Influence of catalyst structure and reaction conditions on anti- Versus syn-Aminopalladation pathways in pd-catalyzed alkene carboamination reactions of N-Allylsulfamides

Article abstract of DOI:10.1002/chem.201402258

The Pd-catalyzed coupling of N-allylsulfamides with aryl and alkenyl triflates to afford cyclic sulfamide products is described. In contrast to other known Pd-catalyzed alkene carboamination reactions, these transformations may be selectively induced to o

Full text of DOI:10.1002/chem.201402258

DOI: 10.1002/chem.201402258
Full Paper
&
Palladium Catalysis
Influence of Catalyst Structure and Reaction Conditions on anti-
versus syn-Aminopalladation Pathways in Pd-Catalyzed Alkene
Carboamination Reactions of N-Allylsulfamides
Ryan M. Fornwald,[a] Jonathan A. Fritz,[b] and John P. Wolfe*[a]
Abstract: The Pd-catalyzed coupling of N-allylsulfamides
with aryl and alkenyl triflates to afford cyclic sulfamide prod-
ucts is described. In contrast to other known Pd-catalyzed
alkene carboamination reactions, these transformations may
be selectively induced to occur by way of either anti- or syn-
aminopalladation mechanistic pathways by modifying the
catalyst structure and reaction conditions.
Introduction
egy would complement existing methods as it would allow for
the conversion of an acyclic N-allylsulfamide into a cyclic sulfa-
mide with the generation of both a CꢀN and a CꢀC bond.
Herein, we describe our studies in this area and our findings
that the stereochemistry of the addition to the alkene can be
controlled by the appropriate choice of catalyst and condi-
tions, which influence the syn- versus anti-aminopalladation
mechanistic pathways in the catalytic cycle.
Cyclic sulfamides are an important class of heterocycle that
have attracted attention in medicinal-chemistry applications as
these functional groups can serve as isosteres for cyclic ureas
and are also known to form attractive electrostatic interactions
with proteins and enzymes.[1] Biologically active compounds
that bear these units have been examined as protease inhibi-
tors,[2] human leukocyte elastase (HLE) inhibitors,[3] renin inhibi-
tors,[4] and norovirus inhibitors.[5] In addition, the SO2 unit can
be cleaved from these compounds to afford synthetically
useful 1,2-diamines.[6,7] Cyclic sulfamides have also been em-
ployed as chiral auxiliaries for asymmetric aldol and alkylation
reactions.[8]
Results and Discussion
Initially, we examined the Pd-catalyzed carboamination be-
tween 1a and 4-bromobenzonitrile. After some exploration,
the use of a catalyst composed of [Pd2(dba)3] and the Buch-
wald X-Phos[12] ligand afforded the desired product 2a in 79%
yield of the isolated product [Eq. (1); dba=dibenzylideneace-
tone]. However, the scope of this reaction was limited to elec-
tron-deficient aryl bromides as a competing Heck arylation oc-
curred in the reactions of the more electron-rich electrophiles.
Classical approaches to the synthesis of cyclic sulfamides fre-
quently involve treatment of 1,2-diamines with sulfamide or re-
lated electrophiles and generally require relatively complex
starting materials.[9] In recent years, a number of metal-cata-
lyzed alkene diamination or oxidative cyclization reactions
have been described that effect the conversion of readily avail-
able substrates into cyclic sulfamide derivatives.[7]
We have previously reported a method for the construction
of cyclic ureas through Pd-catalyzed alkene carboamination re-
actions between acyclic N-allylureas and aryl or alkenyl hal-
ides.[10] We felt that related transformations of N-allylsulfamides
could provide an attractive and simple approach to the gener-
ation of substituted cyclic sulfamides.[11] In addition, this strat-
[a] R. M. Fornwald, Prof. Dr. J. P. Wolfe
Department of Chemistry
We initially postulated that the mechanism of the carboami-
nation reactions of N-allylsulfamides was similar to that of
other nucleophiles, such as ureas or amines.[13] Namely, the oxi-
dative addition of the aryl bromide to a Pd0 center to generate
4, which reacts with substrate 1 and base to afford 5.[14] The
syn-aminopalladation reaction of 5 gives 6, which can undergo
University of Michigan, 930 N. University Ave
Ann Arbor, MI 48109-1055 (USA)
E-mail: jpwolfe@umich.edu
[b] Prof. Dr. J. A. Fritz
Department of Chemistry
Aquinas College, 202 Albertus Hall
1607 Robinson Road SE, Grand Rapids MI 49506-1799 (USA)
reductive elimination to afford the observed product
(Scheme 1).
2
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402258.
Chem. Eur. J. 2014, 20, 1 – 10
1
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
and a screen of bases revealed that the use of LiOtBu provided
further improvement. Finally, switching to the more polar sol-
vent benzotrifluoride resulted in the formation of the desired
product, with only a trace amount of the side product from
the Heck arylation reaction.
We proceeded to examine the scope of Pd-catalyzed carbo-
amination reactions of N-allylsulfamides with a variety of differ-
ent aryl triflates (Table 2). Both electron-withdrawing groups
(Table 2, entries 2, 7, 9, and 13) and electron-donating groups
(Table 2, entries 3, 10, and 12) were tolerated on the aryl triflate
substrate. In addition, the reaction of an ortho-substituted aryl
triflate also proceeded in good yield (Table 2, entry 4). Alkenyl
triflates were also viable substrates (Table 2, entries 5 and 6),
and the reactions proceeded with retention of the alkene ge-
ometry. The RuPhos ligand provided satisfactory results with
most electrophiles that were examined. However, in a few
cases, superior results were obtained with Brettphos, 2-di-tert-
Scheme 1. The syn-aminopalladation mechanism.
We felt that two factors could potentially be the cause of
the Heck arylation side reactions observed with relatively elec-
tron-rich aryl bromides: 1) the formation of a PdꢀN bond (4!
5) may be relatively slow for palladium complexes that are less
electrophilic as a result of the electron-rich aryl groups bound
to the metal center or 2) the aminopalladation step (5!6)
may be reversible,[15] and competing migratory insertion of the
alkene unit into the PdꢀC bond of 4 (which leads to side-prod-
uct 3) may be faster with relatively electron-rich aryl groups.[16]
These factors suggested that the use of aryl triflate substrates
could potentially lead to improved results in Pd-catalyzed car-
boamination reactions of N-allylsulfamides. The oxidative addi-
tion of aryl triflates to the Pd0 center leads to the formation of
cationic palladium complexes,[17] which should undergo more
facile PdꢀN-bond formation due to the increased electrophilici-
ty of these intermediates. In addition, the non-nucleophilic tri-
flate anion is less likely to promote the formation of anionic
complexes that are known to accelerate Heck reactions.[18]
We studied the coupling of 1 with para-tolyl triflate (Table 1)
to test this idea, and our first results when using X-Phos as
ligand were disappointing; namely, a 1:1 mixture of the desired
product and the side product of the Heck reaction (2c/3c) was
obtained. However, after further exploration, we discovered
that the RuPhos ligand provided significantly better results,
butylphosphino-2’-(N,N-dimethylamino)biphenyl
(tBu-Dave-
phos), or 2-di-tert-butylphosphino-2’-(N,N-dimethylamino)bi-
phenyl (tBuXPhos; Table 2, entries 5, 6 and 11, respectively). In
most cases, the Pd-catalyzed carboamination reactions did not
generate significant amounts of undesired side products. How-
ever, in a few instances, side products that result from a com-
peting 6-endocyclization reaction were observed. In addition,
in some cases, reactions of substrates that contained two dif-
ferent groups on the nitrogen atoms (R¼R1) generated side
Table 2. Pd-catalyzed carboamination of N-allylsulfamides.[a]
Entry
R
R1
R2
Product
Yield [%][b]
1
2
3
4
5
6
7
8
9
Bn
Bn
Bn
Bn
Bn
Bn
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
PMB
Me
tBu
PMP
p-Me-C6H4
p-NC-C6H4
p-MeO-C6H4
o-Me-C6H4
1-cyclohexenyl
(E)-1-decenyl[e]
p-Cl-C6H4
p-Me-C6H4
m-F3C-C6H4
p-MeO-C6H4
Ph
2c
2a
2d
2e
2 f
2g
2h
2i
85
90
90
85
87[c]
80[d,e,f]
79
90
86
2j
2k
2l
Table 1. Optimization of carboamination of aryl triflates.[a]
10
11
92
90[g]
12
Me
Bn
2m
84
13
14
tBu
H
Bn
allyl
m-F3C-C6H4
Ph
2n
2o
88[h]
51[i]
[a] Reaction conditions: 1 (1.0 equiv), R2OTf (1.2 equiv), LiOtBu (1.4 equiv),
Pd(OAc)2 (2 mol%), RuPhos (5 mol%), PhCF3 (0.25m), 1008C. [b] Yield of
the isolated product (average of two experiments). [c] The reaction was
conducted with Brettphos as the ligand. [d] The reaction was conducted
with tBu-Davephos as the ligand. [e] The alkenyl triflate was used as a 5:1
mixture of E/Z isomers, and the product was obtained as a 5:1 E/Z mix-
ture. [f] The reaction was conducted using R2OTf (1.4 equiv) and LiOtBu
(1.6 equiv). [g] The reaction was conducted with tBu-X-Phos as the ligand.
[h] The reaction was conducted with 7.5 mol% ligand. [i] The reaction
was conducted with R2OTf (2.4 equiv) and LiOtBu (2.4 equiv). PMB=para-
methoxybenzyl ether, PMP=para-methoxyphenyl.
Entry
Ligand
Base
Solvent
2c/3c
Conversion [%][b]
1
2
3
4
X-Phos
RuPhos
RuPhos
RuPhos
NaOtBu
NaOtBu
LiOtBu
LiOtBu
toluene
toluene
toluene
PhCF3
1:1
9:1
19:1
81
90
100
100[c]
>25:1
[a] Reaction conditions: 1a (1.0 equiv), p-MeC6H4OTf (1.2 equiv), base
(1.4 equiv), [Pd2(dba)3] (2 mol%), ligand (6 mol%), solvent (0.25m), 1008C;
[b] Conversion=percentage of starting material consumed. [c] The reac-
tion was conducted using Pd(OAc)2 (2 mol%) and ligand (5 mol%).
&
&
Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
2
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
products from allylic transposition and cyclization. In a few in-
stances, small amounts of a side product 3 from a Heck reac-
tion were also generated. In cases in which this side product
could not easily be separated by column chromatography, the
side product from the Heck reaction was de-allylated (through
Pd-catalyzed p-allyl formation/trapping) by the addition of 1,3-
bis(diphenylphosphino)propane (DPPP) and morpholine to the
reaction mixture.
The formation of products resulting from the anti addition
to the alkene is in sharp contrast to previously reported alkene
carboamination reactions, which afford syn-addition prod-
ucts.[11] As such, it appears that the mechanism of the Pd-cata-
lyzed reactions of N-allylsulfamides with aryl triflates differs
from other Pd-catalyzed carboamination reactions in which the
PdꢀN bond is generated through syn-aminopalladation of the
alkene (i.e., migratory insertion of the alkene group into the
PdꢀN bond of an intermediate palladium–amido complex).[19]
The mechanism of the reactions between N-allylsulfamides
and aryl triflates most likely proceeds as illustrated in
Scheme 2. Oxidative addition of the aryl triflate to the Pd0
Scheme 2. The anti-aminopalladation mechanism.
center generates the cationic PdII complex 16, which binds to
the alkene moiety of substrate 14 to afford 17. A sequence of
deprotonation and anti-aminopalladation affords 18, which
can undergo CꢀC-bond-forming reductive elimination to pro-
vide the observed product and regenerate the Pd0 catalyst.[20]
Given the relatively low nucleophilicity of the sulfamide group,
it is likely that the aminopalladation step (17!18) is reversi-
ble.[15] The favorability of the anti-aminopalladation pathway
may also be due in part to the low nucleophilicity of the sulfa-
mide group, which may lead to a relatively slow rate of PdꢀN-
bond formation (to generate the palladium–amido complex re-
quired for syn-aminopalladation; Scheme 1).
To further explore the scope of the sulfamide carboamina-
tion reactions, we examined transformations of more highly
substituted substrates. After some exploration, we discovered
that the C-Phos ligand provided higher yields and cleaner reac-
tions than Ruphos in these transformations. Substrate 7, with
an allylic methyl group, was converted into 8 in good yield
with >20:1 d.r. [Eq. (2)], and the presence of a methyl group
on the internal alkene carbon atom was also tolerated in the
conversion of 9 into 10 [Eq. (3)]. Efforts to cyclize substrate 11,
which bears an E-disubstituted alkene, were unsuccessful, with
no reaction observed [Eq. (4)]. However, cyclopentene-derived
substrate 12 was successfully coupled with phenyl triflate to
afford bicyclic product 13 [Eq. (5)]. In contrast to the related
carboamination reactions of other nucleophiles,[13] the carbo-
amination of 12 proceeded with anti addition to the alkene.
Similarly, the deuterated substrate 14 was converted into 15,
the product of anti addition to the alkene with high stereose-
lectivity [Eq. (6)].
The formation of side products from 6-endocyclization most
likely derives from a competing 6-endocyclization reaction of
17; the formation of related side products that derive from 6-
endocyclization pathways has previously been observed in
other Pd-catalyzed alkene difunctionalization reactions that
proceed through anti-heteropalladation reactions.[21] The side
product from an allylic transposition appears to be generated
through the oxidative addition of the N-allylsulfamide to the
Pd0 center to yield an intermediate allylpalladium complex and
a deallylated sulfamide anion, which recombine to form the re-
arranged compound. Control experiments conducted in the
absence of palladium did not lead to rearrangement.
To determine if other experimental variables also influence
the anti- versus syn-aminopalladation pathway, we examined
the coupling of deuterated substrate 14 with phenyl triflate
under a number of different conditions (Table 3), moving from
Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
3
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
lead to a more electrophilic metal center and/or cationic inter-
mediates (e.g., aryl triflate substrates, the relatively polar sol-
Table 3. Influence of reaction conditions.[a]
[22]
vent PhCF3 which may facilitate the generation of cationic
intermediate palladium complexes) favor the anti-aminopalla-
dation pathway. The observed influence of a phosphane-ligand
structure also fits this general pattern as ligands that favor
anti-addition pathways contain electron-donating groups on
the biphenyl unit, which may stabilize cationic intermediates
either due to an increased electron-donating ability of the
phosphane (e.g., Brettphos) or through an electron-donating
interaction between the biphenyl backbone and the metal
center (e.g., RuPhos and C-Phos).
Entry
X
Ligand
M
Solvent
15/19[b]
(15+19)/3b[c]
1
2
3
4
5
6
7
8
9
OTf
OTf
OTf
OTf
OTf
Br
Br
Br
Br
Br
RuPhos
RuPhos
X-Phos
X-Phos
X-Phos
X-Phos
RuPhos
RuPhos
RuPhos
X-Phos
BrettPhos
C-Phos
Li
PhCF3
>20:1
7:1
99:1
94:6[d]
72:28[d]
60:40
93:7
70:30[d]
60:40[d]
60:40
93:7
In contrast, the conditions that lead to a less electrophilic
metal center and/or neutral intermediates (aryl bromide sub-
strates, nonpolar solvents) appear to favor the syn-addition
pathway. Importantly, these experiments also indicate that in-
termolecular[23] Pd-catalyzed carboamination reactions be-
tween aryl halides and alkenes that bear pendant nucleophiles
can proceed through either syn- or anti-aminopalladation path-
ways under the appropriate reaction conditions.[24,25] The use
of conditions that appear to be optimal for the syn-addition
pathway in the coupling of 14 with bromobenzene afforded
19 in 47% yield and 4:1 d.r., whereas the conditions that are
optimal for anti-addition afforded 15 in 90% yield and >20:1
d.r. [Eqs (7) and (8)].
Na
Na
Li
toluene
toluene
dioxane
PhCF3
toluene
toluene
toluene
PhCF3
1:7
1:10
10:1
1:4
1:1
1:1
10:1
1:1
10:1
>20:1
Li
Na
Na
Na
Na
Na
Na
Na
10
11
12
PhCF3
PhCF3
PhCF3
60:40
98:2
99:1
Br
Br
[a] Reaction conditions: 14 (1.0 equiv), Ph-X (1.2 equiv), MOtBu
(1.4 equiv), Pd(OAc)2 (4 mol%), ligand (10 mol%), solvent (0.0625m),
1008C. [b] The ratio of 15/19 as determined by NMR spectroscopic analy-
sis. [c] The ratio of (15+19)/3b as determined by 1H NMR spectroscopic
analysis; in general, no significant amounts of other side products were
generated in these reactions, and the yields estimated by 1H NMR spec-
troscopic analysis were >90% for the combined total of 15+19+3b.
[d] [Pd2(dba)3] (2 mol% complex, 4 mol% Pd) was used in place of
Pd(OAc)2.
To determine whether this interesting influence of the reac-
tion conditions on syn- versus anti-aminopalladation pathways
the “optimal” conditions for triflate coupling to those originally
examined with aryl bromides (Table 3, entry 1 vs. 6, respective-
ly). As shown below, most conditions examined for the reac-
tions of aryl triflates favored the formation of the anti-addition
product 15 (Table 3, entries 1, 2, and 5). However, both the
ligand and the solvent polarity clearly have a significant
impact on the reaction pathway as the use of X-Phos as
a ligand in a nonpolar solvent, such as toluene or dioxane, fa-
vored the generation of the syn-addition product 19 (Table 3,
entries 3 and 4), whereas the anti-addition product predomi-
nated in the PhCF3 solvent (Table 3, entry 5). Reactions in
which 19 was the major stereoisomer afforded comparatively
large amounts of side product 3d from a Heck arylation
reaction.
is limited solely to sulfamides or can be more broadly applica-
ble to other nucleophiles, we examined syn- versus anti-addi-
tion reactions of the related N-allylurea 20 [Eqs (9) and (10)].
Our prior studies illustrated that the coupling of 20 with 4-
bromo-tert-butylbenzene proceeds with syn addition in the
presence of a Pd/bis[(2-diphenylphosphino)phenyl] ether (Dpe-
Phos) catalyst to generate 21.[13d] In contrast, the Pd/RuPhos-
catalyzed coupling of 20 with phenyl triflate proceeds with net
anti addition to afford 22. On the basis of this result, it appears
that it will likely be possible to control the syn- versus anti-ami-
nopalladation pathways in carboamination reactions of other
nucleophilic species. However, further catalyst development
will be necessary to broaden the scope to include internal
alkene substrates, as efforts to apply optimized syn-addition
conditions to cyclopentene-derived substrate 12 afforded
a complex mixture of products (although the anti-addition
product 13 was not formed).
In transformations involving bromobenzene as the electro-
phile, the X-Phos ligand also favored the formation of the syn-
addition product in toluene (Table 3, entry 6). The use of the
RuPhos ligand in toluene afforded a 1:1 mixture of anti/syn ad-
dition products (Table 3, entries 7 and 8). However, a survey of
different, yet related, biaryl phosphanes in the polar solvent
PhCF3 revealed that the anti-addition product was favored for
most ligands, with the exception of X-Phos (1:1 mixture;
Table 3, entry 10), which lacks electron-donating alkoxy or
amino groups on the biphenyl moiety.
Although the Pd-catalyzed carboamination of 14 is mecha-
nistically complex, in general it appears that conditions that
&
&
Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
4
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
centration, unless specified otherwise), followed by aryl trifluoro-
methanesulfonate (1.2 equiv). The resulting mixture was heated to
1008C and ,stirred overnight. The reaction mixture was cooled to
room temperature, quenched with saturated aqueous ammonium
chloride, and extracted with dichloromethane. The combined or-
ganic extracts were dried over anhydrous Na2SO4, filtered, and con-
centrated in vacuo. The crude product was purified by flash chro-
matography on silica gel.
4-[(2,5-Dibenzyl-1,1-dioxido-1,2,5-thiadiazolidin-3-yl)methyl]ben-
zonitrile (2a): The general procedure was employed for the cou-
pling of 1-allyl-1,3-bis-benzylsulfamide (1a; 79 mg, 0.25 mmol) and
4-cyanophenyl trifluoromethanesulfonate (75 mg, 0.30 mmol) using
a catalyst composed of Pd(OAc)2 (1.1 mg, 0.005 mmol) and RuPhos
(5.8 mg, 0.0125 mmol). This procedure afforded 94 mg (90%) of
the product as a white solid. M.p. 107–1088C; 1H NMR (500 MHz,
CDCl3): d=7.46 (d, J=7.9 Hz, 2H), 7.43–7.28 (m, 10H), 6.99 (d, J=
7.9 Hz, 2H), 4.43 (d, J=14.7 Hz, 1H), 4.28 (d, J=13.6 Hz, 1H), 4.23
(d, J=14.7 Hz, 1H), 4.07 (d, J=13.7 Hz, 1H), 3.50 (td, J=3.9, 7.7 Hz,
1H), 3.13 (dd, J=7.2, 9.4 Hz, 1H), 2.91 (dd, J=5.7, 13.6 Hz, 1H),
2.75 (dd, J=5.7, 9.5 Hz, 1H), 2.70 ppm (dd, J=8.4, 13.6 Hz, 1H);
13C NMR (126 MHz, CDCl3): d=141.7, 135.1, 134.7, 132.4, 130.0,
128.9, 128.8, 128.6, 128.3, 118.6, 110.9, 57.0, 51.7, 50.4, 49.3,
39.7 ppm; IR (film): n˜ =2228, 1321, 1158 cmꢀ1; MS (ESI): m/z calcd
for C24H23N3O2S: 418.1584 [M+H]+; found: 418.1581.
Conclusion
We have developed a new approach to the construction of
cyclic sulfamides through the Pd-catalyzed alkene carboamina-
tion of N-allylsulfamide derivatives. The mechanism of these re-
actions is dependent on the reaction conditions and can selec-
tively proceed through either syn- or anti-aminopalladation
pathways. These experiments suggest the use of different cata-
lysts or reaction conditions to control the mechanistic path-
ways will extend beyond sulfamide substrates, which could
have broadly significant implications in a number of different
Pd-catalyzed alkene difunctionalization reactions. Further stud-
ies on the development of other alkene carboheterofunctional-
ization reactions that proceed through anti-heteropalladation
processes are currently underway.
2,5-Dibenzyl-3-(4-methylbenzyl)-1,2,5-thiadiazolidine-1,1-dioxide
(2c): The general procedure was employed for the coupling of 1a
(79 mg, 0.25 mmol) and para-tolyl trifluoromethanesulfonate
(54 mL, 0.30 mmol) using a catalyst composed of Pd(OAc)2 (1.1 mg,
0.005 mmol) and RuPhos (5.8 mg, 0.0125 mmol). This procedure af-
forded 84 mg (83%) of the product as a yellow solid. M.p. 96–
998C; 1H NMR (500 MHz, CDCl3): d=7.49–7.44 (m, 2H), 7.44–7.30
(m, 8H), 7.03 (d, J=7.8 Hz, 2H), 6.81 (d, J=7.9 Hz, 2H), 4.46 (d, J=
14.9 Hz, 1H), 4.33 (dd, J=5.8, 14.3 Hz, 2H), 4.06 (d, J=13.9 Hz, 1H),
3.49 (dtd, J=4.9, 6.6, 9.5 Hz, 1H), 3.08 (dd, J=6.9, 9.4 Hz, 1H), 2.89
(dd, J=4.9, 13.5 Hz, 1H), 2.84 (dd, J=6.3, 9.5 Hz, 1H), 2.61 (dd, J=
9.6, 13.5 Hz, 1H), 2.29 ppm (s, 3H); 13C NMR (126 MHz, CDCl3): d=
136.6, 135.5, 135.0, 132.9, 129.4, 129.0, 128.7, 128.7, 128.6, 128.1,
Experimental Section
General
All the reactions were carried out in a nitrogen atmosphere in
flame-dried glassware, unless otherwise noted. Palladium precata-
lysts and phosphane ligands were purchased from commercial
sources and used without purification. All other reagents were ob-
tained from commercial sources and were used as obtained, unless
otherwise noted. Bulk quantities of lithium tert-butoxide and
sodium tert-butoxide were stored in a glove box and removed in
small amounts (ca. 1–2 g) that were consumed within a few days.
Toluene, THF, diethyl ether, and dichloromethane were purified by
using a GlassContour solvent purification system. Anhydrous ben-
zotrifluoride was obtained from commercial sources and was used
without further purification. Yields refer to the yield of the isolated
products of compounds estimated to be ꢁ95% pure as deter-
57.6, 50.9, 50.7, 49.6, 39.0, 21.0 ppm; IR (film): n˜ =1286, 1160 cmꢀ1
;
MS (ESI): m/z calcd for C24H26N2O2S: 407.1788 [M+H]+; found:
407.1791.
2,5-Dibenzyl-3-(4-methoxybenzyl)-1,2,5-thiadiazolidine-1,1-diox-
ide (2d): The general procedure was employed for the coupling of
1a (79 mg, 0.25 mmol) and 4-methoxyphenyl trifluoromethanesul-
fonate (54 mL, 0.30 mmol) using a catalyst composed of Pd(OAc)2
(1.1 mg, 0.005 mmol) and RuPhos (5.8 mg, 0.0125 mmol). This pro-
cedure afforded 93 mg (88%) of the product as a pale-yellow oil.
1H NMR (500 MHz, CDCl3): d=7.45 (dd, J=1.7, 7.8 Hz, 2H), 7.44–
7.30 (m, 8H), 6.83 (d, J=8.6 Hz, 2H), 6.75 (d, J=8.5 Hz, 2H), 4.44
(d, J=14.8 Hz, 1H), 4.32 (d, J=14.5 Hz, 2H), 4.05 (d, J=13.8 Hz,
1H), 3.76 (s, 3H), 3.46 (ddd, J=5.0, 6.9, 9.7 Hz, 1H), 3.07 (ddd, J=
1.4, 7.0, 8.4 Hz, 1H), 2.86 (dd, J=5.0, 13.6 Hz, 1H), 2.82 (dd, J=6.4,
9.4 Hz, 1H), 2.58 ppm (dd, J=9.4, 13.6 Hz, 1H); 13C NMR (126 MHz,
CDCl3): d=188.0, 158.6, 135.5, 135.0, 130.1, 129.0, 128.7, 128.7,
128.6, 128.1, 128.0, 114.1, 57.6, 55.2, 50.9, 50.7, 49.6, 38.6 ppm; IR
(film): n˜ =1246, 1160 cmꢀ1; MS (ESI): m/z calcd for C24H26N2O3S:
423.1737 [M+H]+; found: 423.1739.
1
mined by H NMR spectroscopic analysis, unless otherwise noted.
The yields reported in the experimental section describe the result
of a single experiment, whereas the yield of the isolated products
reported in Tables 1–3 and Equations (1)–(10) are averages of the
yields for two or more experiments. Thus, the yields reported in
the experimental section may differ from those shown in Tables 1–
3 and Equations (1)–(10).
General procedure for Pd-catalyzed carboamination reac-
tions of N-allylsulfamide and N-allylurea derivatives with
aryl trifluoromethanesulfonates
2,5-Dibenzyl-3-(2-methylbenzyl)-1,2,5-thiadiazolidine-1,1-dioxide
(2e): The general procedure was employed for the coupling of 1a
(79 mg, 0.25 mmol) and ortho-tolyl trifluoromethanesulfonate
(54 mL, 0.30 mmol) using a catalyst composed of Pd(OAc)2 (1.1 mg,
0.005 mmol) and RuPhos (5.8 mg, 0.0125 mmol). This procedure af-
forded 86 mg (85%) of the product as a white solid. M.p. 120–
1228C; 1H NMR (500 MHz, CDCl3): d=7.46–7.30 (m, 10H), 7.07
A test tube was charged with Pd(OAc)2 (2 mol%), phosphane
ligand (5 mol%), sulfamide substrate (1.0 equiv), and LiOtBu
(1.4 equiv). The test tube was purged with N2 and benzotrifluoride
was added (the reactions were conducted at 0.25m substrate con-
Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
(ddd, J=7.2, 14.7, 25.7 Hz, 3H), 6.86 (dd, J=1.4, 7.5 Hz, 1H), 4.37
(s, 2H), 4.30 (d, J=13.7 Hz, 1H), 4.13 (d, J=13.7 Hz, 1H), 3.51 (ddt,
J=5.5, 6.8, 9.4 Hz, 1H), 3.09 (dd, J=6.9, 9.4 Hz, 1H), 2.98 (dd, J=
5.2, 13.6 Hz, 1H), 2.87 (dd, J=5.8, 9.4 Hz, 1H), 2.69 (dd, J=9.6,
13.6 Hz, 1H), 1.99 ppm (s, 3H); 13C NMR (126 MHz, CDCl3): d=
136.3, 135.4, 135.0, 134.4, 130.6, 130.1, 128.9, 128.7, 128.7, 128.7,
128.2, 128.1, 127.1, 126.1, 55.7, 50.7, 50.6, 49.6, 36.8, 19.1 ppm; IR
(film): n˜ =1283, 1164 cmꢀ1; MS (ESI): m/z calcd for C24H26N2O2S:
407.1788 [M+H]+; found: 407.1790.
5-Benzyl-2-(4-methoxybenzyl)-3-(4-methylbenzyl)-1,2,5-thiadia-
zolidine-1,1-dioxide (2i): The general procedure was employed for
the coupling of 1c (87 mg, 0.25 mmol) and para-tolyl trifluorome-
thanesulfonate (54 mL, 0.30 mmol) using a catalyst composed of
Pd(OAc)2 (1.1 mg, 0.005 mmol) and RuPhos (5.8 mg, 0.0125 mmol).
This procedure afforded 95 mg (87%) of the product as a pale-
yellow solid. M.p. 109–1138C; 1H NMR (400 MHz, CDCl3): d=7.42–
7.25 (m, 7H), 6.99 (d, J=7.8 Hz, 2H), 6.92–6.86 (m, 2H), 6.79 (d, J=
7.9 Hz, 2H), 4.36–4.21 (m, 3H), 4.01 (d, J=13.8 Hz, 1H), 3.81 (s, 3H),
3.49–3.37 (m, 1H), 3.02 (dd, J=7.0, 9.4 Hz, 1H), 2.86 (dd, J=5.0,
13.5 Hz, 1H), 2.78 (dd, J=6.2, 9.4 Hz, 1H), 2.56 (dd, J=9.5, 13.5 Hz,
1H), 2.26 ppm (s, 3H); 13C NMR (126 MHz, CDCl3): d=159.5, 136.5,
135.0, 133.0, 130.4, 129.4, 129.0, 128.7, 128.6, 128.1, 127.3, 114.0,
57.1, 55.3, 50.6, 50.3, 49.5, 39.0, 21.0 ppm; IR (film): n˜ =1281,
1158 cmꢀ1; MS (ESI): m/z calcd for C25H28N2O3S: 437.1893 [M+H]+;
found: 437.1885.
2,5-Dibenzyl-3-(cyclohex-1-en-1-ylmethyl)-1,2,5-thiadiazolidine-
1,1-dioxide (2 f): The general procedure was employed for the
coupling of 1a (79 mg, 0.25 mmol) and 1-cyclohexenyl trifluorome-
thanesulfonate (52 mL, 0.30 mmol) using a catalyst composed of
Pd(OAc)2 (1.1 mg, 0.005 mmol) and BrettPhos (6.7 mg,
0.0125 mmol). This procedure afforded 89 mg (90%) of the product
1
as a pale-yellow solid. M.p. 66–688C; H NMR (500 MHz, CDCl3): d=
5-Benzyl-2-methyl-3-(3-(trifluoromethyl)benzyl)-1,2,5-thiadiazoli-
dine-1,1-dioxide (2j): The general procedure was employed for
the coupling of 1d (60 mg, 0.25 mmol) and 3-trifluoromethylphen-
yl trifluoromethanesulfonate (60 mL, 0.30 mmol) using a catalyst
composed of Pd(OAc)2 (1.1 mg, 0.005 mmol) and RuPhos (5.8 mg,
0.0125 mmol). This procedure afforded 78 mg (81%) of the product
as a pale-yellow oil. 1H NMR (500 MHz, CDCl3): d=7.52 (d, J=
7.8 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.40 (d, J=1.6 Hz, 1H), 7.38–
7.29 (m, 6H), 4.31 (d, J=13.9 Hz, 1H), 3.99 (d, J=13.9 Hz, 1H), 3.44
(m, 1H), 3.16 (dd, J=6.9, 9.4 Hz, 1H), 3.12 (dd, J=5.7, 13.6 Hz, 1H),
2.85–2.78 (m, 2H), 2.75 ppm (s, 3H); 13C NMR (126 MHz, CDCl3): d=
136.9, 134.8, 132.7, 131.2 (q, J=33.8 Hz), 129.3, 128.7, 128.6, 128.2,
125.8, 124.1, 123.9 (q, J=272.4 Hz), 59.6, 50.8, 49.5, 38.8, 33.6 ppm;
IR (film): n˜ =1242, 1127 cmꢀ1; MS (ESI): m/z calcd for C18H19F3N2O2S:
385.1192 [M+H]+; found: 385.1193.
7.45 (d, J=7.0 Hz, 2H), 7.42–7.29 (m, 8H), 5.33 (s, 1H), 4.49 (d, J=
15.0 Hz, 1H), 4.36 (d, J=13.8 Hz, 1H), 4.26 (d, J=15.0 Hz, 1H), 4.05
(d, J=13.8 Hz, 1H), 3.47–3.36 (m, 1H), 3.21 (dd, J=7.0, 9.4 Hz, 1H),
2.81 (dd, J=6.6, 9.4 Hz, 1H), 2.23 (dd, J=2.2, 14.0 Hz, 1H), 2.04
(dd, J=9.7, 13.6 Hz, 1H), 1.94–1.80 (m, 2H), 1.73–1.59 (m, 1H),
1.59–1.33 ppm (m, 5H); 13C NMR (126 MHz, CDCl3): d=135.8, 135.7,
135.1, 132.2, 128.7, 128.7, 128.6, 128.0, 127.9, 125.5, 54.8, 50.8, 50.6,
49.9, 41.9, 28.3, 25.1, 22.6, 22.0 ppm; IR (film): n˜ =1286, 1154 cmꢀ1
;
MS (ESI): m/z calcd for C23H28N2O2S: 397.1944 [M+H]+; found:
397.1949.
(E)-2,5-Dibenzyl-3-(undec-2-en-1-yl)-1,2,5-thiadiazolidine-1,1-di-
oxide (2g): The general procedure was employed for the coupling
of 1a (79 mg, 0.25 mmol) and (E)-dec-1-en-1-yl trifluoromethane-
sulfonate (101 mL, 0.35 mmol, 5:1 mixture of E/Z isomers) using
LiOtBu (32 mg, 0.40 mmol) and a catalyst composed of Pd(OAc)2
(1.1 mg, 0.005 mmol) and tBuDavePhos (4.3 mg, 0.0125 mmol). This
procedure afforded 90 mg (79%) of the product as a yellow oil.
The compound was judged to be a 5:1 mixture of E/Z isomers by
1H NMR spectroscopic analysis. Data are given for the major
E isomer: 1H NMR (500 MHz, CDCl3): d=7.51–7.42 (m, 2H), 7.42–
7.29 (m, 8H), 5.44 (dt, J=7.4, 11.0 Hz, 1H), 5.16–5.06 (m, 1H), 4.51
(d, J=15.1 Hz, 1H), 4.36 (d, J=13.7 Hz, 1H), 4.26 (d, J=14.8 Hz,
1H), 4.02 (d, J=13.7 Hz, 1H), 3.33 (ddd, J=5.6, 9.2, 11.1 Hz, 1H),
3.22 (dd, J=7.0, 9.3 Hz, 1H), 2.79 (dd, J=7.1, 9.3 Hz, 1H), 2.27
(dddd, J=5.5, 7.5, 13.5, 15.9 Hz, 1H), 2.16 (dt, J=8.4, 15.2 Hz, 1H),
1.81 (tt, J=6.9, 12.9 Hz, 2H), 1.35–1.18 (m, 12H), 0.91 ppm (q, J=
6.5 Hz, 3H); 13C NMR (126 MHz, CDCl3): d=135.7, 134.9, 134.4,
128.7, 128.7, 128.7, 128.6, 128.1, 128.0, 122.1, 56.3, 50.9, 50.6, 49.6,
31.9, 30.5, 29.5, 29.4, 29.3, 29.3, 27.4, 22.7 ppm, 14.1; IR (film): n˜ =
1304, 1164 cmꢀ1; MS (ESI): m/z calcd for C27H38N2O2S: 455.2727
[M+H]+; found: 455.2735.
5-Benzyl-2-(tert-butyl)-3-(4-methoxybenzyl)-1,2,5-thiadiazoli-
dine-1,1-dioxide (2k): The general procedure was employed for
the coupling of 1e (71 mg, 0.25 mmol) and 4-methoxyphenyl tri-
fluoromethanesulfonate (54 mL, 0.30 mmol) using a catalyst com-
posed of Pd(OAc)2 (1.1 mg, 0.005 mmol) and RuPhos (5.8 mg,
0.0125 mmol). This procedure afforded 90 mg (93%) of the product
as a white solid. M.p. 104–1068C; 1H NMR (500 MHz, CDCl3): d=
7.47–7.32 (m, 5H), 6.79 (d, J=8.6 Hz, 2H), 6.71 (d, J=8.6 Hz, 2H),
4.46 (d, J=13.5 Hz, 1H), 3.77 (d, J=13.6 Hz, 1H), 3.75 (s, 3H), 3.54
(dddd, J=1.3, 4.1, 5.8, 10.4 Hz, 1H), 2.98–2.78 (m, 4H), 1.53 ppm (s,
9H); 13C NMR (126 MHz, CDCl3): d=158.4, 135.4, 130.2, 129.3,
128.8, 128.7, 128.1, 114.0, 57.8, 55.4, 55.2, 49.0, 47.1, 40.8,
˜
28.2 ppm; IR (film): n=1279, 1142 cmꢀ1; MS (ESI): m/z calcd for
C21H28N2O3S: 389.1893 [M+H]+; found: 389.1893.
3,5-Dibenzyl-2-(4-methoxyphenyl)-1,2,5-thiadiazolidine-1,1-diox-
ide (2l): The general procedure was employed for the coupling of
1-allyl-1-benzyl-3-(4-methoxyphenyl)sulfamide
0.25 mmol) and phenyl trifluoromethanesulfonate (49 mL,
0.30 mmol) using catalyst composed of Pd(OAc)2 (1.1 mg,
(1 f;
83 mg,
2-Benzyl-3-(4-chlorobenzyl)-5-methyl-1,2,5-thiadiazolidine-1,1-
dioxide (2h): The general procedure was employed for the cou-
pling of 1b (60 mg, 0.25 mmol) and 4-chlorophenyl trifluorometha-
nesulfonate (52 mL, 0.30 mmol) using a catalyst composed of
Pd(OAc)2 (1.1 mg, 0.005 mmol) and RuPhos (5.8 mg, 0.0125 mmol).
This procedure afforded 68 mg (78%) of the product as a white
a
0.005 mmol) and tBuXPhos (5.3 mg, 0.0125 mmol). This procedure
afforded 91 mg (89%) of the product as a yellow solid. M.p. 95–
978C; 1H NMR (500 MHz, CDCl3): d=7.45–7.30 (m, 7H), 7.29–7.19
(m, 3H), 7.07–6.97 (m, 4H), 4.41 (d, J=14.0 Hz, 1H), 4.21–4.12 (m,
1H), 4.06 (d, J=14.0 Hz, 1H), 3.85 (s, 3H), 3.24 (dd, J=6.5, 9.2 Hz,
1H), 3.03 (dd, J=7.6, 9.4 Hz, 1H), 3.00 (dd, J=4.2, 13.8 Hz, 1H),
2.71 ppm (dd, J=9.5, 13.7 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=
159.2, 135.5, 134.9, 129.2, 128.8, 128.7, 128.7, 128.6, 128.2, 128.1,
127.0, 115.0, 58.6, 55.5, 51.2, 49.7, 38.7 ppm; IR (film): n˜ =1289,
1157 cmꢀ1; MS (ESI): m/z calcd for C23H24N2O3S: 409.1580 [M+H]+;
found: 409.1577.
1
solid. M.p. 133–1358C; H NMR (500 MHz, CDCl3): d=7.41–7.36 (m,
4H), 7.36–7.31 (m, 1H), 7.23 (d, J=8.3 Hz, 2H), 6.92 (d, J=8.3 Hz,
2H), 4.43 (d, J=14.9 Hz, 1H), 4.25 (d, J=14.9 Hz, 1H), 3.51 (dtd, J=
5.2, 6.9, 9.3 Hz, 1H), 3.17 (dd, J=7.0, 9.3 Hz, 1H), 2.89 (dd, J=5.2,
13.6 Hz, 1H), 2.86 (dd, J=6.8, 9.3 Hz, 1H), 2.73 (s, 3H), 2.61 ppm
(dd, J=9.3, 13.6 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=135.3,
134.5, 132.9, 130.4, 128.9, 128.8, 128.7, 128.1, 57.1, 52.5, 51.2, 39.0,
33.2 ppm; IR (film): n˜ =1297, 1149 cmꢀ1; MS (ESI): m/z calcd for
C17H19ClN2O2S: 351.0929 [M+H]+; found: 351.0926.
3-(Benzo[d][1,3]dioxol-5-ylmethyl)-2-benzyl-5-methyl-1,2,5-thia-
diazolidine-1,1-dioxide (2m): The general procedure was em-
&
&
Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
ployed for the coupling of 1b (60 mg, 0.25 mmol) and 3,4-methyle-
nedioxyphenyl trifluoromethanesulfonate (52 mL, 0.30 mmol) using
a catalyst composed of Pd(OAc)2 (1.1 mg, 0.005 mmol) and RuPhos
(5.8 mg, 0.0125 mmol). This procedure afforded 76 mg (84%) of
(ꢂ)-(3R,4R)-4-[(2,5-Dibenzyl-4-methyl-1,1-dioxido-1,2,5-thiadia-
zolidin-3-yl)methyl]benzonitrile (8): The general procedure was
employed for the coupling of 7 (83 mg, 0.25 mmol) and 4-cyano-
phenyl trifluoromethanesulfonate (75 mg, 0.30 mmol) using a cata-
lyst composed of Pd(OAc)2 (1.1 mg, 0.005 mmol) and X-Phos
(6.0 mg, 0.0125 mmol). This procedure afforded 86 mg (80%) of
the product as a white solid. M.p. 102–1088C; This compound was
obtained as a >20:1 mixture of diastereomers as judged by
1H NMR spectroscopic analysis. 1H NMR (500 MHz, CDCl3): d=7.46
(d, J=8.2 Hz, 2H), 7.43–7.31 (m, 8H), 7.30–7.24 (m, 2H), 6.96 (d, J=
8.2 Hz, 2H), 4.36–4.16 (m, 4H), 3.12 (td, J=3.6, 7.1 Hz, 1H), 3.03
(qd, J=3.6, 6.3 Hz, 1H), 2.91 (dd, J=6.5, 13.6 Hz, 1H), 2.73 (dd, J=
7.4, 13.6 Hz, 1H), 0.95 ppm (d, J=6.3 Hz, 3H); 13C NMR (126 MHz,
CDCl3): d=142.2, 135.5, 134.9, 132.3, 130.1, 129.1, 128.8, 128.7,
128.7, 128.2, 128.1, 118.6, 110.8, 64.0, 56.7, 51.9, 48.6, 39.1,
18.6 ppm; IR (film): n˜ =1294, 1132 cmꢀ1; MS (ESI): m/z calcd for
C25H25N3O2S: 432.1740 [M+H]+; found: 432.1740.
1
the product as a yellow oil. H NMR (500 MHz, CDCl3): d=7.45–7.29
(m, 5H), 6.69 (d, J=7.8 Hz, 1H), 6.49–6.42 (m, 2H), 5.91 (m, 2H),
4.43 (d, J=15.0 Hz, 1H), 4.25 (d, J=14.9 Hz, 1H), 3.47 (dtd, J=4.9,
6.9, 9.7 Hz, 1H), 3.17 (dd, J=6.9, 9.4 Hz, 1H), 2.88 (dd, J=6.9,
9.4 Hz, 1H), 2.83 (dd, J=5.0, 13.5 Hz, 1H), 2.72 (s, 3H), 2.53 ppm
(dd, J=9.7, 13.5 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=147.8,
146.6, 135.4, 129.6, 128.8, 128.7, 128.1, 122.1, 109.2, 108.4, 101.0,
57.4, 52.5, 51.0, 39.2, 33.2 ppm; IR (film): n˜ =1246, 1150 cmꢀ1; MS
(ESI): m/z calcd for C18H20N2O4S: 361.1217 [M+H]+; found:
361.1219.
2-Benzyl-5-(tert-butyl)-3-[3-(trifluoromethyl)benzyl]-1,2,5-thiadia-
zolidine-1,1-dioxide (2n): The general procedure was employed
for the coupling of 1g (71 mg, 0.25 mmol) and 3-trifluoromethyl-
phenyl trifluoromethanesulfonate (60 mL, 0.30 mmol) using a cata-
lyst composed of Pd(OAc)2 (1.1 mg, 0.005 mmol) and RuPhos
(5.8 mg, 0.0125 mmol). This procedure afforded 91 mg (85%) of
2,3,5-Tribenzyl-3-methyl-1,2,5-thiadiazolidine-1,1-dioxide
(10):
The general procedure was employed for the coupling of 9
(83 mg, 0.25 mmol) and phenyl trifluoromethanesulfonate (49 mL,
0.30 mmol) using a catalyst composed of Pd(OAc)2 (1.1 mg,
1
the product as a yellow solid. M.p. 104–1068C; H NMR (500 MHz,
CDCl3): d=7.49 (d, J=7.8 Hz, 1H), 7.42–7.29 (m, 6H), 7.26–7.19 (m,
2H), 4.38 (d, J=14.8 Hz, 1H), 4.19 (d, J=14.8 Hz, 1H), 3.53–3.43 (m,
1H), 3.25 (dd, J=6.6, 8.9 Hz, 1H), 3.10–2.98 (m, 2H), 2.74 (dd, J=
9.1, 13.6 Hz, 1H), 1.42 ppm (s, 9H); 13C NMR (126 MHz, CDCl3): d=
137.6, 135.5, 132.6, 131.0 (q, J=32.1 Hz), 129.2, 128.8, 128.6, 128.0,
125.7 (q, J=3.7 Hz), 123.9 (q, J=272.3 Hz), 123.8 (q, J=3.8 Hz),
0.005 mmol) and C-Phos (5.5 mg, 0.0125 mmol). This procedure af-
forded 97 mg (95%) of the product as an off-white solid. M.p. 129–
1318C; H NMR (500 MHz, CDCl3): d=7.54 (d, J=7.2 Hz, 2H), 7.45–
1
7.35 (m, 7H), 7.32 (t, J=7.4 Hz, 1H), 7.22–7.10 (m, 2H), 6.88 (d, J=
6.6 Hz, 1H), 4.42 (s, 2H), 4.38 (d, J=13.6 Hz, 1H), 4.02 (d, J=
13.6 Hz, 1H), 3.17 (d, J=9.3 Hz, 1H), 3.01 (d, J=13.1 Hz, 1H), 2.78
(d, J=13.1 Hz, 1H), 2.70 (d, J=9.2 Hz, 1H), 1.21 ppm (s, 3H);
13C NMR (126 MHz, CDCl3): d=137.0, 135.7, 135.0, 130.3, 129.0,
128.7, 128.6, 128.4, 128.3, 128.2, 127.8, 126.9, 61.8, 54.4, 50.2, 44.9,
43.0, 22.3 ppm; IR (film): n˜ =1299, 1167 cmꢀ1; MS (ESI): m/z calcd
for C24H26N2O2S: 407.1788 [M+H]+; found: 407.1789.
56.2, 56.1, 50.6, 45.6, 38.5, 27.4 ppm; IR (film): n˜ =1302, 1120 cmꢀ1
;
MS (ESI): m/z calcd for C21H25F3N2O2S: 427.1662 [M+H]+; found:
427.1663.
2-Allyl-3-benzyl-1,2,5-thiadiazolidine-1,1-dioxide (2o): The gener-
al procedure was employed for the coupling of 1h (44 mg,
0.25 mmol) and phenyl trifluoromethanesulfonate (98 mL,
0.60 mmol), using LiOtBu (48 mg, 0.60 mmol) and a catalyst com-
posed of Pd(OAc)2 (1.1 mg, 0.005 mmol) and RuPhos (5.8 mg,
0.0125 mmol). This procedure afforded 30 mg (48%) of the product
as a pale-yellow oil. 1H NMR (500 MHz, CDCl3): d=7.37–7.24 (m,
3H), 7.24–7.15 (m, 2H), 5.94 (dddd, J=5.6, 7.7, 10.1, 17.5 Hz, 1H),
5.36–5.25 (m, 2H), 4.44 (t, J=7.5 Hz, 1H), 3.78 (ddt, J=1.5, 5.6,
15.1 Hz, 1H), 3.72 (ddt, J=5.1, 6.8, 8.4 Hz, 1H), 3.67 (ddt, J=1.2,
7.7, 15.1 Hz, 1H), 3.39 (dt, J=6.9, 11.7 Hz, 1H), 3.22 (ddd, J=4.7,
6.7, 11.6 Hz, 1H), 3.07 (dd, J=5.4, 13.5 Hz, 1H), 2.77 ppm (dd, J=
8.3, 13.5 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=136.0, 132.5, 129.3,
128.8, 127.2, 120.0, 61.1, 48.7, 44.9, 39.2 ppm; IR (film): n˜ =3242,
1296, 1159 cmꢀ1; MS (ESI): m/z calcd for C12H16N2O2S: 253.1005
[M+H]+; found: 253.1005.
(ꢂ)-(3aR,4R,6aS)-1,3-Dibenzyl-4-phenylhexahydro-1H-
cyclopenta[c][1,2,5]thiadiazole-2,2-dioxide (13): The general pro-
cedure was employed for the coupling of 1,3-bis-benzyl-1-cyclo-
pent-2-enylsulfamide (12; 86 mg, 0.25 mmol) and phenyl trifluoro-
methanesulfonate (81 mL, 0.50 mmol) using LiOtBu (44 mg,
0.55 mmol) and
a catalyst composed of Pd(OAc)2 (1.1 mg,
0.005 mmol) and C-Phos (8.2 mg, 0.01875 mmol). This procedure
afforded 70 mg (67%) of the product as an off-white solid.
M.p. 118–1208C; This compound was obtained as a >20:1 mixture
of diastereomers as judged by 1H NMR spectroscopic analysis.
1H NMR (500 MHz, C6D6): d=7.28–7.21 (m, 2H), 7.16–7.02 (m, 4H),
6.99–6.89 (m, 7H), 6.65–6.57 (m, 2H), 4.24 (d, J=14.2, 1H), 4.15 (d,
J=14.8, 1H), 4.08 (d, J=14.2, 1H), 4.04 (d, J=14.8, 1H), 3.38 (dd,
J=6.9, 9.2, 1H), 3.27 (dt, J=6.9, 9.2, 1H), 3.11 (dt, J=6.7, 10.8, 1H),
1.74–1.51 (m, 2H), 1.32 (dtd, J=2.8, 6.7, 13.2, 1H), 0.93 ppm (dtd,
J=6.4, 10.7, 12.3, 1H); 13C NMR (126 MHz, CDCl3): d=142.0, 135.2,
134.9, 129.0, 128.8, 128.7, 128.7, 128.3, 128.1, 127.7, 127.2, 126.7,
66.1, 60.2, 51.0, 49.8, 49.6, 33.0, 30.9 ppm; IR (film): n˜ =1310,
1156 cmꢀ1; MS (ESI): m/z calcd for C25H26N2O2S: 419.1788 [M+H]+;
found: 419.1784.
2-Benzyl-6-(4-methoxyphenyl)-4-phenyl-1,2,6-thiadiazinane-1,1-
dioxide (S2): The general procedure was employed for the cou-
pling of 1 f (83 mg, 0.25 mmol) and phenyl trifluoromethanesulfo-
nate (49 mL, 0.30 mmol) using a catalyst composed of Pd(OAc)2
(1.1 mg, 0.005 mmol) and RuPhos (5.8 mg, 0.0125 mmol). The
major product generated in this reaction was 2l (described above),
and a small amount of side-product S2 was also formed. Com-
pound S2 was isolated by careful chromatographic purification
(ꢂ)-(1’S,3S)-2,5-Dibenzyl-1’-deuterio-3-(4-methylbenzyl)-1,2,5-
thiadiazolidine-1,1-dioxide (15): The general procedure was em-
ployed for the coupling of 14 (79 mg, 0.25 mmol) and phenyl tri-
fluoromethanesulfonate (49 mL, 0.30 mmol) using a catalyst com-
posed of Pd(OAc)2 (1.1 mg, 0.005 mmol) and RuPhos (5.8 mg,
0.0125 mmol). This procedure afforded 75 mg (76%) of the product
as a yellow solid. M.p. 74–768C. This compound was obtained as
1
(7 mg, 7%) as a pale-yellow oil. H NMR (500 MHz, CDCl3): d=7.47–
7.42 (m, 4H), 7.42–7.36 (m, 2H), 7.33 (tq, J=1.5, 8.3 Hz, 3H), 7.30–
7.25 (m, 1H), 7.25–7.21 (m, 2H), 6.96–6.92 (m, 2H), 4.69 (d, J=
14.0 Hz, 1H), 4.48 (d, J=14.0 Hz, 1H), 4.24 (t, J=11.8 Hz, 1H), 4.04–
3.94 (m, 1H), 3.83 (s, 3H), 3.61–3.47 (m, 2H), 3.29 ppm (ddd, J=
2.3, 4.1, 14.1 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=158.9, 137.8,
135.5, 134.4, 128.9, 128.8, 128.1, 128.0, 127.7, 127.5, 114.5, 59.1,
55.5, 53.2, 52.7, 36.9 ppm; IR (film): n˜ =1344, 1157 cmꢀ1; MS (ESI):
m/z calcd for C23H24N2O3S: 409.1580 [M+H]+; found: 409.1581.
1
a >20:1 mixture of diastereomers as judged by H NMR spectro-
scopic analysis. Data are given for the major isomer: 1H NMR
(500 MHz, CDCl3): d=7.48–7.43 (m, 2H), 7.43–7.29 (m, 8H), 7.26–
7.15 (m, 3H), 6.92 (dd, J=1.9, 7.6 Hz, 2H), 4.44 (d, J=14.9 Hz, 1H),
Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
4.34 (d, J=14.8 Hz, 1H), 4.32 (d, J=13.8 Hz, 1H), 4.07 (d, J=
13.8 Hz, 1H), 3.51 (td, J=5.0, 6.6 Hz, 1H), 3.08 (dd, J=7.0, 9.4 Hz,
1H), 2.90 (d, J=5.0 Hz, 1H), 2.84 ppm (dd, J=6.2, 9.5 Hz, 1H);
13C NMR (126 MHz, CDCl3): d=136.0, 135.4, 134.9, 129.0, 128.9,
128.7, 128.6, 128.1, 128.1, 127.0, 57.3, 50.9, 50.6, 49.5, 39.1 ppm (t,
J=19.4 Hz); IR (film): n˜ =1324, 1154 cmꢀ1; MS (ESI): m/z calcd for
C23H23DN2O2S: 394.1694 [M+H]+; found: 394.1698.
Acknowledgements
The authors acknowledge the NIH-NIGMS (GM 098314) for fi-
nancial support of this work.
Keywords: addition reactions
palladium · stereoselectivity
· alkenes · heterocycles ·
(ꢂ)-(1’S,3S)-2,5-Dibenzyl-1’-deuterio-3-(4-methylbenzyl)-1,2,5-
thiadiazolidine-1,1-dioxide (15): The general procedure was em-
ployed for the coupling of 14 (79 mg, 0.25 mmol) and bromoben-
zene (32 mL, 0.30 mmol) using NaOtBu (34 mg, 0.35 mmol; in place
[1] A. B. Reitz, G. R. Smith, M. H. Parker, Expert Opin. Ther. Pat. 2009, 19,
1449–1453.
[2] A. Spaltenstein, M. R. Almond, W. J. Bock, D. G. Cleary, E. S. Furfine, R. J.
Hazen, W. M. Kazmierski, F. G. Salituro, R. D. Tung, L. L. Wright, Bioorg.
Med. Chem. Lett. 2000, 10, 1159–1162.
[3] J. Zhong, X. Gan, K. R. Alliston, W. C. Groutas, Bioorg. Med. Chem. 2004,
12, 589–593.
[4] S. H. Rosenberg, J. F. Dellaria, D. J. Kempf, C. W. Hutchins, K. W. Woods,
R. G. Maki, E. de Lara, K. P. Spina, H. H. Stein, J. Cohen, W. R. Baker, J. J.
Plattner, H. D. Kleinert, T. J. Perun, J. Med. Chem. 1990, 33, 1582–1590.
[5] D. Dou, S. R. Mandadapu, K. R. Alliston, Y. Kim, K. O. Chang, W. C. Grou-
tas, Eur. J. Med. Chem. 2012, 47, 59–64.
[6] S. V. Pansare, A. N. Rai, S. N. Kate, Synlett 1998, 623–624.
[7] a) R. I. McDonald, S. S. Stahl, Angew. Chem. 2010, 122, 5661–5664;
Angew. Chem. Int. Ed. 2010, 49, 5529–5532; b) K. MuÇiz, J. Streuff, C. H.
Hçvelmann, A. NfflÇez, Angew. Chem. 2007, 119, 7255–7258; Angew.
Chem. Int. Ed. 2007, 46, 7125–7127; c) K. MuÇiz, C. H. Hçvelmann, E.
Campos-Gómez, J. Barluenga, J. M. Gonzµlez, J. Streuff, M. Nieger, Chem.
Asian J. 2008, 3, 776–788; d) H. Hamaguchi, S. Kosaka, H. Ohno, N.
Fujii, T. Tanaka, Chem. Eur. J. 2007, 13, 1692–1708; e) B. Zhao, W. Yuan,
H. Du, Y. Shi, Org. Lett. 2007, 9, 4943–4945; f) B. Wang, H. Du, Y. Shi,
Angew. Chem. 2008, 120, 8348–8351; Angew. Chem. Int. Ed. 2008, 47,
8224–8227; g) R. G. Cornwall, B. Zhao, Y. Shi, Org. Lett. 2013, 15, 796–
799; h) T. P. Zabawa, D. Kasi, S. R. Chemler, J. Am. Chem. Soc. 2005, 127,
11250–11251.
of LiOtBu) and
a catalyst composed of Pd(OAc)2 (1.1 mg,
0.005 mmol) and C-Phos (5.5 mg, 0.0125 mmol). This procedure af-
forded 91 mg (92%) of the product as a yellow solid. This com-
pound was obtained as a >20:1 mixture of diastereomers as
1
judged by H NMR spectroscopic analysis. The physical properties
and spectroscopic data were identical to those provided above.
2,5-Dibenzyl-(1’R,3S)-1’-deuterio-3-(4-methylbenzyl)-1,2,5-thia-
diazolidine-1,1-dioxide (19): The general procedure was employed
for the coupling of 14 (79 mg, 0.25 mmol) and bromobenzene
(32 mL, 0.30 mmol) using NaOtBu (34 mg, 0.35 mmol; in place of
LiOtBu) and toluene (in place of PhCF3) and a catalyst composed of
Pd(OAc)2 (1.1 mg, 0.005 mmol) and X-Phos (6.0 mg, 0.0125 mmol).
After the starting material had been completely consumed, DPPP
(2.1 mg, 0.0125 mmol) and morpholine (65 mL, 0.75 mmol) in
xylene (1 mL) were added, and the reaction mixture was heated to
1208C for 2 h (this step was employed to facilitate purification by
de-allylating small amounts of a side product from a competing
Heck arylation reaction). The reaction mixture was worked up ac-
cording to the general procedure. This procedure afforded 46 mg
(47%) of the product as a yellow solid. M.p. 74–768C. This com-
pound was obtained as a 4:1 mixture of diastereomers as judged
by 1H NMR spectroscopic analysis. Data are given for the major
[8] F. FØcourt, G. López, A. Van Der Lee, J. Martinez, G. Dewynter, Tetrahe-
dron: Asymmetry 2010, 21, 2361–2366.
[9] For representative examples, see: a) D. Dou, K. C. Tiew, G. He, S. R. Man-
dadapu, S. Aravapalli, K. R. Alliston, Y. Kim, K. O. Chang, W. C. Groutas,
Bioorg. Med. Chem. 2011, 19, 5975–5983; b) S. J. Kim, M. H. Jung, K. H.
Yoo, J. H. Cho, C.-H. Oh, Bioorg. Med. Chem. Lett. 2008, 18, 5815–5818.
[10] a) J. A. Fritz, J. S. Nakhla, J. P. Wolfe, Org. Lett. 2006, 8, 2531–2534;
b) J. A. Fritz, J. P. Wolfe, Tetrahedron 2008, 64, 6838–6852.
[11] For recent reviews, see: a) J. P. Wolfe, Top. Heterocycl. Chem. 2013, 32,
1–38; b) D. M. Schultz, J. P. Wolfe, Synthesis 2012, 44, 351–361.
[12] a) D. S. Surry, S. L. Buchwald, Chem. Sci. 2011, 2, 27–50; b) D. S. Surry,
S. L. Buchwald, Angew. Chem. 2008, 120, 6438–6461; Angew. Chem. Int.
Ed. 2008, 47, 6338–6361.
1
isomer: H NMR (500 MHz, CDCl3): d=7.49–7.43 (m, 2H), 7.43–7.30
(m, 8H), 7.25–7.17 (m, 3H), 6.96–6.89 (m, 2H), 4.44 (d, J=14.8 Hz,
1H), 4.34 (d, J=14.8 Hz, 1H), 4.32 (d, J=13.8 Hz, 1H), 4.07 (d, J=
13.8 Hz, 1H), 3.51 (dt, J=6.5, 9.3 Hz, 1H), 3.09 (dd, J=7.0, 9.4 Hz,
1H), 2.85 (dd, J=6.2, 9.4 Hz, 1H), 2.63 ppm (d, J=9.5 Hz, 1H);
13C NMR (126 MHz, CDCl3): d=136.0, 135.4, 134.9, 129.1, 128.9,
128.7, 128.6, 128.1, 128.1, 127.0, 57.3, 50.9, 50.6, 49.5, 39.2 ppm (t,
J=19.6 Hz); IR (film): n˜ =1323, 1155 cmꢀ1; MS (ESI): m/z calcd for
C23H23DN2O2S: 394.1694 [M+H]+; found: 394.1699.
[13] Our prior studies have illustrated that Pd-catalyzed carboamination re-
actions between aryl bromides and alkenes bearing pendant nucleo-
philes, such as anilines, carbamates, ureas, and hydroxylamines proceed
through syn-addition pathways, see: a) J. E. Ney, J. P. Wolfe, Angew.
Chem. 2004, 116, 3689–3692; Angew. Chem. Int. Ed. 2004, 43, 3605–
3608; b) M. B. Bertrand, J. D. Neukom, J. P. Wolfe, J. Org. Chem. 2008, 73,
8851–8860; c) G. S. Lemen, N. C. Giampietro, M. B. Hay, J. P. Wolfe, J.
Org. Chem. 2009, 74, 2533–2540; d) B. A. Hopkins, J. P. Wolfe, Angew.
Chem. 2012, 124, 10024–10028; Angew. Chem. Int. Ed. 2012, 51, 9886–
9890.
[14] Pd-catalyzed N-arylation reactions of sulfamides are believed to pro-
ceed through intermediates similar to 5, see: L. Alcaraz, C. Bennion, J.
Morris, P. Meghani, S. M. Thom, Org. Lett. 2004, 6, 2705–2708.
[15] It has been illustrated that aminopalladation reactions of relatively elec-
tron-poor nucleophiles are reversible, see: P. B. White, S. S. Stahl, J. Am.
Chem. Soc. 2011, 133, 18594–18597.
(1’S,4S)-1’-Deuterio-4-benzyl-1-methyl-3-(4-nitrophenyl)imidazo-
lidin-2-one (22): The general procedure was employed for the cou-
pling of (Z)-1-(3-d-allyl)-1-methyl-3-(4-nitrophenyl)urea (30 mg,
0.125 mmol) and phenyl trifluoromethanesulfonate (25 mL,
0.15 mmol) using
a catalyst composed of Pd(OAc)2 (0.6 mg,
0.0025 mmol) and RuPhos (2.9 mg, 0.00625 mmol). This procedure
afforded 33 mg (85%) of the product as a bright-yellow solid
(m.p. 167–1688C). This compound was obtained as a 10:1 mixture
1
of diastereomers as judged by H NMR spectroscopic analysis. Data
1
are given for the major isomer: H NMR (500 MHz, C6D6): d=7.99
(d, J=9.3, 2H), 7.55 (d, J=9.3, 2H), 7.10–7.00 (m, 3H), 6.72 (d, J=
7.4, 2H), 3.58 (dt, J=3.3, 8.6, 1H), 2.49 (dt, J=1.7, 3.2, 1H), 2.40
(dd, J=3.1, 8.9, 1H), 2.30 ppm (s, 4H); 13C NMR (126 MHz, CDCl3):
d=156.7, 145.1, 141.9, 135.5, 129.1, 128.9, 127.3, 125.0, 117.7, 53.6,
48.4, 37.4 (t, J=19.2 Hz), 30.8 ppm; IR (film): n˜ =1702 cmꢀ1; MS
(ESI): m/z calcd for C17H16DN3O3: 313.1405 [M+H]+; found:
313.1407.
[16] a) W. Rauf, J. M. Brown, Chem. Commun. 2013, 49, 8430–8440; b) D. L.
Dodds, M. D. K. Boele, G. P. F. van Strijdonck, J. G. de Vries, P. W. N. M.
van Leeuwen, P. C. J. Kamer, Eur. J. Inorg. Chem. 2012, 1660–1671.
[17] In nonpolar solvents, [LnPd(Ar)(OTf)] (OTf=triflate) complexes exist as
tight ion pairs, and these complexes are fully dissociated into solvent-
&
&
Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
8
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
separated ions in polar solvents, see: A. Jutand, A. Mosleh, Organome-
tallics 1995, 14, 1810–1817.
Trifluorotoluene” in The Electronic Encyclopedia of Reagents for Organic
Synthesis. http://mrw.interscience.wiley.com/eros/.
[18] B. P. Carrow, J. F. Hartwig, J. Am. Chem. Soc. 2010, 132, 79–81.
[19] For studies on the mechanism of syn-migratory insertion of alkenes
into PdꢀN bonds, see: a) J. D. Neukom, N. S. Perch, J. P. Wolfe, J. Am.
[23] Although there is an intramolecular component to the reactions de-
scribed herein, the aryl/alkenyl halide and urea substrate are separate
components coupled in an intermolecular process.
[24] We have previously demonstrated that ligand effects can influence
alkene syn- vs. anti-heteropalladation pathways in intramolecular Pd-
catalyzed carboalkoxylation and carboamination reactions, see: J. S.
Nakhla, J. W. Kampf, J. P. Wolfe, J. Am. Chem. Soc. 2006, 128, 2893–
2901.
´
Chem. Soc. 2010, 132, 6276–6277; b) P. S. Hanley, D. Markovic, J. F. Hart-
wig, J. Am. Chem. Soc. 2010, 132, 6302–6303; c) J. D. Neukom, N. S.
Perch, J. P. Wolfe, Organometallics 2011, 30, 1269–1277; d) P. S. Hanley,
J. F. Hartwig, J. Am. Chem. Soc. 2011, 133, 15661–15673; e) Reference
[15].
[20] It has previously been illustrated that Pd-catalyzed arene CꢀH function-
alization/alkene carboamination reactions of N-pentenyl amides pro-
ceed through anti-aminopalladation pathways; these transformations
involve a PdII/PdIV catalytic cycle as opposed to the Pd0/PdII cycle for
the sulfamides described herein, see: P. A. Sibbald, C. F. Rosewall, R. D.
Swartz, F. E. Michael, J. Am. Chem. Soc. 2009, 131, 15945–15951.
[21] M. F. Semmelhack, C. Bodurow, J. Am. Chem. Soc. 1984, 106, 1496–
1498.
[25] Ligands, bases, and oxidants influence syn- versus anti-aminopallada-
tion pathways in Wacker-type oxidative cyclizations of aminoalkenes,
see: a) G. Liu, S. S. Stahl, J. Am. Chem. Soc. 2007, 129, 6328–6335;
b) A. B. Weinstein, S. S. Stahl, Angew. Chem. 2012, 124, 11673–11677;
Angew. Chem. Int. Ed. 2012, 51, 11505–11509; c) X. Ye, P. B. White, S. S.
Stahl, J. Org. Chem. 2013, 78, 2083–2090; d) C; Martínez, Y. Wu, A. B.
Weinstein, S. S. Stahl, G. Liu, K. Muniz, J. Org. Chem. 2013, 78, 6309–
6315.
[22] PhCF3 is more polar than toluene and dioxane as measured by dielec-
tric-constant values (toluene: 2.38; dioxane: 2.21; PhCF3: 9.4) or
EN values (toluene: 0.099, dioxane: 0.164, PhCF3: 0.241), see: a) C; Reich-
ardt, Chem. Rev. 1994, 94, 2319–2358; b) A. Ogawa, K. Tsuchii, “a,a,a-
Received: February 19, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
9
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
&
Palladium Catalysis
R. M. Fornwald, J. A. Fritz, J. P. Wolfe*
&& – &&
Influence of Catalyst Structure and
Reaction Conditions on anti- versus
syn-Aminopalladation Pathways in Pd-
Catalyzed Alkene Carboamination
Reactions of N-Allylsulfamides
A constructive approach: A concise, ef-
ficient approach has led to the synthesis
of cyclic sulfamides by using Pd-cata-
lyzed alkene carboamination reactions
of N-allylsulfamides (see picture; OTf=-
triflate, RuPhos=2-dicyclohexylphosphi-
no-2’,6’-diisopropoxybiphenyl, X-
triisopropylbiphenyl). The mechanism of
these transformations is highly depen-
dent on the catalyst structure and reac-
tion conditions. The reactions can be in-
duced to proceed selectively through
either syn- or anti-aminopalladation
pathways under appropriate conditions.
phos=2-dicyclohexylphosphino-2’,4’,6’-
&
&
Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
10
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!