PdCl2-catalyzed hydrosulfonamidation of homo allylic alcohols: An efficient synthesis of allylic sulfonamides

Article abstract of DOI:10.1016/j.tetlet.2011.01.024

A new protocol for the palladium chloride-catalyzed direct hydrosulfonamidation of homoallylic alcohols with migration of the double bond is described. This method requires no preactivation of alcohols and the reaction is environmentally benign with water

Full text of DOI:10.1016/j.tetlet.2011.01.024

Tetrahedron Letters 52 (2011) 1208–1212
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Tetrahedron Letters
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PdCl2-catalyzed hydrosulfonamidation of homo allylic alcohols: an efficient
synthesis of allylic sulfonamides
⇑
B. Sreedhar , V. Ravi, Deepthi Yada
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new protocol for the palladium chloride-catalyzed direct hydrosulfonamidation of homoallylic alcohols
with migration of the double bond is described. This method requires no preactivation of alcohols and the
reaction is environmentally benign with water as the only by-product. Various homoallylic alcohols on
hydrosulfonamidation with sulfonamides gave the corresponding products in good yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 1 December 2010
Revised 31 December 2010
Accepted 8 January 2011
Available online 13 January 2011
Keywords:
Hydrosulfonamidation
Palladium chloride
Homoallylic alcohols
Sulfonamides
Amines and their derivatives are of fundamental importance as
natural products, pharmacological agents, fine chemicals, and
dyes.1 Furthermore, a plethora of naturally bioactive compounds
such as, alkaloids, amino acids, and nucleotides contain amine
groups. Despite numerous known procedures, the development
of improved methods for the synthesis of amines continues to be
a highly challenging and active area of research.2 In this respect
hydroamination,3 the addition of an N–H bond across carbon–car-
bon unsaturation, offers an efficient, atom-economical route to
nitrogen-containing molecules that are important for fine chemi-
cals, pharmaceuticals, or useful chiral building blocks. Although
several efficient catalysts for the hydroamination of alkynes,4
vinylarenes,5 dienes,6 and electron-deficient alkenes7 have
recently been discovered, general systems for intermolecular
hydroaminations of unactivated olefins remain elusive.8
allylic substitution and the second (ii) is the direct allylic amina-
tion of simple alkenes.12
A transition metal-catalyzed substitution reaction of activated
allylic alcohol derivatives with nitrogen nucleophiles is one of
the most powerful and reliable methods for the synthesis of allylic
amines.13 However, they usually require preactivation of the
parent allylic alcohol to the corresponding allylic halides, carboxyl-
ates, carbonates, phosphates, and related compounds. The reaction
proceeds through
p-allyl metal intermediates, generated by the
oxidative addition of allylic substrates to a low-valence metal
center, and the following nucleophilic addition gives allylic amines
as a consequence of new C–N bond formation. In terms of atom-
economy14 and environmental concerns, however, these catalyses
still have much room for improvement.
The current study was motivated by our recent finding that
hydroazidation of homoallyl alcohols to the corresponding allylic
azides using PdCl2 as a catalyst and TMSN3 as an azide source,
which appears to involve the nucleophilic attack of an azide onto
Allylamines are ubiquitous in various biologically active com-
pounds and their synthesis is an important industrial and synthetic
goal. The allylamine fragment can be encountered in natural prod-
ucts, but often the allylamine is transformed to a range of products
by reduction, oxidation, or other functionalization of the double
bond. Thus allylamines have been used as starting materials for
NR'2
X
the synthesis of numerous compounds such as,
a- and b-amino
R'2NH
R'NX
R
R
R
+
+
acids,9 different alkaloids10, and carbohydrate derivatives.11
The synthesis of allylic amines can, in principle, be divided into
two groups of reactions, which are outlined in Scheme 1. The first
type (i) constitutes allylic amines synthesized by nucleophilic
(i)
R
R
(ii)
R
NHR'
HN
R'
OH
+
Present work
R'NH2
R
R
⇑
Corresponding author. Tel.: +91 40 27193510; fax: +91 40 27160921.
E-mail address: sreedharb@iict.res.in (B. Sreedhar).
Scheme 1. Protocols for the synthesis of allylic amines.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.024

B. Sreedhar et al. / Tetrahedron Letters 52 (2011) 1208–1212
1209
O
O
O
O
S
S
OH
NH
H2N
3 mol % PdCl2
CH2Cl2, reflux
+
1
3
2
Scheme 2.
Table 1
Screening of various solvents and catalysts for reaction of allylic amines from homoallylic alcoholsa
O2
S
H2N
OH
SO2
HN
catalyst
solvent
+
Entry
Catalyst
Solvent
Temp (°C)/time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
PdCl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
1,4-Dioxane
DCE
DMF, DMSO, CH3NO2, H2O
Toluene, xylene
40/8
40/8
40/8
40/8
40/8
40/8
40/8
40/8
60/12
100/12
80/12
100/12
100/12
90
0
0
0
0
Pd(OAc)2
Pd(PPh3)4
Pd/C
Pd(dba)2
Pd(dppf)Cl2
Pd(PPh3)2Cl2
Pd(CH3CN)2Cl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
0
27
42
30
40
Trace
0
0
a
Reaction conditions: homoallylic alcohol (1 mmol), tosylamide (1.2 mmol), catalyst (3 mol %) solvent (3 mL).
Table 2
Table 2 (continued)
Direct hydrosulfonamidation of different homoallylic alcohols with p-toluenesulfon-
amide using PdCl2 for the synthesis of allylic aminesa
Entry
Homoallyl alcohol
Product
Yield (%)
87
OH
Ts
Ts
Entry
Homoallyl alcohol
Product
Yield (%)
90
HN
HN
O
OH
Ts
7
O
O
HN
O
1
OH
OH
OH
Ts
HN
8
9
75
75
70
2
3
91
90
Br
Br
Cl
F
OH
Ts
HN
Ts
Ts
HN
Cl
OH
Ts
HN
OH
HN
10
4
5
84
F
O
OH
OH
Ts
O
HN
OH
Ts
HN
11
12
70
82
F3C
79b
F3C
O
Ts
O
O
HN
OH
Ts
HN
O
O
O
6
84
Reaction conditions as exemplified in typical experimental procedure.22
Yield of the E isomer.
a
O
O
b

1210
B. Sreedhar et al. / Tetrahedron Letters 52 (2011) 1208–1212
a
p
-allyl–palladium complex.15 This prompted an investigation of
THF and 1,4-dioxane and only a trace amount of the product was
formed in dichloroethane, whereas no product was formed in
DMF, DMSO, ACN, nitromethane, water, toluene, and xylene as
the solvents (Table 1, entries 9–13).
analogous reactions involving the addition of N–H bonds to olefins,
since amines seemed to be potential candidates as analogous
nucleophiles in a related process. In this Letter, we describe an effi-
cient system for the hydrosulfonamidation of homoallylic alcohols
to the corresponding allylic sulfonamides with migration of the
double bond using PdCl2 as a catalyst and sulfonamides as an
amine source (Scheme 2).
Under the optimized reaction conditions, various homoallylic
alcohols were subjected to amination with p-toluenesulfonamide
2 and the results are presented in Table 2. The reaction of electron-
ically and structurally diverse homoallylic alcohols such as,
4-methyl, 4-methoxy, 4-isopropyl, 3,4,5-trimethoxyphenyl substi-
tuted homoallylic alcohols with 2 gave the desired products in
good yields, whereas the 2-methoxyphenyl substituted homo-
allylic alcohol gave the product in mixture as E/Z- isomers in the
ratio of 90:10 (entries 1–7) with moderate yield. The presence of
electron-withdrawing substituents on the phenyl ring such as,
chloro, bromo and fluoro, the products were formed in moderate
yields (Table 2, entries 8–11). On the other hand, 1-(naphthalen-
2-yl)but-3-en-1-ol reacted smoothly with 2 to furnish the desired
product in good yield (Table 2, entry 12).
To show the convenience of our approach for the synthesis of
multivalent structures, the homoallylic alcohol derived from
terephthalaldehyde was reacted with 2 under the optimized reac-
tion conditions to afford the bis-allylic sulfonamide product in
good yield (Scheme 3).
Furthermore, the scope of the reaction with respect to sulfon-
amide substrate was also examined and the results are given in
Scheme 4. Both benzenesulfonamide and 2,4,6-triisopropylben-
For initial optimization of the reaction conditions and the
identification of the best palladium source and solvent, 1-phenyl-
but-3-en-1-ol 1 and p-toluenesulfonamide 2 were chosen as model
substrates for the synthesis of allylic sulfonamides and the results
are presented in Table 1. The conditions were optimized and the
best conditions were found to be 3 mol % of PdCl2, 1.2 equiv of 2
with dichloromethane as the solvent (Table 1, entry 1). By virtue
of these optimized conditions, the reaction afforded the desired
product in 90% yield. Reactions with other palladium catalysts such
as, Pd(OAc)2, Pd(PPh3)4, Pd/C, Pd(dba)2, and Pd(dppf)2Cl2 did not
generate the desired product (Table 1, entries 2–6). However, the
reaction with Pd(PPh3)2Cl2, Pd(CH3CN)2Cl2 gave the product in
low yield (Table 1, entries 7 and 8). As can be seen from the table,
the nature of the counter ion as well as the oxidation state of pal-
ladium plays a significant role in this reaction. Subsequently, the
reaction conditions were optimized by employing different sol-
vents. Thus, various polar and non polar solvents were examined
and it was found that the product was obtained in low yield with
Ts
2.5 equiv tosylamide
3 mol%PdCl2
HN
OH
CH2Cl2, reflux, 8 h
NH
OH
Ts
4
5
75% yield
Scheme 3.
O
O
S
R
OH
NH
O
O
3 mol % PdCl2
S
R
H2N
+
CH2Cl2, reflux
NO2
6
7
R =
R =
65%
80%
8
9
0%
0%
O2N
R =
R =
Scheme 4.
O2
S
OH
OH
HN
CH3
O
O
3 mol % PdCl2
S
CH3
H2N
+
+
CH2Cl2, reflux
12 h
1
10
11 76%
12 0%
Scheme 5.

B. Sreedhar et al. / Tetrahedron Letters 52 (2011) 1208–1212
1211
Ts
OH
NH
+
PdCl2
3
1
Ts
NH
OH
OH
Pd2+
Pd+
+
Pd 2+
I
H2N Ts
OH
OH
Pd+
IV
Pd+
Pd+
+ H+
II
OH
Pd2+
OH
Pd+
+
III
Scheme 6.
zene sulfonamides were equally effective for this reaction and gave
the corresponding allylic sulfonamides in good yield. However,
no product was formed with 4-nitrobenzenesulfonamide and 2-
nitrobenzenesulfonamides, having an electron-withdrawing nitro
group, under the optimized reaction conditions. Interestingly, with
methanesulfonamide, which contains a relatively electron-donat-
ing methyl group, we observed the formation of allylic alcohol 11
instead of allylic amine 12 (Scheme 5). This may be attributed to
higher nitrogen basicity leading to lower reactivity in this
catalysis.16
be a meaningful addition to the existing methods for hydrosulfo-
namidation and this conceptually new approach provides
straightforward and efficient access to the allylic amines.
a
Acknowledgment
V.R. thanks Indo French Centre for the Promotion of Advanced
Research (IFCPAR), New Delhi for the financial assistance.
Supplementary data
On the basis of these results, together with the literature re-
ports,17 a plausible reaction course is proposed as shown in
Scheme 6. The catalytic isomerization of alkenes by Pd(II) com-
pounds, has been studied.15,18 The commonly postulated mecha-
nism involves the oxidative addition of an allylic CH bond to the
Pd(II) catalyst to produce a Pd(IV) allyl hydride species. The obser-
vations made in the optimization of reaction conditions, such as
low yield of the product obtained with the Pd(CH3CN)2Cl2 and
Pd(PPh3)2Cl2 and no product being formed with Pd(PPh3)4 and
Pd(dppf)Cl2, would rule out a mechanism involving the oxidative
addition of an allylic C–H bond to the metal, since the propensity
to undergo oxidative addition should increase with increasing elec-
tron density on the metal.19 The key intermediate in the proposed
mechanism is the incipient carbocation I generated through the
interaction of the alkene with the Pd(II) center, with loss of H+ from
I to yield the cationic allyl compound, II. The proton then cleaves
the Pd–C bond in a well precedented step20 to produce the isomer-
ized alkene III and regenerates the catalyst. The formation of II and
H+ from the alkene and Pd(II) may be visualized as a heterolytic
cleavage of the C–H bond by Pd(II). Then, the structure of
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.024.
References and notes
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In summary, we have developed an efficient route for the
synthesis of allylic sulfonamides from homoallylic alcohols through
palladium-catalyzed hydrosulfonamidation of unactivated double
bonds. The new catalytic reaction presented in this Letter could

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22. Typical procedure for the hydrosulfonamidation of homoallyl alcohols: A mixture
of homoallyl alcohol (1 mmol), sulfonamide (1.2 mmol) and palladium chloride
(3 mol %) in dichloromethane (3 mL) was stirred under reflux for 8 h. After
completion of the reaction as indicated by TLC, the reaction mixture was
diluted with water and extracted with dichloromethane (2 Â 10 mL). The
combined organic layers were dried over anhydrous Na2SO4, concentrated in
vacuo and purified by column chromatography on silica gel to afford the pure
product. All products were characterized by IR, 1H NMR, 13C NMR, and mass
spectroscopic techniques. Please see Supplementary data for spectral data of
all compounds.