Copper-catalyzed aliphatic C-H amination with an amidine moiety

Article abstract of DOI:10.1021/ol303302r

A method for amination of aliphatic C-H bonds of N-alkylamidines is described that utilizes Cu(OAc)₂ as the catalyst in the presence of PhI(OAc)₂ and K₃PO₄. The resulting products, dihydroimidazoles and tetrahydropyrimidines, could be converted into the corresponding diamines by hydride reduction.

Full text of DOI:10.1021/ol303302r

ORGANIC
LETTERS
2013
Vol. 15, No. 1
212–215
Copper-Catalyzed Aliphatic CꢀH
Amination with an Amidine Moiety
Hui Chen, Stephen Sanjaya, Yi-Feng Wang, and Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
shunsuke@ntu.edu.sg
Received December 1, 2012
ABSTRACT
A method for amination of aliphatic CꢀH bonds of N-alkylamidines is described that utilizes Cu(OAc)2 as the catalyst in the presence of PhI(OAc)2
and K3PO4. The resulting products, dihydroimidazoles and tetrahydropyrimidines, could be converted into the corresponding diamines by hydride
reduction.
Amination of omnipresent sp3 CꢀH bonds can poten-
tially result in rapid assembly of azaheterocyclic frame-
works as well as various amino compounds, which are the
key components of numerous biologically active natural
alkaloids and potent pharmaceutical drugs.1 Thus, the
exploitation of the catalytic reaction that enables CꢀH
amination with predictable chemo-, regio-, and stereo-
selective manners is one of the most challenging issues in
synthetic chemistry.2 The CꢀH amination reactions
through nitrene insertion have been extensively explored
commonly with assistance of transition metal catalysts as
the-state-of-the-art aliphatic CꢀH amination,3ꢀ6 while
radical-mediated (non-nitrene-based) CꢀH amination re-
7
€
presented by the HofmannꢀLofflerꢀFreytag reaction
has also shown great potential as a radical strategy for
sp3 CꢀH bond functionalization.8
We have recently investigated the molecular transfor-
mation of readily available amidine derivatives that is
initiated by Cu-catalyzed single-electron oxidation of ami-
dine moieties.9 For example, we disclosed Cu-catalyzed
aerobic reactions of N-alkylamidines for CꢀH oxygena-
tion, affording dihydrooxazoles (Scheme 1A).9b The reac-
tion proceeds via 1,5-H-radical shift10 of putative amidinyl
(1) For recent reviews, see: (a) Thomas, G. L.; Johannes, C. W.
Curr. Opin. Chem. Biol. 2011, 15, 516. (b) Tohme, R.; Darwiche, N.;
Gali-Muhtasib, H. Molecules 2011, 16, 9665. (c) Dandapani, S.;
Marcaurelle, L. A. Curr. Opin. Chem. Biol. 2010, 14, 362. (d) Welsch,
M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14,
347. (e) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
Biomol. Chem. 2006, 4, 2337.
(2) For recent reviews on CꢀH amination, see: (a) Roizen, J. L.;
Harvey, M. E.; Du Bois, J. Acc. Chem. Rec. 2012, 45, 911. (b) Du Bois, J.
Org. Process Res. Dev. 2011, 15, 758. (c) Collet, F.; Lescot, C.; Dauban,
P. Chem. Soc. Rev. 2011, 40, 1926. (d) Zalatan, D. N.; Du Bois, J. Top.
Curr. Chem. 2010, 292, 347. (e) Collet, F.; Dodd, R. H.; Dauban, P.
(4) For reports on the transition-metal-free nitrene transfer reactions for
aliphatic CꢀH amination (amidation), see: (a) Ochiai, M.; Miyamoto, K.;
Kaneaki, T.; Hayashi, S.; Nakanishi, W. Science 2011, 332, 448. (b)
Bettinger, H. F.; Filthaus, M.; Bornemann, H.; Oppel, I. M. Angew. Chem.,
Int. Ed. 2008, 47, 4744.
(5) For recent selected reports on Pd-catalyzed allylic CꢀH amina-
tion via π-allyl Pd intermediates, see: (a) Jiang, C.; Covell, D. J.; Stepan,
A. F.; Plummer, M. S.; White, M. C. Org. Lett. 2012, 14, 1386. (b) Qi, X.;
Rice, G. T.; Lall, M. S.; Plummer, M. S.; White, M. C. Tetrahedron 2010,
66, 4816. (c) Shimizu, Y.; Obora, Y.; Ishii, Y. Org. Lett. 2010, 12, 1372.
(d) Rice, G. T.; White, M. C. J. Am. Chem. Soc. 2009, 131, 11707. (e)
Reed, S. A.; Mazzotti, A. R.; White, M. C. J. Am. Chem. Soc. 2009, 131,
11701. (f) Nahra, F.; Liron, F.; Prestat, G.; Mealli, C.; Messaoudi, A.;
Poli, G. Chem.;Eur. J 2009, 15, 11078 and references therein.
(6) Very recently, Brewer reported stereospecific intramolecular
CꢀH amination of 1-aza-2-azoniaallene salts; see: Bercovici, D. A.;
Brewer, M. J. Am. Chem. Soc. 2012, 134, 9890.
ꢀ
Chem. Commun. 2009, 5061. (f) Dıaz-Requejo, M. M.; Perez, P. J. Chem.
Rev. 2008, 108, 3379.
(3) For recent selected reports, see: (a) Wiese, S.; McAfee, J. L.;
Pahls, D. R.; McMillin, C. L.; Cundari, T. R.; Warren, T. H. J. Am.
Chem. Soc. 2012, 134, 10114. (b) Nguyen, Q.; Sun, K.; Driver, T. G.
J. Am. Chem. Soc. 2012, 134, 7262. (c) Paradine, S. M.; White, M. C.
J. Am. Chem. Soc. 2012, 134, 2036. (d) Lebel, H.; Trudel, C.; Spitz, C.
Chem. Commun. 2012, 48, 7799. (e) Harvey, M. E.; Musaev, D. G.; Du
Bois, J. J. Am. Chem. Soc. 2011, 133, 17207. (f) Lyaskovskyy, V.; Olivos
Suarez, A. I.; Lu, H.; Jiang, H.; Zhang, X. P.; de Bruin, B. J. Am. Chem.
Soc. 2011, 133, 12264. (g) King, E. R.; Hennessy, E. T.; Betley, T. A.
J. Am. Chem. Soc. 2011, 133, 4917. (h) Ichinnose, M.; Suematsu, H.;
Yasutomi, Y.; Nishioka, Y.; Uchida, T.; Katsuki, T. Angew. Chem., Int.
Ed. 2011, 50, 9884. (i) Lu, H.; Jiang, H.; Wojtas, L.; Zhang, X. P. Angew.
Chem., Int. Ed. 2010, 49, 10192. (j) Wiese, S.; Badiei, Y. M.; Gephart,
R. T.; Mossin, S.; Varonka, M. S.; Melzer, M. M.; Meyer, K.; Cundari,
T. R.; Warren, T. H. Angew. Chem., Int. Ed. 2010, 49, 8850. (k) Lu, H.;
Tao, J.; Jones, J. E.; Wojtas, L.; Zhang, X. P. Org. Lett. 2010, 12, 1248
and references therein.
(7) (a) Titouania, S. L.; Lavergne, J.-P.; Viallefonta, P.; Jacquierb, E.
Tetrahedron 1980, 36, 2961. (b) Corey, E. J.; Hertler, W. R. J. Am. Chem.
€
Soc. 1960, 82, 1657. (c) Loffler, K.; Freytag, C. Ber. 1909, 42, 3427. (d)
Hofmann, A. W. Ber. 1883, 16, 558.
r
10.1021/ol303302r
Published on Web 12/19/2012
2012 American Chemical Society

radical A formed by single-electron oxidation and depro-
tonation of the amidines, that is followed by CꢀO bond
formation through trapping of the resulting carbon radical
B withmolecular O2 to form superoxyradical C. Reductive
fragmentation of C to the alkoxide followed by cyclization
finally delivers the product. This aerobic CꢀH oxygena-
tion of N-alkylamidines sparked us into exploitation of the
CꢀH amination directed by the amidine moiety under an
inert atmosphere(in the absence ofmolecular O2), inwhich
trapping of the resulting carbon radical species B with the
amidine nitrogen was envisioned. Herein, we report a
copper-catalyzed PhI(OAc)2-mediated oxidative CꢀH
amination of aliphatic CꢀH bonds directed by an ami-
dine moiety(Scheme 1B).
noted that the reaction using 2 equiv of Cu(OAc)2 without
PhI(OAc)2 did not provide 2a at rt (entry 6). The reactions
with PhI(OCOt-Bu)2 proceeded to give a 61% yield of 2a
(entry 7), whereas those with iodosobenezne (PhIO) or with
selectfluor resulted in almost no reaction (entries 8 and 9).
Interestingly, the reaction only with PhI(OAc)2 as an oxidant
proceeded, which was, however, very sluggish and not
completed even after stirring for 48 h (entry 10).
Table 1. Optimization of Reaction Conditionsa
Scheme 1. Aliphatic CꢀH Functionalization with Amidines
entry
Cu salts (mol %)
oxidants
yield (%)b,c
1
CuBr SMe2 (20)
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
ꢀ
49 (35)
58 (26)
52 (36)
80d
3
2
CuTC (20)
3
CuBr2 (20)
Cu(OAc)2 (20)
4
5
Cu2(esp)2 2H2O (10)
62 (15)
0
3
6e,f
7
Cu(OAc)2 (200)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
ꢀ
PhI(OCOt-Bu)2
PhIdO
61 (18)
5 (86)
trace (82)
30 (40)
8
9f
10g
Selectfluor
PhI(OAc)2
a The reactions were carried out using 0.3 mmol of amidine 1a with
PhI(OAc)2 (1.2 equiv) and K3PO4 (2 equiv) in DMF (0.1 M) at rt under
an Ar atmosphere. b 1H NMR yields. c Recovery yields of 1a were shown
in parentheses. d Isolated yields. e The reaction was conducted in the
absenceofPhI(OAc)2. f When the reaction was heated up at 80 °C for 16 h, a
12% yield of 2a was formed along with a 72% recovery of 1a. g The reaction
was run without Cu salts for 48 h. TC = thiphene-2-carboxylate; esp = R,R,
R0,R0,-tetramethyl-1,3-benzenedipropionate; Selectfluor = 1-chloromethyl-
4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).
We commenced our investigation with the Cu-catalyzed
reactions of N-phenyl-N-(2-phenylpropyl)benzimidamide
(1a) using PhI(OAc)2 as a stoichiometric oxidant under an
Aratmosphere(Table1). As expected, when1awas treated
Having optimized the reaction conditions, we next ex-
amined the generality of this CꢀH amination of N-alkyl-
amidines 1 for synthesis of dihydroimidazoles 2 (Scheme 2).
Amination of tertiary CꢀH bonds resulted in efficient
formation of dihydroimidazoles 2 (for 2aꢀe), while the
yield of 4,4-dimethyl-4,5-dihydroimidazole 2f was low. It
is noteworthy that the reaction of amidine 1g bearing
secondary benzylic CꢀH bonds proceeded well to give
dihydroimidazole 2g in 95% yield. By varying substitu-
ents R2 of N-alkylamidines with secondary benzylic CꢀH
bonds, it was shown that various aromatic rings including
2-methylphenyl (for 2h), 2-naphthyl (for 2i), 4-bromo-
phenyl (for 2k), and thienyl groups (for 2l) were tolerated,
although amidine 1j bearing a 1-naphthyl group as R2
gave desired 2j only in 30% yield along with formation of
the corresponding O-acetylamidoxime 3j (30% yield)
generated via N-acetoxylation of 1j and cyanamide 4j11
(26% yield) formed through rearrangement of the 1-napthyl
group (see the Supporting Information (SI) for mode
with CuBr SMe2 (20 mol %) in the presence of PhI(OAc)2
3
(1.2 equiv) and K3PO4 (2 equiv) in DMF, the reaction
proceeded even at rt to afford a CꢀH amination product,
dihydroimidazole 2a, in 49% yield with recovery of a 35%
yield of 1a (entry 1). Further optimization of the reaction
conditions revealed that other Cu sources regardless of their
oxidation states (either I or II) showed the catalytic activity
(entries 2ꢀ5), and the highest yield (80% isolated yield) with
full conversion was provided by Cu(OAc)2 (entry 4). It is
(8) For recent examples for radical-mediated (non-nitrene-based)
aliphatic CꢀH amination reactions, see: (a) Amaoka, Y.; Kamijo, S.;
Hoshikawa, T.; Inoue, M. J. Org. Chem. 2012, 77, 9959. (b) Michaudel,
Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 2547. (c) Ni,
Z.; Zhang, Q.; Xiong, T.; Zheng, Y.; Li, Y.; Zhang, H.; Zhang, J.; Liu, Q.
Angew. Chem., Int. Ed. 2012, 51, 1244. (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. (e) Sakagushi, S.; Hirabayashi, T.; Ishii,
Y. Chem. Commun. 2002, 516. (f) Togo, H.; Harada, Y.; Yokoyama, M.
J. Org. Chem. 2000, 65, 926.
(9) (a) Sanjaya, S.; Chiba, S. Org. Lett. 2012, 14, 5342. (b) Wang,
Y.-F.; Chen, H.; Zhu, X.; Chiba, S. J. Am. Chem. Soc. 2012, 134, 11980.
(c) Wang, Y.-F.; Zhu, X.; Chiba, S. J. Am. Chem. Soc. 2012, 134, 3679.
(10) For reviews, see: (a) Cekovic, Z. Tetrahdron 2003, 59, 8073. (b)
Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095.
(11) The structures of 2n and 4j were determined by X-ray crystal-
lographic analysis; see the SI for more details.
Org. Lett., Vol. 15, No. 1, 2013
213

details). Allylic CꢀH amination of 1m also proceeded to
give 2m in 56% yield.
Table 2. Investigation of the Selectivity on the CꢀH Aminationa
Scheme 2. Substrate Scope on CꢀH Amination of 1a
a Unless otherwise noted, the reactions were carried out using
0.3 mmol of amidines 1 using 20 mol % of Cu(OAc)2 with 1.2 equiv of
PhI(OAc)2 and 2 equiv of K3PO4 in DMF at rt under an Ar atmosphere.
b Isolated yields were recorded above. c The reaction was run at 40 °C.
d The reaction was run using 1.6 equiv of PhI(OAc)2 at 60 °C.
Based on these results, a proposed mechanistic possibi-
lity is outlined in Scheme 3 (the scenario of the reaction
of 1a). Since no reaction was observed only with 2 equiv of
Cu(OAc)2 in the absence of PhI(OAc)2 (Table 1, entry 6),
the present process might be initiated by the formation of
higher valent NꢀCu(III) species I generated from amidine
1a, Cu(OAc)2, and PhI(OAc)2. Subsequent homolytic
cleavage of the NꢀCu(III) bond of I provides N-radical
II, which may undergo a 1,5-H radical shift to afford
C-radical III. Further Cu-mediated one-electron oxidation
of C-radical III generates carbocation IV,12 the intramo-
lecular cyclization of which with the amidine moiety leads
to the formation of dihydroimidazole 2a. The presence of
C-radical and carbocation species III and IV could be
a Unless otherwise noted, the reactions were carried out using
0.3 mmol of amidines 1 using 20 mol % of Cu(OAc)2 with 1.2 equiv of
PhI(OAc)2 and 2 equiv of K3PO4 in DMF at rt under an Ar atmosphere.
b Isolated yields were recorded above. c The reaction was run at 60 °C. d
The reaction was run using 1.8 equiv of PhI(OAc)2 at 60 °C. e 20 mol %
of 1,10-phenanthroline was additionally used for the reaction. f Along
with 2j, O-acetyloxime 3j and N-phenylcyanamide 4j were formed in
30% and 26% yields, respectively. For more details, see the SI.
We further explored the potential of the present CꢀH
amination reactions from the standpoint of several selec-
tivity issues (Table 2). The diastereoselectivity of the CꢀH
amination was first examined by installing the substituent
R5 onto the N-alkylamidines 1. The reactions of 1n and 1o
proceeded smoothly to give the corresponding dihydroi-
midazoles 2n11 and 2o, respectively, in good yields with
perfect trans-selectivity (entries 1 and 2). We next investi-
gated the chemoselectivity of this CꢀH amination using
amidine 1p bearing secondary and tertiary benzylic CꢀH
bonds, which resulted exclusively in tertiary CꢀH amina-
tion product 2p (entry 3). While these CꢀH amination
processes are likely initiated by a 1,5-H-radical shift (see
Scheme 3), blocking the 5-position as the quaternary
carbon enabled six-membered-ring formation via a 1,6-
H-radical shift, affording tetrahydropyrimidines 2q and 2r
in good yields (entries 4 and 5).
Scheme 3. A Proposed Catalytic Cycle
214
Org. Lett., Vol. 15, No. 1, 2013

Table 3. Reductive Transformation of Dihydroimidazoles 2
into Vicinal Diamines 5a
Scheme 4. Reductive Ring Opening of Tetrahydropyrimidine 2q
However, tetrahydropyrimidine 2q totally resisted the
AlH3 reduction (Scheme 4). In this case, reductive ring
opening of tetrahydropyrimidine 2q could be achieved by
treatment of 2q with MeI followed by reduction of the
16
resulting N-methyl iodonium salt with NaBH4 and
subsequent hydrolysis, forming N-methylated 1,3-diamines
6q in 89% yield.
a Unless otherwise noted, the reactions were carried out by treatment
of AlCl3 (1 equiv) in THF with LiAlH4 (3 equiv) at 0 °C followed by
addition of 2 (0.2ꢀ0.3 mmol) and stirring at rt. b Isolated yields were
recorded above. c The reaction was performed with AlCl3 (3 equiv) and
LiAlH4 (9 equiv) under reflux conditions. d The reaction was performed
under reflux conditions.
In summary, copper-catalyzed amidine-directed CꢀH
amination of aliphatic CꢀH bonds has been exploited for
the synthesis of dihydroimidazoles or tetrahydropyrimi-
dines, which could be further converted into the corre-
sponding diamines by hydride reduction. Combined with
facile preparation of N-alkylamidines through the Lewis
acid mediated reaction of the corresponding alkylamines
and carbonitriles,17 the overall process of the present strat-
egy could be summarized as a β- or γ-CꢀH amination of
alkylamines. Further investigations aim to develop other
types of oxidative CꢀH functionalization methodologies
using the amidine moiety as a potential directing group.
proven by the reaction of optically active 1a,13 which re-
sulted in the formation of racemic 2a under the standard
reaction conditions.
Vicinal 1,2-diamine functionalities are privileged as the
structural elements in biologically active molecules as well
as ligands for transition metal catalysts.14 Having devel-
oped a preparation method of dihydroimidazoles 2 through
the present CꢀH amination, concise reductive transforma-
tion of them to the corresponding vicinal diamines 5 was
examined (Table 3). By using aluminum hydride (AlH3,
prepared in situ from LiAlH4 and AlCl3),15 reduction of
dihydroimidazoles 2 proceeded smoothly to give the cor-
responding vicinal 1,2-diamines 5 bearing a benzyl protect-
ing group on one of the nitrogen atoms (marked in red).
Acknowledgment. This work was supported by funding
from Nanyang Technological University and Singapore
Ministry of Education (Academic Research Fund Tier 2:
MOE2012-T2-1-014).
Supporting Information Available. Experimental pro-
cedures, characterization of new compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org
(12) Kochi, J. K.; Bemis, A.; Jenkins, C. L. J. Am. Chem. Soc. 1968,
90, 4616.
(13) Optically active amidine 1a was prepared from commercially
available optically active (R)-(þ)-β-methylphenethylamine; see SI.
(14) For reviews, see: (a) Kizirian, J.-C. Chem. Rev. 2008, 108, 140.
(b) Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006,
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(16) Dal Maso, M.; Orelli, L.; Perillo, I. A. J. Heterocycl. Chem. 1994,
31, 25.
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formations II; Elsevier: Oxford, U.K., 2005; Vol. 5, pp 655ꢀ699.
(15) Brown, H. C.; Yoon, N. M. J. Am. Chem. Soc. 1966, 88, 1464.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 1, 2013
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