Direct Synthesis of Protoberberine Alkaloids by Rh-Catalyzed C-H Bond Activation as the Key Step

Article abstract of DOI:10.1002/chem.201504378

A one-pot reaction of substituted benzaldehydes with alkyne-amines by a Rh-catalyzed C-H activation and annulation to afford various natural and unnatural protoberberine alkaloids is reported. This reaction provides a convenient route for the generation o

Full text of DOI:10.1002/chem.201504378

DOI: 10.1002/chem.201504378
Full Paper
&
Nitrogen Heterocycles
Direct Synthesis of Protoberberine Alkaloids by Rh-Catalyzed
CÀH Bond Activation as the Key Step
[
a]
Jayachandran Jayakumar and Chien-Hong Cheng*
Abstract: A one-pot reaction of substituted benzaldehydes
with alkyne–amines by a Rh-catalyzed CÀH activation and
annulation to afford various natural and unnatural protober-
berine alkaloids is reported. This reaction provides a conven-
ient route for the generation of a compound library of pro-
toberberine salts, which recently have attracted great atten-
tion because of their diverse biological activities. In addition,
pyridinium salt derivatives can also be formed in good yields
from a,b-unsaturated aldehydes and amino–alkynes. This re-
action proceeds with excellent regioselectivity and good
functional group compatibility under mild reaction condi-
tions by using O as the oxidant.
2
Introduction
Protoberberine derivatives, including palmatines and berber-
[
1]
ines, are found in many natural products and have attracted
great attention, because of their diverse biological activities,
such as antimalarial, anti-arrhythmic, antitumor, inhibitory, anti-
leukemia, antibacterial, anti-inflammatory, and cytotoxicity (see
[
2,3]
Figure 1).
Although a few approaches are available for the
Scheme 1. Methods for the synthesis of isoquinoline derivatives.
The transition-metal-catalyzed CÀH activation reactions offer
great opportunities for the synthesis of complex molecules
[
4]
from halide-free starting materials. In recent years, the inter-
III
II
molecular Rh or Ru -catalyzed CÀH activation and cyclization
with alkynes represent a powerful tool for the synthesis of
[
5–7]
highly functionalized heterocycles.
However, in most cases,
Figure 1. Typical protoberberine natural products.
the reactions with unsymmetrical alkynes show low regioselec-
tivity. Consequently, intramolecular reactions are highly attrac-
tive in terms of regioselectivity, high efficiency, and versatility
for fused heterocyclic compounds. A highly enantioselective in-
synthesis of protoberberines, most of the approaches are limit-
ed by the scope and lengthy synthetic sequences
[
3]
III
(
Scheme 1a). As a result, most of the protoberberines used
tramolecular hydroarylation of alkene tethers by Rh -catalyzed
[
8]
for biological studies are still obtained from the extract of the
related plants.
ortho-directed CÀH bond activations is known. However, only
two intramolecular reactions for alkyne tethers have been re-
III
ported recently. Park and co-workers revealed a Rh -catalyzed
intramolecular annulation of alkyne-tethered hydroxamic
esters to afford 3-hydroxyalkylisoquinolones and 6-hydroxyalk-
[
a] Dr. J. Jayakumar, Prof. Dr. C.-H. Cheng
Department of Chemistry
National Tsing Hua University
Hsinchu 30013 (Taiwan)
Fax: (+886)35724698
E-mail: chcheng@mx.nthu.edu.tw
Homepage: http://mx.nthu.edu.tw/%7Echcheng
[
9]
yl-2-pyridones, while MascareÇas, Gulías and co-workers re-
ported a Rh-catalyzed synthesis of tricyclic isoquinolines by the
[10]
intramolecular annulations of alkyne-tethered benzamides.
.
Our continuous interest in the metal-catalyzed CÀH bond ac-
tivation/cyclization reactions and our experience in isoquino-
[
11]
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504378.
[
12]
linium salt synthesis stimulated us to develop a highly effi-
Chem. Eur. J. 2016, 22, 1800 – 1804
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cient methodology for the synthesis of various protoberberine
salts, including five 13-substituted protoberberine alkaloids
in 86% yield (entry 12). Highly substituted 3,4,5-trimethoxy-
benzaldehyde (1m) underwent cyclization with 2a efficiently
to afford 3m in 95% yield (entry 13). However, the reaction of
(
Scheme 1b), by a Rh-catalyzed CÀH bond activation reaction
as the key step. The catalytic reaction features the in
situ formation of an imine moiety, as the directing
group, for the CÀH bond activation and intramolecu-
lar annulation, thus providing a convenient route for
the generation of a compound library of protoberber-
ine salts and natural products for screening their bio-
[a]
Table 1. Results of the reaction of benzaldehydes with alkyne–amines.
III
logical activities. Recently, a few examples of Rh -cat-
alyzed synthesis of isoquinolinium and cinnolinium
[13]
salts have been reported. Our present strategy in-
volves a one-pot synthesis of protoberberine salts by
[b]
Product
Yield [%]
III
the Rh -catalyzed CÀH activation and annulations of
1
2
3
4
5
6
7
8
9
1
1a 2a
1b 2a
1c 2a
1d 2a
1e 2a
1 f 2a
1g 2a
1h 2a
1i 2a
1j 2a
3a: R=4-H
94
85
82
94
86
80
82
78
85
90
84
3b: R=4-tBu
3c: R=4-N(CH
3d: R=4-OMe
3e: R=4-F
3 f: R=4-Cl
3g: R=4-Br
substituted benzaldehydes with 1-(2-aminoethyl)-2-al-
kynylarenes (Scheme 1b).
3 2
)
Results and Discussion
3h: R=4-CF
3
We started the optimization studies for the one-pot
reaction of benzaldehyde (1a) with alkyne–amine 2a
to give protoberberine salt 3a using various rhodiu-
m(III) and ruthenium(II) complexes as the catalysts.
After careful investigation of the reaction conditions,
we found that treating benzaldehyde (1a;
3i: R=4-CO
3j: R=4-NO
3k: R=4-Ph
2
Me
0
2
11 1k 2a
1
2
3
1l 2a
3l
86
0
.36 mmol) with alkyne–amine (2a; 0.30 mmol) in the
presence of [RhCp*(CH CN) ][SbF ] (2.5 mol%) and
3
3
6 2
Cu(BF ) ·6H O (60.0 mol%) in MeOH at 608C under O
2
4
2
2
(
1 atm) for 6 h afforded protoberberine salt 3a in
4% isolated yield (see Table S1 in the Supporting In-
9
formation for details). It is worth noting that dioxy-
gen, an inexpensive oxidant, can be used even
though the catalytic reaction required some copper
source. The structure of 3a containing an isoquinoli-
nium cation and tetrafluoroborate anion was con-
1
1m 2a
3m
95
3n: R=3-OMe
3n’: R=5-OMe
1
13
19
11
firmed by its H, C, F, and B NMR, and mass data.
Substrate 2 was prepared from commercially avail-
able 2-aminoethylarene in four steps in 80–88 yields
14 1n 2a
86 (1:1)
[14]
(
see the Supporting Information). The above condi-
tions were then employed as the standard conditions
for the reactions of various substituted benzalde-
hydes with amino–alkynes to form the corresponding
protoberberine salts 3.
To understand the substrate scope of this catalytic
reaction, we investigated the reactions of p-substitut-
ed benzaldehydes 1b–k with alkyne–amine 2a under
the standard reaction conditions (Table 1). The reac-
tions of electron-donating 4-tert-butyl-, 4-N,N’-di-
methyl-, and 4-methoxy-substituted benzaldehydes
1
5
1o 2a
3o
3p
3q
90
16 1p 2c
85
(
1b–d) with 2a smoothly afforded 3b–d in 82–94%
yields (entries 2–4). Similarly, the reactions of elec-
tron-withdrawing 4-fluoro-, 4-chloro-, 4-bromo-, 4-tri-
fluoromethyl, 4-methylester, and 4-nitro-substituted
benzaldehydes (1e–j) with 2a smoothly afforded 3e–
j in 78–90% yields (entries 5–10). The reaction of 4-
phenylbenzaldehyde (1k) afforded 3k in 84% yield
17
1q 2a
82
(
entry 11) and 2,4-dimethylbenzaldehyde (1l) gave 3l
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are summarized in Table 2. Treatment of methacrylal-
Table 1. (Continued)
dehyde (4a) with 2a in the presence of
[
(
RhCp*(CH CN) ][SbF ] (2.5 mol%) and Cu(BF ) ·6H O
3 3 6 2 4 2 2
60.0 mol%) in MeOH at 608C under O (1 atm) for
2
6
h afforded pyridinium salt 5a in 88% yield. Under
similar reaction conditions, 4a reacted with 2b and
c having a tert-butyl and n-octyl groups, respective-
2
[b]
Product
Yield [%]
ly, attached to the alkyne carbon to give the corre-
sponding pyridinium salts 5b (82%) and 5c (70%).
The reaction of cinnamaldehyde 4b with 2a afforded
3
1
1
2
2
2
2
2
8
9
0
1
2
3
4
2b
2c
1a 2d
2e
2 f
1a 2g
1a 2h
3r: R =3-thiophene
82
88
84
80
78
3
3s: R =Me
3
3t: R =tBu
5
d in 84% yield. It is interesting to note that even a-
3
3u: R =n-Pr
3
methylcinnamaldehyde 4c reacted smoothly with 2a
to give the expected highly substituted pyridinium
salt 5e in 82% yield.
3v: R =cyclopropyl
3
3w: R =cyclohex-1-enyl 81
3
3x: R =n-octyl
76
Based on the known metal-catalyzed directing
group-assisted CÀH bond activation/annulation reac-
[
4–10]
1
2
tions,
a plausible reaction mechanism is proposed
2
2
5
6
1a 2i
2
3y R ,R =O-CH -O
85
for this catalytic reaction (Scheme 2). The catalytic
cycle is probably initiated by the coordination of the
imine nitrogen, which is generated in situ from 1a
III
and 2a, to Rh , followed by the ortho CÀH bond acti-
vation to form the five-membered rhodacycle I. Next,
the coordination of the alkynyl group in I to the Rh
center affords intermediate II. Further insertion of the
alkynyl group into the RhÀC bond affords the bicyclic
seven-membered rhodacycle III. The reductive elimi-
1
2
1a 2j
3z R R =H
88
[
(
a] All reactions were carried out using aryl aldehyde 1 (0.36 mmol), alkyne–amine 2
0.30 mmol), [RhCp*(CH CN) ][SbF (2.5 mol%), Cu(BF ·6H O (60 mol%), O (1 atm),
3
3
6
]
2
4
)
2
2
2
I
and MeOH (2.5 mL) at 608C for 6 h. [b] Isolated yields.
nation of III then affords the final salt 3a and Rh.
II
The Rh species is reoxidized by Cu or O to regener-
2
III
ate the active Rh species for the next catalytic cycle.
m-substituted 3-methoxy benzaldehyde (1n) with 2a provided
two regioisomeric products 3n and 3n’ in a 1:1 ratio in 86%
combined yield (entry 14). meta- and para-Disubstituted ben-
zaldehydes were also viable substrates; thus, the reactions of
The significance of this Rh-catalyzed CÀH activation and an-
nulation reaction was further demonstrated by its application
to the direct synthesis of 13-substituted protoberberine salts.
The synthesis of these natural products using this methodolo-
gy is shown in Scheme 3. The reaction of aldehydes 1r
(0.36 mmol) and 1s (0.36 mmol) with alkyne–amine 2c
(0.30 mmol) in the presence of [RhCp*(CH CN) ][SbF ]
9
-ethyl-9H-carbazole-3-carbaldehyde (1o) and 3,4-dimethoxy-
benzaldehyde (1p) with 2a afforded 3o and 3p in 90 and
5% yields, respectively, with high regioselectivities (entries 15
8
3
3
6 2
and 16). Surprisingly, the reaction of 3,4-methylenedioxyben-
zaldehyde (1q) with 2a proceeded with opposite regioselectiv-
ity to afford 3q in 82% yield (entry 17). It is worth noting that
two possible CÀH bond activation sites are present at the C2
and C6 of 1q; the activation occurred at the sterically hindered
C6 position. The structure of 3q was further confirmed by
(2.5 mol%) and Cu(BF ) ·6H O (60 mol%) in MeOH under O
4 2 2 2
Table 2. Results of rhodium-catalyzed CÀH activation and annulation of
a,b-unsaturated aldehydes and alkyne–amines.
[a,b]
[15]
single-crystal X-ray diffraction.
In addition to 2a, other alkyne–amines (2b–h) were also in-
vestigated. The reaction of 3-thiophene alkyne–amine 2b with
1
a afforded the salt product 3r in 82% yield (entry 18). Simi-
larly, the reactions of methyl-, tert-butyl-, n-propyl-, cycloprop-
yl-, octylalkynyl , and cyclohex-1-enyl amines 2c–h afforded
the corresponding protoberberine salts 3s–x in 76–88% yields
(
entries 19–24). The reaction of benzaldehyde (1a) with
alkyne–amine 2i having a methyl group attached to the alkyn-
yl group and a methylenedioxy moiety connected to the aryl
ring afforded 3y in 85% yield (entry 25). Interestingly, 2-(2-phe-
nylethynyl)phenylethanamine 2j also reacted smoothly with
[
a] Unless otherwise mentioned, all reactions were carried out using a,b-
unsaturated aldehyde (0.36 mmol), alkyne–amine (0.30 mmol),
RhCp*(CH CN) ][SbF (2.5 mol%), Cu(BF ·6H O (60 mol%), O (1 atm),
and MeOH (2.5 mL) at 608C for 6 h. [b] Isolated yields.
1
a to afford 3z in 88% yield (entry 26).
4
2
[
3
3
6
]
2
4
)
2
2
2
The present rhodium-catalyzed CÀH activation reaction also
can be applied to a,b-unsaturated aldehydes and the results
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Scheme 4. Gram-scale reaction. Conditions: benzaldehyde 1a (3.60 mmol),
3 3 6 2
alkyne–amine 2a (3.00 mmol), [RhCp*(CH CN) ][SbF ] (2.5 mol%),
Cu(BF ·6H O (60 mol%), O (1 atm), and MeOH (25 mL) at 608C for 6 h.
4
)
2
2
2
Scheme 2. Proposed mechanism for the formation of protoberberine salt de-
rivatives.
Further, we also investigated the scalability of this CÀH acti-
vation/annulation reaction (Scheme 4). Thus, benzaldehyde
(
1a) was treated with 2a in the presence of [RhCp*(CH CN) ]
3 3
À
(
1 atm) at 608C for 6 h afforded the BF4 salts of 13-methylpa-
[SbF6]2 (2.5 mol%) and Cu(BF ) ·6H O (60 mol%) in MeOH
4 2 2
matine 6 and dehydrocavidine 7 in 94% and 92% isolated
yields, respectively. Similarly, the reactions of 1r and 1s with
under O (1 atm) at 608C for 6 h to afford protoberberinium
salt 3a in 85% isolated yield.
2
2
9
i smoothly afforded 13-methylberberrubine 8 and corysamine
, respectively, in excellent yields. Furthermore, the reaction of
An important synthetic application of the protoberberine
salt is its transformation into 8-oxyprotoberberine. An example
is demonstrated in Scheme 5. The protoberberine salt 3a
(0.30 mmol) was treated with K [Fe(CN) ] (1.80 mmol) and
3
,4-dimethoxybenzaldehyde (1o) with 2c gave 10 in 86%
yield with high regioselectivity. To the best of our knowledge,
this is the first step-economic and high-yielding method for
the formation of protoberberine salts by the Rh-catalyzed CÀH
activation and annulation using aldehydes and alkyne–amines
in a one-pot reaction. It is worth noting that 13-methylpama-
tine 8 has been previously synthesized in five steps with an
overall yield of 12% from 3,4-dimethoxyisoquinoline and dime-
3
6
CsOH (1.20 mmol) in a mixture of H O and MeOH (1:1) at 808C
2
for 10 h to afford 8-oxyprotoberberine 11 in 85% isolated
[
17]
yield.
[3a,c]
thoxybenzyl chloride.
Very recently Donohoe and co-work-
ers reported a synthesis of protoberberine alkaloids by a Pd-
catalyzed sequential enolate arylation of aryl bromides with ke-
tones followed by aromatization and cyclization in overall 47%
[
16]
Scheme 5. Synthesis of 8-oxyprotoberberine 11. Reaction conditions: salt 3a
yield. The total synthesis of other protoberberine alkaloids,
which have been isolated in low yields from plants, were not
3 6 2
(0.30 mmol), K [Fe(CN) ] (1.80 mmol), and CsOH (1.20 mmol) in H O:MeOH
(1:1; 5 mL) at 808C for 10 h.
[
3b]
reported. To the best of our knowledge, we appear to be
the first one for the total synthesis of natural products 6,7, 9,
and 10.
Conclusion
In conclusion, we have developed a novel method for the syn-
thesis of substituted protoberberine salts in high yields by
III
a Rh -catalyzed intramolecular CÀH bond activation/annulation
of aldehydes and alkyne–amines in one-pot reactions. In addi-
tion, pyridinium salts were also formed in good yields from
a,b-unsaturated aldehydes and alkyne–amines. The protocol
was successfully applied to the synthesis of natural products,
such as 13-methylpalmatine (6), dehydrocavidine (7), 13-meth-
ylberberrubine (8), corysamine (9), and pseudohydrocorydaline
(
10), with 65–75% overall yields under mild reaction conditions
by using O as the oxidant. To the best of our knowledge, this
2
is the first step-economic synthesis of highly substituted proto-
berberine alkaloids.
Experimental Section
General procedure for the synthesis of substituted protober-
berine salts (3)
Scheme 3. One-pot synthesis of protoberberine natural products. Reaction
conditions: [a] aryl aldehyde 1 (0.36 mmol), alkyne–amine 2 (0.30 mmol),
[
RhCp*(CH
MeOH (2.5 mL) at 608C for 6 h. [b] NaI (2.0 equiv) and MeOH (3.0 mL) at
08C for 0.5 h. For the crystal structure of compound 7, see the Supporting
3 3 6 2 4 2 2 2
CN) ][SbF ] (2.5 mol%), Cu(BF ) ·6H O (60 mol%), O (1 atm), and
A sealed tube containing [RhCp*(CH CN) ][SbF ] (2.5 mol%) and
3
3
6 2
3
Cu(BF ) ·6H O (60 mol%) was degassed and purged with oxygen
4 2 2
Information.
gas. Then, a mixture of aryl aldehyde 1 (0.36 mmol) and alkyne–
Chem. Eur. J. 2016, 22, 1800 – 1804
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amine 2 (0.30 mmol) in MeOH (2.5 mL) was added to the system
by syringe. The reaction mixture was stirred under an oxygen at-
mosphere (1 atm) at 608C for 6 h, and was then cooled to room
temperature and diluted with CH Cl (10 mL). The mixture was fil-
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Acknowledgements
We thank the Ministry of Science and Technology of the Re-
public of China (MOST 103-2633M-007-001) for supporting this
research.
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Keywords: aldehydes · alkaloids · CÀH activation · copper ·
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Received: October 31, 2015
Published online on December 22, 2015
Chem. Eur. J. 2016, 22, 1800 – 1804
www.chemeurj.org
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