Metal-free directed ortho C-H iodination: Synthesis of 2'-iodobiaryl-2- carbonitriles

Article abstract of DOI:10.1002/ejoc.201300584

Metal-free directed ortho C-H iodination of biaryl-2-carbonitriles was developed. A series of 2'-iodobiaryl-2-carbonitriles were synthesized from substituted biphenylcarbonitriles and naphthylbenzonitriles in reasonably good yields by using bis(pyridine)iodonium(I) tetrafluoroborate (IPy ₂BF₄, Barluenga's reagent) and HBF₄· OEt₂. The biaryl-2-carbonitriles are useful precursors for the synthesis of benzocyclic ketones. Metal-free directed ortho C-H iodination of biaryl-2-carbonitriles is efficiently performed in good yields by using bis(pyridine)iodonium(I) tetrafluoroborate (IPy₂BF₄, Barluenga's reagent) and HBF₄·OEt₂. Copyright

Full text of DOI:10.1002/ejoc.201300584

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300584
Metal-Free Directed ortho C–H Iodination: Synthesis of
2Ј-Iodobiaryl-2-carbonitriles[‡]
Satinath Sarkar,[a] Manoranjan Jana,[b] and Tadigoppula Narender*[a]
Keywords: Iodine / Directed iodination / Biaryls / C–H activation
Metal-free directed ortho C–H iodination of biaryl-2-
carbonitriles was developed. A series of 2Ј-iodobiaryl-2-
carbonitriles were synthesized from substituted biphenyl
carbonitriles and naphthylbenzonitriles in reasonably good
yields by using bis(pyridine)iodonium(I) tetrafluoroborate
(IPy2BF4, Barluenga’s reagent) and HBF4·OEt2. The biaryl-2-
carbonitriles are useful precursors for the synthesis of benzo-
cyclic ketones.
Introduction
C–H bond activation is a major strategy used in the con-
struction of C–heteroatom (C–X) and C–C bonds, and it
has drawn great interest.[1] Organic chemists are focusing
on C–H bond activation owing to its cost effectiveness,
common nature, and atom economy. Major challenges in
this area are chemoselectivity, regioselectivity, ortho selecti-
vity, and choice of metal catalyst and additives. Directed
ortho C–H functionalization requires proper modification
of molecular scaffolds. Over the past few years, novel strate-
gies have been developed for directed ortho functionaliza-
tion of sp2 and sp3 C–H bonds.[2] In this context, methods
for directed ortho C–H halogenation[3] through C–H bond
activation have grown intensively as a result of the number
of approaches that have been developed for directed ortho
C–H iodination.[4] Joshi et al.[5] reported selective ortho C–
H iodination of phenol, anisole, and anilines by using silver
salts as iodination reagents. Buchwald et al.[6] developed
metal-free directed ortho C–H iodination and demonstrated
its application in the synthesis of naturally occurring carb-
azoles. Metal-free directed iodination of arenes with bis(pyr-
idine)iodonium tetrafluoroborate (Scheme 1) was also de-
veloped recently by Barluenga et al.[7]
Scheme 1. Pd-catalyzed cyclization of 2Ј-iodobiaryl-2-carbonitriles,
bis(pyridine)iodonium(I) tetrafluoroborate (IPy2BF4, Barluenga’s
reagent) mediated ortho-iodination, and access to benzocyclic
ketones.
of benzocyclic ketones (Scheme 1). For example, Larock
et al.[8] reported the palladium-catalyzed cyclization of 2Ј-
iodobipheny-2-carbonitrile for the synthesis of 9-benzo-
fluorenone (Scheme 1). Similarly, Barluenga et al.[9] re-
ported easy access to benzocyclic ketones by using iod-
onium chemistry (Scheme 1).
2Ј-Iodobiphenyl-2-carbonitrile was first synthesized by
Grinham et al.,[10] and the Grinham procedure was later
modified by Larock et al.[8] through cyanation of 2,2Ј-di-
iodobiphenyl by using copper cyanide in pyridine under re-
flux; however, this process required complex starting mate-
rials, metal cyanide, and high temperatures. Therefore, an
easy and efficient process is required for the modular con-
struction of these molecules. As part of our ongoing syn-
thetic program on biaryl scaffolds,[11] we intended to syn-
thesize 2Ј-iodobiaryl-2-carbonitriles by metal-free directed
ortho C–H iodination (Scheme 2).
The development of new approaches for directed ortho
C–H iodination is in high demand and quite challenging.
Directed ortho C–H iodination of biaryl-2-carbonitriles has
so far not been used for the synthesis of 2Ј-iodobiaryl-2-
carbonitriles, which are useful intermediates in the synthesis
[a] Medicinal and Process Chemistry Division, CSIR-Central Drug
Research Institute, Chattar Manzil Palace,
Lucknow 226001, India
E-mail: tnarender@rediffmail.com
http://www.cdriindia.org/home.asp
[b] Department of Chemistry, University of Kalyani,
Kalyani, Nadia 741235, W. B., India
[‡] This is CDRI communication no. 8514.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300584.
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S. Sarkar, M. Jana, T. Narender
SHORT COMMUNICATION
Table 1. Optimization of the reaction conditions for the formation
of 3 from 2.[a]
Scheme 2. Strategy towards the synthesis of 2Ј-iodobiphenyl-2-
carbonitrile.
Results and Discussion
We started with the synthesis of the key intermediate,
biphenyl-2-carbonitrile (2), by using a reported Suzuki cou-
pling reaction.[12] We anticipated that the iodonium ion
generated in situ from bis(pyridine)iodonium(I) tetra-
fluoroborate (IPy2BF4, Barluenga’s reagent) could recog-
nize and coordinate through the nitrile group of 2 and assist
in the delivery of the iodonium ion to the ortho position
through a chelation-assisted process. The weak coordina-
tion of the iodonium ion to the nitrile moiety is the key
step for this process. By selecting 2 as a model substrate,
screening of experimental conditions with various iodon-
ium agents and additives was completed, and the results
are summarized in Table 1. The use of HBF4 (4 equiv.) and
Barluenga’s reagent (2 equiv.) produced good yields of the
product (Table 1, entries 1–4). The conversion of 2 was un-
changed with an increase in the reaction time and was also
unaffected with an increase in the number of equivalents
of Barluenga’s reagent and HBF4 (Table 1, entries 5–7). No
product was obtained regardless of whether the reaction
was performed at low temperature or at room temperature
with N-iodosuccinimide (NIS) as the iodonium agent in the
absence and in the presence of HBF4 (Table 1, entries 8–
10). If triflic acid (TfOH)[13] was used instead of HBF4, the
formation of the product was not observed (Table 1, en-
try 11). Furthermore, no product was formed if the reaction
was performed at room temperature with HBF4 (4 equiv.)
and Barluenga’s reagent (2 equiv.; Table 1, entry 12).
Entry Iodonium
Additive
t
[h]
Conv.[b] Yield[c]
agent (equiv.) (equiv.)
[%]
[%]
1
2
3
4
5
6
7
8
IPy2BF4 (1)
IPy2BF4 (1)
IPy2BF4 (1)
IPy2BF4 (2)
IPy2BF4 (2)
IPy2BF4 (3)
IPy2BF4 (3)
NIS (2)
–
24
24
24
24
30
24
30
24
24
24
30
30
–
6
–
–
HBF4 (1)
HBF4 (2)
HBF4 (4)
HBF4 (4)
HBF4 (6)
HBF4 (6)
–
HBF4 (4)
HBF4 (4)
TfOH (4)
HBF4 (4)
22
56
56
56
56
–
15
44
44
44
44
–
9
NIS (2)
NIS (2)
IPy2BF4 (2)
IPy2BF4 (2)
–
–
–
–
10[d]
11
12[d]
–
–
–
–
[a] The reaction was conducted with 2 (1 mmol or 1 equiv.) and the
iodonium agent and the additive (amounts with respect to 2; see
the Supporting Information), unless otherwise noted. [b] Deter-
mined on the basis of the percent yield of recovered 2. [c] Yield of
isolated 3 with respect to 2. [d] Reaction was performed at r.t.
After successful screening of the experimental conditions
with various iodonium agents and additives, we determined
the optimized conditions for the directed ortho C–H iodin-
ation (Table 1, entry 4). The moderate conversions of 2 and
the low yields of 3 might be attributed to the poor electronic
nature of the phenyl ring. Under these optimized condi-
tions, to further investigate the directed ortho C–H iodin-
ation, we prepared biaryl-2-carbonitriles 4–18 (Scheme 3)
by using the same reported Suzuki coupling reaction.[12]
With the use of biaryl-2-carbonitriles 4–17, we explored
the scope of this metal-free directed ortho C–H iodination
process. The structures of 2Ј-iodobiaryl-2-carbonitriles 18–
31 obtained in the metal-free directed ortho C–H iodination
process, the reaction times, and the yields of the isolated
products are depicted in Table 2.
Scheme 3. Synthesis of biaryl-2-carbonitriles 2 and 4–17 through
Suzuki coupling of 2-bromobenzonitriles 1, reaction times, and
yields of the isolated products.
Compounds 18–25 were obtained in moderate yields (45–
59%) upon reaction of 4–10. It appears that electron-donat- other iodinated side products, which might be due to steric
ing groups in the para position weekly activate the C–H interactions between the iodonium ion and the substituents.
bond (Table 2, entry 6), whereas electron-donating groups 2Ј-Iodobiaryl-2-carbonitriles 25 and 26 were obtained in
in the meta position strongly activate the C–H bond good yields, whereas 27 and 28 were obtained in low yields,
(Table 2, entry 13). We did not observe the formation of because the iodonium ion might have been trapped by the
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Metal-Free Directed ortho C–H Iodination
Table 2. 2Ј-Iodobiaryl-2-carbonitriles 17–29 obtained in the metal-free directed ortho C–H iodination of biaryl-2-carbonitrile 4–16, reac-
tion times, and yields of isolated products.
two chloro groups or the two methoxy groups. Interestingly,
A possible reaction mechanism for the formation of 2Ј-
iodination occurred at the ortho position upon performing iodobiphenyl-2-carbonitriles 3 and 18–31 is depicted in
the iodination reaction with 2, 15, and 16, in which the Scheme 5. The first step involves the in situ formation of
para position is free of substituents. An electron-donating the iodonium ion. The combination of Barluenga’s rea-
substituent in the cyanophenyl moiety of 17 (Table 2, en- gent with HBF4·OEt2 and acid protonation of the pyr-
try 14) increased the yield of ortho iodination product 31.
idine molecule results in the generation of the iodonium
To confirm the structures of 25, 26, 29, and 30, we con- ion. The resultant iodonium ion coordinates with two mo-
verted them into known fluorenones and anthracenones lecules biphenyl-2-carbonitrile.[14] In the second step, the
through palladium-catalyzed cyclization by using the re- nitrile group directs aromatic substitution at the ortho po-
ported protocol of Larock et al.[8] (Scheme 4).
sition.
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S. Sarkar, M. Jana, T. Narender
SHORT COMMUNICATION
iodobiaryl-2-carbonitriles that are useful precursors for the
synthesis of benzocyclic ketones. To the best of our knowl-
edge, we are the first group to report metal-free directed
ortho C–H iodination for the synthesis of 2Ј-iodobiaryl-2-
carbonitriles. The interaction between the iodonium ion
and the nitrile is a crucial finding of our work, which may
open some new vistas in metal-free organic transformations.
Experimental Section
General Procedure for the Directed ortho C–H Iodination: Bis(pyrid-
ine)iodonium tetrafluoroborate (2 mmol or 2 equiv.) was dissolved
in dry dichloromethane (10 mL), and the resulting solution was
stirred for 10 min at room temperature. The mixture was then co-
oled to –70 °C and 51–57% HBF4 in diethyl ether (4 mmol or
4 equiv.) was added. After 15 min, biaryl-2-carbonitrile (1 mmol or
1 equiv.) was added at –70 °C, and the resulting mixture was stirred
for 24–30 h. The reaction mixture was poured onto ice and vigor-
ously stirred until the temperature of the mixture had risen to room
temperature. The organic layer was washed with a 5% aqueous
solution of sodium thiosulfate (50 mL), dried with sodium sulfate,
and concentrated under reduced pressure. The crude mixture was
subjected to column chromatography on silica gel (230–400 mesh,
ethyl acetate/hexane) to provide the desired product.
General Procedure for the Pd-Catalyzed Cyclization of 2Ј-Iodobi-
aryl-2-carbonitriles: Et3N (0.3 mmol) was added to a solution of the
2Ј-iodobiaryl-2-carbonitrile (0.25 mmol), Pd(OAc)2 (0.025 mmol),
and Ph3P (0.05 mmol) in DMF (4.5 mL) and water (0.5 mL) under
an argon atmosphere. The reaction mixture was stirred at 130 °C
for 16–22 h. Then, the reaction mixture was cooled to room tem-
perature and poured into diethyl ether (25 mL). The ether solution
was washed with aqueous NH4Cl and dried with Na2SO4. The
crude mixture was subjected to column chromatography on silica
gel (230–400 mesh, ethyl acetate/hexane) to provide the desired
product.
Scheme 4. Palladium-catalyzed cyclization to access fluorenones
and anthracenones.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, and 1H NMR
and 13C NMR spectra of the products.
Acknowledgments
The authors are thankful to Dr. T. K. Chakraborty, Director,
CSIR-CDRI, for his constant encouragement on the program for
the synthesis of natural products. The authors are also thankful to
the Council of Scientific and Industrial Research (CSIR) and the
Department of Science and Technology (DST), New Delhi for fin-
ancial support.
Scheme 5. Possible reaction mechanism for the directed ortho C–H
iodination of biphenyl-2-carbonitrile (2).
Conclusions
[1] a) A. E. Shilov, G. B. Shul’pin, Chem. Rev. 1997, 97, 2879–
2932; b) J. A. Labinger, J. E. Bercaw, Nature 2002, 417, 507–
514; c) K. Godula, D. Sames, Science 2006, 312, 67–72; d) M.
Lafrance, S. I. Gorelsky, K. Fagnou, J. Am. Chem. Soc. 2007,
129, 14570–14571; e) J. W. Delord, T. Droge, F. Liu, F. Glorius,
Chem. Soc. Rev. 2011, 40, 4740–4761; f) J. Yamaguchi, A. D.
Yamaguchi, K. Itami, Angew. Chem. 2012, 124, 132; Angew.
Chem. Int. Ed. 2012, 51, 8960–9009.
[2] a) N. Chatani, T. Asaumi, S. Yorimisu, Y. Ishii, F. Kakiuchi,
S. Murai, J. Am. Chem. Soc. 2000, 122, 12882–12883; b) G.
Dyker, Angew. Chem. 1999, 111, 1808–1822; Angew. Chem. Int.
Ed. 1999, 38, 1698–1712; c) D.-H. Wang, T.-S. Mei, J.-Q. Yu,
J. Am. Chem. Soc. 2008, 130, 17676–17677; d) X. Wang, Y. Lu,
In conclusion, we have developed an efficient metal-free
protocol for the directed ortho C–H iodination of biaryl-2-
carbonitriles. The formation of 2Ј-iodobiaryl-2-carbo-
nitriles was achieved in reasonably good yields for the first
time from substituted biphenylcarbonitriles and naphthyl-
benzonitriles through directed ortho C–H iodination by
using Barluenga’s reagent (IPy2BF4) and HBF4·OEt2. This
efficient process avoids the use of complex starting materi-
als, high temperatures, copper(I) cyanide, transition-metal
catalysts, and iodine acetate. Our method also provides 2Ј-
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Metal-Free Directed ortho C–H Iodination
H.-X. Dai, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 12203–
12205; e) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110,
1147–1169; f) N. Dastbaravardeh, M. Schnürch, M. D. Mihovi-
lovic, Eur. J. Org. Chem. 2013, 2878–2890; g) W. Li, Z. Xu, P.
Sun, X. Jiang, M. Fang, Org. Lett. 2011, 13, 1286–1289; h) W.
Li, P. Sun, J. Org. Chem. 2012, 77, 8362–8366; i) T. Truong, O.
Daugulis, Org. Lett. 2012, 14, 5964–5967; j) G. B. Bajracharya,
O. Daugulis, Org. Lett. 2008, 10, 4625–4628.
[5]
[6]
[7]
S. N. Joshi, S. M. Vyas, H. Wu, M. W. Duffel, S. Parkin, H.-J.
Lehmler, Tetrahedron 2011, 67, 7461–7469.
W. C. P. Tsang, R. H. Munday, G. Brasche, N. Zheng, S. L.
Buchwald, J. Org. Chem. 2008, 73, 7603–7610.
J. Barluenga, J. M. Alvarez-Gutierrez, A. Ballesteros, J. M.
Gonzalez, Angew. Chem. 2007, 119, 1303–1306; Angew. Chem.
Int. Ed. 2007, 46, 1281–1283.
A. A. Pletnev, R. C. Larock, J. Org. Chem. 2002, 67, 9428–
9438.
[8]
[9]
[3] a) A. Iuliano, P. Piccioli, D. Fabbri, Org. Lett. 2004, 6, 3711–
3714; b) D. Kalyani, A. R. Dick, W. Q. Anani, M. S. Sanford,
Org. Lett. 2006, 8, 2523–2526; c) X. Wan, Z. Ma, B. Li, K.
Zhang, S. Cao, S. Zhang, Z. Shi, J. Am. Chem. Soc. 2006, 128,
7416–7417; d) K. L. Hull, W. Q. Anani, M. S. Sanford, J. Am.
Chem. Soc. 2006, 128, 7134–7135; e) A. John, K. M. Nicholas,
J. Org. Chem. 2012, 77, 5600–5605; f) X. Wang, T.-S. Mei, J.-
Q. Yu, J. Am. Chem. Soc. 2009, 131, 7520–7521; g) B. Du, X.
Jiang, P. Sun, J. Org. Chem. 2013, 78, 2786–2791.
J. Barluenga, M. Trincado, E. Rubio, J.-M. Gonzalez, Angew.
Chem. 2006, 118, 3212; Angew. Chem. Int. Ed. 2006, 45, 3140–
3143.
[10] J. W. Barton, A. R. Grinham, J. Chem. Soc. Perkin Trans. 1
1972, 634–637.
[11] T. Narender, S. Sarkar, K. Rajendar, S. Tiwari, Org. Lett. 2011,
13, 6140–6143.
[4] a) R. Giri, X. Chen, J.-Q. Yu, Angew. Chem. 2005, 117, 2150–
2153; Angew. Chem. Int. Ed. 2005, 44, 2112–2115; b) A. Moy-
ano, M. Rosol, R. M. Moreno, C. Lopez, M. A. Maestro, An-
gew. Chem. 2005, 117, 1899–1903; Angew. Chem. Int. Ed. 2005,
44, 1865–1869; c) T.-S. Mei, R. Giri, J.-Q. Yu, Angew. Chem.
2008, 120, 5293–5297; Angew. Chem. Int. Ed. 2008, 47, 5215–
5219; d) T.-S. Mei, D.-H. Wang, J.-Q. Yu, Org. Lett. 2010, 12,
3140–3143; e) H. Aiso, T. Kochi, H. Mutsutani, T. Tanabe, S.
Nishiyama, F. Kakiuchi, J. Org. Chem. 2012, 77, 7718–7724.
[12] C. Liu, Q. Ni, F. Bao, J. Qiu, Green Chem. 2011, 13, 1260–
1266.
[13] J. Barluenga, J. M. Gonzalez, M. A. Garcia-Martin, P. J.
Campos, G. Asensio, J. Org. Chem. 1993, 58, 2058–2060.
[14] M.-J. Crawford, M. Göbel, K. Karaghiosoff, T. M. Klapötke,
J. M. Welch, Inorg. Chem. 2009, 48, 9983–9985.
Received: April 23, 2013
Published Online: September 5, 2013
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