Silver/palladium relay catalyzed 1,3-dipole annulation/allylation reactions to access fully substituted allyl imidazolidines

Article abstract of DOI:10.1039/c9ob02633a

A silver/palladium relay catalyzed 1,3-dipole annulation/allylation reaction of iminoesters and Baylis-Hillman acetates for the construction of fully substituted allyl imidazolidines is reported. The reaction of both iminoesters and Baylis-Hillman acetate

Full text of DOI:10.1039/c9ob02633a

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: R. Han, Y. Ding, X.
Jin and E. Li, Org. Biomol. Chem., 2020, DOI: 10.1039/C9OB02633A.
Volume 15
Number 47
21 December 2017
Pages 9945-10124
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
Accepted Manuscripts are published online shortly after acceptance,
rsc.li/obc
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
ISSN 1477-0520
PAPER
I . J. Dmochowski et al.
Oligonucleotide modifi cations enhance probe stability for
shall the Royal Society of Chemistry be held responsible for any errors
single cell transcriptome in vivo analysis (TIVA)
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
rsc.li/obc

Please do not adjust margins
Page 1 of 5
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C9OB02633A
COMMUNICATION
Silver/palladium relay catalyzed 1,3-dipole annulation/allylation
reactions to access fully substituted allyl imidazolidines
Ruiping Han, a Yue Ding,a Xueke Jin,a and Er-Qing Li,a,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A silver/palladium relay catalyzed 1,3-dipole annulation/allylation palladium-catalyzed allylic amination of Baylis–Hillman
reaction of iminoesters and Baylis-Hillman acetates for the acetates, albeit with moderate regioslectivity (α/γ = 3 : 1 to 6 :
construction of fully substituted allyl imidazolidines is reported. 1).7 Next Liu and co-workers improved the regioslectivity by
Examination of both iminoesters and Baylis-Hillman acetates employing [Pd(C3H5)Cl]2/ferrocene-type diphosphine catalytic
affords the fully substituted allyl imidazolidines in high yields and system.8 In 2011, Alper and co-workers reported
a
regioselectivities. The three component reaction is triggered by palladium/palladium relay catalyzed tandem γ-regioselective
silver-catalyzed 1,3-dipole annulation, followed by the sequential amination and intramolecular cyclocarbonylation reaction.9
palladium catalyzed allylation. Mechanistic studies reveal that the Despite all that, How to extend the substrate-scope of the
dual catalytic system plays the key role in the reaction. The palladium-catalyzed allylic amination reactions into widely N-
developed methodology provides straightforward access to allyl nucleophiles is still challenge. On the basis of our interest in
imidazolidines under simple reaction conditions.
domino reaction,10 we describe herein a silver/palladium relay
catalyzed 1,3-dipole annulation/allylation reaction of
iminoesters 11 and Baylis-Hillman acetates, providing a series of
fully substituted allyl imidazolidines in moderate to good yields
and excellent regioslectivities (Scheme 1).
Dual catalyst relay catalysis, in the light of the combined use of
two different catalysts, provides a powerful strategy for
achieving ideal organic synthesis.1 This is because it can fulfill
chemical transformation that can’t finished by either of the
catalysts solely.2 In this system, each catalyst works either
cooperatively or independently to realize tandem multi-step
synthesis in one pot, which dramatically reduces waste,
solvents, time and so on. Despite important progress made in
this field, it still remains an unmet challenge to skilfully
operate two types of dipolarophilic species resulted from
different substrates concomitantly. Thus the development of a
novel dual catalyst system is highly desirable.
The Baylis–Hillman acetates have emerged as powerful
substrates in organic synthesis,3 which can be employed in
allylic substitution reactions by forming π-allylpalladium
complexes.4 Especially, the catalytic allylic amination, which
provides an efficient approach to give natural products and
biologically active molecules with an allylamino moiety, has
attracted tremendously attention.5 The allylic amination
reaction can result in two regioselective products ( α- and γ-
products). Thus chemists are devoted to highly regioselective
obtain sole product.6 In 2002, Iqbal and co-workers reported a
Scheme 1. Allylic substitution of Baylis–Hillman acetates.
Initially, Baylis–Hillman acetate 1aa and iminoester 2a were
selected as the model substrates to optimize the reaction
conditions. By employing
a bimetallic catalyst system
consisting of [Pd(C3H5)Cl]2 and a Cu complex derived from
Cu(CH3CN)4BF4/PPh3, NEt3 as a base in CH2Cl2 at room
temperature, the reaction proceeded smoothly to give the
corresponding product 3a in 45% yield and complete
regioselectivity (Table 1, entry 1). Screening of catalysts II
a.College of Chemistry, Green Catalysis Center, Zhengzhou University, Zhengzhou
450001, P. R. China.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 5
COMMUNICATION
Journal Name
suggested that [Pd(C3H5)Cl]2 was the best catalyst (Table 1, yield (Table 2, entry 17). In addition, iminoesters VdieewriAvreticdle fOrnolimne
DOI: 10.1039/C9OB02633A
entries 1-6). Next, different Ag(I) and Cu(I) salts were screened, 4-fluoro, and 4-chlorobenzaldehyde could also afford the
and showed that AgNTf2/[Pd(C3H5)Cl]2 dual catalysis was the corresponding products 3r-3s in 27-60% yields (Table 2, entries
optimal catalyst system, giving the product 3a in 47% yield 18-19). Next, we employed Baylis–Hillman carbonates 1b as
(Table 1, entries 1, 7-10). The examination of different solvents substrates to proceed the reaction. Various Baylis–Hillman
and bases indicated that THF and NEt3 were best choice (Table carbonates bearing the electron-withdrawing (Table 2, entries
1, entries 11-18). Notably, clear effect of temperature on the 21-24) and electron-donating groups (Table 2, entry 25) were
reaction was observed (Table 1, entries 19-21). Finally, the employed in the reaction, providing the desired products
3 in
evidently improved yield was obtained by increasing the 37-65% yields. The structures of were characterized by a
3
stoichiometry of iminoester 2a (Table 1, entries 15 22-23).
Table 1. Optimization of the reaction conditions.a
combination of NMR, HRMS spectra, and single crystal X-ray
analysis (3b) (see Supporting Information).12
Table 2. Substrate scope.a
entry
cat. I
cat. II
solvent
yield
(%)b
45
34
38
33
-
1
2
3
4
5
6
7
8
9
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4 Pd2(dba)3.CCl3
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
[Pd(C3H5)Cl]2
Pd(OAc)2
Pd(PPh3)4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1,4-dioxane
toluene
Et2O
entry
1
2
3
4
5
6
7
8
Ar
Ph
R1
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Boc
Boc
Boc
Boc
Boc
Boc
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-F
4-Cl
H
H
H
H
H
yield(%)b
78(3a
67(3b
70(3c
)
)
)
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-NO2C6H4
4-OCH3C6H4
4-CH3C6H4
4-tBuC6H4
4-CF3C6H4
3-ClC6H4
3-FC6H4
3-BrC6H4
3-NO2C6H4
2-ClC6H4
2-BrC6H4
2-thienyl
H
[Ir(COD)Cl]2
[Rh(COD)Cl]2
-
56(3d
65(3e
)
)
Cu(CH3CN)4PF6 [Pd(C3H5)Cl]2
37
37
47
43
56
53
50
59
51
47
49
56
62
67
54
78
76
Cu(OTf)2
AgNTf2
AgOTf
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
44(3f
59(3g
62(3h
)
)
)
10
11
12
13
14
15
16
17c
18d
19e
20f
21g
22f,h
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
9
53(3i
52(3j
70(3k
)
)
)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
THF
CH3CN
CHCl3
THF
THF
THF
THF
THF
THF
THF
64(3l
)
74(3m)
37(3n
42(3o
31(3p
61(3q
)
)
)
)
60(3r
)
23f,i
H
H
27(3s
)
a
Unless otherwise specified, all reactions were carried out
49(3a
58(3b
44(3c
65(3d
)
)
)
)
using 1aa (0.2 mmol) and 2a (0.6 mmol) at room temperature.
4-FC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-CH3C6H4
b
c
d
Isolated yield. Na2CO3 (2.0 equiv) as base. NaHCO3 (2.0
e
f
equiv) as base. Reaction temperature: 40 °C. Reaction
temperature: -10 °C. g Reaction temperature: -20 °C. 2a (4.0
h
51(3f
)
equiv.) was used. i 2a (5.0 equiv.) was used.
H
37(3h
)
a
Unless otherwise specified, all reactions were carried out
With optimized reaction conditions in hand, the substrate
generality of the reaction was next surveyed. As outlined in
using (0.2 mmol) and
1
2
(0.8 mmol) at -10 °C. b Isolated yield.
Owing to demonstrate the practicality of our method, we
performed silver/palladium relay catalyzed 1,3-dipole
annulation/allylation reaction at the gram scale, when Baylis–
Hillman acetate derived from bromobenzaldehyde 1ab and
iminoester 2a were used in the presence of the low loading of
[Pd(C3H5)Cl]2, the reaction proceeded smoothly to afford the
desired adduct 3b in 55 % yield at 21h.
Table 2. The Baylis–Hillman acetates
1 derived from the
aromatic aldehydes bearing either electron-withdrawing or
electron-donating groups in the phenyl rings gave the desired
products
3 in moderate to good yields (Table 2, entries 1-15).
However, the substitution positions of phenyl rings (ortho-,
meta-, or para-) had certain influence on yields, and ortho
substituent resulted in lower yields, probably due to the steric
hindrance (Table 2, entries 15, 16 vs 3, 4, 11, 13). Baylis–
Hillman acetates 1aq derived from 2-thienyl formaldehyde
proceeded smoothly, providing the desired product 3q in 61%
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 3 of 5
Organic & Biomolecular Chemistry
Journal Name
COMMUNICATION
Conclusions
View Article Online
DOI: 10.1039/C9OB02633A
We developed a silver/palladium relay catalyzed 1,3-dipole
annulation/allylation reaction of iminoesters and Baylis-
Hillman acetates, providing the corresponding tri-substituted
alkenes
3 in moderate to good yields and excellent
regioselectivities. The gram scale experiment demonstrated
the practicality of our method. It should be noted that the
reaction owned lower reactive activity step by step, which
certificated the effectiveness of the Ag/Pd relay catalysis
system.
Scheme 2. The preparation of large scale.
In order to verify the reaction mechanism, we carried out
some control experiments. First, only silver catalyst and PPh3
were used, the reaction didn’t occur. Next, we proceeded the
reaction step by step. The first annulation reaction could
proceed smoothly in the presence of silver and PPh3. While the
subsequent reaction could occur only [Pd(C3H5)Cl]2 and PPh3
were applyied, albeit with longer reaction time and lower yield
(Scheme 3).
We are grateful to the National Natural Science Foundation of
China (No. 21702189), China Postdoctoral Science Foundation
(No. 2017M610458, 2018T110737), Postdoctoral Research
Grant in Henan Province (No. 001701006), National Student’s
Platform for Innovation and Entrepreneurship Training
Program (2019cxcy489) and Zhengzhou University of China for
financial support of this research.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
2
(a) L. F. Tietze, Chem. Rev., 1996, 96, 115; (b) J.-C. Wasilke, S.
J. Obrey, R. T. Baker, and G. C. Bazan, Chem. Rev., 2005, 105
,
1001; (c) J. Zhou, Multicatalyst System in Asymmetric
Catalysis (Wiley)., 2014; (d) T. L. Lohr, and T. J. Marks, Nat.
Chem., 2015, 7, 477; (e) T.-Y. Shang, L.-H. Lu, Z. Cao, Y. Liu,
W.-M. He and B. Yu, Chem. Commun., 2019, 55, 5408.
Selected examples, see: (a) A. R. O. Venning, M. R.
Kwiatkowski, J. E. Roque Peña, B. C. Lainhart, A. A.
Scheme 3. Control experiment.
Based on our experiment result and previous literature,8,9,13
a possible catalytic model was proposed. As depicted in
Scheme 4. The in situ formed azomethine ylide coordinated to
Guruparan, E. J. Alexanian, J. Am. Chem. Soc., 2017, 139
,
11595; (b) M. Bakos, Á. Gyömöre, A. Domján and T. Soós,
Angew. Chem. Int. Ed., 2017, 56, 5217; (c) A. Kondoh and M.
Terada, Org. Lett., 2018, 20, 5309; (d) J. Meng, L.-F. Fan, Z.-Y.
the active Ag(I) complex, leading to the intermediate
Conjugate addition of the enolate to another iminoester gave
the enolate intermediate . The following intramolecular
annulation produced the intermediate . And the formation of
Pd(II)/PPh3 complex activated the Baylis–Hillman acetate 1aa
affording the intermediate , which removed monomolecular
acetic acid to give the intermediate . Next, intermediate
A.
Han and L.-Z. Gong, Chem, 2018, 4, 1047; (e) P. Chen, Z.-C.
Chen, Y. Li, Q. Ouyang, W. Du and Y.-C. Chen, Angew. Chem.
Int. Ed., 2019, 58, 4036; (f) Z.-C. Chen, Z. Chen, Z.-H. Yang, L.
B
C
Guo, W. Du, and Y.-C. Chen, Angew. Chem. Int. Ed., 2019, 58
,
15021.
D
3
4
For selected reviews, see: (a) D. Basavaiah, B. S. Reddy and S.
E
F
S. Badsara, Chem. Rev., 2010, 110, 5447; (b) R. Rios, Catal. Sci.
was obtained by coordinating [Pd] with imidazolidinide anion.
Finally, the desired product 3a was obtained by γ-
regioselective allylic substitution reaction (Scheme 4).
Technol., 2012, 2, 267; (c) T.-Y. Liu, M. Xie and Y.-C. Chen,
Chem. Soc. Rev., 2012, 41, 4101; (d) Y. Wei and M. Shi, Chem.
Rev., 2013, 113, 6659; (e) P. Xie and Y. Huang, Org. Biomol.
Chem., 2015, 13, 8578.
(a) B. M. Trost, M. R. Machacek and A. Aponick, Acc. Chem.
Res., 2006, 39, 747; (b) B. M. Trost and F. D. Toste, J. Am.
Chem. Soc., 1998, 120, 815; (c) B. M. Trost, H. C. Tsui and F. D.
Toste, J. Am. Chem. Soc., 2000, 122, 3534; (d) L.-Z. Yu, Z.-Z.
Zhu, X.-B. Hu, X.-Y. Tang and M. Shi, Chem. Commun., 2016,
52, 6581; (e) Y. Wang, S. Jia, E.-Q. Li, and Z. Duan, J. Org.
Chem., 2019, 84, 15323.
5
6
(a) B. M. Trost and M. L. Crawley, Chem. Rev., 2003, 103,
2921; (b) G. Helmchen, A. Dahnz, P. Dubon, M. Schelwies
and R. Weihofen, Chem. Commun., 2007, 675; (c) M. Diéguez
and O. Pàmies, Acc. Chem. Res., 2010, 43, 312; (d) J. F.
Hartwig and L. M. Stanley, Acc. Chem. Res., 2010, 43, 1461.
Selected examples, see: (a) X. Wang, F. Meng, Y. Wang, Z.
Han, Y.-J. Chen, L. Liu, Z. Wang, and K. Ding, Angew. Chem.
Scheme 4. A proposed mechanism.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 5
COMMUNICATION
Journal Name
Int. Ed., 2012, 51, 9276; (b) D. Basavaiah and D. M. Reddy,
Org. Biomol. Chem., 2012, 10, 8774; (c) X. Wang, P. Guo, Z.
Han, X. Wang, Z. Wang, and K. Ding, J. Am. Chem. Soc., 2014,
136, 405; (d) P. Zhou, Y. Liang, H. Zhang, H. Jiang, K. Feng, P.
Xu, J. Wang, X. Wang, K. Ding, C. Luo, M. Liu and Y. Wang,
Eur. J. Med. Chem., 2018, 144, 817; (e) Y.-C. Gong, Y. Wang,
View Article Online
DOI: 10.1039/C9OB02633A
E.-Q. Li, H. Cui and Z. Duan, Adv. Synth. Catal., 2019, 361
,
1389.
7
8
9
S. Rajesh, B. Banerji and J. Iqbal, J. Org. Chem., 2002, 67
,
7852.
Y. Wang, L. Liu, D. Wang and Y.-J. Chen, Org. Biomol. Chem.,
2012, 10, 6908.
H. Cao, T. O. Vieira and H. Alper, Org. Lett., 2011, 13, 11.
10 (a) Q.-Z. Xi, Z.-J. Gan, E.-Q. Li and Z. Duan, Eur. J. Org. Chem.,
2018, 2018, 4917; (b) Z. Gan, Y. Gong, Y. Chu, E.-Q. Li, Y.
Huang and Z. Duan, Chem. Commun., 2019, 55, 10120; (c) M.
Zhi, Z. Gan, R. Ma, H. Cui, E.-Q. Li, Z. Duan and F. Mathey,
Org. Lett., 2019, 21, 3210; (d) Z. Gan, M. Zhi, R. Han, E.-Q. Li,
Z. Duan and F. Mathey, Org. Lett., 2019, 21, 2782; (f) R. Ma,
G. Song, Q. Xi, L. Yang, E.-Q. Li and Z. Duan, Chin. J. Org.
Chem., 2019, 39, 2196.
11 Selected reviews about iminoesters, see: (a) E. E. Maroto, M.
Izquierdo, S. Reboredo, J. Marco-Martínez, S. Filippone and N.
Martín, Acc. Chem. Res., 2014, 47, 2660; (b) J. Adrio and J. C.
Carretero, Chem. Commun., 2014, 50
, 12434; (c) T.
Hashimoto and K. Maruoka, Chem. Rev., 2015, 115, 5366; (d)
B. Bdiri, B.-J. Zhao and Z.-M. Zhou, Tetrahedron: Asymmetry,
2017, 28, 876; (e) X. Fang and C.-J. Wang, Org. Biomol. Chem.,
2018, 16, 2591.
12 CCDC 1960936
(3b
)
contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre.
13 J. Park, R. Heo, J.-Y. Kim, B. W. Yoo, and C. M. Yoon, Bull.
Korean Chem. Soc., 2009, 30, 1195.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C9OB02633A
Ar1
PPh3 (10 mol %)
AgNTf2 (10 mol %)
CO2Et
Ar1
CO2Me
Ar2
N
CO2Me
CO2Et
N
N
+
RO
Ar2
[Pd(C3H5)Cl]2 (5 mol%)
NEt3 (20 mol%)
THF, -10 o
C
Ar2
R = OAc, Boc
CO2Me
(1) Silver/palladium relay catalysis
(2) Three component reactions
(3) 25 examples
A silver/palladium relay catalyzed 1,3-dipole annulation/allylation reaction of iminoesters and
Baylis-Hillman acetates has been developed, providing a seires of fully substituted allyl
imidazolidines in moderate to good yields and excellent regioslectivities.