Iridium-catalyzed asymmetric ring-opening of azabicyclic alkenes with phenols

Article abstract of DOI:10.1021/om3000295

The asymmetric ring-opening of azabicyclic alkenes with a variety of phenols is investigated using an iridium catalyst generated in situ from 2.5 mol % of [Ir(COD)Cl]₂ and 5.0 mol % of (S)-BINAP, which afforded the corresponding 1,2-trans-phenoxyamino products in excellent yield (up to 92%) with moderate to good enantioselectivities (up to 98% ee). The trans-configuration of the product 4b was confirmed by X-ray crystallography.

Full text of DOI:10.1021/om3000295

Article
pubs.acs.org/Organometallics
Iridium-Catalyzed Asymmetric Ring-Opening of Azabicyclic Alkenes
with Phenols
Shai Fang,† Xiuli Liang,† Yuhua Long,† Xiaolu Li,† Dingqiao Yang,*,† Sanyong Wang,‡ and Chunrong Li‡
†Key Laboratory of Theoretical Chemistry of Environment, Ministry of Education, School of Chemistry and Environment, South
China Normal University, Guangzhou 510006, People’s Republic of China
‡Guangdong Food Industry Institute, Guangzhou 510308, People’s Republic of China
S
* Supporting Information
ABSTRACT: The asymmetric ring-opening of azabicyclic
alkenes with a variety of phenols is investigated using an
iridium catalyst generated in situ from 2.5 mol % of
[Ir(COD)Cl]2 and 5.0 mol % of (S)-BINAP, which afforded
the corresponding 1,2-trans-phenoxyamino products in ex-
cellent yield (up to 92%) with moderate to good
enantioselectivities (up to 98% ee). The trans-configuration
of the product 4b was confirmed by X-ray crystallography.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Oxa- and azabicyclic olefins are valuable precursors in
asymmetric synthesis due to their potentials to generate
multiple chiral centers in a single step via asymmetric ring-
opening reactions.1 Transition metal-catalyzed asymmetric ring-
opening reactions of oxa- and azabicyclic olefins have been
investigated for many years, including a variety of metal
catalysts such as Pd,2 Rh,3 Cu,4 Ni,5 Fe,6 and Ru.7 Many
nucleophiles have been used for these reactions, including, not
limited to, amines,1c,3,8 Grignard reagents,4b,c,6,9 organoboronic
acids,2c,10 alcohol,3a,11 carboxylates,12 dialkylzincs,1a,f,g,2a,b,4a,13
alkynes,5a,b,14 organic halides,15 sulfur,16 phenols,17 and
others.18
The N-substituted substrates 1a, 1b, 1c, 1d, and 1e were
prepared on the basis of literature procedures.8a,b In our initial
experiments, we used DPPF (5.0 mol %) to validate the
catalytic activity of the iridium complex in the ring-opening
reactions of N-Ts-azabenzonorbornadiene (1a) with p-chlor-
ophenol as a nucleophile in THF at 80 °C in the presence of
2.5 mol % of [Ir(COD)Cl]2 with 5.0 mol % ligand. The desired
product 2a was obtained in 40% yield (Table 1, entry 1).
Inspired by these results, we subsequently used several chiral
ligands to optimize the reaction conditions.
Among these chiral ligands, we found only (S)-BINAP
offered better results, with yields of 69% and 61% ee (Table 1,
entry 2). All other ligands gave poor results (Table 1, entries
3−6). Therefore, we decided to choose (S)-BINAP as a ligand
for the reactions. Then we studied the impact of catalyst
loading (Table 1, entries 7−10). It was found that with the
increased iridium catalyst loading the enantioselectivities were
also increased. However, it was further found that 2.5 mol % of
[Ir(COD)Cl]2 with 5.0 mol % (S)-BINAP would be a more
suitable loading in terms of the product yield and ee value.
To optimize the reaction and to get better yields and higher
enantioselectivities, we next investigated the effects of different
parameters including solvents, temperature, and additives on
reactivity and enantioselectivity for the reaction (Table 2). At
the beginning, we screened several commonly used solvents
(Table 2, entries 1−7). It was found that the reaction in THF
gave a good yield with moderate ee (Table 2, entry 1). In other
solvents, such as toluene, DME, dioxane, and THP, the
reactions offered excellent ee with low yields (Table 2, entries
3/4 and 6/7), and both CH2Cl2 and CH3CN gave low yields
and ee (Table 2, entries 2 and 5). The impact of reaction
Lautens and co-workers17 had previously reported the Rh-
catalyzed highly efficient asymmetric ring-opening of oxabicy-
clic alkenes with phenols. However, similar asymmetric ring-
opening reactions of azabicyclic olefins with phenol as
nucleophiles remain unknown.
In our previous work,19 we explored asymmetric ring-
opening reactions of oxa- and azabicyclic olefins with amines
including aliphatic amines and aromatic amines in the presence
of iridium catalyst, which afforded the desired products in good
yields with excellent enantioselectivities. To expand the scope
of this novel Ir-catalyzed reaction, we are interested in studying
the asymmetric ring-opening of oxa- and azabicyclic olefins with
oxygen-based nucleophiles in the presence of an iridium
catalyst. Meanwhile, we also tried to optimize the catalytic
system by using some new additives such as AgOTf/Bu4NI in
the reaction. In this paper, we report the first Ir-catalyzed
asymmetric ring-opening of N-substituted azabenzonorborna-
dienes with a variety of phenols. Compared to that of Rh, the
ring-opening reactions catalyzed by Ir were observed to have
better yields and enantioselectivities.
Received: January 13, 2012
Published: March 26, 2012
© 2012 American Chemical Society
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Table 1. Identification of the Optimal Chrial Ligand for Iridium-Catalyzed Asymmetric Ring-Opening of N-Ts-
a
Azabenzonorbornadiene (1a) with p-Chlorophenol
b
c
entry
ligand (mol %)
5.0 DPPF
[Ir(COD)Cl]2 (mol %)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
2.5
2.5
2.5
2.5
2.5
2.5
1.0
1.5
2.0
4.0
40
69
61
51
36
45
64
61
34
54
0
61
12
19
42
41
47
51
59
67
5.0 (S)-BINAP
5.0 (R)-(S)-PPF-PtBu2
5.0 (S)-tol-BINAP
5.0 (R)-Segphos
5.0 (R)-DTBM-Segphos
2.0 (S)-BINAP
3.0 (S)-BINAP
4.0 (S)-BINAP
8.0 (S)-BINAP
a
The reaction was carried out with 1a (0.2 mmol) and 3.0 equiv of p-chlorophenol (0.6 mmol) in THF (2.0 mL) at 80 °C (oil bath temperature).
b
c
Isolated yield after silica gel column chromatography. Determined by HPLC with a Chiralcel AD-H column.
temperature was also examined. It was found that there were no
reactions at 0 and 25 °C (Table 2, entries 8 and 9). At 100 °C,
it was observed that the reaction gave a better ee with moderate
yield (Table 2, entry 10). At higher temperature, such as 120
°C, it was found that the ee was up to 92%, but yield was down
to 36% (Table 2, entry 10). The role of ammonium halide
additives was also explored. It was observed that they had little
positive impact on the reaction (Table 2, entries 12−14). It was
also worth pointing out that in the case of using NH4I the
isolated product was product 2aa with 64% yield (Table 2,
entry 15). To further optimize the reaction, we tested the
impact of silver salts such as AgOTf on the reactions. It was
found that it could facilitate the reaction.3c,4a,13f It was
surprising that the yield and ee value were significantly
improved when AgOTf and Bu4NI were added as additives
to the ring-opening reaction (Table 2, entry 17). We also tried
using Rh complex instead of Ir complex to catalyze the ring-
opening reaction under optimal conditions. It was found that
2a was obtained only as a racemic product (Table 2, entry 18).
The scope of the reaction with the catalytic system was
examined by using a number of phenols with different
substituted groups. The results were shown in Table 3, from
which it could be seen that the position of the substituent on
the benzene ring of phenol had a significant impact on both
yields and enantioselectivities. Among monosubstituted
phenols (Table 3, entries 1−9), meta-substituted phenols
were found to give better yields than that of ortho- and para-
substituted phenols. It was further found that para-substituted
phenols gave higher ee than that of ortho- and meta-substituted.
Moreover, phenol with no substituent group gave the expected
product with reasonable yield and moderate ee value (Table 3,
entry 7). It was also worth pointing out that when the
substitute group R was p-NO2 or p-OCH3, it was found that the
yields and ee values were sharply decreased, which was
probably due to the electronic effects (Table 3, entries 8 and
9). Despite the unfavorable steric and electronic effects in the
case of phenols with multisubstituted groups, it was found that
the ring-opening reactions gave acceptable yields and ee values
(Table 3, entries 10−16). However, it was observed that,
treating 1a with 4-chloro-3-methylphenol (Table 3, entry 15),
the desired product was obtained in high yield (89%) with low
ee value (30%). In the case of 2-naphthol, which has
unfavorable steric hindrance greater than other chosen
nucleophiles (Table 3, entry 16), the desired product gave a
low yield (33%) with moderate ee value (63%).
In order to extend the scope of this reaction to other
substrates, we then investigated several other substrates such as
N-substituted azabenzonorbornadienes, where the N-substi-
tuted group was −Boc (1b), −Ns (1c), −Bs (1d), and −Ac
(1e) (Table 4). The results showed that the nature of the
substitutent groups affected the steric hindrance and electron-
withdrawing effects; these protective groups on the nitrogen
atom were found to negatively impact the reactivity. In those
cases, longer reaction times were observed with remarkably
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Table 2. Condition Screening for the Iridium-Catalyzed Asymmetric Ring-Opening Reaction of N-Ts-Azabenzonorbornadiene
a
(1a) with p-Chlorophenol
b
c
d
entry
solvent
additive
yield (%)
ee (%)
1
THF
69
27
32
22
49
17
8
61
4
2
CH2Cl2
toluene
DME
3
80
92
12
89
89
4
5
CH3CN
dioxane
THP
6
7
e
8
THF
n.r.
n.r.
61
36
9
f
9
THF
g
10
11
12
13
14
15
16
17
18
THF
77
92
71
h
THF
THF
THF
THF
THF
THF
THF
NH4F
NH4Cl
NH4Br
NH4I
n.r.
n.r.
i
trace
Bu4NI
56
74
71
65
88
3
j
AgOTf/Bu4NI
AgOTf/Bu4NI
k
THF
a
The reaction was carried out with 1a (0.2 mmol) and 3.0 equiv of p-chlorophenol (0.6 mmol) in solvent (2.0 mL) at 80 °C (oil bath temperature)
b
c
in the presence of [Ir(COD)Cl]2 (2.5 mol %) and (S)-BINAP (5.0 mol %). 1.0 equiv of additive. Isolated yield after silica gel column
chromatography (0.2 mmol). Determined by HPLC with a Chiralcel AD-H column. Oil temperature was 0 °C. Oil temperature was room
temperature. Oil temperature was 100 °C. Oil temperature was 120 °C. Yield of 2aa was 64%. The loading of AgOTf was 10.0 mol %, and Bu4NI
was 20.0 mol %. The catalyst was 2.5 mol % [Rh(COD)Cl]2.
d
e
f
g
h
i
j
k
lower yields and enantioselectivities. We even did not find any
trace of products 3k and 6a formed (Table 4, entries 3 and 10).
However, product 3e was obtained with an acceptable ee value
(61%) with low yield (24%) (Table 4, entry 2), and product 5a
was also obtained with an acceptable ee value (62%) with
moderate yield (57%) (Table 4, entry 8). Moreover, product 4a
was obtained in higher yield (82%) with lower ee value (39%)
than those of product 2a (Table 4, entry 4). It is also worth
pointing out that m-chlorophenol reacted with 1c to afford the
expected product 4b with acceptable yield (69%) and high ee
value (98%) (Table 4, entry 5).
The absolute configuration of ring-opened product 4b was
demonstrated by X-ray crystallography. The single crystal was
obtained by solvent evaporation from a solution consisting of
dichloromethane, petroleum ether, and ethyl acetate. Its
configuration was assigned as (1R, 2R) and confirmed as the
1,2-trans-configuration, as shown in Figure 1. It is obvious that
the reaction favors the formation of 1,2-trans-phenoxyamino
products.
On the basis of our observations on the reaction, we could
propose the reaction mechanism as outlined in Scheme 1. The
chiral dimeric iridium complex A was first formed. The nitrogen
atom and the double bond of N-Ts-azabenzonorbornadiene
(1a) then reversibly coordinate to the iridium center of the
catalyst to give the intermediate B. Oxidative insertion of the
iridium into the C−N bond of B forms C. Then, phenol
nucleophile attack with configuration inversion was proposed
to occur in an SN2 displacement of the iridium catalyst. The
1,2-trans-phenoxyamino product 2a was subsequently released,
and the iridium complex A was regenerated.
CONCLUSIONS
■
In summary, we have investigated the iridium-catalyzed
asymmetric ring-opening of N-substituted azabicyclic alkenes
with a variety of phenols, which afforded the corresponding
products in good yield with excellent enantioselectivities for the
first time. The reaction results showed that the nature of the
chiral ligand had significant impact on the ring-opening. Future
study will focused on the biological and pharmaceutical
activities of the products. Studies on further expansion of the
scope of this Ir-catalyzed method are also in progress in our
laboratory.
EXPERIMENTAL SECTION
■
General Procedure (I) for the Asymmetric Ring-Opening
Reactions of N-Ts-Azabenzonorbornadiene (1a) with Phenols.
A 5 mL round-bottom flask fitted with a reflux condenser was flame-
dried under a stream of nitrogen and cooled to room temperature.
[Ir(COD)Cl]2 (3.5 mg, 2.5 mol %) and (S)-BINAP (6.5 mg, 5.0 mol
%) were simultaneously added and followed by addition of anhydrous
tetrahydrofuran (2.0 mL). After they were stirred for 10 min, silver
trifluoromethanesulfonate (5.2 mg, 10.0 mol %) was added; then 10
min later, additive Bu4NI (14.8 mg, 20.0 mol %) was added. After they
were stirred for another 10 min, N-Ts-azabenzonorbornadiene (1a)
(59.4 mg, 0.20 mmol) was added and the resulting mixture was heated
to reflux. At the first sign of reflux, phenol nucleophile (3 equiv to 1a)
was added. Then the temperature was continuously increased to 100
°C until the reaction was completed as judged by thin-layer
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Table 3. Scope of Asymmetric Ring-Opening Reactions of N-Ts-Azabenzonorbornadiene (1a) with Phenol and Substituted
a
Phenols
b
c
entry
R
time (h)
product
yield (%)
ee (%)
1
4-Cl
18
18
21
18
17
18
20
22
24
24
36
30
21
23
24
24
2a
2b
2c
2d
2e
2f
74
92
85
34
66
45
61
51
16
64
28
75
65
45
89
33
88
67
47
75
73
53
67
36
37
18
49
65
66
55
30
63
2
3-Cl
3
2-Cl
4
4-CH3
3-CH3
2-CH3
H
5
6
7
2g
2h
2i
8
4-NO2
9
4-OCH3
10
11
12
13
14
15
16
2,4-dibromo
2-bromo-4-chloro
4-bromo-2-fluoro
3,4-difluoro
2j
2k
2l
2m
2n
2o
2p
2,6-dichloro
4-chloro-3-methyl
2-naphthyl
a
The reaction was carried out with 1a (0.2 mmol) and 3.0 equiv of substituted phenols (0.6 mmol), 10.0 mol % of AgOTf, and 20.0 mol % of Bu4NI
b
as additive in THF (2.0 mL) at 100 °C (oil bath temperature) in the presence of [Ir(COD)Cl]2 (2.5 mol %) and (S)-BINAP (5.0 mol %). Isolated
yield after silica gel column chromatography. Determined by HPLC with a Chiralcel AD-H column or OD-H column.
c
Table 4. Scope of Asymmetric Ring-Opening Reactions of Azabicyclic Alkenes 1b, 1c, 1d, and 1e with Different Substituted
a
Phenols
b
c
entry
R1
R
time (h)
product
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
Boc
Boc
Boc
Ns
Ns
Ns
Ns
Bs
4-Cl
54
58
61
45
64
67
58
48
30
71
3a
3e
3k
4a
4b
4c
4e
5a
5b
6a
22
32
61
3-CH3
24
2-bromo-4-chloro
trace
82
4-Cl
3-Cl
2-Cl
3-CH3
4-Cl
3-Cl
4-Cl
39
98
33
38
62
42
69
40
25
57
Bs
66
Ac
n.r.
a
The reaction was carried out with substrate 1b or 1c or 1d or 1e (0.2 mmol) and 3.0 equiv of substituted phenols (0.6 mmol), 10.0 mol % of
AgOTf, and 20.0 mol % of Bu4NI as additive in THF (2.0 mL) at 100 °C (oil bath temperature) in the presence of [Ir(COD)Cl]2 (2.5 mol %) and
b
c
(S)-BINAP (5.0 mol %). Isolated yield after silica gel column chromatography. Determined by HPLC with a Chiralcel AD-H column or OD-H
column.
chromatography. The solvent was removed in vacuo, and the crude
mixture was purified by column chromatography on silica gel (ethyl
acetate/petroleum ether, 1:10, v/v) to give the target product.
(1R,2R)-N-[2-(4-Chlorophenoxy)-1,2-dihydronaphthalen-1-
yl]-4-methylbenzenesulfonamide, 2a. Following the above
general procedure, 2a was obtained as a crystalline solid (62.6 mg,
74%), Rf = 0.22 on silica gel (ethyl acetate/petroleum ether, 1:4, v/v),
mp 106−108 °C. The ee was determined to be 88% using HPLC
analysis on a Chiralcel AD-H column (hexane/2-propanol. 90:10, 1.0
mL/min, λ = 254 nm); retention times were 22.95 min (minor) and
26.72 min (major); [α]20D = −209.2 (c 1.00, CHCl3); IR (KBr, cm−1)
3261(m), 3053(w), 2924(m), 2852(w), 1594(w), 1488(s), 1452(w),
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NMR, elemental analysis, and X-ray structure data for
compound 4b. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yangdq@scnu.edu.cn. Phone: +86 20 39310068. Fax:
+86 20 85210087.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Nos. 21172081 and 20802021) and Produce and
Learning and Research Project of Education Department of
Guangdong Province (No. 2011A090200039) for financial
support. We are also grateful to Dr. Qingqi Chen of MedKoo
Biosciences, for reviewing the manuscript.
Figure 1. ORTEP plot for 4b.
Scheme 1. Working Hypothesis for the Asymmetric Ring-
Opening of N-Ts-Azabenzonorbornadiene (1a) with Phenol
Nucleophiles
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1326(m), 1234(s), 1158(s), 1093(w), 999(w), 920(w), 820(m),
663(m), 571(w), 545(m); 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J =
8.4 Hz, 2H), 7.30−7.26 (m, 3H), 7.20−7.10 (m, 4H), 6.81 (d, J = 7.6
Hz, 1H), 6.73 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 10.0 Hz, 1H), 6.04 (dd,
J = 4.4, 9.6 Hz, 1H), 4.96 (dd, J = 4.4, 4.4 Hz, 1H), 4.70−4.60 (m,
2H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.6, 143.9,
137.5, 132.3, 131.7, 131.4, 129.9, 129.5, 129.2, 128.8, 128.3, 127.7,
127.5, 126.4, 123.8, 117.3, 73.7, 54.3, 21.7; MS (ESI) calcd for
C23H20ClNO3S (M+) 425.09, found 448.27 (M + Na)+. Anal. Calcd
for C23H20ClNO3S: C, 64.86; H, 4.73; N, 3.29; S, 7.53. Found: C,
64.79; H, 4.80; N, 3.43; S, 7.46.
The asymmetric ring-opening reactions of N-Ts-azabenzonorborna-
diene (1a), N-Boc-azabenzonorbornadiene (1b), N-Ns-azabenzonor-
bornadiene (1c), N-Bs-azabenzonorbornadiene (1d), and N-Ac-
azabenzonorbornadiene (1e) with phenols are the same as the
above representative procedure. See Supporting Information for details
of the syntheses of the new compounds 2a−2p, 3a, 3e, 4a−4c, 4e, 5a,
and 5b.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and full characterization data for all
1
new products including optical rotations, IR, MS, H and 13C
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