Angewandte
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sulfonylurea-bridged palladium could be an N,O-donor form
or an N,N-donor form, and the NMR analysis suggested that
the N,O-donor form would be dominant [Eq. (2)].[17] How-
ever, for the sulfonylurea 3aa, derived from the secondary
amine morpholine (2a), the NMR spectrum of the mixture of
sulfonylurea and Pd(OAc)2 was no different from that of the
free sulfonylurea. In addition, when mixing Pd(OAc)2 with
3aa and 3al together, only the change of 3al could be found
(see the Supporting Information for details).
Scheme 3. Proposed mechanism.
To further understand the role of the product sulfonylurea
itself in the reactions, relative rates of the reactions between
1a and different amines were studied (Figure 1b). Regardless
of whether PhNH2 (2b), p-MeOC6H4NH2 (2c), p-ClC6H4NH2
(2d), or MesNH2 (2l) were used, the conversions were
completed in 40 minutes. The rate of the reaction of bulky
alkyl amine tBuNH2 (2s) was also faster, up to 98% in
35 minutes. However, the reaction the secondary amine 2a
gave only 42% product after 1 hour, and required more than
1.5 hours to complete. These results do not accord with the
nucleophilicity of different amines.[18] Together with the
above investigation of the interaction of sulfonylurea and
Pd(OAc)2, one reasonable explanation was that the presence
of different sulfonylurea products would affect the rate of
TsNCO formation. Then we further studied relative rates of
the reactions of 2a with only Pd(OAc)2 and using sulfonylurea
H2L1 as the additive. Clearly, the reaction proceeded at
a much quicker rate when the catalyst was changed from
CO. The reactions are operationally simple and proceed
smoothly under mild reaction conditions to afford highly
functionalized sulfonylureas in outstanding yields, thus dem-
onstrating broad applications in both pharmaceuticals and
pesticides. The gram-scale preparation exhibited nearly
quantitative yield, and the synthesis of Glibenclamide
revealed the promising implementation of our methodology
in total synthesis. In addition, mechanistic studies as well as
NMR spectroscopy, HRMS, and control experiments provide
evidence to support the presence of a bridging ligand as key to
this reaction. Furthermore, the bimetallic palladium species
derived from the product sulfonylurea is superior to Pd-
(OAc)2, and is the real active catalyst during the carbon-
ylation. This work amply demonstrates that palladium-
catalyzed reactions of sulfonylazides show great potential in
the synthesis of functionalized nitrogen-containing com-
pounds, and bridged bimetallic palladium species may play
an important role for palladium nitrene generation from
sulfonylazides.
Pd(OAc)2 to [Pd2L1 (MeCN)2]. It was complete in 40 minutes,
2
the same as other reactions performed in Figure 1b. This data
is important evidence that the sulfonylureas from primary
amines are superior to the acetate ligand in terms of
coordination to palladium, that this product-bridged palla-
dium species, which has higher reactivity, is the real active
catalyst in sulfonylazide carbonylation with primary amines.
Based on the above investigations and other reports of
discrete late-metal nitrenes with CO to give isocyanates,[19]
a possible reaction mechanism was proposed (Scheme 3).
Initially, the in situ generated sulfonylurea product (from
primary amines) combined with Pd(OAc)2 in the presence of
CO to produce a MeCN/CO-coordinated bimetallic palla-
dium complex in the N,N-donor form A, or N,O-donor form
A’, which was suggested as the real active catalyst in this
reaction. Then, reaction of A/A’ with the sulfonylazide took
place along with dinitrogen extrusion to afford the bimetallic
palladium nitrene complex B. Subsequently, insertion of the
s-donor/p-acceptor ligand CO into the palladium nitrene
complex C to produce the sulfonyl isocyanate D with the
regeneration of A/A’. Finally, nucleophilic addition of the
amine component furnishes sulfonylurea as the final product.
In summary, we have developed a novel palladium-
catalyzed nitrene-transfer reaction of sulfonylazides with
Acknowledgments
This project is supported by the National Natural Science
Foundation of China (No. 21302219), Chinese Universities
Scientific Fund (2014RC009), National S&T Pillar Program
of China (2015BAK45B01), and Beijing National Laboratory
of Molecular Sciences (BNLMS). We thank Prof. Zhiyuan
Zhang and Huan Sun of National Institute of Biological
Sciences (Beijing) for LC-MS analysis support. We appreciate
Dr. Yiyang Liu of University of Michigan for correcting this
manuscript. We also acknowledge Prof. Jianbo Wang, Prof.
Fanyang Mo, and Dr. Di Qiu of Peking University for helpful
discussion.
Keywords: azides · carbonylation · palladium ·
reaction mechanisms · structure elucidation
How to cite: Angew. Chem. Int. Ed. 2016, 55, 5545–5549
Angew. Chem. 2016, 128, 5635–5639
5548
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Angew. Chem. Int. Ed. 2016, 55, 5545 –5549