Palladium-Catalyzed Asymmetric Tandem [3+2] Cycloaddition/Allylation Reaction of Methylene-Trimethylenemethane: Access to Chiral Tricyclic Dinitrogen-Fused Heterocycles

Article abstract of DOI:10.1021/acs.orglett.9b01064

A palladium-catalyzed asymmetric tandem [3+2] cycloaddition/allylation of methylene-trimethylenemethane is presented, providing the functionalized chiral hexahydropyrazolo[5,1-a]isoquinoline derivatives in high yields with good to excellent enantioselecti

Full text of DOI:10.1021/acs.orglett.9b01064

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Palladium-Catalyzed Asymmetric Tandem [3+2] Cycloaddition/
Allylation Reaction of Methylene-Trimethylenemethane: Access to
Chiral Tricyclic Dinitrogen-Fused Heterocycles
Biming Mao, Yi Xu, Yuehua Chen, Jipan Dong, Junya Zhang, Kejia Gu, Bing Zheng,
and Hongchao Guo*
Department of Applied Chemistry, China Agricultural University, Beijing 100193, P. R. China
*
S Supporting Information
ABSTRACT: A palladium-catalyzed asymmetric tandem [3+2] cycloaddition/allylation of methylene-trimethylenemethane is
presented, providing the functionalized chiral hexahydropyrazolo[5,1-a]isoquinoline derivatives in high yields with good to
excellent enantioselectivities and moderate to good E:Z ratios. In the one-pot sequential tandem reactions/hydroxylation, (E)-
allylic alcohol products were obtained in good yields with excellent enantioselectivities.
he cycloaddition reactions of palladium-trimethylene-
catalyzed [3+2] cycloaddition of a methylene-TMM donor
with α,β-unsaturated N-acyl pyrroles, providing substituted
vinylidenecyclopentanes in excellent yields and enantioselectiv-
T
methane (Pd-TMM) are very useful tools for the synthesis
1
of cyclic compounds and the total synthesis of natural
2
6
products. In Pd-TMM chemistry, allyl trimethylsilanes had
ities (Scheme 1b). Recently, they used this methodology to
7
extensively been employed as TMM donors for the synthesis of
produce a wide variety of substituted chiral allenes. In Pd-
3
4
various substituted carbocycles and heterocycles since Trost’s
TMM and Pd-methylene-TMM chemistry, these zwitterionic
allylpalladium intermediates generally behave as three-carbon
synthons to react with a multitude of acceptors to furnish the
5
important contribution in 1979 (Scheme 1a). To further
extend Pd-TMM chemistry, in 2013, Trost synthesized
allenylmethyl-substituted trimethylsilane, which was used as a
donor of Pd-methylene-TMM, and reported palladium-
3a,b,4a−i
4j−n
3c,4o
[
3+n] cycloadditions, giving five,
six,
nine -membered carbo- and heterocyclic compounds (Scheme
a,b). To the best of our knowledge, the TMM donor serving as
seven,
and
3d
1
a two-carbon synthon for palladium-catalyzed [3+2] cyclo-
addition has never been reported. We pondered that when Pd-
methylene-TMM meets a dipole, the carbon−carbon double
bond of Pd-methylene-TMM might work as a dipolarophile for
Scheme 1. Palladium-Catalyzed Cycloaddition Reactions of
TMM
1
,3-dipolar cycloaddition and the allylpalladium moiety will
perform further allylation. As part of our continuing efforts with
respect to cycloaddition reactions, herein, we present the first
8
palladium-catalyzed asymmetric tandem [3+2] cycloaddition/
allylation of methylene-TMM to furnish biologically important
functionalized chiral hexahydropyrazolo[5,1-a]isoquinoline de-
rivatives (Scheme 1c).
To test the feasibility of the tandem reaction, we investigated
the model reaction of methylene-TMM donor 1a and
azomethine imine 2a in dichloromethane at room temperature
(
Table 1). To our delight, under catalysis of Pd(PPh ) , the
3 4
desired tandem reaction proceeded smoothly to deliver the
racemic product in 71% yield with a 9:1 E:Z ratio (entry 1).
Several axially chiral phosphoramidite ligands were then
Received: March 26, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01064
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Table 2. Palladium-Catalyzed Tandem [3+2] Cycloaddition/
Allylation of Methylene-TMM
a
b
c
d
entry
Lx
solvent
CH Cl
t (h)
yield (%)
71
E:Z
ee (%)
e
1
−
7
48
48
12
48
24
24
14
12
20
12
9:1
−
−
9:1
−
3:1
−
3:1
−
−
−
2
2
2
2
2
2
f
2
3
4
5
6
7
8
L1
L2
L3
L4
L3
L3
L3
L3
L3
L3
CH Cl
NR
NR
2
f
CH Cl
2
CH Cl
92
NR
81:97
2
f
CH Cl
−
2
DCE
THF
toluene
76
trace
90
86
72
79:80
−
87:95
81:99
85:97
91:97
9
CH CN
2.3:1
3:1
3
e
10
1
toluene
toluene
g
1
99
3:1
a
Unless otherwise indicated, all reactions were performed with 1a
0.15 mmol) and 2a (0.10 mmol) in the presence of Pd(dba) (5 mol
(
2
b
a
%
) and chiral ligand (10 mol %) in 1 mL of solvent. Isolated yield.
Unless otherwise indicated, all reactions were carried out with 1
c
1
d
b
Determined by H NMR analysis. Determined by HPLC analysis
(
0.15 mmol) and 2 (0.10 mmol) in 1 mL of toluene. Isolated yield.
e
c
1
d
using a chiral stationary phase. Pd(PPh ) and Pd (dba) ·CHCl
were used in entries 1 and 10, respectively. No reaction. Using 10
3
4
2
3
3
Determined by H NMR analysis. Determined by HPLC analysis
f
g
e
using a chiral stationary phase. No reaction.
mol % Pd(dba) and 20 mol % ligand.
2
electron-neutral, electron-donating, and electron-withdrawing
groups, were well tolerated, providing the desired products in
high yields with good to excellent enantioselectivities (entries
4−12). Azomethine imines with a methyl substituent on the
aromatic ring provided yields relatively higher than that with a
halogen substituent (entries 10 and 11 vs entries 4−9). Different
substituents at position 4 of the phenyl ring of the benzoyl
protecting group had some effect on the reactivities and
enantioselectivities (entries 13−17). The major isomer of
product 3 was unambiguously assigned to be the E-isomer
examined (entries 2−5). Interestingly, chiral ligand L3 was the
only one that promoted the reaction (entry 4). Under catalysis
of Pd(dba) and axially chiral phosphoramidite ligand L3, the
2
desired product was obtained in 92% yield with 81%:97% ee and
a 9:1 E:Z ratio (entry 4). A quick screening of several solvents
such as 1,2-dichloroethane (DCE), THF, toluene, and CH CN
3
(
entries 8−11, respectively) revealed that toluene is the optimal
solvent, leading to product 3aa in 90% yield with an 87%:95% ee
and a 3:1 E:Z ratio (entry 8). Pd (dba) ·CHCl also facilitated
2
3
3
9
the reaction, but it did not aid in impairing the activity (entry
0). Increasing the loading of the catalyst [using 10 mol %
according to X-ray crystallographic data of product 3ac.
1
During exploration of further transformations of the products,
we observed that the hydroxylation of product 3aa proceeded
well in the presence of K CO , affording only E-isomer 4aa in
Pd(dba) and 20 mol % chiral ligand L3] increased both the
2
yield and the enantioselectivity (entry 13). On the basis of the
screening results presented above, the optimal reaction
2
3
85% yield without any loss of the enantiomeric excess (Scheme
2). Encouraged by this result, we moved to investigate a one-pot
conditions were determined using Pd(dba) (10 mol %) and
2
chiral ligand L3 (20 mol %) as the catalyst in toluene at rt. To
investigate the practicality of the process, a large-scale reaction
Scheme 2. Hydroxylation of Product 3aa
was conducted. In the presence of 10 mol % Pd(dba) and 20
2
mol % L3, the reaction of 2a (2.0 mmol) with 1a (3.0 mmol) was
performed for 15 h, providing 0.65 g of 3aa (92% yield) with a
9
1%:97% ee and a 3:1 E:Z ratio.
After the optimized conditions had been established, various
azomethine imines 2 were investigated in the tandem reaction
1
(
Table 2). The leaving group (R ) of methylene-TMM donors 1
was first explored. When using acetyl or benzoyl as the leaving
group, azomethine imine 2a was completely converted, giving
the corresponding products 3aa and 3ba in good to excellent
yields and enantioselectivities (entries 1 and 2, respectively). In
comparison, Boc-protected donor 1c showed no reactivity
sequential tandem reaction/hydroxylation procedure to synthe-
size allyl alcohol derivatives 4. Using the established reaction
system, Pd-catalyzed tandem reaction of methylene-TMM
donor 1a and azomethine imines 2 was performed for the
given period of time, and then K CO and MeOH were added to
2
3
(
entry 3). With acetyl-protected donor 1a as the substrate,
the flask to promote the hydroxylation. As shown in Table 3, a
various azomethine imines with different substituents, including
variety of azomethine imines were examined. All of these 1,3-
B
DOI: 10.1021/acs.orglett.9b01064
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. One-Pot Synthesis of Allyl Alcohol Derivatives 4
acid, product 3ba was produced in 85% yield (Scheme 3b). In
the reaction of 1c, when phenol was employed in the place of
benzoic acid, a phenoxy ether 3ca was afforded as the tandem
reaction product in 50% yield (Scheme 3c). Treatment of
product 3aa with benzoic acid under standard conditions did not
give product 3ba (Scheme 3d). In addition, when 2.2 equiv of
D O was added to the model reaction mixture, it could afford
2
deuterated 3aa in 90% yield with 15% D incorporation at the
methyl group of propene that linked to alkenes (Scheme 3e).
These results indicated that during palladium catalysis, an
allylation reaction of Pd-methylene-TMM occurred during the
reaction.
According to the control experimental results and some
7
related reports, as shown in Scheme 4, a plausible catalytic cycle
Scheme 4. A Proposed Mechanism
a
Unless otherwise indicated, all reactions were carried out with 1a
b
(
0.15 mmol) and 2 (0.10 mmol) in 1 mL of toluene. Isolated yield.
Determined by HPLC analysis using a chiral stationary phase.
c
dipoles bearing electron-donating and -withdrawing substitu-
ents on the benzene ring or the benzoyl group worked well,
leading to products 3c−3f in good yields with good to excellent
enantioselectivities (entries 1−8).
To gain some insights into the mechanism of this cyclo-
addition reaction, several control experiments were performed.
When 1.2 equiv of benzoic acid was added to the model reaction
mixture, the reaction of methylene-TMM donor 1a and
azomethine imine 2a produced the anticipated product 3aa in
was proposed. In the presence of a palladium catalyst, the
methylene-substituted TMM donor was transformed into Pd-
methylene-TMM complex A with simultaneous release of
TMSOAc. Intermediate A undergoes cycloaddition with
azomethine imine 2a, affording intermediate B. Subsequent
allylation of the acetyloxy anion gave product 3aa.
In conclusion, palladium-catalyzed asymmetric tandem [3+2]
cycloaddition/allylation of methylene-TMM has been achieved
under mild reaction conditions to give the functionalized
2
7% yield and a new product 3ba in 55% yield, in which the
acetyl group of 3aa was replaced by a benzoyl group (Scheme
a). When Boc-protected methylene-TMM donor 1c was used
3
instead of Ac-protected donor 1a, in the presence of benzoic
Scheme 3. Control Experiments
1
,2,3,5,6,10b-hexahydropyrazolo[5,1-a]isoquinoline derivatives
in good to excellent yields with good to excellent enantiose-
lectivities. This is the first example of asymmetric tandem [3+2]
cycloaddition/allylation reaction of Pd-methylene-TMM. The
insecticidal and bactericidal activities of all novel compounds
synthesized by our methodology are being evaluated.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01064.
Experimental procedure, characterization data, and NMR
spectra (PDF)
Accession Codes
CCDC 1898870 and 1898872−1898873 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: hchguo@cau.edu.cn.
C
DOI: 10.1021/acs.orglett.9b01064
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
Pyrrolidines Bearing a Quaternary Center by Palladium-Catalyzed
Asymmetric [3+2] Cycloaddition of Trimethylenemethanes. J. Am.
Chem. Soc. 2013, 135, 2459. (i) Procopiou, G.; Lewis, W.; Harbottle,
G.; Stockman, R. A. Cycloaddition of Chiral tert-Butanesulfinimines
with Trimethylenemethane. Org. Lett. 2013, 15, 2030. (j) Hedley, S. J.;
Moran, W. J.; Prenzel, A. H. G. P.; Price, D. A.; Harrity, J. P. A. Synthesis
of Functionalised Piperidines Through a [3+3] Cycloaddition Strategy.
Synlett 2001, 2001, 1596. (k) Hedley, S. J.; Moran, W. J.; Price, D. A.;
Harrity, J. P. A. Development of a [3+3] Cycloaddition Strategy toward
Functionalized Piperidines. J. Org. Chem. 2003, 68, 4286. (l) Provoost,
O. Y.; Hazelwood, A. J.; Harrity, J. P. A. Pd-catalysed [3+3] Annelations
in the Stereoselective Synthesis of Indolizidines. Beilstein J. Org. Chem.
Hongchao Guo: 0000-0002-7356-4283
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Science Foundation of
China (21572264 and 21871293) and the Chinese Universities
Scientific Fund (2018TC052, 2018TC055, and 2019TC085).
2
007, 3, 8. (m) Shintani, R.; Hayashi, T. Palladium-Catalyzed [3+3]
REFERENCES
■
Cycloaddition of Trimethylenemethane with Azomethine Imines. J.
Am. Chem. Soc. 2006, 128, 6330. (n) Shintani, R.; Park, S.; Duan, W. L.;
Hayashi, T. Palladium-Catalyzed Asymmetric [3+3] Cycloaddition of
Trimethylenemethane Derivatives with Nitrones. Angew. Chem., Int. Ed.
(
1) For selected reviews, see: (a) Trost, B. M. [3+2] Cycloaddition
Approaches to Five-Membered Rings via Trimethylenemethane and Its
Equivalents. Angew. Chem., Int. Ed. Engl. 1986, 25, 1. (b) Trost, B. M.
Transition Metal Templates as Guides for Cycloadditions. Pure Appl.
Chem. 1988, 60, 1615. (c) Lautens, M.; Klute, W.; Tam, W. Transition
Metal-Mediated Cycloaddition Reactions. Chem. Rev. 1996, 96, 49.
d) Harrity, J. P. A.; Allen, B.; Lakeland, C. Utilizing Palladium-
Stabilized Zwitterions for the Construction of N-Heterocycles. Chem. -
Eur. J. 2017, 23, 13830.
2) For selected examples, see: (a) Trost, B. M.; Crawley, M. L. 4-
Aryloxybutenolides As “Chiral Aldehyde” Equivalents: An Efficient
Enantioselective Synthesis of (+)-Brefeldin A. J. Am. Chem. Soc. 2002,
24, 9328. (b) Moran, W. J.; Goodenough, K. M.; Raubo, P.; Harrity, J.
P. A. A Concise Asymmetric Route to Nuphar Alkaloids. A Formal
2
007, 46, 5901. (o) Trost, B. M.; Marrs, C. M. A [3+2] Cycloaddition
and [4+3] Cycloaddition Approach to N-Heterocycles via Palladium-
Catalyzed TMM Reactions with Imines. J. Am. Chem. Soc. 1993, 115,
(
6636.
(
5) (a) Trost, B. M.; Chan, D. M. T. New Conjunctive Reagents. 2-
Acetoxymethyl-3-allyltrimethylsilane for Methylenecyclopentane An-
nulations Catalyzed by Palladium(0). J. Am. Chem. Soc. 1979, 101,
(
6
429. (b) Binger, P.; Schuchardt, U. Palladium(0)-Catalyzed [2σ+2π]
Cycloadditions Methylenecyclopropane to Alkenes. Angew. Chem., Int.
Ed. Engl. 1977, 16, 249.
1
(
6) Trost, B. M.; Maruniak, A. Enantioselective Construction of
Synthesis of (−)-Deoxynupharidine. Org. Lett. 2003, 5, 3427.
c) Mancey, N. C.; Sandon, N.; Auvinet, A.-L.; Butlin, R. J.;
Highly Substituted Vinylidenecylopentanes by Palladium-Catalyzed
Asymmetric [3+2] Cycloaddition Reaction. Angew. Chem., Int. Ed.
(
Czechtizky, W.; Harrity, J. P. A. Stereoselective Approaches to 2,3,6-
Trisubstituted Piperidines. An Enantiospecific Synthesis of Quinolizi-
dine (−)-217A. Chem. Commun. 2011, 47, 9804. (d) Trost, B. M.;
Bringley, D. A.; Zhang, T.; Cramer, N. Rapid Access to Spirocyclic
Oxindole Alkaloids: Application of the Asymmetric Palladium-
Catalyzed [3+2] Trimethylenemethane Cycloaddition. J. Am. Chem.
Soc. 2013, 135, 16720.
2013, 52, 6262.
(
7) (a) Trost, B. M.; Chan, D. M. T. Nature of a trimethylenemethane-
palladium complex. J. Am. Chem. Soc. 1980, 102, 6359. (b) Trost, B. M.;
Zell, D.; Hohn, C.; Mata, G.; Maruniak, A. Enantioselective
Construction of Highly Substituted Vinylidenecylopentanes by
Palladium-Catalyzed Asymmetric [3+2] Cycloaddition Reaction.
Angew. Chem., Int. Ed. 2018, 57, 12916.
(
3) (a) Trost, B. M.; Stambuli, J. P.; Silverman, S. M.; Schworer, U.
̈
(
8) (a) Na, R.; Jing, C.; Xu, Q.; Jiang, H.; Wu, X.; Shi, J.; Zhong, J.;
Palladium-Catalyzed Asymmetric [3+2] Trimethylenemethane Cyclo-
addition Reactions. J. Am. Chem. Soc. 2006, 128, 13328. (b) Trost, B.
M.; Bringley, D. A.; Seng, P. S. Enantioselective Palladium-Catalyzed
Wang, M.; Benitez, D.; Tkatchouk, E.; Goddard, W. A., III; Guo, H.;
Kwon, O. Phosphine-Catalyzed Annulations of Azomethine Imines:
Allene-Dependent [3+2], [3+3], [4+3], and [3+2+3] Pathways. J. Am.
Chem. Soc. 2011, 133, 13337. (b) Zhang, L.; Liu, H.; Qiao, G.; Hou, Z.;
Liu, Y.; Xiao, Y.; Guo, H. Phosphine-Catalyzed Highly Enantioselective
[
3+2] Cycloadditions of Trimethylenemethane with Nitroalkenes. Org.
Lett. 2012, 14, 234. (c) Trost, B. M.; MacPherson, D. T. [4+3]
Cycloaddition of a Trimethylenemethane Fragment. An Approach to
Polyhydroazulenes. J. Am. Chem. Soc. 1987, 109, 3483. (d) Trost, B. M.;
Seoane, P. R. [6+3] Cycloaddition to Nine-Membered Ring Carbo-
cycles. J. Am. Chem. Soc. 1987, 109, 615.
[3+3] Cycloaddition of Morita-Baylis-Hillman Carbonates with C,N-
Cyclic Azomethine Imines. J. Am. Chem. Soc. 2015, 137, 4316. (c) Yang,
W.; Sun, W.; Zhang, C.; Wang, Q.; Guo, Z.; Mao, B.; Liao, J.; Guo, H.
Lewis-Base-Catalyzed Asymmetric [3+3] Annulation Reaction of
Morita−Baylis−Hillman Carbonates: Enantioselective Synthesis of
Spirocyclohexenes. ACS Catal. 2017, 7, 3142. (d) Zhou, L.; Yuan, C.;
Zeng, Y.; Liu, H.; Wang, C.; Gao, X.; Wang, Q.; Zhang, C.; Guo, H.
Phosphine-Catalyzed [5+1] Annulation of δ-Sulfonamido-Substituted
Enones with N-Sulfonylimines: A Facile Synthesis of Tetrahydropyr-
idines. Chem. Sci. 2018, 9, 1831. (e) Yuan, C.; Wu, Y.; Wang, D.; Zhang,
Z.; Wang, C.; Zhou, L.; Zhang, C.; Song, B.; Guo, H. Formal [5+3]
Cycloaddition of Zwitterionic Allylpalladium Intermediates with
Azomethine Imines for Construction of N,O-Containing Eight-
Membered Heterocycles. Adv. Synth. Catal. 2018, 360, 652. (f) Gao,
X.; Xia, M.; Yuan, C.; Zhou, L.; Sun, W.; Li, C.; Wu, B.; Zhu, D.; Zhang,
C.; Zheng, B.; Wang, D.; Guo, H. Enantioselective Synthesis of Chiral
Medium-Sized Cyclic Compounds via Tandem Cycloaddition/Cope
Rearrangement Strategy. ACS Catal. 2019, 9, 1645.
(
4) (a) Jones, M. D.; Kemmitt, R. D. W. J. Reactions between
Trimethylenemethane Metal Complexes and the Carbon-Nitrogen
Double Bond: Nickel and Palladium Catalysed Synthesis of
Pyrrolidines. J. Chem. Soc., Chem. Commun. 1986, 1201. (b) Trost, B.
M.; Matelich, M. C. A Selectivity Control Element for Palladium-
Catalyzed Trimethylenemethane Cycloaddition. J. Am. Chem. Soc.
1
991, 113, 9007. (c) Trost, B. M.; Bonk, P. J. Diastereoselective [3+2]-
Type Heterocyclic Synthesis via [2-(Acetoxymethyl)-3-Allyl]tri-n-
Butylstannane. J. Am. Chem. Soc. 1985, 107, 1778. (d) Trost, B. M.;
Silverman, S. M.; Stambuli, J. P. Palladium-Catalyzed Asymmetric
[
3+2] Cycloaddition of Trimethylenemethane with Imines. J. Am.
Chem. Soc. 2007, 129, 12398. (e) Trost, B. M.; Silverman, S. M.
Enantioselective Construction of Highly Substituted Pyrrolidines by
Palladium-Catalyzed Asymmetric [3+2] Cycloaddition of Trimethyle-
nemethane with Ketimines. J. Am. Chem. Soc. 2010, 132, 8238.
(
9) Crystallographic data for (E)-3ac, (Z)-3ac, and 4aa have been
(
f) Trost, B. M.; Bringley, D. A.; Silverman, S. M. Asymmetric Synthesis
deposited with the Cambridge Crystallographic Data Centre as
deposition numbers CCDC 1898872, 1898873, and 1898870,
respectively.
of Methylenetetrahydrofurans by Palladium-Catalyzed [3+2] Cyclo-
addition of Trimethylenemethane with Aldehydes − A Novel Ligand
Design. J. Am. Chem. Soc. 2011, 133, 7664. (g) Trost, B. M.; Silverman,
S. M. Enantioselective Construction of Pyrrolidines by Palladium-
Catalyzed Asymmetric [3+2] Cycloaddition of Trimethylenemethane
with Imines. J. Am. Chem. Soc. 2012, 134, 4941. (h) Trost, B. M.; Lam,
T. M.; Herbage, M. A. Regio- and Enantioselective Synthesis of
D
DOI: 10.1021/acs.orglett.9b01064
Org. Lett. XXXX, XXX, XXX−XXX