Silver-catalyzed carboazidation of arylacrylamides

Article abstract of DOI:10.1021/ol402138y

A novel and inexpensive method of nontoxic, silver-salt-catalyzed carboazidation of arylacrylamides to afford corresponding azide oxindoles is reported. This reaction system exhibits great functional group tolerance. All products form a crucial skeleton for the synthesis of various indole alkaloids.

Full text of DOI:10.1021/ol402138y

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Silver-Catalyzed Carboazidation of
Arylacrylamides
Xiao-Hong Wei,† Ya-Min Li,† An-Xi Zhou,† Ting-Ting Yang,† and Shang-Dong Yang*,†,‡
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou
730000, P. R. China, and State Key Laboratory for Oxo Synthesis and Selective
Oxidation, Lanzhou Institute of Chemical Physics, Lanzhou 730000, P. R. China
yangshd@lzu.edu.cn
Received June 30, 2013
ABSTRACT
A novel and inexpensive method of nontoxic, silver-salt-catalyzed carboazidation of arylacrylamides to afford corresponding azide oxindoles is
reported. This reaction system exhibits great functional group tolerance. All products form a crucial skeleton for the synthesis of various indole
alkaloids.
Recent advances in transition-metal-catalyzed difunc-
tionalization of alkenes have provided a powerful strategy
for the synthesis of various organic compounds.1 Metal-
catalyzed carbonꢀhetero functionalization of arylacryla-
mides with various nucleophiles in particular has the
potential to incite cyclization and promises a novel path-
way for the synthesis of various functional oxindoles. For
example, the Zhu, Liu, Zecchi, Lu, and Pan groups have
independently developed some new methods of palladium-
catalyzed oxidative carboꢀhetero functionalization of
arylacrylamides, which involve the following nucleophiles:
carbon, TsNH2, CF3ꢀ, t-BuO2H, and DMF.2 More re-
cently, Li and co-workers reporteda Fe-catalyzed oxidative
1,2-alkylarylation of arylacrylamidesto synthesize avariety
of alkoxylated oxindoles.3 At present, the Zhu group
has documented an excellent tandem protocol for the
formation of quaternary oxindoles. Their method involves
visible-light-promoted room-temperature decarboxylation.4
In the past several years, we have focused our efforts on the
development of new and efficient protocols for transition-
metal-catalyzed CꢀP bond formation.5 We have established
a novel efficient protocol for the preparation of various
diphenylphosphoryl oxindoles via silver-catalyzed difunc-
tionalization of arylacrylamides by carbonꢀphosphoryla-
tion and a CꢀH functionalization cascade process as a result
of our endeavors.5d All the evidence indicates that (a) this
transformation involves a radical process and (b) that
Ag-promoted generation of the phosphoryl radical is the
key step. Inspired by these promising results as well as
literature surveys, we hypothesized that the azide might
† Lanzhou University.
‡ Lanzhou Institute of Chemical Physics.
(1) (a) Sibbald, P. A. Palladium-Catalyzed Oxidative Difunctionaliza-
tion of Alkenes: New Reactivity and New Mechanisms; ProQuest: UMI,
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2011. (b) Jacques, B.; Muinz, K. In Catalyzed CarbonꢀHeteroatom Bond
Formation; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2011; p 119; (c)
McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981. (d)
~
Muinz, K. Angew. Chem., Int. Ed. 2009, 48, 9412. (e) Chemler, S. R. Org.
Biomol. Chem. 2009, 7, 3009. (f) Jensen, K. H.; Sigman, M. S. Org.
Biomol. Chem. 2008, 6, 4083. (g) Kotov, V.; Scarborough, C. C.; Stahl,
S. S. Inorg. Chem. 2007, 46, 1910. (h) Li, G.; Kotti, S. R. S. S.; Timmons,
C. Eur. J. Org. Chem. 2007, 17, 2745.
(3) Wei, W.-T.; Zhou, M.-B.; Fan, J.-H.; Liu, W.; Song, R.-J.; Liu,
Y.; Hu, M.; Xie, P.; Li, J.-H. Angew. Chem., Int. Ed. 2013, 52, 3638.
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Y.-M.; Yang, S.-D. Chem.;Eur. J. 2011, 17, 5516. (b) Sun, M.; Zhang,
H.-Y.; Han, Q.; Yang, K.; Yang, S.-D. Chem.;Eur. J. 2011, 17, 9566.
(c) Zhang, H.-Y.; Zhou, A.-X; Li, Y.-M.; Yang, S.-D. Org. Biomol.
Chem. 2012, 10, 9627. (d) Li, Y.-M.; Sun, M.; Wang, H.-L.; Tian, Q.-P.;
Yang, S.-D. Angew. Chem., Int. Ed. 2013, 52, 3972.
(2) (a) Jaegli, S.; Dufour, J.; Wei, H.; Piou, T.; Duan, X.; Vors, J.;
Neuville, L.; Zhu, J. Org. Lett. 2010, 12, 4498. (b) Jaegli, S.; Erb, W.;
Retailleau, P.; Vors, J.; Neuville, L.; Zhu, J. Chem.;Eur. J. 2010, 16,
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r
10.1021/ol402138y
XXXX American Chemical Society

synthesis of alkyl azides by radical addition to olefins
or to the formation of the ubiquitous amino group by
reduction.7 The use of the azidyl radical can alsobe applied
to Huisgen 1,3-dipolar cycloadditions or different variants
of the Staudinger ligation.8 The electrophilic character of
the azidyl radical makes its reaction with olefins especially
interesting.9 The application of azidyl radicals to the
functionalization of unactivated alkenes has seen advances
over the past decades.10 However, until now, transition-
metal-catalyzed direct carboazidation by the addition of
the azidyl radical to alkenes followed by the cascade
carbon radical cyclization processes has never been re-
ported and is highly desirable.
Scheme 1. Silver-Catalyzed Carboazidation of Arylacrylamides
prompt the silver salt to produce an azidyl radical, which in
turn leads to the carboazidation of alkenes and follows CꢀC
bond formation to afford corresponding azide oxindoles.
After much effort, we were able to properly set up the Ag-
catalyzed carboazidation of arylacrylamides (Scheme 1) and
apply it to the synthesis of 3,30-pyrrolidinylspirooxindole
scaffolds such as the CR TH2 receptor antagonist.
Table 1. Reaction Condition Screeninga
Organic azides were extensive in manynitrogen-contain-
ing compounds. This versatile class of important core
structures possesses unique reactivity and may easily be
transformed into various organic functional groups.6 In
particular, the use of organic azides as powerful radical
mediators provides a novel and concise pathway to the
entry
cat. (mol %)
additive (equiv)
yieldb (%)
1
AgNO3 (5)
Mg(NO3)2 6H2O (0.5)
39
62
3
2
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgSbF6 (10)
AgBF4 (10)
AgOAc (10)
AgOTf (10)
Ag2O (10)
Mg(NO3)2 6H2O (0.5)
3
3
Cu(NO3)2 3H2O (0.5)
<10
15
3
4
La(NO3)3 6H2O (0.5)
3
5
Y(NO3)3 6H2O (0.5)
17
3
€
(6) (a) Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
6
Co(NO3)2 6H2O (0.5)
15
3
Chem., Int. Ed. 2005, 44, 5188. (b) Scriven, E. F. V.; Turnbull, K. Chem.
Rev. 1988, 88, 297. (c) Smith, P. A. S. In Azides and Nitrenes: Reactivity
7
Ce(NO3)2 6H2O (0.5)
<10
18
3
8
NaNO3 þ H2O (0.5)
€
and Utility; Scriven, E. F. V., Ed.; Academic Press: Orlando, 1984. (d) Brase,
9
NH4NO3 (0.5)
55
S.; Banert, K. Organic Azides: Syntheses and Applications; Wiley: Chiche-
ster, 2010.
10
11
12
13
14
15
16
17
18
19
Bi(NO3)3 5H2O (0.5)
39
3
(7) (a) Prabhu, K. R.; Pillarsetty, N.; Gali, H.; Katti, K. V. J. Am.
Chem. Soc. 2000, 122, 1554. (b) Hsiao, Y.; Hegedus, L. S. J. Org. Chem.
1997, 62, 3586. (c) Roychowdhury, A.; Illangkoon, H.; Hendrickson,
C. L.; Benner, S. A. Org. Lett. 2004, 6, 489. (d) Saito, Y.; Matsumoto, K.;
Bag, S. S.; Ogasawara, S.; Fujimoto, K.; Hanawa, K.; Saito, I. Tetra-
hedron 2008, 64, 3578. (e) Zhou, L.; Gao, C.; Zhu, D. D.; Xu, W. J.;
Frank Chen, F. Q.; Amit, P.; Echegoyen, L.; Kong, E. S .W. Chem.;
Eur. J. 2009, 15, 1389.
Zr(NO3)4 5H2O (0.5)
71
3
Zr(NO3)4 5H2O (0.8)
86
3
Zr(NO3)4 5H2O (1.0)
79
3
Zr(NO3)4 5H2O (1.0)
17
3
Zr(NO3)4 5H2O (1.0)
23
3
Zr(NO3)4 5H2O (1.0)
N.R.
N.R.
N.R.
N.R.
3
Zr(NO3)4 5H2O (1.0)
3
(8) (a) Jimeno, C.; Renaud, P. Radical Chemistry with Azides, in
€
Zr(NO3)4 5H2O (1.0)
Organic Azides: Syntheses and Applications; Brase, S., Banert, K., Eds.;
3
Zr(NO3)4 5H2O (1.0)
Wiley: Chichester, 2010. (b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2001, 40, 2004. (c) Binder, W. H.; Kluger, C.
Curr. Org. Chem. 2006, 10, 1791. (d) Debets, M. F.; van Berkel, S. S.;
Dommerholt, J.; Dirks, A. J.; Rutjes, F. P. J. T.; van Delft, F. L. Acc.
Chem. Res. 2011, 44, 805. (e) Amblard, F.; Cho, J. H.; Schinazi, R. F.
3
a Reaction conditions: 1a (0.3 mmol), catalyst (10 mol %), MeCN
(2.0 mL), and additive (0.8 equiv) at 110 °C (oil-bath temperature) under
argon atmosphere for 28 h. b Isolated yield.
€
Chem. Rev. 2009, 109, 4207. (f) Kohn, M.; Breinbauer, R. Angew. Chem.,
Int. Ed. 2004, 43, 3106.
(9) Workentin, M. S.; Wagner, B. D.; Lusztyk, J.; Wayner, D. D. M.
J. Am. Chem. Soc. 1995, 117, 119.
In an initial study, we chose the N-methyl-N-arylacryl-
amide 1a as the model substrate to test different azide
compounds in the presence of 5 mol % of AgNO3 and
(10) (a) Stell, L. In Radical in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, p 407. (b) Lapointe, G.; Kapat,
A.; Weidner, K.; Renaud, P. Pure Appl. Chem. 2012, 84, 1633. (c) Zard,
S. Z. Chem. Soc. Rev. 2008, 37, 1603. (d) Minozzi, M.; Nanni, D.;
0.5 equiv ofMg(NO3)2 6H2O in CH3CN at 110 °C. To our
3
€
Spagnolo, P. Chem.;Eur. J. 2009, 15, 7830. (e) Kapat, A.; Konig, A. K;
delight, this reaction works with TMSN3 and affords
the desired product 2a in 39% yield (Table 1, entries 1).
Encouraged by this result, we further optimized the reac-
tion conditions. First, we increased loading of the silver
catalyst to 10 mol %. As a result, the yield of 2a improved
to a rewarding 62% (Table 1, entries 2). Subsequently, we
investigated different nitrates for their potential in this
conversion in the presence of 10 mol % AgNO3 in CH3CN
Montermini, F.; Renaud, P. J. Am. Chem. Soc. 2011, 133, 13890. (f)
Lapointe, G.; Schenk, K.; Renaud, P. Chem.;Eur. J. 2011, 17, 3207. (g)
Weidner, K.; Giroult, A.; Panchaud, P.; Renaud, P. J. Am. Chem. Soc.
2010, 132, 17511. (h) Chouthaiwale, P. V.; Karabal, P. U.; Suryavanshi,
G.; Sudalai, A. Synthesis 2010, 3879. (i) Waser, J.; Gaspar, B.; Nambu,
H.; Carreira, E. M. J. Am. Chem. Soc. 2006, 128, 11693. (j) Chung, R.;
Yu, E.; Incarvito, C. D.; Austin, D. J. Org. Lett. 2004, 6, 3881. (k) Tiecco,
M.; Testaferri, L.; Santi, C.; Tomassini, C.; Marini, F.; Bagnoli, L.;
Temperini, A. Angew. Chem., Int. Ed. 2003, 42, 3131. (l) Magnus, P.;
Lacour, J.; Evans, P. A.; Roe, M. B.; Hulme, C. J. Am. Chem. Soc. 1996,
118, 3406. (m) Trahanovsky, W. S.; Robbins, M. D. J. Am. Chem. Soc.
1971, 93, 5256. (n) Hassner, A.; Levy, L. A. J. Am. Chem. Soc. 1965, 87,
4203.
at 110 °C. Results indicate that Zr(NO3)4 5H2O is the
best choice; the product of 2a improves to 71% yield
3
B
Org. Lett., Vol. XX, No. XX, XXXX

(Table1, entries 3ꢀ11). Wefurtherinvestigatedtheequiva-
lents of Zr(NO3)4 5H2O. The best yield of 2a was obtained
3
Table 2. Silver-Catalyzed Carboazidation of Different
Arylacrylamidesa
with an 0.8 equiv scale (Table 1, entries 12 and 13). We
further examined other silver salts; results indicated that
AgNO3 was the best choice (Table 1, entries 14ꢀ18). In
addition, we noted that decreases in temperature cause
correspondingly lower yields. Meanwhile, the control ex-
periment revealed that use of only Zr(NO3)4 5H2O fails to
prompt the reaction (Table 1, entry 19).
3
Having established optimal reaction conditions (Table 1,
entry 10), we further investigated the scope of arylacryl-
amides. As shown in Table 2, an examination of differ-
ent N-protection groups revealed that methyl and benzyl
were appropriate for the reaction (2a and 2c), but tosyl
and N-free arylacrylamide failed. Various substituted
N-methylarylacrylamides worked very well, and the corre-
sponding products were obtained in good-to-excellent
yields regardless of electron-donating or electron-with-
drawing groups on the para-position (2dꢀl). The arylacryl-
amides containing the ortho-position substituent groups
exhibited a particularly distinct steric hindrance effect, and
lower yields were observed as a result (2mꢀs); Substrates
bearing meta substituents underwent carboazidation
smoothly and readily converted to the product in a 72%
yield with poor regioselectivity (2t). To our delight, the
naphthalene acrylamide was also compatible with the
transformation and successfully provided the product of
2t in 43% lower yield. On the other hand, the tetrahydro-
quinoline derivative of acrylamide afforded tricyclic ox-
indole 2b in 60% yield. Multisubstituted arylacrylamide
was also well tolerated in this carboazidation process,
affording the azide oxindoles with moderate yields (2v and
2w). The N-methyl-N-phenylcyclohex-1-enecarboxamide
was compatible with this transformation as well; the spiro-
oxindole was obtained in 43% yield (2ac). It should be
noted that different heterocyclic substrates such as pyridine,
quinoline, and pyrimidine failed to detect any product as a
result of lower reactivity. Furthermore, the evaluation of
various substituent groups of alkenes were also performed.
No reaction occurred in the case of monosubstituted olefins
(R2 = H). A series of R-substituted olefins bearing differ-
ent functional groups, such as phenyl (2x), benzyl (2y),
phthalimide (2aa), and ester (2ab), were tolerated well in
this transfromation and afforded the desired products in
moderate-to-good yields besides the monosubstituent olefin
(R2 = H). Moreover, we note that the synthesis of 3,4-
dihydroquinolin-2(1H)-one derivatives is also possible un-
der these reaction conditions (2z).
a Reaction conditions: 1aꢀz (0.3 mmol), catalyst (10 mol %), MeCN
(2.0 mL), and additive (0.8 equiv) at 110 °C (oil-bath temperature), under
argon atmosphere for 30 h. b Isolated yield. c 20 mol % catalyst was used.
The spiro-4-pyrrolidinone skeleton exists in an extensive
array of natural products and pharmaceuticals.11
Thus, the development of simple and efficient ways to
construct these compounds is highly desirable. Herein,
products of 2ae and 2af can be easy transferred into a
spiro-4-pyrrolidinone skeleton 4 through use of the re-
ported method,12 which may then be used to synthesize
horsfiline and CR TH2 receptor antagonist with further
modification (Scheme 2).
The detailed mechanism for this carboazidation of
alkenes is indeed similar to our recent report on silver-
catalyzed carbonꢀphosphorylation. Both mechanisms
involve a radical process within which Ag-promoted
(11) (a) Lizos, D. E.; Murphy, J. A. Org. Biomol. Chem. 2003, 1, 117.
(b) Bindra, J. S. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press:
New York, 1973; p 84. (c) Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron
1996, 52, 12651.
(12) Renaud, P.; Ollivier, C.; Panchaud, P. Angew. Chem., Int. Ed.
2002, 41, 3460.
Org. Lett., Vol. XX, No. XX, XXXX
C

proceed by two different pathways: in path A, AgN3 1A
first exhibits cleavage to generate the azidyl radical, which
then reacts with alkene 1a to produce the alkyl radical 2A.
Another possibility for the formation of alkyl radical 2A
involves the direct addition of 1A to alkene 1a to form
Ag(I) species 1B, which then transforms into the alkyl
radical 2A by oxidation (Scheme 4, path B). The resulting
alkyl radical 2A attacks the benzene ring and leads to the
generation of the intermediate 3A by intramolecular cycli-
zation, which then passes by single electron transfer (SET)
under the oxidation withAg(I) to release the product along
with HNO3 and Ag(0). Finally, the Ag(0) is oxidized
to Ag(I) in the presence of HNO3 and realizes catalytic
cycling.
Scheme 2. Showing Utility of Our Protocol
generation of phosphoryl radical is the key step. In our
carboazidation reaction of alkenes silver acts to arouse
the azidyl radical. To certify this assumption and acquire
straightforward proof, we performed chemical trapping
of radicals. We used the well-known radical-trapping
reagents TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy)
and 2,6-di-tert-butyl-4-methylphenol.13 Chemical trapping
was carried out under standardized reaction conditions.
As illustrated in Scheme 3, the addition of 1.0 equivalent
of TEMPO or 2,6-di-tert-butyl-4-methylphenol under
otherwise identical condition led to suppression of the
carboazidation process. To our delight, 2,6-di-tert-butyl-
4-methylphenol trapped the azidyl radical, and the product
of 2-(azidooxy)-1,3-di-tert-butyl-5-methylbenzene was de-
tected in the GCꢀMS.
Scheme 4. Proposed Mechanism for Silver-Catalyzed
Carboazidation of Alkenes
Scheme 3. Radical-Trapping Experiment of Carboazidation
In conclusion, we have disclosed a highly efficient pro-
tocol of silver-catalyzed carboazidation of alkenes and
a subsequent CꢀH functionalization cascade process
that may be used to prepare various azide oxindoles. Our
transformation employs inexpensive, nontoxic silver salt.
Further application of this approach to other substrates is
ongoing in our laboratory.
Acknowledgment. We are grateful for financial support
from the NSFC (Nos. 21072079 and 21272100) and Pro-
gram for New Century Excellent Talents in University
(NCET-11-0215). We thank S. F. Reichard for editing the
manuscript.
Based on the above experiments, we have outlined a
tentative pathway for this transformation. Scheme 4
illustrates our proposed pathway. First, TMSN3 reacts
with AgNO3 to form the intermediate AgN3 1A under
the reaction conditions. Subsequently, the reaction may
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) (a) Montanari, F.; Quici, S.; Henry-Riyad, H.; Tidwell, T. T.
2,2,6,6-Tetramethylpiperidin-1-oxyl. Encyclopedia of Reagents for Or-
ganic Synthesis; Wiley: New York, 2005. (b) Frazier, C. P.; Engelking, J. R.;
Alaniz, J. R. J. Am. Chem. Soc. 2011, 133, 10430.
The authors declare no competing financial interest.
D
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