CuI controlled C-C and C-N bond formation of heteroaromatics through C(sp3)-H activation

Article abstract of DOI:10.1021/ol302640e

A new method for C-C and C-N bond formation of heteroaromatics and C(sp³)-H alkanes was developed with high regioselectivity. The reaction occurred on C8 to give 8-cylcoakylpurines by C-C bond formation only promoted by tBuOOtBu, while it occurred on the amino group to give N6-alkylated purines by C-N bond formation when 2 equiv of CuI were added. A reaction mechanism was also proposed based on our preliminary experimental data.

Full text of DOI:10.1021/ol302640e

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
CuI Controlled CꢀC and CꢀN Bond
Formation of Heteroaromatics through
C(sp3)ꢀH Activation
Ran Xia,† Hong-Ying Niu,‡ Gui-Rong Qu,*,† and Hai-Ming Guo*,†
College of Chemistry and Chemical Engineering, Key Laboratory of Green Chemical
Media and Reactions of Ministry of Education, Henan Normal University, No. 46
Jianshe Road, Xinxiang, 453007, China, and School of Chemistry and Chemical
Engineering, Henan Institute of Science and Technology, No. 1 Hualan Avenue,
Xinxiang 453003, China
quguir@sina.com; guohm518@hotmail.com
Received September 26, 2012
ABSTRACT
A new method for CꢀC and CꢀN bond formation of heteroaromatics and C(sp3)ꢀH alkanes was developed with high regioselectivity. The reaction
occurred on C8 to give 8-cylcoakylpurines by CꢀC bond formation only promoted by tBuOOtBu, while it occurred on the amino group to give N6-
alkylated purines by CꢀN bond formation when 2 equiv of CuI were added. A reaction mechanism was also proposed based on our preliminary
experimental data.
CꢀH Bond direct functionalization is one of the hot topics
in current organic chemistry1 which enables the efficient
construction of carbonꢀcarbon or carbonꢀheteroatom
bonds as a highly atom-economical and direct approach.2
In the past few decades, this area has received a great deal
of interest from chemists and has been widely explored.
Among various CꢀH bond activation types, many efforts
have been made in the direct functionalization of C(sp3)ꢀH
bonds which is more challenging owing to their low
reactivity and the lack of a coordination site for the
transition-metal catalyst.3 C(sp3)ꢀH bond activation can
† Henan Normal University.
‡ Henan Institute of Science and Technology.
(1) (a) Handbook of CꢀH Transformations: Applications in Organic
Synthesis, Vols. 1 and 2; Dyker, G., Ed.; Wiley-VCH: Weinheim, 2005.
(b) Kakiuchi, F.; Murai, S. In Activation of Unreactive Bonds and Organic
Synthesis; Murai, S., Ed.; Springer: Berlin, 1999; pp 47ꢀ79.
(3) For examples of olefination and alkylation at sp3 CꢀH sites
activated by heteroatoms or aromatic rings, see: (a) Chatani, N.;
Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai, S. J. Am.
Chem. Soc. 2001, 123, 10935–10941 and references therein. (b) DeBoef,
B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126, 6556–6557. (c)
Song, C.-X.; Cai, G.-X.; Farrell, T. R.; Jiang, Z.-P.; Li, H.; Gan, L.-B.;
Shi, Z.-J. Chem. Commun. 2009, 40, 6002–6004.
(4) (a) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006,
128, 12634–12635. (b) Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo, E. J.;
Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19598–19601. (c) Giri, R.;
Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.;
Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510–3511. (d) Wang, D.-H.;
Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190–7191.
(e) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
9886–9887. (f) Yoo, E. J.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2010,
132, 17378–17380. (g) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem.
Soc. 2010, 132, 3680–3681.
(2) For reviews, see: (a) Ackermann, L.; Vicente, R.; Kapdi, A. R.
Angew. Chem. 2009, 121, 9976–10011. (b) Ackermann, L.; Vicente, R.;
Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792–9826. (c) Daugulis,
O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074–1086. (d)
Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41,
1013–1025. (e) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174–238. (f) Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichi-
mica Acta 2007, 40, 35–41. (g) Kalyani, D.; Deprez, N. R.; Desai, L. V.;
Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330–7331. (h) Sanford, M.
Top. Organomet. Chem. 2007, 24, 85–116. (i) Godula, K.; Sames, D.
Science 2006, 312, 67–72. (j) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz,
E.; Lemaire, M. Chem. Rev. 2002, 102, 1359–1470. (k) Labinger, J. A.;
Bercaw, J. E. Nature 2002, 417, 507–514. (l) Jia, C.; Kitamura, T.;
Fugiwara, Y. Acc. Chem. Res. 2001, 34, 633–639. (m) Shilov, A. E.;
Shulpin, G. B. Chem. Rev. 1997, 97, 2879–2932.
r
10.1021/ol302640e
XXXX American Chemical Society

be classified as three types: (1) C(sp3)ꢀH bond activation
with the assistance of a directing group in the presence of
transition metals to form versatile functionalized products,
including arylation, olefination, alkylation, etc.;4,5 (2)
C(sp3)ꢀH bond activation adjacent to heteroatoms, dou-
ble bonds, phenyl or electron withdrawing groups,6ꢀ8
which produces a stable intermediate and is relatively
reactive because of the high acidity of the H atom; (3)
the C(sp3)ꢀH bond activation of cycloalkanes to form
CꢀO,9 CꢀN,10 or CꢀC11 bonds, which is still rare by
virtue of the lower reactivity of C(sp3)ꢀH bonds in
cycloalkanes. Li’s group12aꢀd and others12e have done
elegant work in this field using a transition-metal catalyst
(such as Ru, Sc, Fe, etc.) both for activating the C(sp3)ꢀH
bond and subsequent coupling to form CꢀY (Y = O, N,
C) bonds. The progress of the metal-free C(sp3)ꢀH bond
activation was alsoachieved between pyridine N-oxide and
cycloalkanes promoted by tBuOOtBu, although the nitro-
gen heteroaromatics needed to be preactivated and the
regioselectivity of the reaction were not satisfactory.13
Recently, anilines also took part in C(sp3)ꢀH bond ami-
nation through NꢀCu(I) coordination.10d
activities and are widely reported in the literatures.16ꢀ18
The traditional method for the synthesis of 8-alkyl purine
derivatives is the transition-metal catalyzed coupling of 8-H
or 8-halo purines with alkyl metals (Scheme 1, route a).19
2-Alkyl benzothiazole or benzoxazoles were synthesized
through coupling of benzothiazole or benzoxazoles with
alkyl halides20 or N-tosylhydrazones21 catalyzed by a
transition-metal catalyst (Scheme 1, route b). As for the
synthesis of N6-alkylated adenine derivatives, the ortho-
dox method is amination of 6-substituted purines with
various amines.22
Scheme 1. Strategies for the Alkylation of Heteroaromatics
Purine nucleobases and nucleosides display a wide range
of biological activities (cytostatic, antiviral, antagonists
of GnRH, etc.).14,15 C8-Alkyl substituted purines and
N6-alkylated adenine derivatives possess unique biological
ꢀ
(5) (a) Prokopcova, H.; Bergman, S.; Aelvoet, D.; Smout, K. V.;
Herrebout, W.; Veken, B. V.; Meerpoel, L.; Maes, B. U. W. Chem.;
Eur. J. 2010, 16, 13063–13067. (b) Shabashov, D.; Daugulis, O. Org.
Lett. 2005, 7, 3657–3659. (c) Stowers, K. J.; Fortner, K. C.; Sanford,
M. S. J. Am. Chem. Soc. 2011, 133, 6541–6544. (d) Pastine, S. J.;
Gribkov, D.; Sames, V. D. J. Am. Chem. Soc. 2006, 128, 14220–14221.
(e) Simmons, E. M.; Hartwig, J. F. Nature 2012, 483, 70–73.
(6) Li, C.-J. Acc. Chem. Res. 2009, 42, 335–344.
(7) (a) Zhang, G.; Zhang, Y.-H.; Wang, R. Angew. Chem., Int. Ed.
2011, 50, 10429–10432. (b) He, T.; Yu, L.; Zhang, L.; Wang, L.; Wang,
M. Org. Lett. 2011, 13, 5016–5019.
(8) (a) Li, Y.-Z.; Li, B.-J.; Lu, X.-Y.; Lin, S.; Shi, Z.-J. Angew. Chem.,
Int. Ed. 2009, 48, 3817–3820. (b) Ni, Z.-K.; Zhang, Q.; Xiong, T.; Zheng,
Y.-Y.; Li, Y.; Zhang, H.-W.; Zhang, J.-P.; Liu, Q. Angew. Chem., Int.
Ed. 2012, 51, 1244–1247. (c) Xie, P.; Xie, Y.-J.; Qian, B.; Zhou, H.; Xia,
C.-G.; Huang, H.-M. J. Am. Chem. Soc. 2012, 134, 9902–9905. (d) Qian,
B.; Guo, S.-M.; Shao, J.-P.; Zhu, Q.-M.; Yang, L.; Xia, C.-G.; Huang,
H.-M. J. Am. Chem. Soc. 2010, 132, 3650–3651.
Herein, we wish to report a double activation of hetero-
aromatics and C(sp3)ꢀH alkanes with high regioselectiv-
ities. Metal-free conditions gave CꢀC bond formation
products, and adding CuI gave C(sp3)ꢀH bond amination
products.
Initially, we started our study by using 20,30,50-tri-O-
acetyladenosine (1a) and cyclohexane (2a) as model sub-
strates to optimize the reaction conditions (see the Supporting
(9) Iwahama, T.; Syojyo, K.; Sakaguchi, S.; Ishii, Y. Org. Process
Res. Dev. 1998, 2, 255–260.
(10) (a) Field, K. W.; Kovacic, P.; Herskovitz, T. J. Org. Chem. 1970,
35, 2146–2151. (b) Deng, G.-J.; Chen, W.-W.; Li, C.-J. Adv. Synth.
Catal. 2009, 351, 353–356. (c) Michaudel, Q.; Thevenet, D.; Baran, P. S.
J. Am. Chem. Soc. 2012, 134, 2547–2550. (d) Gephart, R. T., III; Huang,
D. L.; Aguila, M. J. B.; Schmidt, G.; Shahu, A.; Warren, T. H. Angew.
Chem., Int. Ed. 2012, 51, 6488–6492.
(18) (a) Vittori, S.; Lorenzen, A.; Stannek, C.; Costanzi, S.; Volpini,
R.; IJzerman, A. P.; Von Frijtag Drabbe Kunzel, J. K.; Cristalli, G.
J. Med. Chem. 2000, 43, 250–260. (b) Calenbergh, S. V.; von Frijtag
Drabbe Kunzel, J. K.; Blaton, N. M.; Peeters, O. M.; Rozenski, J.;
Aerschot, A. V.; Bruyn, A. D.; Keukeleire, D. D.; IJzerman, A. P.;
Herdewijn, P. J. Med. Chem. 1997, 40, 3765–3772.
(11) (a) Yonehara, F.; Kido, Y.; Morita, S.; Yamaguchi, M. J. Am.
Chem. Soc. 2001, 123, 11310–11311. (b) Oshita, M.; Chatani, N. Org.
Lett. 2004, 6, 4323–4325.
(12) (a) Deng, G.-J.; Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008,
47, 6278–6282. (b) Zhang, Y.; Li, C.-J. Eur. J. Org. Chem. 2007, 4654. (c)
Deng, G.-J.; Zhao, L.; Li, C.-J. Org. Lett. 2009, 11, 1171–1174. (d) Guo,
X.-Y.; Li, C.-J. Org. Lett. 2011, 13, 4977–4979. (e) Newhouse, T.; Baran,
P. S. Angew. Chem., Int. Ed. 2011, 50, 3362–3374.
(13) Deng, G.-J.; Ueda, K.; Yanagisawa, S.; Itami, K.; Li, C.-J.
Chem.;Eur. J. 2009, 15, 333–337.
(14) Qu, G.-R.; Xia, R.; Yang, X.-N.; Li, J.-G.; Wang, D.-C.; Guo,
H.-M. J. Org. Chem. 2008, 73, 2416–2419.
(19) (a) Hasnık, Z.; Pohl, R.; Hocek, M. Synthesis 2009, 1309–1317.
´
ꢁ
ꢀ
ꢀ
(b) Hocek, M.; Hockova, D.; Stambasky, J. Collect. Czech. Chem.
Commun. 2003, 68, 837–848. (c) Ogasawara, S.; Maeda, M. Angew.
Chem., Int. Ed. 2008, 47, 8839–8842. (d) Qu, G.-R.; Xin, P.-Y.; Niu,
H.-Y.; Wang, D.-C.; Ding, R.-F.; Guo, H.-M. Chem. Commun. 2011, 47,
11140–11142. (e) Hirth, B.; Barker, R. H., Jr.; Celatka, C. A.; Klinger,
J. D.; Liu, H.-L.; Nare, B.; Nijjar, A.; Phillips, M. A.; Sybertz, E.;
Willert, E. K.; Xiang, Y.-B. Bioorg. Med. Chem. Lett. 2009, 19, 2916–
2919.
(20) (a) Ackermann, L.; Punji, B.; Song, W.-F. Adv. Synth. Catal.
2011, 353, 3325–3329. (b) Ren, P.; Salihu, I.; Scopelliti, R.; Hu, X.-L.
Org. Lett. 2012, 14, 1748–1751. (c) Tran, L. D.; Daugulis, O. Org. Lett.
2010, 12, 4277–4279.
(15) Sangeetha, N. M.; Maitra, U. Chem. Soc. Rev. 2005, 34, 821.
(16) Kavai, I.; Mead, L. H.; Drobniak, J.; Zakrzewski, S. F. J. Med.
Chem. 1975, 18, 3272–3275.
(21) Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int.
Ed. 2012, 51, 775–779.
€
(17) Chang, L. C. W.; Spanjersberg, R. F.; Frijtag Drabbe Kunzel,
(22) Bressi, J. C.; Choe, J.-W.; Hough, M. T.; Buckner, F. S.;
Voorhis, W. C. V.; Verlinde, C. L. M. J.; Hol, W. G.; Gelb, J. M. H.
J. Med. Chem. 2000, 43, 4135–4150.
J. K.; Mulder-Krieger, T.; Brussee, J.; Jzerman, A. P. J. Med. Chem.
2006, 49, 2861–2867.
B
Org. Lett., Vol. XX, No. XX, XXXX

Information). The optimized reaction conditions involved
in tBuOOtBu as the oxidant at 140 °C for 24 h without
solvent under air.
ClorF gaveloweryields(3dvs 3e, 3f vs3g, and 3a vs 3iꢀ3j).
The type of substituent at N9 also had an obvious impact on
the yield. The N9 alkyl-substituted substrates gave higher
yields, while the sugar-substituted substrates gave slightly
lower yields (3d vs 3k, and 3e vs 3lꢀ3m). The 2-position
of 6-chloro-2-iodo-20,30,50-tri-O-acetylpurineside was
hydrogenated to give 3e in 62% yield, and the mechanism
was unclear. It was worth mentioning that all of the
coupling reaction exclusively occurred on the C8 position
of the purines, not on the C2 or other functional groups,
giving excellent regioselectivities. In addition to purines
and purine nucleosides, we were pleased to find that other
nitrogen heteroaromatics (e.g., xanthine, benzothiazole,
and benzoxazole) could also react with cyclohexane at
C(sp3)ꢀH and give the products in high yields (3nꢀ3p).
Scheme 2. Cross-Coupling of Heteroaromatics (1) with Cyclo-
hexane (2a)a
Scheme 3. Cross-Coupling of 1a with Various Cycloalkanes (2)a
a The reactions were carried out with 1a (0.25 mmol), 2a (10 mL),
tBuOOtBu (0.5 mmol), 140 °C, 24 h, under air.
a Unless otherwise mentioned, all of the reactions were carried out
with 1a (0.25 mmol), 2 (10 mL), tBuOOtBu (0.5 mmol), 140 °C, 24 h,
under air. b Benzene (5.0 mL) was used as solvent, and 2.5 mmol of 2f
were used.
With the optimized reaction conditions in hand, the
scope of the reaction with respect to purine derivatives
was investigated (Scheme 2). A number of modified pur-
ines and purine nucleosides, including a nonsugar carbon
substituent at N9, were subjected to the optimized reaction
conditions, affording the desired 8-cyclohexyl purine deri-
vatives in moderate to high isolated yields (56ꢀ93%,
3aꢀ3p). When the hydroxyl group on the 50 position of
the sugar cycle was not protected, the yield of the product
was somewhat low compared with those protected in the
sugar cycle (3a vs 3c). Purine derivatives with stronger
electron-donating groups (NH2, OCH3) at the C6 or C2
position could furnish the desired products in better yields,
but those with electron-withdrawing substituents such as
The tolerance of this reaction to a range of cycloalkanes
was examined (Scheme 3) afterward. In a similar manner
to the reaction of 2a, cyclopentane (2b), cycloheptane (2c),
and cyclooctane (2d) reacted smoothly with 1a to give the
desired products (4bꢀ4d). Decahydronaphthalene (2e)
gave an unseparated mixture, and the ratio of 10:20:30 was
1:3.3:1.2 (4e). Adamantane (2f) only reacted at 3° CH to
Scheme 4. Effect of CuI
(23) (a) Smith, M. B.; March, J. In March’s Advanced Organic
Chemistry Reactions, Mechanisms, and Structure, 6th ed.; Wiley-VCH:
Weinheim, 2007; pp 934ꢀ998. (b) Liu, J.-A.; Petzold, C. J.; Ramirez-
€
Arizmendi, L. E.; Perez, J.; Kenttamaa, H. J. Am. Chem. Soc. 2005, 127,
12758–12759. (c) Gagosz, F.; Zard, S. Z. Org. Lett. 2010, 4, 4345–4348.
(d) Castagnino, E.; Corsano, S.; Barton, D. H. R.; Zard, S. Z. Tetra-
hedron Lett. 1986, 27, 6337–6338.
Org. Lett., Vol. XX, No. XX, XXXX
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give structurally interesting molecule 4f in moderate yield.
Toluene, phenylethane, or 1,2,3,4-tetrahydronaphthalene
gave no product, and the reason was proposed in the
subsequent mechanism discussion. The purines were
not soluble in n-hexane; thus the reaction of purines
with n-hexane only occurred with a trace yield indicated
by TLC.
or 1,2,3,4-tetrahydronaphthalene proceeded smoothly in
moderate yields (5hꢀ5j).
A plausible mechanism for this reaction is proposed. It
might involve a free-radical process23 (see the Supporting
Information for details). The cyclohexyl free radical reacts
at the C8 position of purine by radical additionꢀoxidation
and acquires product 3a. It should be noted that the
reaction was suppressed by a radical scavenger, TEMPO.
A significant isotope effect was observed (kH/kD = 3.8),
suggesting that CꢀH bond cleavage of cyclohexane is the
rate-limiting step. When we added CuI to the reaction, the
cyclohexyl radical can be converted into the cyclohexyl
cation10c which then reacts with the amino group on
account of its more electrophilic property.
Scheme 5. CꢀN Formation of Purines with Various Alkanes (2)a
In conclusion, we have developed a new method to
modify purines (nucleosides), benzothiazole, and benzox-
azole through C(sp3)ꢀH activation with alkanes. The
reaction exclusively occurred on C8 to give 8-cylcoakyl-
purines by CꢀC bond formation under metal-free condi-
tions in the presence of tBuOOtBu, while it occurred on the
amino group to give N6-alkylated purines by CꢀN bond
formation when CuI was added. The preliminary experi-
mental data showed that the CꢀC bond formation reac-
tion presumably involves the production of a cycloalkyl
radical and subsequent radical additionꢀoxidation reac-
tions with heteroaromatics. And the CꢀN bond formation
reaction might be through electrophilic attack on the
amino group by carbocation which was produced by the
oxidation of a carbon radical by CuI. A range of hetero-
aromatics, including purines, purine nucleosides, ben-
zothiazole, and benzoxazole, might be employed and
gave satisfactory yields. Further application of this proto-
col is being developed, and research about the detailed
mechanism is ongoing in our group.
Acknowledgment. We are grateful for financial support
from the National Natural Science Foundation of China
(Grant Nos. 21072047, 21172059, 21272059, and 21202039),
the Program for New Century Excellent Talents in University
of Ministry of Education (No. NCET-09-0122), Excellent
Youth Foundation of Henan Scientific Committee (No.
114100510012), the Program for Changjiang Scholars and
Innovative Research Team in University (IRT1061), the
Program for Innovative Research Team in University of
Henan Province (2012IRTSTHN006), and the Excellent
Youth Program of Henan Normal University.
a 6-Aminopurines (0.25 mmol), 2 (10 mL), tBuOOtBu (0.5 mmol),
CuI (0.5 mmol), 140 °C, 24 h, under air.
When we added CuI to the reaction mixture of 1a
and 2a, the formation of the CꢀN bond was also
observed (Scheme 4; see Supporting Information for
details). The CꢀN formation reaction wasalsoextended to
a variety of 6-aminopurines (nucleosides) and alkanes
(Scheme 5). The 8-alkyl substituted purine nucleosides
gave higher yields (5dꢀ5e), while 8-bromo or 8-H
substituted purine nucleosides gave lower yields (5aꢀ5c
and 5f). Notably, the reaction with toluene, phenylethane,
Supporting Information Available. Experimental de-
tails, optimization of the reaction conditions, proposed
mechanism, copies of all spectra, and full characterization
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX