Iodocarbamation of N-Homopropargyl Carbamates: Mild and Stereoselective Entry to Functionalized Oxazinan-2-ones

Article abstract of DOI:10.1002/ejoc.201700231

An efficient and general iodocarbamation of benzyl N-homopropargylcarbamates has been developed by using iodine as the electrophilic agent. This regio- and stereoselective cyclization yielded (E)-6-iodomethyleneoxazinan-2-ones, which can be further transformed through palladium cross-coupling reactions followed by hydrogenation to produce 1,3-oxazinan-2-ones.

Full text of DOI:10.1002/ejoc.201700231

A Journal of
Accepted Article
Title: Iodocarbamation of homopropargyl N-carbamates: mild and
stereoselective entry to functionalized oxazinan-2-ones
Authors: Pierre Quinodoz, Alexandre Quelhas, Karen Wright, Bruno
Drouillat, Jérôme Marrot, and François Couty
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700231
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700231
Supported by

10.1002/ejoc.201700231
European Journal of Organic Chemistry
FULL PAPER
Iodocarbamation of homopropargyl N-carbamates: mild and
stereoselective entry to functionalized oxazinan-2-ones
Pierre Quinodoz, Alexandre Quelhas, Karen Wright, Bruno Drouillat, Jérôme Marrot and François
Couty* [a]
Abstract: An efficient and general iodocarbamation of
homopropargyl N-Cbz carbamates was developed using iodine as
the electrophilic agent. This regio- and stereoselective cyclization
yields (E)-6-iodomethylen-oxazinan-2-ones, which can be further
transformed through palladium cross-coupling reactions followed by
hydrogenation, to produce 1,3-oxazinan-2-ones.
amino alcohols.10
Previous work 6-8
I2 (3 eq.)
AgBF4 (1.1 eq.)
EDCI (1 eq.)
I
O
O
N
I
O
N
R1
O
R2
N
OEt
+
O
R2
CH2Cl2, r. t.
R2
R1
A
R1
B
Introduction
Major
7 examples
50-75%
R1 = alkyl, aryl
R2 = H, Me
Minor
< 5%
Halocyclization of alkenes and alkynes is a very popular
reaction that has a vast array of variations usually displaying
high regio- and stereoselectivity. Since the seminal report of
Bougault1 with the first report of an iodolactonization, its long
history has only recently culminated in enantioselective
versions,2 and has also found myriad of synthetic applications.3
When N-carbamates are used as the nucleophilic partner, these
moieties react on the activated α- or β-alkene through their
oxygen atom, followed by fragmentation, leading to oxazolidin-2-
ones4 or oxazinan-2-ones5 with moderate to high
diastereoselectivity. When the electrophilic partner is an alkyne,
such halocarbamation reactions are more difficult to control,
since the produced haloalkene is prone to react with the halogen
source. Nevertheless, iodocarbamation of propargyl N-
carbamates A promoted by iodine in the presence of EDCI and
silver tetrafluoroborate as additives has been described6 and
gives stereoselectively (E)-5-iodomethylene oxazolidinones B.
Concerning homopropargyl N-carbamates C or C’, Au(I)7 and
Au(III)8-mediated cyclocarbamations were reported recently and
lead stereoselectively to oxazinan-2-ones D or D’. We report
herein an in depth study of the halocarbamation of
homopropargyl-N-Cbz carbamates and show that molecular
iodine, is a suitable activating agent to promote such reactions
(Scheme 1). This halogen, being cheap and non-toxic, has
always played a central role in such reactions9 but its use alone
without other reagents has never been reported in this particular
type of cyclocarbamation. We also report the reactivity of the
obtained cyclized products towards cross-coupling and reduction
reactions in order to demonstrate their synthetic relevance to
access saturated oxazinan-2-ones, which are precursors of 1,3-
H
R2
O
R2
AuPPh3Cl (5 mol %)
AgSBF6 (5 mol %)
O
CH2Cl2, r. t.
N
O
D
N
O
R1
R1
C
R1 = H, alkyl, aryl, allyl
R2 = H, CO2Et
4 examples
75-91%
H
Br
O
Br
O
Ar
Ar
AuCl3 (10 mol %)
Toluene, r. t.
N
H
O
N
H
O
C'
D'
4 examples
72-82%
This work
I
R3
O
R3
I2
O
R2
R2
CH2Cl2, r. t.
N
R1
OBn
N
R1
O
Scheme 1. Cyclization of propargyl- and homopropargyl N-carbamates
Results and Discussion
The nature of the halogen source (Br2 or NBS, and I2 or NIS)
and of the carbamate (N-Boc, N-Cbz or N-Carbomethoxymethyl)
were first screened in the cyclocarbamation process with N-Bn,
N-carbamoyl homopropargylamines 1-3 (Table 1). Within these
combinations, it soon appeared that iodine (2 equiv.), combined
with N-Cbz carbamate was the best (entry 5). Under these
conditions, an excellent yield (94%) of isolated pure (E)-
oxazinan-2-one 5 was obtained. The structure of this compound
[a]
Institut Lavoisier de Versailles, UMR 8180
Université de Versailles St-Quentin-en-Yvelines, Université Paris
Saclay.
45 av. des Etats-Unis, 78035 Versailles Cedex, France
E-mail: couty@chimie.uvsq.fr; http://www.ilv.uvsq.fr
Fax: +33 (0)1 39 25 44 52
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700231
European Journal of Organic Chemistry
FULL PAPER
was determined by X-ray crystallography (Figure 1, left). It is
noteworthy that crude reaction mixture showed a small amount
(3%) of the (Z)-isomer of 5, that was separated by flash
chromatography. Furthermore, the cyclization reaction was fast
and required only 20mn to reach completion. Other
combinations were far less efficient: reactions with Br2 or NBS
(entries 1,2) were not complete after 20 mn. These electrophiles
also led to by-products 6-7 resulting from reaction of 4 with
bromine or produced HBr (through deprotonation of the t-butyl
cation), thus complicating purification. Structures of 6 and 7
were determined by X-Ray crystallography (Figure 1, right).
Reaction with NIS was also more sluggish and required
protracted reaction time (12 h) to reach completion (entry 6).
With iodine as the electrophile, the nature of the carbamate
proved to be a key parameter (entries 3-5). When a N-Boc group
(entry 3) was used, cyclocarbamation was rapid but the release
of HI also leads to by-products by reaction with the produced
compound. Addition of a base (Et3N, 2 equiv.) as an acid
scavenger did not avoid these side-reactions. Methyl carbamate
reacted more sluggishly and the reaction did not reach
completion after 20 min. Only N-Cbz carbamate, leading to the
formation of benzyl iodide as a neutral by-product through
nucleophilic attack of I- on the benzylic carbon in the cationic
intermediate (as shown by 1H NMR in the crude reaction
mixture) secured stability of the produced alkenyl iodide.
isomer 5 with 3 equivalents of iodine at room temperature. After
20mn, the (Z)-isomer was already detectable by H NMR and
1
the isomerization was almost complete after 7 days, with a 90:10
(Z) :(E) ratio, from which (Z)-5 was isolated pure with a 60%
yield (Scheme 2).
Thermodynamic stabilities of these compounds were also
evaluated by AM1 calculations (B3LYP 6.31G + level of theory),
with SDD and DGDZVP basis set, and showed indeed a slight
increased stability (0.24 Kcal. mol-1 with the SDD basis set and
0.25 Kcal. mol-1 with the DGDZVP basis set) for the (Z)-5 isomer.
Scheme 2. Iodine mediated isomerization of the double bond
Figure 1. X-Ray structures of (E)-5 (left) and of 6 (right). The crystalline lattice
of 6/7 mixture shows a distribution of 6 (61%) and 7 (39%). Only 6 is shown.12
We next examined the scope of this iodocarbamation by varying
the substituents on the nitrogen atom, the homopropargyl chain,
and on the alkyne (Figures 2,3). We also examined the case of a
propargyl N-carbamate 19. Ethynyl N-benzylcarbamates 3 and
8-10 led to excellent yields of (E)-5 and 20-22, the (Z)-isomer
being very minor (1-5%) in the crude reaction mixture. With the
cyclohexylcarbamate 16, the isomerization process is more
rapid, and the yield of isolated (E)-28 was lowered. On the
contrary, electron poor N-Cbz anilines 11-15 reacted more
slowly (90 min are required), so that isomerization occurs more
significantly than with N-Cbz benzylamines. Substituted alkyne
17 gave a good yield of 29, whose (E) stereochemistry was also
confirmed by X-ray radiocrystallography,12 and substituted
substrate 18 gave 30 with high yield and total stereoselectivity.
Finally, cyclization of propargylcarbamate 19 also gave (E)-
oxazolidin-2-one 31 in excellent yield and total stereoselectivity.
Table 1. Experimental conditions optimization.
Entry
R
Reagent
Yield(%)[a]
1
2
t-Bu
t-Bu
Br2
52
53
NBS
3
4
t-Bu
I2
I2
55
75
Me
5
6
Bn
Bn
I2
94
18
NIS
[a] Yields refer to isolated product.
It is worthy to note that reaction time is also a key parameter,
since iodine induces a slow isomerization11 of the kinetically
produced (E)-double bond, so that the (Z)-isomer was also often
detected in the crude mixture, the two diastereoisomers being
easily separated by chromatography. In order to minimize the
presence of this (Z)-side-product, the reaction was followed by
TLC until completion and was quenched immediately with an
aqueous solution of Na2S2O3 to destroy the excess iodine. To
confirm the isomerization process, we reacted isolated (E)-
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10.1002/ejoc.201700231
European Journal of Organic Chemistry
FULL PAPER
Ph
(1.05 eq.)
Ph
H
I
NEt3 (5 eq.)
CuI (0.1 eq.)
PdCl2(PPh3)2 (0.1 eq.)
O
O
THF, r. t. 16h
98%
N
O
N
O
Bn
Bn
(E)-5
32
Ph
PhB(OH)2
Na2CO3 (5 eq.)
Pd(PPh3)4 (5mol %)
O
EtOH/toluene/H2O : 1/2/1
N
O
100°C, 5h
92%
Bn
33
Scheme 3. C-C coupling reactions on (E)-5 occur uneventfully.
Reduction of the iodomethylene moiety in 23 was next
investigated. Surprisingly, this compound was found to be
completely inert under classical hydrogenation conditions (H2,
Pd/C cat., AcOEt, 16h). Enenyne 32 could be hydrogenated to
give fully saturated oxazinan-2-one 34 in fair yield. In order to
evaluate the diastereoselectivity of such reaction, iodomethylene
30 was coupled with phenylacetylene to give 35, which was
hydrogenated to give in modest yield a non-separable mixture
(75:25) of diastereoisomers 36a,b. Structure of major isomer
36a was not unambiguously ascertained but is proposed to be
cis on the basis of AM1 calculations performed on each
compound to determine its preferred conformation, combined
with nOe experiments (see SI and Scheme 4).
Figure 1. Structure of the carbamates 3 and 8-19 used to examine the scope
of the iodocarbamation reaction.13
I
I
I
I
O
O
O
O
N
O
N
O
N
O
N
O
(E)-5
20
21
22
Me
Cl
MeO
92%
98:2
Yield: 94%
(E):(Z) ratio: 97:3
90%
99:1
90%
99:1
I
I
I
I
I
O
O
O
O
O
N
O
N
O
N
O
N
O
N
O
23
24
25
26
27
Me
Me
Cl
Br
I
72%
87:13
65%
88:12
71%
87:13
86%
95:5
72%
87:13
I
I
Me
Ph
O
N
O
I
O
O
O
N
O
N
O
N
O
31
28
29
30
65%a,b
87:13
65%a
75:25
92%
100:0
87%
100:0
Figure 2. Structure and yields of the cyclized products. Yields refers to
isolated pure (E)-isomer. aReaction conducted at 0°C. bStructure of 29 was
determined by X-ray radiocristallography.12
Carbon-carbon coupling reactions on vinylic iodide (E)-5 were
next investigated. Though β-lithio vinyl ether were reported to be
stable,14 lithium-iodide exchange in (E)-5 promoted by n-Buli in
THF at -78°C only led to rapid β-elimination and loss of CO2 and
gave N-Bn homopropargylamine as the only isolable product.
On the other hand, Sonogashira and Suzuki-Miyaura cross-
couplings15 occurred uneventfully and gave 32 and 33 with high
yields and full retention of configuration in the alkene (Scheme
3).
Scheme 4. Hydrogenations of enynes leads to oxazinan-2-ones.
Conclusions
In conclusion, we have developed an efficient iodine-mediated
iodocarbamation of diversely substituted homopropargyl-
carbamates. We have also demonstrated that both (E) and (Z)
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10.1002/ejoc.201700231
European Journal of Organic Chemistry
FULL PAPER
NCH2CH2), 2.76 (t, J = 6.3 Hz, 2H, NCH2CH2), 2.35 (s, 3H, Me) ppm.; 13
C
isomers of the produced iodomethylene are accessible as
respectively kinetic or thermodynamic products. Furthermore,
reactivity towards reduction and functionalization of the vinylic
RMN (75 MHz, CDCl3) : 151.7 (Cq), 150.4 (Cq), 137.9 (Cq), 132.7 (Cq),
129.5 (CAr), 128.2 (CAr), 58.0 (CHI), 52.5 (CH2Ar), 42.2 (NCH2CH2), 26.3
(NCH2CH2), 21.1 (Me) ppm.; IR (film) νmax 3069, 2910, 2850, 1709, 1697,
1638, 1425, 1133, 754 cm-1; ESIHRMS (positive mode) calcd. for
C13H15INO2 [M+H]+: 344.0148, found 344.0149.
iodide
was
evaluated.
Thus,
through
a
cross-
coupling/hydrogenation sequence, we obtained functionalized
saturated oxazinan-2-ones, synthetically relevant as 1-3-
aminoalcohol precursors.
(E)-3-(4-chlorobenzyl)-6-(iodomethylene)-1,3-oxazinan-2-one 21
Reaction time: 20 mn. White solid (326 mg, 90%); m.p. 100-102°C, Rf
=0.40 (AcOEt/EP : 20/80); 1H RMN (300 MHz, CDCl3) : δ (ppm) : δ = 7.35
(d, J = 8.4 Hz, 2H, Ar), 7.25 (d, J = 8.4 Hz, 2H, Ar), 5.90 (s, 1H, CHI),
4.55 (s, 2H, CH2Ar), 3.23 (t, J = 6.3 Hz, 2H, NCH2CH2), 2.79 (t, J = 6.2
Hz, 2H, NCH2CH2) ppm.; 13C RMN (75 MHz, CDCl3) : 151.5 (Cq), 150.4
(Cq), 134.4 (Cq), 134.0 (Cq), 129.5 (CAr), 129.1 (CAr), 58.4 (CHI), 52.2
(CH2Ar), 42.5 (NCH2CH2), 26.3 (NCH2CH2) ppm.; IR (film) νmax 3069,
2920, 1696, 1638, 1477, 1426, 1133, 1081, 1011, 755 cm-1; ESIHRMS
(positive mode) calcd. for C12H12ClIO2 [M+H]+: 363.9609, found 363.9601.
Experimental Section
1
General information: H and 13C NMR spectra were recorded at 200 or
300 and 75 MHz, respectively; chemical shifts (δ) are reported in ppm
and coupling constants (J) reported in Hertz and rounded up to 0.1 Hz.
Splitting patterns are abbreviated as follows: singlet (s), doublet (d),
triplet (t), quartet (q), septuplet (sep), multiplet (m), broad (br), or a
combination of these. Solvents were used as internal standard when
assigning NMR spectra (δ H: CDCl3 7.26 ppm ; δ C: CDCl3 77.0 ppm).
Assignments for signals from 1H and 13C in the NMR spectra were
validated by two-dimensional correlated spectroscopy (2D COSY) and
Heteronuclear Multiple Bond Correlation (HMBC). IR data were collected
with an ATR-FT-IR spectrometer. All reactions were carried out under
argon. Column chromatography was performed on silica gel (230–400
mesh) with use of various mixtures of CH2Cl2, EtOAc, petroleum ether
(35-60°C fraction) (PE) and methanol. TLC was performed on Merck
Kieselgel 60 F254 plates. Melting points are uncorrected. THF was
distilled under argon from sodium using benzophenone as indicator.
Dichloromethane was distilled from calcium hydride. Isomeric ratios were
determined by NMR analysis of crude reaction mixtures before
purification.
(E)-6-(iodomethylene)-3-(4-methoxybenzyl)-1,3-oxazinan-2-one 22
Reaction time: 20 mn. White solid (323 mg, 90%); m.p. 105-107°C, Rf
=0.60 (AcOEt/EP : 30/70); 1H RMN (300 MHz, CDCl3) : δ (ppm) : δ = 7.15
(d, J = 8.7Hz, 2H, Ar), 6.80 (d, J = 8.7 Hz, 2H, Ar), 5.78 (s, 1H, CHI), 4.44
(s, 2H, CH2Ar), 3.73 (s, 3H, OMe), 3.13 (t, J = 6.4 Hz, 2H, NCH2CH2),
2.68 (t, J = 6.3 Hz, 2H, NCH2CH2) ppm.; 13C RMN (75 MHz, CDCl3) :
159.5 (Cq), 151.7 (Cq), 150.3 (Cq), 129.6 (Cq), 127.8 (CAr), 114.2 (CAr),
58.0 (CHI), 55.3 (OMe), 52.2 (CH2Ar), 42.1 (NCH2CH2), 26.3 (NCH2CH2)
ppm.; IR (film) νmax 3065, 2970, 2917, 1696, 1638, 1513, 1416, 1127,
830 cm-1; ESIHRMS (positive mode) calcd. for C13H15INO3 [M+H]+:
360.0097, found 360.0096.
General procedure for iodine mediated iodocarbation
(E)-6-(iodomethylene)-3-phenyl-1,3-oxazinan-2-one 23
Homopropargylcarbamate 3 or 8-19 (1 mmol) was dissolved in distilled
dichloromethane (6 mL) and iodine (2 eq.) was then added at 0°C. The
mixture was allowed to warm up to room temperature and was stirred
until complete TLC conversion (from 15 min to 2 hours). It was then
quenched by adding a saturated aqueous Na2S2O3 (10 mL) and stirred
vigorously for 10 minutes. The phases were separated and the aqueous
layer extracted with dichloromethane (3 x 15 mL). The organic layers
were then washed with brine, dried on MgSO4 and the solvent was
evaporated. The residue was purified by flash chromatography (eluent
PE/EtOAc).
Reaction time: 90 mn. White solid (226 mg, 72%); m.p. 138-140°C, Rf
=0.30 (AcOEt/EP : 15/85); 1H RMN (300 MHz, CDCl3) : δ (ppm) : 7.46-
7.28 (m, 5H, Ph), 5.99 (t, J = 1.0 Hz, 1H, CHI), 3.77 (t, J = 6.3 Hz, 2H,
NCH2CH2), 3.01 (td, J = 6.3, 1.0 Hz, 2H, NCH2CH2) ppm.; 13C RMN (75
MHz, CDCl3) : 151.6 (Cq), 149.2 (Cq), 141.9 (Cq), 129.3 (CAr), 127.2 (CAr),
125.1 (CAr), 58.4 (CHI), 46.5 (NCH2CH2), 26.9 (NCH2CH2) ppm.; IR (film)
νmax 3065, 1711, 1643, 1496, 1479, 1398, 1139, 760 cm-1; ESIHRMS
(positive mode) calcd. for C11H11INO2 [M+H]+: 315.9835, found 315.9842.
(E)-3-(4-chlorophenyl)-6-(iodomethylene)-1,3-oxazinan-2-one 24
(E)-3-benzyl-6-(iodomethylene)-1,3-oxazinan-2-one (E)-5
Reaction time: 90 mn. White solid (227 mg, 65%); m.p. 122-124°C, Rf
=0.60 (AcOEt/EP : 20/80); 1H RMN (300 MHz, CDCl3) : δ (ppm) : 7.36 (d,
J = 8.7 Hz, 2H, Ar), 7.25 (d, J = 8.6 Hz, 2H, Ar), 5.97 (s, 1H, CHI), 3.71 (t,
J = 6.2 Hz, 2H, NCH2CH2), 2.98 (t, J = 6.2 Hz, 2H, NCH2CH2) ppm.; 13C
RMN (75 MHz, CDCl3) : 151.3 (Cq), 149.0 (Cq), 140.3 (Cq), 132.7 (Cq),
129.4 (CAr), 126.4 (CAr), 58.8 (CHI), 46.4 (NCH2CH2), 26.8 (NCH2CH2)
ppm.; IR (film) νmax 3061, 1708, 1697, 1641, 1421, 1321, 1149, 822 cm-1;
ESIHRMS (positive mode) calcd. for C11H10ClINO2 [M+H]+: 349.9452,
found 349.9448.
Reaction time: 20 mn. White solid (309 mg, 94%); m.p. 80-82°C, Rf =0.3
(AcOEt/EP : 20/80); 1H RMN (300 MHz, CDCl3) : δ (ppm) : 7.42-7.24 (m,
5H, Ph), 5.87 (s, 1H, CHI), 4.58 (s, 2H, CH2Ph), 3.22 (t, J = 6.3 Hz, 2H,
NCH2CH2), 2.77 (t, J = 6.3 Hz, 2H, NCH2CH2) ppm.; 13C RMN (75 MHz,
CDCl3) : 151.7 (Cq), 150.4 (Cq), 135.8 (Cq), 128.9 (CAr), 128.1 (CAr),
128.1 (CAr), 58.3 (CHI), 52.8 (CH2Ph), 42.4 (NCH2CH2), 26.3 (NCH2CH2)
ppm.; IR (film) νmax 3056, 1717, 1634, 1423, 1210, 1130, 740, 713, 693
cm-1; ESIHRMS (positive mode) calcd. for C12H13INO2 [M+H]+: 329.9991,
found 329.9991.
(E)-3-(4-bromophenyl)-6-(iodomethylene)-1,3-oxazinan-2-one 25
(E)-6-(iodomethylene)-3-(4-methylbenzyl)-1,3-oxazinan-2-one 20
Reaction time: 90 mn. White solid (279 mg, 71%); m.p. 135-138°C, Rf
=0.70 (AcOEt/EP : 15/85); 1H RMN (300 MHz, CDCl3) : δ (ppm) : 7.54 (d,
J = 8.7 Hz, 2H, Ar), 7.22 (d, J = 8.7 Hz, 2H, Ar), 5.99 (s, 1H, CHI), 3.74 (t,
J = 6.2 Hz, 2H, NCH2CH2), 3.01 (t, J = 6.2 Hz, 2H, NCH2CH2) ppm.; 13C
RMN (75 MHz, CDCl3) : 151.3 (Cq), 148.9 (Cq), 140.8 (Cq), 132.4 (Cq),
126.7 (CAr), 120.6 (CAr), 58.8 (CHI), 46.3 (NCH2CH2), 26.8 (NCH2CH2)
Reaction time: 20 mn. White solid (316 mg, 92%); m.p. 93-95°C, Rf
=0.45 (AcOEt/EP : 20/80); 1H RMN (300 MHz, CDCl3) : δ (ppm) : δ = 7.19
(d part of AB syst., J = 8.7 Hz, 2H, Ar), 7.16 (d part of AB syst., J = 8.7
Hz, 2H, Ar), 5.87 (s, 1H, CHI), 4.55 (s, 2H, CH2Ar), 3.21 (t, J = 6.3 Hz, 2H,
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10.1002/ejoc.201700231
European Journal of Organic Chemistry
FULL PAPER
ppm.; IR (film) νmax 3059, 1708, 1697, 1641, 1490, 1467, 1422, 1322,
1150, 822, 721 cm-1; ESIHRMS (positive mode) calcd. for C11H10BrINO2
[M+H]+: 393.8940, found 393.8949.
1492, 1408, 1137, 1116, 694 cm-1; ESIHRMS (positive mode) calcd. for
C17H15INO2 [M+H]+: 392.0148, found 392.0143.
(E)-3-benzyl-5-(iodomethylene)-1,3-oxazolidin-2-one 31
(E)-3-(3,5-dimethylphenyl)-6-(iodomethylene)-1,3-oxazinan-2-one 26
Reaction time: 20 mn. White solid (290 mg, 92%); m.p. 104-106°C,Rf
=0.4 (AcOEt/EP : 10/90); 1H RMN (300 MHz, CDCl3) : δ (ppm) : 7.47-
7.25 (m, 5H, Ph), 5.75 (t, J = 2.7 Hz, 1H, CHI), 4.51 (s, 2H, CH2Ph), 3.97
(d, J = 2.7 Hz, 2H, CH2CHI) ppm; 13C RMN (75 MHz, CDCl3) : 155.40
(Cq), 148.31 (Cq), 134.61 (Cq), 129.13 (CAr), 128.48 (CAr), 128.2 (CAr)5,
50.91 (CHI), 50.29 (CH2CHI), 48.05 (CH2Ph) ppm.; IR (film) νmax3069,
2948, 1769, 1664, 1422, 1226, 1051, 741, 692 cm-1; ESIHRMS (positive
mode) calcd. for C13H15INO2 [M+H]+: 315.9829, found 315.9824..
Reaction time: 90 mn. White solid (247 mg, 72%); m.p. 138-140°C, Rf
=0.60 (AcOEt/EP : 20/80); 1H RMN (300 MHz, CDCl3) : δ (ppm) : 6.93 (s,
3H, Ar), 5.96 (s, 1H, CHI), 3.70 (t, J = 6.3 Hz, 2H, NCH2CH2), 2.98 (t, J =
6.3 Hz, 2H, NCH2CH2), 2.33 (s, 6H, Me) ppm.; 13C RMN (75 MHz,
CDCl3) : 151.7 (Cq), 149.2 (Cq), 141.7 (Cq), 139.2 (Cq), 129.1 (CAr), 123.0
(CAr), 58.2 (CHI), 46.7 (NCH2CH2), 26.9 (NCH2CH2), 21.2 (Me) ppm.; IR
(film) νmax 3065, 2913, 1716, 1637, 1481, 1409, 1154, 1113 cm-1;
ESIHRMS (positive mode) calcd. for C13H15INO2 [M+H]+: 344.0147,
found 344.0148.
Pd-catalyzed coupling reactions
(E)-6-(iodomethylene)-3-(naphthalen-1-yl)-1,3-oxazinan-2-one 27
Sonogashira cross-coupling. In
a flame dried roundbottom, the
oxazinanone (1 mmol) was dissolved in dry THF (15 mL). Copper iodide
(0.1 mmol, 19 mg), triethylamine (5 mmol, 0.7 mL) and phenylacetylene
(1.05 mmol, 115 µL) were added. The reaction mixture was degased by
argon bubbling for 15 min and palladium catalyst PdCl2(PPh3)2 was
added afterwards. After stirring 12h at room temperature, THF was
removed, the crude product dissolved in EtOAc and water, then extracted
with EtOAc (3x 20 mL). The organic layers were washed with brine, dried
on MgSO4 and the solvent was evaporated. The residue was purified by
flash chromatography (eluent PE/EtOAc).
Reaction time: 90 mn. White solid (314 mg, 86%); m.p. 183-185°C, Rf
=0.40 (AcOEt/EP : 20/80); 1H RMN (300 MHz, CDCl3) : δ (ppm) : 7.97-
7.85 (m, 2H, Ar), 7.85-7.76 (m, 1H, Ar), 7.65-7.42 (m, 4H, Ar), 6.08 (s, 1H,
CHI), 3.86-3.67 (m, 2H, NCH2CH2), 3.25-3.01 (m, 2H, NCH2CH2) ppm.;
13C RMN (75 MHz, CDCl3) : 151.8 (Cq), 149.4 (Cq), 138.1 (Cq), 134.8 (Cq),
129.2 (Cq), 129.0 (CAr), 128.8 (CAr), 127.3 (CAr), 126.6 (CAr), 125.8 (CAr),
124.9 (CAr), 121.8 (CAr), 58.8 (CHI), 47.3 (NCH2CH2), 26.9 (NCH2CH2)
ppm.; IR (film) νmax 3059, 1708, 1641, 1412, 1320, 1152, 1109, 805, 778,
746 cm-1; ESIHRMS (positive mode) calcd. for C15H13INO2 [M+H]+:
365.9991, found 365.9990.
Suzuki-Miyaura cross-coupling. In
a sealed tube, a solution of
oxazinanone (1 mmol.) in toluene (5 mL), a solution of phenylboronic
acid (244 mg,2 mmol.) in absolute EtOH (3 mL) and a 2M aqueous
solution of Na2CO3 (3 mL) were stirred together while argon was
bubbled through the mixture for 15 min. Pd(PPh3)4 (57 mg, 5 mol%) was
then added and the mixture was stirred at 100°C under argon for 5h,
then cooled to room temperature and poured into EtOAc and water. The
aqueous layer was extracted with EtOAc. The combined organic layers
were washed with brine, then dried over MgSO4. The residue was then
purified by flash chromatography.
(E)-3-cyclohexyl-6-(iodomethylene)-1,3-oxazinan-2-one 28
Reaction time: 20 mn at 0°C. White solid (209 mg, 65%); m.p. 126-128°C,
Rf =0.60 (AcOEt/EP : 30/70); 1H RMN (300 MHz, CDCl3) : δ (ppm) : 5.82
(s, 1H, CHI), 4.20-4.05 (m, 1H, NCH), 3.24 (t, J = 6.3 Hz, 2H, NCH2CH2),
2.78 (t, J = 6.2 Hz, 2H, NCH2CH2), 1.90-1.52 (m, 6H, Cy), 1.44-1.34
(m,3H, Cy), 1.08 (m, 1H, Cy) ppm; 13C RMN (75 MHz, CDCl3) : 151.6
(Cq), 149.8 (Cq), 57.1 (CHI), 56.0 (NCH), 37.5 (NCH2CH2), 29.7 (Cy),
26.8 (NCH2CH2), 25.5 (Cy), 25.3 (Cy) ppm.; IR (film) νmax 3062, 2914,
2849, 1705, 1638, 1420, 1305, 1175, 1112, 819, 739 cm-1; ESIHRMS
(positive mode) calcd. for C11H17INO2 [M+H]+: 322.0304, found 322.0304.
(E)-3-benzyl-6-(3-phenylprop-2-yn-1-ylidene)-1,3-oxazinan-2-one 32
Yellow solid (297 mg, 98%); m.p. 117-119°C, Rf =0.30 (AcOEt/EP :
20/80); 1H RMN (300 MHz, CDCl3) : δ (ppm) : 7.50-7.19 (m, 10H, Ph),
5.54 (s, 1H, PhCCCH), 4.63 (s, 2H, CH2Ph), 3.30 (t, J = 6.3 Hz, 2H,
NCH2CH2), 2.91 (t, J = 6.2 Hz, 2H, NCH2CH2) ppm.; 13C RMN (75 MHz,
CDCl3) : 157.7 (Cq), 150.4 (Cq), 135.8 (Cq), 131.2 (CAr), 128.9 (CAr),
128.4 (CAr), 128.2 (CAr), 128.1 (CAr), 128.1 (CAr), 123.2 (Cq), 94.1 (Cq),
90.6 (PhCCCH), 83.5 (PhCCCH), 52.9 (CH2Ph), 42.3 (NCH2CH2), 23.9
(NCH2CH2) ppm.; IR (film) νmax 3053, 2910, 2847, 1720, 1632, 1485,
1429, 1139, 753 cm-1; ESIHRMS (positive mode) calcd. for C20H17NO2
[M+H]+: 304.1338, found 304.1343.
(E)-3-benzyl-6-(1-iodoethylidene)-1,3-oxazinan-2-one 29
Reaction time: 20 mn at 0°C. White solid (223 mg, 65%); m.p. 110-112°C,
Rf =0.30 (AcOEt/EP : 15/85); 1H RMN (300 MHz, CDCl3) : δ (ppm) : 7.41-
7.24 (m, 5H, Ph), 4.59 (s, 2H, CH2Ph), 3.19 (t, J = 6.3 Hz, 2H, NCH2CH2),
2.84 (td, J = 6.3, 1.3 Hz, 2H, NCH2CH2), 2.51 (t, J = 1.3 Hz, 3H, Me)
ppm; 13C RMN (75 MHz, CDCl3) : 150.8 (Cq), 145.4 (Cq), 136.0 (Cq),
128.8 (CAr), 128.2 (CAr), 128.0 (CAr), 78.0 (Cq), 52.8 (NCH2Ph), 42.8
(NCH2CH2), 29.0 (NCH2CH2), 24.9 (Me) ppm.; IR (film) νmax 2942, 2907,
1711, 1660, 1444, 1204, 1168, 1104, 1076, 697, 604 cm-1; ESIHRMS
(positive mode) calcd. for C13H15INO2 [M+H]+: 344.0148, found 344.0153.
(E)-3-benzyl-6-benzylidene-1,3-oxazinan-2-one 33
(R,E)-6-(iodomethylene)-3,5-diphenyl-1,3-oxazinan-2-one 30
Yellow solid (257 mg, 92%); m.p. 86-88°C, Rf =0.75 (AcOEt/EP : 20/80);
[α]D20 = -297 (c.1.55, CHCl3); 1H RMN (300 MHz, CDCl3) : δ (ppm) :
7.39-6.95 (m, 10H, Ph), 6.28 (s, 1H, CHPh), 4.54 (s, 2H, CH2Ph), 3.12 (t,
Reaction time: 90mn. White solid (340 mg, 87%); m.p. 162-164°C, Rf
J = 6.1 Hz, 2H, NCH2CH2), 2.75 (t, J = 6.1 Hz, 2H, NCH2CH2) ppm.; 13
C
1
=0.30 (AcOEt/EP : 5/95); [α]D20 = -61 (c.1.4, CHCl3); H RMN (300 MHz,
RMN (75 MHz, CDCl3) : 151.4 (Cq), 148.3 (Cq), 136.1 (Cq), 134.3 (Cq),
128.9 (CAr), 128.7 (CAr), 128.5 (CAr), 128.2 (CAr), 128.0 (CAr), 126.9 (CAr),
110.2 (CHPh), 52.7 (CH2Ph), 42.7 (NCH2CH2), 23.1 (NCH2CH2) ppm.;
IR (film) νmax 3050, 2894, 1701, 1656, 1492, 1445, 1419, 1219, 1133,
694 cm-1; ESIHRMS (positive mode) calcd. for C18H18NO2 [M+H]+:
280.1338, found 280.1342.
CDCl3) : δ (ppm) : 7.54-7.13 (m, 9H, Ph), 6.99 (d, J = 5.6 Hz, 2H, Ph),
6.20 (s, 1H, CHI), 4.61-4.53 (m, 1H, CHPh), 4.29 (dd, J = 12.4, 3.8 Hz,
1H, NCHH), 3.79 (dd, J = 12.4, 2.0 Hz, 1H, NCHH) ppm.; 13C RMN (75
MHz, CDCl3) : 153.3 (Cq), 149.0 (Cq), 141.7 (Cq), 136.5 (Cq), 129.3 (CAr),
129.2 (CAr), 128.0 (CAr), 127.3 (CAr), 127.1 (CAr), 125.4 (CAr), 60.3 (CHI),
53.1 (NCH2), 41.7 (CHPh) ppm.; IR (film) νmax 3065, 3021, 1707, 1631,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700231
European Journal of Organic Chemistry
FULL PAPER
(R,E)-3,5-diphenyl-6-(3-phenylprop-2-yn-1-ylidene)-1,3-oxazinan-2-
one 35
Acknowledgements
The University of Versailles St-Quentin-en-Yvelines, University
Paris-Saclay and the CNRS are acknowledged for funding. PQ
acknowledges l’École polytechnique for a PhD grant.
Brown oil (354 mg, 97%); Rf =0.30 (AcOEt/EP : 5/95); [α]D20 = -297
(c.1.55, CHCl3); 1H RMN (300 MHz, CDCl3) : δ (ppm) : 7.37-7.12 (m,
13H, Ph), 6.98 (d, J = 8.3 Hz, 2H, Ph), 5.69 (s, 1H, PhCCCH), 4.63 (dd,
J = 3.8, 2.1 Hz, 1H, NCH2CHPh), 4.24 (dd, J = 12.3, 3.9 Hz, 1H,
NCHHCHPh), 3.78 (dd, J = 12.3, 2.2 Hz, 1H, NCHHCHPh) ppm.; 13C
RMN (75 MHz, CDCl3) : 159.4 (Cq), 149.0 (Cq), 141.9 (Cq), 137.4 (Cq),
131.3 (CAr), 129.4 (CAr), 129.2 (CAr), 128.3 (CAr), 128.3 (CAr), 127.9 (CAr),
127.3 (CAr), 127.1 (CAr), 125.4 (CAr), 123.1 (Cq), 94.9 (Cq), 92.2
(PhCCCH), 83.3 (Cq), 52.7 (NCH2CHPh), 39.3 (NCH2CHPh) ppm.; IR
(film) νmax 3062, 3034, 1724, 1634, 1490, 1401, 1162, 1130, 753, 689
cm-1; ESIHRMS (positive mode) calcd. for C25H20NO2 [M+H]+: 366.1494,
found 366.1491.
Keywords: halocarbamation • iodine • oxazinan-2-one
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General procedure for hydrogenations
The oxazinanone (1 mmol) was dissolved in EtOAc (4 mL) and 10% Pd
on charcoal (1 wt eq.) was added. The mixture was stirred under a H2
atmosphere (1 bar) for 12 hours, it was then filtered on Celite®. The
solvent was evaporated and residue purified by flash chromatography
(eluent PE/EtOAc).
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(R,S)-3-benzyl-6-(3-phenylpropyl)-1,3-oxazinan-2-one 34
1
Oil (188 mg, quant.); Rf =0.30 (AcOEt/EP : 25/75); H RMN (300 MHz,
CDCl3) : δ (ppm) : 7.40-7.13 (m, 10H, Ph), 4.63 and 4.51 (two d, J = 14.9
Hz, 2H, NCH2Ph), 4.28-4.17 (m, 1H, OCH), 3.29-3.08 (m, 2H,
NCH2CH2), 2.66 (t, J = 7.1 Hz, 2H, PhCH2CH2CH2), 2.18 (s, 1H), 1.98-
1.54 (m, 6H, PhCH2CH2CH2 and NCH2CH2) ppm.; 13C RMN (75 MHz,
CDCl3) : 154.2 (Cq), 141.8 (Cq), 136.8 (Cq), 128.7 (CAr), 128.4 (CAr),
128.4 (CAr), 128.1 (CAr), 127.6 (CAr), 125.9 (CAr), 77.0 (OCH) 52.5
(NCH2Ph), 43.7 (NCH2CH2), 35.6 (PhCH2CH2CH2), 34.5, 27.2 and 26.5
(NCH2CH2 and PhCH2CH2CH2) ppm.; IR (film) νmax 2926, 2869, 1681,
1449, 1260, 1131, 729, 698 cm-1; ESIHRMS (positive mode) calcd. for
C20H24NO2 [M+H]+: 310.1807, found 310.1811.
(5R,6S)-3,5-diphenyl-6-(3-phenylpropyl)-1,3-oxazinan-2-one 36a and
(5R,6R)-3,5-diphenyl-6-(3-phenylpropyl)-1,3-oxazinan-2-one 36b
[7]
[8]
[9]
R. Robles-Machin, J. Adrio, J. C. Carretero, J. Org. Chem. 2006, 71,
5023-5026.
Oil (171 mg, 46%.); Rf =0.40 (Major) and 0.25 (minor) (AcOEt/EP :
25/75); 1H RMN (300 MHz, CDCl3) : δ (ppm) : 7.35-6.95 (m, 15HM and
15Hm, Ph), 4.65-4.48 (m, 1HM and 1Hm, OCH), 4.00 (dd, J = 11.8, 5.7 Hz,
1HM, NCHH), 3.85-3.68 (m, 1HM and 1Hm, NCHH), 3.64 (dd, J = 11.8,
5.4 Hz, 1Hm, NCHH), 3.34-3.24 (m, 1HM, CHPh), 3.12 (td, J = 10.8, 5.4
Hz, 1Hm, CHPh), 2.50 (t, J = 7.3 Hz, 2HM and 2Hm, CH2Ph), 1.95-1.33
(m, 4HM and 4Hm, CH2CH2CH2Ph) ppm.; 13C RMN (75 MHz, CDCl3) :
Y. K. Kumar, G. R. Kumar, M. S. Reddy, Org. Biomol. Chem. 2016, 14,
1252-1260.
For reviews, see: a) A. N. French, S. Bissmire, T. Wirth, Chem. Soc.
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18, 948-951. b) M. Zheng, S. B. Herzon, J. Org. Chem. 2015, 80, 8604-
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M
152.8 (CqM), 151.9 (Cqm), 142.7 (CqM), 142.5 (Cqm), 141.7 (Cq and m),
137.4 (CqM), 137.0 (Cqm), 129.8 (CAr), 129.4 (CAr), 129.2 (CAr), 129.0
(CAr), 128.4 (CAr), 128.4 (CAr), 128.3 (CAr), 128.0 (CAr), 127.9 (CAr), 127.7
(CAr), 127.1 (CAr), 126.8 (CAr), 126.1 (CAr), 125.9 (CAr), 125.8 (CAr), 125.6
(CAr), 81.3 (OCmH), 80.0 (OCMH), 54.9 (NCmH2), 53.7 (NCMH2), 44.1
(CmHPh), 41.0 (CMHPh), 35.42 (CmH2Ph), 35.37 (CMH2Ph), 32.4
(CmH2CH2CH2Ph), 31.1 (CMH2CH2CH2Ph), 27.1 (CH2CMH2CH2Ph), 26.0
(CH2CmH2CH2Ph) ppm.; IR (film) νmax 3059, 3024, 2929, 1692, 1494,
1420, 1152, 752, 695 cm-1; ESIHRMS (positive mode) calcd. for
C25H26NO2 [M+H]+: 372.1964, found 372.1957.
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iodine radical on the alkene, see: S. S. Hepperle, Q. Li, A. L. L. East, J.
Phys. Chem. A, 2005, 109 (48), 10975–10981.
[12] X-Ray structures of (E)-5, 6/7 mixture and 29 were deposited at the
Cambridge database and were allocated numbers: 1510880, 1510879
and 1515802 respectively.
[13] These homopropargylic carbamates were prepared by alkylation of the
corresponding amine with 4-methanesulfonyl butyne followed by Cbz
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10.1002/ejoc.201700231
European Journal of Organic Chemistry
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protection (see SI). For compound 11-16 and 18, see: P. Quinodoz, K.
Wright, B. Drouillat, O. R. P. David, J. Marrot, F. Couty. Chem.
Commun. 2016, 52, 10072-10075.
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Tetrahedron, 2003, 59, 2067-2081. b) K. Cherry, J. Thibonnet, A.
Duchêne, J.-L. Parrain, M. Abarbry, Tetrahedron Lett. 2004, 47, 2063-
2066.
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1996, 40, 7255-7258.
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10.1002/ejoc.201700231
European Journal of Organic Chemistry
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FULL PAPER
Halocarbamation reaction*
Pierre Quinodoz, Alexandre Quelhas,
Karen Wright, Bruno Drouillat, Jérôme
Marrot and François Couty*
Page No. – Page No.
Iodocarbamation of homopropargyl
N-carbamates: mild and
stereoselective entry to
functionalized oxazinan-2-ones
Iodocarbamation of N-Cbz homopropargylamines gives high yields of stereodefined 6-iodomethylene oxazin-2-
ones, that can further be transformed into oxazinan-2-ones.
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