Silver/Rhodium Relay Catalysis Enables C?H Functionalization of In Situ Generated Isoquinolines with Sulfoxonium Ylides: Construction of Hexahydrodibenzo[a,g]quinolizine Scaffolds

Article abstract of DOI:10.1002/adsc.202100141

Employing silver/rhodium relay catalysis strategy, an intramolecular electrophilic cyclization and C?H activation followed by cascade hydrogenation and reductive amination has been developed. The acylmethylated isoquinoline derivatives could be afforded with broad substrate scope in 23–88% yields, which could be further transformed to the core skeleton of hexahydrodibenzo[a,g]quinolizine as drug-candidates. Moreover, this reaction was achieved in a gram-scale. A reasonable reaction mechanism has been proposed based on a series of control and KIE experiments. (Figure presented.).

Full text of DOI:10.1002/adsc.202100141

UPDATES
DOI: 10.1002/adsc.202100141
Silver/Rhodium Relay Catalysis Enables CÀ H Functionalization
of In Situ Generated Isoquinolines with Sulfoxonium Ylides:
Construction of Hexahydrodibenzo[a,g]quinolizine Scaffolds
Quanzhe Li,a Ruixing Liu,b Yin Wei,b,* and Min Shia, b,*
a
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Key Laboratory for Advanced Materials and Feringa
Nobel Prize Scientist Joint Research Center, School of Chemistry & Molecular Engineering, East China University of Science
and Technology, Meilong Road No.130, Shanghai, 200237 (People’s Republic of China)
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
b
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
Fax: (+86)-21-6416-6128
E-mail: weiyin@sioc.ac.cn; mshi@mail.sioc.ac.cn
Manuscript received: February 1, 2021; Revised manuscript received: March 6, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100141
complicated multistep operations. Thus, it is highly
desirable to develop a creative synthetic route that
enables facile preparation of a wide range of such
polyheterocyclic derivatives.
Abstract: Employing silver/rhodium relay catalysis
strategy, an intramolecular electrophilic cyclization
and CÀ H activation followed by cascade hydro-
genation and reductive amination has been devel-
Bimetallic relay catalysis involving two metal
oped. The acylmethylated isoquinoline derivatives
catalysts in one reaction system,[5–7] demonstrates
could be afforded with broad substrate scope in 23–
excellent chemo-, stereo- and regio-selectivities with-
88% yields, which could be further transformed to
out the isolation of unstable intermediates in a wide
the core skeleton of hexahydrodibenzo[a,g]
quinolizine as drug-candidates. Moreover, this re-
range of reactions, and displays unique potential in
bond functioalization reactions. Jeon and co-workers[8]
action was achieved in a gram-scale. A reasonable
reported an outstanding work involving a relay of Ir-
reaction mechanism has been proposed based on a
catalyzed hydrosilylation of phenyl acetates and Rh-
series of control and KIE experiments.
catalyzed CÀ H silylation with traceless acetal directing
groups in 2016 (Scheme 1, a). However, the difficulties
lie in the compatibility of two metals and it is still a
Keywords: bimetallic relay catalysis; hexahydrodi-
benzo [a,g]quinolizine; sulfoxonium ylide; Silver/
Rhodium,; CÀ H functionalization
challenging task at the present stage. As versatile
carbene precursors, sulfoxonium ylides[9] were widely
ulitized because of their high flexibility, stability and
The azapolycyclic motifs are privileged scaffolds
found in many natural products and pharmaceutically
active compounds.[1] Among these different types of
azapolycyclic
motifs,
hexahydrodibenzo[a,g]
quinolizine derivatives constituted core scaffolds,
could be a used as drug-candidates for the treatment of
neurological diseases (DC037029 or DC037081, Fig-
ure 1).[2] Moreover, tetrahydroprotoberberine alkaloids
such as STY containing azapolycyclic motif can
Figure 1. Representative examples of drug-candidates contain-
ing hexahydrodibenzo[a,g]quinolizine skeletons.
selectively bind with G-quadruplex DNA, which has diverse reactivity. In 2017, Aissa[10] and others[11]
been often studied as a target for anti-cancer drug reported the Cp*Rh(III)-catalyzed CÀ H functionaliza-
(Figure 1).[3] In recent decades, numerous methods tion of arenes with sulfoxonium ylides as carbene
have been developed to construct similar structural precursors and coupling partners (Scheme 1, b).
motifs,[4] however, those methods usually suffer from Although directing group-assisted CÀ H bond function-
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Table 1. Optimization of reaction conditions for the synthesis
of 4a.
Entry[a]
1
Catalyst Ag salt Solvent
Temp/ Yield/ Yield/
[b]
[b]
°
[ C]
%
3a
%
4a
Scheme 1. Bimetallic relay catalysis strategy and construction
of hexahydrodibenzo[a,g]quinolizine scaffolds with sulfoxo-
nium ylides.
1
2
3
4
5
6
7
1b cat.1
1b cat.2
1b cat.3
1b cat.4[e]
1b cat.1
1c cat.1
1d cat.1
1a cat.1
1a cat.1
1e cat.1
1f cat.1
1g cat.1
1h cat.1
1i cat.1
1a cat.1
AgSbF6 DCE
AgSbF6 DCE
AgSbF6 DCE
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
–
–
–
–
–
63
–
31
–
–
34
–
–
–
36
–
–
DCE
AgSbF6 TFE
AgSbF6 TFE
AgSbF6 TFE
AgSbF6 TFE
AgSbF6 TFE
AgSbF6 TFE
AgSbF6 TFE
AgSbF6 TFE
AgSbF6 TFE
AgSbF6 TFE
AgSbF6 TFE:
DCE
alization strategies can achieve the desired transforma-
tion with high reactivity and selectivity, the limitations
of directing group strategy are that directing groups are
often difficult to install and manipulate after processes
are completed.[12] Inspired by the applications of
sulfoxonium ylides in CÀ H activation and bimatellic
relay catalysis, we hypothesized to design CÀ H bond
functionalization reactions involving sulfoxonium
ylides with bimetallic relay catalysis strategy. Herein,
we wish to report an intramolecular electrophilic
cyclization and CÀ H activation using bimetallic relay
catalysis strategy followed by cascade hydrogenation
(Scheme 1, this work). Interestingly, this protocol led
to an efficient method to access hexahydrodibenzo[a,g]
quinolizine derivatives, which are an integral part of
drug-candidate for the treatment of neurological dis-
eases.
–
8[c]
9[d]
10[d]
11[d]
12[d]
13[d]
14[d]
15[d]
38
61
63
59
55
61
63
65
(65)[f]
–
–
–
–
–
(1:1)
16[d]
17[d]
1a cat.1
1a cat.1
AgSbF6 TFE:DCE 70
–
–
55
40
(1:1)
AgSbF6 TFE:DCE 100
(1:1)
[a] Reaction conditions: 1 (0.2 mmol), 2 a (1.5 equiv.),
[RhCp*Cl2]2 (5.0 mol%), silver salt (50.0 mol%) and silver
salt (1.0 equiv.) were added in solvent (2.0 mL), under an Ar
atmosphere for 36 h, in a sealed tube.
We initiated our studies by exploring the coupling
of O-alkyl benzaldoxime derivative (R=H) 1b with
ylide 2a for this cyclization and acylmethylation. In
the presence of [RhCp*Cl2]2 (5.0 mol%), AgSbF6
[b] NMR yield using 1,3,5-trimethoxybenzene as an internal
standard.
°
(50.0 mol%) and PivOH (1.0 equiv.) in DCE at 80 C,
[c] One step, one-pot method.
the alkylated product 4a was achieved in 34% yield
(Table 1, entry 1). Catalyst screening revealed that
[RhCp*Cl2]2 was the most effective one and the only
use of [RhCp*(MeCN)3][SbF6]2 as catalyst did not
give the desired product, suggesting the silver salt is
essential for this transformation (Table 1, entries 2–4).
Using TFE (2,2,2-trifluoroethanol) as solvent increased
the yield of 4a to 36% (Table 1, entry 5). Several
substrates 1 having different protecting groups R
(methyl group 1c, pivaloyl group 1d and benzyl group
1a) were tested with 2a under [RhCp*Cl2]2, AgSbF6
°
[d] Reaction conditions: 1 (0.2 mmol), silver salt (5.0 mol%) in
solvent (1.0 mL) under an Ar atmosphere for 6 h, and then
followed by 2a (1.5 equiv.), [RhCp*Cl2]2 (5.0 mol%), silver
salt (45.0 mol%), additive (1.0 equiv.) and solvent (1.0 mL)
for another 30 h, in a sealed tube.
[e] Purified by a column chromatography on silica gel (DCM/
MeOH=100/1) to remove trace amount of silver salt (see
Supporting Information).
[f] Isolated yield.
and PivOH in TFE at 80 C. We noticed that employing (Table 1, entry 7). To further improve the yield, 1a
substrate 1c only afforded 3a[13] in 63% yield (Table 1, was added with AgSbF6 (5.0 mol%) in TFE at 80 C
°
entry 6); when substrate 1a was used, the reaction was for 6 hours followed by 2a, [RhCp*Cl2]2 (5.0 mol%),
conducted by one step, one-pot method, affording 3a AgSbF6 (45.0 mol%) and PivOH (1.0 equiv.). Fortu-
in 31% yield and 4a in 38% yield (Table 1, entry 8). nately, the desired product 4a was obtained in 61%
The reaction went complex using 1d as substrate yield (Table 1, entry 9). The electronic property of the
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Table 3. Substrate scope of 1.[a,b]
protecting group R in substrates 1e–1i did not affect
the product yield significantly (Table 1, entries 10–14).
Considering that it is a two-step process, the mixed
solvent was also tested; the combination of TFE:DCE
afforded a better result, providing 4a in 65% yield
(Table 1, entry 15) with the 73% yield of benzaldehyde
detected (for details see the Supporting Information at
page S15). The examination of reaction temperature
°
revealed that the reaction carried out at 80 C gave the
best result (Table 1, entries 16–17).
Under the optimized reaction conditions, we first
investigated the scope of various decorated sulfoxo-
nium ylides 2 (Table 2). The substrates 2 having either
electron-withdrawing or -donating groups present on
the benzene ring were all compatible in this reaction,
providing the desired products (4a–n) in 54–81%
yields, indicating that the electronic property of R1 and
steric hindrance of the phenyl rings did not have a
significant impact on the product yield. Notably, the
sulfoxonium ylides were not limited to those having
aryl substituents; alkyl and heteroaryl sulfoxonium
ylides were also suitable for this reaction, affording the
desired products (4o–4t) in 51–88% yields. For the
naphthalene-containing substrate 2u afforded 4u with
a slightly decreased yield in 50%. In the case of
substrate 2v, in which 1,3-benzodioxole is contained,
the corresponding product 4v was also produced in
65% yield.
Under the optimal conditions, a wide range of
substrates 1 successfully underwent these reactions,
providing the desired products in good yields (Table 3).
[a] Reaction conditions: 1 (0.2 mmol), silver salt (5.0 mol%) in
solvent (1.0 mL) under an Ar atmosphere for 6 h, and then
followed by 2a (1.5 equiv.), [RhCp*Cl2]2 (5.0 mol%), silver
salt (45.0 mol%), additive (1.0 equiv.) and solvent (1.0 mL)
for another 30 h, in a sealed tube.
Table 2. Reaction scope of sulfoxonium ylides 2.[a,b]
[b] Isolated yield.
[c] 2 (0.36 mmol) was used.
Substrate 1 with electron-donating and -withdrawing
substituents (including methyl, halides and methoxy
substituents) at the 4-position and 5-position of the
benzene ring all reacted with excellent efficiencies,
affording products 4w–4aa in 50–73% yields. The X-
ray diffraction pattern of 4aa, whose structure had
been unambiguously determined, is shown in Support-
ing Information. Replacing the benzene ring by
naphthalene ring, the reaction was less facile, and the
product 4ab was isolated in 23% yield. For substrate
1ac containing 1,3-benzodioxole, 4ac and 4ad were
obtained in 74% and 51% yields, respectively, when
benzoyl sulfoxonium ylide and methyl sulfoxonium
ylide were used. Sterically hindered substrate 1ae
could also undergo this process, delivering the corre-
sponding product 4ae in 52% yield under a slightly
modified reaction condition. The electronic properties
and steric hindrance performances were also tested on
[a] Reaction conditions: 1a (0.2 mmol), silver salt (5.0 mol%) in
solvent (1.0 mL) under an Ar atmosphere for 6 h, and then
followed by 2 (1.5 equiv.), [RhCp*Cl2]2 (5.0 mol%), silver
salt (45.0 mol%), additive (1.0 equiv.) and solvent (1.0 mL)
for another 30 h, in a sealed tube.
[b] Isolated yield.
[c] 2 (0.4 mmol) was used.
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R2 position in substrate 1. Substrate 1 bearing electron- (1.0 atm)[14] at room temperature for 48 hours. The
withdrawing and -donating substituents, such as, meth- product 6z could also be afforded in 43% under the
yl, tert-butyl, halide, and ester at the 4-, 5-, and 6- standard condition. As for the substrates with electron-
positions of the benzene ring turned out to be rich 1,3-benzodioxole 4ac, 4ad and 4ao, higher
applicable under optimal reaction conditions, produc- pressure of hydrogen (20.0 atm) was needed with
ing the desired annulated products 4af–4ak in yields AcOH replaced by TFA, affording 6ac, 6ad and 6ao
of 45%–74%. For substrate 1aj, CÀ H bond activation in 32%, 31% and 31% yields, respectively. The X-ray
occurred on the less bulky site to obtain 4aj in 45% data of 6ac are indicated in the Supporting Informa-
yield. For the substrate 1al containing naphthalene tion.
moiety, the desired product 4al was accessed with an
The scale-up experiments of 4a and 6a were also
increased yield in 78%. Fortunately, using (E)-1am as carried out as shown in Scheme 2. For a 4.0 mmol
substrate, the desired product 4am could also be scale reaction, the product 4a (0.814 g) could be
obtained in 53% while (Z)-1am could not undergo this achieved in 63% yield by prolonging the reaction time
reaction.[13] Employing substrate 1an containing indole to 48 hours. The systhesis of hexahydrodibenzo[a,g]
moiety, the corresponding products 4an and 5an could quinolizine 6a was also successful without decreasing
be obtained using 1.2 and 2.0 equiv. of the sulfoxo- product yield when 2.0 mmol of 4a was employed.
nium ylide in 66% and 45% yields, respectively. It is
As shown in Scheme 3, the deuterium labeled
worth noting that substrate 1ao having 1,3-benzodiox- kinetic experiment and several control experiments
ole moiety underwent the reaction to afford single were conducted to gain some insights into the reaction
regioselective product 4ao in 52%; the high regiose- mechanism. The kinetic isotope effect of this reaction
lectivity probably roots in the electronic property of was measured on the basis of parallel experiments, and
1,3-benzodioxole moiety. For substrate 1ap containing a kH/kD value of 5.7 was obtained (Scheme 3, a), which
1,3-benzodioxole and methyl groups, the correspond- suggests that the CÀ H activation might be involved in
ing products 4ap and 4aq were obtained in 34% and the turnover-limiting process. Upon treatment of 3a
44% yields, respectively, when benzoyl sulfoxonium
ylide and methyl sulfoxonium ylide were used.
Unfortunately, we failed to get the desired product 4ar
after several attempts under different reaction con-
ditions.
To further demonstrate the synthetic utility of this
method, the obtained product 4 was used as substrate
for the synthesis of hexahydrodibenzo[a,g]quinolizine
compound. As summarized in Table 4, the desired
product 6a was isolated in 65% yield in the presence
of PtO2 and AcOH under hydrogen atmosphere
Scheme 2. Large-scale synthesis of 4a and 6a.
Table 4. The synthesis of hexahydrodibenzo[a,g]quinolizine
6.[a,b]
[a] Reaction conditions: 4 (0.2 mmol), acid (0.6 mmol), PtO2
(5.0 mol%) in MeOH (2.0 mL) under H2 (1.0 atm–20.0 atm)
for 48 h.
[b] Isolated yield.
Scheme 3. Control experiments.
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with 2a in the presence of treated [RhCp*- tolerant in this reaction, affording acylmethylated
(MeCN)3][SbF6]2 (silver content was measured by isoquinoline derivatives in 23–88% yields. The prod-
ICP-OES,[15] see Supporting Information at page S8) ucts could be further transformed to interesting
°
and PivOH in TFE:DCE (1:1) at 80 C, the product 4a compounds applied in the synthesis of potential drug-
could be accessed in 81% yield, indicating that candidate molecule for the treatment of neurological
Cp*RhX2 complex[16] is the active catalyst (Scheme 3, diseases. More importantly, this work discovered new
b). Treatment of 1a with AgSbF6 in TFE:DCE (1:1) reaction model about the synthesis of azapolycyclic
for 3 hours produced 3a in 85% yield; heating compound, which will help organic chemists to design
compound 1a without AgSbF6 for 12 hours afforded new reaction model in the synthesis of alkaloids.
3a only in 18% yield after 12 h. These results
suggested that Ag(I) played an important role in the
formation of cyliczed isoquinoline product 3a and the
Experimental Section
active Cp*RhX2 complex (Scheme 3, c).
General Procedure for Synthesis of 4a
On the basis of the results of above control
experiments and previous work,[10,13] a mechanism for
Ag/Rh relay catalysis reaction is suggested as shown
in Scheme 4. Coordination of Ag(I) with the alkyne
moiety of 1a generates an intermediate A, which
initiates an intramolecular electrophilic cyclization,
To a stirred solution of 1a (0.2 mmol) was added AgSbF6
(5.0 mol%) in TFE:DCE=1:1 (1.0 mL) under argon atmos-
°
phere. The resulted mixture was stirred at 80 C for 6 h. Then,
sulfoxonium ylide 2a (0.3 mmol), AgSbF6 (45.0 mol%),
[RhCp*Cl2]2 (5.0 mol%), PivOH (0.2 mmol) and TFE:DCE=
1:1 (1.0 mL) were added for another 30 h. After the filtration
producing a cyclized intermediate B. Subsequent and the removal of solvent under reduced pressure, the residue
bimolecular E2-type elimination[13] and protonation
afford isoquinoline derivative 3a containing new
directing group with the release of benzaldehyde,
was purified by a column chromatography on silica gel
(petroleum ether/ethyl acetate=10/1) to afford the correspond-
ing compounds 4a in 65% yield.
which can be detected in the experiment (see Support-
ing Information at page S5 and S15 for the details).
The pre-catalyst [RhCp*Cl2]2, AgSbF6 and/or PivOH
would generate active Cp*RhX2 complex via ligand
exchange which coordinates to the in situ generated 3a
to afford a five-membered rhodacyclic intermediate C.
Then, sulfoxonium ylide 2a attacks the metal center of
intermediate C to deliver intermediate D, which under-
goes α-elimination of DMSO to afford the carbenoid
species E. The migratory insertion of complex E leads
to an intermediate F. Finally, the protonolysis of F
delivers the final product 4a and regenerates the
Rh(III) catalyst.
In conclusion, we have developed a synthesis of the
core skeleton of hexahydrodibenzo[a,g]quinolizine
General Procedure for Synthesis of 6a
To a solution of 4a (0.2 mmol) in 2.0 mL of freshly distilled
anhydrous MeOH was added PtO2 (0.1 equiv.) and AcOH
(3.0 equiv.) at room temperature under H2 (1.0 atm) atmosphere
for 48 hours. After the reaction completion monitored by TLC
analysis, the residue was purified by a silica gel flash
chromatography on silica gel (eluent: petroleum ether/EtOAc=
50/1) to afford compound 6a in 65% yield.
Supporting Information Available
Detailed descriptions of experimental procedures and their
spectroscopic data as well as the crystal structures are presented
in the Supporting Information. CCDC 2006002 (4aa) and
through intramolecular electrophilic cyclization and CCDC 2031004 (6ac) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif.
CÀ H activation followed by cascade hydrogenation
and reductive amination using silver/rhodium relay
catalysis strategy. A wide range of substrates could be
Acknowledgements
We are grateful for the financial support from the Strategic
Priority Research Program of the Chinese Academy of Sciences
(Grant No. XDB20000000), the National Natural Science
Foundation of China (21372250, 21121062, 21302203,
20732008, 21772037, 21772226, 21861132014 and 91956115).
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Adv. Synth. Catal. 2021, 363, 1–7
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UPDATES
Silver/Rhodium Relay Catalysis Enables CÀ H Functionaliza-
tion of In Situ Generated Isoquinolines with Sulfoxonium
Ylides: Construction of Hexahydrodibenzo[a,g]quinolizine
Scaffolds
Adv. Synth. Catal. 2021, 363, 1–7
Q. Li, Dr. R. Liu, Dr. Y. Wei*, Prof. Dr. M. Shi*