Copper-catalyzed aminooxygenation of N-allylamidines with PhI(OAc) 2

Article abstract of DOI:10.1021/ol302525m

A Cu-catalyzed aminoacetoxylation of N-alkenylamidines has been achieved using PhI(OAc)₂ as an oxygen source for synthesis of 4-acetoxymethyl-4,5-dihydroimidazoles, which could be further converted into 2,3-diaminopropanol derivatives using AlH

Full text of DOI:10.1021/ol302525m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper-Catalyzed Aminooxygenation
of N‑Allylamidines with PhI(OAc)2
Stephen Sanjaya 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 September 13, 2012
ABSTRACT
A Cu-catalyzed aminoacetoxylation of N-alkenylamidines has been achieved using PhI(OAc)2 as an oxygen source for synthesis of
4-acetoxymethyl-4,5-dihydroimidazoles, which could be further converted into 2,3-diaminopropanol derivatives using AlH3 as a reductant.
Oxidative functionalization of alkenes is one of the
most fundamental and important processes in organic
synthesis.1 Among various types of the reactions, transition-
metal-mediated/catalyzed aminooxygenation of alkenes
has been studied extensively because the products, vicinal
aminoalcohols, are privileged as the structural elements in
biologically active molecules as well as ligands for transi-
tion metal catalysts.2 Although diverse approaches have
recently been developed for aminooxygenation of alkenes
such as Chemler’s copper-mediated/-catalyzed intra-
molecular aminooxygenation of alkenes with sulfonamide
or aniline nitrogens3 as well as others,4,5 there remains a
demand for exploitation of the catalytic aminooxygenation
that enables realization of predictable chemo- and regio-
selectivity.
We have recently studied copper-catalyzed aerobic oxida-
tive functionalization of aliphatic CꢀH bonds and CꢀC
unsaturated bonds (alkene and alkyne) installed on amidine
moieties such as CꢀH oxygenation,6 diamination of alkenes,7
and aminooxygenation of alkyne (Scheme 1 aꢀc).8 These
reactions of amidines have driven our continuous investi-
gation to develop copper-catalyzed aminooxygenation of
N-alkenylamidines. The group of Zhang and Zhu recently
reported a copper-catalyzed aerobic reaction of N-allyla-
midines that affords formylimidazoles via the sequence
of aminooxygenation of the alkene and aromatization
(1) For recent reviews, see: (a) de Figueiredo, R. M. Angew. Chem.,
Int. Ed. 2009, 48, 1190. (b) Cardona, F.; Goti, A. Nat. Chem. 2009, 1, 269.
(b) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887. (c) Wolfe, J. P.
Synlett 2008, 2913. (d) Kotov, V.; Scarborough, C. C.; Stahl, S. S. Inorg.
Chem. 2007, 46, 1910. (e) Li, G.; Kotti, S. R. S. S.; Timmons, C. Eur. J.
(5) For recent selected reports on aminooxygenation of alkenes
catalyzed by transition metals, see: (a) Mancheno, D. E.; Thornton,
A. R.; Stoll, A. H.; Kong, A.; Blakey, S. B. Org. Lett. 2010, 10, 4110.
(b) Wardrop, D. J.; Bowen, E. G.; Forslund, R. E.; Sussman, A. D.;
Weerasekera, S. L. J. Am. Chem. Soc. 2010, 132, 1188. (c) Liskin, D. V.;
Sibbald, P. A.; Rosewall, C. F.; Michael, F. E. J. Org. Chem. 2010, 75,
6294. (d) Michaelis, D. J.; Williamson, K. S.; Yoon, T. P. Tetrahedron
2009, 65, 5118. (e) Michaelis, D. J.; Shaffer, C. J.; Yoon, T. P. J. Am.
Chem. Soc. 2007, 129, 1866. (f) Desai, L. P.; Sanford, M. S. Angew.
Chem., Int. Ed. 2007, 46, 5737. (g) Liu, G.; Stahl, S. S. J. Am. Chem. Soc.
2006, 128, 7179. (h) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am.
Chem. Soc. 2005, 127, 7690. (i) Noack, M.; Gottlich, R. Chem. Commun.
2002, 536.
(6) Wang, Y.-F.; Chen, H.; Zhu, X.; Chiba, S. J. Am. Chem. Soc.
2012, 134, 11980.
(7) Wang, Y.-F.; Zhu, X.; Chiba, S. J. Am. Chem. Soc. 2012, 134,
3679.
~
Org. Chem. 2007, 2745. (f) Minatti, A.; Muniz, K. Chem. Soc. Rev. 2007,
36, 1142. (g) Chemler, S. R.; Fuller, P. H. Chem. Soc. Rev. 2007, 36, 1153.
(2) For reviews, see: (a) Donohoe, T. J.; Callens, C. K. A.; Flores, A.;
Lacy, A. R.; Rathi, A. H. Chem.;Eur. J. 2011, 17, 58. (b) Bergmeier,
S. C. Tetrahedron 2000, 56, 2561.
(3) (a) Paderes, M. C.; Belding, L.; Fanovic, B.; Dudding, T.; Keister,
J. B.; Chemler, S. R. Chem.;Eur. J. 2012, 18, 1711. (b) Sequeira, F. C.;
Bovino, M. T.; Chipre, A. J.; Chemler, S. R. Synthesis 2012, 44, 1481.
(c) Paderes, M. C.; Chemler, S. R. Eur. J. Org. Chem. 2011, 3679.
(d) Chemler, S. R. J. Organomet. Chem. 2011, 696, 150. (e) Paderes,
M. C.; Chemler, S. R. Org. Lett. 2009, 11, 1915. (f) Sherman, E. S.;
Chemler, S. R. Adv. Synth. Catal. 2009, 351, 467. (g) Fuller, P. H.; Kim,
J.-W.; Chemler, S. R. J. Am. Chem. Soc. 2008, 130, 17638.
€
(8) Toh, K. K.; Sanjaya, S.; Sahnoun, S.; Chong, S. Y.; Chiba, S. Org.
Lett. 2012, 14, 2290.
(9) Wang, H.; Wang, Y.; Liang, D.; Liu, L.; Zhang, J.; Zhu, Q.
(4) For reports on Sharpless’ aminohydroxylation of alkenes, see:
~
Adv. Synth. Catal. 2002, 344, 1169. (c) Li, G.; Chang, H.-T.; Sharpless,
K. B. Angew. Chem., Int. Ed. 1996, 35, 451.
(a) Muniz, K. Chem. Soc. Rev. 2004, 33, 166. (b) Nilov, D.; Reiser, O.
Angew. Chem., Int. Ed. 2011, 50, 5678.
r
10.1021/ol302525m
XXXX American Chemical Society

(Scheme 1d).9 In this context, we have strived to develop
aminooxygenation of alkenes with amidine moieties to
target nonaromatized dihydroimidazole derivatives using
alternative oxygen sources to molecular oxygen that can
be achieved under milder reaction conditions.10
Scheme 2. Synthesis of 4-Acetoxymethyl-4,5-dihydroimidazoles
via Aminooxygenation of Alkenes and Their Conversion to
2,3-Diamino-1-propanols: Stepwise Strategy on Regioselective
Aminohydroxylation of Allylamine (This Work)
Scheme 1. Oxidative Functionalization of CꢀH Bonds,
Alkenes, and Alkynes with an Amidine Moiety
Table 1. Optimization of Reaction Conditionsa
Cu(OAc)2
(mol %)
ligand
base
yield
(%)b
entry
(mol %)
(1 equiv)
1
20
20
20
20
20
15
10
15
200
0
ꢀ
ꢀ
59
2
2,20-bipyridine (20)
pyridine (20)
ꢀ
62
3
ꢀ
60
Herein, we report copper-catalyzed aminoacetoxylation
of N-allylamidines with PhI(OAc)2 as the oxygen source
and the reoxidant to maintain the catalytic turnover
for synthesis of 4-acetoxymethyl-4,5-dihydroimidazoles,
which could be further converted into 2,3-diamino-1-pro-
panols by reduction with AlH3. With the advantageof easy
preparation of N-allylamidines by the Lewis acid mediated
reaction of the corresponding allylamines and carboni-
triles, the overall process could be regarded as regioselec-
tive aminohydroxylation of allylamines (Scheme 2).
Our study commenced with the reaction of N-allyl-N-
phenylbenzamidine (1a) with 20 mol % of Cu(OAc)2 and
1.2 equiv of PhI(OAc)2 in DMF (Table 1, entry 1), which
provided 5-exo cyclization product 4-acetoxymethyl-4,5-
dihydroimidazole 2a exclusively in 59% yield as the sole
product even at room temperature. By screening nitrogen
ligands as an additive (entries 2ꢀ4), 1,10-phenanthroline
was found to improve the reaction yield to 71% yield
(entry 4). Further optimization of the reaction conditions
4
1,10-phenanthroline (20)
1,10-phenanthroline (20)
1,10-phenanthroline (15)
1,10-phenanthroline (10)
chiral bis-oxazoline (15)d
ꢀ
ꢀ
71
5
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
71
6
86c
70
7
8
40 (48)e
0
9f
10
ꢀ
0
a Unless otherwise noted, the reactions were carried out using
0.5 mmol of amidines 1a. b Isolated yields were recorded. c The reaction
was carried out using 4.1 mmol (0.97 g) of 1a, giving 3.5 mmol (1.04 g) of
2a. d 2,20-Methylene bis[(4R,5S)-4,5-diphenyl-2-oxazoline] was used (see
Supporting Information for more details). e The enantiomeric excess
examined by the chiral HPLC (see Supporting Information for more
details). f The reaction was conducted in the absence of PhI(OAc)2.
by examining inorganic bases revealed that the presence
of K3PO4 (1 equiv) rendered the formation of 2a more
efficient (86% yield in gram scale preparation) even under
a 15 mol % catalytic loading (entry 6), while usage of
10mol % catalystsdropped the yieldof2a to 70% (entry7).
The reaction with a chiral bis-oxazoline ligand, 2,20-methy-
lene bis[(4R,5S)-4,5-diphenyl-2-oxazoline], provided 48%
ee of 2a, which suggests that copper species could most
likelybeinvolvedinthepresentNꢀCbondformingprocess
(entry 8). It was confirmed that the reaction of 1a only with
(10) As a preliminary result, we have found aminooxygenation of
N-allylamidines with TEMPO as an oxygen source, wheareas the
process needed a stoichiometric amount of Cu(OAc)2 with a high
reaction temperature (80 °C), giving dihydroimidazoles in moderate
yields; see: Sanjaya, S.; Chua, S. H.; Chiba, S. Synlett 2012, 23, 1657.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Substrate Scope for Synthesis of 4-Acetoxymethyl-
4,5-dihydroimizazolesa,b
Scheme 4. A Proposed Catalytic Cycle
Scheme 5. Conversion of 4-Acetoxymethyl-4,5-dihydroimida-
zoles into 2,3-Diamino-1-propanolsa,b
a Unless otherwise noted, the reactions were carried out using 2.5ꢀ6.6
mmol of amidines 1 with Cu(OAc)2 (15 mol %) and 1,10-phenanthroline
(15 mol %) in the presence of K3PO4 (1 equiv) and PhI(OAc)2 (1.2 equiv)
at rt under a N2 atmosphere (see Supporting Information for more
details). b Isolated yields are recorded above. c 0.5 mmol of 1b was used.
dAs a side reaction, N-acetoxylation proceeded to give O-acetyloxime in
7% yield. e 1.2 mmol of 1m was used, and dimer 2m0 was formed in 17%
yield as a mixture of meso and diastereomer forms.
a Thereactions were carried out bytreatment of AlCl3 (1 equiv) in THF
with LiAlH4 (3 equiv) at 0 °C followed by addition of dihydroimidazoles
2 (1.1ꢀ3.7 mmol) and stirring at room temperature (see Supporting
Information for more details). b Isolated yields were recorded.
2 equiv of Cu(OAc)2 and that with 1.2 equiv of PhI(OAc)2
do not form 2a at all (entries 9 and 10).
and allyl groups could be installed to provide the corre-
sponding dihydroimidazoles in good yields (for 2j, 2k). By
introducing a substituent on R3, the construction of the
quaternary carbon center at the C(4) of dihydroimidazoles
was achieved, while the yield of 2m bearing a phenyl group
was moderate and dimer 2m0 was isolated as a side product
in 17% yield.11
Based on these results, a proposed catalytic cycle of this
aminoacetoxylation is outlined in Scheme 4.12 Since it was
confirmed that no reaction is observed by treatment of
amidine 1aonly with2 equiv ofCu(OAc)2 or with 1.2 equiv
of PhI(OAc)2 in DMF at room temperature,13 the present
With the optimized conditions in hand, we next exam-
ined the substrate scope for the synthesis of 4-acetoxy-
methyl-4,5-dihydroimidazoles 2 (Scheme 3). By varying
substituents R1 of amidines 1, it was shown that various
kinds of aromatic rings could be installed. The reactions
proceeded smoothly with sterically hindered aromatic
rings as R1 (2bꢀ2d). While the reaction with an electron-
rich 4-methoxybenzene ring afforded the corresponding
imidazole 2e, the yield was moderate (52%) and the
corresponding O-acetyloxime was formed in 7% yield as
a side product. Halogen substituents were tolerated, as the
CꢀX (X = Cl or Br) bond remained intact (for 2f, 2g). The
present process allowed for installation of 2- and 3-thienyl
groups on R1 (for 2h, 2i). As the substituents R2, benzyl,
(11) The amidine 1n and 1o bearing 3,3-dimethylallyl and 3-phenallyl
groups, respectively, gave complex mixtures of unidentified compounds;
see Supporting Information for more details.
Org. Lett., Vol. XX, No. XX, XXXX
C

processmight beinitiated by the formation ofhigher valent
NꢀCu(III) species I generated from amidine 1, Cu(OAc)2,
and PhI(OAc)2. The resulting N-Cu(III) species I under-
goes 5-exo aminocupration onto the alkenyl moiety to
give organocopper(III) species II.14 The subsequent reac-
tion of II with an acetate ion, probably via an SN2 type
substitution reaction,15 forms the CꢀO bond to afford
4-acetoxymethyl-4,5-dihydroimidazole 2 along with CuOAc
III that could maintain further catalytic turnover with
PhI(OAc)2.
oxidative intramolecular aminooxygenation, we finally
explored their concise transformation to 2,3-diamino-1-
propanols (Scheme 5). It was found that reduction of 2 by
aluminum hydride (AlH3, prepared in situ from LiAlH4
and AlCl3)16 proceeded smoothly to give 2,3-diamino-1-
propanols 3 in good to moderate yields.
In summary, we have developed Cu-catalyzed aminoox-
ygenation of alkenes with amidine moieties for synthesis
of 4-acetoxymethyl-4,5-dihydroimidazoles, which could
be further converted into 2,3-diamino-1-propanols with
concise AlH3 reduction. Further investigation related to
the scope, detailed mechanisms, development of an asym-
metric version of the process, and synthetic applications of
the present strategy to other azaheterocycles is currently
underway.
Having developed a preparation method of 4-acet-
oxymethyl-4,5-dihydroimidazoles 2 through the present
(12) Blakey reported aminoacetoxylation of N-(4-pentenyl)nosylamides
catalyzed by Cu(CH3CN)4PF6 with PhI(OAc)2 (see ref 5a), while the
reactions from the substrates bearing a terminal alkene provided piper-
idine derivatives as a major product via 6-endo cyclization. The result
could be rationalized by the proposed reaction mechanism including
electrophilic activation of the alkene by the putative Cu(III) species
followed by nucleophilic attack of the acetate ion. In contrast, the present
reaction delivered 5-exo cyclization product 2 exclusively even from 1l
and 1m. Based on these observations, the pathway involving electrophilic
activation of the alkene is most likely ruled out from the mechanistic
possibilities of the present process.
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).
(13) Chang recently reported intramolecular diamination and amino-
oxygenation of alkene using PhI(OAc)2 under transition metal-free
conditions; see: Kim, H. J.; Cho, S. H.; Chang, S. Org. Lett. 2012, 14,
1424.
(14) Organocopper species II might be under equilibrium with car-
bon radical species and Cu(OAc)2. In the reaction of 1m, dimerization of
the radical species might deliver the dimer 2m0.
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.
(15) Seayad, J.; Seayad, A. M.; Chai, C. L. L. Org. Lett. 2010, 12,
1412.
(16) Brown, H. C.; Yoon, N. M. J. Am. Chem. Soc. 1966, 88, 1464.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX