Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate

Article abstract of DOI:10.1021/acs.orglett.6b02722

A mild aerobic intramolecular aminoacetoxylation method for the synthesis of pyrrolidine and indoline derivatives was achieved using molecular oxygen as the oxidant. A catalytic NO_x species acts as an electron transfer mediator to access a high-valent palladium intermediate as the presumed active oxidant.

Full text of DOI:10.1021/acs.orglett.6b02722

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of
Alkenes Enabled by Catalytic Nitrate
Jiaming Li, Robert H. Grubbs,* and Brian M. Stoltz*
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, 1200 East California Boulevard, MC 101-20, Pasadena, California 91125, United
States
S
* Supporting Information
ABSTRACT: A mild aerobic intramolecular aminoacetoxyla-
tion method for the synthesis of pyrrolidine and indoline
derivatives was achieved using molecular oxygen as the
oxidant. A catalytic NOx species acts as an electron transfer
mediator to access a high-valent palladium intermediate as the
presumed active oxidant.
umerous alkene difunctionalization reactions enabled by
palladium catalysts have been developed as efficient
are rare, presumably because the oxidation of the intermediate
alkylpalladium(II) species using O2 as the sole oxidant is
kinetically challenging;7 hence, care must be taken to avoid facile
β-hydride elimination immediately (Scheme 1). Recently, NOx
species have been shown to be effective electron transfer
mediators capable of facilitating the aerobic oxidation of
alkylpalladium(II) intermediates to their high-valent counter-
parts.8 Sanford and co-workers reported that nitrate/nitrite
could serve as a redox cocatalyst in the aerobic acetoxylation of
unactivated C(sp3)−H bonds via C−O bond reductive
elimination of a high-valent palladacycle (Scheme 2A).9 Very
N
transformations for the construction of useful organic building
blocks.1 For example, palladium-catalyzed amination of alkenes
has been applied as a new strategy to synthesize nitrogen-
containing heterocycles.2 Arising from a key aminopalladation
step, an alkylpalladium(II) intermediate can undergo versatile
pathways to generate different structural motifs (Scheme 1).2a In
Scheme 1. Aminopalladation and Subsequent
Transformations
Scheme 2. Pd-Catalyzed Aerobic Methods Enabled by NOx
Species
the past decade, aminooxygenation has been achieved by
oxidizing the alkylpalladium(II) intermediate into high-valent
palladium (PdIV or PdIII) followed by C−O bond-forming
reductive elimination. However, a stoichiometric amount of a
3
strong oxidant, such as PhI(OAc)2 or NFSI,4 is typically
required to access the high-valent palladium intermediate.
Recently, milder conditions have also been developed using
H2O2 as an environmentally tractable and inexpensive oxidant,5
but aerobic conditions are still in high demand from a
sustainable perspective.
A classic and well-studied example of a palladium-catalyzed
aerobic homogeneous transformation is the Wacker process.
This transformation was developed in the 1950s using O2 as the
terminal oxidant in combination with a Cu salt as a redox
cocatalyst to facilite the reoxidation of Pd0 to PdII.6 In contrast,
reports of alkene difunctionalizations under aerobic conditions
recently, the Grubbs group reported a palladium-catalyzed
aerobic alkene diacetoxylation method mediated by a catalytic
amount of silver nitrite (Scheme 2B).10 We reasoned that a
palladium-catalyzed aerobic aminooxygenation reaction might
be possible using this electron transfer mediator strategy, as an
NOx species could be a kinetically suitable mediator in the
Received: September 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02722
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
aerobic oxidation of the alkylpalladium(II) intermediate formed
after aminopalladation.
Table 2. Aminoacetoxylation of Aliphatic Amines
We started our investigation by subjecting acetyl-protected
aminoalkene substrate 1a to our previously published
intermolecular diacetoxylation reaction conditions (Table 1,
Table 1. Reaction Optimization
T
yield
ab
,
entry
1
NOx source
AgNO2
(°C)
solvent
(%)
11
35
AcOH/Ac2O/MeNO2
(10:5:3)
2
3
4
5
6
7
8
9
AgNO2
35
35
35
35
35
35
35
35
35
35
23
AcOH/Ac2O (8:1)
AcOH/Ac2O (8:1)
AcOH/Ac2O (8:1)
AcOH/Ac2O (8:1)
AcOH/Ac2O (8:1)
AcOH/Ac2O (8:1)
AcOH/Ac2O (8:1)
AcOH/Ac2O (8:1)
AcOH/Ac2O (8:1)
AcOH/Ac2O (8:1)
AcOH/Ac2O (6:1)
50
32
41
48
35
48
40
17
56
0
NaNO2
NBu4NO2
i-BuONO
NaNO3
a
The amine substrate (0.5 mmol) was treated with PdCl2(PhCN)2 (5
Fe(NO3)3
AgNO3
mol %) and Cu(NO3)2·3H2O (5 mol %) in AcOH/Ac2O (6:1, 10.5
mL) under an O2 atmosphere (1 atm) at 23 °C for 16 h. Yields of
isolated products.
b
NOBF4
c
10
Cu(NO3)2·3H2O
−
Cu(NO3)2·3H2O
a
11
Table 3. O-Allylaniline Substrate Scope
c
12
62
a
Yields were determined by GC with tridecane as an internal standard.
b
Methyl ketone and alkene isomers were observed as byproducts by
c
1H NMR spectroscopy. CuCl2·2H2O was not added.
entry 1).10 We were delighted to find that the desired cyclization
product 2a was indeed formed on the first attempt, albeit in only
11% yield. In order to optimize the reaction, we altered the
components of the solvent mixture and observed a substantial
boost in yield by removing MeNO2 as the cosolvent (entry 2).
Since the NOx species acts as a key catalytic component, we
examined a broad range of metal nitrates, metal nitrites, and
alkyl nitrites. Most of the tested NOx species proved to be
capable electron transfer mediators, affording the product in
moderate yields (entries 2−10). However, the reaction did not
give cyclized product without addition of any NOx sources
(entry 11). Copper nitrate trihydrate gave the highest yield
among the tested NOx species, while other types of NOx species
showed marginally lower reactivity. Finally, by lowering the
temperature to 23 °C and increasing the ratio of Ac2O, we
achieved a further improvement in the yield (entry 12).
Next, we evaluated the substrate scope and functional group
tolerance under our optimized conditions. Linear aliphatic
amines with geminal disubstitutions were converted to the
corresponding pyrrolidine products in good yields (Table 2).
We also tested a series of o-allylaniline derivatives and obtained a
variety of indoline derivatives 4a−i in moderate to excellent
yields (30−95% yield; Table 3). A variety of substituents and
functional groups are well-tolerated, including fluoro, chloro,
methyl ester, trifluoromethyl, and, to a lesser extent, nitro and
cyano groups. Notably, we also tested the reaction under air, and
product 4a was obtained in good yield (80% yield; Table 3,
entry 2).
b
entry
1
product
R1
R2
yield (%)
4a
4a
4b
4c
4d
4e
4f
H
H
H
H
Me
H
H
H
H
H
H
87
80
89
95
88
80
65
58
30
32
c
2
H
3
4
Me
H
5
F
6
Cl
7
COOMe
CF3
8
4g
4h
4i
9
NO2
10
CN
a
The amine substrate (0.5 mmol) was treated with PdCl2(PhCN)2 (5
mol %) and Cu(NO3)2·3H2O (5 mol %) in AcOH/Ac2O (6:1, 10.5
mL) under an O2 atmosphere (1 atm) at 23 °C for 16 h. Yields of
b
c
isolated products. Under 1 atm air instead of oxygen.
intermediate II by an NOx species (possibly NO2 as suggested
by previous literature11,12) with molecular oxygen as the
terminal oxidant. We envision that high-valent palladium
intermediate II can then undergo the C−O bond-forming
reductive elimination to release cationic intermediate III,10
which forms the aminoacetoxylation product 2a upon acetolysis.
The source of additional oxygen atoms in the product has not
been verified, but a previous 18O labeling study showed that the
oxygen came from the AcOH solvent.10 Although the role of
copper still remains elusive, the presence of copper is clearly
advantageous, as a decrease in yield was observed when no
source of Cu was added.13 The other necessary solvent
component, Ac2O, could possibly sequester H2O generated in
the catalytic system.9
On the basis of our observations and previous mechanistic
studies, we propose the catalytic cycle shown in Figure 1.
Aminopalladation of the substrate 1a likely forms Pd(II)
intermediate I, which can be oxidized to high-valent palladium
In summary, we have reported a mild, aerobic intramolecular
aminoacetoxylation method. This chemistry provides another
B
DOI: 10.1021/acs.orglett.6b02722
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Am. Chem. Soc. 2007, 129, 6328−6335. (c) Bertrand, M. B.; Neukom, J.
D.; Wolfe, J. P. J. Org. Chem. 2008, 73, 8851−8860. (d) Muniz, K.;
̃
Hovelmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130, 763−773.
̈
(e) Ye, X.; Liu, G.; Popp, B. V.; Stahl, S. S. J. Org. Chem. 2011, 76,
1031−1044.
(3) Selected examples of alkene difunctionalization using high-valent
iodine reagents: (a) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am.
Chem. Soc. 2005, 127, 7690−7691. (b) Streuff, J.; Hovelmann, C. H.;
̈
Nieger, M.; Muniz, K. J. Am. Chem. Soc. 2005, 127, 14586−14587.
̃
(c) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179−7181.
(d) Desai, L. V.; Sanford, M. S. Angew. Chem., Int. Ed. 2007, 46, 5737−
5740. (e) Neufeldt, S. R.; Sanford, M. S. Org. Lett. 2013, 15, 46−49.
(f) Martínez, C.; Wu, Y.; Weinstein, A. B.; Stahl, S. S.; Liu, G.; Muniz,
̃
K. J. Org. Chem. 2013, 78, 6309−6315. (g) Chen, H.; Kaga, A.; Chiba, S.
Org. Lett. 2014, 16, 6136−6139.
(4) Alkene difunctionalization using NFSI as the oxidant: (a) Sibbald,
P. A.; Rosewall, C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc.
2009, 131, 15945−15951. (b) Liskin, D. V.; Sibbald, P. A.; Rosewall, C.
F.; Michael, F. E. J. Org. Chem. 2010, 75, 6294−6296. (c) Engle, K. M.;
Mei, T.-S.; Wang, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2011, 50, 1478−
1491. (d) Ingalls, E. L.; Sibbald, P. A.; Kaminsky, W.; Michael, F. E. J.
Am. Chem. Soc. 2013, 135, 8854−8856.
(5) (a) Zhu, H.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2014, 136, 1766−
1769. (b) Zhu, H.; Chen, P.; Liu, G. Org. Lett. 2015, 17, 1485−1488.
(6) Reviews of Wacker oxidation and selected examples: (a) Takacs, J.
M.; Jiang, X. Curr. Org. Chem. 2003, 7, 369−396. (b) Cornell, C. N.;
Sigman, M. S. Inorg. Chem. 2007, 46, 1903−1909. (c) Keith, J. A.;
Henry, P. M. Angew. Chem., Int. Ed. 2009, 48, 9038−9049. (d) Dong, J.
J.; Browne, W. R.; Feringa, B. L. Angew. Chem., Int. Ed. 2015, 54, 734−
744. (e) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc.
2005, 127, 17778−17788. (f) Trend, R. M.; Ramtohul, Y. K.; Ferreira,
E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2003, 42, 2892−2895.
(g) Wickens, Z. K.; Morandi, B.; Grubbs, R. H. Angew. Chem., Int. Ed.
2013, 52, 11257−11260. (h) Wickens, Z. K.; Skakuj, K.; Morandi, B.;
Grubbs, R. H. J. Am. Chem. Soc. 2014, 136, 890−893.
Figure 1. Proposed catalytic cycle. For clarity, the full ligand set on
palladium is not shown. Intermediate II could be a different high-valent
palladium species such as PdIII.
example of a catalytic NOx species serving as a compatible
electron transfer mediator to access a high-valent palladium
species with molecular oxygen as the terminal oxidant. Ongoing
mechanistic studies of this unique catalytic system, including a
full stereochemical analysis, would be beneficial to the
development of novel stereoselective methods. Finally, in
today’s renaissance of NOx redox chemistry, we anticipate that
efficient utilization of the oxidation potential of O2 will enable
access to even more environmentally benign processes rather
than consuming other high-energy/high-cost stoichiometric
oxidants.
ASSOCIATED CONTENT
* Supporting Information
■
S
(7) (a) Zhang, J.; Khaskin, E.; Anderson, N. P.; Zavalij, P. Y.;
Vedernikov, A. N. Chem. Commun. 2008, 31, 3625−3627. (b) Wang,
A.; Jiang, H.; Chen, H. J. Am. Chem. Soc. 2009, 131, 3846−3847.
(c) Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654−14655.
(d) Tang, F.; Zhang, Y.; Rath, N. P.; Mirica, L. M. Organometallics
2012, 31, 6690−6696. (e) Khusnutdinova, J. R.; Rath, N. P.; Mirica, L.
M. J. Am. Chem. Soc. 2012, 134, 2414−2422.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02722.
Experimental procedures and compound characterization
(PDF)
AUTHOR INFORMATION
Corresponding Authors
(8) (a) Fairlamb, I. J. S. Angew. Chem., Int. Ed. 2015, 54, 10415−
10427. (b) Gerken, J. B.; Stahl, S. S. ACS Cent. Sci. 2015, 1, 234−243.
(c) Liang, Y.-F.; Li, X.; Wang, X.; Yan, Y.; Feng, P.; Jiao, N. ACS Catal.
2015, 5, 1956−1963. (d) Zultanski, S. L.; Stahl, S. S. J. Organomet.
Chem. 2015, 793, 263−268. For a review of the NO2/NO redox cycle
in transition-metal chemistry, see: (e) Ford, P. C.; Lorkovic, I. M.
Chem. Rev. 2002, 102, 993−1018.
■
*E-mail: rhg@caltech.edu.
*E-mail: stoltz@caltech.edu.
Notes
The authors declare no competing financial interest.
(9) Stowers, K. J.; Kubota, A.; Sanford, M. S. Chem. Sci. 2012, 3,
3192−3194.
ACKNOWLEDGMENTS
■
(10) Wickens, Z. K.; Guzman
Ed. 2015, 54, 236−240.
́
, P. E.; Grubbs, R. H. Angew. Chem., Int.
The authors thank the NIH (R01GM031332 and
R01GM080269) and Caltech for financial support. Dr. Scott
C. Virgil (Caltech) is thanked for assistance with GC analysis.
Dr. David VanderVelde (Caltech) and Dr. Mona Shahgholi
(Caltech) are acknowledged for help in structural determination
and characterizations.
(11) (a) Thiemann, M.; Scheibler, E.; Wiegand, K. W. Nitric Acid,
Nitrous Acid, and Nitrogen Oxides. In Ullmann’s Encyclopedia of
Industrial Chemistry; Wiley-VCH: Weinheim, Germany, 2005.
(b) Laue, W.; Thiemann, M.; Scheibler, E.; Wiegand, K. W. Nitrates
and Nitrites. In Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-
VCH: Weinheim, Germany, 2005.
́
(12) Campora, J.; Palma, P.; del Río, D.; Carmona, E.; Graiff, C.;
REFERENCES
■
Tiripicchio, A. Organometallics 2003, 22, 3345−3347.
(1) Selected reviews of Pd-catalyzed alkene difunctionalization
(13) See Table S1 in the Supporting Information for control
experiments and Table S2 for catalyst ratio studies. Possible
heterobimetallic Pd/Cu catalyst species were suggested by previous
computational studies. See: Jiang, Y.-Y.; Zhang, Q.; Yu, H.-Z.; Fu, Y.
ACS Catal. 2015, 5, 1414−1423.
reactions: (a) Muniz, K. Angew. Chem., Int. Ed. 2009, 48, 9412−9423.
̃
(b) Xu, L.-M.; Li, B.-J.; Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39,
712−733. (c) Sehnal, P.; Taylor, R. J. K.; Fairlamb, I. J. S. Chem. Rev.
2010, 110, 824−889. (d) Hickman, A. J.; Sanford, M. S. Nature 2012,
484, 177−185. (e) Coombs, J. R.; Morken, J. P. Angew. Chem., Int. Ed.
2016, 55, 2636−2649.
(2) Pd-catalyzed amination reactions: (a) McDonald, R. I.; Liu, G.;
Stahl, S. S. Chem. Rev. 2011, 111, 2981−3019. (b) Liu, G.; Stahl, S. S. J.
C
DOI: 10.1021/acs.orglett.6b02722
Org. Lett. XXXX, XXX, XXX−XXX