Pd(II)-catalyzed enantioselective intramolecular oxidative amination utilizing (+)-camphorsulfonic acid

Article abstract of DOI:10.1016/j.tetlet.2017.07.090

An enantioselective Pd(II)-catalyzed intramolecular oxidative amination reaction was developed utilizing the commercially available chiral X-type ligand (1S)-(+)-camphorsulfonic acid. The Wacker-type cyclization produced chiral indoline products with enantioselectivies up to 45% ee. Electronic structure calculations employing density functional theory support a trans-aminopalladation mechanism.

Full text of DOI:10.1016/j.tetlet.2017.07.090

Accepted Manuscript
Pd(II)-catalyzed enantioselective intramolecular oxidative amination utilizing
(+)-camphorsulfonic acid
Andrew H. Aebly, Trevor J. Rainey
PII:
S0040-4039(17)30959-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.090
TETL 49172
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 May 2017
21 July 2017
26 July 2017
Please cite this article as: Aebly, A.H., Rainey, T.J., Pd(II)-catalyzed enantioselective intramolecular oxidative
amination utilizing (+)-camphorsulfonic acid, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.07.090
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Pd(II)-Catalyzed Enantioselective
Intramolecular Oxidative Amination
Utilizing (+)-Camphorsulfonic acid
Andrew H. Aebly and Trevor J. Rainey
Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana, 59717

1
Tetrahedron Letters
journal hom epage: www.els evier.com
Pd(II)-catalyzed enantioselective intramolecular oxidative amination utilizing (+)-
camphorsulfonic acid
Andrew H. Aeblya and Trevor J. Raineya∗
a Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59717, United State of America
ARTICLE INFO
ABSTRACT
Article history:
Received
An enantioselective Pd(II)-catalyzed intramolecular oxidative amination reaction was developed
utilizing the commercially available chiral X-type ligand (1S)-(+)-camphorsulfonic acid. The
Wacker-type cyclization produced chiral indoline products with enantioselectivies up to 45% ee.
Received in revised form
Accepted
Electronic structure calculations employing density functional theory support
aminopalladation mechanism.
a trans-
Available online
Keywords:
2017 Elsevier Ltd. All rights reserved
.
Oxidative Amination
Pd(II) catalysis
Chiral sulfonic acid
Indolines
———
∗ Corresponding author. Tel.: +1-650-484-7214; e-mail: tjrainey@gmail.com

2
Tetrahedron
Introduction
The Pd-catalyzed Wacker-type oxidative functionalization of
Catalyst (10 mol%)
Ligand (1, 20 mol%)
unactivated alkenes and alkynes has garnered significant
attention over the past three decades.1 Although progress has
been made regarding mechanistic elucidation,2 efficiency, and
catalyst re-oxidation (including the use of aerobic conditions),3
the number of enantioselective examples, specifically with the
formation of chiral centers with C–N bonds, remains low.4 To
date, enantioselective oxidative amination has almost exclusively
utilized bidentate nitrogenous ligands to impart asymmetric
induction.5 Despite the utility of this scaffold, these electron-
donating L-type ligands can dramatically attenuate the
electrophilicity of the Pd-alkene complex. In contrast, we sought
to explore the use of chiral X-type ligands for the synthesis of
indoline derivatives through intramolecular oxidative amination.
Surprisingly, the use of chiral X-type ligands in palladium
catalysis has received very little attention. Beginning in 1990,
Alper utilized a BINOL-derived chiral phosphoric acid ((S)-(+)-
1,1’-Binaphthyl-2,2’-diyl hydrogenphosphate—1a) for the
enantioselective palladium-catalyzed hydrocarboxylation of vinyl
arenes.6 More recently, in the development of asymmetric
counteranion-directed catalysis (ACDC),7 List applied similar
chiral phosphoric acid ligands towards an enantioselective
Overman rearrangement and enantioselective allylations of
aldehydes.8 Ooi found success in pairing chiral binaphtholate9
and phosphate ions10 with achiral ammonium-phosphine ligands
in asymmetric allylation of α-nitro esters and benzofurans.
Similarly, Gong combined a chiral phosphoramidite and a chiral
phosphoric acid to elicit facial-selective nucleophilic attack on a
π-allyl-Pd complex in the asymmetric allylic alkylation of
pyroazol-5-ones.11 Hu developed a three-component reaction for
the synthesis of pyrrole derivatives through a chiral phosphoric
acid-ligated palladium-carbenoid-mediated transformation with
good enantio- and diastereoselectivity.12 Yao applied the chiral
phosphoric acid (S)-TRIP (1b) in combination with Pd(II) in an
enantioselective oxa-Diels-Alder reaction.13 Lastly, our group has
synthesized spiroketones through an asymmetric Pd(II)/chiral
phosphoric acid-catalyzed semipinacol rearrangement.14 ,15
p-benzoquinone (2 eq)
benzene, 48 h, r.t.
2a
3a
1c
1a
1b
Entry
Catalyst
Ligand
Yield 3a (%)b
% eec
1
2
3
4
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
1a
1b
1c
29
6d
17
14
55
56
<5d
8d
40
41
Pd[(+)-CSA]2 no ligand
1c
no catalyst
Pd(OAc)2
n.d.
6
no ligand
n.d.
aReagents and conditions: 2a (0.05 mmol), Pd(OAc)2 (0.005 mmol), ligand
(0.01 mmol), 1,4-benzoquinone (0.2 mmol), benzene (0.5 mL).
bIsolated yield.
cDetermined by chiral HPLC.
dConversion determined by crude 1H-NMR
Table 2. Reaction optimizationa
Catalyst (10 mol%)
(+)-CSA (20 mol%)
oxidant
benzene, 48 h, r.t.
2a
3a
Results and discussion
Entry
Catalyst
Oxidant
Yield 3a (%)b
% eec
With the established success of chiral phosphoric acid ligands
by our group and others, initial attempts to convert 2a to the
desired product 3a began with BINOL-derived phosphoric acids
1a and 1b. Unfortunately, only moderate conversion and poor
enantioselectivity were observed with this class of ligands (Table
1, entries 1 and 2).16 At this time we decided to examine the use
of chiral sulfonic acid ligands and were pleased to discover that
commercially available (1S)-(+)-10-camphorsulfonic acid ((+)-
CSA—1c) greatly improved the enantioselectivity (Table 1, entry
3). We hypothesized that acid-promoted ligand exchange was
affording Pd[(+)-CSA]2 as the active catalyst; indeed, stepwise
synthesis and application of Pd[(+)-CSA]2 in this transformation
afforded nearly identical results to those obtained using the
standard conditions (Table 1, entry 4). No appreciable reaction
occurred upon omission of the palladium source (Table 1, entry
5); likewise, addition of the sulfonic acid proved essential for
reactivity (Table 1, entry 6). After selecting (+)-CSA as the
optimal ligand for the enantioselective transformation, further
reaction optimization was conducted (Table 2).
1
2
3
Pd(CH3CN)2Cl2 BQ (2 eq)
73
40
53
55
85e
74
38
8e
34
12
32
54
11
38
24
40
19
44
41
n.d.
44
10
n.d.
44
Pd2(dba)3
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
BQ (2 eq)
BQ (2 eq)
BQ (2 eq)
BQ (2 eq)
BQ (2 eq)
BQ (2 eq)
BQ (2 eq)
O2
4
5d
6f
7g
8f,h
9f
10f
11f
MnO2
O2/BQ (20 mol%)
BQ (2 eq)
12f,I Pd(OAc)2
13f,j Pd(OAc)2
BQ (2 eq)
40
44
aReaction conditions: substrate (0.1 mmol), Pd(OAc)2 (0.01 mmol), 1c (0.02
mmol), 1,4-benzoquinone (0.2 mmol), benzene (1.0 mL), 48 h, 22 oC.
bIsolated yield.
cDetermined by chiral HPLC.
d60 °C
eConversion determined by crude 1H-NMR
f(+)-NaCSA (10 mol%) added.
g(+)-NaCSA (1 equiv) added.
hNo (+)-CSA
iReaction performed in toluene.
jReaction performed in dichloromethane.
Table 1. Ligand selectiona

3
Table 3. Pd(II)-catalyzed oxidative aminationa
Entry
Substrate
Product
Yield (%)b % eec
1
2
2a
3a
3b
74
55
44
38
2b
2c
2d
2e
2f
3
4
5
6
3c
3d
3e
3f
76
70
67
66
43
42
45
13
7d 2g
3g
3h
53
54
0
8e 2h
29
9e 2i
10e 2j
3i
3j
55
62
27
27
11e 2k
3k
3l
68
66
27
0
12f 2l
13g 2m
14g 2n
15h 2o
3m
3n
3o
46
0
52
44
44
0

4
Tetrahedron
aReaction conditions: substrate (0.1 mmol), Pd(OAc)2 (0.01 mmol), 1c (0.02
mmol), (+)-NaCSA (0.01 mmol), 1,4-benzoquinone (0.2 mmol), benzene (1.0
mL), 60 h, 22 oC.
bIsolated yield.
cDetermined by chiral HPLC
d60 h, 50 oC
e5 h, 22 oC
f18 h, 22 oC
g24 h, 50 oC
h72 h, 50 oC
Scheme 1. Proposed Mechanism
in these transformations is unsurprising given that the source of
chirality in the ligand is distant from the Pd-alkene complex.
To shed light on the mechanism of these transformations, we
evaluated key intermediates and transition states relevant to both
trans- and cis-aminopalladation mechanisms using computational
methods for model substrate 4a; for computational expediency
methanesulfonic acid was substituted for (+)-CSA. (Scheme 1).
Previous work from our group has highlighted the imporance
of low levels of adventitious water on Brønsted acid/Pd(II)-
catalyzed reactions.14 A similar observation was made for the
current transformation; this was further borne out in the
mechanistic calculations which evaluated water and
benzoquinone as neutral ligands during the key C–N forming
event. Under the reaction conditions, Pd(OAc)2 undergoes acid-
promoted ligand exchange to yield a Pd(OMs)2(H2O)2 complex.
Coordination to the substrate with loss of a water ligand gives
complex C. From this common intermediate, facile general base-
catalyzed trans-aminopalladation takes place via transition state
E (∆G‡ 6.2 kcal/mol) to give intermediate F; for comparison, the
non-base-catalyzed reaction has a markedly higher activation
energy of 26.3 kcal/mol, relative to intermediate D. Ultimately,
ligand dissociation followed by β-hydride elimination furnishes
the observed product. Alternatively, cis-aminopalladation was
found to proceed via the unusual activated complex B, in which
the sulfonamide group is unligated to the Pd center. This yields
the hydrogen bond-stabilized intermediate A; ligand loss, proton
transfer, and β-hydride elimination furnishes the observed
product. These results suggest that the trans-aminopalladation
Pd(OAc)2 proved to be the best palladium source and an elevated
reaction temperature resulted in decreased enantioselectivity
(Table 2, entry 5). The addition of the sodium salt of (+)-
camphorsulfonic acid [(+)-NaCSA] was found to improve the
yield without affecting the enantioselectivity. However, the
addition of (+)-NaCSA alone did not generate the active catalyst
(Table 2, entry 8). While molecular oxygen was a competent
oxidant for the reaction, p-benzoquinone (BQ) provided higher
overall yields. Lastly, benzene was determined to be the ideal,
non-coordinating solvent for the reaction.17
With the optimized conditions in hand we sought to explore
the limitations and scope of the catalyst system. A variety of
substrates cyclized to produce indolines with varying levels of
enantioselectivity (Table 3). The tosyl-protecting group proved to
be superior in reactivity and enantioselectivity in comparison to
the meslyate.
Tri-substituted substrates, while requiring longer reaction
times, gave higher yields and increased enantioselectivity. Para-
substituted derivatives proceeded smoothly to give good yields
and moderate enantioselectivity. However, upon subjecting
ortho-substituted substituents to the reaction conditions, a marked
decrease in enantioselectivity was observed. These findings are
consistent with the literature.18 The formation of tosylcarbamate
5 occurred with similar enantioselectivity to indoline derivatives
3, while morpholine derivative 6 could also be formed, albeit
with no enantioselectivity. The modest enantioselectivity attained

5
pathway is favored over the cis- (∆G‡ 6.2 vs 26.3 kcal/mol).
Additional calculation details are available in the Supporting
Information.
8. (a) Mukherjee, S.; List, B., J. Am. Chem. Soc. 2007, 129, 11336;
(b) Jiang, G.; List, B., Angew. Chem. Int. Ed. 2011, 50, 9471; (c)
Jiang, G.; Halder, R.; Fang, Y.; List, B., Angew. Chem. Int. Ed.
2011, 50, 9752.
9. Ohmatsu, K.; Ito, M.; Kunieda, T.; Ooi, T., Nat. Chem. 2012, 4,
473.
Conclusion
10. Ohmatsu, K.; Ito, M.; Kunieda, T.; Ooi, T., J. Am. Chem. Soc.
2013, 135, 590.
11. Tao, Z.-L.; Zhang, W.-Q.; Chen, D.-F.; Adele, A.; Gong, L.-Z., J.
Am. Chem. Soc. 2013, 135, 9255.
In summary, to our knowledge, we have developed the first
enantioselective Pd-catalyzed transformation utilizing a chiral
sulfonic acid ligand. Novel chiral indoline products were
synthesized with up to 45% ee. Computation studies suggest that
a trans-aminopalladation pathway is operative.
12. Zhang, D.; Qiu, H.; Jiang, L.; Lv, F.; Ma, C.; Hu, W., Angew.
Chem. Int. Ed. 2013, 52, 13356.
13. Yu, S.-Y.; Zhang, H.; Gao, Y.; Mo, L.; Wang, S. W.; Zao, Z.-J., J.
Am. Chem. Soc. 2013, 135, 11402.
Experimental
14. Chai, Z.; Rainey, T. J., J. Am. Chem. Soc. 2012, 134, 3615.
15. (a) Jiang, T.; Bartholomeyzik, T.; Mazuela, J.; Willersinn, J.;
Backvall, J. E., Angew. Chem. Int. Ed. 2015, 54, 6024; (b) Yan, S.
B.; Zhang, S.; Duan, W. L., Org. Lett. 2015, 17, 2458; (c) Nelson,
H. M.; Williams, B. D.; Miro, J.; Toste, F. D., J. Am. Chem. Soc.
2015, 137, 3213.
General procedure for the enantioselective oxidative
amination
To a flame-dried 2-dram vial was added Pd(OAc)2 (2.2 mg,
0.01 mmol) and (+)-CSA (4.6 mg, 0.02 mmol). Benzene (0.4
mL) was charged and the mixture was then stirred under an argon
atmosphere at 20 °C for 20 min. To the vial was then added a
solution of the substrate (0.1 mmol), benzoquinone (21.8 mg, 0.2
mmol) and (+)-CSA-Na+ (2.5 mg, 0.01 mmol) in benzene (0.6
mL). The vial was capped then stirred for the indicated time with
heating, as indicated in Table 2. Upon reaction completion, the
reaction mixture was diluted with EtOAc (3 mL) then stirred
vigorously with sat. Na2S2O3 (4 mL). The organic layer was then
washed sequentially with sat. Na2S2O3 (2 x 5 mL), sat. K2CO3 (2
x 5 mL), and water (5 mL) then dried over anhydrous MgSO4 and
concentrated in vacuo. The crude product was purified by silica
column chromatography (4:1 hexanes/Et2O or 10–20%
EtOAc/Hex).
16. See Supplementary Material for further examination of phosphoric
acid ligands.
17. See Supplementary Material for a more detailed screening of
reaction solvents.
18. Jiang, F.; Wu, Z.; Zhang, W., Tetrahedron Lett. 2010, 51, 5124.
Supplementary Material
Supplementary data (synthetic procedures, spectral data, chiral
HPLC traces and details of the electronic structure calculations,
including Cartesian coordinates) can be found at…
Acknowledgments
We gratefully thank Montana State University for their
financial support. Dr. Benjamin Naab is thanked for early work
employing CSA. Professor Robert Szilagyi (Montana State
University) is thanked for helpful discussions concerning the
electronic structure calculations.
References and notes
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2981.
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S., J. Org. Chem. 2013, 78, 2083.
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Kotov, V.; Scarborough, C. C.; Stahl, S. S., Inorg. Chem. 2007,
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I. A.; Spencer, L. C.; Stahl, S. S., Tetrahedron 2009, 65, 5084; (g)
He, W.; Yip, K.-T.; Zhu, N.-Y.; Yang, D., Org. Lett. 2009, 11,
5626; (h) Yang, G.; Shen, C.; Zhang, W., Angew. Chem. Int. Ed.
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B.; Tam, C. P.; Stahl, S. S., Org. Lett. 2011, 13, 2830.
5. Notable exception, reference 3b explores chiral N-heterocyclic
carbene ligands with poor enantioselectivity.
6. Alper, H.; Hamel, N., J. Am. Chem. Soc. 1990, 112, 2803.
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Highlights
•
•
•
•
Catalytic enantioselective construction of nitrogen-containing heterocycles
Use of a chiral sulfonic acid ligand to impart asymmetric induction
High-level electronic structure calculations were carried out
A trans-aminopalladation mechanism is proposed