Grignard additions to cyclic sulfamidate imines: Synthesis of n-substituted quaternary sulfamidate building blocks

Article abstract of DOI:10.1055/s-0029-1218778

The addition of Grignard reagents to cyclic sulfamidate imines has been developed as a facile method for the synthesis of N-substituted quaternary sulfamidates. By way of ring opening with an appropriate nucleophile, versatile synthons for 1,2-amino alcohols, 1,2-diamines, and β-amino acids are produced. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1218778

PAPER
2361
Grignard Additions to Cyclic Sulfamidate Imines: Synthesis of N-Substituted
Quaternary Sulfamidate Building Blocks
Grignard
A
ddi
t
tions to
a
C
yclic Su
n
lfamidate Im
l
ines ey Chang, Ernest E. Lee*
Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, QC, H9H 3L1, Canada
Fax +1(514)4284939; E-mail: ernest_lee@merck.com
Received 18 January 2010; revised 28 March 2010
Dedicated in memory of Professor Keith Fagnou
pared from amino alcohols and diols,5 intramolecular
Abstract: The addition of Grignard reagents to cyclic sulfamidate
imines has been developed as a facile method for the synthesis of N-
substituted quaternary sulfamidates. By way of ring opening with
an appropriate nucleophile, versatile synthons for 1,2-amino alco-
hols, 1,2-diamines, and b-amino acids are produced.
amidation6 and asymmetric intramolecular amidation of
sulfamate esters.7 The advantage of preparing cyclic sul-
famidates 2 from their corresponding imines 1 lies in the
ability to generate an array of substituted products from a
common starting substrate. Once suitably protected, the
resulting cyclic sulfamidate could be displaced by a vari-
ety of nucleophiles and deprotected under mild acidic
conditions.8 Indeed, the attractiveness of this substrate
class has not gone unnoticed: Zhou4a,b has demonstrated
their use as asymmetric hydrogenation substrates, while
Tang4c has shown their use as aziridination substrates with
sulfur ylides. Blakey has also shown two examples of a
seven-membered sulfamidate imine, which was generated
by way of a metallonitrene/alkyne metathesis that was
trapped in situ with methyl and allyl Grignard reagents.9
Key words: cyclic imine, Grignard addition, sulfamidate imine, N-
substituted quaternary stereocenter
Chiral amines play a fundamental role as building blocks
for the synthesis of natural products, drugs, chiral ligands
and auxiliaries.1 Nucleophilic additions of carbon nucleo-
philes to aldimines and ketimines are powerful methods
for the synthesis of chiral nitrogen-substituted tertiary and
quaternary stereocenters, respectively (Scheme 1).2 These
amine functional groups, which are synthetically useful
on their own, possess greater synthetic value when pre-
pared adjacent to a reactive leaving group or leaving
group synthon that could be displaced with nucleophiles
such as alkoxides, amines and cyanides to produce 1,2-
amino-alcohols, diamines and amino nitriles.3
O
O
1. PG
2. Y = –OH, HNR3
O
O
PG
R2MgBr
S
S
HN
R1
HN
R1
N
2
O
O
–CN, HSR3
3. H+
Y
R1
R2
R2
1
2
3
PG
PG
PG
Scheme 2 Addition to cyclic sulfamidate imines
R2M
HN
R1
Y = –OH, HNR3
–CN, HSR3
N
HN
R1
2
X
Y
X
R1
R2
R2
The prerequisite imines 1a and 1b were readily prepared
in two steps from a-hydroxyacetophenone and acetol, re-
spectively.6,10 We were pleased to discover that treatment
of the cyclic sulfamidate imine 1a with MeMgCl or
MeMgBr at –78 °C afforded the desired addition product,
albeit in low HPLC assay yields (31% and 32%, respec-
tively; Table 1, entries 1 and 2).
Scheme 1 Addition to imines and a-functionalization
The outcome of nucleophilic addition reaction to imines is
often influenced by the presence of enolizable protons, the
nature of the imine N-substitution, and the imine E/Z geo-
metry. Moreover, the utility of the transformation is also
affected by the ease with which the imine activating group
can be removed after the addition. As part of our efforts to
develop methods for the rapid synthesis of chiral amines
that can be readily diversified with adjacent heteroatoms,
we investigated the potential use of cyclic sulfamidate
imines 14 (Scheme 2) in Grignard addition chemistry. The
cyclic sulfamidate imine functional group would serve to
constrain the imine geometry in addition to activating the
imine towards nucleophilic addition. The resultant cyclic
sulfamidate products are well known, and have been pre-
The yield could be further improved by utilization of
MeMgI under identical conditions. A survey of solvents
demonstrated the large impact they make on the reaction
conversion. Most notably, amongst ethereal solvents,
methyl tert-butyl ether (MTBE) proved to be far superior
to tetrahydrofuran and diethyl ether. Performing the reac-
tion at –22 and 0 °C resulted in improved HPLC yields of
73 and 91%, respectively. Increased amounts of Grignard
reagent (2.0 equiv) or substitution of MTBE for dichlo-
romethane under these optimized conditions resulted in a
slight decrease in assay yield. Typically, the remaining
mass balance in the reactions carried out at low tempera-
ture or in diethyl ether and tetrahydrofuran consisted
mainly of starting imine. The poor conversion was attrib-
uted to competing deprotonation of the starting imine, as
SYNTHESIS 2010, No. 14, pp 2361–2366
Advanced online publication: 05.05.2010
DOI: 10.1055/s-0029-1218778; Art ID: M00310SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

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S. Chang, E. E. Lee
PAPER
Table 1 Methylmagnesium Halide Addition to Cyclic Sulfamidate
Table 2 Grignard Addition to Cyclic Phenyl Sulfamidate Imines
Imines
O
O
O
O
O
O
S
S
RMgX (1.2 equiv)
MTBE, 0 °C
HN
R
N
O
O
S
O
S
O
HN
N
MeMgX
O
Ph
O
Ph
Ph
Ph
1a
2
1a
2a
Entry Product
R
X
Grignard Isolated
Entry Solvent
Temp
Grignard
Equiv
HPLC yield
(%)
solvent
Et2O
Et2O
Et2O
THF
Et2O
THF
yield (%)
(°C)
–78
–78
–78
–78
–78
–78
–78
–22
0
1
2
3
4
5
6
2a
2a
2b
2c
2d
2e
Me
Me
Et
Br
I
61
67
84
68
86
71
1
2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
MeMgCl
MeMgBr
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.2
1.2
2.0
31
32
64
36
0
Br
Br
Br
Br
3
i-Pr
allyl
Bn
4
5
6
Et2O
21
68
73
91
84
82
O
7
MTBE
MTBE
MTBE
CH2Cl2
MTBE
7
2f
Br
THF
69
O
8
8
9
2g
2h
2h
2i
vinyl
Br
Br
I
THF
THF
THF
THF
16
–
9
Ph
10
11
0
10
11
Ph
–
0
PhC≡C
Br
–
evidenced by quenching of the reaction with deuterium
oxide. For example, deuterium oxide quench of the reac-
tion between 1a and MeMgI in tetrahydrofuran at 0 °C
provided an 8:1 mixture of mono-deuterated imine 1a and
addition product.
counterpart 1a, reacted smoothly with alkyl Grignard re-
agents (Me, Et, allyl and benzyl; 65–83% isolated yield,
Table 3, entries 1–4). Both sp2 and sp-hybridized carbon
nucleophiles such as phenyl and ethynyl Grignard re-
agents still reacted poorly (13 and 25% yield, respective-
ly). However, in contrast to imine 1a, modest yields of
addition product could be obtained with vinyl, 4-fluo-
rophenyl and phenylethynyl Grignard reagents (36, 57
and 49% yields, respectively).
Under the optimized conditions (1.2 equiv Grignard re-
agent in MTBE at 0 °C), utilization of MeMgBr or MeMgI
gave comparable isolated yields of 61 and 67%, respec-
tively (Table 2, entries 1 and 2). As a result of this compa-
rable reactivity, a survey of bromo-Grignard reagents was
conducted because of their greater commercial availabili-
ty in comparison to their iodo-analogues. The reaction
proceeded smoothly with the more hindered ethyl and iso-
propyl Grignard reagents, providing the cyclic sulfami-
date products in 84 and 65% yield, respectively. With
activated allyl and benzyl Grignard reagents, the addition
was also accomplished in good isolated yields (86 and
71%). The acetal-containing Grignard reagent provided
the addition product in 69% yield. Interestingly, sp2 and
sp-hybridized carbon nucleophiles such as vinyl, phenyl,
and phenyl-ethynyl, reacted poorly (<16% yield). More-
over, no improvement in reactivity was observed upon
substitution of PhMgBr for PhMgI. The poor isolated
yields for these nucleophiles were also attributed to com-
peting deprotonation of the starting imine substrate. For
example, deuterium oxide quench of the reaction de-
scribed in Table 2, entry 9 provided only mono-deuterated
imine 1a.
The reaction proved to be amenable to modest scale-up;
when the reaction was performed on a 1.1 gram (5.7
mmol) scale with imine 1a and ethyl magnesium bromide,
the addition product 2b was obtained in comparable yield
(89%) to that obtained on a 0.25 mmol scale (84%). To
further demonstrate the known utility of cyclic sulfami-
dates,4,8 2b was protected as the benzylcarbamate 4 under
standard conditions (Scheme 3). Compound 4 was then
ring opened with benzylamine to give intermediate 5,
which, upon acidification, underwent desulfonylation and
cyclization to provide the protected urea 6 in 63% yield
over three steps.
In conclusion, the addition of Grignard reagents to cyclic
sulfamidate imines has been developed as a method for
the preparation of cyclic sulfamidates bearing N-substi-
tuted quaternary stereocenters. The products are versatile
intermediates for a variety of substitution reactions, al-
lowing for the rapid synthesis of a diverse array of com-
pounds.
We next turned our attention to the cyclic sulfamidate
imine derived from acetol 1b. This imine, like its phenyl
Synthesis 2010, No. 14, 2361–2366 © Thieme Stuttgart · New York

PAPER
Grignard Additions to Cyclic Sulfamidate Imines
2363
O
O
O
O
O
Cbz
Ph
O
O
O
Cbz
S
O
S
S
N
HN
Et
S
HN
Et
N
EtMgBr (1.2 equiv)
MTBE, 0 °C
N
1 M HCl
BnNH2, MeCN
CbzCl, NaOt-Bu
O
O
NBn
O
OH
Ph
Ph
Ph
Ph
Et
Et
NHBn
4
1a
1.1 g, 5.7 mmol
2b
89%, 5.4 mmol
6
5
63%, 3.4 mmol
Scheme 3 Addition and ring opening on increased scale
13C NMR (100 MHz, CDCl3): d = 141.1, 129.2, 128.6, 125.0, 80.3,
Table 3 Grignard Addition to Cyclic Methyl Sulfamidate Imines
65.4, 27.5.
O
O
HRMS-ESI: m/z [M + Na]+ calcd: 236.0352; found: 236.0353.
O
O
S
S
HN
R
N
RMgX (1.2 equiv)
MTBE, 0 °C
O
O
4-Ethyl-4-phenyl[1,2,3]oxathiazolidine 2,2-Dioxide (2b)
Reaction time: 2 h. Flash chromatography (hexanes–EtOAc,
5→25%).
1b
2
Yield: 84%; white solid; mp 90 °C; Rf = 0.4 (hexanes–EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): d = 7.40 (m, 2 H), 7.33 (m, 3 H), 4.67
(d, J = 8.8 Hz, 1 H), 4.63 (s, 1 H), 4.62 (d, J = 8.8 Hz, 1 H), 2.18
(dq, J = 14.0, 7.6 Hz, 1 H), 2.04 (dq, J = 14.0, 7.6 Hz, 1 H), 0.82 (t,
J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 139.5, 129.0, 128.4, 125.3, 79.5,
68.9, 33.1, 8.2.
Entry
Product
R
Grignard
solvent
Isolated yield
(%)
1
2
3
4
5
6
7
8
9
2j
Me
Et2O
Et2O
Et2O
THF
THF
THF
Et2O
THF
THF
81
83
82
65
36
13
57
25
49
2k
2l
Et
allyl
Bn
HRMS-ESI: m/z [M + Na]+ calcd: 250.0508; found: 250.0510.
2m
2n
2a
2o
2p
2q
4-Isopropyl-4-phenyl[1,2,3]oxathiazolidine 2,2-Dioxide (2c)
Reaction time: 5 h. Flash chromatography (hexanes–EtOAc,
5→45%).
vinyl
Ph
Yield: 65%; white solid; mp 122 °C; Rf = 0.4 (hexanes–EtOAc,
5:1).
1H NMR (400 MHz, CDCl3): d = 7.39 (m, 2 H), 7.31 (m, 1 H), 7.29
(m, 2 H), 4.78 (d, J = 8.8 Hz, 1 H), 4.66 (d, J = 8.8 Hz, 1 H), 4.57
(s, 1 H), 2.34 (qq, J = 6.8, 6.8 Hz, 1 H), 1.00 (d, J = 6.8 Hz, 3 H),
0.78 (d, J = 6.8 Hz, 3 H).
4-FC6H4
HC≡C
PhC≡C
13C NMR (100 MHz, CDCl3): d = 138.6, 128.7, 128.3, 126.0, 78.0,
All solvents and Grignard reagents were commercially available
and were used without further purification. Flash column chroma-
tography was carried out on silica gel (60 Å, 230–400 mesh) and
was performed with reagent grade solvents. 1H NMR and 13C NMR
spectroscopic data were obtained with a Bruker Avance 400 spec-
trometer. HRMS were recorded with an Agilent 6169A spectrome-
ter. Melting points were determined by thermal gravimetric
analysis.
71.4, 36.4, 17.5, 16.9.
HRMS-ESI: m/z [M + Na]+ calcd: 264.0665; found: 264.0667.
4-Allyl-4-phenyl[1,2,3]oxathiazolidine 2,2-Dioxide (2d)
Reaction time: 3 h. Flash chromatography (hexanes–EtOAc,
5→35%).
Yield: 86%; white solid; mp 85 °C; Rf = 0.4 (hexanes–EtOAc, 5:1).
1H NMR (400 MHz, CDCl3): d = 7.37 (m, 5 H), 5.48 (m, 1 H), 5.28
(d, J = 10.0 Hz, 1 H), 5.24 (d, J = 17.2 Hz, 1 H), 4.77 (s, 1 H), 4.69
(d, J = 8.8 Hz, 1 H), 4.56 (d, J = 8.8 Hz, 1 H), 2.88 (dd, J = 14.0,
8.0 Hz, 1 H), 2.82 (dd, J = 14.0, 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 139.7, 130.6, 129.1, 128.6, 125.2,
122.3, 78.1, 67.2, 44.4.
Grignard Addition to Imine 1a; General Procedure
A round-bottom flask was charged with imine 1a (50 mg, 0.25
mmol) and purged with N2. MTBE was added and the reaction was
cooled to 0 °C. Grignard reagent (0.30 mmol, 1.2 equiv) was added
dropwise and the solution was stirred at 0 °C for the time indicated.
The reaction was quenched with 0.5 M HCl (2 mL), extracted with
EtOAc (10 mL), washed with brine, dried over MgSO4, filtered and
concentrated. The crude product was then purified by silica gel
chromatography.
HRMS-ESI: m/z [M + Na]+ calcd: 262.0508; found: 262.0510.
4-Benzyl-4-phenyl[1,2,3]oxathiazolidine 2,2-Dioxide (2e)
Reaction time: 4.5 h. Flash chromatography (hexanes–EtOAc,
5→35%).
4-Methyl-4-phenyl[1,2,3]oxathiazolidine 2,2-Dioxide (2a)
Reaction time: 6.5 h. Flash chromatography (hexanes–EtOAc,
10→40%).
Yield: 71%; white solid; mp 140 °C; Rf = 0.4 (hexanes–EtOAc,
5:1).
1H NMR (400 MHz, CDCl3): d = 7.35 (m, 3 H), 7.19 (m, 3 H), 7.07
(m, 2 H), 6.77 (m, 2 H), 4.85 (d, J = 8.8 Hz, 1 H), 4.67 (s, 1 H), 4.61
(d, J = 8.8 Hz, 1 H), 3.42 (d, J = 13.6 Hz, 1 H), 3.34 (d,
J = 13.6 Hz, 1 H).
Yield: 61% with MeMgBr, 67% with MeMgI; white solid; mp
82 °C; Rf = 0.3 (hexanes–EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): d = 7.41 (m, 4 H), 7.36 (m, 1 H), 4.64
(d, J = 8.8 Hz, 1 H), 4.61 (s, 1 H), 4.58 (d, J = 8.8 Hz, 1 H), 1.82 (s,
3 H).
Synthesis 2010, No. 14, 2361–2366 © Thieme Stuttgart · New York

2364
S. Chang, E. E. Lee
PAPER
13C NMR (100 MHz, CDCl3): d = 139.1, 133.5, 130.5, 128.9, 128.6,
Yield: 82%; colorless oil; Rf = 0.5 (hexanes–EtOAc, 7:3).
128.5, 127.6, 125.3, 78.0, 68.4, 45.6.
1H NMR (400 MHz, CDCl3): d = 5.75 (m, 1 H), 5.24 (d, J = 9.6 Hz,
1 H), 5.21 (d, J = 17.2 Hz, 1 H), 4.67 (s, 1 H), 4.34 (d, J = 8.8 Hz,
1 H), 4.20 (d, J = 8.8 Hz, 1 H), 2.52 (dd, J = 14.0, 8.0 Hz, 1 H), 2.38
(dd, J = 14.0, 8.0 Hz, 1 H), 1.41 (s, 3 H).
HRMS-ESI: m/z [M + Na]+ calcd: 312.0665; found: 312.0669.
4-(2-[1,3]Dioxan-2-ylethyl)-4-phenyl[1,2,3]oxathiazolidine 2,2-
Dioxide (2f)
13C NMR (100 MHz, CDCl3): d = 130.7, 121.2, 78.5, 62.1, 42.9,
Reaction time: 3 h. Flash chromatography (hexanes–EtOAc,
10→50%).
23.9.
HRMS-ESI: m/z [M + Na]+ calcd: 200.0352; found: 200.0350.
Yield: 69%; light-yellow oil; Rf = 0.2 (hexanes–EtOAc, 5:1).
1H NMR (400 MHz, CDCl3): d = 7.36 (m, 4 H), 7.29 (m, 1 H), 6.44
(s, 1 H), 4.53 (m, 3 H), 4.10 (dd, J = 10.8, 4.8 Hz, 2 H), 3.74 (dd,
J = 12.0, 12.0 Hz, 2 H), 2.37 (m, 1 H), 2.12 (m, 2 H), 1.61 (m, 1 H),
1.48 (m, 1 H), 1.33 (d, J = 12.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 140.6, 129.0, 128.1, 125.5, 100.4,
79.2, 68.0, 67.0, 67.0, 33.4, 29.1, 25.4.
4-Benzyl-4-methyl[1,2,3]oxathiazolidine 2,2-Dioxide (2m)
Reaction time: 5 h. Flash chromatography (hexanes–EtOAc,
0→35%).
Yield: 65%; colorless oil; Rf = 0.4 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): d = 7.34 (m, 3 H), 7.27 (d, J = 7.0 Hz,
2 H), 4.58 (s, 1 H), 4.50 (d, J = 8.8 Hz, 1 H), 4.29 (d, J = 8.8 Hz,
1 H), 3.21 (d, J = 13.6 Hz, 1 H), 2.91 (d, J = 13.6 Hz, 1 H), 1.41 (s,
3 H).
HRMS-ESI: m/z [M + Na]+ calcd: 336.0876; found: 336.0880.
4-Phenyl-4-vinyl[1,2,3]oxathiazolidine 2,2-Dioxide (2g)
Reaction time: 4 h. Flash chromatography (hexanes–EtOAc,
10→60%).
13C NMR (100 MHz, CDCl3): d = 134.7, 130.6, 128.7, 127.5, 79.1,
63.1, 44.3, 23.6.
HRMS-ESI: m/z [M + Na]+ calcd: 250.0508; found: 250.0508.
Yield:16%; brown oil; Rf = 0.4 (hexanes–EtOAc, 5:1).
1H NMR (400 MHz, CDCl3): d = 7.48 (m, 5 H), 6.14 (dd, J = 15.6,
8.8 Hz, 1 H), 5.47 (d, J = 8.8 Hz, 1 H), 5.44 (d, J = 15.6 Hz, 1 H),
4.75 (s, 2 H), 4.67 (s, 1 H).
4-Methyl-4-vinyl[1,2,3]oxathiazolidine 2,2-Dioxide (2n)
Reaction time: 6.5 h. Flash chromatography (hexanes–EtOAc,
15→50%).
13C NMR (100 MHz, CDCl3): d = 148.6, 137.3, 129.2, 129.0, 126.0,
Yield:36%; colorless oil; Rf = 0.3 (hexanes–EtOAc, 7:3).
118.8, 78.3, 69.0.
1H NMR (400 MHz, CDCl3): d = 5.90 (dd, J = 17.2, 10.8 Hz, 1 H),
5.46 (d, J = 17.2 Hz, 1 H), 5.33 (d, J = 10.8 Hz, 1 H), 4.60 (s, 1 H),
4.38 (d, J = 8.8 Hz, 1 H), 4.30 (d, J = 8.8 Hz, 1 H), 1.55 (s, 3 H).
HRMS-ESI: m/z [M + Na]+ calcd: 248.0352; found: 248.0348.
Grignard Addition to Imine 1b; General Procedure
A round-bottom flask was charged with imine 1b (50 mg, 0.38
mmol) and purged with N2. MTBE was added and the reaction was
cooled to 0 °C. Grignard reagent (0.45 mmol, 1.2 equiv) was added
dropwise and the mixture was stirred at 0 °C for the time indicated.
The reaction was quenched with 0.5 M HCl (2 mL), extracted with
EtOAc (10 mL), washed with brine, dried over MgSO4, filtered and
concentrated. The crude product was then purified by silica gel
chromatography.
13C NMR (100 MHz, CDCl3): d = 137.6, 117.4, 79.0, 63.5, 24.1.
HRMS-ESI: m/z [M + Na]+ calcd: 186.0195; found: 186.0194.
4-Methyl-4-phenyl[1,2,3]oxathiazolidine 2,2-Dioxide (2a)
Reaction time: 7 h. Flash chromatography (hexanes–EtOAc,
0→30%).
Yield:13%; colorless oil.
4-(4-Fluorophenyl)-4-methyl[1,2,3]oxathiazolidine 2,2-Dioxide
(2o)
Reaction time: 6 h. Flash chromatography (hexanes–EtOAc,
0→40%).
4,4-Dimethyl[1,2,3]oxathiazolidine 2,2-Dioxide (2j)
Reaction time: 6.5 h. Flash chromatography (hexanes–EtOAc,
10→60%).
Yield: 81%; white solid; Rf = 0.2 (hexanes–EtOAc, 7:3).
Yield: 57%; colorless oil; Rf = 0.3 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): d = 4.26 (s, 2 H), 4.18 (s, 1 H), 1.47
1H NMR (400 MHz, CDCl3): d = 7.42 (m, 2 H), 7.07 (m, 2 H), 4.98
(s, 1 H), 4.61 (d, J = 8.8 Hz, 1 H), 4.55 (d, J = 8.8 Hz, 1 H), 1.78 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 162.5 (d, J = 246.0 Hz), 137.0 (d,
J = 3.0 Hz), 127.0 (d, J = 8.0 Hz), 115.9 (d, J = 22.0 Hz), 80.3, 65.0,
27.4.
(s, 6 H).
13C NMR (100 MHz, DMSO-d6): d = 81.0, 60.3, 26.0.
HRMS-ESI: m/z [M + Na]+ calcd: 174.0195; found: 174.0200.
4-Ethyl-4-methyl[1,2,3]oxathiazolidine 2,2-Dioxide (2k)
Reaction time: 7 h. Flash chromatography (hexanes–EtOAc,
10→55%).
HRMS-ESI: m/z [M + Na]+ calcd: 254.0258; found: 254.0261.
4-Ethynyl-4-methyl[1,2,3]oxathiazolidine 2,2-Dioxide (2p)
Reaction time: 7 h. Flash chromatography (hexanes–EtOAc,
15→50%).
Yield: 83%; pale-yellow oil; Rf = 0.3 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): d = 4.29 (d, J = 8.8 Hz, 1 H), 4.23 (d,
J = 8.8 Hz, 1 H), 4.18 (s, 1 H), 1.81 (dq, J = 14.0, 7.2 Hz, 1 H), 1.66
(dq, J = 14.0, 7.2 Hz, 1 H), 1.42 (s, 3 H), 0.98 (t, J = 7.6 Hz, 3 H).
Yield: 25%; colorless oil; Rf = 0.3 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): d = 4.78 (s, 1 H), 4.60 (d, J = 8.4 Hz,
1 H), 4.36 (d, J = 8.4 Hz, 1 H), 2.64 (s, 1 H), 1.72 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 81.4, 79.1, 74.9, 56.2, 26.7.
HRMS-ESI: m/z [M + Na]+ calcd: 184.0039; found: 184.0041.
13C NMR (100 MHz, CDCl3): d = 79.5, 63.4, 31.8, 23.3, 8.1.
HRMS-ESI: m/z [M + Na]+ calcd: 188.0352; found: 188.0353.
4-Allyl-4-methyl[1,2,3]oxathiazolidine 2,2-Dioxide (2l)
Reaction time: 5 h. Flash chromatography (hexanes–EtOAc,
5→30%).
Synthesis 2010, No. 14, 2361–2366 © Thieme Stuttgart · New York

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Grignard Additions to Cyclic Sulfamidate Imines
2365
4-Methyl-4-phenylethynyl[1,2,3]oxathiazolidine 2,2-Dioxide
(2q)
Reaction time: 6 h. Flash chromatography (hexanes–EtOAc,
0→35%).
Chem. Rev. 1998, 98, 1407. (h) Enders, D.; Reinhold, U.
Tetrahedron: Asymmetry 1997, 8, 1895. For selected recent
examples, see: (i) Zuend, S. J.; Coughlin, M. P.; Lalonde, M.
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3722. (k) Fu, P.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2008, 130, 5530. (l) Notte, G. T.; Leighton, J. L.
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Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2008, 73, 940.
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Chem. Soc. 2006, 128, 7687. (s) Basra, S.; Fennie, M. W.;
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H.; Nakamura, S.; Hattori, M.; Ozeki, S.; Shibata, N.; Toru,
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Cabello, N.; Rinchard, L.; Caille, J.-C.; Alexakis, A.
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Synthesis of b-Amino Acids; Juaristi, E., Ed.; Wiley-VCH:
New York, 1997. (e) Ager, D. J.; Prakash, I.; Schaad, D. R.
Chem. Rev. 1996, 96, 835.
Yield: 49%; colorless oil; Rf = 0.50 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): d = 7.43 (m, 2 H), 7.34 (m, 3 H), 4.96
(s, 1 H), 4.44 (d, J = 8.4 Hz, 1 H), 3.67 (d, J = 8.4 Hz, 1 H), 1.80 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 131.7, 129.3, 128.3, 120.7, 86.3,
85.8, 79.3, 56.9, 26.8.
HRMS-ESI: m/z [M + Na]+ calcd: 260.0352; found: 260.0355.
CBz-Protection, Nucleophilic Ring-Opening and Cyclization
A round-bottom flask was charged with a solution of t-BuONa (0.79
g, 8.2 mmol, 1.5 equiv) in DME (38 mL) and purged with N2. Cyclic
sulfamidate 2b (1.24 g, 5.4 mmol) was added and the reaction was
stirred for 1.5 h. Benzyl chloroformate (2.0 mL, 14.0 mmol, 2.5
equiv) was then added and the reaction was stirred for 17 h. The re-
action was quenched with H2O (15 mL) and extracted with EtOAc.
The organic phase was washed with brine (20 mL), dried over
MgSO4, filtered and concentrated. The crude product was purified
by silica gel chromatography (hexanes–EtOAc, 5→30%) to provide
Cbz-protected cyclic sulfamidate [Rf = 0.6 (hexanes–EtOAc, 7:3)].
A round-bottom flask was charged with protected cyclic sulfami-
date 4 (5.4 mmol), MeCN (25 mL) and purged with N2. Benzyl-
amine (0.89 mL, 8.2 mmol, 1.5 equiv) was added and the reaction
was heated to 80 °C and stirred for 28 h. The reaction was cooled,
diluted with EtOAc (20 mL), 1 M HCl (20 mL) was added and the
mixture was stirred at r.t. for 2 h. The organic layer was separated,
washed with 1 M NaOH (25 mL), dried over MgSO4, filtered and
concentrated. The crude product was purified by silica gel chroma-
tography.
(4) (a) Wang, Y.-Q.; Yu, C.-B.; Wang, D.-W.; Wang, X.-B.;
Zhou, Y.-G. Org. Lett. 2008, 10, 2071. (b) Zhou, Y.-G.;
Wang, Y.-Q.; Yu, C.-B. CN-101423504, 2009. (c) Zhu,
B.-H.; Zheng, J.-C.; Yu, C.-B.; Sun, X.-L.; Zhou, Y.-G.;
Shen, Q.; Tang, Y. Org. Lett. 2010, 12, 504.
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1-Benzyl-4-ethyl-4-phenylimidazolidin-2-one (6)
Flash chromatography (hexanes–EtOAc, 30→80%).
2007, 46, 786. (b) Rönnholm, P.; Södergren, M.;
Hilmersson, G. Org. Lett. 2007, 9, 3781. (c) Bower, J. F.;
Švenda, J.; Williams, A. J.; Charmant, J. P. H.; Lawrence, R.
M.; Szeto, P.; Gallagher, T. Org. Lett. 2004, 6, 4727.
(d) Nicolaou, K. C.; Snyder, S. A.; Longbottom, D. A.;
Nalbandian, A. Z.; Huang, X. Chem. Eur. J. 2004, 10, 5581.
(e) Williams, A. J.; Chakthong, S.; Gray, D.; Lawrence, R.
M.; Gallagher, T. Org. Lett. 2003, 5, 811. (f) Cohen, S. B.;
Halcomb, R. L. J. Am. Chem. Soc. 2002, 124, 2534.
(g) Nicolaou, K. C.; Huang, X.; Snyder, S. A.; Rao, P. B.;
Bella, M.; Reddy, M. V. Angew. Chem. Int. Ed. 2002, 41,
834. (h) Posakony, J. J.; Tewson, T. J. Synthesis 2002, 766.
(i) Posakony, J. J.; Grierson, J. R.; Tewson, T. J. J. Org.
Chem. 2002, 67, 5164. (j) Cohen, S. B.; Halcomb, R. L.
Org. Lett. 2001, 3, 405. (k) Atfani, M.; Wei, L.; Lubell, W.
D. Org. Lett. 2001, 3, 2965. (l) Wei, L.; Lubell, W. D. Can.
J. Chem. 2001, 79, 94. (m) Wei, L.; Lubell, W. D. Org. Lett.
2000, 2, 2595.
Yield: 0.94 g (3.35 mmol, 63%); white solid; mp 111 °C; Rf = 0.30
(hexanes–EtOAc, 3:2).
1H NMR (400 MHz, CDCl3): d = 7.24 (m, 10 H), 5.39 (s, 1 H), 4.59
(d, J = 14.8 Hz, 1 H), 4.28 (d, J = 14.8 Hz, 1 H), 3.42 (d,
J = 8.8 Hz, 1 H), 3.39 (d, J = 8.8 Hz, 1 H), 1.89 (m, 2 H), 0.80 (t,
J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 160.9, 144.6, 137.0, 128.7, 128.6,
128.4, 128.2, 128.0, 127.5, 127.2, 127.0, 124.9, 60.6, 57.6, 47.3,
34.3, 8.1.
HRMS-ESI: m/z [M + Na]+ calcd: 281.1648; found: 281.1656.
Acknowledgment
The authors thank Louis-Charles Campeau, Carmela Molinaro and
David Powell for helpful discussions.
(6) (a) Toumieux, S.; Compain, P.; Martin, O. R.; Selkti, M.
Org. Lett. 2006, 8, 4493. (b) Wehn, P. M.; Du Bois, J. Org.
Lett. 2005, 7, 4685. (c) Fiori, K. W.; Fleming, J. J.; Du Bois,
J. Angew. Chem. Int. Ed. 2004, 43, 4349. (d) Fleming, J. J.;
Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 2028.
(e) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am.
Chem. Soc. 2001, 123, 6935.
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C.-M. Angew. Chem. Int. Ed. 2002, 41, 3465. (b) Liang,
J.-L.; Yuan, S.-X.; Huang, J.-S.; Che, C.-M. J. Org. Chem.
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Tetrahedron Lett. 2005, 46, 5403. (d) Fruit, C.; Müller, P.
Tetrahedron: Asymmetry 2004, 15, 1019.
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Synthesis 2010, No. 14, 2361–2366 © Thieme Stuttgart · New York

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S. Chang, E. E. Lee
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Synthesis 2010, No. 14, 2361–2366 © Thieme Stuttgart · New York