Asymmetric Synthesis of Six-Membered Cyclic Sulfamides via Palladium-Catalyzed Alkene Carboamination Reactions

Article abstract of DOI:10.1055/s-0036-1591574

The asymmetric synthesis of six-membered cyclic sulfamides via palladium-catalyzed alkene carboamination reactions of N -homoallylsulfamides with aryl halides is described. High levels of enantioselectivity were obtained with a catalyst composed of Pd ₂ dba ₃ and (S)-Siphos-PE.

Full text of DOI:10.1055/s-0036-1591574

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–I
special topic
A
en
Z. J. Garlets, J. P. Wolfe
Special Topic
Synthesis
Asymmetric Synthesis of Six-Membered Cyclic Sulfamides via
Palladium-Catalyzed Alkene Carboamination Reactions
O
O
O
O
Zachary J. Garlets
Pd2(dba)3 (1 mol%)
(S)-Siphos-PE (5 mol%)
Bn
R
S
Bn
+
Bn
R
S
Bn
N
N
John P. Wolfe*
0
0
0
0
0-
0
0
2
7-
5
3
8
6-
2
7
3
N
N
H
Ar–Br
Ar
t-BuONa, water
xylenes, 120 °C
R
Department of Chemistry, University of Michigan,
930 N. University Ave., Ann Arbor, MI, 48109-1055,
USA
R
13 examples
31–94% yield
up to 98:2 er
jpwolfe@umich.edu
Published as part of the Special Section dedicated to
Scott E. Denmark on the occasion of his 65th birthday
Received: 06.02.2018
Accepted after revision: 03.04.2018
Published online: 03.05.2018
cyclic sulfamides.7 Finally, our group has demonstrated the
diastereoselective generation of six-membered sulfamides
bearing a fused ring through Pd-catalyzed alkene carbo-
amination reactions between aryl triflates and sulfamides
derived from 2-allylpyrrolidine or 2-allylpiperidine.8
Despite the work devoted to generating cyclic sul-
famides, only two methods have been reported that employ
transition-metal catalysts for the asymmetric synthesis of
cyclic sulfamides, both of which provide five-membered
rather than six-membered heterocycles. The Shi group de-
scribed the asymmetric synthesis of cyclic sulfamides using
a chiral Pd-catalyst to effect the diamination of dienes with
N,N′-di-tert-butylthiadiaziridine 1,1-dioxide.5f Although the
transformations proceed with good yields and selectivities,
the dithiaziridinone derivative is not commercially avail-
able, and the method is limited to conjugated diene sub-
strates; examples with simple alkenes have not been de-
scribed. In 2016, our group reported an enantioselective
synthesis of five-membered cyclic sulfamides via Pd-cata-
lyzed alkene carboamination reactions between aryl bro-
mides and N-allylsulfamides 1 bearing a N-t-Bu protecting
group (Scheme 1, eq 1).9 These transformations provided
the desired products 2 in good chemical yields and good
enantioselectivities for a variety of different substrate com-
binations.
DOI: 10.1055/s-0036-1591574; Art ID: ss-2018-c0078-st
Abstract The asymmetric synthesis of six-membered cyclic sulfamides
via palladium-catalyzed alkene carboamination reactions of N-homo-
allylsulfamides with aryl halides is described. High levels of enantio-
selectivity were obtained with a catalyst composed of Pd2dba3 and (S)-
Siphos-PE.
Key words palladium, asymmetric catalysis, alkenes, sulfamides,
heterocycles
The development of methods for efficient chemo- and
stereoselective construction of new carbon–nitrogen bonds
is of significant and longstanding interest to the synthetic
community. Specifically, the creation of new methods for
accessing cyclic sulfamides is attractive, as these represent
important structural motifs present in a number of phar-
maceutically relevant compounds.1 In addition, the SO2
group can be excised from cyclic sulfamides to provide 1,3-
diamines,2 which are also displayed in a variety of natural
products and bioactive compounds.3 Chiral 1,3-diamines
have also been used for the construction of chiral ligands
and chiral auxiliaries for asymmetric synthesis.4
In recent years, several groups have explored the use of
transition-metal catalysis for the synthesis of both five- and
six-membered cyclic sulfamides.5 Although the use of met-
al catalysis for the synthesis of six-membered sulfamides is
less explored than the corresponding five-membered ring
compounds, several important developments have been de-
scribed. Du Bois and co-workers described a C–H function-
alization strategy which utilized a Rh-catalyst for the syn-
thesis of six-membered sulfamides.6 In addition, Zhang and
co-workers have elegantly employed metalloradical activa-
tion of azides by a cobalt(II) catalyst for a variety of trans-
formations toward the synthesis of different six-membered
Given the scarcity of catalytic asymmetric five-mem-
bered cyclic-sulfamide-forming reactions, it is perhaps not
surprising that the asymmetric synthesis of six-membered
cyclic sulfamides by transition-metal catalysis has yet to be
reported. In this communication, we describe the first ex-
amples of the catalytic asymmetric synthesis of six-mem-
bered cyclic sulfamides through Pd-catalyzed alkene carbo-
amination reactions of acyclic N-homoallylsulfamides.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

B
Z. J. Garlets, J. P. Wolfe
Special Topic
Synthesis
Encouraged by this initial result, we elected to explore
the scope of this method with respect to the aryl bromide
electrophile (Table 1). The electronic properties of the elec-
trophile had no significant influence on the enantioselec-
tivity; both electron-rich and electron-poor aryl bromides
reacted to afford enantioenriched cyclic sulfamides in
>95:5 er (entries 1–6). However, the use of 2-bromotoluene
as the electrophile led to the formation of 6h in low yield
and moderate enantioselectivity (85:15 er) (entry 7). Ef-
forts to use aryl iodides as electrophiles led to unsatisfacto-
ry results; the reaction of 4-iodobiphenyl proceeded in a
modest 42% yield and an average 82:18 er (entry 8), and en-
antioselectivities were not reproducible with this substrate,
ranging from 82:18 to 91.5:8.5 er. Different substituents on
the homoallyl chain [R = Me, Et, and R–R = –(CH2)4–] were
well tolerated (entries 9–12).
O
O
Pd2(dba)3 (1 mol%)
O
O
N
tBu
S
Bn
(S)-Siphos-PE (5 mol%)
S
tBu
N
N
Bn
(1)
H
PhBr
N
+
t-BuONa, water
xylenes, 120 °C
1
2
Ph
96% yield, 93:7 er
O
O
O
O
Pd2(dba)3 (1 mol%)
(S)-Siphos-PE (5 mol%)
tBu
S
Bn
tBu
S
Bn
N
N
H
N
N
(2)
PhBr
+
Ph
t-BuONa, water
xylenes, 120 °C
3
4
not observed
Scheme 1 Synthesis of five- vs six-membered cyclic sulfamides
These transformations effect the enantioselective forma-
tion of the ring and one C–N bond, with concomitant gener-
ation of a C–C bond external to the ring.
Table 1 Asymmetric Synthesis of Six-Membered Cyclic Sulfamidesa
On the surface, the generation of six-membered rings
by an extension of our approach to the asymmetric con-
struction of five-membered cyclic sulfamides would appear
to be a straightforward process. However, as shown in
Scheme 1, although the coupling of N-allylsulfamide 1 with
bromobenzene provided 2 in excellent yield and 93:7 er (eq
1), attempts to achieve an analogous transformation of N-
homoallylsulfamide 3 failed to afford the desired product 4.
Instead, decomposition of the substrate to a complex mix-
ture of products was observed.
O
O
O
O
Pd2(dba)3 (1 mol%)
(S)-Siphos-PE (5 mol%)
Bn
R
S
Bn
Bn
R
S
Bn
N
N
N
N
H
Ar–X
+
Ar
t-BuONa, water
xylenes, 120 °C
R
R
5a–c
5a: R = Me
6b–l
5b: R–R = -(CH2)4-
5c: R = Et
Entry
Substrate
Ar–X
Yield (%)b
erc
Although the lack of desired reactivity of 3 was disap-
pointing, we felt that a change in the substrate structure
may lead to improved results. Our prior studies on the con-
struction of five-membered cyclic sulfamides revealed that
the N-tert-butyl group on the non-cyclizing nitrogen was
critical for reactivity, presumably due to a Thorpe–Ingold-
type effect10 that positioned the alkene closer to the cycliz-
ing nitrogen atom. We thought that moving the steric bulk
from the non-cyclizing nitrogen in 3 to the carbon adjacent
to the nitrogen atom on the homoallyl chain may facilitate
reactivity through a similar effect. As such, substrate 5a was
easily prepared in three steps using standard chemistry: (1)
conversion of acetone into the corresponding N-benzyl
imine, (2) addition of allylmagnesium bromide to afford the
homoallylic secondary amine, and (3) sulfonylation of the
secondary amine to afford 5a. We were gratified to find that
when substrate 5a was subjected to the standard reaction
conditions, the desired cyclization product 6a was formed
with 93% yield and 95:5 er (Scheme 2, eq 3).11
1
2
3
5a
87 (6b)
97:3
97:3
Br
90d (6b)
Ph
5a
5a
75 (6c)
57 (6d)
96.5:3.5
98:2
Br
Br
MeO
4
5
6
7
8
5a
5a
5a
5a
5a
75 (6e)
94 (6f)
65e (6g)
31 (6h)
42 (6b)
96.5:3.5
96.5:3.5
97:3
Br
F3C
Br
F
Br
Cl
O
O
O
O
Pd2(dba)3 (1 mol%)
(S)-Siphos-PE (5 mol%)
Bn
S
Bn
Bn
S
Bn
85:15
N
N
Br
N
N
(3)
H
PhBr
+
Me
Ph
Me
t-BuONa, water
Me
xylenes, 120 °C
Me
Me
5a
6a
93% yield, 95:5 er
82:18f
I
Scheme 2 Synthesis of six-membered cyclic sulfamide 6a
Ph
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

C
Z. J. Garlets, J. P. Wolfe
Special Topic
Synthesis
Table 1 (continued)
membered ring-forming reactions the use of the (S)-Siphos-
PE catalyst affords the S-enantiomer of the products, we
suggest that both transformations proceed through similar
mechanisms, which are analogous to the mechanism
shown to operate for other alkene carboamination or
carboalkoxylation reactions that afford syn-addition prod-
ucts.13 As shown in Scheme 4, the reaction is initiated by
oxidative addition of the aryl halide to Pd(0) to afford 7. Co-
ordination of the sulfamide with concomitant deprotona-
tion forms the Pd-amido complex 8, which is staged to un-
dergo syn-migratory insertion of the alkene into the Pd–N
bond to provide 9.14 Reductive elimination of 9 yields the
heterocycle and also regenerates the Pd catalyst. Alternative
mechanistic pathways involving initial carbopalladation of
the alkene appear less likely, as we have previously shown
that these pathways are not in operation in other related
systems.14a,c
Entry
9
Substrate
Ar–X
Yield (%)b
erc
95.5:4.5
5b
92 (6i)
Br
OC6H4-p-F
10
11
12
5b
5b
5c
92 (6j)
90 (6k)
92 (6l)
96.5:3.5
97:3
Br
CF3
Br
OMe
Br
95:5
LnPd(0)
Ar–Br
6a
a Reaction conditions: substrate 5 (1.0 equiv), R–X (2.0 equiv), t-BuONa
(2.0 equiv), H2O (2.0 equiv), [Pd2(dba)3] (1 mol%), (S)-Siphos-PE (5 mol%),
xylenes (0.125 M), 120 °C, 18 h. Reactions were conducted on a 0.20 mmol
scale.
O
O
Ar
Br
b Yield of isolated product (average of two or more experiments).
c Enantiomeric ratios were determined by chiral HPLC analysis.
d The reaction was conducted on 1.0 mmol scale.
Bn
S
Bn
Ar
Pd
Ln
N
N
PdLn
Me
7
e The product contained ca. 5–10% of an unidentified impurity.
f Enantiomeric ratios ranged from 82:18 to 91.5:8.5.
Me
9
5a
NaOtBu
O
O
Bn
Pd
Bn
S
L
N
N
In order to further explore the scope of this method, we
also examined the reactivity of sulfamides bearing addi-
tional substituents. However, thus far, attempts to accom-
plish the asymmetric carboamination of 5d bearing a 1,1-
disubstituted alkene have been unsuccessful (Scheme 3, eq
4). In addition, substrate 5e bearing substitution at the
allylic position was unreactive (Scheme 3, eq 5).
Me
Ar
tBuOH, NaBr
Me
8
Scheme 4 Catalytic cycle
In conclusion, we have developed an enantioselective
Pd-catalyzed alkene carboamination reaction for the syn-
thesis of six-membered cyclic sulfamides. The starting N-
homoallylsulfamides are readily prepared in three steps,
and the cyclic sulfamides are formed in high enantioselec-
tivity and good to excellent chemical yield. These transfor-
mations represent the first examples of asymmetric metal-
catalyzed carboamination reactions for the synthesis of six-
membered cyclic sulfamides from acyclic precursors. Future
work will focus on expanding the scope of this reaction.
Br
O
O
Pd2(dba)3 (1 mol%)
(S)-Siphos-PE (5 mol%)
Bn
S
Bn
no
reaction
N
N
(4)
H
+
Me
t-BuONa, water
xylenes, 120 °C
Me
5d
Ph
O
O
Pd2(dba)3 (1 mol%)
(S)-Siphos-PE (5 mol%)
Bn
S
Bn
no
reaction
N
N
(5)
H
Ph–Br
+
t-BuONa, water
xylenes, 120 °C
5e
Reactions were carried out under nitrogen in flame-dried or oven-
dried glassware unless otherwise specified. Tris(dibenzylideneace-
tone)dipalladium and (S)-Siphos-PE were purchased from Strem
Chemical Co. and used without further purification. Dichlorometh-
ane, diethyl ether, tetrahydrofuran, and toluene were purified using a
GlassContour solvent system. Xylenes were purified by distillation
over CaH2 prior to use in reactions. All other solvents and aryl halides
were purchased from commercial sources and used as received. Yields
refer to isolated compounds that are estimated to be >95% pure as
judged by 1H NMR unless otherwise noted. The yields reported in the
Scheme 3 Attempted cyclization of sulfamides bearing additional sub-
stituents
Our prior studies on the asymmetric synthesis of five-
membered cyclic sulfamides indicated that the reactions
proceed via net syn addition to the alkene.9,12 Given the fact
that the transformations described in this manuscript em-
ploy similar reaction conditions, and for both five- and six-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

D
Z. J. Garlets, J. P. Wolfe
Special Topic
Synthesis
supporting information describe the result of a single experiment,
whereas the yields reported in Scheme 2 (eq 3) and Table 1 are aver-
age yields of two or more experiments. Thus, the yields reported in
the experimental section may differ from those in Scheme 2 (eq 3)
and in Table 1. Column chromatography was performed using Silicy-
cle silica gel (mesh size 230-400). Melting points were determined
using a Thomas Hoover UNI-Melt capillary melting point apparatus.
Optical rotations were recorded using a Jasco P-2000 polarimeter. IR
spectra were recorded using a Nicolet iS50 FT-IR spectrophotometer.
1H NMR, 13C NMR and 19F NMR spectra were recorded using Varian
VNMR spectrometers. HRMS spectra were obtained using a Micro-
mass AutoSpec Ultima Magnetic Sector Mass spectrometer.
N′-Benzyl-N-(tert-butyl)-N-(but-3-en-1-yl)sulfamide (3)
General procedure 2 was employed for the sulfonylation of N-(tert-
butyl)but-3-en-1-amine15 (1.34 g, 10.5 mmol) with 3-(N-benzylsulfo-
nyl)oxazolidin-2-one (2.43 g, 9.5 mmol). This procedure afforded the
title compound (670 mg, 24%) as a colorless solid; mp 44–47 °C.
IR (neat): 3322, 1317, 1135, 1088 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 7.38–7.33 (m, 4 H), 7.33–7.29 (m, 1 H),
5.80–5.73 (m, 1 H), 5.09 (dd, J = 17.0, 1.5 Hz, 1 H), 5.04 (d, J = 10.2 Hz,
1 H), 4.21 (t, J = 6.1 Hz, 1 H), 4.16 (d, J = 6.1 Hz, 2 H), 3.34–3.30 (m, 2
H), 2.46–2.41 (m, 2 H), 1.46 (s, 9 H).
13C NMR (175 MHz, CDCl3): δ = 136.8, 135.2, 129.0, 128.3, 128.1,
116.9, 58.9, 47.6, 46.6, 36.8, 29.6.
HRMS (ESI+): m/z [M + H]+ calcd for C15H25N2O2S: 297.1631; found:
α,α-Disubstituted Homoallylic Amines; General Procedure 1
The α,α-disubstituted homoallylic amine substrates were prepared
from the corresponding ketones on a 60 mmol scale (unless other-
wise noted) by a two-step procedure involving imine formation fol-
lowed by Grignard addition to the imine.
297.1629.
N-Benzyl-N′-benzyl-N-(2-methylpent-4-en-2-yl)sulfamide (5a)
General procedure 1 was used for the preparation of N-benzyl-2-
methylpent-4-en-2-amine from acetone (4.4 mL, 60 mmol), benzyl-
amine (6.6 mL, 60 mmol), 4 Å molecular sieves (12 g), and CH2Cl2 (30
mL), with a reaction time of 4 h. This procedure afforded crude N-
benzylpropan-2-imine, which was then dissolved in THF (150 mL)
and treated with allylmagnesium bromide (150 mmol, 1 M solution
in Et2O). Work-up and subsequent purification by column chromatog-
raphy afforded N-benzyl-2-methylpent-4-en-2-amine as a yellow oil
(9.9 g, 87% over two steps).
The requisite symmetrical ketone (1 equiv), primary amine (1 equiv),
4 Å molecular sieves (200 mg/mmol), and CH2Cl2 (2 M) were added to
a flame-dried flask (equipped with a stir bar) that had been cooled
under a stream of nitrogen. The mixture was vigorously stirred at r.t.
until the starting materials had been completely consumed, as deter-
mined by TLC analysis. The mixture was then filtered through Celite
and the solvent was removed under reduced pressure to afford the
corresponding ketimine.
1H NMR (500 MHz, CDCl3): δ = 7.36–7.28 (m, 4 H), 7.25–7.21 (m, 1 H),
5.93–5.82 (m, 1 H), 5.15–5.08 (m, 2 H), 3.72 (s, 2 H), 2.25 (d, J = 7.4 Hz,
2 H), 1.15 (s, 6 H).
A flame-dried round-bottom flask equipped with a stir bar was
cooled under a stream of nitrogen and charged with allylmagnesium
bromide (1 M in Et2O). This solution was cooled to 0 °C and then a
solution of the ketimine (0.4 M in THF) was added dropwise. The re-
action was warmed to r.t., and then stirred overnight. The flask was
subsequently cooled to 0 °C in an ice bath, and the reaction was slow-
ly quenched with saturated aqueous ammonium chloride (75 mL).
The mixture was transferred to a separating funnel, the layers were
separated, and the aqueous layer was extracted with Et2O (3 × 200
mL). The organic layers were combined and washed with brine (200
mL), dried over anhydrous sodium sulfate, filtered, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography on silica gel.
General procedure 2 was used to sulfonylate N-benzyl-2-methylpent-
4-en-2-amine (4.3 g, 22.5 mmol) with 3-(N-benzylsulfonyl)oxazoli-
din-2-one (5.2 g, 20.4 mmol). This procedure afforded the title com-
pound (3.0 g, 41%) as a colorless solid; mp 75–77 °C.
IR (neat): 3330, 1453, 1320, 1132 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.42 (d, J = 7.5 Hz, 2 H), 7.36–7.20 (m, 8
H), 5.92–5.80 (m, 1 H), 5.12 (s, 1 H), 5.09 (s, 1 H), 4.58 (s, 2 H), 4.17 (t,
J = 5.5 Hz, 1 H), 4.13 (d, J = 5.4 Hz, 2 H), 2.64 (d, J = 7.3 Hz, 2 H), 1.44 (s,
6 H).
13C NMR (125 MHz, CDCl3): δ = 140.1, 136.9, 134.5, 128.9, 128.6,
128.2, 128.1, 127.2, 118.7, 62.6, 50.8, 47.7, 46.0, 27.9.
Homoallylicsulfamides; General Procedure 2
HRMS (ESI+): m/z [M + H]+ calcd for C20H27N2O2S: 359.1788; found:
359.1791.
Transformations were carried out on a 20 mmol scale unless other-
wise noted. A flame-dried two-neck round-bottom flask equipped
with a stir bar, a condenser, and a septum was cooled under a stream
of nitrogen. This flask was charged with DMAP (0.20 equiv) and the
requisite N-subsituted-2-oxooxazolidin-3-sulfonamide substrate (1.0
equiv). Anhydrous MeCN (100 mL) was added followed by Et3N (3.0
equiv). This mixture was heated at 80 °C for 15 min with stirring, and
then the homoallylic amine was added dropwise. The resulting mix-
ture was stirred at 80 °C for 16–18 h. The reaction mixture was then
cooled to r.t., and the solvent was removed under reduced pressure.
The crude product was dissolved in EtOAc (50 mL) and washed twice
with equal portions of 1 M HCl (50 mL for each wash), and once with
brine (50 mL). The organic layer was dried over sodium sulfate, fil-
tered, and the solvent was removed under reduced pressure. The
crude material was purified by column chromatography using hex-
anes/EtOAc as the eluent.
N-Benzyl-N′-benzyl-N-(1-allylcyclohexyl)sulfamide (5b)
General procedure 1 was used for the preparation of 1-allyl-N-ben-
zylcyclohexan-1-amine from cyclohexanone (2.1 mL, 20 mmol), ben-
zylamine (2.2 mL, 20 mmol), 4 Å molecular sieves (4 g), and CH2Cl2
(10 mL), with a reaction time of 4 h. The solution was filtered through
Celite, and the solvent was removed under reduced pressure to afford
crude N-benzylcyclohexanimine, which was dissolved in THF (50 mL)
and treated with allylmagnesium bromide (50 mmol, 1 M solution in
Et2O). Work-up and subsequent purification by column chromatogra-
phy afforded 1-allyl-N-benzylcyclohexan-1-amine as a yellow oil (3.1
g, 68% over two steps).
1H NMR (500 MHz, CDCl3): δ = 7.37 (d, J = 6.9 Hz, 2 H), 7.31 (t, J = 7.6
Hz, 2 H), 7.25–7.21 (m, 1 H), 6.02–5.94 (m, 1 H), 5.14–5.07 (m, 2 H),
3.65 (s, 2 H), 2.26 (d, J = 7.4 Hz, 2 H), 1.72–1.30 (m, 10 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

E
Z. J. Garlets, J. P. Wolfe
Special Topic
Synthesis
General procedure 2 was used to sulfonylate 1-allyl-N-benzylcyclo-
hexan-1-amine (3.1 g, 13.9 mmol) with 3-(N-benzylsulfonyl)oxazoli-
din-2-one (3.2 g, 12.5 mmol) to afford the title compound (1.23 g,
25%) as a colorless solid; mp 77–79 °C.
1H NMR (400 MHz, CDCl3): δ = 7.36 (d, J = 6.7 Hz, 2 H), 7.31 (t, J = 7.5
Hz, 2 H), 7.23 (t, J = 7.1 Hz, 1 H), 4.91 (s, 1 H), 4.73 (s, 1 H), 3.76 (s,
2 H), 2.24 (s, 2 H), 1.85 (s, 3 H), 1.18 (s, 6 H).
General procedure 2 was used to sulfonylate N-benzyl-2,4-dimethyl-
pent-4-en-2-amine (2.4 g, 12 mmol) with 3-(N-benzylsulfonyl)oxaz-
olidin-2-one (2.56 g, 10.0 mmol) to afford the title compound (1.4 g,
37%) as a viscous oil.
IR (neat): 3333, 1455, 1414, 1333, 1148 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.43 (d, J = 7.4 Hz, 2 H), 7.35–7.22 (m,
6 H), 7.18–7.15 (m, 2 H), 6.03–5.93 (m, 1 H), 5.19–5.11 (m, 1 H), 4.59
(s, 2 H), 4.11 (d, J = 5.7 Hz, 2 H), 4.06 (t, J = 5.7 Hz, 1 H), 2.79 (d, J = 7.2
Hz, 2 H), 2.19 (d, J = 12.8 Hz, 2 H), 1.81 (td, J = 12.7, 3.7 Hz, 2 H), 1.67–
1.53 (m, 3 H), 1.48–1.35 (m, 2 H), 1.27–1.15 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 140.3, 137.0, 134.6, 128.8, 128.6,
128.2, 128.0, 127.3, 127.2, 118.5, 66.4, 50.2, 47.8, 38.4, 35.3, 25.3,
23.1.
IR (neat): 3300, 1317, 1134 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.43 (d, J = 7.4 Hz, 2 H), 7.35–7.21 (m, 8
H), 4.93–4.91 (m, 1 H), 4.79 (s, 1 H), 4.60 (s, 2 H), 4.23 (t, J = 6.1 Hz,
1 H), 4.12 (d, J = 6.1 Hz, 2 H), 2.64 (s, 2 H), 1.81 (s, 3 H), 1.50 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 142.2, 140.1, 137.0, 128.9, 128.6,
128.2, 128.0, 127.3, 127.2, 116.2, 63.3, 50.8, 48.3, 47.7, 28.3, 25.3.
HRMS (ESI+): m/z [M + H]+ calcd for C23H31N2O2S: 399.2101; found:
399.2103.
HRMS (ESI+): m/z [M + H]+ calcd for C21H29N2O2S: 373.1944; found:
373.1948.
N-Benzyl-N′-benzyl-N-(3-ethylhex-5-en-3-yl)sulfamide (5c)
N-Benzyl-N′-benzyl-N-(2,2-dimethylbut-3-en-1-yl)sulfamide (5e)
General procedure 1 was used for the preparation of N-benzyl-3-eth-
ylhex-5-en-3-amine from 3-pentanone (3.2 mL, 30 mmol), benzyl-
amine (3.3 mL, 30 mmol), 4 Å molecular sieves (6 g), and CH2Cl2 (15
mL), with a reaction time of 24 h. The solution was filtered through
Celite, and the solvent was removed under reduced pressure to afford
crude N-benzylpentan-3-imine, which was then dissolved in THF (75
mL) and treated with allylmagnesium bromide (75 mmol, 1 M solu-
tion in Et2O). Work-up and subsequent purification by column chro-
matography afforded N-benzyl-3-ethylhex-5-en-3-amine as a yellow
oil (2.6 g, 40% over two steps).
1H NMR (500 MHz, CDCl3): δ = 7.36 (d, J = 6.9 Hz, 2 H), 7.31 (t, J = 7.6
Hz, 2 H), 7.25–7.21 (m, 1 H), 5.89–5.79 (m, 1 H), 5.17–5.05 (m, 2 H),
3.61 (s, 2 H), 2.17 (dt, J = 7.4, 1.3 Hz, 2 H), 1.42 (qd, J = 7.4, 2.2 Hz, 4 H),
0.86 (t, J = 7.4 Hz, 6 H).
2,2-Dimethylbut-3-enoic acid16 (1.1 g, 10 mmol) was suspended in
CH2Cl2 (30 mL) and trimethylamine (2.8 mL, 20 mmol) was added.
The mixture was cooled to 0 °C, and then ethyl chloroformate (0.96
mL, 10 mmol) was added dropwise. The solution was stirred at 0 °C
for 30 min, and then benzylamine (1.3 mL, 12 mmol) was added
dropwise. The reaction was warmed to r.t., and then stirred at r.t.
overnight. The reaction was then quenched with saturated sodium bi-
carbonate (30 mL). The mixture was transferred to a separating fun-
nel, the layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3 × 30 mL). The organic layers were combined and
washed with brine (100 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure. The crude product
was purified by flash chromatography on silica gel to afford N-benzyl-
2,2-dimethylbut-3-enamide as a yellow oil (1.3 g, 65%).
General procedure 2 was used to sulfonylate N-benzyl-3-ethylhex-5-
en-3-amine (2.64 g, 12.2 mmol) with 3-(N-benzylsulfonyl)oxazoli-
din-2-one (2.83 g, 11 mmol) to afford the title compound (450 mg,
11%) as a colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.36–7.31 (m, 2 H), 7.30–7.27 (m, 1 H),
7.25–7.21 (m, 3 H), 6.02 (dd, J = 17.4, 10.6 Hz, 1 H), 5.23 (d, J = 17.5 Hz,
1 H), 5.19 (d, J = 10.6 Hz, 1 H), 4.41 (d, J = 5.7 Hz, 2 H), 1.33 (s, 6 H).
N-Benzyl-2,2-dimethylbut-3-enamide was added to a flame-dried
three-necked round-bottom flask equipped with a reflux condenser.
Anhydrous Et2O (13 mL) was added, and then the solution was cooled
to 0 °C. Lithium aluminum hydride (20 mL, 1 M solution in Et2O, 20
mmol) was added dropwise, and then the mixture was heated to re-
flux with stirring overnight. The reaction mixture was quenched us-
ing the Fieser work-up. First, the mixture was diluted with Et2O (10
mL) and then cooled to 0 °C. Then, H2O (750 μL) was added dropwise,
followed by the dropwise addition of 15% aqueous sodium hydroxide
(750 μL). H2O (2.2 mL) was added and the mixture was allowed to
warm to r.t. and then stirred for 15 min. The mixture was dried over
magnesium sulfate, filtered through a plug of Celite, and concentrated
in vacuo. The crude product was purified by flash chromatography on
silica gel to afford N-benzyl-2,2-dimethylbut-3-en-1-amine as a yel-
low oil (1.0 g, 82%).
IR (neat): 3296, 1318, 1144 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 7.45 (d, J = 7.5 Hz, 2 H), 7.34–7.31 (m, 2
H), 7.30–7.24 (m, 4 H), 7.18–7.15 (m, 2 H), 5.90 (ddt, J = 17.1, 10.2, 7.2
Hz, 1 H), 5.14–5.12 (m, 1 H), 5.12–5.10 (m, 1 H), 4.59 (s, 2 H), 4.14 (d,
J = 6.1 Hz, 2 H), 4.08 (t, J = 6.1 Hz, 1 H), 2.64 (d, J = 7.3 Hz, 2 H), 1.89–
1.78 (m, 4 H), 0.94 (t, J = 7.4 Hz, 6 H).
13C NMR (175 MHz, CDCl3): δ = 140.3, 137.1, 134.5, 128.8, 128.6,
128.2, 128.0, 127.6, 127.2, 118.5, 69.9, 50.8, 48.0, 39.7, 28.4, 8.9.
HRMS (ESI+): m/z [M + H]+ calcd for C22H31N2O2S: 387.2101; found:
387.2106.
N-Benzyl-N′-benzyl-N-(2,4-dimethylpent-4-en-2-yl)sulfamide (5d)
General procedure 1 was used for the preparation of N-benzyl-2,4-di-
methylpent-4-en-2-amine from acetone (4.4 mL, 60 mmol), benzyl-
amine (6.6 mL, 60 mmol), 4 Å molecular sieves (12 g) and CH2Cl2 (30
mL), with a reaction time of 4 h. The solution was filtered through
Celite, and the solvent was removed under reduced pressure to afford
crude N-benzylpropan-2-imine which was dissolved in THF (150 mL)
and treated with allylmagnesium chloride (150 mmol, 1 M solution in
Et2O). Work-up and subsequent purification by column chromatogra-
phy afforded N-benzyl-2,4-dimethylpent-4-en-2-amine as a yellow
oil (3.05 g, 25% over two steps).
1H NMR (500 MHz, CDCl3): δ = 7.34–7.29 (m, 4 H), 7.26–7.21 (m, 1 H),
5.78 (dd, J = 17.2, 11.1 Hz, 1 H), 5.02–4.95 (m, 2 H), 3.79 (s, 2 H), 2.43
(s, 2 H), 1.03 (s, 6 H).
General procedure 2 was used to sulfonylate N-benzyl-2,2-dimethyl-
but-3-en-1-amine (1.0 g, 5.3 mmol) with 3-(benzylsulfonyl)oxazoli-
din-2-one (1.24 g, 4.85 mmol) to afford the title compound (1.61 g,
93%) as a colorless solid; mp 69–71 °C.
IR (neat): 3310, 2965, 1320, 1131 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

F
Z. J. Garlets, J. P. Wolfe
Special Topic
Synthesis
1H NMR (500 MHz, CDCl3): δ = 7.40 (d, J = 7.4 Hz, 2 H), 7.37–7.27 (m, 6
H), 7.22–7.18 (m, 2 H), 5.93 (dd, J = 17.5, 10.7 Hz, 1 H), 5.06 (d, J = 17.5
Hz, 1 H), 5.02 (d, J = 10.6 Hz, 1 H), 4.50 (s, 2 H), 4.10 (d, J = 6.0 Hz, 2 H),
4.07–4.01 (t, J = 6.1 Hz, 1 H), 3.21 (s, 2 H), 1.09 (s, 6 H).
mg, 0.010 mmol), t-BuONa (38.0 mg, 0.40 mmol), a reaction tempera-
ture of 120 °C, and a reaction time of 18 h in xylenes (1.6 mL) and H2O
(7 μL). This procedure afforded the title compound (80 mg, 78%) as a
white solid; mp 174–178 °C; [α]D23 –154.5 (c 1.98, CH2Cl2).
13C NMR (125 MHz, CDCl3): δ = 147.3, 136.9, 136.6, 128.87, 128.86,
128.84, 128.10, 128.05, 112.4, 58.2, 53.5, 47.7, 39.5, 25.5; one signal is
missing due to incidental equivalence.
HRMS (ESI+): m/z [M + H]+ calcd for C20H26N2O2S: 359.1793; found:
359.1788.
IR (neat): 1488, 1452, 1332, 1153, 1137 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.56 (d, J = 8.3 Hz, 2 H), 7.46 (d, J = 8.1
Hz, 2 H), 7.43 (t, J = 7.2 Hz, 6 H), 7.36–7.29 (m, 5 H), 7.27–7.22 (m, 2
H), 7.12 (d, J = 8.0 Hz, 2 H), 4.72 (d, J = 15.8 Hz, 1 H), 4.64 (d, J = 16.8
Hz, 1 H), 4.49–4.41 (m, 1 H), 4.32 (d, J = 15.8 Hz, 1 H), 4.15 (d, J = 16.8
Hz, 1 H), 2.92 (dd, J = 13.7, 5.0 Hz, 1 H), 2.64 (dd, J = 13.6, 10.0 Hz, 1 H),
2.07 (t, J = 13.3 Hz, 1 H), 1.46 (dd, J = 14.3, 2.6 Hz, 1 H), 1.32 (s, 3 H),
1.14 (s, 3 H).
Asymmetric Pd-Catalyzed Carboaminations; General Procedure 3
Transformations were carried out on 0.2 mmol scale unless otherwise
noted. An oven-dried test tube equipped with a stir bar and a rubber
septum was cooled under a stream of nitrogen and charged with
Pd2(dba)3 (1 mol%), (S)-Siphos-PE (5 mol%), the sulfamide substrate
(1.0 equiv), and t-BuONa (2.0 equiv). The flask was purged with N2,
and then the aryl or alkenyl halide (1.40–2.0 equiv), H2O (0 or 2.0
equiv), and xylenes (0.125 M) were added. The resulting mixture was
heated to 120 °C with stirring for 18 h. The reaction mixture was then
cooled to r.t., and saturated aqueous ammonium chloride (1 mL) was
added. The mixture was extracted with EtOAc (3 × 2 mL) and then the
combined organic layers were dried over anhydrous Na2SO4, filtered
through a plug of Celite, and concentrated in vacuo. The crude prod-
uct was purified by flash chromatography on silica gel using hex-
anes/EtOAc as the eluent.
13C NMR (125 MHz, CDCl3): δ = 140.9, 140.4, 139.7, 138.3, 136.4,
129.6, 129.0, 128.61, 128.55, 128.1, 127.52, 127.45, 127.43, 127.2,
127.1, 60.5, 57.2, 50.1, 45.8, 40.5, 38.9, 31.0, 23.0; 1 carbon signal is
missing due to incidental equivalence.
HRMS (ESI+): m/z [M + H]+ calcd for C32H35N2O2S: 511.2414; found:
511.2413.
The enantiopurity was determined to be 97:3 er by chiral HPLC analy-
sis when 4-bromobiphenyl served as the electrophile (Chiralcel ODH,
15 cm × 4.6 mm, 7% i-PrOH/hexanes, 1.00 mL/min, λ = 254 nm, tR
=
16.5 and 29.7 min).
When 4-iodobiphenyl was used as the electrophile, the enantioselec-
tivity was less reproducible providing enantiomeric ratios that
ranged from 82:18 to 91.5:8.5.
This reaction was also conducted on 1 mmol scale using 4-bromobi-
phenyl as the electrophile. General procedure 3 was employed for the
coupling of N-benzyl-N′-benzyl-N-(2-methylpent-4-en-2-yl)sul-
famide (5a) (358.50 mg, 1.0 mmol) and 4-bromobiphenyl (466 mg,
2.0 mmol) using a catalyst composed of Pd2(dba)3 (9.2 mg, 0.01
mmol) and (S)-Siphos-PE (25.3 mg, 0.05 mmol), t-BuONa (192 mg, 2.0
mmol), a reaction temperature of 120 °C, and a reaction time of 18 h
in xylenes (8.0 mL) and H2O (36 μL). The reaction was conducted in a
25 mL round-bottom flask rather than in a test tube. This procedure
afforded the title compound (458 mg, 90%) as a white solid. The enan-
tioselectivity was determined to be 97:3 er.
(S)-(–)-2,5,6-Tribenzyl-3,3-dimethyl-1,2,6-thiadiazinane 1,1-Diox-
ide (6a)
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(2-methylpent-4-en-2-yl)sulfamide (5a) (72.0 mg, 0.20
mmol) and bromobenzene (42 μL, 0.4 mmol) using a catalyst com-
posed of Pd2(dba)3 (1.8 mg, 0.002 mmol) and (S)-Siphos-PE (5.1 mg,
0.010 mmol), t-BuONa (38.0 mg, 0.60 mmol), a reaction temperature
of 120 °C, and a reaction time of 18 h in xylenes (1.6 mL) and H2O (7
μL). This procedure afforded the title compound (80 mg, 92%) as a col-
orless solid; mp 149–153 °C; [α]D23 –65 (c 1.6, CH2Cl2).
IR (neat): 1495, 1452, 1330, 1151, 1136 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.43 (d, J = 7.9 Hz, 4 H), 7.32 (td, J = 7.5,
2.6 Hz, 4 H), 7.28–7.21 (m, 4 H), 7.21–7.17 (m, 1 H), 7.06 (d, J = 7.0 Hz,
2 H), 4.71 (d, J = 15.8 Hz, 1 H), 4.64 (d, J = 16.8 Hz, 1 H), 4.41 (dddd,
J = 12.7, 10.1, 4.8, 2.9 Hz, 1 H), 4.30 (d, J = 15.8 Hz, 1 H), 4.14 (d,
J = 16.8 Hz, 1 H), 2.89 (dd, J = 13.6, 4.8 Hz, 1 H), 2.58 (dd, J = 13.6, 10.2
Hz, 1 H), 2.03 (dd, J = 14.3, 12.2 Hz, 1 H), 1.39 (dd, J = 14.3, 2.9 Hz, 1 H),
1.28 (s, 3 H), 1.12 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 140.4, 138.4, 137.4, 129.2, 128.8,
128.6, 128.5, 128.1, 127.5, 127.4, 127.2, 126.9, 60.4, 57.3, 50.1, 45.8,
40.9, 38.7, 31.0, 22.9.
(S)-(–)-2,6-Dibenzyl-3,3-dimethyl-5-(naphthalen-2-ylmethyl)-
1,2,6-thiadiazinane 1,1-Dioxide (6c)
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(2-methylpent-4-en-2-yl)sulfamide (5a) (72.0 mg, 0.20
mmol) and 2-bromonaphthalene (83 mg, 0.40 mmol) using a catalyst
composed of Pd2(dba)3 (1.8 mg, 0.002 mmol) and (S)-Siphos-PE (5.1
mg, 0.010 mmol), t-BuONa (38.0 mg, 0.40 mmol), a reaction tempera-
ture of 120 °C, and a reaction time of 18 h in xylenes (1.6 mL) and H2O
(7 μL). This procedure afforded the title compound (72 mg, 74%) as a
colorless solid; mp 168–172 °C; [α]D23 –43 (c 1.7, CH2Cl2).
HRMS (ESI+): m/z [M + H]+ calcd for C26H31N2O2S: 435.2101; found:
435.2106.
IR (neat): 1495, 1452, 1331, 1151, 1136 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.81–7.77 (m, 1 H), 7.75–7.70 (m, 2 H),
7.48–7.41 (m, 7 H), 7.35–7.28 (m, 4 H), 7.26–7.19 (m, 3 H), 4.75 (d,
J = 15.8 Hz, 1 H), 4.64 (d, J = 16.8 Hz, 1 H), 4.51 (dddd, J = 12.6, 10.0,
4.8, 2.8 Hz, 1 H), 4.35 (d, J = 15.8 Hz, 1 H), 4.14 (d, J = 16.8 Hz, 1 H),
3.05 (dd, J = 13.5, 4.8 Hz, 1 H), 2.73 (dd, J = 13.6, 10.2 Hz, 1 H), 2.08
(dd, J = 14.3, 12.2 Hz, 1 H), 1.41 (dd, J = 14.4, 2.9 Hz, 1 H), 1.26 (s, 3 H),
1.11 (s, 3 H).
The enantiopurity was determined to be 95:5 er by chiral HPLC analy-
sis (Chiralcel ODH, 15 cm × 4.6 mm, 3% i-PrOH/hexanes, 0.8 mL/min, λ
= 210 nm, tR = 16.7 and 22.3 min).
(S)-(–)-5-([1,1′-Biphenyl]-4-ylmethyl)-2,6-dibenzyl-3,3-dimethyl-
1,2,6-thiadiazinane 1,1-Dioxide (6b)
13C NMR (125 MHz, CDCl3): δ = 140.4, 138.4, 134.9, 133.6, 132.5,
128.63, 128.55, 128.52, 128.1, 128.0, 127.8, 127.7, 127.6, 127.5,
127.24, 127.18, 126.3, 125.8, 60.5, 57.4, 50.2, 45.8, 41.1, 38.8, 31.0,
22.9.
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(2-methylpent-4-en-2-yl)sulfamide (5a) (72.0 mg, 0.20
mmol) and 4-bromobiphenyl (104 μL, 0.40 mmol) using a catalyst
composed of Pd2(dba)3 (1.8 mg, 0.002 mmol) and (S)-Siphos-PE (5.1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

G
Z. J. Garlets, J. P. Wolfe
Special Topic
Synthesis
HRMS (ESI+): m/z [M + H]+ calcd for C30H33N2O2S: 485.2257; found:
485.2260.
The enantiopurity was determined to be 96.5:3.5 er by chiral HPLC
analysis (Chiralcel ODH, 15 cm × 4.6 mm, 4% i-PrOH/hexanes, 0.50
mL/min, λ = 210 nm, tR = 15.6 and 17.9 min).
The enantiopurity was determined to be 96.5:3.5 er by chiral HPLC
analysis (Chiralcel ADH, 25 cm × 4.6 mm, 4% i-PrOH/hexanes, 1.0
mL/min, λ = 254 nm, tR = 30.4 and 33.5 min).
(S)-(–)-2,6-Dibenzyl-5-(4-fluorobenzyl)-3,3-dimethyl-1,2,6-thiadi-
azinane 1,1-Dioxide (6f)
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(2-methylpent-4-en-2-yl)sulfamide (5a) (72.0 mg, 0.20
mmol) and 1-bromo-4-fluorobenzene (44 μL, 0.40 mmol) using a cat-
alyst composed of Pd2(dba)3 (1.8 mg, 0.001 mmol) and (S)-Siphos-PE
(5.1 mg, 0.010 mmol), t-BuONa (38.0 mg, 0.40 mmol), a reaction tem-
perature of 120 °C, and a reaction time of 18 h in xylenes (1.6 mL) and
H2O (7 μL). This procedure afforded the title compound (82 mg, 91%)
as a colorless solid; mp 132–133 °C; [α]D23 –68 (c 1.7, CH2Cl2).
(S)-(–)-2,6-Dibenzyl-5-(4-methoxybenzyl)-3,3-dimethyl-1,2,6-
thiadiazinane 1,1-Dioxide (6d)
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(2-methylpent-4-en-2-yl)sulfamide (5a) (72.0 mg, 0.20
mmol) and 4-bromoanisole (50 μL, 0.40 mmol) using a catalyst com-
posed of Pd2(dba)3 (1.8 mg, 0.002 mmol) and (S)-Siphos-PE (5.1 mg,
0.010 mmol), t-BuONa (38.0 mg, 0.40 mmol), a reaction temperature
of 120 °C, and a reaction time of 18 h in xylenes (1.6 mL) and H2O (7
μL). This procedure afforded the title compound (55 mg, 59%) as a col-
orless solid; mp 135–138 °C; [α]D23 –78 (c 1.2, CH2Cl2).
IR (neat): 1495, 1452, 1330, 1153, 1137 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.42 (d, J = 7.2 Hz, 2 H), 7.39 (d, J = 7.1
Hz, 2 H), 7.35–7.28 (m, 4 H), 7.27–7.22 (m, 2 H), 7.02–6.96 (m, 2 H),
6.91 (t, J = 8.6 Hz, 2 H), 4.69 (d, J = 15.8 Hz, 1 H), 4.63 (d, J = 16.8 Hz, 1
H), 4.36 (dddd, J = 12.3, 8.8, 5.3, 2.9 Hz, 1 H), 4.28 (d, J = 15.8 Hz, 1 H),
4.15 (d, J = 16.8 Hz, 1 H), 2.84 (dd, J = 13.8, 5.4 Hz, 1 H), 2.56 (dd,
J = 13.9, 9.6 Hz, 1 H), 2.04 (dd, J = 14.3, 12.1 Hz, 1 H), 1.39 (dd, J = 14.3,
2.9 Hz, 1 H), 1.30 (s, 3 H), 1.14 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 161.8 (d, JC–F = 243.8 Hz), 140.30,
138.16, 133.0 (d, JC–F = 3.8 Hz), 130.5 (d, JC–F = 7.5 Hz), 128.60, 128.55,
128.1, 127.6, 127.4, 127.2, 115.6 (d, JC–F = 21.2 Hz), 60.4, 57.3, 50.2,
45.8, 39.9, 38.8, 30.9, 23.1.
IR (neat): 1604, 1512, 1494, 1454, 1329, 1152, 1136 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.42 (d, J = 7.6 Hz, 4 H), 7.32 (td, J = 7.5,
1.4 Hz, 4 H), 7.27–7.21 (m, 2 H), 6.97 (d, J = 8.6 Hz, 2 H), 6.77 (d, J = 8.5
Hz, 2 H), 4.70 (d, J = 15.9 Hz, 1 H), 4.63 (d, J = 16.8 Hz, 1 H), 4.35 (dddd,
J = 12.5, 10.1, 4.8, 2.8 Hz, 1 H), 4.28 (d, J = 15.8 Hz, 1 H), 4.13 (d,
J = 16.8 Hz, 1 H), 3.77 (s, 3 H), 2.82 (dd, J = 13.7, 4.8 Hz, 1 H), 2.52 (dd,
J = 13.7, 10.2 Hz, 1 H), 2.00 (dd, J = 14.3, 12.3 Hz, 1 H), 1.39 (dd,
J = 14.3, 2.8 Hz, 1 H), 1.28 (s, 3 H), 1.11 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 158.5, 140.4, 138.4, 130.1, 129.3,
128.6, 128.5, 128.1, 127.5, 127.4, 127.2, 114.2, 60.4, 57.5, 55.4, 50.0,
45.7, 40.0, 38.7, 31.0, 22.8.
19F NMR (471 MHz, CDCl3): δ = –116.35 to –116.21 (m).
HRMS (ESI+): m/z [M + H]+ calcd for C27H33N2O3S: 465.2206; found:
HRMS (ESI+): m/z [M + H]+ calcd for C26H30FN2O2S: 453.2012; found:
465.2204.
453.2007.
The enantiopurity was determined to be 98:2 er by chiral HPLC analy-
sis (Chiralcel ADH, 25 cm × 4.6 mm, 4% i-PrOH/hexanes, 1.00 mL/min,
λ = 205 nm, tR = 32.9 and 38.9 min).
The enantiopurity was determined to be 96.5:3.5 er by chiral HPLC
analysis (Chiralcel ODH, 15 cm × 4.6 mm, 4% i-PrOH/hexanes, 0.50
mL/min, λ = 210 nm, tR = 16.1 and 17.7 min).
(S)-(–)-2,6-Dibenzyl-3,3-dimethyl-5-[4-(trifluoromethyl)benzyl]-
(S)-(–)-2,6-Dibenzyl-5-(4-chlorobenzyl)-3,3-dimethyl-1,2,6-thia-
1,2,6-thiadiazinane 1,1-Dioxide (6e)
diazinane 1,1-Dioxide (6g)
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(2-methylpent-4-en-2-yl)sulfamide (5a) (72.0 mg, 0.20
mmol) and 4-bromobenzotrifluoride (56 μL, 0.40 mmol) using a cata-
lyst composed of Pd2(dba)3 (1.8 mg, 0.001 mmol) and (S)-Siphos-PE
(5.1 mg, 0.010 mmol), t-BuONa (38.0 mg, 0.40 mmol), a reaction tem-
perature of 120 °C, and a reaction time of 18 h in xylenes (1.6 mL) and
H2O (7 μL). This procedure afforded the title compound (74 mg, 73%)
as a colorless solid; mp 159–161 °C; [α]D23 –77 (c 1.5, CH2Cl2).
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(2-methylpent-4-en-2-yl)sulfamide (5a) (72.0 mg, 0.20
mmol) and 1-bromo-4-chlorobenzene (77 mg, 0.4 mmol) using a cat-
alyst composed of Pd2(dba)3 (1.8 mg, 0.002 mmol) and (S)-Siphos-PE
(5.1 mg, 0.010 mmol), t-BuONa (38.0 mg, 0.60 mmol), a reaction tem-
perature of 120 °C, and a reaction time of 18 h in xylenes (1.6 mL) and
H2O (7 μL). This procedure afforded the title compound (72 mg, 77%)
23
as a colorless solid; mp 145–148 °C; [α]D –80 (c 1.5, CH2Cl2). This
material contained ca. 5–10% of an inseparable impurity. Data are for
the title compound.
IR (neat): 1495, 1452, 1328, 1154, 1136 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.44 (dd, J = 11.0, 7.8 Hz, 4 H), 7.36–
7.20 (m, 8 H), 7.12 (d, J = 8.0 Hz, 2 H), 4.64 (t, J = 16.3 Hz, 2 H), 4.42
(dddd, J = 12.0, 9.1, 6.1, 3.1 Hz, 1 H), 4.31 (d, J = 15.8 Hz, 1 H), 4.18 (d,
J = 16.8 Hz, 1 H), 2.92 (dd, J = 14.0, 6.1 Hz, 1 H), 2.68 (dd, J = 14.0, 9.0
Hz, 1 H), 2.09 (dd, J = 14.3, 11.9 Hz, 1 H), 1.41 (dd, J = 14.3, 3.1 Hz, 1 H),
1.32 (s, 3 H), 1.16 (s, 3 H).
13C NMR (176 MHz, CDCl3): δ = 141.4, 140.2, 137.8, 129.4, 129.1 (q, JC–
F = 31.7 Hz), 128.61, 128.58, 128.1, 127.6, 127.4, 127.2, 125.6 (q, JC–F
3.5 Hz), 124.3 (q, JC–F = 272.8 Hz), 60.4, 56.9, 50.4, 45.8, 40.5, 39.0,
30.7, 23.4.
IR (neat): 1493, 1452, 1320, 1136 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.45–7.40 (m, 2 H), 7.38 (d, J = 7.0 Hz, 2
H), 7.31 (ddd, J = 9.8, 8.4, 6.7 Hz, 4 H), 7.27–7.22 (m, 2 H), 7.20–7.16
(m, 2 H), 6.98–6.94 (m, 2 H), 4.69 (d, J = 15.8 Hz, 1 H), 4.63 (d, J = 16.8
Hz, 1 H), 4.36 (dddd, J = 12.3, 8.8, 5.4, 2.9 Hz, 1 H), 4.28 (d, J = 15.8 Hz,
1 H), 4.15 (d, J = 16.8 Hz, 1 H), 2.84 (dd, J = 13.8, 5.4 Hz, 1 H), 2.56 (dd,
J = 13.9, 9.5 Hz, 1 H), 2.04 (dd, J = 14.3, 12.1 Hz, 1 H), 1.38 (dd, J = 14.3,
3.0 Hz, 1 H), 1.30 (s, 3 H), 1.14 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 140.3, 138.1, 135.8, 132.6, 130.4,
128.9, 128.6, 128.6, 128.0, 127.6, 127.4, 127.2, 60.4, 57.1, 50.2, 45.7,
40.1, 38.7, 30.9, 23.1.
=
19F NMR (377 MHz, CDCl3): δ = –62.54.
HRMS (ESI+): m/z [M + H]+ calcd for C27H30F3N2O2S: 503.1975; found:
HRMS (ESI+): m/z [M + H]+ calcd for C26H30ClN2O2S: 469.1711; found:
469.1710.
503.1977.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

H
Z. J. Garlets, J. P. Wolfe
Special Topic
Synthesis
The enantiopurity was determined to be 97:3 er by chiral HPLC analy-
sis (Chiralcel ADH, 15 cm × 4.6 mm, 4% i-PrOH/hexanes, 1.0 mL/min,
λ = 210 nm, tR = 26.2 and 28.6 min).
(S)-(–)-1,3-Dibenzyl-4-[3-(trifluoromethyl)benzyl]-2-thia-1,3-di-
azaspiro[5.5]undecane 2,2-Dioxide (6j)
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(1-allylcyclohexyl)sulfamide (5b) (80.0 mg, 0.20 mmol) and
3-bromobenzotrifluoride (56 μL, 0.40 mmol) using a catalyst com-
posed of Pd2(dba)3 (1.8 mg, 0.002 mmol) and (S)-Siphos-PE (5.1 mg,
0.010 mmol), t-BuONa (38.0 mg, 0.40 mmol), a reaction temperature
of 120 °C, and a reaction time of 18 h in xylenes (1.6 mL) and H2O
(7 μL). This procedure afforded the title compound (98 mg, 90%) as a
colorless solid; mp 119–121 °C; [α]D23 –70 (c 1.6, CH2Cl2).
(S)-(–)-2,6-Dibenzyl-3,3-dimethyl-5-(2-methylbenzyl)-1,2,6-thia-
diazinane 1,1-Dioxide (6h)
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(2-methylpent-4-en-2-yl)sulfamide (5a) (72.0 mg, 0.20
mmol) and 1-bromo-2-methylbenzene (48 μL, 0.4 mmol) using a cat-
alyst composed of Pd2(dba)3 (1.8 mg, 0.002 mmol) and (S)-Siphos-PE
(5.1 mg, 0.010 mmol), t-BuONa (38.0 mg, 0.60 mmol), a reaction tem-
perature of 120 °C, and a reaction time of 18 h in xylenes (1.6 mL) and
H2O (7 μL). This procedure afforded the title compound (26 mg, 29%)
as a colorless solid; mp 118–124 °C; [α]D23 –44.2 (c 2.0, CH2Cl2).
IR (neat): 1495, 1453, 1327, 1154, 1116, 1074 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.46–7.39 (m, 3 H), 7.38–7.20 (m, 11
H), 4.68 (d, J = 2.5 Hz, 1 H), 4.65 (d, J = 4.7 Hz, 1 H), 4.37–4.25 (m, 3 H),
2.95 (dd, J = 14.0, 5.7 Hz, 1 H), 2.69 (dd, J = 14.0, 9.2 Hz, 1 H), 2.17 (d,
J = 11.7 Hz, 1 H), 2.06 (dd, J = 14.6, 3.0 Hz, 1 H), 1.83 (t, J = 13.2 Hz,
1 H), 1.65–1.42 (m, 6 H), 1.18 (q, J = 13.0 Hz, 1 H), 1.00 (q, J = 13.0 Hz,
1 H), 0.83 (q, J = 12.8 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 140.5, 138.5, 137.8, 132.3, 131.0 (q,
JC–F = 32.5 Hz), 129.2, 128.6, 128.5, 128.1, 127.7, 127.1, 125.8 (q, JC–F
3.75 Hz), 124.1 (q, JC–F = 270 Hz), 123.7 (q, JC–F = 3.75 Hz), 63.9, 56.6,
50.7, 44.9, 40.5, 38.1, 31.1, 29.8, 25.3, 22.9, 22.6; 1 carbon signal is
missing.
19F NMR (471 MHz, CDCl3): δ = –62.65 (s).
IR (neat): 1604, 1494, 1452, 1320, 1138 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.47–7.41 (m, 4 H), 7.32 (q, J = 7.5 Hz, 4
H), 7.28–7.22 (m, 2 H), 7.13–7.02 (m, 4 H), 4.74 (d, J = 15.9 Hz, 1 H),
4.65 (d, J = 16.8 Hz, 1 H), 4.42 (tdd, J = 9.9, 4.7, 2.3 Hz, 1 H), 4.30 (d,
J = 15.9 Hz, 1 H), 4.14 (d, J = 16.8 Hz, 1 H), 2.85 (dd, J = 13.9, 4.6 Hz, 1
H), 2.62 (dd, J = 13.9, 10.0 Hz, 1 H), 2.19 (s, 3 H), 2.09 (t, J = 14.3 Hz, 1
H), 1.40 (dd, J = 14.3, 2.9 Hz, 1 H), 1.27 (s, 3 H), 1.13 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 140.4, 138.5, 136.5, 135.7, 130.7,
129.7, 128.6, 128.5, 128.0, 127.5, 127.4, 127.2, 126.9, 126.2, 60.4, 56.2,
50.1, 45.8, 38.83, 37.99, 31.0, 22.8, 19.7.
=
HRMS (ESI+): m/z [M + H]+ calcd for C30H34F3N2O2S: 543.2288; found:
543.2292.
HRMS (ESI+): m/z [M + H]+ calcd for C27H33N2O2S: 449.2257; found:
449.2258.
The enantiopurity was determined to be 96.5:3.5 er by chiral HPLC
analysis (Chiralcel ADH, 25 cm × 4.6 mm, 6% i-PrOH/hexanes, 1.0
mL/min, λ = 210 nm, tR = 15.4 and 18.9 min).
The enantiopurity was determined to be 85:15 er by chiral HPLC
analysis (Chiralcel ADH, 25 cm × 4.6 mm, 4% i-PrOH/hexanes, 1.0
mL/min, λ = 210 nm, tR = 13.9 and 23.3 min).
(S)-(–)-1,3-Dibenzyl-4-(3-methoxybenzyl)-2-thia-1,3-di-
azaspiro[5.5]undecane 2,2-Dioxide (6k)
(S)-(–)-1,3-Dibenzyl-4-[3-(4-fluorophenoxy)benzyl]-2-thia-1,3-di-
azaspiro[5.5]undecane 2,2-Dioxide (6i)
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(1-allylcyclohexyl)sulfamide (5b) (80.0 mg, 0.20 mmol) and
3-bromoanisole (51 μL, 0.40 mmol) using a catalyst composed of
Pd2(dba)3 (1.8 mg, 0.002 mmol) and (S)-Siphos-PE (5.1 mg, 0.010
mmol), t-BuONa (38.0 mg, 0.40 mmol), a reaction temperature of
120 °C, and a reaction time of 18 h in xylenes (1.6 mL) and H2O (7 μL).
This procedure afforded the title compound (89 mg, 88%) as a color-
less solid; mp 141–144 °C; [α]D23 –52 (c 1.9, CH2Cl2).
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(1-allylcyclohexyl)sulfamide (5b) (80.0 mg, 0.20 mmol) and
1-bromo-3-(4-fluorophenoxy)benzene (107 mg, 0.40 mmol) using a
catalyst composed of Pd2(dba)3 (1.8 mg, 0.002 mmol) and (S)-Siphos-
PE (5.1 mg, 0.010 mmol), t-BuONa (38.0 mg, 0.40 mmol), a reaction
temperature of 120 °C, and a reaction time of 18 h in xylenes (1.6 mL)
and H2O (7 μL). This procedure afforded the title compound (98 mg,
84%) as a colorless solid; mp 122–125 °C; [α]D23 –65 (c 1.6, CH2Cl2).
IR (neat): 1584, 1496, 1452, 1327, 1150, 1111 cm–1
.
IR (neat): 1497, 1441, 1330, 1198, 1157, 1110 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 7.5 Hz, 4 H), 7.32 (t, J = 7.6
Hz, 4 H), 7.24 (q, J = 7.1 Hz, 2 H), 7.17 (t, J = 7.9 Hz, 1 H), 6.74 (dd,
J = 8.2, 2.5 Hz, 1 H), 6.70–6.66 (m, 1 H), 6.60 (t, J = 2.0 Hz, 1 H), 4.68
(dd, J = 16.4, 13.1 Hz, 2 H), 4.29 (dd, J = 30.4, 16.6 Hz, 3 H), 3.76 (s, 3
H), 2.89 (dd, J = 13.5, 4.6 Hz, 1 H), 2.58 (dd, J = 13.5, 10.3 Hz, 1 H), 2.18
(d, J = 12.2 Hz, 1 H), 2.09 (dd, J = 14.6, 2.6 Hz, 1 H), 1.74 (t, J = 12.0 Hz
1 H), 1.65–1.36 (m, 6 H), 1.24–1.08 (m, 1 H), 1.07–0.91 (m, 1 H), 0.90–
0.73 (m, 1 H).
1H NMR (700 MHz, CDCl3): δ = 7.43–7.38 (m, 4 H), 7.34–7.28 (m, 4 H),
7.26–7.20 (m, 3 H), 7.04–6.99 (m, 2 H), 6.92–6.88 (m, 2 H), 6.85–6.81
(m, 2 H), 6.67 (t, J = 2.0 Hz, 1 H), 4.67 (dd, J = 16.5, 11.7 Hz, 2 H), 4.31
(d, J = 15.7 Hz, 1 H), 4.28–4.21 (m, 2 H), 2.86 (dd, J = 13.6, 4.9 Hz, 1 H),
2.57 (dd, J = 13.6, 10.0 Hz, 1 H), 2.20–2.14 (m, 1 H), 2.07 (dd, J = 14.6,
2.9 Hz, 1 H), 1.74 (t, J = 14.1 Hz, 1 H), 1.63–1.47 (m, 5 H), 1.41 (d,
J = 13.1 Hz, 1 H), 1.17 (qt, J = 13.4, 3.7 Hz, 1 H), 1.02 (qt, J = 13.8, 4.0
Hz, 1 H), 0.84 (qt, J = 13.4, 4.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 159.9, 140.7, 139.1, 138.4, 129.7,
128.6, 128.5, 128.1, 127.5, 127.1, 127.0, 121.4, 114.6, 112.5, 63.9, 56.9,
55.4, 50.4, 44.9, 41.0, 38.2, 31.1, 29.5, 25.3, 22.9, 22.6.
13C NMR (176 MHz, CDCl3): δ = 158.9 (d, JC–F = 242.9 Hz), 157.9, 153.1
(d, JC–F = 3.5 Hz), 140.6, 139.6, 138.2, 130.1, 128.6, 128.5, 128.1, 127.5,
127.1, 127.0, 124.0, 120.5 (d, JC–F = 8.8 Hz), 119.1, 117.0, 116.5 (d, JC–F
22.9 Hz), 63.8, 56.8, 50.4, 44.9, 40.7, 38.2, 31.0, 29.5, 25.3, 23.0, 22.6.
19F NMR (471 MHz, CDCl3): δ = –120.00 to –120.07 (m).
HRMS (ESI+): m/z [M + H]+ calcd for C35H38FN2O3S: 585.2582; found:
=
HRMS (ESI+): m/z [M + H]+ calcd for C30H37N2O3S: 505.2519; found:
505.2523.
The enantiopurity was determined to be 97:3 er by chiral HPLC analy-
sis (Chiralcel ADH, 25 cm × 4.6 mm, 6% i-PrOH/hexanes, 1.0 mL/min,
λ = 210 nm, tR = 32.5 and 35.2 min).
585.2582.
The enantiopurity was determined to be 95.5:4.5 er by chiral HPLC
analysis (Chiralcel ADH, 25 cm × 4.6 mm, 6% i-PrOH/hexanes, 1.0
mL/min, λ = 210 nm, tR = 24.6 and 33.5 min).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

I
Z. J. Garlets, J. P. Wolfe
Special Topic
Synthesis
(S)-(–)-2,6-Dibenzyl-3,3-diethyl-5-(naphthalen-1-ylmethyl)-1,2,6-
thiadiazinane 1,1-Dioxide (6l)
EP858999 A1, 1998. (d) Anderson, J. T.; Chekler, E. L. P.;
Ellsworth, E. L.; Erickson, B. K.; Gilbert, A. M.; Ricketts, A. P.;
Thompson, D. P.; Unwalla, R. J.; Verhoest, P. R. US2014/155390
A1, 2014. (e) De Lucca, G. V. J. Org. Chem. 1998, 63, 4755.
(2) Jagt, R. B. C.; Toullec, P. Y.; Geerdink, D.; de Vries, J. G.; Feringa,
B. L.; Minnaard, A. J. Angew. Chem. Int. Ed. 2006, 45, 2789.
(3) Ji, X.; Huang, H. Org. Biomol. Chem. 2016, 14, 10557.
(4) For selected examples of the use of 1,3-diamines in asymmetric
synthesis, see: (a) Kodama, K.; Sugawara, K.; Hirose, T. Chem.
Eur. J. 2011, 17, 13584. (b) Hirose, T.; Sugawara, K.; Kodama, K.
J. Org. Chem. 2011, 76, 5413. (c) Yao, Q. J.; Judeh, Z. M. A. Tetra-
hedron 2011, 67, 4086. (d) Mayans, E.; Gargallo, A.; Alvarez-
Larena, A.; Illa, O.; Ortuno, R. M. Eur. J. Org. Chem. 2013, 1425.
(5) For the synthesis of five-membered cyclic sulfamides, see:
(a) Zabawa, T. P.; Chemler, S. R. Org. Lett. 2007, 9, 2035.
(b) McDonald, R. I.; Stahl, S. S. Angew. Chem. Int. Ed. 2010, 49,
5529. (c) Chávez, P.; Kirsch, J.; Streuff, J.; Muñiz, K. J. Org. Chem.
2012, 77, 1922. (d) Lu, H.; Lang, K.; Jiang, H.; Wojtas, L.; Zhang,
X. P. Chem. Sci. 2016, 7, 6934. (e) Fornwald, R. M.; Fritz, J. A.;
Wolfe, J. P. Chem. Eur. J. 2014, 20, 8782. (f) Cornwall, R. G.; Zhao,
B.; Shi, Y. Org. Lett. 2013, 15, 796.
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(3-ethylhex-5-en-3-yl)sulfamide (5c) (77.0 mg, 0.20 mmol)
and 1-bromonaphthalene (56 μL, 0.40 mmol) using a catalyst com-
posed of Pd2(dba)3 (1.8 mg, 0.002 mmol) and (S)-Siphos-PE (5.1 mg,
0.010 mmol), t-BuONa (38.0 mg, 0.40 mmol), a reaction temperature
of 120 °C, and a reaction time of 18 h in xylenes (1.6 mL) and H2O
(7 μL). This procedure afforded the title compound (89 mg, 86%) as a
colorless solid; mp 58–62 °C; [α]D23 –59 (c 2.2, CH2Cl2).
IR (neat): 1495, 1454, 1331, 1153 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.82–7.78 (m, 1 H), 7.70 (d, J = 8.2 Hz,
1 H), 7.61–7.57 (m, 2 H), 7.51 (d, J = 7.4 Hz, 2 H), 7.48–7.40 (m, 4 H),
7.40–7.35 (m, 2 H), 7.34–7.28 (m, 3 H), 7.27–7.22 (m, 2 H), 4.59 (d,
J = 15.1 Hz, 1 H), 4.51 (d, J = 15.1 Hz, 1 H), 4.47 (d, J = 16.6 Hz, 1 H),
4.36 (d, J = 16.6 Hz, 1 H), 4.15 (ddt, J = 14.4, 9.4, 4.3 Hz, 1 H), 3.34 (dd,
J = 13.7, 4.6 Hz, 1 H), 3.08 (dd, J = 13.7, 10.0 Hz, 1 H), 2.35 (dd, J = 14.9,
12.1 Hz, 1 H), 1.67 (dq, J = 15.1, 7.6 Hz, 1 H), 1.60–1.37 (m, 3 H), 1.31
(dd, J = 15.0, 4.1 Hz, 1 H), 0.70 (t, J = 7.3 Hz, 3 H), 0.35 (t, J = 7.5 Hz,
3 H).
13C NMR (125 MHz, CDCl3): δ = 140.1, 137.8, 134.0, 133.7, 131.9,
129.0, 128.78, 128.75, 128.5, 128.1, 127.9, 127.64, 127.58, 127.2,
126.3, 125.8, 125.5, 123.6, 66.0, 56.3, 52.8, 46.2, 39.2, 30.5, 29.4, 29.0,
9.2, 7.9.
HRMS (ESI+): m/z [M + H]+ calcd for C32H37N2O2S: 513.2570; found:
513.2572.
(6) Kurokawa, T.; Kim, M.; Du Bois, J. Angew. Chem. Int. Ed. 2009, 48,
2777.
(7) (a) Lu, H.; Jiang, H.; Wojtas, L.; Zhang, X. P. Angew. Chem. Int. Ed.
2010, 49, 10192; Angew. Chem. 2010, 122, 10390. (b) Lu, H.; Hu,
Y.; Jiang, H.; Wojtas, L.; Zhang, X. P. Org. Lett. 2012, 14, 5158.
(c) Lu, H.; Li, C.; Jiang, H.; Lizardi, C. L.; Zhang, X. P. Angew. Chem.
Int. Ed. 2014, 53, 7028Angew. Chem. 2014, 126, 7148.
(8) Babij, N. R.; McKenna, G. M.; Fornwald, R. M.; Wolfe, J. P. Org.
Lett. 2014, 16, 3412.
The enantiopurity was determined to be 95:5 er by chiral HPLC analy-
sis (Chiralcel ODH, 15 cm × 4.6 mm, 2% i-PrOH/hexanes, 0.75 mL/min,
λ = 210 nm, tR = 17.1 and 20.2 min).
(9) Garlets, Z. J.; Parenti, K. R.; Wolfe, J. P. Chem. Eur. J. 2016, 22,
5919.
(10) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735.
(11) The absolute configuration was determined by X-ray crystallo-
graphic characterization of 6d which aligns with the absolute
configuration of the five-membered cyclic sulfamides using this
same system. See the Supporting Information for full experi-
mental details.
(12) The stereochemistry of addition was determined through anal-
ysis of a transformation of a substrate bearing a deuterated
alkene. See reference 9 for additional information.
Funding Information
The authors thank the NIH (GM 071650) for financial support of this
work. Z.J.G. wishes to thank Eli Lilly for a summer research fellowship
and University of Michigan Rackham Graduate School for a Henry
Earle Riggs Dissertation Fellowship. We acknowledge funding from
NSF grant CHE-0840456 for X-ray diffractometer instrumentation.
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(13) For reviews on Pd-catalyzed alkene carboamination or car-
boalkoxylation reactions between aryl/alkenyl halides/triflates
and alkenes bearing tethered nucleophiles, see: (a) Garlets, Z. J.;
White, D. R.; Wolfe, J. P. Asian J. Org. Chem. 2017, 6, 636.
(b) Wolfe, J. P. Top. Heterocycl. Chem. 2013, 32, 1. (c) Schultz, D.
M.; Wolfe, J. P. Synthesis 2012, 44, 351. (d) Wolfe, J. P. Synlett
2008, 2913.
(14) For studies on the mechanism of syn-migratory insertion of
alkenes into Pd–N bonds, see: (a) Neukom, J. D.; Perch, N. S.;
Wolfe, J. P. J. Am. Chem. Soc. 2010, 132, 6276. (b) Hanley, P. S.;
Marković, D.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 6302.
(c) Neukom, J. D.; Perch, N. S.; Wolfe, J. P. Organometallics 2011,
30, 1269. (d) Hanley, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2011,
133, 15661. (e) White, P. B.; Stahl, S. S. J. Am. Chem. Soc. 2011,
133, 18594.
Acknowledgment
We acknowledge Dr. J. W. Kampf for X-ray crystallographic analyses of
6d.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591574.
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References
(1) (a) Reitz, A. B.; Smith, G. R.; Parker, M. H. Expert Opin. Ther. Pat.
2009, 19, 1449. (b) Winum, J.-Y.; Scozzafava, A.; Montero, J.-L.;
Supuran, C. T. Expert Opin. Ther. Pat. 2006, 16, 27. (c) De Lucca,
G. V.; Lam, P. Y.-S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.
(15) Song, L.; Fang, X.; Wang, Z.; Liu, K.; Li, C. J. Org. Chem. 2016, 81,
2442.
(16) Fekner, T.; Müller-Bunz, H.; Guiry, P. J. Org. Lett. 2006, 8, 5109.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I