c
6d
72
65
59
55
42
73 : 27
61 : 39b
75 : 25
74 : 26
75 : 25
Ph
p-MeOC6H4
p-IC6H4
a The reaction was carried out on 1a 1 mmol, crotylSnBu3 1 mmol,
Bu2SnCl21 mmol, RN
of Bu2SnCl2.
C
O 3 mmol scale. b Bu2SnI2 was used instead
=
=
the methyl substituent at C-1 of the allyl moiety and the iodine
substituent on tin in the transition state (IV).14
Alternatively, ◦when crotyltri-n-butyltin and n-Bu2SnHal2 were
preheated at 60 C for 2 h, the subsequent reaction with 1a, fol-
lowed by addition to an isocyanate, afforded oxazolidinones 6a–d,
which included 1-methylallyl groups on the ring (Table 2). Namely,
erythro-isomers were obtained as the major diastereomers. In this
case, using n-Bu2SnCl2 afforded both a higher yield and a higher
dr compared with the use of n-Bu2SnI2.
The regio- and diastereoselectivities were determined in the
crotylation step, as shown in Scheme 4. (Z)-Crotyltin B was
formed through (1-methylallyl)tin A irrespective of the E/Z-
stereochemistry of the starting crotyltri-n-butyltin,13b,c and reacted
with one of the carbonyl groups of 1a at the terminal g¢¢-
carbon of B. The crotylation proceeded through a six-membered
chair-like transition state (V), predominantly affording erythro-
g-adducts 6.15
Scheme 6 Difference in diastereo-selectivity between 6 and 8.
In the last stage, we performed the reaction using benzil (1c)
under the conditions that form a g-adduct (Scheme 7). As a
result, a hydroxyl-substituted oxazolidinone ring 9 was obtained
where no b-elimination of tin alkoxide had occurred, because
Scheme 4 Reaction route to 6.
Scheme 7 Synthesis of 9.
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the substrate bore no b-hydrogen. Interestingly, high chelation
control of the three contiguous stereogenic centers in product 9 was
accomplished. Thus, the stereochemistry between the methylallyl
side chain and the ring carbon was threo, and that between the
two ring carbons was erythro. The reaction proceeded through a
bicyclic chelation transition state (VII) to give threo g-crotylation
adduct. The erythro selectivity on the oxazolidinone ring could
be explained in terms of steric repulsion between the allylic and
benzoyl group in VIII.
In conclusion, a one-pot synthesis of nitrogen heterocyclic
compounds was initiated by the allylation of dicarbonyls 1.
Regio- and diastereoselective carbon–carbon bond formation was
established on the side chains of the rings.
This research was supported by a Japan Science and Technology
Agency Potentiality Verification Stage Project, a Grant-in-Aid
for Scientific Research from the Ministry of Education, Science,
Sports, and Culture Japan, The Mizuho-Espec Foundation, The
Kurata Memorial-Hitachi Science and Technology Foundation
and The Naito Foundation.
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