Palladium/Lewis Acid Co-catalyzed Divergent Asymmetric Ring-Opening Reactions of Azabenzonorbornadienes with Alcohols

Article abstract of DOI:10.1021/acs.orglett.6b02300

By fine tuning the combinations of chiral palladium catalysts and Lewis acids, both the additional and reductive asymmetric ring-opening reactions of azabenzonorbornadienes with alcohols were accomplished with good chemoselectivity, regioselectivity, and enantioselectivity. It was proven that the reductive ring-opening products were generated through a transfer-hydrogenation process with alcohols as hydrogen source.

Full text of DOI:10.1021/acs.orglett.6b02300

Letter
pubs.acs.org/OrgLett
Palladium/Lewis Acid Co-catalyzed Divergent Asymmetric Ring-
Opening Reactions of Azabenzonorbornadienes with Alcohols
†
†
Fan Yang, Jingchao Chen, Jianbin Xu, Fujie Ma, Yongyun Zhou, Madhuri Vikas Shinde,
and Baomin Fan*
YMU-HKBU Joint Laboratory of Traditional Natural Medicine, Yunnan Minzu University, 650500 Kunming, China
*
S Supporting Information
ABSTRACT: By fine tuning the combinations of chiral palladium catalysts and Lewis acids, both the additional and reductive
asymmetric ring-opening reactions of azabenzonorbornadienes with alcohols were accomplished with good chemoselectivity,
regioselectivity, and enantioselectivity. It was proven that the reductive ring-opening products were generated through a transfer-
hydrogenation process with alcohols as hydrogen source.
he asymmetric ring-opening (ARO) reactions of oxa/
azabenzonorbornadienes can directly generate substituted
the additional ring-opening products. The reductive ring-
opening products were found to be generated via a transfer-
hydrogenation reaction with alcohols as the hydrogen source.
Although the asymmetric transfer-hydrogenation reactions had
T
chiral dihydronaphthalenes, which are ubiquitous substructures
1
in natural products and pharmaceuticals, as products.
12
Pioneered by Lautens, the ARO reactions of oxabenzonorbor-
nadienes have been greatly developed in the past decades, and
various nucleophiles have been successfully applied as effective
been extensively studied by many groups, the successful
applications of primary alcohols as hydrogen source are still
13
rare. By fine-tuning the catalytic conditions, we realized the
highly chemo-, regio-, and enantioselective control for these
two ring-opening reactions. Herein, we describe the palladium/
Lewis acid co-catalyzed divergent ARO reactions of azabenzo-
norbornadienes using a wide range of alcohols as nucleophiles
and reductants, respectively (Scheme 1).
2
ring-opening reagents. Though the products of the ARO
reactions of azabenzonorbornadienes have great application
potential in organic synthesis, the corresponding achievements
were relatively fewer. Before our studies, only the ARO
3
reactions of azabenzonorbornadienes with amines and organic
4
zinc reagents were well established, generating the correspond-
ing products for a wide range of substrates and with high
enantioselectivities. Aryl boronic acids and terminal alkynes
Scheme 1. Divergent ARO Reactions of
Azabenzonorbornadienes with Alcohols
5
6
had been applied to react with azabenzonorbornadienes to
generate the ring-opening products smoothly. However, bulky
steric hindrance in nucleophiles seemed necessary to ensure
high enantioselectivities. Catalyzed by iridium complexes, the
7
ARO reactions of azabenzonorbornadienes with alcohols and
8
phenols were also reported, but the results were not
satisfactory due to low to moderate ee’s obtained in many
cases. The development of new and efficient catalysts or
catalytic systems for ARO reactions of azabenzonorbornadienes
is still interesting and necessary.
Our journey commenced with the ARO reactions of
azabenzonorbornadienes 1a with methanol by screening a
suitable chiral ligand in the presence of AgBF as a co-catalyst
4
(Table 1). The initial test was carried out by (R)-Binap and
gave the desired additional ring-opening product 3aa in 89%
yield with an enantiomeric excess of 92% (Table 1, entry 1).
Surprisingly, a small amount of reductive ring-opening product
a was also generated in this reaction. By employing other
bidentate chiral ligands, we noted that (R)-P-Phos led to an
excellent reaction yield for 3aa but lowered the enantiose-
As a part of our ongoing research in the asymmetric
chemistry of oxa/azabenzonorbornadienes, we have proven that
the combinations of different chiral transitional-metal com-
plexes with some Lewis acids could form highly efficient co-
catalytic systems for the ARO reactions of not only
4
9
10
oxabenzonorbornadienes but also azabenzonorbornadienes.
During our study of the ARO reactions of azabenzonorborna-
dienes with alcohols, we serendipitously found that the
reductive ring-opening products were generated along with
Received: August 3, 2016
11
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02300
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Letter
a
Table 1. Reaction Conditions Screening for the Divergent ARO Reactions
3
aa
4a
b
c
b
c
entry
ligand
Lewis acid
time (h)
yield (%)
ee (%)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
(R)-Binap
AgBF4
8
7
89
95
92
72
70
75
0
5
2
(R)-P-Phos
AgBF4
(R)-SDP
AgBF4
3
63
29
59
46
4
(R,R)-BDPP
AgBF4
48
1.5
1
68
13
(R,R)-DIOP
AgBF4
60
36
(R)-Phanephos
(R)-Difluorphos
(R)-Difluorphos
(R)-Difluorphos
(R)-Difluorphos
(R)-Difluorphos
(R)-Phanephos
(R)-Phanephos
AgBF4
34
79
97
98
97
97
96
65
60
AgBF4
5
96
trace
32
AgOTf
CuOTf
Cu(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
15
48
8
61
69
68
70
71
93
96
20
76
10
11
12
13
83
16
26
0.6
1.5
42
55
trace
trace
94
d
94
a
Reaction conditions: Pd(OAc) (0.01 mmol), Lewis acid (0.02 mol), and chiral ligand (0.012 mol) in toluene (1 mL) was stirred at room
2
temperature for 30 min under Ar. 1a (0.2 mmol) and 2a (0.6 mmol) were added, and the reaction mixture was stirred at 60 °C for indicated period
b
1
c
d
of time. Yields were calculated on the basis of H NMR using 1,3-benzodioxole as internal standard. Determined by HPLC analysis. The reaction
was performed at 40 °C.
a
lectivity of the reaction (Table 1, entry 2), and the use of (R)-
SDP, (R,R)-BDPP, and (R,R)-DIOP led to a dramatic decrease
in both the yield and the enantioselectivity along with the
generation of reductive ring-opening product 4a (Table 1,
entries 3−5). It is worth noting that when (R)-Phanephos was
used as the chiral ligand the chemoselectivity of the reaction
was reversed and 4a became to the major product (Table 1,
entry 6). To our delight, an excellent result was achieved by
Scheme 2. Scope of the Additional ARO Reactions
(R)-Difluorphos and afforded the asymmetric ring-opening
product 3aa exclusively in 96% yield with 97% ee (Table 1,
entry 7). When the Lewis acid was switched to AgOTf and
Cu(OTf) , 3aa remained the major product (Table 1, entries 8
2
and 10). However, when CuOTf or Zn(OTf) was used as the
2
co-catalyst, the yields of 4a increased to 76% and 55%,
respectively (Table 1, entries 9 and 11). It could be seen that
both the chiral ligand and Lewis acid can greatly affect the
selectivity of the present reaction. (R)-Phanephos was then
tested again in this reaction by employing Zn(OTf) as the
2
Lewis acid, since Zn(OTf) is more economical than CuOTf. It
2
was a delight that 4a was afforded exclusively with excellent
yield and enantioselectivity (Table 1, entry 12). Further
experiments were carried out by screening other reaction
parameters, such as reaction temperature and the amount of
methanol, and a reaction temperature of 40 °C with 3 equiv of
methanol were found to be the optimal conditions (Table 1,
entry 13, see the Supporting Information for additional
condition screening results and the chemical structures of the
chiral ligands).
To investigate the scope of the additional ARO reaction, a set
of alcohols were examined in the reaction of 1a. As the results
summarized in Scheme 2 show, excellent enantioselectivities
were achieved and the reaction yields were generally moderate
to high. For example, high yields were obtained by using simple
primary alcohols, and the long-chain alcohols or secondary
alcohols slightly lowered the reaction yields (Scheme 2, 3aa−
ae). The absolute configuration of the product 3ae was
a
Reaction conditions: Pd(OAc)2 (0.01 mmol), (R)-Difluorphos
(0.012 mmol), and AgBF (0.02 mmol) in toluene (1 mL) were
4
stirred at room temperature for 30 min under Ar. 1a−f (0.2 mmol)
and 2a−i (0.6 mmol) were added, and the reaction mixture was stirred
at 60 °C. Yields refer to isolated yields of purified products. The
enantiomeric excesses were determined by HPLC analysis using chiral
stationary phases. *The reaction was performed at 40 °C.
14
assigned as 1S,2S by X-ray crystallographic analysis. The aryl
alcohols such as benzyl alcohol and 2-phenylethanol were also
suitable nucleophiles for the present reaction (Scheme 2, 3af−
B
DOI: 10.1021/acs.orglett.6b02300
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Organic Letters
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a
ag). Benzyl alcohols with different substitutions on the phenyl
ring gave moderate yields, whereas 2-chlorobenzyl alcohol gave
a low yield probably due to steric effects (Scheme 2, 3ah−am).
Various electronically modified azabenzonorbornadienes were
synthesized and used for the substrate scope study of this
additional ARO reaction. Except for dibromo-substitued
azabenzonorbornadiene 1b which gave a good yield but a
relatively lower ee, all of the azabenzonorbornadienes were
transformed to the corresponding ring-opening products in
good yields and high ee’s (Scheme 2, 3ba−fa).
Scheme 4. Scope of the Reductive ARO Reactions
To shed light on the hydrogen source of the asymmetric
ring-opening reaction that gives 4a, several deuterium-labeling
experiments were performed (Scheme 3). When CH OD was
3
Scheme 3. Deuterium-Labeling Experiments
a
employed, deuterium was only incorporated into the amine
group of the product (Scheme 3, a). When this reaction was
Reaction conditions: Pd(OAc) (0.01 mmol), (R)-Phanephos (0.012
2
mmol), and Zn(OTf) (0.02 mmol) in toluene (1 mL) was stirred at
2
performed with CD OH, about 89% deuterium was found in
the 1,2-dihydronaphthalene structure of the product (Scheme
room temperature for 30 min under Ar. 1a (0.2 mmol) and 2a (1.0
mmol) were added, and the reaction mixture was stirred at 40 °C.
Yields refer to isolated yields of purified products. The enantiomeric
excesses were determined by HPLC analysis using chiral stationary
phases.
3
3
, b). This result indicates that the hydrogen atom on the 1,2-
dihydronaphthalene moiety was derived exclusively from the
methyl group of CH OD. Another deuterium-labeling experi-
3
ment that was carried out with CD OD showed 82% deuterium
3
incorporated into the 1,2-dihydronaphthalene moiety and 46%
deuterium incorporated into the amine group; this result was
inconsistent with the former experiments (Scheme 3, c). Thus,
was proven that the product 4a was generated from a transfer-
hydrogenation process employing methanol as hydrogen
source. To the best of our knowledge, this represents the first
example of a highly enantioselective transfer-hydrogenation
reaction with methanol as reductant.
With the optimal reaction conditions of reductive ARO
reaction of azabenzonorbornadiene in hand (Table 1, entry 13),
a wide range of alcohols were subsequently tested as hydrogen
sources. As shown in Scheme 4, simple primary alcohols
HPLC analysis. To study the substituent effects on
azabenzonorbornadiene substrates, derivatives with various
substituted groups on the phenyl ring were subsequently tested
by employing methanol as reductant. In general, high
enantioselectivities were obtained for all of the substrates, and
the features of substitution groups mainly affected reaction
yields. For example, an excellent result was obtained by using
dimethyl-substituted azabenzonorbornadiene (Scheme 4, 4c),
and the bromo groups remained intact in the product, enabling
further elaboration (Scheme 4, 4b). Although the dimethoxy-
substituted substrate 1c showed good performance (Scheme 4,
(methanol and ethanol) and benzyl alcohols reacted with 1a
4c), strong electron-donating groups slightly reduced the
smoothly to generate the reductive product 4a in good yields
and with high enantioselectivities. It should be noted that
benzaldehyde (19 mg, 0.18 mmol), which was the oxidative
product of benzyl alcohol, was also isolated from the reaction
mixtures when benzyl alcohol was used as reductant. Primary
alcohols with long chains, as well as secondary alcohols, could
also serve as suitable hydrogen sources with high enantiose-
lectivities. To determine the absolute configuration of product
reaction yields (Scheme 4, 4d−f).
In conclusion, the additional ring-opening products and the
reductive ring-opening products were generated, respectively,
by the reactions of azabenzonorbornadienes with alcohols in
high yields with high enantioselectivities. The two correspond-
ing ARO reactions showed wide substrates scope and good
functional group tolerance. A transfer-hydrogenation procedure
was proven in this reductive reaction, and alcohols played the
role of reductants.
4
a, it was converted to 5, which agreed with the commercially
available chemical (S)-1,2,3,4-tetrahydro-1-naphthylamine by
C
DOI: 10.1021/acs.orglett.6b02300
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Organic Letters
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(
8) Fang, S.; Liang, X.-L.; Long, Y.-H.; Li, X.-L.; Yang, D.-Q.; Wang,
ASSOCIATED CONTENT
Supporting Information
■
S.-Y.; Li, C.-R. Organometallics 2012, 31, 3113−3118.
(
*
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9) (a) Liu, S.-S.; Li, S.-F.; Chen, H.-L.; Yang, Q.-J.; Xu, J.-B.; Zhou,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02300.
Y.-Y.; Yuan, M.-L.; Zeng, W.-M.; Fan, B.-M. Adv. Synth. Catal. 2014,
356, 2960−2964. (b) Li, S.-F.; Xu, J.-B.; Fan, B.-M.; Lu, Z.-W.; Zeng,
C.-Y.; Bian, Z.-X.; Zhou, Y.-Y.; Wang, J. Chem. - Eur. J. 2015, 21,
9
003−9007. (c) Chen, J.-C.; Liu, S.-S.; Zhou, Y.-Y.; Li, S.-F.; Lin, C.-
Y.; Bian, Z.-X.; Fan, B.-M. Organometallics 2015, 34, 4318−4322.
10) (a) Fan, B.-M.; Li, S.-F.; Chen, H.-L.; Lu, Z.-W.; Liu, S.-S.; Yang,
Q.-J.; Yu, L.; Zhou, Y.-Y.; Wang, J. Adv. Synth. Catal. 2013, 355, 2827−
832. (b) Lu, Z.-W.; Wang, J.; Han, B.-Q.; Li, S.-F.; Zhou, Y.-Y.; Fan,
Optimization tables, experimental details, proposed
mechanism, characterization data, and X-ray analyses
(
(
PDF)
2
AUTHOR INFORMATION
Corresponding Author
E-mail: adams.bmf@hotmail.com.
B.-M. Adv. Synth. Catal. 2015, 357, 3121−3125. (c) Zeng, C.-Y.; Yang,
■
*
F.; Chen, J.-C.; Wang, J.; Fan, B.-M. Org. Biomol. Chem. 2015, 13,
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003, 5, 1621−1624. (c) Mannathan, S.; Cheng, C.-H. Adv. Synth.
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Notes
Catal. 2014, 356, 2239−2246.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
21572198, 21362043, 21302162) and the Department of
■
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(b) Tsuchiya, Y.; Hamashima, Y.; Sodeoka, M. Org. Lett. 2006, 8,
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Imamoto, T.; Zhang, W.-B. Org. Lett. 2013, 15, 3690−3693.
Education of Yunnan Province (ZD2015012) for financial
support.
(
14) X-ray crystallographic data of 3ae have been deposited with the
Cambridge Crystallographic Data Centre (http://www.ccdc.cam.ac.
uk/) under accession code CCDC 1436042.
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