N-(Alkylsulfamoyl)aldimines: Easily deprotected precursors for diarylmethylamine synthesis

Article abstract of DOI:10.1016/j.tetasy.2013.04.006

The sequential reaction of chlorosulfonyl isocyanate with t-BuOH, t-BuNH₂ and TFA allows formation of H₂NSO ₂NHBu^t. Condensation of the latter with Ar¹CHO in the presence of Ti(OEt)₄ provides the activated imines Ar ¹CHNSO₂NHBu^t (59-89%). Commercially available boronic acids add to these imines with good stereoselectivity (76-98% ee) using readily available diene ligands. Simple deprotection with 5% w/w water in pyridine affords free Ar¹CHNH₂Ar².

Full text of DOI:10.1016/j.tetasy.2013.04.006

Tetrahedron: Asymmetry 24 (2013) 599–605
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
N-(Alkylsulfamoyl)aldimines: easily deprotected precursors for
diarylmethylamine synthesis
Rosemary H. Crampton a, Martin Fox b, Simon Woodward a,
⇑
a School of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom
b Chirotech Technology Centre, Dr. Reddy’s Laboratories EU Ltd, Unit 410 Cambridge Science Park, Milton Road, Cambridge CB4 0PE, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 March 2013
Accepted 9 April 2013
The sequential reaction of chlorosulfonyl isocyanate with t-BuOH, t-BuNH2 and TFA allows formation of
H2NSO2NHBut. Condensation of the latter with Ar1CHO in the presence of Ti(OEt)4 provides the activated
imines Ar1CH@NSO2NHBut (59–89%). Commercially available boronic acids add to these imines with
good stereoselectivity (76–98% ee) using readily available diene ligands. Simple deprotection with 5%
w/w water in pyridine affords free Ar1CHNH2Ar2.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
PG
Ar2
PG
often
NH2
Ar2
N
cat. RhIL*
HN
problematic
Over the last decade or so since Miyaura introduced the rho-
dium-catalysed addition of arylboron reagents to activated imines
(2000)1 a large range of catalytic systems have been developed and
the attainment of highly enantioselective (>90% ee) versions can be
assured in many cases.2 A more pressing problem in this area is to
obtain protecting groups that simultaneously strongly activate
imine 1 to addition reactions, but also allow for mild deprotection
of the addition products 2 to the commercially interesting diarylm-
ethylamines 3 (Scheme 1).3 N-Tosyl protected imines A are used
widely but the harsh (acidic or highly reducing) removal condi-
tions required for 2 cleave many other groups.4 N-Nosylarylimines
B offer improvements but any functionalities in 3 must be tolerant
to strong nucleophiles (e.g., PhSH).5 N,N-Dimethylsulfamoyl pro-
tected imines C are robust, but can require transamination under
forcing microwave promotion conditions to effect their removal.6
Formyl protection D does offer deprotection under mildly acidic
conditions, but in this case the imines need to be stored as their
sulfinate adducts to avoid decomposition.7 N-Diphenylphosphi-
noyl groups E have been popularised by Ellman and others, but
add significantly to the imine mass.8 Finally, Boc protection F can
be used, but this group is sometimes too labile.9 In seeking to bal-
ance the requirements of imine activation, protecting group stabil-
ity and ease of removal we have suggested that the use of a simple
–SO2– function can be effective, as in 4, and can be removed under
mildly basic conditions (5% water in pyridine), conditions that are
complementary to groups A–D.10 However, the presence of two
stereocentres in 4 complicates their ee assay. In order to avoid such
+ Ar 2B(OH)2
Ar1
Ar1
Ar1
1
2
3
PG = protecting group, including
O2
S
O2
S
O2
S
NMe2
NO2
A
B
C
O
O
O
PPh2
OtBu
H
D
E
F
H
N
O
H
N
H
N
Ar1
Ar1
O2S
S
O2
Ar2
Ar2
5
4
Scheme 1. Typical approach to 2-arylethylamines.
issues, we proposed that the use of a simple ‘dummy’ amine in the
sulfamoyl group –SO2NHR should prove useful. Recently, Lam used
substrates 5, which are restricted to the use of salicyladehyde de-
rived aldimines.11 This prompted us to disclose our own approach
which places no restrictions on Ar1.
⇑
Corresponding author. Fax: +44 115 9513564.
E-mail address: simon.woodward@nottingham.ac.uk (S. Woodward).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.04.006

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R. H. Crampton et al. / Tetrahedron: Asymmetry 24 (2013) 599–605
in acyclic 9 does not appear to have been used in additions to imi-
2. Results and discussion
nes, although it is clearly closely related to RCH@NSO2NR2
structures.6
2.1. Synthesis of sulfamyl imine acceptors 9
2.2. Catalytic 1,2-arylboron additions to sulfamyl imines 9
For an efficient route to the required imines 9 (Scheme 2) we
used the chemistry of Masui12 to access the intermediate sulfa-
mides 7 directly from N-alkylsulfamoylcarbamates 6. The latter
can be easily prepared by sequential addition of tert-BuOH and
aqueous solutions of RNH2 to widely available chlorosulfonyl iso-
cyanate; the chemistry presumably proceeds via the Burgess-like
intermediate 8. No extensive purification of intermediates 6 is nec-
essary prior to hydrolysis but representative compound 6b was
fully characterised since it is a new chemical entity compared to
6a and 6c.12–14 Conversion of 6 into 7 was attained by treatment
with TFA in CH2Cl2 at ambient temperature to afford the known
7 in 79–95% yield.14,15 Preliminary trials using PhCHO revealed
that imines 9 were best prepared by Ti(OEt)4 induced dehydra-
tions, other conditions (cat. H+/Dean–Stark, MgSO4, CuSO4) affor-
ded low/trace yields.
Our aim was to obtain a system that would enable simple ac-
cess to a wide range of protecting group free diaryl amines 3 using
simple and widely available (commercial) reagents. Among the ar-
ray of ligands and organoboron sources used for catalytic asym-
metric additions to imines, the most readily available are simple
boronic acids [ArB(OH)2) and the commercialised ligands LA–LB
(Scheme 3) in the presence of a widely available rhodium source
[RhCl(CH2@CH2)2]2.
iPr
O
O
Me
i t-BuOH
ii pyridine
(R,R)-LB
Scheme 3. Chiral ligands used herein.
(R,R,R)-LA
O2
S
O2
S
O2
S
TFA
R
Boc
R
H2N
N
H
N
H
OCN
N
H
Cl
iii RNH2
Ref. 12
R
R
O2
83%
95%
79%
Our initial optimisation concentrated on imines 9a–d as repre-
sentative examples of electron neutral and moderately electron
deficient imines in the presence of the RhI-L based catalyst
(3 mol % based on 9 using LA or LB). The biphasic conditions of
Zhou16 proved to be the most appropriate for the use of boronic
acids (Table 1).
7a
Me
t-Bu
Ph
82%
89%
78%
6a
6b
6c
Me
t-Bu
Ph
Boc
S
N
N
7b
7c
8
O2
S
R
While interesting levels of enantioselectivity (84–91%) were
realised in the 4-ClPhB(OH)2 additions to N-methyl/phenyl substi-
tuted 9b (runs 1–2 and 7), additions to more electron deficient 9a
uniformly resulted in lower ee values and appreciable hydrolysis to
4-ClPhCHO together with additional by-products (runs 3–4 and 8).
The presence of these species prevented accurate ee assay on the
small amounts of 10 formed. Despite systematic variation of the
reaction conditions (solvent, base and catalyst types), no overall
system could be identified to completely inhibit the hydrolysis of
the N-methyl derivatives 9a–b. Potassium carbonate was useful
in some cases (run 4), but synthetically useful levels of enantiose-
lectivity could not be realised. We then turned our attention to the
N-tert-butyl derivatives 9c–d. While high ee values were realised
(81–94%) unusual system dependent hydrolysis was observed
(runs 5–6 and 9–10). While the system based on Hayashi’s (R,R)-
bod ligand LB gave an optimal ee for 4-ClPhB(OH)2 addition to
9d, the same catalyst reproducibly promoted extensive hydrolysis
of 9c. Moderate results were attained with LA (runs 5–6). The yields
attained of addition products 10 are a composite of: (i) imine elec-
trophilicity (promoting both the addition and hydrolysis); (ii) ste-
ric/electronic nature of the arylboronic acid (controlling the rate of
catalyst loading and hydrodeboration); and (iii) ligand affects con-
trolling the rate of catalyst loading and addition.4 Disentangling
these factors for a given system is not easy. While the results using
N-tert-butyl derivatives 9c–d were encouraging, they did raise two
key questions: (i) given the tendency of these starting materials to
show catalyst system dependent hydrolysis, does a wide enough
range of synthetic utility exist and is any pattern of reactivity
apparent? (ii) Are the final products 10 easily deprotected and does
this result in any stereochemical erosion of the ee realised in the
catalytic addition? The first of these questions is addressed in
Table 2 and Scheme 4.
O2
S
O
N
Ti(OEt)4
N
R
+
H
H2N
N
H
Ar
THF Δ
H
Ar
H
6
Ar
R
Desirable properties for 9
9a
9b
9c
Me
4-ClPh
Ph
67%
free RNH2
water
Me
86%
85%
soluble
t-Bu
4-ClPh
Ph
O2
R
S
N
H
t-Bu
t-Bu
9d
83%
N
not co-eluted
with potential
Ar1Ar2CHNH2
products
9e
9f
9g
9h
4-FPh
59%
84%
88%
76%
Ar
H
t-Bu 4-CF3Ph
t-Bu 4-MePh
hydrolytic stability
t-Bu 3-MePh
t-Bu 3-MeOPh
9i
89%
Scheme 2. Preparation of activated imines used herein.
Investigation of an extensive range of R-substituents in 914 indi-
cated that the tert-butyl ‘dummy group’ was superior to all others
for the following reasons; (i) while the SO2NHBut group can be eas-
ily removed under the same conditions as the deprotection of 410
(mild pyridine reflux with 5% w/w water), the compounds are
hydrolytically robust in routine usage (much more so than the
methyl derivatives 9a–b); (ii) the released t-BuNH2 is water
soluble, thus facilitating its simple separation; other substituents
(e.g., benzyl or aryl derivatives) required chromatographic separa-
tions; and (iii) the tert-butyl derivatives 9c–9i were frequently
found to be crystalline entities facilitating purification. Surpris-
ingly, given these highly attractive features, the protecting group

R. H. Crampton et al. / Tetrahedron: Asymmetry 24 (2013) 599–605
601
Table 1
Optimisation of catalytic ArB(OH)2 addition to 9a
Ar2B(OH)2 (2 equiv.)
promoter (3.8 equiv.)
O2
S
O2
S
R
R
N
H
HN
O
N
H
N
+
[RhCl(CH2=CH2)2]2
1.5 mol%
Ar1
Ar2
Ar1
Ar1
H
H
10
LA or LB 3.3 mol%
9
Run
Ar1
R
Ar2
Solvent and base
Yield 10 (ee) (%)
Hydrol (%)
Using ligand LA
1
2
3
4
5
6
Ph
Ph
4-ClPh
4-ClPh
Ph
Me
Me
Me
Me
tBu
tBu
4-ClPh
4-ClPh
Ph
Ph
4-ClPh
Ph
CH2Cl2 KF
Toluene KF
CH2Cl2 KF
Toluene K2CO3
Toluene KF
Toluene KF
79 (85)
73 (84)
42 (n/d)
87 (71)
83 (86)
89 (81)
13
15
17
7
<2
<2
4-ClPh
Using ligand LB
7
8
9
Ph
4-ClPh
Ph
Me
Me
tBu
tBu
4-ClPh
Ph
4-ClPh
Ph
CH2Cl2 KF
CH2Cl2 KF
Toluene KF
Toluene KF
82 (91)
6 (n/d)
84 (94)
17 (n/d)
2
92
0
10
4-ClPh
69
a
Reactions were carried out using 9 (0.5 mmol), Ar2B(OH)2 (1.0 mmol), [RhCl(C2H4)2]2 (1.5 mol %), LA (3.3 mol %) and a base (3.8 equiv) in solvent (1 mL) and water (1 mL)
for 16 h at 35 °C. Yields were determined by isolation, except for runs 3, 8 and 10, which were determined from 1H NMR conversions. Enantioselectivities were determined by
HPLC as described in Section 4.5.
Non-tolerated imine/boronic acid combinations for LB
Table 2
Tolerated combinations of ArB(OH)2 and 9a
3-MeOPh / Ph
19% yield
4-FPh / Ph
12% yield
4-ClPh / Ph
17% yield
Ph / 3-MePh
7% yield
Ar2B(OH)2 (2 equiv.)
O2
S
KF (3.8 equiv.)
toluene:H2O, 35°C
O2
S
tBu
4-CF3Ph/Ph
17% yield
4-MePh / Ph
12% yield
3-MePh / Ph
7% yield
tBu
N
H
Yields
HN
N
H
N
of 10
[RhCl(CH2=CH2)2]2
1.5 mol%
Ar1
Ar2
Ar1
H
Scheme 4. Imine/boronic acid combinations leading to extensive imine hydrolysis
(isolated yields of 10 given).
L
A or LB 3.3 mol%
10
9
9
Ar1
Ar2
Ph
L used
10
Yield (ee) (%)
yield of 10) are summarised in Scheme 4. No useful addition yields
to the 4-MePh imine 9g with either LA or LB were obtained.
9c
9d
9d
9d
9d
9d
9d
9d
9d
9d
9d
9d
9e
9f
4-ClPh
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-FPh
4-CF3Ph
3-MePh
3-MeOPh
LA
(S)-10a
(R)-10a
(R)-10a
(R)-10b
(R)-10b
(R)-10c
(R)-10c
(R)-10d
(R)-10d
(R)-10e
(R)-10f
(R)-10f
(S)-10b
(S)-10c
(S)-10e
(S)-10f
89 (81)
83 (86)
84 (94)
42 (87)
90 (95)
32 (90)
84 (98)
68 (78)
71 (95)
35 (76)
37 (84)
91 (97)
41 (80)
71 (78)
53 (85)
34 (86)
4-ClPh
4-ClPh
4-FPh
4-FPh
4-CF3Ph
4-CF3Ph
4-MePh
4-MePh
3-MePh
3-MeOPh
3-MeOPh
Ph
LA
LB
LA
LB
LA
LB
LA
LB
LA
LA
LB
LA
LA
LA
LA
2.3. Deprotection of sulfamide addition products 10
The main reason for the development of our monoalkyl sulfam-
ide addition products 10 was that they would undergo facile
deprotection to the free diarylmethylamines 3 under mild basic
conditions with good recovery and no racemisation. In a trial
run, (R)-10a (86% ee) was subjected to an aqueous pyridine depro-
tection protocol (Scheme 5). This provided a very high yielding
Ph
Ph
Ph
9h
9h
O2
tBu
5% w/w water
in pyridine
S
N
H
a
9
(0.5 mmol), Ar2B(OH)2 (1.0 mmol),
NH2
HN
Reactions were carried out using
[RhCl(C2H4)2]2 (1.5 mol %), LA or LB (3.3 mol %) and KF (3.8 equiv) in toluene/water
(2 mL, 1:1) for 16 h at 35 °C. Yields were determined by isolation. Enantioselec-
tivities were determined by HPLC as described in Section 4.5.
Δ 16 h
Ph
4-ClPh
Ph
(R)-3a
4-ClPh
79%
isolated
(R)-10a
(86% ee)
Ac2O
For the additions to the phenyl-based 9d, a significant range of
Ar2B(OH)2 was tolerated regardless of the ligand used. One excep-
tion to this was the addition of 3-MePhB(OH)2 where almost com-
plete hydrolysis of the starting imine was observed to give 10e in
very low yield (7%) when using LB. For the substituted imines 9c
and 9e–h, there were very significant issues of hydrolysis in sys-
tems using LB. Systems that were intolerant of this ligand (<20%
NHAc
(10 equiv.)
Ph
4-ClPh
(87% ee)
very high yielding
(R)-11a
Scheme 5. Representative conditions for the racemisation-free deprotection of 10
and protecting group exchange.

602
R. H. Crampton et al. / Tetrahedron: Asymmetry 24 (2013) 599–605
conversion to the free amine (R)-3a with literature properties that
could be isolated in 79% yield. Such species are not commonly iso-
lated due to polarity/basicity issues resulting in material loss. More
conveniently, the direct treatment of the reaction mixture contain-
ing (R)-3a with excess Ac2O resulted in the in situ protecting group
exchange to (R)-11a (87% ee) allowing us to confirm that essen-
tially no racemisation had taken place within the error on the HPLC
assay ( 1%). In fact, the ee measurement on 11 was by far the most
convenient method in all cases.
sulfamides with excellent enantiomeric excess. However, in some
cases extensive hydrolysis of the precursor imine is observed. This
could be moderated by the use of ligand LA. Deprotection of the
resultant addition products with 5% w/w water in pyridine is very
high yielding and proceeds without a loss of enantiomeric excess.
Overall the procedure is complementary to existing routes to 3 that
normally require harsher deprotection strategies under either
acidic or reductive conditions, or in the presence of strong
nucleophiles.
Application of the deprotection strategy across a range of com-
pounds allowed facile access to a full range of deprotected primary
amines (Table 3) without degradation of the enantioselectivity.
While conversion of 10–3 was very high yielding, isolation of the
amines was simplified by the formation of their acetamides (in
an analogous way to Scheme 5). All of the compounds had proper-
ties identical to materials provided by our previous deprotections
of 4.10 Summary conditions for the ee determinations are given
in Section 4 (Table 4).
4. Experimental
4.1. General
The general instrumentation used has been described previ-
ously.10,14 All reactions involving air sensitive materials were car-
ried out under argon using standard Schlenk techniques. Ligands
LA–LB were commercial products or prepared by literature
procedures.17
Table 3
Mild base-promoted deprotection of 10a
4.2. Representative preparation of N-alkylsulfamoylcarbamates
tert-butyl N-tert-butylsulfamoylcarbamate 6b
O2
tBu
S
NHR
N
H
5% w/w water-pyridine
(S) for CIP
HN
Chlorosulfonyl isocyanate (8.7 mL, 0.1 mol, 1 equiv) in toluene
(10 mL) was added dropwise to a stirred solution of tert-butanol
(9.4 mL, 0.1 mol, 1 equiv) in toluene (100 mL) at 3 °C over
30 min. The colourless suspension was stirred at 3 °C for 45 min,
then pyridine (17.7 mL, 0.22 mol, 2.2 equiv) was added dropwise
over 15 min and the suspension stirred at 7 °C for 60 min. Next,
tert-butylamine (40–70 wt% in H2O, 0.6 mol, 6 equiv) was added
dropwise at 5 °C over 30 min and the biphasic mixture was stirred
for 2 h at 5 °C. The layers were separated and the aqueous phase
was washed with toluene (100 mL). The combined organic phases
were washed with water (100 mL). The combined aqueous were
acidified with 2 M HCl to pH 1 and the precipitate was collected
by filtration to afford the product 6b as a colourless crystalline so-
lid (4.51 g, 89%). Rf 0.69 (5% MeOH/CH2Cl2); mp 151 °C dec; IR
Ar1 > Ar2
Ar1
Ar2
Ar1
Δ 16 h
Ar2
10
3
R = H
Ac2O
11 R = Ac
3
Ar1
Ar2
Chirality
Yield 11 (%)
ee 11 (%)
3a
3b
3c
3d
3e
3f
Ph
Ph
Ph
Ph
3-MePh
Ph
4-ClPh
4-FPh
4-CF3Ph
4-MePh
Ph
(R)
(R)
(R)
(R)
(S)
(R)
79
88
99
78
78
73
86
87
98
95
85
97
3-MeOPh
a
Reactions were carried out using isolated samples of 10 prepared from 9
(CHCl3) m
max/cmꢀ1 3401, 2939, 1737, 1435, 1403, 1143; 1H NMR
(0.5 mmol).
(400.1 MHz, CDCl3) dH 7.11 (s, 1H, NHBoc), 5.03 (s, 1H,
NHC(CH3)3)), 1.50 (s, 9H, COOC(CH3)3), 1.36 (s, 9H, NHC(CH3)3);
13C NMR (100.6 MHz, CDCl3) dC 150.2 (C), 83.5 (C), 55.0 (C), 29.4
(CH3), 28.1 (CH3); HRMS (ESI Positive) calcd for C9H20N2O4S,
[M+Na] 275.1036, found 275.1042; Anal. Calcd for C9H20N2O4S:
C, 42.84; H, 7.99; N, 11.10%. Found: C, 42.62; H, 7.97; N, 11.05%.
Other derivatives of 6 were prepared in analogous manner and
had properties that matched the literature.13,14
3. Conclusion
In conclusion, an N-tert-butyl-sulfamyl group has been devel-
oped as a new activating group for imines. The imines are prepared
by condensation of N-tert-butyl-sulfamide and an arylaldehyde in
the presence of Ti(OEt)4. The required N-tert-butyl-sulfamide can
be readily prepared from tert-BuNH2 and chlorosulfonyl isocyanate
in two high yielding steps. The rhodium catalysed addition of aryl
boronic acids proceeded in varying yields; the optimum yield was
achieved with the LB ligand and the unsubstituted benzaldehyde
derived imine 9d. These aryl additions give enantioenriched
4.3. General procedure for the formation of sulfamides 7
Trifluoroacetic acid (240 mmol) in CH2Cl2 (20 mL) was added
dropwise to a stirred suspension of N-alkylsulfamoylcarbamate 6
Table 4
Enantiopurity determination using 11a
3
Ar1
Ar2
HPLC conditionsb
½aꢁD
11c (%)
11a
11b
11c
11d
11e
11f
Ph
Ph
Ph
Ph
3-MePh
Ph
4-ClPh
4-FPh
4-CF3Ph
4-MePh
Ph
OD, 95:5, 1 mL minꢀ1 tS = 22.2, tR = 33.6 min
OD, 95:5, 1 mL minꢀ1 tS = 8.8, tR = 13.6 min
ꢀ1.1 (c 1.3) 87% ee (R)d
ꢀ1.2 (c 1.1) 95% ee (R)
+33.6 (c 0.62) 89% ee (S)e
ꢀ1.7 (c 1.0) 97% ee (R)
+1.3 (c 1.1) 85% ee (S)
n/d
OD-H, 90:10, 1 mL minꢀ1 tS = 6.6, tR = 11.0 min
OD-H, 90:10, 1 mL minꢀ1 tS = 8,0, tR = 10.1 min
AHꢀH+AD in series, 95:5, 1 mL minꢀ1 tS = 27.6, tR = 32.0 min
OD, 95:5, 1 mL minꢀ1 tS = 13.7, tR = 27.9 min
3-MeOPh
a
b
c
Carried out on acetamides prepared directly from in situ 3 (0.3–0.5 mmol) by the chemistry of Table 4.
Data in the form: column type, ratio of hexanes/iso-PrOH, flow rate, enantiomer elution order. A detector wavelength of 200 nm was used in all cases.
At ambient temperature in CHCl3 unless otherwise stated.
In EtOH.
d
e
Literature value, ref. 18b.

R. H. Crampton et al. / Tetrahedron: Asymmetry 24 (2013) 599–605
603
(80 mmol) in CH2Cl2 (100 mL) at 0 °C. The solution was stirred
overnight and allowed to warm to ambient temperature. The solu-
tion was concentrated in vacuo and the residue was taken up in
EtOAc (75 mL), washed with sat. NaHCO3 solution (2 ꢂ 50 mL),
dried (Na2SO4) and concentrated to a colourless oil. Compound
7b required no purification. All other species were isolated by col-
umn chromatography (5% MeOH/CH2Cl2) as crystalline solids or
pale oils with literature properties.14,15 Rf 7a 0.24 (10:1 CH2Cl2/
MeOH), 1H NMR (400.1 MHz, acetone-d6) dH 5.81 (brs, 2H, NH2),
5.51 (brs, 1H, NHCH3), 2.71 (d, J = 5.2 Hz, 3 H, NHCH3); 7b Rf 0.16
(5% MeOH/CH2Cl2), 1H NMR (400.1 MHz, CDCl3) dH 6.40 (brs, 2H,
NH2), 6.30 (brs, 1H, NHC(CH3)3), 1.24 (s, 9H, C(CH3)3); Rf 7c 0.22
(5% MeOH/CH2Cl2), 1H NMR (400.1 MHz, DMSO-d6) dH 9.46 (s,
1H, NHPh), 7.28–7.23 (m, 2H, CHaryl), 7.17–7.14 (m, 2H, CHaryl),
7.06 (brs, 2H, NH2) 6.96 (tt, J = 7.2, 1.1 Hz, 1H, CHaryl).
7.49 (dt, J = 8.4, 2.0 Hz, 2H, CHaryl), 4.46 (s, 1H, NHC(CH3)3)), 1.39
(s, 9H, C(CH3)3); 13C NMR (100.6 MHz, CDCl3) dC 166.4 (CH),
140.7 (C), 131.8 (CH), 131.1 (C), 129.6 (CH), 55.1 (C), 30.2 (CH3);
HRMS (ESI Positive) calcd for C11H15ClN2O2S, [M+Na] 297.0435,
found 297.0441; Anal. Calcd for C11H15ClN2O2S: C, 48.08; H, 5.50;
N, 10.20%. Found: C, 48.05; H, 5.48; N, 10.21%.
4.4.4. N-tert-Butyl-N0-[phenylmethylidene]sulfamide 9d
Prepared from 7b (1.14 g, 7.50 mmol) and benzaldehyde
(0.84 mL, 8.25 mmol) purified by column chromatography (4:1
pet. ether/EtOAc) to give a colourless solid (1.49 g, 83%). Rf 0.33
(4:1 pet. ether/EtOAc); mp 103–106 °C; IR (CHCl3)
m
max/cmꢀ1
3386, 2980, 1613, 1576, 1391, 1333, 1150, 998, 864; 1H NMR
(400.1 MHz, CDCl3) dH 8.92 (s, 1H, N@CH), 7.93–7.91 (m, 2H, CHar-
yl), 7.62 (tt, J = 7.4, 1.5 Hz, 1H, CHaryl), 7.53–7.49 (m, 2H, CHaryl),
4.50 (s, 1H, NHC(CH3)3)), 1.39 (s, 9H, C(CH3)3); 13C NMR
(100.6 MHz, CDCl3) dC 167.8 (CH), 134.2 (CH), 132.7 (C), 130.7
(CH), 129.1 (CH), 55.0 (C), 30.2 (CH3); HRMS (ESI Positive) calcd
for C11H16N2O2S, [M+Na] 263.0825, found 263.0815. Anal. Calcd
for C11H16N2O2S: C, 54.98; H, 6.71; N, 11.66%. Found: C, 54.82; H,
6.68; N, 11.71%.
4.4. General method for the synthesis of sulfamyl imines 9
N-Alkylsulfamide 7 (3.63 mmol, 1 equiv) was added to a stirred
solution of arylaldehyde (4.00 mmol, 1.1 equiv) and Ti(OEt)4
(1.95 g, 7.26 mmol, 2 equiv) in THF (10 mL). The solution was stir-
red at reflux for 7 h, allowed to cool and then poured into stirred
brine (100 mL), EtOAc (50 mL) was added and the mixture was stir-
red vigorously. The mixture was then filtered through CeliteÒ and
flushed with further EtOAc. The filtrate was separated and the
aqueous layer was back extracted with EtOAc (50 mL). The com-
bined organic layers were washed with brine (50 mL), dried
(Na2SO4) and concentrated to a cream solid. Purification by column
chromatography or trituration gave the products as colourless to
cream solids (yellow for 9f).
4.4.5. N-tert-Butyl-N0-[4-fluorophenylmethylidene]sulfamide 9e
Prepared from 7b (1.14 g, 7.50 mmol) and 4-fluorobenzalde-
hyde (0.88 ml, 8.25 mmol) purified by column chromatography
(4:1 pet. ether/EtOAc) to afford a cream solid (1.15 g, 59%). Rf
0.31 (4:1 pet. ether/EtOAc); mp 103–105 °C; IR (CHCl3) mmax
/
cmꢀ1 3386, 2939, 1601, 1510, 1333, 1242, 1149, 999; 1H NMR
(400.1 MHz, CDCl3) dH 8.88 (s, 1H, N@CH), 7.96–7.91 (m, 2H, CHar-
yl), 7.22–7.17 (m, 2H, CHaryl), 4.63 (s, 1H, NHC(CH3)3)), 1.39 (s, 9H,
C(CH3)3); 13C NMR (100.6 MHz, CDCl3) dC 166.4 (C, d, 1JCF = 256 Hz),
3
4.4.1. N-Methyl-N0-[4-chlorophenylmethylidene]sulfamide 9a
Prepared from 7a (1.10 g, 10 mmol) and 4-chlorobenzaldehyde
(1.55 g, 11 mmol) and purified by column chromatography (2:1
pet. ether/EtOAc) to give a colourless solid (1.60 g, 67%). Rf 0.23
166.3 (CH), 133.1 (CH, d, JCF = 10.2 Hz), 129.0 (C), 116.6 (CH, d,
2JCF = 21.8 Hz), 55.0 (C), 30.1 (CH3); 19F NMR (376.5 MHz, CDCl3)
dF ꢀ102.5; HRMS (ESI Positive) calcd for C11H15FN2O2S, [M+Na]
281.0730, found 281.0724. Anal. Calcd for
C11H15FN2O2S: C,
(2:1 pet. ether/EtOAc); mp 135–137 °C; IR (CHCl3)
m
max/cmꢀ1
51.15; H, 5.85; N, 10.84%. Found: C, 51.10; H, 5.85; N, 10.84%.
3388, 1611, 1594, 1338, 1162, 842; 1H NMR (400.1 MHz, CDCl3)
dH 8.88 (s, 1H, N@CH), 7.88 (dt, J = 8.4, 2.3 Hz, 2H, CHaryl), 7.50
(dt, J = 8.4, 2.2 Hz, 2H, CHaryl), 4.44 (br q, J = 5.2 Hz, 1H, NH), 2.84
(q, J = 5.2 Hz, 3 H, CH3); 13C NMR (100.6 MHz, CDCl3) dC 168.5
(CH), 141.1 (C), 132.0 (CH), 130.8 (C), 129.6 (CH), 29.9 (CH3); HRMS
(ESI Positive) calcd for C8H9N2O2S, [M+Na] 254.9965, found
254.9974; Anal. Calcd for C8H9N2O2S: C, 41.29; H, 3.90; N,
12.04%. Found: C, 41.24; H, 3.86; N, 11.82%.
4.4.6. N-tert-Butyl-N0-[4-(trifluoromethyl)phenylmethylidene]
sulfamide 9f
Prepared from 7b (1.14 g, 7.50 mmol) and 4-(trifluoro-
methyl)benzaldehyde (1.13 mL, 8.25 mmol) purified by column
chromatography (2:1 pet. ether/EtOAc) to give the product as a yel-
low solid (1.93 g, 84%). Rf 0.27 (4:1 pet. ether/EtOAc); mp 103–
106 °C; IR (CHCl3) m
max/cmꢀ1 3386, 2980, 1619, 1324, 1175, 1151,
1000; 1H NMR (400.1 MHz, CDCl3) dH 8.96 (s, 1H, N@CH), 8.04 (d,
J = 8.0 Hz, 2H, CHaryl), 7.77 (d, J = 8.0 Hz, 2H, CHaryl), 4.68 (s, 1H,
NHC(CH3)3), 1.40 (s, 9H, C(CH3)3); 13C NMR (100.6 MHz, CDCl3) dC
4.4.2. N-Methyl-N0-[phenylmethylidene]sulfamide 9b
Prepared from 7a (3.30 g, 30 mmol) and benzaldehyde (3.37 mL,
33 mmol), trituration with hexanes gave a cream solid (5.09 g, 86%).
2
166.1 (CH), 135.7 (C), 135.3 (C, q, JCF = 32.8 Hz), 130.7 (CH),
3
1
Rf 0.19 (4:1 pet. ether/EtOAc); mp 127–130 °C; IR (CHCl3)
m
max/cmꢀ1
126.1 (CH, q, JCF = 3.8 Hz), 123.4 (C, q, JCF = 271 Hz), 55.2 (C),
30.1 (CH3); 19F NMR (376.5 MHz, CDCl3) dF ꢀ63.3; HRMS (ESI Posi-
tive) calcd for C12H15F3N2O2S, [M+Na] 331.0699, found 331.0689.
Anal. Calcd for C12H15F3N2O2S: C, 46.75; H, 4.90; N, 9.09%. Found:
C, 46.70; H, 4.88; N, 8.97%.
3386, 1610, 1578, 1336, 1161, 842; 1H NMR (400.1 MHz, CDCl3) dH
8.93 (s, 1H, N@CH), 7.96–7.93 (m, 2H, CHaryl), 7.64 (tt, J = 1.6, 7.4 Hz,
1H, CHaryl), 7.55–7.51 (m, 2H, CHaryl), 4.42 (d, J = 5.2 Hz, 1H, NHCH3),
2.84 (d, J = 5.2 Hz, 3 H, NHCH3); 13C NMR (100.6 MHz, CDCl3) dC
170.0 (CH), 134.6 (CH), 132.3 (C), 130.9 (CH), 129.2 (CH), 29.9
(CH3); HRMS (ESI Positive) calcd for C8H10N2O2S, [M+Na]
221.0355, found 221.0359; Anal. Calcd for C8H10N2O2S: C, 48.47;
H, 5.08; N, 14.13%. Found: C, 48.28; H, 5.14; N, 13.99%.
4.4.7. N-tert-Butyl-N0-[4-methylphenylmethylidene]sulfamide
9g
Prepared from 7b (1.14 g, 7.50 mmol) and p-tolualdehyde
(0.98 ml, 8.25 mmol) purified by column chromatography (4:1
pet. ether/EtOAc) to afford a cream solid (1.69 g, 88%). Rf 0.39
4.4.3. N-tert-Butyl-N0-[4-chlorophenylmethylidene]sulfamide
9c
(4:1 pet. ether/EtOAc); mp 131–134 °C; IR (CHCl3)
m
max/cmꢀ1
Prepared from 7b (1.40 g, 9.2 mmol) and 4-chlorobenzaldehyde
(1.42 g, 10.1 mmol) purified by column chromatography (4:1 pet.
ether/EtOAc) to give a colourless solid (1.21 g, 85%). Rf 0.32 (4:1
3386, 2979, 1603, 1569, 1332, 1148, 998, 872; 1H NMR
(400.1 MHz, CDCl3) dH 8.87 (s, 1H, N@CH), 7.81 (d, J = 8.0 Hz, 2H,
CHaryl), 7.31 (d, J = 8.0 Hz, 2H, CHaryl), 4.38 (brs, 1H, NHC(CH3)3)),
2.45 (s, 3 H, ArCH3), 1.38 (s, 9H, C(CH3)3); 13C NMR (100.6 MHz,
CDCl3) dC 167.7 (CH), 145.5 (C), 130.8 (CH), 130.1 (C), 129.9 (CH),
54.9 (C), 30.1 (CH3), 21.9 (CH3); HRMS (ESI Positive) calcd for
pet. ether/EtOAc); mp 111–114 °C; IR (CHCl3)
m
max/cmꢀ1 3386,
2980, 1614, 1595, 1334, 1150, 999, 868; 1H NMR (400.1 MHz,
CDCl3) dH 8.87 (s, 1H, N@CH), 7.85 (dt, J = 8.4, 2.1 Hz, 2H, CHaryl),

604
R. H. Crampton et al. / Tetrahedron: Asymmetry 24 (2013) 599–605
C12H18N2O2S, [M+Na] 277.0981, found 277.0982. Anal. Calcd for
12H18N2O2S: C, 56.67; H, 7.13; N, 11.01%. Found: C, 56.70; H,
7.13; N, 10.92%.
J = 6.7 Hz, 1H, NHCH), 4.85 (d, J = 6.7 Hz, 1H, NHCH), 4.02 (s, 1H,
NHC(CH3)3), 1.18 (s, 9H, C(CH3)3); 13C NMR (100.6 MHz, CDCl3) dC
140.9 (C), 140.0 (C), 133.2 (C), 128.8 (CH), 128.7 (CH), 128.6 (CH),
127.8 (CH), 127.4 (CH), 60.8 (CH), 54.2 (C), 29.5 (CH3); HRMS (ESI
C
4.4.8. N-tert-Butyl-N0-[3-methylphenylmethylidene]sulfamide
9h
Positive) calcd for C17H21ClN2O2S, [M+Na] 375.0904, found
375.0916. Anal. Calcd for C17H21ClN2O2S: C, 57.86; H, 6.00; N,
7.94%. Found: C, 57.63; H, 6.02; N, 7.77%. HPLC: Daicel Chiralpak
OD-H, 95:5 hexanes/iPrOH; 1.0 mL/min; 200 nm; (S)-enantiomer
Prepared from 7b (1.14 g, 7.50 mmol) and m-tolualdehyde
(0.97 mL, 8.25 mmol) purified by column chromatography (4:1
pet. ether/EtOAc) to give a cream solid (1.44 g, 76%). Rf 0.26 (4:1
tS = 22.2 min, (R)-enantiomer tR = 30.1 min; ½aꢁD ¼ ꢀ1:9 (c 1.09,
pet. ether/EtOAc); mp 85–88 °C; IR (CHCl3)
m
max/cmꢀ1 3386,
CHCl3) for 81% ee material. A sample of (R)-10a (83% yield, 94%
ee) was prepared from 9d and LB which showed equivalent proper-
ties aside from its specific rotation.
2937, 1583, 1391, 1333, 1149, 997; 1H NMR (400.1 MHz, CDCl3)
dH 8.88 (s, 1H, N@CH), 7.73–7.69 (m, 2H, CHaryl), 7.44–7.37 (m,
2H, CHaryl), 4.51 (brs, 1H, NH), 2.42 (s, 3 H, ArCH3), 1.39 (s, 9H,
C(CH3)3); 13C NMR (100.6 MHz, CDCl3) dC 168.1 (CH), 139.0 (C),
135.2 (CH), 132.6 (C), 130.9 (CH), 129.0 (CH), 128.2 (CH), 55.0
(C), 30.2 (CH3), 21.2 (CH3); HRMS (ESI Positive) calcd for
C12H18N2O2S, [M+H] 277.0981, found 277.0989. Anal. Calcd for
4.5.2. (R)-N-tert-Butyl-N0-(4-fluorophenyl)(phenyl)
methylsulfamide (R)-10b
Prepared from 9d (120 mg, 0.50 mmol) using LB and purified by
column chromatography (4:1 pet. ether/EtOAc) to give a colourless
solid (151 mg, 90%). Rf 0.25 (4:1 pet. ether/EtOAc); mp 133–135 °C;
C12H18N2O2S: C, 56.67; H, 7.13; N, 11.01%. Found: C, 56.58; H,
7.13; N, 11.01%.
IR (CHCl3) m
max/cmꢀ1 3383, 2980, 1606, 1510, 1322, 1144, 991; 1H
NMR (400.1 MHz, CDCl3) dH 7.36–7.26 (m, 7 H, CHaryl), 7.04–6.98
(m, 2H, CHaryl), 5.60 (d, J = 6.8 Hz, 1H, NHCH), 4.89 (d, J = 6.8 Hz,
1H, NHCH), 4.05 (s, 1H, NHC(CH3)3), 1.17 (s, 9H, C(CH3)3); 13C
4.4.9. N-tert-Butyl-N0-[3-methoxyphenylmethylidene]sulfamide
9i
1
Prepared from 7b (1.14 g, 7.50 mmol) and 3-methoxybenzalde-
hyde (1.00 ml, 8.25 mmol) purified by column chromatography
(4:1 pet. ether/EtOAc) to afford a cream solid (1.80 g, 89%). Rf
NMR (100.6 MHz, CDCl3) dC 162.1 (C, d, JCF = 246 Hz), 141.1 (C),
4
3
137.1 (C, d, JCF = 2.9 Hz), 129.2 (CH, d, JCF = 8.8 Hz), 128.8 (CH),
2
127.9 (CH), 127.4 (CH), 115.5 (CH, d, JCF = 20.3 Hz), 61.0 (CH),
0.26 (4:1 pet. ether/EtOAc); mp 90–93 °C; IR (CHCl3)
m
max/cmꢀ1
54.4 (C), 29.5 (CH3); 19F NMR (376.5 MHz, CDCl3) dF ꢀ114.1; HRMS
(ESI Positive) calcd for C17H21FN2O2S, [M+Na] 359.1200, found
359.1197; Anal. Calcd for C17H21FN2O2S: C, 60.69; H, 6.29; N,
8.33%. Found: C, 60.58; H, 6.26; N, 8.22%; HPLC: Daicel Chiralpak
OD-H, 95:5 hexanes/iPrOH; 1.0 mL/min; 200 nm; (S)-enantiomer
3386, 2941, 1581, 1333, 1150, 998, 869; 1H NMR (400.1 MHz,
CDCl3) dH 8.87 (s, 1H, N@CH), 7.48–7.39 (m, 3 H, CHaryl), 7.16
(ddd, J = 8.0, 2.8, 1.6 Hz, 1H, CHaryl), 4.57 (brs, 1H, NHC(CH3)3)),
3.87 (s, 3 H, OCH3), 1.39 (s, 9H, C(CH3)3); 13C NMR (100.6 MHz,
CDCl3) dC 167.8 (CH), 160.1 (C), 134.0 (C), 130.1 (CH), 124.4 (CH),
121.1 (CH), 113.4 (CH), 55.5 (CH3), 55.0 (C), 30.1 (CH3); HRMS
(ESI Positive) calcd for C12H18N2O3S, [M+Na] 293.0930, found
293.0927. Anal. Calcd for C12H18N2O3S: C, 53.31; H, 6.71; N,
10.36%. Found: C, 53.26; H, 6.67; N, 10.24%.
tS = 20.1 min, (R)-enantiomer tR = 25.2 min; ½aꢁD ¼ þ0:5 (c 0.97,
CHCl3) for 95% ee material. A sample of (S)-10b (41% yield, 80%
ee) was prepared from 9e and LA, which showed equivalent prop-
erties aside from its specific rotation.
4.5.3. (R)-N-tert-Butyl-N0-(4-trifluoromethylphenyl)(phenyl)
methylsulfamide (R)-10c
4.5. General method for the rhodium catalysed boronic acid
addition to sulfamyl imines 9
Prepared from 9d (120 g, 0.50 mmol) using LB and purified by
column chromatography (4:1 pet. ether/EtOAc) to give a colourless
solid (162 mg, 84%). Rf 0.13 (4:1 pet. ether/EtOAc); mp 140–143 °C;
A flame dried Schlenk was charged with [RhCl(C2H4)2]2 (2.9 mg,
7.5
lmol, 1.5 mol %), ligand (16.5
l
mol, 3.3 mol %) and toluene
IR (CHCl3) m
max/cmꢀ1 3382, 2979, 1421, 1326, 1169, 1144, 991; 1H
(0.4 mL). The orange solution was stirred at ambient temperature
for 10 min. Toluene (0.6 mL), water (1 mL), Ar2B(OH)2 (1 mmol,
2 equiv), KF (110.4 mg, 1.9 mmol, 3.8 equiv) and sulfamyl imine 9
(0.5 mmol, 1 equiv) were added sequentially. The biphasic mixture
was gently stirred at 35 °C for 16 h. Water (10 mL) was then added
and washed with CH2Cl2 (2 ꢂ 20 mL). The combined organic layers
were washed with brine (10 mL), dried (Na2SO4) and concentrated.
If necessary, undesired by-products could be removed by stirring
the residue in 1:1 CH2Cl2/2 M HCl (10 mL). Purification by column
chromatography gave the final products 10 (see individual
conditions).
Authentic racemic samples of 10 were prepared by PhMgCl
(4.0 equiv) addition to 9 (0.50 mmol) in THF (10 mL) at 0 °C. The
reactions were allowed to return to ambient temperature while
being stirred (18 h) followed by standard work-up. Alternatively
Ar2Li was pre-formed in THF at ꢀ78 °C and treated with 9d (3 h,
ꢀ78 °C) followed by aqueous quenching and an identical workup.
NMR (400.1 MHz, CDCl3) dH 7.60 (d, J = 8.0 Hz, 2H, CHaryl), 7.49 (d,
J = 8.8 Hz, 2H, CHaryl), 7.40–7.28 (m, 5 H, CHaryl), 5.67 (d, J = 6.4 Hz,
1H, CHNH), 4.83 (d, J = 6.8 Hz, 1H, CHNH), 3.98 (s, 1H, NHC(CH3)3),
1.19 (s, 9H, C(CH3)3); 13C NMR (100.6 MHz, CDCl3) dC 145.3 (C),
2
140.6 (C), 129.8 (C, q, JCF = 32 Hz), 128.9 (CH), 128.2 (CH), 127.8
3
(CH), 127.5 (CH), 125.5 (CH, q, JCF = 3.6 Hz), 124.0 (C, q,
1JCF = 271 Hz), 61.2 (CH), 54.4 (C), 29.5 (CH3); 19F NMR
(376.5 MHz, CDCl3) dF ꢀ62.5; HRMS (ESI Positive) calcd for
C18H21F3N2O2S, [M+Na] 409.1168, found 409.1167. Anal. Calcd for
C18H21F3N2O2S: C, 55.95; H, 5.48; N, 7.25%. Found: C, 55.95; H,
5.47; N, 7.12%; HPLC: Daicel Chiralpak OD-H, 95:5 hexanes/iPrOH;
1.0 mL/min; 200 nm; (S)-enantiomer tS = 13.6 min, (R)-enantiomer
tR = 22.1 min; ½aꢁD ¼ ꢀ3:7 (c 1.35, CHCl3) for 98% ee material. A
sample of (S)-10c (71% yield, 78% ee) was prepared from 9f and
LA which showed equivalent properties aside from its specific
rotation.
4.5.4. (R)-N-tert-Butyl-N0-(4-methylphenyl)(phenyl)
methylsulfamide (R)-10d
4.5.1. (S)-N-tert-Butyl-N0-(4-chlorophenyl)(phenyl)
methylsulfamide (S)-10a
Prepared from 9d (127 mg, 0.50 mmol) using LB and purified by
column chromatography (4:1 pet. ether/EtOAc) to give a colourless
solid (119 mg, 71%). Rf 0.33 (4:1 pet. ether/EtOAc); mp 147–149 °C;
Prepared from 9c (137.4 mg, 0.50 mmol) using LA and purified
by column chromatography (4:1 pet. ether/EtOAc) to give a white
solid (156.8 mg, 89%); Rf 0.29 (4:1 pet. ether/EtOAc); mp 157–
IR (CHCl3)
m
max/cmꢀ1 3384, 3011, 1321, 1144, 990; 1H NMR
159 °C; IR (CHCl3)
m
max/cmꢀ1 3383, 2980, 1491, 1324, 1145; 1H
(400.1 MHz, CDCl3) dH 7.34–7.32 (m, 4 H, CHaryl), 7.30–7.25 (m,
NMR (400.1 MHz, CDCl3) dH 7.36–7.26 (m, 9H, CHaryl), 5.59 (d,
1H, CHaryl), 7.22–7.20 (m, 2H, CHaryl), 7.15–7.13 (m, 2H, CHaryl),

R. H. Crampton et al. / Tetrahedron: Asymmetry 24 (2013) 599–605
605
5.59 (d, J = 6.4 Hz, 1H, NHCH), 4.74 (d, J = 6.4 Hz, 1H, NHCH), 3.84
(brs, 1H, NHC(CH3)3), 2.33 (s, 3 H, ArCH3), 1.17 (s, 9H, C(CH3)3);
13C NMR (100.6 MHz, CDCl3) dC 141.4 (C), 138.3 (C), 137.5 (C),
129.4 (CH), 128.7 (CH), 127.6 (CH), 127.5 (CH), 127.4 (CH), 61.5
(CH), 54.3 (C), 29.6 (CH3), 21.0 (CH3); HRMS (ESI Positive) calcd
for C18H24N2O2S, [M+Na] 355.1451, found 355.1450. Anal. Calcd
for C18H24N2O2S: C, 65.05; H, 7.28; N, 8.43%. Found: C, 64.98; H,
7.30; N, 8.20%; HPLC: Daicel Chiralpak OD-H, 95:5 hexanes/iPrOH;
1.0 mL/min; 200 nm; (S)-enantiomer tS = 21.1 min, (R)-enantiomer
4.6. Deprotection and acetylation of sulfamides 10, formation of
3 and 11
A solution of sulfamide 10 (typically ca. 0.4 mmol) in 5% water–
pyridine (10 mL) was stirred at reflux overnight. Removal of the
solvents afforded the amines 3 directly. Alternatively, the solution
was allowed to cool and acetic anhydride (10 equiv) was added
and stirred at ambient temperature for 7 h. Subsequently 1 M
HCl (20 mL) was added and the mixture extracted with Et2O
(2 ꢂ 15 mL). The combined organic extracts were washed with
2 M HCl (2 ꢂ 20 mL), water (20 mL) and brine (20 mL), dried
(Na2SO4) and concentrated to give the product with no further
purification necessary. Full data for both the amines7,14 and their
acyl derivatives14,18 are available. Summary data for the ee assays
on the acetamides 11 are given in Table 4.
tR = 26.1 min. ½aꢁD ¼ þ3:9 (c 0.99, CHCl3) for 95% ee material.
4.5.5. (S)-N-tert-Butyl-N0-(3-methylphenyl)(phenyl)
methylsulfamide (S)-10e
Prepared from 9h (120 mg, 0.50 mmol) and LA purified by col-
umn chromatography (4:1 pet. ether/EtOAc) to give a colourless
solid (89 mg, 54%). Rf 0.30 (4:1 pet. ether/EtOAc); mp 90–93 °C;
IR (CHCl3)
m
max/cmꢀ1 3384, 2978, 1391, 1324, 1144, 990; 1H NMR
Acknowledgment
(400.1 MHz, CDCl3) dH 7.34–7.19 (m, 6 H, CHaryl), 7.14–7.06 (m,
3 H, CHaryl), 5.57 (d, J = 6.8 Hz, 1H, CHNH), 4.91 (d, J = 6.4 Hz, 1H,
CHNH), 4.05 (s, 1H, NHC(CH3)3), 2.32 (s, 3 H, ArCH3), 1.15 (s, 9H,
C(CH3)3); 13C NMR (100.6 MHz, CDCl3) dC 141.4 (C), 141.2 (C),
138.3 (C), 128.60 (CH), 128.55 (CH), 128.4 (CH), 128.2 (CH), 127.6
(CH), 127.5 (CH), 124.5 (CH), 61.6 (CH), 54.2 (C), 29.5 (CH3), 21.4
(CH3); HRMS (ESI Positive) calcd for C18H24N2O2S, [M+Na]
355.1451, found 355.1450. Anal. Calcd for C18H24N2O2S: C, 65.03;
H, 7.28; N, 8.43%. Found: C, 65.03; H, 7.28; N, 8.41%; HPLC: Daicel
Chiralpak AD, 95:5 hexanes/iPrOH; 1.0 mL/min; 200 nm; (S)-enan-
One of us (R.H.C.) is grateful to Dr. Reddy’s and the University of
Nottingham for support of a scholarship.
References
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3. For example, levocetirizine (an oral antihistamine) is particularly interesting,
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Senanayake, C. H.; Wald, S. A. Org. Proc. Res. Dev. 2001, 5, 110–115.
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2011, 133, 1248–1250; (b) Oi, S.; Moro, M.; Fukuhara, H.; Kawanishi, T.; Inoue,
Y. Tetrahedron 2003, 59, 4351–4361.
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13. (a) Iso, Y.; Irie, T.; Iwaki, T.; Kii, M.; Sendo, Y.; Motokawa, K.; Nishitani, Y. J.
Antibiot. 1996, 49, 478–484; (b) Winum, J. Y.; Toupet, L.; Barragan, V.;
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17. LA is available through the chemistry of Ref. 4b. LB: (R,R)-Ph-bod is available
from Sigma–Aldrich, Cat. No. 707171.
tiomer tS = 26.3 min, (R)-enantiomer tR = 35.6 min. ½aꢁD ¼ ꢀ2:0 (c
1.10, CHCl3) for 85% ee material. A sample of (R)-10e (35% yield,
76% ee) was prepared from 9d and LA which showed equivalent
properties aside from its specific rotation.
4.5.6. (R)-N-tert-Butyl-N0-(3-methoxyphenyl)(phenyl)
methylsulfamide (R)-10f
Prepared from 9d (120 mg, 0.50 mmol) and LB and purified by
column chromatography (4:1 pet. ether/EtOAc) to give a colourless
solid (158 mg, 91%). Rf 0.28 (4:1 pet. ether/EtOAc); mp 100–103 °C;
IR (CHCl3) m
max/cmꢀ1 3383, 2969, 1600, 1321, 1240, 1042; 1H NMR
(400.1 MHz, CDCl3) dH 7.34–7.32 (m, 6 H, CHaryl), 6.92–6.88 (m, 2H,
CHaryl), 6.82–6.80 (m, 1H, CHaryl), 5.59 (d, J = 6.4 Hz, 1H, NHCH), 4.80
(d, J = 6.8 Hz, 1H, NHCH), 3.91 (brs, 1H, NHC(CH3)3), 3.78 (s, 3 H,
OCH3), 1.18 (s, 9H, C(CH3)3); 13C NMR (100.6 MHz, CDCl3) dC 159.8
(C), 142.9 (C), 141.2 (C), 129.7 (CH), 128.6 (CH), 127.6 (CH), 127.5
(CH), 119.8 (CH), 113.4 (CH), 112.9 (CH), 61.6 (CH), 55.2 (CH3),
54.2 (C), 29.5 (CH3); HRMS (ESI Positive) calcd for C18H24N2O3S,
[M+Na] 371.1400, found 371.1390. Anal. Calcd for C18H24N2O3S: C,
62.04; H, 6.94; N, 8.04%. Found: C, 61.90; H, 6.91; N, 8.06%; HPLC:
Daicel Chiralpak AD, 95:5 hexanes/iPrOH; 0.5 mL/min; 200 nm;
(S)-enantiomer tS = 95.6 min, (R)-enantiomer tR = 104.0 min.
½ ꢁ ¼ ꢀ1:0 (c 1.26, CHCl3) for 97% ee material. A sample of (S)-10f
a D
18. (a) Sanz, R.; Martinez, A.; Guilarte, V.; Alvarez-Gutierrez, J. M.; Rodriguez, F.
Eur. J. Org. Chem. 2007, 4642–4645; (b) Awano, T.; Ohmura, T.; Suginome, M. J.
Am. Chem. Soc. 2011, 133, 20738–20741.
(34% yield, 86% ee) was prepared from 9h and LA which showed
equivalent properties aside from its specific rotation.