Tandem Coupling of Azide with Isonitrile and Boronic Acid: Facile Access to Functionalized Amidines

Article abstract of DOI:10.1002/anie.201700539

Amidine is a notable nitrogen-containing structural motif found in bioactive natural products and pharmaceuticals. Herein, a novel rhodium(I)-catalyzed tandem reaction of readily accessible azides with isonitriles and boronic acids via a carbodiimide intermediate is achieved. This protocol offers an alternative approach toward N-sulfonyl-, N-acyl-, and N- phosphoryl-functionalized, as well as general N-aryl and N-alkyl amidines with broad substrate scope. In addition, functionalized guanidines can also been synthesized when amines are used instead. The accomplishment of estrone-derived amidine and glibenclamide bioisosteres further reveals the practical utility of this strategy.

Full text of DOI:10.1002/anie.201700539

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201700539
German Edition: DOI: 10.1002/ange.201700539
Synthetic Methods
Tandem Coupling of Azide with Isonitrile and Boronic Acid: Facile
Access to Functionalized Amidines
Zhen Zhang, Baoliang Huang, Guanyu Qiao, Liu Zhu, Fan Xiao, Feng Chen, Bin Fu, and
Zhenhua Zhang*
Abstract: Amidine is a notable nitrogen-containing structural
motif found in bioactive natural products and pharmaceuticals.
Herein, a novel rhodium(I)-catalyzed tandem reaction of
readily accessible azides with isonitriles and boronic acids via
a carbodiimide intermediate is achieved. This protocol offers
an alternative approach toward N-sulfonyl-, N-acyl-, and N-
phosphoryl-functionalized, as well as general N-aryl and
N-alkyl amidines with broad substrate scope. In addition,
functionalized guanidines can also been synthesized when
amines are used instead. The accomplishment of estrone-
derived amidine and glibenclamide bioisosteres further reveals
the practical utility of this strategy.
As a prominent class of nitrogen-containing structural
motifs, amidines are ubiquitous in bioactive natural products
and pharmaceuticals.[1] In particular, N-sulfonyl,[2] N-acyl,[3]
and N-phosphoryl[4] amidines exhibit a broad range of
biological and pharmacological activities because of their
special N functional groups. Therefore, the development of
practical and efficient methods for their syntheses is highly
desirable. Generally, the approach involves the nucleophilic
attack of an amine on an imine intermediate bearing a leaving
group, and usually requires mutiple steps and relatively hash
reaction conditions (Scheme 1a).[5,6] Such transformations via
palladium imine intermediates have also been developed.[6]
Very recently, Wu et al. reported a palladium-catalyzed
construction of amidines from arylboronic acids and isocya-
nides.[6c] However, the use of a stoichiometric amount of an
oxidant, Cu(OAc)2, was necessary, and neither N-sulfonyl-,
N-acyl-, nor N-phosphoryl-fuctionalized amidines could be
achieved. Alternatively, the synthesis of N-sulfonyl and
N-phosphoryl amidines through a copper-catalyzed three-
component reaction via a ketenimine intermediate has been
explored (Scheme 1b).[7] Unfortunately, C-aryl-substituted
amidines cannot be obtained by this route. Carbodiimide is
another intermediate for accessing amidines, but the require-
ment of either Grignard or organolithium reagents and the
lack of convenient access to functionalized carbodiimides
limit the application of this approach (Scheme 1c).[8]
Recently, transition metal catalyzed coupling of carbodi-
Scheme 1. Previous strategies to synthesize functionalized amidines.
Bt=1-benzotriazolyl, LG=leaving group.
imides with organic halides has also been developed.[9]
Nevertheless, such a catalytic method to form functionalized
amidines has rarely been reported.
Rhodium-catalyzed coupling of organoboron reagents
with unsaturated systems is a powerful strategy for construct-
[10]
À
ing C C bonds. This protocol has seen widespread appli-
cation in the arylation of activated alkenes/alkynes,[10a,b]
ketones,[10c] imines,[10c] and isocyanates.[11] To the best of our
knowledge, the catalytic reaction of carbodiimides with
arylboronic/alkenylboronic acids to form amidines has not
been explored.
In contrast, organic azides have been identified as
a convenient nitrogen source in the formation of N-containing
[12d,13]
compounds.[12] While C H amination
and aziridina-
À
tion[14] are two classical nitrene transformations, transition
metal catalyzed reaction of azides with s-donor/p-acceptor
ligands has also showed synthetic value in the convenient
synthesis of isocyanate[15] and carbodiimide[16,17] intermedi-
ates. As a continuation of our studies,[17] we report herein
a rhodium(I)-catalyzed tandem coupling of commercially
available and air-stable sulfonyl, acyl, and phosphoryl azide
with isonitrile and arylboronic acid, and it provides facile
access to N-sulfonyl, N-acyl, and N-phosphoryl functionalized
amidines, respectively (Scheme 1d). It is worth mentioning
that the mild reaction conditions of this reaction effectively
prevent the incidental Curtius rearrangement of acyl azides.
In addition, this process to form amidines is also compatible
with general aryl azides.
[*] Z. Zhang, B. Huang, G. Qiao, L. Zhu, F. Xiao, F. Chen, Prof. Dr. B. Fu,
Prof. Dr. Z. Zhang
Department of Applied Chemistry, China Agricultural University
2 West Yuanmingyuan Road, Beijing 100193 (China)
E-mail: zhangzhh@cau.edu.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201700539.
At the outset, sulfonyl azide was selected as a pioneer to
react with tBuNC (2a) in the presence of a rhodium(I)
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catalyst. To our delight, TsN3 (1a) reacted with 2a smoothly
under 5 mol% [Rh(cod)acac] catalysis at room temperature,
and addition of phenylboronic acid (3a) furnished amidine
(4an) in 62% yield through a single rhodium(I)-catalyzed
process [Eq. (1); acac = acetylacetonate, cod = 1,5-cycloocta-
diene, M.S. = molecular sieves, Ts = 4-toluenesulfonyl].[18]
The unstable sulfonyl carbodiimide intermediate was difficult
to isolate and characterize. When benzoyl azide (1b) was used
instead, the less reactive intermediate benzoyl carbodiimide
5a was isolated in 67% yield by flash silica gel column.
Further coupling with phenyl boronic acid (3a) afforded the
N-acyl amidine 4ca in 76% yield [Eq. (2)].[18]
revealed that substrates bearing EWGs (electron-withdraw-
ing groups) exhibit higher reactivity than those with EDGs
(electron-donating groups; 4ai, 4aj). When using benzyl- or
alkyl-substituted isonitriles, the amidine products were
obtained with slightly decreased yields (4am, 4an). In
addition, hetero aromatic boronic acid and alkyl-substituted
sulfonyl azides could also participate, albeit with relatively
low yield (4ao). While phosphoryl azides performed with
slightly poor efficiency relative to sulfonyl azides, the
N-phosphoryl amidines with different substituents were also
produced in synthetically acceptable yield (4ba–bd). Notably,
this protocol readily tolerated alkenylboronic acids, which
reacted with diverse azides and isonitriles to provide the
desired amidine products with comparable yield (4ap–ar,
4be).
Besides functionalized N-sulfonyl and N-phosphoryl
azides, this rhodium(I)-catalyzed tandem transformation to
amidines could also be applied to general aryl azides
(Table 2). Aryl azides bearing EWGs furnished the desired
Table 2: The examination of substrate generality of amidines with aryl
azides.[a]
After the preliminary inspection of reactivity features and
optimization of reaction conditions, we further studied the
generality of this process (Table 1). Generally, the reaction
tolerated a range of substituted sulfonyl azides with Br, CF3,
and MeO groups. A survey of various arylboronic acid
Table 1: The examination of substrate generality of N-sulfonyl and
N-phosphoryl amidines.[a]
[a] RhI (0.01 mmol), 1 (0.22 mmol), 2 (0.2 mmol) were added in 1,4-
dioxane (2 mL), the mixture was stirred for 2 h at RT. Then 3 (0.4 mmol)
was added, and the reaction run for 14 h at 1208C. Yield of isolated
product. [b] K3PO4 (0.1 mmol) was added. [c] DCC was selected as
starting material to react with 3.
products in excellent yield (4dc), whereas EDGs retarded the
reaction (4db). In contrast, a brief examination of aryl
boronic acids showed that electron-rich substrates gave
preferable results (4de, 4df). Notably, benzyl (4dg) and aryl
isonitrile (4dh) proved to be compatible with the reaction
conditions. When alkenyl boronic acids were used instead,
this protocol also showed a good reaction efficiency toward
C-alkenyl-substituted amidines as well (4di–dk). In addition,
N,N’-dicyclohexylbenzimidamide was afforded at elevated
temperature utilizing dicyclohexylcarbodiimide (DCC) as
a starting material, albeit with 34% yield (4dl).
[a] RhI (0.01 mmol), 1 (0.22 mmol), 2 (0.2 mmol) were added in 1,4-
dioxane (2 mL), the mixture was stirred at RT for 2 h. Then 3 (0.4 mmol)
and 4 ꢀ M.S. (20 mg) were added, and the reaction run for 14 h at 1108C.
Yield of isolated product.
Although the single rhodium(I)-catalyzed tandem process
for N-acyl amidine formation only gave 4ca in 32% yield
upon isolation, the use of purified acyl carbodiimide to couple
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with arylboronic acid would provide better results in the
presence of the additive K3PO4/K2CO3 (Table 3).[18] In the
study of the scope of acyl azides, both EDGs, such as methyl,
methoxy (4cb, 4ce), and EWGs, such as chloro and trifluoro-
Table 3: The examination of substrate generality of N-acyl amidines.[a]
[a] RhI (0.01 mmol), 5 (0.2 mmol), 3 (0.4 mmol), K3PO4 (0.1 mmol) and
4 ꢀ M.S. (20 mg) were added in 1,4-dioxane (2 mL), and the mixture was
stirred for 10 h at 1108C. Yield of isolated product. [b] K3PO4 was
replaced by K2CO3. [c] [Rh(cod)acac] (7 mol%) was added.
Scheme 2. The late-stage amidination and guanidination of bioactive
compounds.
methyl (4cc, 4cd), were well tolerated. Likewise, changing
substituents on aryl boronic acids had no significant impact on
catalytic efficacy (4ch–cl). Notably, thiophene-substituted
acyl azide and boronic acid were also amenable to direct
conversion, albeit with 7% rhodium loading (4cg, 4cm).
When the acyl carbodiimide was derived from an aryl
isonitrile, only a trace amount of product was detected (4cn).
Apart from functionalized amidines, N-sulfonyl-, N-acyl-,
and N-phosphoryl-substituted guanidines could also be
obtained in good yield under mild reaction conditions when
utilizing amines as a nucleophilic reagent (Table 4).[18] These
functionalized guanidines have also been widely used in
pharmaceuticals and agrochemicals.[19]
Having revealed a more convenient to construct function-
alized amidine and guanidine motif, we applied this reaction
to synthesize bioactive molecules. The treatment of estrone-
derived arylboronic acid (3b) with azide and isonitrile
successfully accomplished a estrone-derived amidine (8;
Scheme 2). Glibenclamide is a sulfonylurea antidiabetic
drug.[20] Glibenclamide-derived amidine (9a) could be syn-
thesized expediently from sulfonylazide 1c, tBuNC (2a), and
phenylboronic acid (3a). When amines were used instead,
glibenclamide-derived guanidines were achieved in desirable
yield (9b, 9c). Notably, BM-208 (9b) is a bioisostere of
glibenclamide and potent insulin releasing agent.[21]
A plausible mechanism was proposed in Scheme 3.
Initially, under the assistance of rhodium(I), 1a reacts with
2a to generate the intermediate B with release of N2 gas
simultaneously. Next, reductive elimination of B regenerated
the rhodium(I)-catalyst and liberated the carbodiimide C. For
the generation of amidine, the catalytic cycle was initiated
through transmetalation of the phenyl group from boron to
rhodium(I) to produce phenylrhodium D. Afterwards, the
addition of the species D to carbodiimide C formed the
N-bound rhodium(I) complex E, which could undergo pro-
tonolysis with 3a to furnish the rhodium(I) boronate F and
release the product 4an. The intermediate F further regen-
erated D through b-aryl elimination.[22]
Table 4: Syntheses of N-sulfonyl, N-acyl, and N-phosphoryl guanidi-
nes.[a]
[a] RhI (0.01 mmol), 1 (0.2 mmol), 2 (0.22 mmol) and 6 (0.24 mmol)
were added in 1,4-dioxane (2 mL), the mixture was reacted for 2 h at RT.
Yield of isolated product. [b] K2CO3 (0.4 mmol) was added.
Scheme 3. Proposed mechanism.
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In summary, we have developed a novel strategy to access
N-sulfonyl, N-acyl, and N-phosphoryl functionalized, as well
as general N-aryl and N-alkyl amidines directly from azide,
isonitrile, and aryl/alkenylboronic acids using only a single
rhodium(I) catalyst. Functionalized guanidines could also be
obtained in excellent yield when using amine as a nucleophilic
reagent. Broad substrate scope and good functional-group
tolerance are key characteristics of this protocol. In addition,
the synthetic study of estrone-derived amidines and gliben-
clamide derivatives further revealed the promising imple-
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Acknowledgments
This project is supported by National Natural Science
Foundation of China (No. 21672256, 21302219), National
S&T Pillar Program of China (2015BAK45B01), Chinese
Universities Scientific Fund (2016RC040), and Beijing
National Laboratory of Molecular Sciences (BNLMS). We
appreciate Dr. Yiyang Liu of University of Michigan for
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Conflict of interest
The authors declare no conflict of interest.
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Keywords: azides · boron · reaction mechanisms · rhodium ·
synthetic methods
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Manuscript received: January 16, 2017
Final Article published: && &&, &&&&
4
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Angewandte
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Communications
Synthetic Methods
Z. Zhang, B. Huang, G. Qiao, L. Zhu,
F. Xiao, F. Chen, B. Fu,
Z. Zhang*
&&&& — &&&&
Tandem Coupling of Azide with Isonitrile
and Boronic Acid: Facile Access to
Functionalized Amidines
In tandem: A rhodium(I)-catalyzed
as well as general N-aryl and N-alkyl
tandem reaction of readily accessible
azides with isonitriles and boronic acids
via a carbodiimide intermediate offers an
alternative approach towards N-sulfonyl-,
N-acyl-, and N-phosphoryl-functionalized
amidines with broad substrate scope. The
synthesis of estrone-derived amidine and
glibenclamide bioisosteres reveals the
practical utility of this strategy.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!