Molecular iodine catalyzed cross-dehydrogenative coupling reaction between two sp3 C-H bonds using hydrogen peroxide

Article abstract of DOI:10.1021/ol303389t

A useful method for molecular iodine catalyzed oxidative C-C bond formation between tertiary amines and a carbon nucleophile using hydrogen peroxide as the terminal oxidant is reported. This is the first report of a molecular iodine catalyzed cross-dehydrogenative coupling (CDC) reaction between two sp ³ C-H bonds.

Full text of DOI:10.1021/ol303389t

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Molecular Iodine Catalyzed
Cross-Dehydrogenative Coupling
Reaction between Two sp3 CꢀH
Bonds Using Hydrogen Peroxide
Tomoya Nobuta, Norihiro Tada, Akitoshi Fujiya, Atsumasa Kariya, Tsuyoshi Miura,
and Akichika Itoh*
Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan
itoha@gifu-pu.ac.jp
Received December 11, 2012
ABSTRACT
A useful method for molecular iodine catalyzed oxidative CꢀC bond formation between tertiary amines and a carbon nucleophile using hydrogen
peroxide as the terminal oxidant is reported. This is the first report of a molecular iodine catalyzed cross-dehydrogenative coupling (CDC) reaction
between two sp3 CꢀH bonds.
Iodine source catalyzed CꢀH oxidation with various
stoichiometricoxidantshasattractedgreatinterestbecause
iodine sources have low toxicity and are inexpensive
compared with transition metal catalysts. Ishihara et al.1
and others2 have reported novel CꢀH oxidations using a
catalytic amount of quaternary ammonium iodide with aq
H2O2 or tert-butyl hydroperoxide as terminal oxidants,
which generate only water or tert-butanol waste products.
This mild CꢀH oxidation can produce CꢀO or CꢀN
bonds, or both. CꢀC bond formation is one of the most
fundamental reactions in organic synthesis because most
organic molecules are made up of CꢀC bonds. Cross-
dehydrogenative coupling (CDC) reactions between two
CꢀH bonds are powerful CꢀC bond forming methods,
and various types of CDC reactions have been developed
in recent years.3 The oxidation of a CꢀH bond adjacent to
a nitrogen atom of tertiary amines to iminium ions has
attracted great interest because a synthetically and biolo-
gically useful Mannich-type product is obtained from
relatively simple precursors. Murahashi et al. have pio-
neered the Ru catalyzed oxidative cyanation of tertiary
amines,4 and Li et al. have reported copper catalyzed CDC
reactions.5 Recently, various CDC methods have been
reported, using transition metal catalysts, such as Fe,6
(3) For reviews on cross-dehydrogenative coupling, see: (a) Yeung,
C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (b) Klussmann, M.;
Sureshkumar, D. Synthesis 2011, 353. (c) Li, C.-J. Acc. Chem. Res. 2009,
42, 335. (d) Murahashi, S.-I.; Zhang, D. Chem. Soc. Rev. 2008, 37, 1490.
(4) (a) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am.
Chem. Soc. 2008, 130, 11005. (b) Murahashi, S.-I.; Komiya, N.; Terai, H.
Angew. Chem., Int. Ed. 2005, 44, 6931. (c) Murahashi, S.-I.; Komiya, N.;
Terai, H.; Nakae, T. J. Am. Chem. Soc. 2003, 125, 15312.
(1) (a) Uyanik, M.; Okamoto, H.; Yasui, T.; Ishihara, K. Science
2010, 328, 1376. (b) Uyanik, M.; Suzuki, D.; Yasui, T.; Ishihara, K.
Angew. Chem., Int. Ed. 2011, 50, 5331. (c) Uyanik, M.; Ishihara, K.
ChemCatChem 2012, 4, 177.
(2) (a) Liu, Z.; Zhang, J.; Chen, S.; Shi, E.; Xu, Y.; Wan, X. Angew.
Chem., Int. Ed. 2012, 51, 3231. (b) Xie, J.; Jiang, H.; Cheng, Y.; Zhu, C.
Chem. Commun. 2012, 48, 979. (c) Chen, L.; Shi, E.; Liu, Z. J.; Chen, S.;
Wei, W.; Li, H.; Xu, K.; Wan, X. B. Chem.;Eur. J. 2011, 17, 4085. (d)
Ma, L.; Wang, X.; Yu, W.; Han, B. Chem. Commun. 2011, 47, 11333. (e)
Wei, W.; Zhang, C.; Xu, Y.; Wan, X. Chem. Commun. 2011, 47, 10827.
(f) Froehr, T.; Sindlinger, C. P.; Kloeckner, U.; Finkbeiner, P.; Nacht-
sheim, B. J. Org. Lett. 2011, 13, 3754.
(5) (a) Basle, O.; Li, C.-J. Chem. Commun. 2009, 4124. (b) Basle, O.;
Li, C.-J. Green Chem. 2007, 9, 1047. (c) Li, Z.; Li, C.-J. J. Am. Chem. Soc.
2005, 127, 6968. (d) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672. (e)
Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997. (f) Li, Z.; Li, C.-J. J. Am. Chem.
Soc. 2004, 126, 11810.
(6) (a) Ghobrial, M.; Harhammer, K.; Mihovilovic, M. D.;
Schnurch, M. Chem. Commun. 2010, 46, 8836. (b) Liu, P.; Zhou,
C.-Y.; Xiang, S.; Che, C.-M. Chem. Commun. 2010, 46, 2739. (c) Zeng,
T.; Song, G.; Moores, A.; Li, C.-J. Synlett 2010, 2002. (d) Han, W.; Ofial,
A. R. Chem. Commun. 2009, 6023. (e) Rao Volla, C. M.; Vogel, P. Org.
Lett. 2009, 11, 1701. (f) Chiavarino, B.; Cipollini, R.; Crestoni, M. E.;
Fornarini, S.; Lanucara, F.; Lapi, A. J. Am. Chem. Soc. 2008, 130, 3208.
r
10.1021/ol303389t
XXXX American Chemical Society

Table 1. Study of Reaction Conditionsa
Scheme 1. Molecular Iodine Catalyzed CDC Reaction with
aq H2O2
iodine
source
V,7 Rh,8 Au,9 or Pt,10 or photocatalysts, such as Ir(ppy)2-
(dtbbpy)þ,11 Ru(bpy)32þ,12 or eosin Y.13 In addition, metal-
free methods using a stoichiometric amount of an oxidant,
such as PhI(OAc)2,14 DDQ,15 or the tropylium ion,16 have
been reported. However, the catalytic metal-free oxidative
CDC reaction of tertiary amines with a carbon nucleo-
phile, without photoirradiation, has not been reported.
From our study of oxidation with iodine sources,17 we
found that tertiary amines can be oxidized with catalytic
molecular iodine in the presence of hydrogen peroxide.
Here we report the first molecular iodine catalyzed oxida-
tive CꢀC bond formation through the CDC reaction
between two sp3 CꢀH bonds, using hydrogen peroxide
as the terminal oxidant (Scheme 1).
temp
3aa
entry
(equiv)
(°C)
(%)b
1
I2 (0.05)
I2 (0.05)
I2 (0.05)
ꢀ
rt
67
2
40
60
40
40
40
40
40
40
40
40
40
40
89 (82)
3
87
4
4
5c
6
I2 (0.05)
I2 (0.1)
10
96 (93)
7
nBu4NI (0.1)
Mgl2 (0.1)
Cal2 (0.1)
KI (0.1)
Nal (0.1)
Lil (0.1)
I2 (0.1)
24
8
17
9
14
10
11
12
13d
15
6
6
76 (67)
Table 1 showsthe reaction conditions for oxidativeCꢀC
bond formation from N-phenyl tetrahydroisoquinoline
(1a), as the substrate, in nitromethane (2a). We obtained
the corresponding aza-Henry product 3aa in good yield
when we used 0.05 equiv of molecular iodine and 2 equiv of
aq H2O2 at 40 °C (entries 1ꢀ3), and we found that both of
the reagents were necessary (entries 4 and 5). By increasing
the amount of molecular iodine to 0.1 equiv, we obtained
3aa in 93% yield (entry 6). We found that molecular iodine
was the most effective of the iodine sources tested for this
oxidation, and when we used other iodine sources we
obtained only low yields of 3aa (entries 6ꢀ12). Interest-
ingly, CꢀC bond formation proceeded in good yield when
we used 5 equiv of 2a in MeCN (entry 13).
a Reaction conditions: 1a (0.3 mmol), iodine source, and 35% aq
H2O2 (2 equiv) in 2a (3 mL) were stirred for 12 h. b 1H NMR yields.
Numbers in parentheses are isolated yields. c The reaction was per-
formed without aq H2O2. d The reaction was performed with 5 equiv of
2a in MeCN (3 mL).
Scheme 2 presents the scope and limitations of CDC
reactions between N-aryl tetrahydroisoquinolines (1) and
nitroalkanes 2 under the optimized reaction conditions. In
general, the corresponding aza-Henry products (3aa, 3ba,
3ca, 3da, 3ea, 3fa) were obtained in good yields with
nitromethane (2a) as the coupling partner, regardless of
whether there was an electron-donating or -withdrawing
group on the N-aryl group aromatic ring. Using nitroethane
(2b), CꢀC bond formations proceeded smoothly to afford
the desired products (3ab, 3bb, 3eb, 3fb) in moderate to good
yields. Unfortunately, N,N-dimethyl-p-toluidine was a poor
substrate.
In addition to oxidative aza-Henry reactions, we applied
our method to oxidative Mannich reactions (Scheme 3).
The corresponding Mannich products (5aa, 5ca) were
obtained in good yields using activated methylene com-
pounds such as dimethyl malonate. Next, we attempted
oxidative coupling between tertiary amines and nonacti-
vated ketones. Under the optimized conditions shown in
Table 1, the corresponding oxidative Mannich product
was not obtained in acetone. However, in the presence of
5 equiv of acetic acid, CꢀC bond formation proceeded
smoothly. In general, using acetone and 4-methyl-2-pen-
tanone, the desired products (5ab, 5bb, 5cb, 5db, 5eb, 5ac)
were obtained in good yields, regardless of whether there
was an electron-donating or -withdrawing group on the
N-aryl group aromatic ring.
(7) (a) Alagiri, K.; Kumara, G. S. R.; Prabhu, K. R. Chem. Commun.
2011, 47, 11787. (b) Sud, A.; Sureshkumar, D.; Klussmann, M. Chem.
Commun. 2009, 3169.
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Chem. Soc. 2006, 128, 5648.
(9) Xie, J.; Li, H.; Zhou, J.; Cheng, Y.; Zhu, C. Angew. Chem., Int. Ed.
2012, 51, 1252.
(10) Shu, X.-Z.; Yang, Y.-F.; Xia, X.-F.; Ji, K.-G.; Liu, X.-Y.; Liang,
Y. M. Org. Biomol. Chem. 2010, 8, 4077.
(11) Condie, A. G.; Gonzalez-Gomez, J. C.; Stephenson, C. R. J.
J. Am. Chem. Soc. 2010, 132, 1464.
(12) (a) Freeman, D. B.; Furst, L.; Condie, A. G.; Stephenson,
C. R. J. Org. Lett. 2012, 14, 94. (b) Rueping, M.; Vila, C.; Koenigs,
R. M.; Poscharny, K.; Fabry, D. C. Chem. Commun. 2011, 47, 2360.
(13) (a) Liu, Q.; Li, Y.-N.; Zhang, H.-H.; Chen, B.; Tung, C. H.; Wu,
L.-Z. Chem.;Eur. J. 2012, 18, 620. (b) Hari, D. P.; Konig, B. Org. Lett.
2011, 13, 3852.
(14) Shu, X.-Z.; Xia, X.-F.; Yang, Y.-F.; Ji, K.-G.; Liu, X.-Y.; Liang,
Y.-M. J. Org. Chem. 2009, 74, 7464.
(15) Su, W.; Yu, J.; Li, Z.; Jiang, Z. J. Org. Chem. 2011, 76, 9144.
(16) Allen, J. M.; Lambert, T. H. J. Am. Chem. Soc. 2011, 133,
1260.
(17) (a) Nobuta, T.; Hirashima, S.; Tada, N.; Miura, T.; Itoh, A. Org.
Lett. 2011, 13, 2576. (b) Kanai, N.; Nakayama, H.; Tada, N.; Itoh, A.
Org. Lett. 2010, 12, 1948. (c) Nobuta, T.; Hirashima, S.; Tada, N.;
Miura, T.; Itoh, A. Synlett 2010, 2335. (d) Nakayama, H.; Itoh, A.
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Pharm. Bull. 2006, 54, 1620.
We performed several control experiments to at-
tempt to resolve the reaction mechanism. It has been
known that tetrahydroisoquinolines can be oxidized to
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. CDC Reaction of Amines with Nitroalkanesa
Scheme 3. CDC Reaction of Amines with Carbonyl
Compoundsa
a Reaction conditions: 1 (0.3 mmol), I2 (0.1 equiv) and 35% aq H2O2
(2 equiv) in 4 (3 mL) was stirred. b Isolated yields. c 4a (1 mL) was used. d
AcOH (5 equiv) was added. e 4/MeOH (2/1 mL) was used.
a Reaction conditions: 1 (0.3 mmol), I2 (0.1 equiv), and 35% aq H2O2
(2 equiv) in 2 (3 mL) were stirred. b Isolated yields. c 2/MeOH (2/1 mL)
was used. d dr = 61:39. e dr = 65:35. f dr = 64:36. g dr = 60:40. h N,N-
Dimethyl-p-toluidine was used as substrate.
3,4-dihydroisoquinolines with a stoichiometric amount of
molecular iodine in ethanol.18,19 However, when we used 1
equiv of molecular iodine in the absence of aq hydrogen
peroxide, we obtained 3aa only in 16% yield and recovered
75% of 1a (Scheme 4, eq 1). This result suggests that the
oxidation of amines requires both molecular iodine and
hydrogen peroxide. The iodination of several compounds,
including electron-rich aromatics, olefins, and ketones,
with molecular iodine is accelerated by hydrogen
peroxide,20 and in one of these reactions, hypoiodous acid
(HOI)21 has been considered to be an active species.20f In
fact, the NaI/H2O2/acid system22 that is known to generate
Scheme 4. Study of Reaction Mechanism
(18) Dyke, S. F.; Kinsman, R. G. In The Chemistry of Heterocyclic
Compounds: Isoquinolines, Vol. 38, Part 1; Grethe, G., Ed.; John Wiley
and Sons, Inc.: New York, NY, 1981; p 51.
(19) (a) Shirasaka, T.; Takuma, Y.; Shimpuku, T.; Imaki, N. J. Org.
Chem. 1990, 55, 3767. (b) Dominguez, E.; Lete, E. J. Heterocycl. Chem.
1984, 21, 525.
(20) (a) Pavlinac, J.; Zupan, M.; Stavber, S. Org. Biomol. Chem. 2007,
5, 699. (b) Pavlinac, J.; Zupan, M.; Stavber, S. J. Org. Chem. 2006, 71,
1027. (c) Pavlinac, J.; Zupan, M.; Stavber, S. Synthesis 2006, 2603. (d)
Jereb, M.; Zupan, M.; Stavber, S. Chem. Commun. 2004, 5, 2614. (e)
Omura, K. J. Org. Chem. 1996, 61, 2006. (f) Ohta, H.; Motoyama, T.;
Ura, T.; Ishii, Y.; Ogawa, M. J. Org. Chem. 1989, 54, 1668.
(21) (a) Lengyel, I.; Epstein, I. R.; Kustin, K. Inorg. Chem. 1993, 32,
5880. (b) Barnes, I.; Bedker, K. H.; Starcke, J. Chem. Phys. Lett. 1992,
196, 578. (c) Paquette, J.; Ford, B. L. Can. J. Chem. 1985, 63, 2444.
(22) (a)Barluenga, J.;Marco-Arias, M.;Gonzalez-Bobes, F.;Ballesteros,
A.; Gonzalez, J. M. Chem. Commun. 2004, 2616. (b) Barluenga, J.; Marco-
Arias, M.; Gonzalez-Bobes, F.; Ballesteros, A.; Gonzalez, J. M. Chem.;Eur.
J. 2004, 10, 1677.
HOI or its protonated form was effective in the oxidation
of tertiary amines, and the desired products were obtained
in 65% yield (Scheme 4, eq 2). Furthermore, BHT, a
radical inhibitor, scarcely suppressed our CDC reaction
(Scheme 4, eq 3).
Scheme 5 shows a plausible path for this oxidation,
which we postulate after considering all of the results
Org. Lett., Vol. XX, No. XX, XXXX
C

nitroalkane 2 or a carbonyl compound 4, to form the
desired product 7. Hydrogen iodide, generated by the
addition of a nucleophile to 6, is reoxidized to HOI by
hydrogen peroxide.22
Scheme 5. Plausible Path
In conclusion, we report molecular iodine catalyzed
oxidative CꢀC bond formation by a CDC reaction be-
tween tertiary amines and a carbon nucleophile. This novel
reaction is interesting because it uses catalytic molecular
iodine and aq H2O2 as the terminal oxidant. The applica-
tion of this oxidation to other reactions is now in progress
in our laboratory.
presented above. Theactivespecies arenotyetclear, butwe
suppose that the tertiary amine 1 is oxidized to the iminium
ion 6 by HOI,23,24 which is generated from molecular
iodine and hydrogen peroxide.20f The iminium ion 6 under-
goes the addition of a carbon nucleophile, such as a
Acknowledgment. This work was supported by a
Grant-in-Aid for Young Scientists (B) (No. 24790015)
from the Japan Society for the Promotion of Science
(JSPS).
(23) Hydrogen peroxide is probably activated by hydrogen iodide
generated from molecular iodine in situ. For a report on the oxidative
power of protonated hydrogen peroxide, see: Φiestad, A. M. L.; Petersen,
A. C.; Bakken, V.; Vedde, J.; Uggerud, E. Angew. Chem., Int. Ed. 2001, 40,
1305.
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
˚
(24) Protonated hypoiodous acid is also possible as an active species;
ꢀ
see: Barluenga, J.; Marco-Arias, M.; Gonzalez-Bobes, F.; Ballesteros,
ꢀ
A.; Gonzalez, J. M. Chem.;Eur. J. 2004, 10, 1677.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX