Synthesis of N-vinyloxazolidinones and morpholines from amino alcohols and vinylsulfonium salts: Analysis of the outcome's dependence on the N-protecting group by nanospray mass spectrometry

Article abstract of DOI:10.1002/ejoc.201101272

The effect of the nature of the N-protecting group on 1,2-amino alcohols in annulation reactions with diphenylvinylsulfonium triflate has been investigated. Although tosyl and sulfinamide groups give morpholines in high yields, the use of N-Cbz leads to a high-yielding synthesis of N-vinyloxazolidinones. The reactions were monitored by nanospray MS/MS, which revealed why reactions are successful and the fate of reactive intermediates in the unsuccessful reactions.

Full text of DOI:10.1002/ejoc.201101272

FULL PAPER
DOI: 10.1002/ejoc.201101272
Synthesis of N-Vinyloxazolidinones and Morpholines from Amino Alcohols and
Vinylsulfonium Salts: Analysis of the Outcome’s Dependence on the
N-Protecting Group by Nanospray Mass Spectrometry
Muhammad Yar,[a][‡] Sven P. Fritz,[a] Paul J. Gates,[a] Eoghan M. McGarrigle,[a] and
Varinder K. Aggarwal*[a]
Keywords: Mass spectrometry / Protecting groups / Reaction mechanisms / Heterocycles / Amino alcohols
The effect of the nature of the N-protecting group on 1,2-
amino alcohols in annulation reactions with diphenylvi-
nylsulfonium triflate has been investigated. Although tosyl
and sulfinamide groups give morpholines in high yields, the
use of N-Cbz leads to a high-yielding synthesis of N-vinyl-
oxazolidinones. The reactions were monitored by nanospray
MS/MS, which revealed why reactions are successful and the
fate of reactive intermediates in the unsuccessful reactions.
cannot.[3a] We have therefore investigated these reactions in
more detail and found that the use of N-Cbz-carbamates
leads to a one-step high-yielding synthesis of N-vinyloxaz-
olidinones, which are very useful intermediates in organic
synthesis in their own right.[7] Furthermore, by monitoring
the reaction by MS/MS analysis,[8] we were able to not only
identify the events and therefore the mechanism of the suc-
cessful reactions but also the competing reaction pathways
that ultimately lead to undesired outcomes in the unsuccess-
ful reactions.
Introduction
The direct conversion of 1,2-amino alcohols or 1,2-di-
amines into morpholines or piperazines are important
transformations, particularly in the field of medicinal chem-
istry.[1,2] We recently reported a simple method for this
transformation: the reaction of a 1,2-amino alcohol/1,2-di-
amine with diphenylvinylsulfonium triflate (1)[3–5] or bro-
moethyldiphenylsulfonium triflate (2) in the presence of
base (Scheme 1).[6]
The reactions reported herein are unique because related
amides and carbamates give very different products. For ex-
ample, it has been reported that the reactions of amides
with diphenylvinylsulfonium triflate (1) lead to 1,2-amino
esters[5k] [Equation (1)] and reactions of carbamates give
oxazolidinones[5h] [Equation (2)].
(1)
Scheme 1. Influence of the N-protecting group (N-PG) on the an-
nulation reaction.
Although a range of amino substituents can be used in
these transformations, including sulfonamides,[3a,6a] sulfin-
amides,[6b] aromatic and heteroaromatic groups,[6a] carbonyl-
based protecting groups (e.g., amides and Boc-carbamates)
(2)
[a] School of Chemistry, University of Bristol,
Cantock’s Close, Bristol, BS8 1TS, UK
Fax: +44-117-927-7985
Results and Discussion
We began our studies with a series of amide- and carba-
mate-derived amino alcohols 3a–f[9] and tested them with
sulfonium salt 1 in the presence of a range of bases (Et3N,
DBU, NaH, KOtBu). Although the amino alcohol bearing
an N-Ts group 3a led to morpholine 4a under a variety of
E-mail: V.Aggarwal@bristol.ac.uk
[‡] Current address: Department of Chemistry,
Government College University,
Katchery Road, 54000 Lahore, Pakistan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101272.
160
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 160–166

Synthesis of N-Vinyloxazolidinones and Morpholines
conditions (Table 1, Entry 1), the N-carbonyl compounds, preformed oxazolidinone 7f with the vinylsulfonium salt 1
except for the N-benzyloxy-carbamate, gave a mixture of and KOtBu did not furnish any N-vinyloxazolidinone 5f,
highly polar compounds (Table 1, Entries 2–5). However, which suggests that this pathway is unlikely to be operative.
with KOtBu as base the use of the benzyloxy-carbamate led Pathway B involves the initial conjugate addition of the N-
to the formation of N-vinyloxazolidinone 5f in high yield carbamate 3f to the vinylsulfonium salt 1 followed by ylide-
(Table 1, Entry 6). This reaction turned out to be general alcohol proton transfer, alkoxide-promoted elimination and
for a range of substituted N-benzyloxy-derived amino finally cyclisation. Indeed, by monitoring the reaction using
alcohols 3f–k, which gave N-vinyloxazolidinones 5f–k in nanospray MS/MS analysis[8] we were able to detect inter-
good-to-high yields in all cases (Table 2, Entries 1–6).[10]
mediates 10f and 11f along pathway B as well as the prod-
uct 5f (Figure 1). Taken together, these observations provide
strong evidence that the reaction of the benzyloxy-carb-
amate 3f with the vinylsulfonium salt 1 occurs along path-
way B.
Table 1. Results of annulation reactions with vinylsulfonium triflate
1.
Entry
3
PG
Product
Yield [%]
75
1
2
3
4
5
6
a
b
c
d
e
f
Ts
Boc
CH3CO
PhCO
CF3CO
PhCH2OCO
4a
–
–
–
–
[a]
–
–
–
–
[a]
[a]
[a]
5f
86[b]
[a] A mixture of highly polar compounds was obtained. Other
bases (Et3N, DBU, NaH) gave similar results. [b] Alternative bases
were not effective in this reaction.
Table 2. Results of annulation reactions with vinylsulfonium triflate
1.
Entry
R
RЈ
Product
Yield [%]
1
2
3
4
5
6
CH3
Ph
Ph
iPr
2,2-diMe
H
Ph
H
Ph
H
H
H
5f
5g
5h
5i
86
89
90
66
70
64
5j
Scheme 2. Possible pathways for the formation of vinyloxazol-
idinone 5f.
5k
The simple and straightforward synthesis of N-vinyl-
The nanospray MS/MS analysis allowed not only the
oxazolidinones is noteworthy as they have attracted signifi- identification of neutral species (e.g., [5f + H]+), but also
cant attention in recent years. They have been used in [4+2] the easy identification of the cationic sulfonium salt inter-
hetero-Diels–Alder reactions,[7a–7c] in palladium[7d,7e] and mediates (e.g., [10f + H]+). We therefore sought to use this
chromium[7f]-mediated transformations and in polymerisa- technique to try to discover the fate of unsuccessful reac-
tion reactions.[7g,7h] Although numerous methods have been tions involving N-Boc-carbamate 3b and amide 3d and to
reported for their synthesis,[11] our protocol is especially identify the intermediates in the successful annulation reac-
mild, practical and uses readily available starting materials. tions with sulfonamide 3a groups (Scheme 3).
Two possible pathways (A or B) can be advanced to ac-
The reactions of N-Boc 3b and N-COPh 3d amino
count for the formation of N-vinyloxazolidinones 5f–k alcohols with vinylsulfonium salt 1 followed the same path-
(Scheme 2). Pathway A involves the initial formation of ox- way and initially mirrored the reaction of the N-benzyloxy-
azolidinone 7f followed by conjugate addition, proton carbamate 3f group (compare Figure 1 with Figures 2 and
transfer and subsequent elimination. However, treatment of 3).
Eur. J. Org. Chem. 2012, 160–166
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
161

M. Yar, S. P. Fritz, P. J. Gates, E. M. McGarrigle, V. K. Aggarwal
FULL PAPER
Figure 2. Nanospray MS spectrum of the reaction of N-Boc-carba-
mate 3b with vinylsulfonium salt 1.
Figure 1. Nanospray MS spectrum of the reaction of hydroxycar-
bamate 3f with vinylsulfonium salt 1.
Scheme 3. Reaction pathways of various protected amino alcohols 3a,b,d,f under annulation conditions.
Common intermediates 10b/d, and 11b/d were clearly the possibility that it was the isomeric N-vinyltosylamide
identified. However, it seems that if cyclisation to the N- 11a (Figure 4).
carbonyl substituent cannot occur (amide, d series) or is
The final outcome of the reactions of protected amino
especially slow (N-Boc, b series), the alcohol preferentially alcohols with the vinylsulfonium salt 1 is thus dependent
reacts with another equivalent of the vinylsulfonium salt 1 on the fate of the key alkoxide sulfonium salts 10a,b,d,f. Up
leading to the polar sulfonium salts 13/14, which were read- to that point, all of the protected amino groups behave in
ily identified (Figure 2 and Figure 3).[12]
the same way, undergoing conjugate addition and subse-
Monitoring the successful annulation reaction of the sul- quent alcohol-ylide proton transfer. In the case of sulfon-
fonamide 3a clearly revealed the sulfonium salt intermediate amide groups, the key alkoxide 10a acts as a nucleophile
10a and the product 4a. The MS/MS of the signal assigned and leads to ring closure to give the morpholine. In the
to product 4a gave the same fragmentation pattern as the cases of the amide and carbamate groups, the alkoxide acts
isolated and fully characterised morpholine 4a eliminating as a base, instead leading to N-vinyl amides/carbamates.
162
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 160–166

Synthesis of N-Vinyloxazolidinones and Morpholines
Figure 5. Proposed major conformation of alkoxide intermediates
derived from carbamate- (15) and sulfonamide-protected (16)
amino alcohols.
Conclusions
We have discovered a new, facile, one-step synthesis of
N-vinyloxazolidinones 5f–k from simple N-Cbz-amino
alcohols 3f–k and vinylsulfonium salt 1. The pathway for
their formation has been mapped out by monitoring the
reactions by nanospray MS/MS analysis. More importantly,
this technique has enabled us to identify the products and
therefore understand why reactions with sulfonamide or N-
Cbz groups succeed (although give different products) and
why others with N-Boc and amide groups do not.
Figure 3. Nanospray MS spectrum of the reaction of N-COPh-car-
bamate 3d with vinylsulfonium salt 1.
Experimental Section
General Procedure A
Cbz Protection of β-Amino Alcohols: β-Amino alcohol (6.6 mmol,
1 equiv.) was dissolved in a 1 m aqueous NaOH solution (7.3 mmol,
1.1 equiv.), stirred for 5 min at 0 °C and then benzyl chloroformate
(7.3 mmol, 1.1 equiv.) was added dropwise. A solid material ap-
peared immediately. The reaction mixture was stirred for 2 h at
room temperature. The product was separated by filtration, washed
with water, dried under high vacuum and recrystallised from etha-
nol or purified by flash chromatography to afford the target com-
pound.
Figure 4. Nanospray MS spectrum of the reaction of sulfonamide
3a with the vinylsulfonium salt 1.
Benzyl [(1S,2R)-2-Hydroxy-1-methylphenylethyl]carbamate (3f):[14]
Following general procedure A. Yield 93%; white solid. Rf = 0.20
(EtOAc/PE, 3:7). M.p. 114–116 °C (ethanol) (ref.[14] 111–113 °C).
[α]2D2 = +41 (c = 1.5, CHCl3) {ref.[14] [α]2D5 = –38.7 (c = 1.5, CHCl3)
Unhindered carbamates can undergo ring closure to the
oxazolidinones 5, but with hindered carbamates and amides
they undergo further addition to another vinylsulfonium
salt to give the highly polar sulfonium salts 13 and 14
(Scheme 3).
Clearly the alkoxide 10 can act either as a nucleophile or
base. We hypothesise that its behaviour is dependent on the
nature of the N substituent. Amide/carbamate groups fav-
our E2 elimination whereas sulfonamide and sulfinamide
groups favour SN2 displacement. The reasons for the dif-
fering behaviour of the different N substituents may be re-
1
for the enantiomer}. H NMR (400 MHz, CDCl3): δ = 7.41–7.28
(m, 10 H, ArH), 5.13 (s, 2 H, PhCH2), 5.06 (br. d, J = 7.5 Hz, 1
H, NH), 4.92–4.85 (m, 1 H, PhCHOH), 4.11–4.05 (m, 1 H, NCH),
2.72 (br. s, 1 H, OH), 1.01 (d, J = 7.0 Hz, 3 H, CH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 156.6 (C=O), 140.7 (C), 136.4 (C),
128.6 (CH), 128.3 (CH), 128.3 (CH), 128.2 (CH), 127.7 (CH), 126.3
(CH), 76.7 (CHOH), 66.9 (CH2Ph), 52.4 (NCH), 14.5 (CH3) ppm.
The spectroscopic data are consistent with those reported.[14]
lated to the conformation. In the case of amide or carba- Benzyl (R)-2-Hydroxy-1-phenylethylcarbamate (3g):[15] Following
general procedure A. Yield 87%; white solid. Rf = 0.26 (EtOAc/
PE, 3:7). M.p. 98–100 °C (ethanol) [ref.[15] 111–113 °C (EtOAc/hex-
ane)]. [α]2D2 = –36 (c = 1.0, CH3OH) {ref.[15] [α]2D0 = –35.1 (c = 1,
mate groups 15, a hydrogen bond between the carbonyl and
CH groups may favour a conformation in which SN2 is not
possible and E2 becomes the preferred pathway (Figure 5).
Similar hydrogen bonds between sulfonium and phospho-
nium salts with carbonyl compounds and boranes have
been found to be energetically favourable.[13] In the case of
sulfonamides 16 the weaker hydrogen bond and the added
steric hindrance arising from the bulkier sulfone may lead
to a conformation in which E2 elimination is less favoured
and so nucleophilic substitution occurs instead.
1
CH3OH)}. H NMR (400 MHz, CDCl3): δ = 7.38–7.24 (m, 10 H,
ArH), 5.59 (br. s, 1 H, NH), 5.11 (d, J = 12.0 Hz, 1 H, PhCHHO),
5.06 (d, J = 12.0 Hz, 1 H, PhCHHO), 4.87–4.80 (m, 1 H, NCH),
3.90–3.75 (m, 2 H, CH2OH), 2.30 (br. t, J = 6.0 Hz, 1 H, OH) ppm.
13C NMR (100 MHz, CDCl3): δ = 156.5 (C=O), 139.2 (C), 136.2
(C), 128.9 (CH), 128.6 (CH), 128.3 (CH), 128.0 (CH), 126.72 (CH),
126.68 (CH), 67.1 (PhCH2), 66.5 (CH2OH), 57.2 (NCH) ppm. The
spectroscopic data are consistent with those reported.[15]
Eur. J. Org. Chem. 2012, 160–166
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
163

M. Yar, S. P. Fritz, P. J. Gates, E. M. McGarrigle, V. K. Aggarwal
FULL PAPER
Benzyl (1R,2S)-2-Hydroxy-1,2-diphenylethylcarbamate (3h):[16] Fol-
lowing general procedure A, except in this case the β-amino alcohol
was dissolved in THF/H2O (5 mL, 3:1) and then 1 m aqueous
solid. Rf = 0.4 (EtOAc/PE, 3:7). [α]2D4 = +25 (c = 1.0, CH2Cl2)
{ref.[20] [α]2D5 = –26 (c = 1.1, CH2Cl2) for the enantiomer}. 1H NMR
(400 MHz, CDCl3): δ = 7.45–7.31 (m, 5 H, ArH), 6.83 (dd, J =
NaOH was added. Yield 85%; white solid. Rf = 0.71 (EtOAc/PE, 16.5, 9.5 Hz, 1 H, CH=CH2), 5.71 (d, J = 7.5 Hz, 1 H, PhCH),
3:7). M.p. 173–174 °C (ethanol) [ref.[16] 172–173 °C (ethanol)].
4.50 (dd, J = 9.5, 1.5 Hz, 1 H, CH=CHH), 4.41 (dd, J = 16.5,
1.5 Hz, 1 H, CH=CHH), 4.35–4.41 (m, 1 H, NCH), 0.86 (d, J =
[α]2D2 = –61 (c = 1.0, CHCl3) {ref.[16] [α]2D2 = –67.4 (c = 1, CHCl3)}.
1H NMR (270 MHz, CDCl3): δ = 7.30–7.20 (m, 5 H, ArH), 7.16– 6.5 Hz, 3 H, CH3) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 134.1
7.13 (m, 6 H, ArH), 6.96–6.93 (m, 4 H, ArH), 5.55 (br. d, J = (C), 128.78 (CH), 128.73 (CH), 128.70 (CH), 125.9 (CH), 94.1
7.5 Hz, 1 H), 5.20–5.02 (m, 4 H, PhCH2, 2 PhCH), 2.50 (br. s, 1 (CH2), 79.2 (CH), 53.9 (CH), 12.9 (CH3) ppm. The spectroscopic
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.1 (C=O), 139.8 data are consistent with those reported.[20]
(C), 137.4 (C), 136.4 (C), 128.6 (CH), 128.2 (CH), 128.0 (CH),
(S)-4-Phenyl-3-vinyloxazolidin-2-one (5g):[21] Following general pro-
127.9 (CH), 126.6 (CH), 76.9 (OCH), 67.1 (PhCH2), 60.9
cedure B using benzyl (R)-2-hydroxy-1-phenylethylcarbamate (3g;
(NCH) ppm. The spectroscopic data are consistent with those re-
40 mg, 0.15 mmol), KOtBu (36 mg, 0.32 mmol) and diphenylvi-
ported.[17]
nylsulfonium salt 1 (79 mg, 0.22 mmol). After column chromatog-
Benzyl (؎)-1-Hydroxy-3-methylbutan-2-ylcarbamate (3i):[17] Fol-
raphy (EtOAc/PE, 3:7) the title compound (25 mg, 89%) was iso-
lowing general procedure A. Yield 74%; white solid. Rf = 0.25 lated as a white solid. Rf = 0.07 (EtOAc/PE, 3:7). [α]2D2 = +112 (c
1
(EtOAc/PE, 3:7). M.p. 48–50 °C (CH2Cl2) [ref.[17] 57–59 °C (benz- = 1.25, CH2Cl2) {ref.[21] [α] = +113 (c = 1.25, CH2Cl2)}. H NMR
ene/hexane)]. 1H NMR (400 MHz, CDCl3): δ = 7.15–7.37 (m, 5 H, (400 MHz, CDCl3): δ = 7.44–7.32 (m, 5 H, ArH), 6.83 (dd, J =
ArH), 5.46 (d, J = 9.2 Hz, 1 H, NH), 4.96–5.19 (m, 2 H, CH2), 16.0, 9.5 Hz, 1 H, HC=CH2), 5.02 (dd, J = 9.0, 5.5 Hz, 1 H,
3.34–3.73 (m, 4 H, NCH, PhCH2, OH), 1.80 (sept., J = 7.0 Hz, 1
PhCH), 4.72 (dd, J = 9.0, 9.0 Hz, 1 H, CHHO), 4.31 (dd, J = 9.5,
H, Me2CH), 0.91 (d, J = 11.5 Hz, 3 H, CH3), 0.88 (d, J = 11.5 Hz, 1.5 Hz, 1 H, HC=CHH), 4.13 (dd, J = 9.0, 5.5 Hz, 1 H, CHHO),
3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.2 (CO), 4.08 (dd, J = 16.0, 1.5, Hz, 1 H, HC=CHH) ppm. 13C NMR
136.3 (C), 128.2 (CH), 127.8 (CH), 127.7 (CH), 66.4 (CH2), 62.9 (100.5 MHz, CDCl3): δ = 155.9 (C=O), 138.1 (C), 129.5 (CH),
(CH2), 58.2 (CH), 28.9 (CH), 19.2 (CH3), 18.3 (CH3) ppm. The 128.9 (CH), 128.8 (CH), 125.9 (CH), 96.0 (CH2), 70.7 (CH2), 58.3
spectroscopic data are consistent with those reported.[17]
(CH) ppm. The spectroscopic data are consistent with those re-
ported.[21]
Benzyl 1-Hydroxy-2-methylpropan-2-ylcarbamate (3j):[18] Following
general procedure A. Yield 81%; clear oil. Rf = 0.31 (EtOAc/PE,
(4R,5S)-4,5-Diphenyl-3-vinyloxazolidin-2-one (5h):[22] Following ge-
neral procedure B using benzyl (1R,2S)-2-hydroxy-1,2-diphenyl-
ethylcarbamate (3h; 60 mg, 0.18 mmol), KOtBu (40 mg, 0.36 mmol)
and diphenylvinylsulfonium salt 1 (77 mg, 0.21 mmol). After col-
umn chromatography (EtOAc/PE, 3:7) the title compound (43 mg,
90%) was isolated as a white solid. Rf = 0.85 (EtOAc/PE, 3:7). M.p.
169–171 °C (EtOAc) (ref.[21] m.p. 170–171 °C). [α]2D2 = +22 (c = 1,
CHCl3) {ref.[22] [α]D = +21.7 (c = 0.775, CHCl3)}. 1H NMR
(270 MHz, CDCl3): δ = 7.12–6.83 (m, 11 H, ArH, CH=CH2), 5.91
(d, J = 8.5 Hz, 1 H, CH), 5.24 (d, J = 8.5 Hz, 1 H, CH), 4.36 (dd,
J = 9.5, 1.0 Hz, 1 H, CH=CHH), 4.08 (dd, J = 16.0, 1.0 Hz, 1 H,
CH=CHH) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 155.5 (CO),
133.8 (C), 133.4 (C), 128.7 (CH), 128.5 (CH), 128.4 (CH), 128.3
(CH), 128.0 (CH), 127.1 (CH), 126.4 (CH), 96.3 (CH2), 80.6 (CH),
63.3 (CH) ppm. The spectroscopic data are consistent with those
reported.[22]
1
3:7). H NMR (400 MHz, CDCl3): δ = 7.22–7.41 (m, 5 H, ArH),
5.27 (s, 1 H, NH), 5.05 (s, 2 H, CH2), 4.09 (br. s, 1 H, OH), 3.56
(d, J = 4.2 Hz, 2 H, PhCH2), 1.27 (s, 6 H, 2 CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 155.9 (CO), 136.2 (C), 128.3 (CH), 127.9
(CH), 127.8 (CH), 69.8 (CH2), 66.3 (CH2), 54.1 (C), 24.0
(CH3) ppm. The spectroscopic data are consistent with those re-
ported.[18]
Benzyl 2-Hydroxyethylcarbamate (3k):[19] Following general pro-
cedure A. Yield 68%; white solid. Rf = 0.12 (EtOAc/PE, 3:7). M.p.
52–54 °C (CH2Cl2) [ref.[19] 62–63 °C (benzene/hexane)]. 1H NMR
(400 MHz, CDCl3): δ = 7.19–7.41 (m, 5 H, ArH), 5.75 (t, J =
5.1 Hz, 1 H, NH), 5.06 (s, 2 H, PhCH2), 3.69 (br. s, 1 H, OH), 3.61
(t, J = 5.1 Hz, 2 H, CH2), 3.27 (q, J = 5.3 Hz, 2 H, CH2) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 156.9 (CO), 136.2 (C), 128.2 (CH),
127.81 (CH), 127.76 (CH), 66.5 (CH2), 61.4 (CH2), 43.2
(CH2) ppm. The spectroscopic data are consistent with those re-
ported.[19]
(؎)-4-Isopropyl-3-vinyloxazolidin-2-one (5i):[23] Following general
procedure B using benzyl (Ϯ)-1-hydroxy-3-methylbutan-2-ylcarb-
amate (3i; 100 mg, 0.42 mmol), KOtBu (95 mg, 0.85 mmol) and di-
phenylvinylsulfonium salt 1 (185 mg, 0.51 mmol). After column
chromatography (Et2O/hexanes, 75:25) the title compound (43 mg,
66%) was isolated as a clear oil. Rf = 0.70 (Et2O/hexanes, 75:25).
1H NMR (400 MHz, CDCl3): δ = 6.69 (dd, J = 16.0, 9.5 Hz, 1 H,
CH=CH2), 4.30–4.44 (m, 2 H, CH=CHH, CHH), 4.08–4.24 (m, 2
H, CH=CHH, CHH), 3.97 (dt, J = 8.5, 3.5 Hz, 1 H, NCH), 2.36
(sept.d, J = 7.0, 3.5 Hz, 1 H, Me2CH), 0.85 (d, J = 7.0 Hz, 3 H,
CH3), 0.77 (d, J = 7.0 Hz, 3 H, CH3) ppm. 13C NMR (100.5 MHz,
CDCl3): δ = 155.6 (CO), 128.8 (CH), 94.0 (CH2), 62.9 (CH2), 57.9
(CH), 25.9 (CH), 17.8 (CH3), 13.8 (CH3) ppm. The spectroscopic
data are consistent with those reported.[23]
General Procedure B
Synthesis of N-Vinyloxazolidinones: A stirred solution of N-pro-
tected β-amino alcohol (1.0 equiv.) in CH2Cl2 (0.06 m) was treated
with base (2.0 equiv.) at 0 °C under nitrogen. After 10 min a solu-
tion of diphenylvinylsulfonium salt 1 (1.2 equiv.) in CH2Cl2 (0.1 m)
was added dropwise over 2 min and the reaction was stirred for 3 h
at 0 °C and then for 12 h at room temp. The reaction was then
quenched with saturated ammonium chloride solution (5 mL), ex-
tracted with CH2Cl2 (3ϫ30 mL), washed with brine (10 mL), dried
with MgSO4, filtered and concentrated under vacuum. The product
was then purified by using flash column chromatography on silica.
(4R,5S)-4-Methyl-5-phenyl-3-vinyloxazolidin-2-one (5f):[20] Follow-
4,4-Dimethyl-3-vinyloxazolidin-2-one (5j):[24] Following general pro-
ing general procedure B using benzyl (1S,2R)-1-hydroxy-1- cedure B using benzyl 1-hydroxy-2-methylpropan-2-ylcarbamate
phenylpropan-2-ylcarbamate (3f; 20 mg, 0.07 mmol), KOtBu (3j; 100 mg, 0.44 mmol), KOtBu (99 mg, 0.88 mmol) and diphenyl-
(16 mg, 0.14 mmol) and diphenylvinylsulfonium salt 1 (26 mg,
0.073 mmol). After column chromatography (EtOAc/PE, 3:7) the
title compound (12 mg, 86%) was isolated as a colourless gummy
vinylsulfonium salt 1 (195 mg, 0.54 mmol). After column
chromatography (Et2O/hexanes, 75:25) the title compound (44 mg,
70%) was isolated as a clear oil. Rf = 0.52 (Et2O/hexanes, 75:25).
164
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 160–166

Synthesis of N-Vinyloxazolidinones and Morpholines
1H NMR (400 MHz, CDCl3): δ = 6.46 (dd, J = 16.5, 10.0 Hz, 1 H,
CH=CH2), 4.94 (dd, J = 16.5, 1.0 Hz, 1 H, CH=CHH), 4.54 (dd,
J = 10.0, 1.0 Hz, 1 H, CH=CHH), 4.03 (s, 2 H, CH2), 1.49 (s, 6 H,
2 CH3) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 155.1 (CO),
127.6 (CH), 96.5 (CH2), 75.2 (CH2), 58.5 (C), 24.7 (CH3) ppm. The
spectroscopic data are consistent with those reported.[24]
[3]
For the generation of morpholines via vinylsulfonium salts, see:
a) M. Yar, E. M. McGarrigle, V. K. Aggarwal, Angew. Chem.
2008, 120, 3844; Angew. Chem. Int. Ed. 2008, 47, 3784–3786; b)
M. Hansch, O. Illa, E. M. McGarrigle, V. K. Aggarwal, Chem.
Asian J. 2008, 3, 1657–1663; c) J. Bornholdt, J. Felding, J. L.
Kristensen, J. Org. Chem. 2010, 75, 7454–7457; d) J. An, N. J.
Chang, L. D. Song, Y. Q. Jin, Y. Ma, J. R. Chen, W. J. Xiao,
Chem. Commun. 2011, 47, 1869–1871.
3-Vinyloxazolidin-2-one (5k):[25] Following general procedure B
using benzyl 2-hydroxyethylcarbamate (3k; 700 mg, 3.57 mmol),
KOtBu (801 mg, 7.14 mmol) and diphenylvinylsulfonium salt 1
(1546 mg, 4.27 mmol). After column chromatography (Et2O/hex-
anes, 75:25) the title compound (258 mg, 64%) was isolated as a
yellow oil. Rf = 0.45 (Et2O/hexanes, 1:1). 1H NMR (400 MHz,
CDCl3): δ = 6.73 (dd, J = 15.8, 8.9 Hz, 1 H, CH=CH2), 4.28–
4.40 (m, 3 H, CH=CHH, CH2), 4.21 (dd, J = 15.8, 1.2 Hz, 1 H,
CH=CHH), 3.58–3.66 (m, 2 H, CH2) ppm. 13C NMR (100.5 MHz,
CDCl3): δ = 155.1 (CO), 129.3 (NCH), 93.2 (CH=CH2), 62.0
(CH2), 41.6 (CH2) ppm. The spectroscopic data are consistent with
those reported.[25]
[4]
[5]
For the generation of morpholines via vinyl selenones, see: L.
Bagnoli, C. Scarponi, M. G. Rossi, L. Testaferri, M. Tiecco,
Chem. Eur. J. 2011, 17, 993–999.
For related work on the application of vinylsulfonium salts in
synthesis, see: a) K. H. Kim, L. S. Jimenez, Tetrahedron: Asym-
metry 2001, 12, 999–1005; b) H. Yamanaka, J. Matsuo, A. Ka-
wana, T. Mukaiyama, Chem. Lett. 2003, 32, 626–627; c) J. Mat-
suo, H. Yamanaka, A. Kawana, T. Mukaiyama, Chem. Lett.
2003, 32, 392–393; d) H. Yamanaka, J. Matsuo, A. Kawana, T.
Mukaiyama, ARKIVOC 2004, 42–65; e) M. G. Unthank, N.
Hussain, V. K. Aggarwal, Angew. Chem. 2006, 118, 7224; An-
gew. Chem. Int. Ed. 2006, 45, 7066–7069; f) C. G. Kokotos,
E. M. McGarrigle, V. K. Aggarwal, Synlett 2008, 2191–2195;
g) M. G. Unthank, B. Tavassoli, V. K. Aggarwal, Org. Lett.
2008, 10, 1501–1504; h) C. S. Xie, D. Y. Han, J. H. Liu, T. Xie,
Synlett 2009, 3155–3158; i) S. Catalan-Munoz, C. A. Muller,
S. V. Ley, Eur. J. Org. Chem. 2010, 183–190; j) R. Maeda, K.
Ooyama, R. Anno, M. Shiosaki, T. Azema, T. Hanamoto, Org.
Lett. 2010, 12, 2548–2550; k) C. S. Xie, D. Y. Han, Y. Hu, J. H.
Liu, T. A. Xie, Tetrahedron Lett. 2010, 51, 5238–5241; l) M.
Yar, M. G. Unthank, E. M. McGarrigle, V. K. Aggarwal,
Chem. Asian J. 2011, 6, 372–375.
For the direct use of bromoethylsulfonium triflate in annu-
lation reactions, see: a) M. Yar, E. M. McGarrigle, V. K. Ag-
garwal, Org. Lett. 2009, 11, 257–260; b) S. P. Fritz, A. Mumtaz,
M. Yar, E. M. McGarrigle, V. K. Aggarwal, Eur. J. Org. Chem.
2011, 3156–3164; c) E. M. McGarrigle, S. P. Fritz, L. Favereau,
M. Yar, V. K. Aggarwal, Org. Lett. 2011, 13, 3060–3063.
For applications of N-vinyloxazolidinones, see: a) C. Gaulon,
R. Dhal, T. Chapin, V. Maisonneuve, G. Dujardin, J. Org.
Chem. 2004, 69, 4192–4202; b) F. Gohier, K. Bouhadjera, D.
Faye, C. Gaulon, V. Maisonneuve, G. Dujardin, R. Dhal, Org.
Lett. 2007, 9, 211–214; c) A. Pałasz, Org. Biomol. Chem. 2005,
3, 3207–3212; d) J. Montgomery, G. M. Wieber, L. S. Hegedus,
J. Am. Chem. Soc. 1990, 112, 6255–6263; e) J. J. Masters, L. S.
Hegedus, J. Tamariz, J. Org. Chem. 1991, 56, 5666–5671; f) M.
Miller, L. S. Hegedus, J. Org. Chem. 1993, 58, 6779–6785; g)
A. Kutner, J. Org. Chem. 1961, 26, 3495–3498; h) G. M. Mi-
yake, D. A. DiRocco, Q. Liu, K. M. Oberg, E. Bayram, R. G.
Finke, T. Rovis, E. Y.-X. Chen, Macromolecules 2010, 43,
7504–7514.
General Procedure C
Preparation of Sample Reactions for the Tandem MS Investigation:
A stirred solution of the N-protected β-amino alcohol (1.0 equiv.)
in CH2Cl2 (0.07 m) was treated with base (2.0 equiv.) at 0 °C under
nitrogen. After 10 min a solution of diphenylvinylsulfonium salt 1
(1.2 equiv.) in CH2Cl2 (0.1 m) was added dropwise over 2 min, the
reaction was stirred at 0 °C for 3 h and then warmed to room tem-
perature. Aliquots of the reaction solution were diluted with
CH2Cl2 (HPLC grade) and subjected to tandem MS analysis.
[6]
[7]
Major peaks in the mass spectra were assigned to the proposed
structures based on fragmentation in the MS/MS experiments.
Supporting Information (see footnote on the first page of this arti-
cle): General methods, experimental procedures, and spectroscopic
and analytical data for all compounds.
Acknowledgments
S.P.F. thanks the Engineering and Physical Sciences Research
Council (EPSRC) for a scholarship. M.Y. thanks the Higher Edu-
cation Commission of Pakistan and the University of Bristol for
support of a studentship. V.K.A. thanks the Royal Society for a
Wolfson Research Merit Award, the EPSRC for a Senior Research
Fellowship, and Merck for research support.
[8]
For applications of MS/MS in mechanistic investigations, see:
a) W. Schrader, P. P. Handayani, J. Zhou, B. List, Angew. Chem.
2009, 121, 1491; Angew. Chem. Int. Ed. 2009, 48, 1463–1466;
b) L. S. Santos, Eur. J. Org. Chem. 2008, 235–253; c) W.
Schrader, P. P. Handayani, C. Burstein, F. Glorius, Chem. Com-
mun. 2007, 716–718; d) C. D. F. Milagre, H. M. S. Milagre,
L. S. Santos, M. L. A. Lopes, P. J. S. Moran, M. N. Eberlin,
J. A. R. Rodrigues, J. Mass Spectrom. 2007, 42, 1287–1293; e)
C. A. Marquez, F. Fabbretti, J. O. Metzger, Angew. Chem. 2007,
119, 7040; Angew. Chem. Int. Ed. 2007, 46, 6915–6917; f)
C. A. M. Abella, M. Benassi, L. S. Santos, M. N. Eberlin, F.
Coelho, J. Org. Chem. 2007, 72, 4048–4054; g) C. Marquez,
J. O. Metzger, Chem. Commun. 2006, 1539–1541; h) L. S. San-
tos, L. Knaack, J. O. Metzger, Int. J. Mass Spectrom. 2005, 246,
84–104; i) L. S. Santos, C. H. Pavam, W. P. Almeida, F. Coelho,
M. N. Eberlin, Angew. Chem. 2004, 116, 4430; Angew. Chem.
Int. Ed. 2004, 43, 4330–4333; j) A. A. Sabino, A. H. L. Mach-
ado, C. R. D. Correia, M. N. Eberlin, Angew. Chem. 2004, 116,
4489; Angew. Chem. Int. Ed. 2004, 43, 4389; k) S. Meyer, R.
Koch, J. O. Metzger, Angew. Chem. 2003, 115, 4848; Angew.
Chem. Int. Ed. 2003, 42, 4700–4703; l) J. Griep-Raming, S.
[1] For a review, see: a) R. Wijtmans, M. K. S. Vink, H. E. Schoe-
maker, F. L. van Delft, R. H. Blaauw, F. P. J. T. Rutjes, Synthe-
sis 2004, 641–662.
[2] For recent examples, see: a) B. A. Lanman, A. G. Myers, Org.
Lett. 2004, 6, 1045–1047; b) M. C. Wilkinson, Tetrahedron
Lett. 2005, 46, 4773–4775; c) R. Pedrosa, C. Andrés, P. Mendi-
guchía, J. Nieto, J. Org. Chem. 2006, 71, 8854–8863; d) M.
DЈhooghe, T. Vanlangendonck, K. W. Törnroos, N. De Kimpe,
J. Org. Chem. 2006, 71, 4678–4681; e) M. Breuning, M. Win-
nacker, M. Steiner, Eur. J. Org. Chem. 2007, 2100–2106; f) R.
Madsen, L. U. Nordstrom, Chem. Commun. 2007, 5034–5036;
g) M. Penso, V. Lupi, D. Albanese, F. Foschi, D. Landini, A.
Tagliabue, Synlett 2008, 2451–2454; h) J. P. Wolfe, M. L. Le-
athen, B. R. Rosen, J. Org. Chem. 2009, 74, 5107–5110; i)
M. K. Ghorai, D. Shukla, K. Das, J. Org. Chem. 2009, 74,
7013–7022; j) W. J. Xiao, L. Wang, Q. S. Liu, D. S. Wang, X.
Li, X. W. Han, Y. G. Zhou, Org. Lett. 2009, 11, 1119–1122; k)
D. L. Aubele, J. J. Jagodzinski, D. A. Quincy, M. S. Dappen,
L. H. Latimer, R. K. Hom, R. A. Galemmo, A. W. Konradi,
H. L. Sham, Tetrahedron Lett. 2011, 52, 2471–2472.
Eur. J. Org. Chem. 2012, 160–166
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
165

M. Yar, S. P. Fritz, P. J. Gates, E. M. McGarrigle, V. K. Aggarwal
FULL PAPER
Meyer, T. Bruhn, J. O. Metzger, Angew. Chem. 2002, 114, 2863;
Angew. Chem. Int. Ed. 2002, 41, 2738–2742; m) C. Adlhart, C.
Hinderling, H. Baumann, P. Chen, J. Am. Chem. Soc. 2000,
122, 8204–8214; n) A. O. Aliprantis, J. W. Canary, J. Am.
Chem. Soc. 1994, 116, 6985–6986.
[13] a) R. Robiette, J. Richardson, V. K. Aggarwal, J. N. Harvey, J.
Am. Chem. Soc. 2006, 128, 2394–2409; b) R. Robiette, G. Y.
Fang, J. N. Harvey, V. K. Aggarwal, Chem. Commun. 2006,
741–743; c) V. K. Aggarwal, J. N. Harvey, J. Richardson, J. Am.
Chem. Soc. 2002, 124, 5747–5756; for the importance of hydro-
gen bonds between formyl C–H bonds and carbonyl groups,
see: d) E. J. Corey, W. L. Lee, Chem. Commun. 2001, 1321–
1329.
[14] A. Bernardi, S. Cardani, T. Pilati, G. Poli, C. Scolastico, R.
Villa, J. Org. Chem. 1988, 53, 1600–1607.
[15] D. C. Horwell, J. Hughes, J. C. Hunter, M. C. Pritchard, R. S.
Richardson, E. Roberts, G. N. Woodruff, J. Med. Chem. 1991,
34, 404–414.
[9] For the synthesis of amides and carbamates, see: a) A. Ber-
nardi, S. Cardani, T. Pilati, G. Poli, C. Scolastico, R. Villa, J.
Org. Chem. 1988, 53, 1600–1607; b) D. C. Horwell, J. Hughes,
J. C. Hunter, M. C. Pritchard, R. S. Richardson, E. Roberts,
G. N. Woodruff, J. Med. Chem. 1991, 34, 404–414; c) Y. Qin,
C. H. Wang, Z. Y. Huang, X. Xiao, Y. Z. Jiang, J. Org. Chem.
2004, 69, 8533–8536.
[10] We have not been able to find conditions or bases that enable
the use of bromoethylsulfonium triflate 2 in place of vinylsulfo-
nium triflate 1 in the formation of N-vinyloxazolidinones.
[11] For the synthesis of N-vinyloxazolidinones, see: a) W. E.
Walles, W. F. Tousignant, T. Houtman Jr., US Patent 2891058,
1959; b) O. Tamura, M. Hashimoto, Y. Kobayashi, T. Katoh,
K. Nakatani, M. Kamada, I. Hayakawa, T. Akiba, S. Terash-
[16] Y. Qin, C. H. Wang, Z. Y. Huang, X. Xiao, Y. Z. Jiang, J. Org.
Chem. 2004, 69, 8533–8536.
[17] G. D. K. Kumar, S. Baskaran, J. Org. Chem. 2005, 70, 4520–
4523.
[18] B. Wang, W. Zhang, L. Zhang, D.-M. Du, G. Liu, J. Xu, Eur.
J. Org. Chem. 2008, 350–355.
ima, Tetrahedron Lett. 1992, 33, 3487–3490; c) T. Akiba, M. [19] C. Kashima, K. Harada, Y. Fujioka, T. Maruyama, Y. Omote,
Hashimoto, Y. Kobayashi, T. Katoh, K. Nakatani, M. Kam-
ada, I. Hayakawa, S. Terashima, Tetrahedron 1994, 50, 3905–
3914; d) T. Akiba, O. Tamura, S. Terashima, Org. Synth. 1998,
75, 45–52; e) T. Shono, Y. Matsumura, K. Tsubata, Y. Sugih-
ara, S. Yamane, T. Kanazawa, T. Aoki, J. Am. Chem. Soc. 1982,
104, 6697–6703; f) C. Gaulon, P. Gizecki, R. Dhal, G. Dujar-
din, Synlett 2002, 252–256; g) C. Gaulon, R. Dhal, G. Dujar-
din, Synthesis 2003, 2269–2272; h) J. L. Brice, J. E. Meerdink,
S. S. Stahl, Org. Lett. 2004, 6, 1845–1848; i) X. Zhang, Y.
Zhang, J. Huang, R. P. Hsung, K. C. M. Kurtz, J. Oppenhei-
mer, M. E. Petersen, I. K. Sagamanova, L. Shen, M. R. Tracey,
J. Org. Chem. 2006, 71, 4170–4177; see also ref.[7d]
J. Chem. Soc. Perkin Trans. 1 1988, 535–539.
[20] C. Gaulon, R. Dhal, G. Dujardin, Synthesis 2003, 2269–2272.
[21] J. Montgomery, G. M. Wieber, L. S. Hegedus, J. Am. Chem.
Soc. 1990, 112, 6255–6263.
[22] O. Tamura, M. Hashimoto, Y. Kobayashi, T. Katoh, K. Nakat-
ani, M. Kamada, I. Hayakawa, T. Akiba, S. Terashima, Tetra-
hedron Lett. 1992, 33, 3487–3490.
[23] J. L. Brice, J. E. Meerdink, S. S. Stahl, Org. Lett. 2004, 6, 1845–
1848.
[24] T. B. Nguyen, A. Martel, R. Dhal, G. Dujardin, J. Org. Chem.
2008, 73, 2621–2632.
[25] C. Gaulon, P. Gizecki, R. Dhal, G. Dujardin, Synlett 2002,
[12] These reactions gave highly polar mixtures and we were unable
to isolate and characterize sulfonium salts 13 and 14 by any
conventional workup methods.
952–956.
Received: August 31, 2011
Published Online: November 8, 2011
166
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 160–166