Chemical Science
Edge Article
the sulfone product. In practice, aer 1 h reaction at 50 ꢀC with signicant drop in conversion to the desired sulfone (entries 2–6).
0.95 equivalents of benzyl bromide and two equivalents of base, Pleasingly, the addition of water,15 together with a slight modi-
analysis of the crude reaction mixture showed formation of the cation to the rst, palladium-catalysed step, in which the amount
sulnate salt and hydrazone by-product. A second electrophile of aminomorpholine was slightly reduced (to 1.2 equiv.), allowed
was then added and the temperature increased to 100 ꢀC to give a 91% isolated yield of the sulfone (10a) to be realised (entry 9).
solely the sulfone incorporating the second electrophile. This These optimised reaction conditions employed 2.5 equivalents of
method (Method II, Table 2) was explored with a small number both benzyl bromide and base (entry 9), and the total reaction
of electrophiles that had previously given lower yields using time for this one-pot process was 21 hours. Reduction of the
Method I. Although little or no improvement was observed for reaction temperature to 90 ꢀC was necessary to prevent hydrolysis
entries 8 or 9, in which secondary and tertiary alkyl iodides were of benzyl bromide which occurred at 100 ꢀC.
employed, Method II gave a much cleaner reaction and a
With the optimised conditions in hand, benzyl bromide
signicant improvement in yield for the synthesis of an was reacted with a range of halide coupling partners (Table 4).
a,b-unsaturated sulfone (entry 10) and the aryl sulfones (entry As described in previous reports from our laboratory, slower
11 and 12) formed by reaction with an electron-poor aryl uo- reacting substrates, such as those with electron-withdrawing
ride7b and an iodonium salt,7c,d respectively. For entries 8–12, in groups, were found to give improved yields when extra DABSO
which only moderate yields of the sulfones were obtained, the (1.1 equiv. total) was employed.11a,c Aryl iodides with neutral
remainder of the mass balance was predominantly un-reacted and electron-donating substituents gave excellent yields of the
sulnate anion, presumably due to the lower reactivity of this desired sulfones (entries 1–14, Table 4); however, when an aryl
series of electrophiles.
bromide was used as the coupling partner, in place of the
Having established two complementary methods for the corresponding iodide, a reduced yield was obtained and
degradation and functionalization of dialkyl amino- reects the lower reactivity of aryl bromides in the Pd-cata-
sulfonamides, the next task was the development of one-pot lysed aminosulfonylation step (entry 8).11a,c Substrates with
reaction conditions to synthesise the sulfone directly from the ortho-substituents were well tolerated (entries 6 and 11). Aryl
aryl-, heteroaryl- or alkenyl iodides. 4-Iodotoluene was iodides with electron-withdrawing groups (entries 15 and 16)
selected as the test substrate, and was employed in the palla- gave lower yields; we attributed this to stabilisation of the
dium-catalysed aminosulfonylation reaction, and aer 16 h, sulnate salt consequently reducing their reactivity towards
K2CO3 and benzyl bromide were added. The highest yield of the electrophile. Entry 16 demonstrates that an aryl chloride
sulfone achieved using this method was 57% (entry 1, Table 3), substituent remains intact during the transformation and so
despite a large excess (4 equiv.) of benzyl bromide and base can potentially be used as a handle for subsequent function-
being used. Sulnate salts are known to have a low solubility in alization of the product. Heteroaryl iodides gave moderate
organic solvents, and as such, literature precedent suggests that yields, which is in agreement with the yields obtained in the
polyethylene glycol, DMSO and DMF are good solvents for parent N-aminosulfonamide forming reactions (entries
sulfone formation from the sulnate salt.7g,14 Unfortunately, 17–20).11a,c Pleasingly, alkenyl iodides gave the corresponding
addition of these solvents for the alkylation step resulted in a sulfones in moderate to good yields (entries 21–23). That sulde
(entry 12), amine (entries 13 and 14) and olen (entries 21–23)
functionalities were employed without issue, highlights the
Table 3 Optimisation of the one-pot conditions for conversion of 4-iodotoluene
to sulfone 10aa
tolerance of the process to oxidation-sensitive functional groups.
4-Aminomorpholine was employed as the standard hydrazine
component in all of the examples discussed above; however,
alternative hydrazines are also viable, for example, entry 9 was
also performed using 1-aminopiperidine with almost identical
results.
We next investigated the scope of the electrophilic compo-
nent. 1-Ethoxy-4-iodotoluene was used as the standard aryl
halide, and Method I or II (see Table 2) was employed, as
appropriate. A range of benzylic bromides could all be incor-
porated using Method I (entries 1–3). Allylic bromides delivered
higher yields of the desired sulfones when Method II was
utilized (entries 4 and 5), as did cyclohexene oxide (entry 6).7f,g
Alkyl iodides (entries 7 and 8) gave reasonable yields, although
interestingly side-products corresponding to the derived sul-
nate esters were not observed (cf. Table 2). Under the mild
aqueous basic conditions, the ester group incorporated in entry
9 was tolerated well. Implementing Method II allowed an elec-
tron-poor aryl uoride to be employed as the electrophile,
delivering a diaryl sulfone product, albeit in low yield (Table 5,
entry 10).7b,16
Entry
K2CO3 equiv.
BnBr equiv.
Co-solventb
Yieldc (%)
1
2
3
4
5
6
7
8
9
4
4
4
4
—
57
EtOH
PEG-400
Diglyme
DMSO
DMF
H2O
10d
0d
2.5
2.5
2.5
2.5
4
2.5
2.5
2.5
2.5
4
0d
15d
15d
80
2
2.5
2
2.5
H2O
H2O
87e
91e,f
a
Reaction conditions: 4-iodotoluene (1 equiv.), Pd(OAc)2 (10 mol%),
PtBu3$HBF4 (20 mol%), 4-aminomorpholine (1.5 equiv.), DABSO (0.6
equiv.), DABCO (0.5 equiv.), 70 ꢀC, 16 h, 1,4-dioxane, [0.3 M]; then
b
c
BnBr, K2CO3, 20 h, 100 ꢀC. 0.5 mL of added solvent. Isolated yield.
d
e
Determined by 1H NMR spectroscopy. Second step; 1.2 equiv. of N-
aminomorpholine employed and heated to 90 ꢀC. f 5 h for second step.
Chem. Sci.
This journal is ª The Royal Society of Chemistry 2013