Stereoselective synthesis of all-cis boryl tetrahydroquinolines via copper-catalyzed regioselective addition/cyclization of o-aldiminyl cinnamate with B2Pin2

Article abstract of DOI:10.1039/c8ob03195a

A copper catalyzed intramolecular 1,2-carboboration of o-aldiminyl cinnamate has been realized in both regio- and stereoselective fashions. This reaction provides a convenient entry to highly valuable and otherwise challenging cis-2,3,4-trisubstituted tetrahydroquinolines carrying a 4-boryl group. An unusual non-Michael addition intermediate or alternatively, a cyclic enolate is proposed to account for the intriguing all-cis configuration in the final products.

Full text of DOI:10.1039/c8ob03195a

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Stereoselective synthesis of all-cis boryl
tetrahydroquinolines via copper-catalyzed
regioselective addition/cyclization of o-aldiminyl
cinnamate with B2Pin2†
Cite this: DOI: 10.1039/c8ob03195a
Ya-Ping Bi, He-Min Wang, Hong-Yu Qu, Xian-Chen Liang, Ying Zhou, Xue-Ying Li,
Defeng Xu, Mei-Hua Shen * and Hua-Dong Xu
*
A copper catalyzed intramolecular 1,2-carboboration of o-aldiminyl cinnamate has been realized in both
regio- and stereoselective fashions. This reaction provides a convenient entry to highly valuable and
otherwise challenging cis-2,3,4-trisubstituted tetrahydroquinolines carrying a 4-boryl group. An unusual
non-Michael addition intermediate or alternatively, a cyclic enolate is proposed to account for the intri-
guing all-cis configuration in the final products.
Received 24th December 2018,
Accepted 21st January 2019
DOI: 10.1039/c8ob03195a
rsc.li/obc
Introduction
There are numerous natural and synthetic tetrahydroquino-
lines (THQs) that exhibit appealing biological activities and
therapeutic values (Fig. 1).1 Therefore the construction of the
characteristic THQ framework continues to be a significant
objective for organic and medicinal chemists despite of the
availability of various methods in the literature.2 Particularly,
methodologies for novel THQ scaffolds bearing new functional
groups would be highly appreciated. In this context, the incor-
poration of a boryl group within these alkaloids would be of
immense value, because boryl groups are not only facile
handles for diverse transformations,3 but also highly valuable
Scheme 1 Copper-catalyzed borylative addition/cyclization cascade of
o-benzaldiminyl styrene for indolinyl and THQ boronic esters.
Table 1 Establishment of conditions for the borylative addition/cycliza-
tion of o-aldiminyl cinnamatea
Entry
Ligand
x (equiv.)
Yieldb
1
2
3
4
5
6
7
8
dppf
dppf
dppp
dppb
P(o-MePh)3
PyBox
dppb
2.5
1.1
1.1
1.1
1.1
1.1
0
0% (4a′, 61%)c
51%
63%
79%
70%
Fig. 1 Selected natural and synthetic agents containing the THQ core.
42%
0%
dppb
1.1
0%d
Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology,
School of Pharmaceutical Engineering and Life Science, Changzhou University,
Changzhou, Jiangsu Province 213164, China. E-mail: shenmh@cczu.edu.cn,
hdxu@cczu.edu.cn
†Electronic supplementary information (ESI) available: Details of experiments,
compound characterization, crystallographic data and spectroscopic data. CCDC
1878321. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c8ob03195a
a Reactions were conducted on a 0.2 mmol scale in 2 mL THF at rt for
1 h. b Isolated yields were reported. c Overnight instead, 4a′ was iso-
lated in 61% yield. d Without the copper salt.
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components in their own rights, finding important appli- to the alkene group and subsequent stereoselective trapping of
cations in materials science,4 chemical biology5 and pharma- the thereby formed organocopper intermediate with the
ceutical industry.6
pendent imine. We envisioned that switching terminal styrene
Borylcopper7 initiated domino reactions have been proved 1 to α,β-unsaturated ester like 3a would reverse the direction of
to be powerful to achieve complex structures carrying a boryl borylative addition and accordingly afford boryl THQ 4a, and
group from simple functional groups such as alkenes and during the course of this study, Zhong et al. reported a boryl-
alkynes.8 In this endeavor, we9 and others10 have developed an ative cyclization of α,β-unsaturated esters.8b Under the conditions
efficient copper catalyzed carboboration protocol for selective established previously in our laboratory (Table 1, entry 1),
synthesis of cis-indolinyl boronic esters from 2-iminostyrene the overnight reaction of 3a with B2Pin2/t-BuOLi/t-BuOH
(Scheme 1 top). Herein, we wish to report a copper catalyzed combination in THF using Cu(OTf)2/dppf as a precatalyst did
domino reaction for selective construction of 4-boryl THQs not deliver the predicted product 4a, but instead delivered only
(Scheme 1 bottom).
THQ 4a′ 11 in 61% yield. The latter was reasoned to arise from
the base promoted protodeboronation of the former. The
excess BuOLi (2.5 equiv.) employed herein may account for the
non-productive process, and reduction of both the base
amount to 1.1 equiv. and reaction time to 1 h resulting in the
isolation of the desired THQ in 51% yield without the detec-
tion of its deborylative byproduct 4a′ (entry 2). Brief screening
Results and discussion
The generation of boryl indoline 2 was accomplished by initial
regioselective syn-addition of a borylcopper complex (CuBpin)
Table 2 The influence of substituents on the aryl aldimine moietya
Entry
1
Substrate
Product, yieldb
Entry
11
Substrate
Product, yieldb
2
3
12
13
4
5
14
15
6
7
8
16
17
18
9
19
20
Complicated
Complicated
10
a Reactions were conducted on a 0.2 mmol scale in 2 mL THF at rt for 0.5–1 h. b Isolated yields were reported.
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of ligands distinguished the bidentate phosphorus ligand efficiently via the reaction of related aldimine 3p (entry 15).
dppb from its analogous dppf and dppp, as the highest yield 2-Furanyl and 2-thiophenyl THQs 4q–r were also produced in
of 79% was accomplished with dppb (entry 4 vs. entries 2 & 3). high yields from the corresponding aldimines 3q–r (entries 16
Monodentate P(o-MePh)3 is also a feasible ligand which and 17). Though the same reaction of N–H indonyl aldimine
afforded 4a in 70% yield (entry 5). Tridentate nitrogen ligand 3s failed to deliver the correlative 2-indonyl THQ 4s, its
PyBox exhibited moderate effectiveness on this carboboration N-protected congener 3t was successfully converted to 4t in
process (entry 6). Without t-BuOLi, the catalytic cycle shut 75% yield (entry 18). A complex reaction mixture was obtained
down completely as observed in entry 7, which underlines the after treatment of 2-pyridinaldimine 3u under the standard
indispensability of the alkoxide base for this reaction. In the conditions, which might be complicated by non-productive
absence of the copper pre-catalyst, this reaction didn’t occur reaction of pyridine with reducing agent B2(pin)2 (entry 19).
either (entry 8), ruling out the alternative of base and/or ligand Similarly, cinnamaldimine 3v with multiple potential boryl-
promoted conjugate addition.12 The above outcomes validate ative addition modes gave a complex reaction as well (entry 20).
the initially hypothesized addition/cyclization cascade.
Next we elected to examine the effect of the substitution at
With the optimized conditions in hand, we set out to the anilinyl section on this tandem reaction (Table 3).
explore the reaction scope by examining the imines 3 derived Substrates with electron donating groups as well as electron
from various aldehydes (Table 2). Benzaldimines 3b–e with withdrawing groups at the position para to the aryl amine
OMe, Me, Br and Cl groups at the para position were all trans- group are all viable reactants, nevertheless giving the corres-
formed into the corresponding boryl THQs smoothly with ponding THQs 4w–4ae in moderate to good yields (entries 1–8,
good to high yields (entries 1–4, 64–75% yield). ortho-I, Br and 45–63%). Interestingly, both meta and ortho methylation in
F substituents also tolerate this transition metal catalyzed 3af–3ai led to a great enhancement of yields (entries 9–12). At
cascade to give good yields (entries 5–7), but o-NO2 does not this stage, a practical copper-catalyzed methodology for the
seem to be compatible with the reductive conditions since 4i synthesis of structurally unique 2-aryl-3-carboxylate-4-boryl
was obtained in only 26% yield (entry 8). Substrates with meta THQs has been developed through an addition/cyclization
substitution performed well and high yields were obtained as cascade.
manifested by the reactions of 3j–l (entries 9–11, 72–86%
The structure of these THQs is assigned by NMR and mass
yield). Not surprisingly, benzaldimines 3m–o with two substi- spectra. The relative stereochemistry of 4t was established
tuents are good substrates as well for this reaction (entries unambiguously to be all-cis for 2,3,4-trisubstitution by single
12–14). This tandem addition/cyclization process also applied crystal X-ray analysis (Fig. 2). The same relative configuration
to other aryl aldimines. 2-Naphthalenyl THQ 4p was formed is assigned to other products by analogy through comparisons
Table 3 The influence of substituents on the cinnamate phenyl ringa
Entry
1
Substrate
Product, yieldb
Entry
7
Substrate
Product, yieldb
2
3
4
8
9
10
5
6
11
12
a Reactions were conducted on a 0.2 mmol scale in 2 mL THF at rt for 0.5–1 h. b Isolated yields were reported.
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Fig. 2 Molecular structure of 4t (CCDC 1878321†).
of their relative polarities and characteristic NMR signals. It is
noteworthy that this all-cis-configuration in boryl THQs 4 is
intriguing and unusual, especially, when compared with 3,4-
trans THQs 6a 13 and 6b 14 resulting from the corresponding
conjugate addition/cyclization reactions documented pre-
viously (Scheme 2). In those two reactions, the formation of
enolate intermediates 5 (the Michael adducts) after the initial
addition step was suggested to explain the preferred 2,3-cis-3,4-
trans configuration within 6a and 6b. In the current copper
catalyzed addition/cyclization cascade, the nascent organocop-
per intermediate 7 formed by syn-addition of CuBpin to the
trans-C–C double bond (a product of 1,2-addition or a non-
Michael adduct) might coordinate and react with the pendent
imine electrophile immediately before its latent isomerization
to copper enolate 8, and therefore without losing the relative
stereochemistry. The cyclization of organocopper 7 to THQ 4
then might proceed through a transition state like TS-I in a
stereoselective fashion to create a cis-triad in the N-heterocycle
ring, an overall carboboration product. Alternatively, according
to Zhong’s proposal,8b,c cyclic enolate 8 with a B–O coordi-
nation interaction might form and then transform to all-cis 4
via a boat transition state TSII (Scheme 2).
Scheme 3 Showcases of synthetic applications of boryl THQ.
ence of a catalytic amount of AgNO3 afforded substituted qui-
noline 12 15 in 87% yield.
Conclusion
In summary, we have developed a copper catalyzed tandem
borylative addition/cyclization reaction, rendering efficient
construction of highly valuable all-cis 4-boryl-THQs that are
otherwise difficult to access. The unusual stereoselectivity
occurring in this intramolecular carboboration of aryl acrylates
may reflect the non-Michael nature of the initial borocupration
step or a cyclic enolate with B–O coordination. The synthetic
value of the products was also embodied by a couple of useful
transformations.
Conflicts of interest
To demonstrate the synthetic usefulness of the boryl THQs
from our method, several reactions common to alkyl boronic
acid esters were carried out with 4r as the starting material
(Scheme 3). Suzuki coupling with 3-methylphenyl bromide 9
underwent smoothly to give 10 in 42% yield. Submission of 4r
to H2O2/NaOH combination produced 11 in excellent yield.
Deborylation can also be achieved efficiently by treatment with
K2CO3 in wet THF. Oxidation of 4r with Selectfluor in the pres-
There are no conflicts to declare.
Acknowledgements
The authors thank the National Natural Science Foundation of
China (21402014 and 21672027), the QingLan Project of
Jiangsu Province (2016) and the Six-Talent-Peaks Program of
Jiangsu (2016) for financial support. This work was also sup-
ported by the High-Level Entrepreneurial Talent Team of
Jiangsu Province (2017-37).
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