Triple role of phenylselenonyl group enabled a one-pot synthesis of 1,3-oxazinan-2-ones from α-isocyanoacetates, phenyl vinyl selenones, and water

Article abstract of DOI:10.1021/ja506031h

Reaction of α-substituted α-isocyanoacetates with phenyl vinyl selenones in the presence of a catalytic amount of base (DBU or Et₃N, 0.05-0.1 equiv) followed by addition of p-toluenesulfonic acid (PTSA, 0.1-0.2 equiv) afforded 4,4,5-trisubstituted 1,3-oxazinan-2-ones in good to excellent yields. Enantiomerically enriched heterocycles can also be prepared using a Cinchona alkaloid-derived bifunctional organocatalyst for the Michael addition step. The phenylselenonyl group served as an activator for the Michael addition, a leaving group and a latent oxidant in this integrated reaction sequence.

Full text of DOI:10.1021/ja506031h

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Article
Triple Role of Phenylselenonyl Group Enabled a One-pot Synthesis of 1,3-
Oxazinan-2-ones From #-Isocyanoacetates, Phenyl Vinyl Selenones and Water
Thomas Buyck, Qian Wang, and Jieping Zhu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja506031h • Publication Date (Web): 28 Jul 2014
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Journal of the American Chemical Society
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Triple Role of Phenylselenonyl Group Enabled a One-pot
Synthesis of 1,3-Oxazinan-2-ones From α-
Isocyanoacetates, Phenyl Vinyl Selenones and Water**
Thomas Buyck, Qian Wang and Jieping Zhu*
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Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Polytechnique
Fédérale de Lausanne, EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
ABSTRACT: Reaction of α-substituted α-isocyanoacetates with phenyl vinyl selenones in the presence of a catalytic
amount of base (DBU or Et3N, 0.05-0.1 equiv) followed by addition of p-toluenesulfonic acid (PTSA, 0.1-0.2 equiv) afforded
4,4,5-trisubstituted 1,3-oxazinan-2-ones in good to excellent yields. Enantiomerically enriched heterocycles can also be
prepared using Cinchona alkaloid-derived bifunctional organocatalyst for the Michael addition step. Phenylselenonyl
group served as an activator for the Michael addition, a leaving group and a latent oxidant in this integrated reaction
sequence.
INTRODUCTION
such a triple roles of phenylselenonyl group has never
been exploited previously in a one-pot transformation.
We document also an enantioselective synthesis of 1 (R =
aryl, R1 = H) using chiral Cinchona alkaloid-derived bi-
functional organocatalyst for the initial Michael addition
step.
Isocyanoacetates, by virtue of their multifunctionalities
and easily modulable reactivities, have attracted atten-
tions of synthetic chemists for several decades and many
useful transformations have been developed.1 Among
them, the propensity of these chemical entities to under-
go [2+3] cycloaddition with dipolarphiles, taking ad-
vantage of the nucleophilicity of the α-carbon and the
carbene-like reactivity of the divalent carbon of isocyano
group has been extensively exploited. Indeed, a number of
Lewis acid- and small organomolecule-catalyzed [2+3]
cycloaddition of α-isocyanoacetates with aldehydes,2
imines,3 azodicarboxylates4 and polarized carbon-carbon
double bonds such as nitroalkenes,5 α,β-unsaturated ke-
tones,6 maleimides,7 carbodiimides,8 triple bonds9 etc10
have been elegantly developed for the access to biologi-
cally relevant 5-membered heterocycles (eq 1, Scheme 1).
Mechanistically, these reactions are initiated by enanti-
oselective aldol, Mannich or Michael reactions followed
by intramolecular nucleophilic addition of resulting anion
to the pendant isocyano group. It has been established
that any Lewis-acid-catalyzed nucleophilic addition of α-
isocyanoacetates to polarized double bond provided inev-
itably the [2+3] cycloadduct, the same trend holds for
organocatalytic processes.11 We report herein a completely
different reaction involving α-isocyanoacetates, phenyl
vinyl selenone12 and water that leads to the formation of
4,4,5-trisubstituted 1,3-oxazinan-2-ones 1 (eq 2, Scheme 1).
In this operationally simple transformation, four chemical
bonds were created by a formal [3+2+1] process. Key to
the success is the ability of phenylselenonyl group to act
as an activator for Michael addition, as a leaving group
and as a latent oxidant. To the best of our knowledge,
Scheme 1. Integrated one-pot synthesis of 1,3-oxazinan-2-
ones 1
[3+2] cycloaddition of α-isocyanoacetates with polarized double bonds
EWG
Lewis acid
CN
CO2Me
+
EWG
eq 1
N
R
COOMe
or Brønsted base
R
This work: Formal [3+2+1] cycloaddition of α−isocyanoacetates with
phenyl vinyl selenones and water
Base (cat)
tBuOH, rt
O
O
CN
CO2Me
+
SeO2Ph
eq 2
HN
R1
CO2Me
R1
then PTSA (cat)
H2O, 35 °C
R
R
2
3
1
R1
SeO2Ph
R1
3
1,3-Oxazinan-2-one 1 is a core structure found in many
bioactive compounds displaying antibacterial,13 anti-
inflammatory,14 antidiabetes15 and anti-HIV activities.16 It is
also a structural unit found in a number of natural prod-
ucts such as maytansinoids that are potent antitumor
agents.17 In addition, these 6-membered cyclic carbamates
have also been used as key intermediates in the synthesis
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Page 2 of 7
a abbreviations: PTSA = p-toluenesulfonic acid; PPTS = pyri-
dinium p-toluenesulfonate.
of drugs (Prozac®),18 bioactive natural products such as
(+)-nagamycin19 and L-ristosamine,20 a carbohydrate con-
stituent of ristomycin belonging to vancomycin family
glycopeptides.21 Among many existing methodologies,
halonium-mediated22 or metal-catalyzed23 6-exo-trig-
cyclization, intramolecular 6-exo-Michael addition24 of
properly functionalized homoallylamines/homoallylic
alcohols, allylic C-H amination25 and tethered aminohy-
droxylation of olefins26 are the most popular ones. Inher-
ent to the activation and cyclization modes, these meth-
ods were difficultly applicable to the synthesis of 6-
unsubstituted 1,3-oxazinan-2-ones. The conceptually
different but operationally simple one-pot synthesis of
1
2
3
4
5
6
7
8
The transformation turned out to be general and the
structure of enantiomerically enriched 1,3-oxazinan-2-
ones synthesized by this protocol is enlisted in Scheme 2.
As it is evident, the reaction was not sensitive to the elec-
tronic effect of the aromatic ring and heteroarene (furan)
is well tolerated. The structure as well as the absolute
configuration of compound 1d was confirmed by single
crystal X-ray structural analysis (Figure 1).28
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4,4,5-trisubstituted 1,3-oxazinan-2-ones
1
from α-
substituted α-isocyanoacetates, phenyl vinyl selenones
and water represents therefore an interesting alternative
to the existing synthetic methods.
Figure 1. X-ray structure of (R)-1d
RESULTS AND DISCUSSION
We have recently reported an enantioselective synthe-
sis of α,α-disubstituted α-isocyanoacetates 4.27 In an at-
tempt to convert the isocyano group to the N-formamide
under mild acidic conditions, we observed the formation
of 1,3-oxazinan-2-one 1a and 2-methoxy-5,6-dihydro-4H-
1,3-oxazine 5a in a 4 to 1 ratio (Scheme 2). Intrigued by
this unprecedented transformation involving formally an
oxidative cyclization sequence, conditions were opti-
mized towards the formation of 1,3-oxazinan-2-one 1a by
Scheme 3. Integrated one-pot synthesis of 1,3-oxazinan-2-
ones 1.
O
O
SeO2Ph Conditionsa
H2O
R2
R1
CN
CO2Me
HN
R1
+
CO2Me
R
R
O
R2
2
1
3
t
t
O
O
varying the solvents (MeOH, toluene, BuOH, BuOH-
THF, DMF), the catalysts (PTSA•H2O, PPTS, AcOH,
PhSeO2H, Zn(OTf)2, Pd/C, PdCl2), and the temperature
(rt, 35 °C, 60 °C). The best conditions found consisted of
O
O
1a FG = H, 75%
1b FG = Me, 74%
1c FG = OMe, 83%
1f FG = F, 72%
1g FG = Br, 68%
1h FG = CF3, 77%
1i FG = NO2, 65%
HN
HN
CO2Me
Br
CO2Me
t
performing the reaction in BuOH in the presence of
PTSA•H2O (0.1 equiv) at 35 °C. Under these conditions, 4a
(e.r. 98.1:1.9) was converted to 1a (e.r. 96.8:3.2) in 86%
yield with very little erosion of enantiomeric purity.
FG
O
1d 68%
O
O
O
O
HN
HN
HN
CO2Me
CO2Me
CO2Me
MeO2C
O
Scheme 2. Oxidative cyclization of 4a to 1,3-oxazinan-2-
one 1a.a
O
O
1e 65%
1j 74%
1k 68%
MeO
O
O
O
O
O
O
O
O
CO2Me
CN
+
N
HN
Ph
HN
HN
HN
R
Me
CO2Me
R
R
R
CO2Me
CO2Me
CO2Me
CO2Me
SeO2Ph
(R)-4a R = Ph
PTSA.H2O, MeOH, rt
AcOH, MeOH, rt
n
CbzHN
(R)-1a R = Ph
(R)-5a R = Ph
1l 74%
1m n = 2, 80%
1n n = 3, 83%
1o R = Ph, 75%, d.r. 1:1
1p R = Bn, 58%, d.r. 2:1
52%
0%
13%
0%
0%
0%
t
PTSA.H2O, tBuOH, 35 °C 86%
aConditions A for R = Aryl: Et3N (0.1 equiv), BuOH (c 0.25
t
PPTS, tBuOH, 35 °C
80%
M), rt then PTSA•H2O (0.2 equiv) in BuOH (final c 0.05 M),
35 °C; Conditions B for R = Alkyl: DBU (0.05 equiv), tBuOH (c
O
O
O
O
t
O
O
0.25 M), rt then PTSA•H2O (0.1 equiv) in BuOH (final c 0.05
O
O
HN
M), 35 °C.
HN
HN
HN
CO2Me
CO2Me
MeO
CO2Me
The enantio-enriched quaternary α-isocyanoacetates 4
were synthesized by a chiral Cinchona alkaloid-catalyzed
Michael addition of α-substituted-α-isocyanoacetates 2 to
phenyl vinyl selenone (3a).27 The fact that PPTS (pyridini-
um p-toluenesulfonate, Scheme 2) can catalyze the dom-
ino oxidative cyclization of Michael adduct 4 to 1 as effi-
CO2Me
O
Me
Br
(R)-1b
Y: 66%
e.r. 95:5
(R)-1c
Y: 70%
e.r. 94.5:5.5
(R)-1d
Y: 65%
e.r. 91.8:8.2
(R)-1e
Y: 49%
e.r. 97:3
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ciently as PTSA (p-toluenesulfonic acid) prompted us to Integrated one-pot enantioselective synthesis of 1 is also
1
2
3
4
5
6
7
8
investigate the direct synthesis of 1 from 2 and 3 by an
integrated Brønsted base-catalyzed Michael addition and
Brønsted acid-catalyzed oxidative cyclization of the re-
sulting Michael adducts.29,30 Indeed, PTSA is a strong acid
(pKa = 4.8 in H2O) capable of protonating most of the
Brønsted bases leading to the corresponding ammonium
p-toluenesulfonate similar to PPTS.
possible. As shown in Scheme 5, enantioselective Michael
addition between 2e and 3 in toluene in the presence of a
bifunctional organocatalyst 732 followed by adding a solu-
tion of PTSA in BuOH afforded 1e in 80% yield with an
e.r. of 96.4 to 3.6. However, 7 failed to catalyze the enan-
t
tioselective
Michael
addition
of
α-alkyl-α-
isocyanoacetates to phenyl vinyl selenone, hence the
corresponding alkyl substituted oxazinanone 1.
We started with the racemic version using methyl α-
phenyl-α-isocyanoacetate 2a (R = Ph) and 3a (R1 = R2 = H)
as test substrates (Scheme 3). The optimum conditions
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Scheme 5. Integrated one-pot enantioselective synthesis
of 1,3-oxazinan-2-one.
t
found are as follows: Et3N (0.1 equiv), BuOH (c 0.25 M),
t
room temperature then PTSA•H2O (0.2 equiv) in BuOH
O
O
O
(final c 0.05 M), 35 °C. Under these conditions, reaction of
2a with 3a afforded directly (±)-1a in 75% yield. It is inter-
esting to note that dihydropyrrole resulting from the
[3+2] cycloaddition (cf eq 1, Scheme 1) was not observed.
As it is shown in Scheme 3, the scope of the reaction was
Cat* (0.1 equiv)
Tol (0.25 M), -40 °C
CN
CO2Me
O
HN
SeO2Ph
CO2Me
then PTSA (0.2 equiv)
tBuOH (0.05 M), 35 °C
2e
3
(R)-1e
Y: 80%
e.r: 96.4:3.6
Cat*
OH
N
quite
general.
α-Isocyanoacetates
bearing
arenes/heteroarenes with different electronic properties
(electron-rich and -poor) all participated in the reaction
to give the corresponding 4,4-disubstituted 1,3-oxazinan-
2-ones (1a-1j). The yields (> 65%) are excellent consider-
ing that four chemical bonds are created in this one-pot
process. The average yield of per chemical bond for-
mation is therefore higher than 90%.
OnBu
N
7
To gain mechanistic insights on the conversion of 4 to
1, a set of control experiments were conducted using 4a as
a reference compound. The oxidative cyclization of 4a
worked equally well under strictly inert atmosphere
(glove box) indicating that isocyanate resulting from the
adventitious air oxidation of isocyano group might not be
the intermediate. No reaction took place when the same
With α-alkyl substituted α-isocyanoacetates, a stronger
base (DBU) is needed to catalyze the Michael reaction
due to the reduced aciditity of the α-CH of compound 2.
t
Under optimized conditions [DBU (0.05 equiv), BuOH (c
0.25 M), room temperature then PTSA•H2O (0.1 equiv) in
tBuOH (final c 0.05 M), 35 °C], the one-pot procedure
worked well to produce the 4-alkyl-4-methoxycarbonyl-
1,3-oxazinan-2-ones (1k-1n) in good to excellent yields
(Scheme 3).
t
reaction was carried out in anhydrous BuOH in the pres-
ence of anhydrous PTSA. On the other hand, by adding
H218O (18O content 97.7%) into the above reaction mixture,
we observed the formation of the same product with dou-
ble and mono 18O incorporation in a ratio of 89 to 7
To further explore the scope of this transformation, E-
(prop-1-en-1-ylselenonyl)benzene (E-3b, R1 = H, R2 = Me)
and it's Z-isomer (Z-3b, R1 = Me, R2 = H) were prepared.
Interestingly, while E-3b was inactive, reaction of 2a with
Z-3b under standard conditions afforded 4,4',5-
trisubstituted oxazinanone 1o in 75% yield as a mixture of
two diastereomers (d.r. 1:1). Likewise, methyl α-benzyl-α-
isocyanoacetate reacted with Z-3b to furnish 1p in 58%
yield (d.r. 2:1).
13
(Scheme 6). The up-field shift of C NMR signals of car-
bamate carbonyl (C2) and C6 in 1a-18O2 relative to 1a
18
16
18
16
[∆δ(C=O)
= -3.5 Hz, ∆δ(C6)
= -3.3 Hz] is observed,
O
–
O
O – O
which is in agreement with literature precedents.33 This
labelling experiment clearly indicated that two molecules
of water were involved in the conversion of oxidative
cyclization of 4 to 1.
To illustrate the synthetic potential of this cyclic car-
bamate, compound 1m was converted to spiropiperidi-
none 6, a core structure of a series of NK1 antagonists
(Scheme 4).31
Scheme 6. 18O labeling experiment
O18
HN
O
18
CO2Me
PTSA, H218O
tBuOH, 35 °C
CN
Ph
+
PhSeSePh
Scheme 4. Synthesis of spiropiperidinone.
CO2Me
Ph
1a-18O2
SeO2Ph
4a
O
O
O
O
Raney Nickel, H2
HN
HN
Based on the results of aforementioned control exper-
iments, a possible reaction pathway accounting for the
formation of 1 from 4 is depicted in Scheme 7. Acid-
catalyzed hydration of isocyano group led to N-
alkylformimidic acid 8. The initial stereochemistry of the
O
CO2Me
1m
MeOH (0.01 M)
rt, 86%
NH
CbzHN
6
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C=N bond is of no consequence as it is readily isomerized Theoretically, two equivalents of water were required to
1
2
3
4
5
6
7
8
via the N-formamide form 9. Intramolecular nucleophilic
displacement of phenylselenonyl group by amide oxygen34
would afford 5,6-dihydro-4H-1,3-oxazine 10 with concur-
rent release of benzeneseleninic acid, which would be in
equilibrium with its benzeneseleninic anhydride (BSA).
Alternatively, intermolecular displacement of phenylsele-
nonyl group by water followed by intramolecular inser-
tion of isocyano group to OH bond could also account for
the formation of 10. Trapping of 10 by a molecule of water
under acidic conditions would produce 11 that could be
oxidized by BSA to 1 via intermediate 12.35 Alternatively,
phenylseleninylation of 12 at the nitrogen atom followed
by selenoxide elimination and tautomerization of the
resulting iminoalcohol to amide could also be operating.36
This reaction pathway could also account for the for-
mation of imidate 5 observed in our initial experiment
when methanol was used as solvent. In this case, metha-
nol could compete with water to trap 10 leading to 13.
Oxidation of secondary amine to imine by benzene-
seleninic anhydride would provide 2-methoxy-5,6-
dihydro-4H-1,3-oxazine (5).36 We were able to isolate di-
phenyldiselenide, a reduced form of benzeneseleninic
acid,37 from the reaction mixture. Overall, the integrated
reaction system involving 2, 3 and two molecules of water
is an oxidative multicomponent reaction (ABC2)38 with an
internal redox process.39 A tiny percentage of 4 or 9 may
undergo the retro-Michael/Michael addition reaction
before the cyclization, accounting therefore for the slight
decreases of enantiomeric excess of products relative to
the starting materials.
convert 4 to oxazinone 1 according to above mechanistic
consideration. To check the optimum amount of water
needed for this transformation, the reaction of 4a in an-
t
hydrous BuOH and PTSA was performed in the presence
of various equivalents of water. While no reaction took
place in the absence of water, adding 2 equivalents of H2O
is enough to drive the reaction to completion.40
9
Conclusion
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In summary, we developed a novel and efficient one-
pot synthesis of 1,3-oxazinan-2-ones from simple starting
materials. The integrated reaction system comprised of a
Brønsted base-catalyzed Michael addition of α-
isocyanoacetates to phenyl vinyl selenone followed by an
unprecedented Brønsted acid-catalyzed domino oxidative
cyclization sequence that converted the isocyano group to
the carbamate function. Four chemical bonds were creat-
ed in this operationally simple transformation. Key to the
success is the ability of phenylselenonyl group to act as an
activator for Michael addition, as a leaving group and as a
latent oxidant. To the best of our knowledge, such a triple
roles of phenylselenonyl group has never been exploited
previously in a one-pot transformation.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, spec-
troscopic and crystallographic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Scheme 7. One-pot synthesis of 1,3-oxazinan-2-one (1):
Possible reaction pathway.
AUTHOR INFORMATION
Corresponding Author
E-mail: jieping.zhu@epfl.ch
H
OH
CO2Me
O
H
CO2Me
CN
H+, H2O
Author Contributions
CO2Me
N
R
HN
R
All authors have given approval to the final version of the
manuscript.
R
SeO2Ph
SeO2Ph
SeO2Ph
4
8
9
H2O
+
(PhSeO)2O
PhSe(O)OH
H+, H2O
ACKNOWLEDGMENT
O
Ph
Se
O
Financial supports from EPFL (Switzerland), Swiss National
Science Foundation (SNSF), the COST action (CM0905) and
Swiss State Secretariat for Education and Research (SER) are
gratefully acknowledged.
H
HO
O
O
O
HN
N
HN
CO2Me
CO2Me
R
R
CO2Me
R
12
11
10
REFERENCES
PhSeSePh
+
PhSe(O)OH
H+
MeOH
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(40) The yield of 1a: 85%, (2 equiv of H2O), 90% (4 equiv of
H2O), 96% (10 equiv of H2O). The reaction can be performed in
the presence of a large excess of water (100 equiv, 93%). For
details, see Supporting Information. We thank referees for sug-
gesting these control experiments.
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H
+
H
Brønsted base
(0.05-0.1 equiv)
tBuOH, rt
H
O
H
O
SeO2Ph
O
O
HN
R1
R1
C
then PTSA
(0.1-0.2 equiv)
35 °C
N
CO2Me
R
CO2Me
R
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