Direct Synthesis of Enolizable N-Sulfonyl Ketimines under Microwave Irradiation

Article abstract of DOI:10.1002/ejoc.201600022

N-sulfonyl imines are widely used as substrates for a range of transformations. Access to N-sulfonyl aldimines is straightforward through direct condensation between the parent aldehyde and the sulfonamide. However, this approach is not efficient for the

Full text of DOI:10.1002/ejoc.201600022

DOI: 10.1002/ejoc.201600022
Communication
Imine Synthesis
Direct Synthesis of Enolizable N-Sulfonyl Ketimines Under
Microwave Irradiation
Pablo Ortiz,[a] Juan F. Collados,[a] and Syuzanna R. Harutyunyan*[a]
Abstract: N-sulfonyl imines are widely used as substrates for not efficient for the synthesis of enolizable N-sulfonyl ketimines.
a range of transformations. Access to N-sulfonyl aldimines is
straightforward through direct condensation between the par-
ent aldehyde and the sulfonamide. However, this approach is
Herein we report a rapid and facile methodology for obtaining
these products using microwave irradiation.
Introduction
are generally not efficient when applied to enolizable ketim-
ines.[16] The lower electrophilicity of the ketone compared to
the aldehyde, together with the relatively low nucleophilic
power of sulfonamide, make this transformation difficult
(Scheme 1, b).
The carbonyl group is arguably the most important functional
group in synthetic chemistry due to the numerous transforma-
tions it can undergo. Its analogue C=N bond is not less relevant,
especially considering the widespread applications of imines in
organic synthesis. However, contrary to their carbonyl counter-
parts (aldehydes and ketones), imines are less stable and sel-
dom commercially available, and therefore they usually have to
be synthesized.
Among the various types, N-sulfonyl imines are the most
commonly used because of the strong activating power pro-
vided by the sulfonyl moiety.[1] As a consequence, N-sulfonyl
imines, in particular N-tosyl imines, are ubiquitous in organic
transformations. To name but a few, they have been used as
substrates for cycloadditions,[2–6] aziridines[7] and oxazolines[8]
preparations, as well as nucleophilic additions[9–12] and reduc-
tions.[13,14]
To overcome the reactivity problem, different strategies have
been applied. Regarding the ketone partner, its transformation
into oximes has allowed successful reactions with both sulfinyl
chlorides[17,18] and sulfonyl cyanides[19] to yield N-sulfonyl ket-
imines. Examples of the opposite approach, involving the modi-
fication of the nucleophile, have also been reported: sulfinam-
ides, which are more nucleophilic than sulfonamides, have been
condensed with the carbonyl group, followed by oxidation to
the desired N-sulfonyl ketimine.[20,21] This latter method, devel-
oped by Ruano et al., is generally considered the most reliable
method for the synthesis of N-sulfonyl ketimines.[13,14,22–24] Al-
though trustworthy, the method has some significant draw-
backs. It involves the handling of peracids and peroxy com-
pounds and is time consuming, since it requires several syn-
thetic operations such as: 1) the preparation of the sulfinamide
(only the chiral molecule is commercially available) 2) the con-
densation with the corresponding ketone, requiring 36 h of re-
flux, and finally 3) the oxidation of the N-sulfinyl imine with
MCPBA.[20,21] In fact, Ruano et al. acknowledge that “In theory,
the ideal procedure for obtaining N-sulfonylimines would involve
the condensation of carbonyl compounds with sulfonamides.”[20]
Other routes for the preparation of N-sulfonyl ketimines,
such as palladium-catalyzed isomerization of N-tosyl aziridi-
nes[25] or an aza-pinacol rearrangement,[26] have been reported
as well. However, these methods are based on starting materials
that are not commercially available and require prior synthesis.
Another multi-step procedure includes the palladium-catalyzed
cross-coupling reaction between organoboronic acids and
tosylbenzimidoyl chlorides.[27]
Due to their widespread use, several methodologies for pre-
paring N-sulfonyl imines have been described. There are a myr-
iad of methods reported for the synthesis of N-sulfonyl
aldimines by (Lewis) acid-catalyzed reactions of aldehydes with
sulfonamides (Scheme 1, a).[15] These methodologies, however,
Scheme 1. Direct synthesis of N-sulfonyl imines.
[a] Stratingh Institute for Chemistry, University of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
E-mail: s.harutyunyan@rug.nl
A quick survey of the available methodologies for the syn-
thesis of enolizable N-sulfonyl ketimines makes it apparent that
this still remains challenging.[28] As part of our ongoing work
on nucleophilic additions to N-sulfonyl ketimines, we required
http://www.sr-harutyunyan.com/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600022.
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Communication
a reliable and quick procedure for their preparation. Direct con- so the latter was chosen as the reaction solvent for the subse-
densation of sulfonamides with ketones requires acid catalysis quent studies.
and long reaction times under reflux, due to the overall low
reactivity of the reagents. Moreover, this approach generally re-
sults in low yields, owing to the kinetic instability and ease of
enolization of N-sulfonyl ketimines under harsh reaction condi-
tions. We reasoned that microwave irradiation (MWI) could be
an alternative strategy to address the issues related to the react-
ivity of the reagents and the low yields. MWI has previously
been used for the synthesis of N-sulfinyl imines,[29,30] using the
relatively more nucleophilic sulfinamides. MWI has also been
used for the synthesis of N-sulfonyl aldimines starting from the
more reactive aldehydes.[31,32]
Next, the effect of different ratios of the reagents on the
reaction conversion was tested. Using two equivalents of Ts-
NH2 had only a slight, positive impact on the conversion,
(Table 1, entry 5) and further optimization revealed 1.2 equiv.
as the optimal excess of the reagent. On the other hand, an
excess of 1a had no effect on the conversion. As expected, the
reaction outcome was strongly dependent on the temperature
at which it was carried out. The conversion rose from to 64 %
to 80 %, and peaked at 92 % when running the reaction at
100, 125 and 150 °C, respectively (Table 1, entries 6, 7 and 8,
respectively). It is worth noting that it takes less than two mi-
nutes to reach 150 °C, which is not possible with a standard
reflux system, and the power required for this corresponds to
that needed for an office light bulb (60 W). Higher temperatures
were also tested in an attempt to reach full conversion, but side
products became predominant due to decomposition. Extend-
ing the reaction time from the standard 2–4 h was not benefi-
cial either. Further optimization indicated that even one hour is
sufficient to reach the maximum conversion (Table 1, entries 9
and 10 respectively), but shortening it further had a deleterious
effect (Table 1, entry 11).
Results and Discussion
We began our investigation on a model reaction, namely the
condensation between acetophenone 1a and p-toluenesulfona-
mide (Ts-NH2), using Ti(OEt)4 as both Lewis acid and drying
agent. Titanium ethoxide was chosen rather than the com-
monly used chlorides in order to avoid the HCl formed upon
quenching, which can catalyze imine hydrolysis. Some of the
reported microwave-assisted methods for the synthesis of N-
sulfonyl aldimines are run solvent free,[29,31,32] and so was our
first attempt (Table 1, entry 1). In this case the reaction crude
was highly viscous and revealed less than 50 % conversion to
the desired N-sulfonyl imine 2a. Therefore we decided to run
the reaction with a solvent (Table 1, entries 2–4). Results were
slightly better with dicholoroethane (DCE) than with toluene.
However, the environmental impact outweighed the benefits,
Finally, we investigated the last reaction parameter remain-
ing, the Lewis acid. The crucial role of Ti(OEt)4 was exemplified
when Ti(OiPr)4 was used instead, as it resulted in significantly
reduced conversion (50 vs. 92 %, Table 1, entries 12 and 8).
Significantly, with Lewis acids derived from other metals, such
as BF3, AlCl3 or ZnCl2, only starting material was recovered
(Table 1, entry 13). Adding extra dehydrating agent (MgSO4)
did not have any influence on the conversion. Importantly, we
could lower the number of equivalents of Ti(OEt)4 from 2 to 1
without any impact on the conversion (Table 1, entry 15).
Table 1. Optimization of reaction conditions.[a]
Having solved one of the major issues in the synthesis of
enolizable ketimines, namely the conversion, we moved to the
next problem: product isolation. The kinetic instability of imines
often causes low isolated yields even when the conversion is
high.[21,33] Purification by column chromatography using either
silica or neutral aluminum oxide as well as their passivated ana-
logues led to partial hydrolysis of the ketimine product. To over-
come this problem we attempted crystallization. Unfortunately,
the traces of remaining Ts-NH2 prevented selective product
crystallization. Despite these difficulties encountered in the pu-
rification, the acetophenone-derived N-tosyl imine 2a could be
obtained with 75 % yield after fast column chromatography
(Table 2, entry 1).
Entry
Equiv.
Ts-NH2
Time
[min]
Temp.
[°C]
Lewis acid
(2 equiv.)
Solvent
Conv.
[%][b]
1
2
3
4
5
6
7
8
1
1
1
1
120
120
120
120
120
120
120
120
240
60
100
100
100
100
100
100
125
150
150
150
150
150
150
150
150
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
Ti(OiPr)4
B, Al, Zn[c]
Ti(OEt)4
Ti(OEt)4
–
49
59
61
49
64
64
80
92
94
93
89
50
0
toluene
DCE
DCM
2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
Next we investigated the scope of the reaction. In order to
compare our method with those previously reported, both
yields are presented in Table 2. It should be noted that, unfortu-
nately, many of the reports using ketimines do not report the
actual yields for their synthesis. We compare our methodology
against the reported direct condensation yields (one-step reac-
tion between the ketone and the sulfonamide) as well as
against multi-step synthesis protocols, most of which can be
attributed to Ruano's method.[20]
9
10
11
12
13
14[d]
15[e]
30
120
120
60
93
93
60
[a] Reaction conditions: 1a (1 mmol), p-toluenesulfonamide, dry solvent
(0.5 mL) and Lewis acid (2 equiv.), stirred under microwave irradiation (60 W).
[b] Conversion was estimated by 1H NMR spectroscopy. [c] BF3·OEt2, AlCl3
and ZnCl2 were independently tested. [d] MgSO4 was added. [e] 1 equiv. of
Ti(OEt)4 was used.
The initial substrate scope involved the synthesis of aryl alkyl
ketimines. The presence of electron-donating groups (EDG) in
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Table 2. Substrate scope.
the aromatic ring resulted in relatively lower yields of the imine,
due to ketone deactivation. Hence, imines 2b and 2c with p-
Me and p-OMe substituents, respectively, were isolated in 67 %
and 62 % yield (Table 2, entries 2 and 3 respectively). N-tosyl
imine 2d with a more electron-rich aromatic ring, such as thio-
phene, was isolated in a good 70 % yield (Table 2, entry 4).
Surprisingly, introducing an electron-withdrawing group in the
aromatic ring did not enhance the conversion. In fact, product
2e was obtained with slightly lower conversion (78 %) than in
the case of ketones with EDG (Table 2, entry 5). An additional
drawback of the activated substrate was more rapid hydrolysis
of the corresponding ketimine, leading to only 44 % of isolated
yield.
To examine the role of sterics, both substrates with ortho
substituents in the aromatic ring as well as substrates with
bulky alkyl groups, were tested. A methyl group in ortho posi-
tion was tolerated, providing product 2f with 62 % of isolated
yield (Table 2, entry 6). The bulkiness of the alkyl moiety had a
stronger impact on the reaction outcome. The imine 2g, with a
tert-butyl group instead of the methyl of the benchmark aceto-
phenone-derived 2a, was formed in 57 % conversion (Table 2,
entry 7). Interestingly, isopropyl bearing imine 2h could not
be obtained, due to complete tautomerisation to the enamine
product. The trend towards enamine formation was also ob-
served when the R2 was Et. The enamine product (15 %) was
formed next to the desired product 2i, which was obtained
with 42 % isolated yield (Table 2, entry 9).
Next we applied the methodology to the synthesis of dialkyl
ketimines. N-Tosyl imine 2j was obtained in 54 % isolated yield
(Table 2, entry 10). The product 2k with the bulkier tert-butyl
group was obtained in higher yield, 60 %, probably due to the
less pronounced enolization pathway (Table 2, entry 11). The
synthesis of a diaryl ketimine was also attempted. N-tosyl imine
2l, derived from benzophenone, was obtained with an excellent
yield of 84 % (Table 2, entry 12).
Finally, to assess the viability of the method for the synthesis
of other N-sulfonyl imine derivatives, the influence of the sub-
stituent in the sulfonamide (R3) moiety was investigated. Re-
placing the aryl with an alkyl group in the sulfonamide de-
creased the reactivity of the corresponding Ts-NH2, and the ace-
tophenone-derived tert-butyl N-sulfonyl imine 2m, as well as
methyl N-sulfonyl imine 2n, were obtained in 54 % and 37 %
yields, respectively (Table 2, entries 13 and 14). As expected,
the synthesis of N-sulfonylmesityl imine 2o provided the prod-
uct with a modest 27 % yield, but this is nevertheless signifi-
cantly higher than what is possible with the previously reported
method (Table 2, entry 15).[12] Most yields lie in the moderate
to good range, but it should be noted that these surpass the
yields of all previous methods based on direct condensations.
When compared to Ruano's[20] and other multistep synthe-
ses,[26,27] this one-step synthesis provides similar yields, using
an operationally far simpler procedure, reduced amounts of rea-
gents, and remarkably shorter reaction times. To further prove
the synthetic utility of the methodology we scaled up the syn-
thesis to 6.5 mmol of acetophenone 1a. N-Tosyl imine product
2a was obtained in 1.2 g (66% yield, see Supporting Informa-
tion for details).
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the synthesis of N-sulfonyl ketimines, via direct condensation of
ketones and sulfonamides, assisted by MWI. Microwave-assisted
synthesis of imines from the commercially available ketones
and sulfonamides allows completing the transformation in one
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Experimental Section
Procedure for the Synthesis of N-Sulfonyl Imines: A 10 mL micro-
wave vial equipped with a stirrer was charged with the ketone
(1 mmol), the sulfonamide (1.2 mmol), dry toluene (0.5 mL) and
Ti(OEt)4 (1 mmol). The vial was closed and heated at 150 °C for 1 h
using microwave irradiation. After completion, it was let to cool
down to room temperature, diluted with 5 mL of AcOEt, quenched
with 1 mL of NaHCO3, and filtered through a pad of celite. The
solvent was evaporated in vacuo and the crude was analysed by 1H
NMR spectroscopy. Conversion was estimated by comparing the
integration of signals corresponding to the product and to the unre-
acted ketone. In the case of volatile ketones the comparison was
done against the remaining p-toluenesulfonamide. The crude prod-
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tures of n-pentane and AcOEt as the eluent.
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Acknowledgments
Financial support from the Netherlands Organisation for Scien-
tific Research (NWO) through VIDI and ECHO grants is gratefully
acknowledged.
Keywords: Microwave chemistry · Imines · Ketimines ·
Condensation reactions
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Received: January 8, 2016
Published Online: February 17, 2016
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