Carbodiimide insertion into sulfonimides: one-step route to azepine derivatives via a two-atom saccharin ring expansion

Article abstract of DOI:10.1039/c6cc07331j

A previously unknown insertion of carbodiimides into sulfonimides enables the first one-step, two-atom expansion of the saccharin 5-membered ring into a 7-membered benzo[1,2,4]thiadiazepine, and a two-atom chain extension of a non-cyclic sulfonimide. This reaction is enhanced by copper salts, which allow it to be conducted mechanochemically, in a solvent-free manner.

Full text of DOI:10.1039/c6cc07331j

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Carbodiimide insertion into sulfonimides: one-step route to
azepine derivatives by a two-atom saccharin ring expansion
Davin Tan and Tomislav Friščića
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
previously unknown insertion of carbodiimides into This discovery reveals a novel two-atom insertion reaction,
sulfonimides enables the first one-step, two-atom expansion of applicable to cyclic, as well as linear sulfonimides, opening a so
the saccharin 5-membered ring into
7-membered far unique8,9 one-step route for direct expansion of saccharin.
a
benzo[1,2,4]thiadiazepine, and a two-atom chain extension of a
non-cyclic sulfonimide. Reaction is enhanced by copper salts,
which allow it to be conducted mechanochemically, in a solvent-
free manner.
Coupling reactions are central to organic synthesis,1,2
leading to simpler, cleaner and often faster transformations,
valuable in pharmaceutical synthesis.3 With our interest in
clean, solvent-free synthesis by mechanochemistry, i.e.
reactions induced or sustained by milling or grinding,4 we
recently demonstrated copper-catalysed carbon-nitrogen (C-N)
coupling reactions of sulfonamides, leading to anti-diabetic
sulfonyl-urea drugs,5 and a new route to sulfonylguanidines by
coupling of sulfonamides with carbodiimides.6
We now describe a previously unknown carbodiimide
insertion reaction, leading to one-step expansion of saccharin
into azepines (Fig. 1a). This work was inspired by a 1971
report7 by Lerch and Moffatt, who focused on
functionalization of arylsulfonamides and sulfonanilides with
methylthiomethyl groups, but also provided a side note on
adduct
formation
between
saccharin
and
di(cyclohexyl)carbodiimide (DCC). The adduct, characterised
1
only by H nuclear magnetic resonance (NMR), was proposed
to be a guanidine resulting from N-H group addition onto DCC
(Figure 1b). As such couplings were recently shown to require
a copper catalysts,6 we were intrigued to re-investigate this
report.
We now show that the adduct is, in fact,
a
benzo[1,2,4]thiadiazepine, formed by an unsuspected
expansion of the saccharin sulfonimide ring by a carbodiimide.
Fig. 1. (a) Herein reported insertion of carbodiimides into saccharin; (b) previously
proposed structure of 1;7 (c) structure of 1 as established by X-ray diffraction, with
hydrogen atoms on carbon omitted for clarity; (d) overlay of FTIR-ATR spectra of
reactants and crude reaction mixtures for attempted reactions of saccharin with DCC
and DTBC, showing complete conversion with DCC, and no reaction with DTBC and (e)
molecular structures of 2, 3 and 4 based on single crystal X-ray diffraction, with
hydrogen atoms bonded to carbon omitted for clarity.
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Azepines are attractive targets due to their medicinal use, and stoichiometric auxiliary reagents. Such transformations
different thiadiazepines have been investigated in treatment include, e.g. the
of Alzheimer’s disease, different types of cancer, and diabetes
mellitus.10 While the syntheses of thiadiazepines have mostly
Table 1. Reactions of saccharin with carbodiimides in solution without a
catalyst, and by LAG (CH3NO2,
η
=0.25 mL/mg) with 10 mol% CuCl.
focused
on
benzo[1,2,5]-,11
benzo[1,3,4]-12
and
benzo[1,4,5]thiadiazepines,13 only a few reports have dealt
with benzo[1,2,4]thiadiazepines.14
Solution yield Mechanochemistry
Carbodiimide
Product
(%)a
95
yield (%)a
78
N
Cy
C
Cy
1
2
In agreement with previous work,7 stirring or refluxing of
N
N
N
N
N
N
C
96
95
saccharin and DCC in ethyl acetate (EtOAc), acetone, or
1
N
acetonitrile gave a precipitate (
1
), characterised by H and 13C
b
-
b
-
b
-
C
C
C
C
N
N
N
NMR, high-resolution mass spectrometry (HR-MS) and powder
X-ray diffraction (PXRD). While 1H NMR data was consistent
with the original report, single crystal X-ray structure
b
b
b
-
Si
Si
-
-
3
4
95
98
85
80
determination revealed
1 is in fact a benzo[1,2,4]thiadiazepine
(Fig. 1c) resulting from DCC insertion into the saccharine ring.
Next, we explored reactivity of other commercially
available carbodiimides (Fig 1c, Table 1). While di(isopropyl)-
(DIC), 1-tert-buyl-3-ethyl- (TBEC), and di(p-tolyl)carbodiimide
N
aIsolated yields after column purification; bno reaction.
To demonstrate scalability, syntheses of
1 and 3 were
(DPTC) readily gave
2 (96% yield), 3 (98% yield) and 4 (95%
repeated on 5 mmol scale mechanochemically (LAG for 4 h,
using 10% mol CuCl) and in solution (overnight reflux in
yield), respectively, no reaction was observed with sterically
demanding di(tert-butyl)- (DTBC) and di(trimethylsilyl)-
carbodiimide (DTMSC). Lack of reactivity with DTBC and
DTMSC was evidenced by FTIR-ATR spectra of crude reaction
mixtures after solvent removal, which all exhibited the
characteristic carbodiimide band at 2000-2200 cm-1 (Fig 1d).
acetone, no catalyst). For
(85%) of product, while solution synthesis gave 1.4 g (92%).
For , LAG and solution yields were 1.4 g (88%) and 1.3 g
1, mechanochemistry gave 1.3 g
3
(85%), respectively.
Compounds
PXRD, and single crystal X-ray diffraction, which confirmed
they are benzo[1,2,4]thiadiazepines resulting from
2-4 were characterised by NMR, MS, FTIR-ATR,
carbodiimide insertion (Fig. 1e). Whereas the non-symmetrical
TBEC could yield two isomeric products, we observed only one,
resulting from the insertion of the less sterically hindered
ethyl-substituted side of TBEC.
With our interest in solvent-free reactivity,5,6,15 we also
attempted the insertion reactions by mechanochemistry. No
reaction was observed by milling of saccharin and DIC, either
neat, or by liquid-assisted grinding (LAG)16 using catalytic
amounts of EtOAc or CH3NO2 (50
mixture, =0.25
L/mg17). Next, we explored using catalytic
CuCl, strategy that previously enabled coupling of
carbodiimides with sulfonamides. Indeed, LAG with 10 mol%
CuCl led to the quantitative formation of , obtained as a
ꢀL per 200 mg of reaction
η
ꢀ
a
2
white powder after a simple isolation protocol involving brief
milling with an aqueous solution of the disodium salt of
ethylenediaminetetraacetic acid (Na2H2EDTA), followed by
washing with deionized water.§ Formation of
2 was evident
from the FTIR-ATR spectrum of the crude reaction mixture,
which showed complete disappearance of DIC (Fig. 2a). That
the insertion took place by LAG is also confirmed by the PXRD
pattern of the crude reaction mixture, which revealed an
Fig. 2. PXRD patterns for: (a) crude LAG reaction mixture of DIC and saccharin in
presence of CuCl, and (b) simulated for 2. (c) Comparison of FTIR-ATR spectra of DIC,
saccharin and their crude mechanochemical reaction mixtures with and without CuCl.
The FTIR-ATR and PXRD data confirm the formation of 2 by LAG in presence of CuCl.
Symbol for mechanochemical transformation is adopted from the work of Hanusa
group.4h
excellent fit to the pattern simulated for crystal structure of
2
(Fig. 2b). Overall, reactivity by LAG was identical to that in
solution: DCC, DIC, TBEC and DPTC readily gave
reaction was seen with DTBC or DTBSC (Table 1).
1-4, while no
The facile expansion of saccharin is remarkable,
considering that literature examples of saccharin ring
expansion are rare and based on multi-step reactions involving
formation of an 8-membered ring by N-alkylation with
Leakadine and intramolecular nucleophilic ring expansion,18
2 | J. Name., 2012, 00, 1-3
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and the Gabriel-Colman rearrangement19 in presence of methylsaccharin have so far failed, suggesting that the
stoichiometric base.20
sulfonimide N-H group may be important for the insertion.
Finally, we explored if the ring expansion can be applied to
Moreover, whereas examples of ring expansion reactions
21
with carbodiimides are known, these are largely chemically isocyanate electrophiles. Attempts to react saccharin and
very different systems as they necessitate the use of a metal cyclohexylisocyanate in solution or by milling were
catalyst and strained 3- and 4-membered ring reactants.21-23 To unsuccessful.
However,
explore if the herein reported carbodiimide insertion, which in cyclohexylisocyanate in presence of 10 mol% CuCl led to
solution takes place even without catalyst, may be due to ring quantitative formation of a new product ( ), characterized by
strain, we explored reactivity of an acyclic analogue of NMR, MS and FTIR-ATR (Fig. 4e). X-ray crystallography (Fig. 4f)
saccharin, 4-methyl-N-tosylbenzamide ( ). Compound was revealed is a saccharyl-urea that would be expected from a
prepared by a Steiglich coupling of p-tolylsulfonamide and copper-catalyzed C-N coupling analogous to that seen with
toluic acid. Milling
with DIC in presence of CuCl over 2 h gave sulfonamides.4 Similar results were observed with n-butyl, 2-
30% conversion to a new compound, , which was also chloroethyl, and phenylisocyanates, giving 10, and 11
obtained in 55% conversion by overnight reaction in acetone respectively, all characterized by spectroscopic methods.
LAG
of
saccharin
and
8
5
5
8
5
6
9,
,
(Fig. 3a,b).
Compounds 10 and 11 (Fig. 5c) were also characterized by
single crystal X-ray diffraction. Consequently, reactions of
saccharin with isocyanates resemble those of sulfonamides.6
Table 2. Reactivity of saccharin with isocyanates by LAG (CH3NO2, η=0.25
mL/mg) with 10 mol% CuCl.
Compound
R-NCO
Cy-NCO
Yield (%)
95a
8
9
n-butyl-NCO
2-Cl-ethyl-NCO
Ph-NCO
71a
10
11
80a
65b
aisolated yield after workup; bconversion.
We suggest two potential mechanisms for the observed
carbodiimide insertion. One is via the formation of a short-
lived adduct that rapidly rearranges (Scheme 1, top). However,
reaction monitoring by in situ IR spectroscopy did not yet offer
any evidence for a reaction intermediate, and we speculate
the reaction might be taking place by a more direct, concerted
pathway (Scheme 1, bottom). In either case, catalytic role of
copper may be explained by simultaneous coordination to
sulfonylimide and carbodiimide reagents, bringing them into
close proximity for reaction.
Proposed Mechanism 1
O
O
O
R
R
N
C
N
N
R
R
N
N
NH
N
NH
R
S
S
HN
O
R
O2
S
O
O2
Fig. 4. (a) Synthesis of 5 from p-tolylsulfonamide and p-toluic acid in presence of 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC); (b) insertion reaction of 5 with
carbodiimides. Molecules of (c) 6 and (d) 7, based on single crystal X-ray diffraction. (e)
Coupling of saccharin and CyNCO to form 7. Structures of: (f) 8 and (g) 11, based on
single crystal X-ray diffraction, with hydrogen atoms bonded to carbons omitted for
clarity.
Proposed Mechanism 2
R
N
C
N
O
O
R
O
R
N
N
C
N
NH
R
NH
O
N
H
R
S
O
N
S
S
R
O2
O2
Scheme 1. Proposed mechanisms for the observed carbodiimide insertion reaction.
In summary, we reported a previously not known one-step
insertion reaction of a two-atom carbodiimide fragment into
cyclic or linear sulfonimides. Reaction may be enhanced by
CuCl, which also allows it to be performed without bulk
solvent. The insertion yields thiadiazepines from saccharin and
in at least two cases enabled a chain extension of a linear
sulfonimide. To the best of our knowledge, this is the first
route for direct expansion of saccharin, in one step and
without auxiliary reagents, and the fact that it leads to
thiadiazepines should make it attractive for green and
pharmaceutical synthesis. We are now conducting
Eventually,
shown by 1H NMR spectroscopy, by overnight reflux in
acetonitrile in the presence of 20% mol CuCl. Compound was
characterised by 1H NMR, MS and FTIR-ATR. X-ray single crystal
diffraction revealed is the product of carbodiimide insertion
into the C-N bond of the sulfonimide moiety of (Fig. 3c),
which extended the length of the molecule by two atoms.
Insertion also took place with DCC, yielding (Fig. 3d).
Formation of and demonstrates that a ring structure is not
6 was obtained in quantitative conversion, as
6
6
5
7
6
7
crucial for the insertion, and that the reaction is also applicable
to chain extension. Attempts to achieve a reaction with N-
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We acknowledge the NSERC Discovery Grant, Canada
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0.50 mmol of sulfonamide, 0.50 mmol carbodiimide or isocyanate were milled for 2
h with 10-20 mol% CuCl and CH3NO2 as the LAG liquid. Then, 3 mL water and 20-40
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