Silver-Catalyzed Tandem C=C Bond Hydroazidation/Radical Addition/Cyclization of Biphenyl Acetylene: One-Pot Synthesis of 6-Methyl Sulfonylated Phenanthridines

Article abstract of DOI:10.1021/acs.orglett.7b01771

A silver-catalyzed tandem carbon-carbon triple bond hydroazidation, radical addition, and cyclization of biphenyl acetylene is described under mild conditions, leading to the formation of 6-methyl sulfonylated phenanthridines in good yields. In this novel cascade reaction, most of the atoms are incorporated into the product without cleavage of the C=C bond. Mechanistic studies suggest the reaction should proceed through an iminyl radical reactive intermediate.

Full text of DOI:10.1021/acs.orglett.7b01771

Letter
pubs.acs.org/OrgLett
Silver-Catalyzed Tandem CC Bond Hydroazidation/Radical
Addition/Cyclization of Biphenyl Acetylene: One-Pot Synthesis of
6‑Methyl Sulfonylated Phenanthridines
Jiawei Tang,† Paramasivam Sivaguru,† Yongquan Ning,† Giuseppe Zanoni,§ and Xihe Bi*,†,‡
†Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal
University, Changchun 130024, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
§Department of Chemistry, University of Pavia, Via le Taramelli 12, 27100 Pavia, Italy
S
* Supporting Information
ABSTRACT: A silver-catalyzed tandem carbon−carbon triple
bond hydroazidation, radical addition, and cyclization of
biphenyl acetylene is described under mild conditions, leading
to the formation of 6-methyl sulfonylated phenanthridines in
good yields. In this novel cascade reaction, most of the atoms
are incorporated into the product without cleavage of the C
C bond. Mechanistic studies suggest the reaction should proceed through an iminyl radical reactive intermediate.
reacting arylalkyl alkynes with N-iodosuccinimide (NIS) and
TMSN3;6 very recently, Shi and co-workers developed a gold-
catalyzed nitrogenation of alkynes to carbamides and amino-
tetrazoles.7 In all reported nitrogenation reactions, the substrate
alkyne was cleaved into two or three parts, but all of the
dissection parts were reassembled into a single product.3−7
Efficient alternative procedures have been continuously
pursued for the synthesis of heterocycles via nitrogenation of
CC using TMSN3 via one-pot tandem processes. In light of
this landscape and in consideration of the versatility and
convenience of silver-based radical reactions of alkynes,8,9 in
this report we disclose for the first time a silver-catalyzed
nitrogenation of biphenyl acetylene toward the synthesis of
phenanthridines by sequential CC hydroazidation, radical
addition, and cyclization reactions (Figure 1b). Phenanthridine
and their derivatives are common structural components in a
variety of natural products and medicinally relevant synthetic
compounds.10 In addition to their pharmaceutical potency,11
some phenanthridine-based compounds are used as ligands in
coordination chemistry.12 Unlike previous work,3−7 in the
synthetic method we describe herein both carbon atom of the
alkyne are incorporated in the final phenantridine products,
without the cleavage of the carbon−carbon triple bond.
lkynes are found in various natural products, bioactive
1
Acompounds, and organic materials. Because they can be
readily converted into a variety of other functional groups,
alkynes are versatile intermediates in organic synthesis.2 In
recent years, significant attention has been placed on the
nitrogenation of carbon−carbon triple bonds (CC) using
trimethylsilyl azide (TMSN3) as a nitrogenating agent (Figure
1a). In the literature, only a few reports describe this kind of
nitrogenation: Jiao and their co-workers devised a silver-
catalyzed synthesis of nitriles by nitrogenation of alkynes using
TMSN3;3 Jiao and Echavarren described the direct synthesis of
amides4 and tetrazoles5 by nitrogenation of alkynes with
TMSN3; recently, Yanada et al. synthesized diazidoketones by
In the initial design, biphenyl acetylene (1a) as substrate and
TMSN3 and sodium p-toluenesulfinate (2a) as reagents were
utilized for the optimization studies of the reaction conditions
(Table 1). In a scouting experiment, 1a (1 equiv) was reacted
for 6 h with TMSN3 (1.5 equiv) and 2a (1.5 equiv) in DMSO
(2 mL) and H2O (2 equiv) at 70 °C, using 20 mol % of
Ag2CO3 as catalyst, affording the desired phenanthridine in
Received: June 12, 2017
Figure 1. Nitrogenation of CC bond using TMSN3.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01771
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 1. Scope of Biphenyl Acetylenes
b
entry
[M] cat.
solvent
DMSO
T (°C)
yield (%)
1
Ag2CO3
Ag3PO4
AgF
70
70
70
70
70
70
70
70
70
100
50
36
63
2
DMSO
DMSO
DMSO
DMSO
DMSO
DCE
3
29
4
Pd(OAc)2
CuI
0
5
0
6
Mn(OAc)3
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
0
7
trace
trace
48
8
1,4-dioxane
NMP
9
10
11
DMSO
DMSO
55
51
a
Reaction conditions: 1a (0.5 mmol), TMSN3 (0.75 mmol), 2a (0.75
mmol), catalyst (20 mol %), and H2O (2.0 equiv) in solvent (2 mL)
b
for 6 h. Isolated yields.
36% yield (entry 1). In order to improve the product yield,
other silver salt sources were screened as catalysts; with
Ag3PO4, the product was obtained in an increased 63% yield
(entry 2), whereas no improvement was achieved with AgF as
catalyst (29% yield, entry 3). Other metal salts such as
Pd(OAc)2, CuI, and Mn(OAc) were not productive catalysts
for this transformation (entries 4−6). The effect of few polar
solvents was also evaluated: in 1,2-dichloroethane (DCE) or
1,4-dioxane only amounts of phenanthridine 3a below 5%
(trace) (entries 7 and 8) were observed, whereas in N-
methylpyrrolidone (NMP) product 3a was obtained in
moderate yield (48%, entry 9). Finally, we screened the impact
of temperature and found that the yield was negatively affected
by either increasing or decreasing the reaction temperature
(entries 10 and 11).
The scope of the reaction was investigated using substituted
biphenyl acetylenes under the optimal conditions identified in
the preliminary study (Table 1, entry 2); the results are
summarized in Scheme 1. We initially explored the effect of
substituents on the B ring of the biphenyl acetylene substrate.
All substrates with either an electron-donating or electron-
withdrawing group on the B ring provided the desired product
in moderate to good yields. In particular, fluorine and
trifluoromethyl groups at the C-4′ position of the biphenyl
acetylenes 1d and 1g afforded products 3d and 3g in 74% and
69% yield, respectively. Both C-4′ electron-donating sub-
stitutents in 1b, 1c, 1h, and 1i and halogens in 1e and 1f also
reacted efficiently, affording the corresponding products in
moderate to good yields (43%−62%). Compound 3e was
further characterized by single-crystal X-ray analysis and the
structure of the phenantridine product could be unambiguously
confirmed (see the Supporting Information). Biphenyl
acetylene with a methyl substituent in the more sterically
encumbered C-2′ position of the B ring productively reacted to
afford product 3j in 57% yield. Acetylene substrates containing
a pyridine and a naphthalene moiety productively reacted and,
respectively, afforded 3k and 3l in good yield. When the methyl
group was in the C-3′ position, product 3m was obtained in
61% yield and without any detectable amount of the
a
Reaction conditions: 1 (0.5 mmol), TMSN3 (0.75 mmol), 2a (0.75
mmol), Ag3PO4 (20 mol %), and H2O (2.0 equiv) in DMSO (2 mL)
at 70 °C for 6 h. Yields (%) are calculated on the basis of isolated
product.
regioisomer 3m′. This exquisite selectivity suggests that the
cyclization might occur at the more sterically hindered position.
A disubstituted B-ring could also be part of a viable substrate,
for instance, 3′,5′-dimethyl biphenyl acetylene was transformed
into phenanthridine 3n in good yield.
Next, we examined the effect of the substitution pattern on
the A ring of the biphenyl acetylene substrate. Biphenyl
acetylenes with substituents at either the C-4 or C-5 position
were reactive and afforded the corresponding products 3o−s in
46−69% yield. Moreover, 5,6-dimethoxy-substituted biphenyl
acetylene also afforded the corresponding product 3t in high
yield (72%). Biphenyl acetylenes having a naphthyl or a
piperonyl group could also respectively be converted into
desired products 3u and 3v in good yields.
Furthermore, we have explored the scope of different sodium
sulfinates; the results are summarized in Scheme 2. Both aryl
and alkyl sodium sulfinates were compatible with the optimized
conditions, providing the desired phenanthridine derivatives
3w−3z in yields (59−65%) that are comparable to that
B
DOI: 10.1021/acs.orglett.7b01771
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
In order to ascertain whether the described sequential
reaction proceeds by a radical or an ionic mechanism, we have
carried out control experiments whose results are summarized
in Table 2. In a first experiment, biphenyl vinyl azide 8 was
Scheme 2. Scope of Sodium Sulfinates
a
Table 2. Mechanistic Investigations
a
Reaction conditions: 1 (0.5 mmol), TMSN3 (0.75 mmol), 2 (0.75
mmol), Ag3PO4 (20 mol %) and H2O (2.0 equiv) in DMSO (2 mL) at
70 °C for 6 h. Yields (%) are calculated based on isolated product.
b
entry
variation of the standard conditions
3a (%)
1
2
3
4
without TMSN3
35
reported for 3a in Table 1. From these results, we concluded
that there is no significant difference in the reaction rate and
product yield when the substituent group of sodium sulfinate is
changed.
With the purpose of gaining more insight into the versatility
of this silver-catalyzed three-component synthetic protocol, we
have applied this chemistry to the synthesis of other rings
(Scheme 3). When alkynes 4a and 4b were used as substrates,
with TMSN3
65
under nitrogen atmosphere
in the presence of TEMPO
trace
0
a
Standard conditions: vinyl azide 8 (0.5 mmol), TMSN3 (0.75 mmol),
2 (0.75 mmol) and Ag3PO4 (20 mol %) in DMSO (2 mL) at 70 °C for
b
1
6 h. The yields are estimated based on H NMR of crude reaction
mixtures.
reacted with sodium p-toluenesulfinate in the absence of
TMSN3 under the optimized conditions, thus delivering
product 3a in a diminished 35% yield (entry 1). In the
presence of TMSN3 (1.5 equiv), the desired product 3a was
formed in a typical good yield (65%, entry 2), thus confirming
TMSN3 as a necessary reactant. However, when performed
under a nitrogen atmosphere, the reaction proceeded
sluggishly, providing only traces of 3a (entry 3), thus suggesting
a pivotal role of atmospheric oxygen in this reaction. The
sulfonylation reaction was shut down by addition of TEMPO
(1.5 equiv) in the mixture (entry 4), implying the likelihood of
radical process.
a
Scheme 3. Further Development of the Protocol
With reference to literature precedence,3,9,13 and based on
these experimental results, we propose the following possible
mechanistic pathway for this transformation (Scheme 4). The
Scheme 4. Plausible Reaction Mechanism
a
Reaction conditions: alkyne (0.5 mmol), TMSN3 (0.75 mmol), 2a
(0.75 mmol), Ag3PO4 (20 mol %), and H2O (2.0 equiv) in DMSO (2
mL) at 70 °C for 6 h. Isolated product yield.
trisubstituted pyrroles 5a and 5b were obtained in 57% and
61% yields, respectively. The structure of compound 5a was
confirmed by X-ray crystallographic analysis (see the
Supporting Information). By this method, we have finally
successfully synthesized a new class of isoindolinones 7a−7c
from alkynes 6a−6c in good yields (43−72%).
azide anion would attack the substrate alkyne 1 that is activated
by the silver catalyst to generate the organosilver complex A.
The latter would extract a proton from water to produce vinyl
azide B and release the cationic silver. The sulfonyl radical,
which is generated from sodium sulfinate by the action of the
silver catalyst and TMSN3 or atmospheric oxygen, would add to
C
DOI: 10.1021/acs.orglett.7b01771
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(5) Gaydou, M.; Echavarren, A. M. Angew. Chem., Int. Ed. 2013, 52,
13468.
(6) Okamoto, N.; Sueda, T.; Minami, H.; Miwa, Y.; Yanada, R. Org.
Lett. 2015, 17, 1336.
(7) Qin, C.; Su, Y.; Shen, T.; Shi, X.; Jiao, N. Angew. Chem., Int. Ed.
2016, 55, 350.
(8) For a comprehensive review of silver-based radical reactions, see:
Fang, G.; Cong, X.; Zanoni, G.; Liu, Q.; Bi, X. Adv. Synth. Catal. 2017,
359, 1422.
(9) For examples of our reports on silver catalysis, see: (a) Fang, G.;
Liu, J.; Fu, J.; Liu, Q.; Bi, X. Org. Lett. 2017, 19, 1346. (b) Liu, Z.; Li,
Q.; Liao, P.; Bi, X. Chem. - Eur. J. 2017, 23, 4756. (c) Ning, Y.; Wu, N.;
Yu, H.; Liao, P.; Li, X.; Bi, X. Org. Lett. 2015, 17, 2198. (d) Liu, Z.; Liu,
J.; Zhang, L.; Liao, P.; Song, J.; Bi, X. Angew. Chem., Int. Ed. 2014, 53,
5305. (e) Liu, Z.; Liao, P.; Bi, X. Org. Lett. 2014, 16, 3668. (f) Liu, J.;
Liu, Z.; Liao, P.; Bi, X. Org. Lett. 2014, 16, 6204. (g) Liu, J.; Fang, Z.;
Zhang, Q.; Liu, Q.; Bi, X. Angew. Chem., Int. Ed. 2013, 52, 6953.
(10) For some examples, see: (a) Suffness, M.; Cordell, G. A. The
Alkaloids; Academic Press: New York, 1985; Vol. 25, pp 17−189.
(b) Nakanishi, T.; Suzuki, M. J. Nat. Prod. 1998, 61, 1263.
(c) Nakanishi, T.; Suzuki, M.; Saimoto, A.; Kabasawa, T. J. Nat.
Prod. 1999, 62, 864. (d) Nakanishi, T.; Suzuki, M. Org. Lett. 1999, 1,
985. (e) Nakanishi, T.; Masuda, A.; Suwa, M.; Akiyama, Y.; Hoshino-
Abe, N.; Suzuki, M. Bioorg. Med. Chem. Lett. 2000, 10, 2321. (f) Abdel-
Halim, O. B.; Morikawa, T.; Ando, S.; Matsuda, H.; Yoshikawa, M. J.
Nat. Prod. 2004, 67, 1119.
vinyl azide B to generate the iminyl radical C upon loss of
nitrogen. The iminyl radical C would undergo intramolecular
cyclization with the aryl moiety (ring A), yielding radical
species D that is stabilized by resonance. Compound D would
be subsequently oxidized by the silver catalyst forming the aryl
cation E, which would finally deprotonate to product 3.
Regarding the formation of pyrroles 5 and isoindolinones 7, the
condensation of an amine intermediate onto a ketone and the
cyclization onto the ester group could be involved.14
In conclusion, we have developed a silver-catalyzed protocol
for the construction of 6-methyl sulfonylated phenanthridine
through a tandem CC bond hydroazidation, radical addition,
and cyclization of biphenyl acetylenes. In this reaction, the
carbon atom sequence of the alkyne substrate was preserved
and incorporated into the product. The silver catalyst played a
dual role as activator of the nitrogenation of biphenyl acetylene
as well as an oxidant for the generation of the reactive sulfonyl
radical species. The synthetic method here described features
mild reaction conditions, atom-economy, simple operations
under ambient atmosphere, broad substrate scope, and good
yields of isolated product. Control experiments supported the
proposal of consecutive radical addition and cyclization
processes. Further exploration of this reaction is ongoing in
our laboratory.
(11) (a) Ishikawa, T. Med. Res. Rev. 2001, 21, 61. (b) Denny, W. A.
Curr. Med. Chem. 2002, 9, 1655. (c) Zhu, S.; Ruchelman, A. L.; Zhou,
N.; Liu, A.; Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. 2005, 13, 6782.
(d) Bernardo, P. H.; Wan, K. F.; Sivaraman, T.; Xu, J.; Moore, F. K.;
Hung, A. W.; Mok, H. Y. K.; Yu, V. C.; Chai, C. L. L. J. Med. Chem.
2008, 51, 6699. (e) Dubost, E.; Dumas, N.; Fossey, C.; Magnelli, R.;
Butt-Gueulle, S.; Ballandonne, C.; Caignard, D. H.; Dulin, F.; Santos, J.
S. d.-O.; Millet, P.; Charnay, Y.; Rault, S.; Cailly, T.; Fabis, F. J. Med.
Chem. 2012, 55, 9693. (f) Rajagopalan, R.; Lin, T.-S.; Karwa, A. S.;
Poreddy, A. R.; Asmelash, B.; Dorshow, R. B. ACS Med. Chem. Lett.
2012, 3, 284.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01771.
■
S
Experimental procedures, X-ray crystallographic data,
1
spectral data, and H and 13C NMR spectra (PDF)
(12) Park, G. Y.; Wilson, J. J.; Song, Y.; Lippard, S. Proc. Natl. Acad.
Sci. U. S. A. 2012, 109, 11987.
AUTHOR INFORMATION
■
(13) For the synthesis of phenanthridine derivatives with vinyl azides,
see: (a) Sun, X.; Yu, S. Chem. Commun. 2016, 52, 10898. (b) Mackay,
E. G.; Studer, A. Chem. - Eur. J. 2016, 22, 13455. (c) Wang, Y.-F.;
Lonca, G. H.; Le Runigo, M. L.; Chiba, S. Org. Lett. 2014, 16, 4272.
(14) For our recent report on the silver-catalyzed stereoselective
aminosulfonylation of alkynes, see: Ning, Y.; Ji, Q.; Liao, P.; Anderson,
E. A.; Bi, X. Angew. Chem., Int. Ed. 2017, DOI: 10.1002/
anie.201705122.
Corresponding Author
*E-mail: bixh507@nenu.edu.cn.
ORCID
Xihe Bi: 0000-0002-6694-6742
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSFC (21522202, 21372038).
REFERENCES
■
(1) For examples, see: (a) Bohlmann, F.; Burkhardt, H.; Zdero, C. In
Naturally Occurring Acetylenes; Academic Press: New York, 1973.
(b) Shi Shun, A. L. K.; Tykwinski, R. R. Angew. Chem., Int. Ed. 2006,
45, 1034. (c) Minto, R. E.; Blacklock, B. J. Prog. Lipid Res. 2008, 47,
233. (d) Shao, Z.; Peng, F. Angew. Chem., Int. Ed. 2010, 49, 9566.
(e) Chen, M.; Zheng, X.; Li, W.; He, J.; Lei, A. J. Am. Chem. Soc. 2010,
132, 4101.
(2) For reviews, see: (a) Gilmore, K.; Alabugin, I. V. Chem. Rev.
2011, 111, 6513. (b) Godoi, B.; Schumacher, R. F.; Zeni, G. Chem.
Rev. 2011, 111, 2937. (c) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev.
2010, 39, 1302. (d) Meldal, M.; Tornoe, C. W. Chem. Rev. 2008, 108,
2952.
(3) Shen, T.; Wang, T.; Qin, C.; Jiao, N. Angew. Chem., Int. Ed. 2013,
52, 6677.
(4) Qin, C.; Feng, P.; Ou, Y.; Shen, T.; Wang, T.; Jiao, N. Angew.
Chem., Int. Ed. 2013, 52, 7850.
D
DOI: 10.1021/acs.orglett.7b01771
Org. Lett. XXXX, XXX, XXX−XXX