Synthesis of N-Sulfonyl Arylaldimines Developed by Retesting an Old Process

Article abstract of DOI:10.1021/acs.orglett.5b03686

By simply heating the mixture of an arylaldehyde and a sulfonylisocyanate in a solvent or in neat form under catalyst- and additive-free conditions, the desired N-sulfonylimine was produced with the release of carbon dioxide. The method is characterized b

Full text of DOI:10.1021/acs.orglett.5b03686

Letter
pubs.acs.org/OrgLett
Synthesis of N‑Sulfonyl Arylaldimines Developed by Retesting an Old
Process
Dayun Huang, Xuesong Wang, Xingyong Wang, Wenwen Chen, Xinyan Wang,* and Yuefei Hu*
Department of Chemistry, Tsinghua University, Beijing 100084, China
S
* Supporting Information
ABSTRACT: By simply heating the mixture of an arylaldehyde and a
sulfonylisocyanate in a solvent or in neat form under catalyst- and
additive-free conditions, the desired N-sulfonylimine was produced
with the release of carbon dioxide. The method is characterized by its
unique clean efficiency, convenience, and scalability, but it was
reported to fail half a century ago.
Scheme 2, the desired N-tosylimine 1 was synthesized efficiently
by the reaction of an aldehyde with N-tellurinyl tosylamide
lectron-deficient imines are also called activated imines. The
Emost prominent among them are N-sulfonylimines, which
are not only the most activated imines but also those stable
enough to be isolated and stored.1 As excellent electrophiles, they
have been used widely in various organic transformations. As
shown in Figure 1,2−6 N-sulfonyl arylaldimines (1) are the most
popular ones due to their relatively easier preparation.
Scheme 2. Methods Not Based on Dehydration
Figure 1. Various organic transformations of 1.
In the literature, a number of methods have been developed for
the synthesis of 1.7−12 As shown in Scheme 1, the most
Scheme 1. Synthesis of 1 by Dehydration
(TsNTeO, method a)12a or with N-sulfinyl tosylamide (TsNSO,
method b).12b Both methods initially carried out a thermal [2 +
2] cycloaddition to form a four-membered ring intermediate.
Then, the intermediate underwent a horizontal [2 + 2]
cycloreversion to give N-tosylimine 1 with the release of TeO2
or SO2. Since TeO2 is an insoluble solid and SO2 is a gas, the
reaction equilibria were irreversibly shifted toward the products,
but these methods have been rarely used for this purpose,
presumably because of inaccessible reagents, high costs, and
unpleasant smells.
Herein, we report a new protocol, method c, for the efficient
synthesis of N-sulfonylimine 1 that involves simple heating of
arylaldehyde 2 with sulfonyl isocyanate 4 in a solvent or neat.
Since many sulfonyl isocyanates 4 are commercially available
substrates and CO2 is the only byproduct of method c, the
drawbacks associated with methods a and b are overcome
completely.
commonly used methods8−11 are those based on the dehydration
between an arylaldehyde 2 and a sulfonamide 3. The dehydration
theoretically is an ideal pathway, but it is not an easy process to
accomplish in practice due to the very low nucleophilicity of 3.
Usually, this problem can be improved by activating the carbonyl
group of 2 with Lewis acids,8 Brønsted acids,9 or dehydrating
reagents.10 Recently, a novel organocatalytic method was
reported,11 in which the carbonyl group was activated by
converting it into an iminium salt in the presence of pyrrolidine
(10 mol %) and 4 Å molecular sieves (1 g/mmol). To date, the
dehydration methods used often suffer from harsh conditions,
tedious workups, and/or the production of large amounts of
waste.
During this investigation, our attention was drawn to two
Received: December 28, 2015
methods12 that did not use the dehydration strategy. As shown in
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03686
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Organic Letters
Letter
a
After understanding the pathway of methods a and b, we
realized that their drawbacks might be overcome by using
tosylisocyanates 4a (TsNCO) as an alternative to TsNTeO or
TsNSO. Disappointingly, the investigation showed that the
reaction between 4-methylbenzaldehyde (2a) and 4a had been
reported by King13 in 1960, but it failed to give the desired
product N-tosylimine 1a. As shown in Scheme 3, this failure was
Table 2. Effect of Solvent on the Reaction of 2a and 4a
b
entry
solvent
temp (°C)
time (min)
yield of 1a (%)
1
2
3
4
5
6
7
8
THF
70
120
100
110
130
90
60
60
60
60
60
60
40
60
trace
50
DME
Scheme 3. King’s Original Work
dioxane
C6H5Me
C6H5Cl
DCE
58
65
70
93
DCE
90
93
DCE
60
83
a
The solution of 2a (5 mmol) and 4a (5 mmol) in different solvent (5
b
mL) was refluxed. Isolated yield was obtained by recrystallization.
attributed to the poor hydrolytic stability of 1a because only the
hydrolytic products 2a and tosylamide (3a) were isolated from
the reaction. Since then, no such methodology study has been
reported in the literature for over half a century.
However, we know now that 1a is a quite stable compound
that can be prepared by different methods and purified by
recrystallization8b,9e,f or chromatography.7a,c,e,10e Therefore, we
believed that King’s experiment and conclusion were incorrect
and needed to be retested. As shown in Table 1, when King’s
To generalize this novel method, the scope of substrates was
tested initially under conditions A (at reflux in DCE). As shown
in Scheme 4, when 4a was fixed, most electron-donating group
(EDG)-substituted aldehydes (2a−2j) reacted smoothly to give
excellent yields of products 1a−1j. To our surprise, the EDG-
substituted aldehydes 2l−2m did not give satisfactory yields of
1l−1m. However, these problems were easily resolved by
treating them under conditions B (by heating neat). In fact,
conditions B proved to be an essential choice for the synthesis of
Table 1. Effect of Temperature on the Neat Reaction of 2a and
a
4a
Scheme 4. Scope of the Method
b
entry temp (°C) reaction time (solidification time) yield of 1a (%)
1
2
50
70
12 h (∼4 h)
12 h (∼6 h)
12 h (∼7 h)
3 h (N/A)
70
76
84
90
3
90
c
4
120
a
The neat mixture of 2a (5 mmol) and 4a (5 mmol) was heated at
b
different temperature. Isolated yield was obtained by recrystallization.
c
Substrate 2a was exhausted.
experiment was repeated by heating the neat mixture of 2a and 4a
at 50 °C for 12 h (entry 1), two important phenomena were
observed: (a) CO2 was slowly released, and (b) the reaction
mixture had solidified completely within 4 h. To our delight, the
desired 1a was obtained in 70% yield after workup. We
hypothesized that a reduction in the yield of 1a might be caused
by a solidification of the reaction system, wherein further release
of CO2 was being blocked off and some unreacted substrates
were trapped within. Thus, the reaction temperature was
gradually elevated, and the yield of 1a was increased by the
increase of the reaction time and temperature (entries 2 and 3).
Eventually, we found that when the reaction was conducted at
120 °C (entry 4), no solidification occurred (the melting point of
1a is 111−112 °C), and 1a was obtained in 90% yield within 3 h.
These results were in full agreement with our hypothesis.
Encouraged by these exciting results, we tested the same
reaction in different solvents. As shown in Table 2, this reaction
tolerated a wide range of solvents, and the best results were
obtained in DCE at reflux, whereupon 1a was obtained in 93%
yield within 40 min. The higher efficiency might be due to the
more facile release of CO2 in solution.
a
b
A: The reaction was boiled in DCE. B: The reaction was heated in
neat.
B
DOI: 10.1021/acs.orglett.5b03686
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Letter
1n−1s. Although 1n−1q could be obtained in excellent yields at
120 °C, 150 °C had to be used to obtain an excellent yield of 1r−
1s. Very similar to 4a, the commercially available sulfonyliso-
cyanates 4b and 4c worked well in the syntheses of 1t−1x. Under
conditions A and B, 1a was prepared on a 50 g scale in 95 and
91% yields, respectively. As expected, alkylaldehydes (as
enolizable aldehydes) were not suitable substrates for this
method.
water-free conditions was developed and was characterized by its
unprecedented cleanliness, efficiency, convenience, and scal-
ability. Finally, the method was successfully applied in two
tandem syntheses of fluorenes. It may be expected that this
method will not only change the synthesis of N-sulfonyl
arylaldimines but also change their synthetic transformations
subsequently.
Since the aza-Friedel−Crafts reaction is a typical application5
of N-tosyl arylaldimine 1 and its product easily undergoes further
electrophilic reaction,5d,14 tandem reactions were expected by
using 2-formyl biphenyl (2t) as a substrate. As shown in Scheme
5, the desired tosylimine 1y was obtained in 83% yield by heating
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03686.
1
Experiments, characterization, H and 13C NMR spectra
for all products 1a−1y, 5, and 6 (PDF)
Scheme 5. Tandem Synthesis of Fluorenes 5 and 6
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wangxinyan@mail.tsinghua.edu.cn.
*E-mail: yfh@mail.tsinghua.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by NNSFC (Nos. 21472107 and
21372142).
■
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