New spiro phosphinooxazolines for palladium-catalyzed asymmetric allylic amination

Article abstract of DOI:10.1016/j.tetlet.2018.09.044

The new conformational rigid spiro phosphinooxazolines 1 were synthesized from 7-bromo-1-indanone. The asymmetric catalytic potential of them was demonstrated in the asymmetric palladium catalyzed allylic amination. High yields and enantioselectivities were obtained with alkylamines.

Full text of DOI:10.1016/j.tetlet.2018.09.044

Accepted Manuscript
New spiro phosphinooxazolines for palladium-catalyzed asymmetric allylic
amination
Yanfeng Gao, Zhongxuan Qiu, Rui Sun, Nanxing Gao, Guorui Cao, Dawei Teng
PII:
S0040-4039(18)31134-1
https://doi.org/10.1016/j.tetlet.2018.09.044
TETL 50283
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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23 July 2018
14 September 2018
17 September 2018
Please cite this article as: Gao, Y., Qiu, Z., Sun, R., Gao, N., Cao, G., Teng, D., New spiro phosphinooxazolines for
palladium-catalyzed asymmetric allylic amination, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.09.044
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Tetrahedron Letters
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New spiro phosphinooxazolines for palladium-catalyzed asymmetric allylic
amination
Yanfeng Gao#, Zhongxuan Qiu#, Rui Sun, Nanxing Gao, Guorui Cao, and Dawei Teng∗
College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
ARTICLE INFO
ABSTRACT
Article history:
Received
The new conformational rigid spiro phosphinooxazolines 1 were synthesized from 7-bromo-1-
indanone. The asymmetric catalytic potential of them was demonstrated in the asymmetric
palladium catalyzed allylic amination. High yields and enantioselectivities were obtained with
alkylamines.
Received in revised form
Accepted
Available online
2018 Elsevier Ltd. All rights reserved.
Keywords:
spiro-phosphine oxazoline
asymmetric synthesis
allyl amination
1,3-diphenylallyl acetate
Introduction
Transition metal-catalyzed asymmetric allylic substitution has
become a powerful method in the formation of carbon-carbon
and carbon-heteroatom bond1-3. The enantioselective allylic
amination is an important reaction for the synthesis of chiral
allylamines which are ubiquitous in biologically active motifs
and natural products4-8. Many efforts have been devoted to the
design and synthesis of the chiral ligands. The rigid conformation
of chiral ligand is an important factor for high enantioselectivity
in asymmetric catalysis. The ligands with rigid backbone could
reduce the conformation obscurity of catalyst and create an
effective asymmetric environment around the central metal,
which could lead to high enantioselectivities in asymmetric
reactions9. However, there are only a few investigations on the
catalyst’s rigidity of backbones10. The phosphinooxazolines such
as PHOX have proven to be efficient ligands in asymmetric
allylic substitution11-13. Bidentate ligands with a more rigid linker
between the two coordinating sites can form more rigid
metallocycle with fewer available conformations and thus
enhance the enantiofacial differentiation14-15. Herein, we report a
new spiro phosphinooxazolines and their asymmetric catalytic
potential in palladium catalyzed asymmetric allylic amination.
Figure 1. The phosphinooxazoline ligands.
Results and discussion
The synthetic route of the ligands was outlined in Scheme 1.
The (R)-aminoacid 6 was synthesized by a modified Warmuth
method16. Asymmetric Strecker reaction of 7-bromoindanone 3
with (S)-phenylglycinol and trimethylsilyl cyanide catalyzed by
p-toluenesulfonic acid gave amino carbonitrile 4, which was
directly subjected to hydrolysis with sulfuric acid to afford (R)-
aminocarboxamide 5 in 81% yield.
Scheme 1. Synthesis of spiro phosphinooxazolines
———
# These authors contributed equally to this work.
∗ Corresponding author. Tel.: +86-532-84022879; e-mail: dteng@qust.edu.cn

2
NHBn
OAc
Reaction conditions: a. (i) TsOH, S-phenylglycinol, toluene, reflux (ii)
TMSCN, DCM, 0℃; b. 90% H2SO4, -20 ℃; c. (i) Pb(OAc)4, DCM/ MeOH,
0 ℃ (ii) 6M HCl, reflux; d. Borane dimethyl sulfide complex, THF, reflux; e
(i) RCOCl, Et3N, DCM, 0 ℃ (ii) MsCl, DIPEA, DCM, 0 ℃; f. n-BuLi,
PPh2Cl, THF, -78 ℃
1a
/[Pd(C3H5)Cl]2
BnNH2
BSA,THF, rt, 12h
11a
9a
10a
Entry
BSA
(equiv)
1.0
Catalyst Temp. Time Solvent Yieldb eecd
(℃) (h) [%]
rt 12 44
Treatment of 5 with lead tetraacetate, followed by hydrolysis
with hydrochloric acid afforded 6. Reduction of 6 by borane
dimethyl sulfide complex afforded enantiopure (R)-amino
alcohol 7 in 90% yield. Oxazoline 8 was synthesized by adapting
literature methods17. N-acylation of 7 with acyl chloride in the
presence of diisopropylethylamine, followed by addition of
mesyl chloride furnished the ring cyclization in 79-91% yields.
Lithiation of 8 with n-butyllithium followed by addition of
diphenylphosphine chloride afforded the desired spiro
phosphinooxazolines 1. The total yields were 80%, 75%, and
87% for 1a, 1b, and 1c respectively.
(equiv)
0.03
0.03
0.03
0.03
0.04
0.05
0.04
0.04
0.04
0.04
0.04
0.04
0.04
[%]
95.3
95.5
95.4
94.8
95.8
95.7
96.2
96.1
96.8
96.5
96.2
96.4
96.3
1
2
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCM
2.0
rt
12
12
12
12
12
12
12
2
49
51
51
63
63
89
90
84
89
89
95
3
3.0
rt
4
4.0
rt
5
3.0
rt
6
3.0
rt
With the spiro phosphinooxazolines in hand, we investigated
the asymmetric allylic amination reaction using E-1,3-
diphenylallyl actate and benzylamine. The initial reactions were
performed with the combination of spiro phosphinooxazoline 1a
with various palladium sources in tetrahydrofuran at room
temperature. The results are summarized in Table 1. Reactions
using PdCl2(dppf)2 and Pd(Ph3P)4 lead to moderate yields and
low enantioselectivities (Entry 1-2). The enantioselectivities were
improved significantly when Pd(OAc)2, Pd2(dba)3, and
[Pd(C3H5)Cl]2 were used (Entry 3-5). We found that the best
result was achieved using [Pd(C3H5)Cl]2 as palladium source.
The enantioselectivity reached 95.5% ee (Entry 5). The other
ligands 1b and 1c showed slightly lower enantioselectivities
compared to 1a (Entry 6-7). Compared with the classical PHOX
7
3.0
40
60
40
40
40
40
40
8
3.0
9
3.0
10
11
12
13
3.0
6
3.0
12
6
3.0
3.0
6
Toluene 85
aReaction conditions: E-1,3-diphenylallyl acetate 9a (0.6 mmol), benzylamine
10a (1.80 mmol), Solvent (2mL). bIsolated yield. cDetermined by HPLC
analysis. dThe absolute configurations were assigned as R by comparison with
literature data 18
.
ligand 2a, spiro phosphinooxazolines
enantioselectivity (Entry 8).
1
showed better
Table 3. Scope of nucleophiles in asymmetric allylic
aminationa
Table 1. Asymmetric allylic aminationa
1a (4.5mol%)
R1 R2
OAc
Ph
N
[Pd(C3H5)Cl]2 (2mol%)
R1 R2
OAc
NHBn
N
H
Pd/ligand (3mol%)
Ph
Ph
Ph
BSA (3equiv)
BnNH2
9a
10
CH2Cl2, 40°C, 6h
11
THF, r.t, 12h
9a
10a
11a
yieldb
[%]
36
eec, d
[%]
0.7
Entry
Ligand
Metal Salt
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1c
2a
PdCl2(dppf)2
Pd(Ph3P)4
Pd(OAc)2
41
36
33.7
92.9
95.9
95.5
93.6
93.7
88.1
Pd2(dba)3
24
33
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
34
41
39
aReaction conditions: E-1,3-diphenylallyl acetate 9a (0.6 mmol), benzylamine
10a (1.80 mmol), ligand (0.021 mmol), palladium compound (0.018 mmol),
THF (2mL). bIsolated yield. cDetermined by HPLC analysis. dThe absolute
configurations were assigned as R by comparison with literature data 18
.
We then explored the optimum reaction condition. The results
were showed in Table 2. The reaction yields were greatly
influenced by the amount of N,O-Bis(trimethylsilyl)acetamide
(BSA), reaction temperature, catalyst loading, and solvents,
while the enantioselectivities were little affected. The reaction
yields increased as the equivalent of BSA and catalyst added.
When 3 equivalents of BSA and 0.04 equivalent of catalyst
loading were added, the yield was reached 63.1% (Entry 1-6).
Optimization of the temperature showed that the yield improved
significantly when the reaction was warmed to 40℃ (Entry 7).
Examination of different solvents and reaction time disclosed that
dichloromethane was the best solvent of choice and the best
reaction time was 6 hours (Entry 9-13).
aReaction conditions: E-1,3-diphenylallyl actate 9a (0.6 mmol), benzylamine
10a (1.8 mmol), ligand (0.027 mmol), palladium compound (0.012 mmol),
BSA (1.8mmol), DCM (2mL). bIsolated yield.cDetermined by HPLC analysis.
dThe absolute configurations were assigned as R by comparison with
literature data18.
Table 2. Optimization of the reaction conditionsa

3
Next, the scope of the nucleophiles was studied using spiro
phosphinooxazoline 1a under optimum reaction condition. The
results were shown in Table 3. For alkylamines, the desired
products 11a-11j were obtained in excellent yields and
enatioselectivities both for primary and secondary amines.
Benzylamine and substituted benzylamines gave the products in
high yields and enatioselectivities (11a-11c). The electron
property of the aromatic ring of benzylamine has no effect on the
yields and enatioselectivities. The steric hindrance has some
effect on the enantioselectivity. The excellent yields and
enantioselectivities were obtained for n-butylamine (11g), whilst
slightly lower ee value when isobutylamine was used (11h).
Compared with the PHOX ligand, spiro phosphinooxazolines 7
had better enatioselectivities with benzylamine as the nucleophile
(11a, 96.8% ee vs. 89% ee)12. The aromatic amines were not as
good nucleophiles as the alkylamines in terms of yields and
enatioselectivities. The substituents on the rings of aromatic
amines influenced the reaction significantly. The reactions
proceeded in good yields with anilines, but the
enantioselectivities were inferior to alkylamines (11j-11l).
Scheme 2.The plausible reaction mechanism
Conclusions
In summary,
phosphinooxazolines were developed and synthesized. The
asymmetric catalytic potential of them were demonstrated in the
asymmetric palladium catalyzed allylic aminations, affording the
corresponding chiral allylamines in high yields and
enatioselectivities. Further investigations of these new spiro
phosphinooxazolines in asymmetric catalysis are underway and
will be reported in due course.
the
new
conformationally
rigid
To further explore the scope of the reaction, the palladium
catalyzed allylic aminations were examined using symmetrical
and unsymmetrical allylacetates under optimum conditions. As
seen in Table 4, for the symmetrical allylacetate 9b, the catalyst
showed high yields and good enatioselectivities (11m-11o). For
the unsymmetrical allylacetate 9c, the catalyst showed high
yields and regioselectivities, but the enatioselectivities was
decreased greatly (11p-11r).
References and notes
1.
(a) B. M. Trost and D. L. Van Vranken, Chem. Rev. 1996, 96, 395–422;
(b) A. Pfaltz and M. Lautens, In Comprehensive Asymmetric Catalysis;
E. Jacobsen, A. Pfaltz and H. Yamamoto, Eds.; Springer: New York,
NY, 1999, 2, 833–884; (c) G. Helmchen and A. Pfaltz, Acc. Chem. Res.
2000, 33, 336–345.
Table 4. Substrate scope of asymmetric allylic aminationa
1a
R1 R2
N
OAc
R4
(4.5mol%)
2.
3.
(a) B. M. Trost and M. L. Crawley, Chem. Rev. 2003, 103, 2921–2943;
(b) H. Yorimitsu and K. Oshima, Angew. Chem., Int. Ed. 2005, 44,
4435–4439; (c) S.-L. You and L.-X. Dai, Angew. Chem., Int. Ed. 2006,
45, 5246–5248
R1 R2
N
H
[Pd(C3H5)Cl]2 (2mol%)
R3
R4
R3
BSA (3equiv)
9b
9c
R
R
3 = R4 = 4-OCH3-Ph
3 = Ph, R4 = CH3
10
CH2Cl2, 40°C, 6h
11
(a) L. Zhan and S. Ma, Angew. Chem., Int. Ed. 2008, 47, 258–297; (b)
B. M. Trost, T. Zhang and J. D. Sieber, Chem. Sci. 2010, 1, 427–440;
(c) P. Tosatti, A. Nelson and S. P. Marsden, Org. Biomol. Chem. 2012,
10, 3147–3163; (d) B. M. Trost, Org. Process Res. Dev. 2012, 16, 185–
194; (e) A. Lumbroso, M. L. Cooke and B. Breit, Angew. Chem., Int.
Ed. 2013, 52, 1890–1932; (f) C.-X. Zhuo, C. Zheng and S.-L. You, Acc.
Chem. Res. 2014, 47, 2558–2573
O
N
HN
HN
MeO
OMe
MeO
OMe
OMe
MeO
b
b
b
4.
5.
(a) T. Hayashi, A. Yamamoto, Y. Ito, E. Nishioka, H. Miura and K.
Yanagi, J. Am. Chem. Soc. 1989, 111, 6301–6311; (b) J. Park, S. Lee,
K. Ahn and C. Cho, Tetrahedron Lett. 1995, 36, 7263–7265; (c) J. Park,
S. Lee, K. Ahn and C. Cho, Tetrahedron Lett. 1996, 37, 6137–6140.
(a) S.-L. You, X.-Z. Zhu, Y.-M. Luo, X.-L. Hou and L.-X. Dai, J. Am.
Chem. Soc. 2001, 123, 7471–7472; (b) M. Mori, M. Nakanishi, D.
Kajishima and Y. Sato, J. Am. Chem. Soc. 2003, 125, 9801–9807; (c) R.
Weihofen, O. Tverskoy and G. Helmchen, Angew. Chem., Int. Ed. 2006,
4, 5546– 5549; (d) I. Dubovyk, I. Watson and A. Yudin, J. Am. Chem.
Soc. 2007, 129, 14172–14173; (e) D. Popa, R. Marcos, S. Sayalero, A.
Vidal-Ferran and M. Pericas, Adv. Synth. Catal. 2009, 351, 1539– 1556.
(a) Z. Liu and H. Du, Org. Lett. 2010, 12, 3054–3057; (b) P. Tosatti, J.
Horn, A. J. Campbell, D. House, A. Nelson and S. P. Marsden, Adv.
Synth. Catal. 2010, 352, 3153–3157; (c) J.-B. Xia, W.-B. Liu, T.-M.
Wang and S.-L. You, Chem. Eur. J. 2010, 16, 6442–6446.
11m
11o
91%Yield
94%Yield
86.5%ee cd
11n
93%Yield
91.2%eecd
80.9%eecd
O
N
HN
HN
b
b
11q
95%Yield
14.3%eecd
11r
93%Yield
b
11p
95%Yield
13.1%eecd
8.7%eecd
aReaction conditions: allyl actates 9 (0.6 mmol), amines 10 (1.8 mmol),
ligand (0.027 mmol), palladium compound (0.012 mmol), BSA(1.8 mmol),
DCM (2mL). bIsolated yield. Determined by HPLC analysis. dThe absolute
configurations of 11m-11o were assigned as R by comparison with literature
data18, The absolute configurations of 11p-11r were assigned as S by
comparison with literature data19, 20
6.
7.
c
(a) K.-Y. Ye, H. He, W.-B. Liu, G. Helmchen, L-X. Dai and S.-L You, J.
Am. Chem. Soc. 2011, 133, 19006–19014; (b) K.-Y. Ye, L.-X. Dai and
S.-L.You, Org. Biomol. Chem. 2012, 10, 5932– 5939; (c) J. Wang, J.
Chen, C. W. Kee and C.-H. Tan, Angew. Chem., Int. Ed. 2012, 51,
2382–2386.
.
A plausible mechanism was proposed to account for the
observed stereochemistry of the products. As is shown in Scheme
2, the W-type allyl transition state of Pd-η3-allyl intermediate
formed preferentially over its M-type counterpart, due to the
steric interaction between the two phenyl rings of the phosphine
and those of (E)-1,3-diphenylallyl acetate. Thus, the N-
nucleophiles would attack trans to the P atom to afford the
corresponding products.
8.
9.
(a) L. Du, P. Cao, J. Xing, Y. Lou, L. Jiang, L. Li and J. Liao, Angew.
Chem., Int. Ed. 2013, 52, 4207-4211; (b)B. Feng, H.-G. Cheng, J.-R.
Chen, Q.-H. Deng, L.-Q. Lu and W.- J. Xiao, Chem. Commun. 2014,
50, 9550–9553.
P. von Matt, A. Pfaltz. Angew. Chem., Int. Ed. 1993, 32, 566-568.
10. G. J. Dawson, C. G. Frost, J. M. Williams, S. J. Coote. Tetrahedron Lett.
1993, 34, 3149-3150.
11. J. Sprinz, G. Helmchen. Tetrahedron Lett. 1993, 34, 1769-1772.
12. P. von Matt, O. Loiseleur, G. Koch, et al. Tetrahedron Asymmetry, 1994,
5(4), 573-584.

4
13. X. Zhang, W. Liu, Q. Cheng, S. You. Organometallics, 2016, 35, 2467-
2472.
14. X. Zhang. Enantiomer 1999, 4, 541-547.
15. J. M. Brown, P. A. Chaloner. Homogeneous Catalysis with Metal
Phosphine Complexes; Pignolet, L. H., Ed.; Plenum: New York, 1983;
137-144.
16. R. Warmuth, T. E. Munsch, R. A. Stalker, et al. Tetrahedron, 2001,
57(30), 6383-6397.
17. G. Farkas, J. Bakos, S. Balogh, et al. Tetrahedron Asymmetry, 2011,
22(24), 2104-2109.
18. M. Coll, O. Pàmies, M. Diéguez. Org. Lett, 2014, 16(7), 1892-1896.
19. T. Wang, F. Wang, F. Yang, et al. Chem. Commun. 2014, 50(29), 3802-
3805.
20. C. Xia, J. Shen, D. Liu, et al. Org. Lett, 2017, 19(16), 4251-4254.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at doi:

5
Graphical Abstract
New spiro phosphinooxazolines for
palladium-catalyzed asymmetric allylic
amination
Leave this area blank for abstract info.
Yanfeng Gao#, Zhongxuan Qiu#, Rui Sun, Nanxing Gao, Guorui Cao, and Dawei Teng∗
College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
The new conformationally rigid spiro phosphinooxazolines ligands were synthesized from 7-bromo-1-indanone. The
asymmetric catalytic potential of them was demonstrated in the asymmetric palladium catalyzed allylic amination. High
yields and enantioselectivities were obtained with alkylamines.

6
Tetrahedron Letters
The new rigid spiro phosphinooxazolines ligands were
synthesized.
New spiro ligands for palladium-catalyzed asymmetric allylic
amination were detected.
High yields and enantioselectivities were obtained with
alkylamine.