Highly selective palladium-catalyzed intramolecular aminonitroxylation of alkenes

Article abstract of DOI:10.1055/s-0030-1259701

A palladium-catalyzed intramolecular oxidative aminonitroxylation of unactivated alkenes, in which AgNO₃ functioned as a mild nitrate reagent in the presence of PhI(OAc)₂, has been developed. Mechanistic studies suggest that this sel

Full text of DOI:10.1055/s-0030-1259701

LETTER
891
Highly Selective Palladium-Catalyzed Intramolecular Aminonitroxylation of
Alkenes
I
ntramolecular
h
A
minonitro
u
xylation of
A
j
lkene
s
un Chen,a Tao Wu,b Guosheng Liu,*b Xingliang Zhena
a
Department of Chemistry, Changsha University of Science and Technology, Changsha 410114, P. R. of China
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Road, Shanghai 200032, P. R. of China
b
Fax +86(21)64166128; E-mail: gliu@mail.sioc.ac.cn
Received 28 October 2010
Dedicated to Professors Xiyan Lu and Lixin Dai
O
O
N
Abstract: A palladium-catalyzed intramolecular oxidative amino-
nitroxylation of unactivated alkenes, in which AgNO3 functioned as
a mild nitrate reagent in the presence of PhI(OAc)2, has been devel-
oped. Mechanistic studies suggest that this selective aminonitroxy-
lation reaction likely resulted from a new oxidant PhI(ONO2)2
generated in situ from AgNO3 and PhI(OAc)2.
S
cat. Pd(II), PhI(OAc)2
NaO2Ct-Bu, CH2Cl2
NHBoc
O
(1)
O
OAc
R = NHBoc
(Muñiz, 2008)
S
R
NH
ONO2
(2)
cat. (NCN)Pd, PhI(OAc)2
AgNO3, DCE
Key words: palladium, alkenes, difunctionalization, silver, amino-
nitroxylation
R = 4-MeC6H4
(this work)
N
Ts
(NCN)Pd:
Palladium-catalyzed oxidation reactions are important
transformations in organic synthesis.1 Recently, a number
of palladium-catalyzed difunctionalization reactions of
olefins that provide versatile strategies to synthesize mol-
ecules with vicinal diheteroatom substitution have been
reported.2 Transformations involving these alkyl-PdIV in-
termediates are particularly attractive because these com-
plexes can readily undergo reductive elimination
reactions to form C–O, C–N, and C–C bonds, which have
proven to be difficult to achieve with catalytic PdII/Pd0 cy-
cles.3–5 For instance, Sorensen, Stahl, and others have re-
ported that Pd-catalyzed aminoacetoxylation and
diacetoxylation employing PhI(OAc)2 to trap the interme-
diate C–Pd bond and lead to the formation of C–OAc
bond.4a–d Muñiz have reported a systematic study on the
intramolecualr palladium-catayzed diamination of alkene
with a similar strategy.5a–c It was found that the reaction of
alkene bearing sulfonylurea protecting group in nitrogen
atom afforded aminoacetoxylation of alkenes, rather than
diamination.5c This reaction occurs with high selectivity
regarding the transfer of the second nucleophile, which
orginated from the oxidant [e.g., PhI(OAc)2] but not from
the anionic base (Scheme 1, equation 1). Herein, we re-
port a palladium-catalyzed intramolecular aminonitroxy-
lation of alkenes by using PhI(OAc)2 as the oxidant, in
which the second nucleophile comes exclusively from the
additive AgNO3. In addition, both pincer palladium com-
plex and silver nitrate played important roles in this highly
selective transformation (Scheme 1, equation 2).
Me2N Pd NMe2
Br
Scheme 1
Very recently, we reported a palladium-catalyzed in-
tramolecular aminofluorination reaction of alkenes, in
which AgF played an important role for the C–F bond for-
mation.6 During the course of the study, a remarkable ef-
fect of selectivity by silver salt was also discovered:
treating N-tosyl aminoalkene 1a with PhI(OAc)2/AgNO3
in the presence of Pd(OAc)2 catalyst afforded an unex-
pected aminonitroxylation product 2a as the major prod-
uct. It is noteworthy that the second nucleophile was
originated from AgNO3, rather than oxidant. The ami-
noacetoxylation of alkenes leading to product 4a occurred
as a side product (Table 1, entry 1). After a series of opti-
mizations, the highly selective aminonitroxylation was
achieved with (NCN)Pd complex, which completely in-
hibited the aminoacetoxylation reaction (entry 2). Fur-
thermore, when NaNO3 was used instead of AgNO3, 4a
was the only product. This observation is reminiscent of
the corresponding results reported by Muñiz (entry 3).
The reaction with (NCN)PdBr catalyst still provided ami-
noacetoxylation product 4a as the major product, along
with a small amount of 2a (entry 4). These observations
indicated that AgNO3 is crucial to this high selectivity of
aminonitroxylation reaction.7
The intramolecular aminonitroxylation of alkenes is pro-
posed to consist of two important steps: an aminopallada-
tion (AP) of alkene and subsequent oxidative C–O bond
formation via reductive elimination (RE). This sequence
raises the question of the stereochemical course. Deuteri-
um-labeled substrate (E)-1a-d1 was shown to transform
SYNLETT 2011, No. 7, pp 0891–0894
Advanced online publication: 08.03.2011
DOI: 10.1055/s-0030-1259701; Art ID: W31410ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

892
S. Chen et al.
LETTER
Table 1 The Screen Results on Intramolecular Aminooxygenationa
tion to afford the aminonitroxylation product (Scheme 3,
path II).
Pd(II) (5 mol%)
PhI(OAc)2 (2 equiv)
ONO2
and/or
OAc
Compared with NaNO3, as mentioned above, the silver
ion played an important role for this transformation. Ac-
cording to the path I, if the formation of PhI(ONO2)2 can
be achieved, the aminonitroxylation reaction would occur
in the absence of silver ion. Otherwise, the silver ion is
necessary for the success of the reaction as predicted by
path II. Based on this hypothesis, two experiments were
conducted: (1) A mixture of PhI(OAc)2 and AgNO3 in
DCE were stirred for three hours, then the organic layer
was used to react with 1a in the presence of Pd catalyst.12
The reaction afforded the aminonitroxylation product in
good yield (Scheme 4, equation 1). (2) A reaction was
conducted by using HNO3 instead of AgNO3, and the sim-
ilar result was obtained (Scheme 4, equation 2). Those re-
sults indicated that the silver ion is not necessary for this
transformation and are consistent with the mechanism
pathway I. However, the silver ion should play a role in
promoting the formation of PhI(ONO2)2.
NHTs
additive (3 equiv)
DCE, r.t.
N
N
1a
Ts
2a
Ts
4a
Entry Pd
Additive
AgNO3
Time (h) Yield Ratio of
(%)b 2a/4ac
1
2
3
4
Pd(OAc)2
19
24
48
48
73
71
54
78
3.2:1
100:0
0:100
1:2.7
(NCN)PdBr
Pd(OAc)2
AgNO3
NaNO3
NaNO3
(NCN)PdBr
a All the reactions were conducted on a 0.1 mmol scale.
b 1H NMR Yield with 1,3,5-trimethoxybenzene as internal standard.
c Determined by 1H NMR.
into diastereomerically pure anti-2a-d1 selectively
(Scheme 2). The overall stereochemical outcome suggest-
ed that the inversion of configuration happened during the
reaction:8 The reaction either proceed through cis-AP fol-
lowed by SN2-type RE (path a)4b,5b or trans-AP followed
by directed RE (path b).4a For the former step, although
both cis- and trans-AP of alkenes have been reported to
address the 5-exo fashion, the 6-endo ring closure gener-
ally proceeded via trans-AP.9 Thus, the directed RE path-
way of PdIV complex should be expected for the C–O
bond formation.4c,10
path I:
PhI(OAc)2 + 2 AgNO3
PhI(ONO2)2
+ 2 AgOAc
O
N
N
N
O
O
directed
RE
PhI(ONO2)2
PdII
product
product
PdIV
N
N
O
path II
O
N
N
Ag
N
(NCN)PdBr (5 mol%)
PhI(OAc)2 (2 equiv)
directed
RE
ONO2
O
AgNO3
PdIV
PdIV
D
NHTs
AgNO3 (3 equiv)
DCE, r.t.
72% rs 9:1
N
D
N
N
Ts
anti-2a-d1
(E)-1a-d1
Scheme 3 The possible mechanism for selective Csp3–O reductive
elimination
PdIIL
[O]
PdIV
L
cis-AP
path a
SN2 RE
N
Ts
D
N
D
addition Bu4NCl
(no solid precipitate)
Ts
ONO2
D
D
NHTs
top clear
organic layer
N
(E)-1a-d1
Ts
anti-2a-d1
(NCN)Pd 5 mol%
PhI(OAc)2
+ 1a (1 equiv)
3 h
+ AgNO3
PdIIL
D
PdIV
L
path b
[O]
DCE
trans-AP
directed RE
N
N
D
Ts
Ts
ONO2
above organic solution
NHTs
Scheme 2 A possible pathway for the Pd-catalyzed aminonitroxyla-
tion of alkenes
(1)
(NCN)PdBr (5 mol%)
N
Ts
2a
84% rs 8:1
1a
1a
There are two possiblities for the formation of aminoni-
troxylation product: 1) PhI(NO3)2, generated in situ from
PhI(OAc)2 and AgNO3, acts as an oxidant to achieve ami-
nonitroxylation (Scheme 3, path I); 2) a strong interaction
between Pd and AgNO3, which was recently reported by
Albrecht,11 possibly results in a intramolecualr nitroxyla-
(NCN)PdBr (5 mol%)
PhI(OAc)2 (2 equiv)
ONO2
(2)
NHTs
HNO3 (70%, 3 equiv)
DCE, r.t.
N
Ts
2a
78% rs 9:1
Scheme 4
Synlett 2011, No. 7, 891–894 © Thieme Stuttgart · New York

LETTER
Intramolecular Aminonitroxylation of Alkenes
893
Table 2 Palladium-Catalyzed Intramolecular Aminonitrooxylation of Alkenesa
R1
R1
R2
R2
ONO2
+
R1 R2
(NCN)PdBr (5 mol%)
PhI(OAc)2 (2 equiv)
ONO2
NHTs
N
N
AgNO3 (3 equiv)
DCE, r.t.
Ts
Ts
1
2
3
Entry
1
Alkene
Substituents
Major product
Yield of 2 + 3 (%)b
Ratio of 2/3c
ONO2
1a Z = Ts
2a
83
91:9
NHZ
N
Z
2
3
1b Z = Ac
1c Z = Cbz
2b
2c
0
0
R
ONO2
R
R
R
4
1d R = Ph
1e R = Bn
2d
2e
89
86:14
NHTs
N
Ts
5
6
69
85
88:12
90:10
1f R = CO2Me
2f
ONO2
n
n
7
1g n = 1
2g
78
82:18
NHTs
N
Ts
8
9
1h n = 3
1i n = 4
2h
2i
85
80
88:12
87:13
ONO2
10
1j
2j
92
97:3
97:3
NHTs
N
Ts
ONO2
11
12
13
1k
1l
2k
2l
79
65
63
NHTs
NHTs
N
Ts
ONO2
80:20
(2l 1.5:1)d
(3l 1.1:1)d
N
Ts
ONO2
85:15
1m
2m
(2m 3:1)d
(3m n.d.)
N
NHTs
Ts
a Reactions were conducted on a 0.2 mmol scale.
b Isolated yield.
c The ratio of regioselectivity which determined by 1H NMR.
d The ratio of trans/cis, the diastereoselectivity determined by 1H NMR.
Based on the optimized conditions, the substrate scope of ing products with good yields and excellent
the aminonitroxylation reaction was then investigated diastereoselectivity (entries 10 and 11). In contrast, the
(Table 2). Compared to N-tosyl alkene 1a with a 83% substrates 1l–m exhibited good reactivity, moderate regio-
yield in 91:9 regioselectivity, substrates N-acetyl alkene selectivity, and poor diastereoselectivity (entries 12 and
1b and N-Cbz alkene 1c did not afford any aminonitroxy- 13).
lation products (entries 1–3). The reactions of 1d–i afford-
ed products 2d–i in good yields, with moderate to good
regioselectivity (entries 4–9). Substrates 1j and 1k, with
one substituent in the b-carbon position, underwent in-
tramolecular aminonitroxylation to afford the correspond-
In summary, a highly chemoselective palladium-cata-
lyzed intramolecular oxidative aminonitroxylation of un-
activated alkenes have been developed, in which AgNO3
functioned as a mild nitrate reagent in the presence of
PhI(OAc)2. Mechanistic studies suggested that two key
Synlett 2011, No. 7, 891–894 © Thieme Stuttgart · New York

894
S. Chen et al.
LETTER
H. J. Am. Chem. Soc. 2009, 131, 3846. (f) Park, C. P.; Lee,
J. H.; Yoo, K. S.; Jung, K. W. Org. Lett. 2010, 12, 2450.
Aminoarylation, see: (g) Rosewall, C. F.; Sibbald, P. A.;
Liskin, D. V.; Michael, F. E. J. Am. Chem. Soc. 2009, 131,
9488. Aminohalogenation, see: (h) Michael, F. E.; Sibbald,
P. A.; Cochran, B. M. Org. Lett. 2008, 10, 793.
steps in the reaction were possibly involved in the forma-
tion of C–N and C–O bonds: trans-aminopalladation (en-
do) of alkene and directed reductive elimination of PdIV
complex.
(5) For oxidative diamination of alkenes, see: (a) Streuff, J.;
Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc.
2005, 127, 14586. (b) Muñiz, K. J. Am. Chem. Soc. 2007,
129, 14542. (c) Muñiz, K.; Hövelmann, C. H.; Streuff, J.
J. Am. Chem. Soc. 2008, 130, 763. (d) Sibbald, P. A.;
Michael, F. E. Org. Lett. 2009, 11, 1147.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(6) Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131,
This work was supported by the Chinese Academy of Science, the
National Natural Science Foundation of China (20821002,
20872155, 20972175, and 20923005), the National Basic Research
Program of China (973-2009CB825300), and the Science and Tech-
nology Commission of the Shanghai Municipality (08PJ1411600
and 08dj1400100).
16354.
(7) In comparison to the standard conditions, the reaction of 1a
still afforded the aminonitroxylation product in 78% yield in
the absence of palladium catalyst, but the poor regioselec-
tivity of 2a and 3a (49:51) and slow rate indicated that this
reaction was catalyzed by a palladium complex. For the
acid-catalyzed amination of alkene by hypervalent iodine
reagents, see: (a) Lovick, H. M.; Michael, F. E. J. Am. Chem.
Soc. 2010, 132, 1249. (b) Wardrop, D. J.; Bowen, E. G.;
Forslund, R. E.; Sussman, A. D.; Weerasekera, S. L. J. Am.
Chem. Soc. 2010, 132, 1188.
References and Notes
(1) For reviews on the oxidative reaction of olefins, see:
(a) Stahl, S. S. Angew. Chem. Int. Ed. 2004, 43, 3400.
(b) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
(8) The same stereochemical behavior has been reported.4a,b,5b,6
(9) (a) For the recent studies on the aminopalladation, see:
Watson, M. P.; Overman, L. E.; Bergman, R. G. J. Am.
Chem. Soc. 2007, 129, 5031. (b) Neukom, J. D.; Perch, N.
S.; Wolfe, J. P. J. Am. Chem. Soc. 2010, 132, 6276.
(c) Hanley, P. S.; Markovic, D.; Hartwig, J. F. J. Am. Chem.
Soc. 2010, 132, 6302. (d) Liu, G.; Stahl, S. S. J. Am. Chem.
Soc. 2007, 129, 6328.
(10) The alternative path a in Scheme 2 is less likely, but cannot
be excluded at this moment. This is because the differen-
tiation of cis- and trans-aminopalladation is very difficult.
(11) (a) Heckenroth, M.; Neels, A.; Garnier, M. G.; Aebi, P.;
Ehlers, A. W.; Albrecht, M. Chem. Eur. J. 2009, 15, 9375.
(b) Heckenroth, M.; Kluser, E.; Neels, A.; Albrecht, M.
Angew. Chem. Int. Ed. 2007, 46, 6293.
Sottocornola, S. Chem. Rev. 2007, 107, 5318.
(2) For reviews on difuctionalization of alkenes, see:
(a) Jensen, K. H.; Sigman, M. S. Org. Biomol. Chem. 2008,
6, 4083. (b) Kotov, V.; Scarborough, C. C.; Stahl, S. S.
Inorg. Chem. 2007, 46, 1910. (c) Deprez, N. R.; Sanford,
M. S. Inorg. Chem. 2007, 46, 1924.
(3) For the reviews on the oxidative reaction of alkenes
involving PdIV intermediate, see: (a) Muñiz, K. Angew.
Chem. Int. Ed. 2009, 48, 9412. (b) Lyons, T. W.; Sanford,
M. S. Chem. Rev. 2010, 110, 1147. (c) Xu, L. M.; Li, B. J.;
Yang, Z.; Shi, Z. J. Chem. Soc. Rev. 2010, 39, 712.
(4) For selective examples for aminoacetoxylation, see:
(a) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem.
Soc. 2005, 127, 7690. (b) Liu, G.; Stahl, S. S. J. Am. Chem.
Soc. 2006, 128, 7179. Aminooxygenation, see: (c) Desai, L.
V.; Sanford, M. S. Angew. Chem. Int. Ed. 2007, 46, 5737.
Dioxygenation, see: (d) Li, Y.; Song, D.; Dong, V. M. J. Am.
Chem. Soc. 2008, 130, 2962. (e) Wang, A.; Jiang, H.; Chen,
(12) The organic layer contained no Ag ion, which was demon-
strated by addition of Bu4NCl – no AgCl precipitated from
the organic layer.
Synlett 2011, No. 7, 891–894 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.