Palladium-catalysed α-allylation of chiral sulfinimines derived from symmetric cyclic ketones

Article abstract of DOI:10.1016/j.tetlet.2017.02.008

A diastereoselective mono-allylation reaction at the α-position of symmetric cyclic ketones by using tert-butanesulfinamide as a chiral auxiliary is explored. Excellent yields and high diastereomeric ratios were achieved under palladium(0) catalysis in th

Full text of DOI:10.1016/j.tetlet.2017.02.008

Accepted Manuscript
Palladium-catalysed α-Allylation of Chiral Sulfinimines Derived from Sym-
metric Cyclic Ketones
Jiangnan Li, Rafid S. Dawood, Shuanglin Qin, Tongtong Liu, Shuangwei Liu,
Robert A. Stockman, Shende Jiang, Guang Yang
PII:
S0040-4039(17)30171-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.008
TETL 48619
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 December 2016
23 January 2017
3 February 2017
Please cite this article as: Li, J., Dawood, R.S., Qin, S., Liu, T., Liu, S., Stockman, R.A., Jiang, S., Yang, G.,
Palladium-catalysed α-Allylation of Chiral Sulfinimines Derived from Symmetric Cyclic Ketones, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.008
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TOC
Palladium-catalysed α-Allylation of Chiral Sulfinimines Derived from
Symmetric Cyclic Ketones
Jiangnan Li,a, b Rafid S. Dawood,c Shuanglin Qin, a, b Tongtong Liu, a Shuangwei Liu, a Dr. Robert A. Stockman,c,*
Prof. Dr. Shende Jiang b and Dr. Guang Yang a,*

Palladium-catalysed α-Allylation of Chiral Sulfinimines
Derived from Symmetric Cyclic Ketones
Jiangnan Li,a, b Rafid S. Dawood,c Shuanglin Qin, a, b Tongtong Liu, a Shuangwei Liu, a Robert A.
Stockman,c,* Shende Jiang b and Guang Yang a,*
a
College of Pharmacy, The State Key Laboratory of Medicinal Chemical Biology, Nankai
University, Tianjin, 300071, People's Republic of China
b School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, People’s
Republic of China
c School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK
Jiangnan Li and Rafid S. Dawood are contributed equally to this work.
Abstract
A diastereoselective mono-allylation reaction at the α-position of symmetric cyclic ketones by using
tert-butanesulfinamide as a chiral auxiliary is explored. Excellent yields and high diastereomeric
ratios were achieved under palladium(0) catalysis in the presence of a readily available achiral
phosphine ligand.
Key words:
Allylation
Asymmetric synthesis
Chiral auxiliaries
Diastereoselectivity
Palladium catalysis
 Robert A. Stockman. Tel.: +44-01159513252; e-mail: robert.stockman@nottingham.ac.uk
 Guang Yang. Tel.: +86-15620268270; e-mail: Guang.yang@nankai.edu.cn
Introduction
The palladium(0)-catalyzed asymmetric allylation at the α-position of a carbonyl group (Tsuji-Trost
type reaction) proves as a powerful C-C bond formation method to construct a number of complex
carbon skeletons.[1] To diastereoselectively obtain these chiral centers, utilization of the chiral
auxiliaries was among the most significant strategies. Up to date, there were quite limited
publications concerning the chiral auxiliaries for ketones.[3,4,5,6] Among them, Ender’s
SAMP/RAMP hydrazone was the best-known and widely applied methodology for the formation of
alpha-chiral ketones. [3] To achieve good yield and d.r. value, the reaction conditions were harsh
(using strong bases, such as LDA, under temperature as low as – 95 ºC), and the removal of the

hydrazine was difficult, typically by means of ozone.
[7,8]
Chiral sulfinimines were firstly demonstrated in Ellman’s reports.
Previously, It proved as an
ideal chiral auxiliary for various asymmetric ketones[9]. Firstly, the transformation of ketones into
chiral sulfinimines was straightforward and efficient. Moreover, their removal under the optimised
conditions led to no epimerization of the chiral ketones[9]. Herein, the diastereoselective
palladium(0)-catalyzed diastereoselective mono-allylation reactions of chiral sulfinimines were
reported, which are generated from the symmetric cyclic ketones with tert-butanesulfinamide.[7,8]
Scheme 1. Overview
Results and Discussion
Following the recent successful application of asymmetric ketones as substrates[9], furthering its
application in symmetric cyclic ketones is growingly relevant. Initially, the allylation reaction was
investigated with the stable chiral cyclic sulfinimine 2a as a substrate, which was prepared from the
cheap symmetric cyclopentanone 1a. The reaction was performed in THF and was catalysed by
commercially available Pd(PPh3)4 (0.05 mmol), with allyl methyl carbonate 6 as allyl source (Table
1). In addition, Various bases were screened during the optimisation. LiHMDS and n-BuLi
delivered complex mixtures of products (Entry 1 and 2). With NaHMDS used as the base, the
reaction provided 3a with 25% isolated yield and 2:1 d.r. (Entry 3). The reaction performed with
both of KHMDS and LDA used as bases resulted in improved yield (42% and 52%) but poor d.r.
(Entry 4 and 5). KOt-Bu led to di-allyaltion products 4a and 5a as main product, which were
inseprartable mixtures. (Entry 6). The use of DBU enabled the full conversion of starting material
2a within 2 h. However, the desired product 3a was obtained in poor yield (35%) and poor d.r. (1.5:1)
with 20% di-allylation products (Entry 7). Fortunately, both TEA and DIPEA delivered reasonable
3a yield at 60 ºC without 4a and 5a detected in a short reaction time (less than 8 h, Entry 8 and 10).
Higher temperature led to more di-allylation products and poor d.r. in short time (Entry 9 and 11).
When 0.5 mmol of DIPEA was used, the starting material could not be consumed conpletely, and 3a
was the only isolated product with 25% yield (Entry 12). Furthermore, the allylation could not be
carried out without the addition of DIPEA (Entry 13).
Table 1. Base Screen a

Entry
1
Base
T / ºC
-78 to rt
-78 to rt
-78 to rt
65
Time/h Yield of 3ac
d.r.b
NA
NA
2:1
LiHMDS
n-BuLi
NaHMDS
KNMDS
LDA
4
4
4
4
4
18
2
8
4
8
4
8
Complex mixture
2
Complex mixture
3
25%
4
42%
4:1
5
65
52%
3:1
6
KOt-Bu
DBU
65
3a (trace), 4a+5a (>20%)
3a (35%), 4a+5a (>20%)
59%c
ND
1.5:1
3:1
7
40
8
TEA
60
9
TEA
80
3a (56%), 4a+5a (13%)
66%c
2.5:1
4:1
10
11
12
DIPEA
DIPEA
DIPEA
(0.5 mmol)
No base
60
80
3a (49%), 4a+5a (9%)
25%
2.5:1
5:1
60
13
60
8
No react
NA
a Reactions were performed using 1.0 mmol substrate 2a in THF (0.1 M), with Pd(PPh3)4 (0.05
b
mmol), allyl ester 6 (1.2 mmol) and various bases (1.5 mmol). d.r. values of Product 3a were
determined by crude 1H NMR. c Isolated yield.
It seemed that under the best reaction conditions so far, DIPEA should be used as bases at 60 ºC,
which rendered it necessary to optimise the reaction. This could be done by exploring the effect of
various commercially available achiral ligands (Table 2). For convenient exchange of multiple
Phosphine ligands, Pd2(dba)3 was used as palladium(0) source.[4] Compared with PPh3, P(Oi-Pr)3
was not an active ligand for this reaction (Entry 1 and 2) since there was no reaction at 60 ºC at all
when PCy3 was used as ligand and DIPEA was used as base. When the temperature rose to 80 ºC, 3a
was isolated in 38% yield with starting material recovered (Entry 3). Notably, no diallylation
products were observed. When bis-phosphine ligands dppp and dppf were used, the reaction failed
to lead to full conversion of starting material. However, the mono-allylated products were cleanly
obtained (Entry 4 and 5). P(n-Bu)3 proved to be the most efficient. Among those conditions, the
reactions were performed at 60 ºC, which led to a 77% yield with 8:1 d.r. (Entry 6). When the inner
temperature was increased to 80 ºC, the allylation was completed in 18 h and was achieved in 88%
isolated yield with 8:1 d.r. (Entry 7). Additionally, Although higher concentations of the reaction
solution (0.25 M) accelerated the reaction process, poorer diastereo-selectivity (d.r. = 2:1) was
observed (Entry 8). Increasing the amount of carbonate 6 (2.5 mmol) would completely consume
the starting material 2a within a shorter period. However, the formation of the di-allylated product
4a and 5a dominated under these conditions (Entry 9). Additionally, when there was no addition of
phosphine ligands, no reaction occurred at all (Entry 10).

Table 2. Ligands Screena
Entry
Ligands
PPh3
Bases
T / ºC
60
Time/h Yield of 3ac
d.r.b
3:1
1
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
18
24
62%
0%
2
P(Oi-Pr)3
PCy3
60
NA
ND
5:1
3
60 to 80 48
38%
48%
37%
77%
88%
85%
4
dppp
60
60
60
80
80
80
80
18
18
48
18
18
8
5
dppf
5.5:1
8:1
6
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
No ligand
7
8:1
8d
9e
2:1
3a (35%), 4a+5a (40%) 5:1
0 NA
10
18
a
Reactions were performed using 1.0 mmol substrate 2a in THF (0.1 M), with Pd2(dba)3 (0.025
mmol), Ligands (0.05-0.10 mmol) allyl carbonate 6 (1.5 mmol) and various bases (1.5 mmol). b d.r.
values of Product 3a were determined by crude 1H NMR. c Isolated yield. d Reactions were performed
using 1.0 mmol substrate 2a in THF (0.25 M). e 2.5 mmol of Allyl carbonate 6 and 2.5 mmol of DIPEA
were used.
Following the above encourging optimisation, (Table 2, Entry 6), the scope of substrates was further
explored. A series of chiral sulfinimines derived from symmetrical cyclic ketones, underwent the
diastereoselective allylation reaction with the catalyst generated from palladium(0) and P(n-Bu)3 in
situ. Fortunately, most substrates were converted into the desired allylation products in good yield
and with high diastereo-selectivity (Table 3). For substrates containing four-membered rings (2b),
the best d.r. value of 3b obtained under the optimised conditions was 14:1 (Entry 1). Excellent
diastereoselectivity was achieved when cyclic substrates with seven-, eight- and even
twelve-membered rings (3d, 3e, 3f) were employed (Entry 3, 4 and 5). Most of the products were
obtained with good yield and high d.r. (> 25:1). Also, it turned out that substrates possessing a
six-membered ring were highly sensitive to both moisture and temperature. Freshly distilled solvent
need to be used. After the careful purification by silica gel, compound 3c was obtained in 80% yield
with 18:1 d.r.. The other six-membered product 3g was decomposed slowly during the purification
process. As a result, only 64% isolated yield of compound 3g was achieved. However, the
diastereoselectivity was excellent (d.r. > 25:1). Subsequently, we proceeded to investigate the effect
of α- and β-substitution on the allylic carbonates (3h, 3i, 3j), and as expected, good yields and high
d.r. were also achieved (Entry 7, 8 and 9). Notably, for the Entry 8, only linear product 3i was
observed.
Table 3. Allylation of Chiral Sulfinimines Derived from Various Ketones [a]

Entry Sulfinimines Yield[b] Allyl carbonates
Allylation products
Yield[b] d.r.[c]
1
2
3
76%
81%
90%
75%
80%
85%
14:1
18:1
20:1
6
6
6
2b
2c
3b
3c
3d
2d
4
5
92%
83%
94%
81%
>25:1
>25:1
6
6
6
2e
3e
2f
3f
3g
3h
3i
6
7
8
9
74%
90%
90%
92%
64%
82%
85%
87%
>25:1
>25:1
>25:1
>25:1
2g
2d
2d
8
9
8
2e
3j
a Reactions were performed using 1.0 mmol substrate 2 in THF (0.1 M) at 80 ºC, with Pd2(dba)3
b
(0.025 mmol), P(n-Bu)3 (0.10 mmol), allyl carbonate (1.5 mmol) and DIPEA (1.5 mmol).
Isolated yield. c d.r. values were determined by crude 1H NMR analysis.

It is quite difficult to distinctly identify the absolute configuration of product 3a. Based on recently
reported results[9], it would be tentatively assigned as S at the α-position of sulfinimines 3a. As its
proof, hydrolysed product 7a derived from 3a in 69% yield was based on previously optimised
conditions (Scheme 2). Also, the comparison was drawn between the specific rotation of compound
(S)-7a ([α]D31 - 164, 2.0 in ether) and what was reported in previous literature ([α]D23 + 189, (R)-7a,
2.03 in ether) [10]. The specific rotation of compound (S)-7c was -16.7, and according to the
literature it was found as -15.8, as shown in the table 4. It suggested the results were consistent with
prediction in our previous report[9].
Scheme 2. Hydrolysis of compounds 3a and 3c
Table 4. Comparison of the specific rotation of 7c and 7d with those in previous literatures
Compounds Specific rotation
Lit.
7a
7c
- 164 (c = 2.0, ether)
+189 (c = 2.03, ether for R isomer)[10]
-15.8 (c = 3.0, MeOH)[11]
- 16.7 (c = 3.0, MeOH)
Conclusion
In summary, this reprot has demonstrated the diastereoselective palladium(0)-catalysed
mono-allylation reaction of cyclic chiral sulfinimines, which were derived from the symmetric
cyclic ketones. Commercially available Pd2(dba)3 was still used in conjunction with the simple and
readily available ligand P(n-Bu)3 and DIPEA as a base. Some substitued allyl carbonates were also
successfully applied in this chemistry. All of the products bearing mono-allyl group at the α-position
of chiral sulfinimines were obtained in high yield, with good to excellent diastereoselectivity. The
application of this chemitry in total synthesis of natural product was studied in due time, which will
be published elsewhere.
Acknowledgments
This work was supported by a General Financial Grant from the Natural Science Foundation of
Tianjin (no. 16JCQNJC13300) to G. Y.

References
[1] B. M. Trost, D. L. Van Vranken, Chem. Rev. 1996, 96, 395.
[2] a) D. A. Evans, J. M. Takacs, Tetrahedron Lett. 1980, 44, 4233; b) P. E. Sonnet, R. R. Heath, J.
Org. Chem. 1980, 45, 3137; c) J. W. ApSimon, R. P. Segium, Tetrahedron 1979, 35, 2797; d) T.
Mukaiyama, Tetrahedron 1981, 37, 4111; e) W. S. Knowles, Acc. Chem. Res. 1983, 16, 106; f) S. E.
Gibson, M. P. Casstaldi, Angew. Chem. Int. Ed. 2006, 45, 4718; Angew. Chem. 2006, 118, 4834; g) D.
A. Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem. Soc. 1982, 104, 1737; h) D. A. Evans, J. M.
Takacs, L. R. McGee, Pure Appl. Chem. 1981, 53, 1109; i) M. Braun, T. Meier, F. Laicher, P. Meletis,
M. Fidan, Adv. Synth. Catal. 2008, 350, 303; j) A. I. Meyers, D. R. Williams, M. Druelinger, J. Am.
Chem. Soc. 1976, 98, 3032; k) H. L. Wehrmeister, J. Org. Chem. 1962, 27, 4418; l) A. I. Meyers, G.
Knaus, K. Kamata, J. Am. Chem. Soc. 1974, 96, 268; m) A. I. Meyers, G. Knaus, K. Kamata, M. E.
Ford, J. Am. Chem. Soc. 1976, 98, 567; n) A. I. Meyers, G. Knaus, J. Am. Chem. Soc. 1974, 96, 6508;
o) W. Oppolzer, R. Moretti, S. Thomi, Tetrahedron Lett. 1989, 30, 5603; p) W. Oppolzer, S. Chapuis,
G. Bernardinelli, Helv. Chim. Acta. 1984, 67, 1367; q) M. Vandewalle, J. Van der Eychen, W.
Oppolzer,
C. Vullioud, Tetrahedron 1986, 42, 4035; r) W. Oppozler, Pure Appl. Chem. 1990, 62, 1241; s) G.
Jiang, B. List, Angew. Chem. Int. Ed. 2011, 50, 9471; Angew. Chem. 2011, 123, 9643.
[3] a) D. Enders, H. Eichenauer, Angew. Chem. Int. Ed. Engl. 1976, 15, 549; Angew. Chem. 1976, 88,
579; b) D. Enders, B. B. Lohray, Angew. Chem. Int. Ed. Engl. 1987, 26, 351; Angew. Chem. 1987, 99,
359; c) D. Enders, U. Reinhold, Angew. Chem. Int. Ed. Engl. 1995, 34, 1219; Angew. Chem. 1995,
107, 1332; d) D. Enders, H. Wahl, W. Bettary, Angew. Chem. Int. Ed. Engl. 1995, 34, 455; Angew.
Chem. 1995, 107, 527; e) A. Job, C. F. Janeck, W. Bettray, P. Peters, D. Enders, Tetrahedron 2002,
58, 2253; f) D. Enders, T. Schafer, W. Mies, Tetrahedron 1998, 54, 10239; g) D. Enders, K. Funabiki,
Org. Lett. 2001, 3, 1575.
[4] For Stoltz methods, see: a) D. C. Behenna, B. M. Stoltz, J. Am. Chem. Soc. 2004, 126, 15044; b)
J. T. Mohr, T. Nishimata, D. C. Behenna, B. M. Stoltz, J. Am. Chem. Soc. 2006, 128, 11348; c) J. T.
Mohr, D. C. Behenna, A. M. Harned, B. M. Stoltz, Angew. Chem. Int. Ed. 2005, 44, 6924; Angew.
Chem. 2005, 117, 7084; for selective total synthesis of natural products, see: d) J. A. Enquist, B. M.
Stoltz, Nature 2008, 453, 1228; e) R. M. Mcfadden, B. M. Stoltz, J. Am. Chem. Soc. 2006, 128,
7738.
[5] a) B. M. Trost, G. M. Schroeder, J. Am. Chem. Soc. 1999, 121, 6759; b) B. M. Trost, J. Xu, J. Am.
Chem. Soc. 2005, 127, 2846; c) B. M. Barry, K. Lehr, D. J. Michealis, J. Xu, A. K. Buckl, J. Am.
Chem. Soc. 2010, 132, 8915; d) B. M. Barry, J. Xu, T. Schmidt, J. Am. Chem. Soc. 2009, 131, 18343;
e) B. M. Trost, D. J. Michaelis, J. Charpentier, J. Xu, Angew. Chem. Int. Ed. 2012, 51, 204; Angew.
Chem. 2012, 124, 208.
[6] For publications from other groups, see: a) X. Zhao, D. Liu, H. Guo, Y. Liu, W. Zhang, J. Am.
Chem. Soc. 2011, 133, 19354; b) X. Huo, M. Quan, G. Yang, X. Zhao, D. Liu, Y. Liu, W. Zhang, Org.
Lett. 2014, 16, 1570; c) X. Huo, G. Yang, D. Liu, Y. Liu, I. D. Gridnev, W. Zhang, Angew. Chem. Int.
Ed. 2014, 53, 6776; Angew. Chem. 2014, 126, 6894; d) I. Ibrahem, A. Córdova, Angew. Chem. Int.
Ed. 2006, 45, 1952; Angew. Chem. 2006, 118, 1986; e) I. Usui, S. Schmidt, B. Breit, Org. Lett. 2009,
11, 1453; f) S. You, L. Hou, L. Dai, X. Zhu, Org. Lett. 2001, 3, 149; g) X. Zhao, D. Liu, F. Xie, Y.
Liu, W. Zhang, Org. Biomol. Chem. 2011, 9, 1871.
[7] G. Liu, D. A. Cogan, J. A. Ellman, J. Am. Chem. Soc. 1997, 119, 9913.

[8] For a recent review on the application of tert-Butanesulfinamide, see: a) J. A. Ellman, T. D.
Owens, T. P. Tang, Acc. Chem. Res. 2002, 35, 984; b) M. T. Robak, M. A. Herbage, J. A. Ellman,
Chem. Rev. 2010, 110, 3600.
[9] J. Li, S. Jiang, G. Procopiou, R. A. Stockman, G. Yang, Euro. J. Org. Chem. 2016, 3500.
[10] S. Hashimoto, Y. Miyazaki, S. Ikegami, Synth. Commun. 1992, 22,2717.
[11] a) A. I. Meyers, D. R. Williams, G. W. Erickson, S. White, M. Druelinger, J. Am. Chem. Soc.
1981, 103, 3081. b) K. Hiroi, J. Abe, K. Suya, S. Sato, T. Koyama, J. Org. Chem. 1994, 59, 203.

Highlights:
Using commercial available catalysis and achiral ligand
Mono-allylation
Good yields and dr values
Substitution tolerance