Iodine-catalyzed allylic alkylation of sulfonamides and carbamates with allylic alcohols at room temperature

Article abstract of DOI:10.1016/j.tetlet.2008.02.079

A highly efficient iodine-catalyzed allylic alkylation of a wide variety of sulfonamides and carbamates with allylic alcohols is reported herein. The reaction is operationally straightforward and proceeds under very mild conditions at room temperature in

Full text of DOI:10.1016/j.tetlet.2008.02.079

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2620–2624
Iodine-catalyzed allylic alkylation of sulfonamides and
carbamates with allylic alcohols at room temperature
Wenhan Wu, Weidong Rao, Ya Qin Er , Joanna Kejun Loh , Chai Yun Poh ,
Philip Wai Hong Chan *
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
Received 8 January 2008; revised 30 January 2008; accepted 15 February 2008
Available online 19 February 2008
Abstract
A highly efficient iodine-catalyzed allylic alkylation of a wide variety of sulfonamides and carbamates with allylic alcohols is reported
herein. The reaction is operationally straightforward and proceeds under very mild conditions at room temperature in good to excellent
yields (up to 99%).
Ó 2008 Elsevier Ltd. All rights reserved.
Establishing methods to access allylated nitrogen com-
pounds efficiently is currently an active area in organic syn-
thesis due to their importance as intermediates in synthetic
strategies to bioactive natural products and pharmaceuti-
cally interesting compounds.1 Among the myriad of works
devoted to this reaction, those directed towards new meth-
ods that make use of inexpensive and readily available elec-
trophiles, mild reaction conditions, simple manipulation,
atom-economy, and environmentally friendly catalysts
have become very topical.2–8 Indeed, a recent notable
example was the use of allylic alcohols as the allylating
reagent in the presence of a metal catalyst (usually Pd)
which furnished H2O as the only side product.4 The respec-
tive groups of Shibasaki5 and Liu6 showed that a similar
approach could be employed for the allylic alkylation of
less nucleophilic sulfonamide and carbamate substrates at
room temperature through the use of the Lewis acids
Bi(OTf)3 and AuCl3 as catalysts. Despite these advances,
it remains a challenge to develop a metal catalyst-free
and operationally simple version of this useful carbon–
nitrogen bond forming reaction that can be accomplished
under mild conditions. In this context, we envisioned that
I2 (5 mol%)
NHR1
OH
NH2R1
+
R2
R3
R2
R3
CaSO4, CH2Cl2
air, rt, 1-18 h
1
2
3
R1 = SO2Ar, CO2R2
R2, R3 = alkyl, aryl
Scheme 1.
*
Corresponding author. Tel.: +65 6316 8760; fax: +65 6791 1961.
E-mail address: waihong@ntu.edu.sg (P. W. H. Chan).
Equal contributions to this work.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.079

W. Wu et al. / Tetrahedron Letters 49 (2008) 2620–2624
2621
molecular iodine would hold promise as a catalyst for
amide allylation with allylic alcohols. An inexpensive, com-
mercially available reagent that has a high tolerance to air
and moisture, we and others have recently shown molecu-
lar iodine to be versatile in mediating a wide variety of
organic transformations in excellent yields and with high
selectivity.7 Recently, we reported that molecular iodine
could mediate the allylic alkylation of 1,3-dicarbonyl com-
pounds in good to excellent yields.8 In view of this work,
we were keen to examine whether the same catalytic proto-
col could be extended to the allylic alkylation of sulfona-
mides and carbamates with allylic alcohols. As part of an
ongoing program on carbon-nitrogen bond formations in
our group,9 we report herein the allylic alkylation of a wide
variety of sulfonamides and carbamates with allylic alco-
hols catalyzed by molecular iodine that proceeded in good
to excellent yields (up to 99%), at room temperature, and
without the need for inert and moisture-free reaction con-
ditions (Scheme 1).
We found that treating a solution of p-toluenesulfonyl-
amide 1a (1 equiv), (E)-1,3-di-p-tolylprop-2-en-1-ol 2a
(1.5 equiv) and CaSO4 (50 mg) in CH2Cl2 with 5 mol %
of iodine as catalyst in an open round-bottom flask at
room temperature for 2.5 h gave the best result, furnishing
(E)-1,3-di-p-tolyl-N-tosylprop-2-en-1-amine 3a in 85% yield
(Table 1, entry 1).10 The retention of trans-stereochemistry
in the allylated product was confirmed by 1H NMR analy-
Table 1
Optimization of the reaction conditionsa
Fig. 1. ORTEP drawings of (a) 3a and (b) 3v with thermal ellipsoids at
50% probability levels.11
O
Me
S
NH2
O
sis and X-ray crystal structure determination, as shown in
Figure 1a.11 On the other hand, slightly lower product
yields of 67–68% were observed when the reaction was car-
ried out in the absence of a drying reagent or conversely in
an oven-dried closed reaction vessel under an argon atmo-
sphere, suggesting that a trace amount of water promotes
the allylation reaction (entries 2 and 5). Similarly, lower
product yields of 65–70% were obtained on changing the
NHTs
1a
I2, solvent
+
OH
additive, r.t.
Me
Me
3a
Me
Me
2a
Entry
Solvent
Additive
Yieldb (%)
˚
drying reagent to MgSO4 or 4 A MS, and with C6H6 as
1
2c
3
4
5
6d
7
8
9
10
11
12
a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
1,4-Dioxane
MeCN
THF
CaSO4
CaSO4
MgSO4
85
67
70
70
68
the solvent (entries 3, 4 and 12). In contrast, analogous
reactions conducted without a drying reagent in other sol-
vents were less effective and lower product yields of 9–50%
were obtained for reactions in CHCl3, 1,4-dioxane, MeCN,
THF or PhMe (entries 7–11). As anticipated, no reaction
was observed in the absence of the iodine catalyst and both
starting materials were recovered in quantitative yields
(entry 6).
To define the scope of the iodine-catalyzed reactions, we
applied this process to a series of substituted sulfonamides
and carbamates 1a–g and allylic alcohols 2a–i. As shown in
entries 1–8 in Table 2, allylation of a variety of para-
substituted arylsulfonamides with allylic alcohols bearing
electron-withdrawing and electron-donating groups pro-
ceeded in good to excellent yields comparable to those
obtained in the analogous metal-catalyzed reactions.4–6
˚
4 A MS
—
—
—
—
—
—
—
—
e
—
38
45
50
37
9
PhMe
C6H6
65
All reactions were performed at room temperature for 3 h with an
I2:1a:2a ratio = 1:20:30.
b
Isolated yield.
c
Reaction conducted in a dry closed reaction vessel under an Ar
atmosphere.
d
Reaction conducted in the absence of I2 catalyst.
No reaction after 5 h based on TLC analysis.
e

2622
W. Wu et al. / Tetrahedron Letters 49 (2008) 2620–2624
Table 2
Iodine-catalyzed allylation of sulfonamides and carbamates 1a–g with allylic alcohols 2a–ia
OH
O
S
O
O
O
R
NH2
N
H
O
RO
NH2
R1
R2
2b, R1 = R2 = H
1b, R = OMe
1c, R = F
1d, R = Bn
1e, R = iPr
1f, R = tBu
1g
2c, R1 = R2 = Br
2d, R1 = Cl, R2 = Me
2e, R1 = Br, R2 = OEt
OH
OH
OH
Me
O
O
R
Ph
Me
2f
2g, R = Me
2h, R = Ph
2i
Entry
Substrates
Product
Yieldb (%)
1
2
3
1a + 2b
1a + 2c
1a + 2d
3b, R1 = R2 = H, R3 = Me
3c, R1 = R2 = Br, R3 = Me
3d0, R1 = Cl, R2 = R3 = Me
3d00, R1 = R3 = Me, R2 = Cl
3e0, R1 = Br, R2 = OEt, R3 = Me
3e00, R1 = OEt, R2 = Br, R3 = Me
3f, R1 = R2 = Me, R3 = OMe
3g, R1 = R2 = H, R3 = OMe
3h, R1 = R2 = Me, R3 = F
3i, R1 = R2 = H, R3 = F
85
65
89c
R3
O
S
4
1a + 2e
61d
HN
O
5
6
7
8
1b + 2a
1b + 2b
1c + 2a
1c + 2b
86
89
51
72
R1
R2
O
9
10
11
12
13
14
1d + 2b
1e + 2b
1f + 2b
1f + 2a
1f + 2c
1f + 2d
3j, R1 = R2 = H, R3 = Bn
92
96
93
93
66
94e
HN
OR3
3k, R1 = R2 = H, R3 = iPr
3l, R1 = R2 = H, R3 = tBu
3m, R1 = R2 = Me, R3 = tBu
3n, R1 = R2 = Br, R3 = tBu
3o0, R1 = Cl, R2 = Me, R3 = tBu
3o00, R1 = Me, R2 = Cl, R3 = tBu
R1
R2
O
N
O
15
16
1g + 2b
1a + 2f
3p
94
64
Ph
Ph
NHTs
3q
Ph
Me
NHR
Me
O
O
17
18
1a + 2g
1f + 2g
3r, R = Ts
3s, R = Boc
62
66
NHR
Ph
NHR
74f
92f
O
O
O
O
+
19
20
1a + 2h
1f + 2h
3t, R = Ts
3u, R = Boc
Ph
NHR
21
22
1a + 2i
1f + 2i
3v, R = Ts
3w, R = Boc
81
73
Me
a
All reactions were performed at room temperature for 3 h with an I2:1:2 ratio = 1:20:30 in a solution of CH2Cl2.
Isolated yield.
Isolated as an inseparable mixture of regioisomers in the ratio = 2.6:1.
Isolated as an inseparable mixture of regioisomers in the ratio = 2:1.
Isolated as an inseparable mixture of regioisomers in the ratio = 2.8:1.
Isolated as an inseparable mixture of regioisomers in the ratio = 1.7:1.
b
c
d
e
f

W. Wu et al. / Tetrahedron Letters 49 (2008) 2620–2624
2623
In summary, we have demonstrated a practical and
operationally simple method for the allylation of sulfon-
amides and carbamates with allylic alcohols under atmo-
spheric conditions at room temperature that proceeded in
good to excellent yields. The present protocol is applicable
to a variety of sulfonamides, carbamates and allylic alco-
hols containing electron-withdrawing, electron-donating
and sterically demanding substrate combinations. Efforts
are currently underway to examine the scope and mecha-
nism of this carbon–nitrogen bond formation strategy.
I2 (5 mol%)
Ph
Ph
Ph
Ph
1a (1.5 equiv)
NHTs
Ph
O
Ph
CH2Cl2, r.t.
16 h
4a
3b
95% yield
Scheme 2.
The present procedure was also shown to work well for the
allylation of a variety of alkyl substituted carbamates, giv-
ing the corresponding allylated adducts in good to excellent
yields (entries 9–14). Notably, this included the allylation
of cyclic carbamate 1g with 2b, which gave 3p in excellent
yield (entry 15). In cases where it was envisaged that reac-
tions with allylic alcohols containing two very different
substituents such as an aryl and alkyl group as in 2f–g
and 2i would lead to a mixture of regioisomeric products,
the exclusive formation of only one product indicates that
the present procedure is regioselective (entries 16–18 and 21
and 22). This was further confirmed by X-ray structure
analysis of 3v, as shown in Figure 1b.11 The allylations of
1a and 1f with either 2d, 2e or 2h, which contain two
slightly different para-substituted aryl groups, were the
only examples to give poor regioselectivity. In these
reactions the corresponding allylated adducts 3d, 3e, 3o,
3t and 3u were furnished as a mixture of inseparable regioi-
somers in ratios ranging from 1.7 to 2.8:1 (entries 3, 4, 14
and 19, 20). Consistent with our earlier findings for the
analogous allylation of 1,3-dicarbonyl compounds,8 in all
the above reactions competitive formation of an ether
side-product resulting from dimerization of 2 (see later
and Scheme 2) was observed by TLC analysis.
Although currently unclear, we tentatively propose that
the mechanism of the present procedure proceeds in a man-
ner similar to that for the allylation of 1,3-dicarbonyl com-
pounds with allylic alcohols.8 This involves the formation
of an allylic carbocation species from the reaction of the
allylic alcohol 2 with HI generated in situ. The regioselec-
tivities obtained in these reactions could be due to subse-
quent attack at the sterically less hindered carbon of this
presumed allylic carbocation intermediate by 1 or another
molecule of 2 to produce the reactive dimer 4 of the type
shown in Scheme 2, which reacts further in the presence
of 1 to give the allylated product 3. To support the possible
involvement of such intermediates, we undertook the
following experiments. The dimer 4a, obtained as a mixture
of diastereomers from the reaction of 2b with 5 mol % of
iodine following the literature procedure,8 could be con-
verted to 3b in 95% yield on treatment with 1.5 equiv of
1a and 5 mol % of iodine catalyst in CH2Cl2 for 16 h at
room temperature (Scheme 2). In addition, 3b was
furnished in a comparable yield of 90% for the analogous
reaction of 1a with 2b under the same conditions as those
described in Table 2, entry 1 but with NaI (5 mol %) and
trifluoroacetic acid (5 mol %) in place of iodine as catalyst.
Acknowledgements
This work is supported by a University Research Com-
mittee Grant (RG55/06), and Supplementary Equipment
Purchase Grant (RG134/06) from Nanyang Technological
University.
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round-bottom flask open to air at room temperature was added
molecular iodine (15 lmol, 5 mol %). The reaction was stirred for 3 h
and then quenched with aqueous Na2S2O3 (10 mL) and extracted with
CH2Cl2 (10 mL). The organic layer was washed with brine (10 mL),
dried over anhydrous MgSO4, concentrated, and purified by flash silica
gel column chromatography (n-hexane/EtOAc as eluent) to give 3.
11. CCDC 673120 and 673121 (3a and 3v, respectively) contain the
supplementary crystallographic data for this Letter. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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10. Typical experimental procedure: To a CH2Cl2 (1 mL) solution of 1
(0.3 mmol, 1 equiv), 2 (0.45 mmol, 1.5 equiv) and CaSO4 (50 mg) in a