Iridium-catalyzed asymmetric ring-opening reactions of oxabicyclic alkenes with secondary amine ucleophiles

Article abstract of DOI:10.3762/bjoc.5.53

Iridium-catalyzed asymmetric ring-opening reactions of oxabicyclic alkenes with various aliphatic and aromatic secondary amines are reported for the first time. The reaction gave the corresponding trans-1,2-dihydronaphthalenol derivatives in good yields w

Full text of DOI:10.3762/bjoc.5.53

Iridium-catalyzed asymmetric ring-opening
reactions of oxabicyclic alkenes with
secondary amine nucleophiles
Dingqiao Yang*, Ping Hu, Yuhua Long, Yujuan Wu, Heping Zeng, Hui Wang
and Xiongjun Zuo
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 53.
School of Chemistry and Environment, South China Normal
University, Guangzhou 510006, People’s Republic of China, Fax:
(+86)-20-39310187; Phone: (+86)-20-85210087
doi:10.3762/bjoc.5.53
Received: 19 June 2009
Accepted: 24 July 2009
Published: 09 October 2009
Email:
Dingqiao Yang* - yangdq@scnu.edu.cn
Associate Editor: M. Rueping
* Corresponding author
© 2009 Yang et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
chiral bisphosphine ligand; iridium catalyst; oxabicyclic alkenes;
ring-opening reaction
Abstract
Iridium-catalyzed asymmetric ring-opening reactions of oxabicyclic alkenes with various aliphatic and aromatic secondary amines
are reported for the first time. The reaction gave the corresponding trans-1,2-dihydronaphthalenol derivatives in good yields with
moderate enantioselectivities in the presence of 2.5 mol % [Ir(COD)Cl]2 and 5 mol % bisphosphine ligand (S)-p-Tol-BINAP. The
trans-configuration of 3f was confirmed by X-ray crystallography.
Introduction
Substituted dihydronaphthalenes are important molecules with group of Lautens and others reported rhodium-catalyzed asym-
different biological activities [1-5]. Therefore, the synthesis of metric ring-opening of oxabenzonorbornadiene with a wide
these molecules has been an attractive research topic in recent range of nucleophiles including thiols [10], phenols [11],
years. Among the many reported methods for the preparation of organoboronic acids [12,13], dialkylzincs [14,15], carboxylates
the dihydronaphthalene skeleton, transition metal-catalyzed [16], sulfur nucleophiles [17], and various amines [18,19].
asymmetric ring-opening (ARO) of oxabicyclic alkenes is one
of the most attractive because this reaction could potentially In addition to rhodium catalysts, other transition metal catalysts
create two chiral centers in a single step.
may be used for asymmetric ring-opening reactions of oxabi-
cyclic alkenes. These include complexes of copper [20-25],
Pioneering work in this field was first described by Caple et al. palladium [14,15,26-31], iron [32], and nickel [33-36].
[6] and the group of Lautens [7-9]. In the past decades, the Recently, we reported for the first time iridium-catalyzed asym-
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Beilstein Journal of Organic Chemistry 2009, 5, No. 53.
metric ring-opening of N-Boc-azabenzonorbornadiene with a which prompted us to screen other ligands. Among the several
wide range of secondary amines [37].
chiral ligands we had tested, (S)-BINAP and (S)-p-Tol-BINAP
were found to give better yields and reasonable enantio-
In this article, we will report ARO reactions of oxabicyclic selectivities. Moreover, in the case of (S)-p-Tol-BINAP, the
alkenes with aliphatic and aromatic secondary amine nucleo- enantioselectivity is slightly higher than for (S)-BINAP (52% ee
philes using iridium-complex catalysts, which provide a fast vs 35% ee); therefore, we decided to use (S)-p-Tol-BINAP as
and efficient access to chiral molecules with the dihydronaph- the ligand for this ring-opening reaction.
thalene skeleton.
Using (S)-p-Tol-BINAP as our standard ligand, we next invest-
Results and Discussion
igated the effect of different solvents on reactivity and enantio-
The ARO reaction involves many components of the chemical selectivity (Table 1). Among the solvents examined for asym-
agents; we first attempted to optimize the ligand to iridium cata- metric ring-opening of oxabenzonorbornadiene 1a, THF was
lyst system (Scheme 1). In our initial experiments, we chose an found to be the best in terms of yield and enantioselectivity
achiral 1,1′-bis(diphenylphosphino)ferrocene (DPPF) ligand to (Table 1, entry 6). Reactions in toluene and dioxane afforded
validate the catalytic activity of the iridium complex. The the desired product 2a in 70% and 76% yields, respectively.
product 2a was obtained in high yield (80%) in the presence of However, the enantioselectivities were slightly lower (Table 1,
2.5 mol % [Ir(COD)Cl]2 and 5 mol % DPPF in THF after 5 h.
entries 3 and 4). On the other hand, temperature had a remark-
able impact on reactivity and enantioselectivity. At room
Encouraged by this result, we then ran the asymmetric version temperature, the reaction failed to give the corresponding ring-
of the same reaction using different kinds of chiral bisphos- opened product 2a (Table 1, entry 7). A sluggish reaction was
phine ligands as shown in Scheme 1. We first examined ferro- observed at 65 °C (Table 1, entry 8), whereas at a higher
cenyl bisphosphine ligand, (R,S)-PPF-PtBu2, which was identi- temperature, such as 100 °C, the reaction gave a better yield and
fied as the ligand giving the best reactivity and excellent moderate enantioselectivity (Table 1, entry 9).
enantioselectivity in Rh-catalyzed system [11-15]. Unfortu-
nately, the desired ring-opened product 2a was obtained only in Based on the above findings, we decided to use the following
low yield (47%) with reasonable enantioselectivity (51% ee) in reaction condition as a standard to run the ARO reactions,
the iridium-catalyzed system. This suggested that (R,S)-PPF- which consisted of 2.5 mol % [Ir(COD)Cl]2, 5 mol % (S)-p-
PtBu2 was not an ideal ligand in iridium-catalyzed reactions, Tol-BINAP, and 3.0 equiv of substituted N-alkylaniline in THF
Scheme 1: Identification of optimal chiral ligand for iridium-catalyzed asymmetric ring-opening of oxabenzonorbornadiene 1a with N-methylaniline.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 53.
Table 1: Screening conditions for iridium-catalyzed asymmetric ring-opening of oxabenzonorbornadiene 1a with N-methylaniline.a
Entry
Solvent
Temperature (°C)
Time (h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
DME
100
90
12
12
8
48
36
70
76
65
87
n.r.
58
89
16
21
34
46
50
52
–
CH3CN
Toluene
Dioxane
THF
110
110
100
80
8
12
8
THF
THF
25
48
12
5
THF
65
53
46
THF
100
aThe reaction was carried out with 1a (0.34 mmol) and 3.0 equiv of N-methylaniline (1.0 mmol) in a solvent (2.0 mL) in the presence of [Ir(COD)Cl]2
(2.5 mol %) and (S)-p-Tol-BINAP (5.0 mol %). bIsolated yields after silica gel column chromatography. cDetermined by HPLC with a Chiralcel AD
column.
Table 2: Scope of ring-opening of oxabenzonorbornadiene 1a with substituted N-alkylaniline.a
Entry
R3
R4
Product
Time (h)
Yield (%)b
ee (%)c
1
CH3
H
2a
2b
2c
–
8
87
75
48
n.r.
n.r.
56
70
65
71
n.r.
85
52
56
74
–
2
CH2CH3
CH2CH=CH2
Cyclohexyl
CH3
H
12
24
60
24
24
12
12
12
60
6
3
H
4
H
5
2-Cl
3-Cl
4-Cl
4-F
–
–
6
CH3
2d
2e
2f
2g
–
72
55
51
65
–
7
CH3
8
CH3
9
CH3
4-Br
4-NO2
4-OCH3
10
11
CH3
CH3
2h
50
aThe reaction was carried out with 1a (0.34 mmol) and 3.0 equiv of substituted N-alkylaniline (1.0 mmol) in THF (2.0 mL) at 80 °C in the presence of
[Ir(COD)Cl]2 (2.5 mol %) and (S)-p-Tol-BINAP (5.0 mol %). bIsolated yields after silica gel column chromatography. cDetermined by HPLC with a Chir-
alcel AD column.
at 80 °C. The results of the ARO of oxabenzonorbornadiene 1a nucleophile, we obtained the product 2c in 48% yield with 74%
are shown in Table 2.
ee (Table 2, entry 3). The reaction using N-cyclohexylaniline
failed to give any ring-opened product because of the steric
hindrance of the bulky group (Table 2, entry 4).
The results demonstrated that the size of the alkyl group on
nitrogen in the nucleophile significantly influenced the react-
ivity and enantioselectivity. For instance, in the reaction of 1a We then investigated the effect of substituent groups on the
with N-methylaniline, which has a small group on N-atom, the aromatic ring of N-methylaniline. In 4-chloro-N-methylaniline,
ring-opening product 2a was obtained in 87% yield and 52% ee the reaction gave the desired product 2e in high yield with
(Table 2, entry 1), whereas in the reaction of 1a with moderate enantioselectivity (Table 2, entry 7). When 3-chloro-
N-ethylaniline, which has a larger group on N-atom, the yield N-methylaniline was used, the corresponding product 2d was
decreased to 75%, but the enantioselectivity was slightly obtained in slightly lower yield with slightly higher enantio-
increased (Table 2, entry 2). When N-allylaniline was used as a selectivity (Table 2, entry 6). However, the reaction failed to
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Beilstein Journal of Organic Chemistry 2009, 5, No. 53.
give the expected product when ortho-substituted a low yield (16%) was obtained without halide ion additives
N-methylanilines were used (Table 2, entry 5). Various para- (Table 3, entry 1). Therefore, simply changing the halide ligand
substituted N-methylanilines were shown to give the expected on the iridium catalyst from chloride to iodide or bromide leads
products in high yields with moderate enantioselectivities to improvements in the reactivity and enantioselectivity. On the
(Table 2, entries 8, 9 and 11). From Table 2, it was also found other hand, the difference in enantioselectivity between the
that the electronic property of the N-methylaniline had a signi- fluoro and the iodo complexes is particularly striking with
ficant impact on the reactivity. Electron-rich amines had higher piperidine as the nucleophile. With the Ir–F catalyst, 2i is
reactivity than electron-deficient amines (Table 2, entries 1–3, formed in only 32% yield and 40% ee. Changing to the Ir–I
5, and 10).
complex gives 2i in 90% yield and 49% ee (Table 3, entries 2
and 5).
To evaluate the scope of the reaction, we also examined various
aliphatic secondary amines under optimized reaction conditions, Having examined a wide range of secondary amines, it was
and the results are summarized in Table 3. In most cases, found that the sterically hindered nucleophiles enhanced the
aliphatic secondary amines reacted smoothly with 1a to give the enantioselectivities (up to 89% ee). Inspired by this observation,
corresponding ring-opened products (2i–l) in high yields (up to we then examined more sterically hindered substrate 1b or 1c in
90%) with enantioselectivity ranging between 49% ee and the presence of 2.5 mol % [Ir(COD)Cl]2, 5 mol % (S)-p-Tol-
65% ee (Table 3, entries 5–8). We also found that the halide BINAP, and 3.0 equiv of secondary amine nucleophiles in THF,
ions might play an important role in transition metal-catalyzed at reflux. The results are summarized in Table 4 and Table 5.
ARO reactions, in which the reactivity and enantioselectivity
could be significantly improved by choosing a suitable halide The reactions of substrate 1b, which contained methoxy groups
ion. It was found that the reaction yields and enantio- on the 5- and 8-positions, with various secondary amines
selectivities increased in the order of F<Cl<Br<I (Table 3, provided ring-opened products 3a–j in yields from 65% to 83%
entries 2–5). But under the optimized reaction conditions, only and enantioselectivities from 41% to 89%. We further found
Table 3: ARO of oxabenzonorbornadiene 1a with various aliphatic secondary amines.a
Entry
1
HNR3R4
Additiveb
–
Product
Time (h)
24
Yield (%)c
16
ee (%)d
45
2i
2
3
4
5
NH4F
NH4Cl
NH4Br
NH4I
24
24
24
12
32
45
60
90
40
43
45
49
6
7
NH4I
NH4I
2j
20
8
72
88
65
53
2k
8
NH4I
2l
15
78
56
aThe reaction was carried out with 1a (0.34 mmol) and 3.0 equiv of aliphatic secondary amine (1.0 mmol) in THF (2.0 mL) at 80 °C in the presence of
[Ir(COD)Cl]2 (2.5 mol %) and (S)-p-Tol-BINAP (5.0 mol %). bAdditive is 1.0 equiv relative to 1a. cIsolated yields after silica gel column chromatography.
dDetermined by HPLC with a Chiralcel AD column.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 53.
Table 4: ARO of oxabenzonorbornadiene 1b with various secondary amines.a
Entry
1
HNR3R4
Product
Time (h)
12
Yield (%)b
81
ee (%)c
76
3a
2
3
3b
3c
20
8
70
68
81
43
4
5
6
3d
3e
3f
12
12
12
65
74
70
45
54
89
7
8
9
3g
3h
3i
6
83
71
79
41
63
54
12
12
10
3j
12
75
56
aThe reaction was carried out with 1b (0.34 mmol) and 3.0 equiv of secondary amine (1.0 mmol) in THF (2.0 mL) at reflux in the presence of
[Ir(COD)Cl]2 (2.5 mol %) and (S)-p-Tol-BINAP (5.0 mol %). The NH4I additive is 1.0 equiv relative to 1b. bIsolated yields after silica gel column chroma-
tography. cDetermined by HPLC with a Chiralcel AD column.
that the substituent groups on the substrate did not apparently assigned as (1S,2S), and the hydroxyl group and 4-bromo-N-
influence the yields, whereas the ee values increased, in some methylaniline group are in a trans relationship (Figure 1).
cases, to as high as 89% ee (Table 4, entry 6).
Based on our studies in this article, the reaction mechanism is
The absolute configuration of ring-opened product 3f was proposed as shown in Scheme 2. The chiral dimeric iridium
demonstrated by X-ray crystallography. The single crystal was complex A is first formed. The dimer A is cleaved by solvation
obtained by evaporation of the solvent from its solution in (THF) to become monomer B. The oxygen atom and the double
dichloromethane and petroleum ether. Its configuration was bond of oxabenzonorbornadiene 1a are then reversibly coordi-
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Beilstein Journal of Organic Chemistry 2009, 5, No. 53.
Table 5: Iridium-catalyzed asymmetric ring-opening reaction of substrate 1c.a
Entry
Nucleophile
Ligand
Product
Time (h)
Yield (%)b
ee (%)c
1
2
3
4
5
2-Piperazin-1-ylbenzonitrile
4-Fluorophenylpiperazine
2-Fluorophenylpiperazine
1-(4-Methoxyphenyl)piperazine
3,4-Dichlorophenylpiperazine
(S)-p-Tol-BINAP
(S)-p-Tol-BINAP
(S)-p-Tol-BINAP
(S)-p-Tol-BINAP
(S)-p-Tol-BINAP
4a
4b
4c
4d
4e
24
24
24
24
24
70
68
73
62
27
37
49
38
59
16
aConditions: [Ir(COD)Cl]2 (2.5 mol %) and ligand (5.0 mol %) were dissolved in THF and stirred for 10–20 min. Then NH4I was added and the mixture
stirred for another 10–20 min. The substrate 1c was added and the mixture heated to reflux. The nucleophiles were added on the first sign of reflux.
bIsolated yields after silica gel column chromatography. cDetermined by HPLC with a Chiralcel AD column or AD column.
Figure 1: ORTEP plot for 3f.
nated to the iridium center of the catalyst to give the interme- catalyzed ARO reactions, which provided potential applica-
diate C. Oxidative insertion of C in to the C–O bond forms D. tions in asymmetric synthesis of chiral building blocks. The 1,2-
Then, attack of the secondary amine nucleophile along with trans-configuration of the product was confirmed by X-ray
configurational inversion is proposed to occur in an SN2′ crystallography. The search for an optimized ligand aiming to
displacement of the iridium catalyst. The trans-1,2-dihydro- enhance enantioselectivity and the extension of this reaction to
naphthalenol product 2 is subsequently released and the iridium other types of substrates and nucleophiles are currently under
monomer B is regenerated.
investigation in our labs.
Conclusion
Experimental
In summary, we have explored the iridium-catalyzed ARO reac- General procedure (I) for the asymmetric ring-opening
tion of oxabicyclic alkenes with N-alkylated anilines or reactions of oxabenzonorbornadiene 1a with substituted
N-substituted piperazine nucleophiles; the reactions gave the N-alkylaniline: A 5.0 mL round-bottom flask fitted with a
desired products in moderate to good yields with good enantio- reflux condenser was flame-dried under a stream of nitrogen
selectivities. The iridium-catalyzed ARO reactions described in and cooled to room temperature. [Ir(COD)Cl]2 (5.8 mg,
this article featured lower cost compared with rhodium- 2.5 mol %) and (S)-p-Tol-BINAP (10.7 mg, 5 mol %) were
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Beilstein Journal of Organic Chemistry 2009, 5, No. 53.
Scheme 2: Proposed mechanism for the ARO of oxabenzonorbornadiene 1a with secondary amine nucleophiles.
simultaneously added, followed by an addition of anhydrous +110.8 (c 1.00, CHCl3). IR (KBr, cm−1): 3514(s), 2980(s),
tetrahydrofuran (2.0 mL). After they were stirred for about 10 2869(s), 1645(w), 1599(w), 1500(s), 1381(s), 1297(m), 1136(s),
min, oxabenzonorbornadiene 1a (50.0 mg, 0.347 mmol) was 934(m), 845(m), 794(m). 1H NMR (400 MHz, CDCl3): δ 7.54
added and the resulting mixture was heated to reflux. On the (d, J = 4.8 Hz, 1H), 7.28–7.23 (m, 4H), 7.13–7.10 (m, 1H), 6.96
first sign of reflux, nucleophile (3.0 equiv to 1a) was added. (d, J = 8.4 Hz, 2H), 6.80 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 10.0
The temperature was continuously increased to 80 °C until the Hz, 1H), 5.94–5.90 (m, 1H), 5.10 (d, J = 9.6 Hz, 1H), 4.73 (dd,
reaction was complete as determined by thin layer chromato- J = 2.4, 2.4 Hz, 1H), 2.84 (d, J = 2.4 Hz, 3H), 2.38 (br s, 1H).
graphy. The reaction mixture was then concentrated in vacuo 13C NMR (100 MHz, CDCl3): δ 150.2, 136.5, 131.9, 129.7,
and purified by column chromatography (silica gel: 200–300 129.2, 128.1, 127.9, 127.7, 126.4, 125.6, 118.1, 114.7, 70.0,
mesh) to give the target product.
63.5, 33.4. MS (ESI) m/z Calcd for C17H17NO (M+): 251.13;
Found: 251.83. Anal. Calcd for C17H17NO: C, 81.24; H, 6.82;
(1S,2S)-2-[Methyl(phenyl)amino]-1,2-dihydronaphthalen-1- N, 5.57. Found: C, 81.52; H, 6.92; N, 5.73.
ol (2a): Following the general procedure (I), 2a was obtained as
a colorless oil (76.0 mg, 87%). Rf = 0.17 on silica gel (ethyl See Supporting Information for details of the syntheses of the
acetate:petroleum ether = 1:20, v/v). The ee was determined to new compounds 2b-l, 3a-j, and 4a-d.
be 52% using HPLC analysis on a Chiralcel AD column
(hexane/2-propanol = 95/5, 0.5 mL/min, λ = 254 nm); Reten-
tion times were 32.9 min (major) and 36.5 min (minor). [α]D20
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Beilstein Journal of Organic Chemistry 2009, 5, No. 53.
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Supporting Information
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14884–14892. doi:10.1021/ja034845x
Experimental procedures and full characterization data for
all the new compounds including optical rotations, IR,
1H NMR and 13C NMR, MS and elemental analysis are
provided in the Supporting Information. In addition, X-ray
structure data for compound 3f are given.
19.Webster, R.; Böing, C.; Lautens, M. J. Am. Chem. Soc. 2009, 131,
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Supporting Information File 1
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[http://beilstein-journals.org/bjoc/content/supplementary/
1860-5397-5-53-S1.doc]
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Acknowledgments
We are grateful to the National Natural Science Foundation of
China (No. 20772036) and the Natural Science Foundation of
Guangdong Province (No. 8251063101000002 and No.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 53.
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