Iridium-catalyzed anti-stereocontrolled asymmetric ring opening of azabicyclic alkenes with primary aromatic amines

Article abstract of DOI:10.1021/om100722f

A novel iridium-catalyzed ring-opening reaction of azabicyclic alkenes with a variety of primary aromatic amines is reported, which afforded the corresponding 1,2-trans-diamine derivatives in high yields (up to 96%) with excellent enantioselectivities (up

Full text of DOI:10.1021/om100722f

5936 Organometallics 2010, 29, 5936–5940
DOI: 10.1021/om100722f
Iridium-Catalyzed Anti-Stereocontrolled Asymmetric Ring Opening of
Azabicyclic Alkenes with Primary Aromatic Amines
Dingqiao Yang,*,† Yuhua Long,*,† Yujuan Wu,† Xiongjun Zuo,† Qingqiang Tu,†
Shai Fang,† Lasheng Jiang,† Sanyong Wang,‡ and Chunrong Li‡
†School of Chemistry and Environment, South China Normal University, Guangzhou 510006, People’s
Republic of China, and ‡Guangdong Food Industry Institute, Guangzhou 510308, People’s Republic of China
Received July 24, 2010
A novel iridium-catalyzed ring-opening reaction of azabicyclic alkenes with a variety of primary
aromatic amines is reported, which afforded the corresponding 1,2-trans-diamine derivatives in high
yields (up to 96%) with excellent enantioselectivities (up to 97% ee) under relatively mild conditions. The
trans configuration of product 2b was confirmed by X-ray crystallography.
Transition-metal-catalyzed asymmetric ring-opening (ARO)
reactions have been demonstrated to be useful methods for the
synthesis of chiral building blocks.1 Many ARO reactions offer
excellent enantioselectivities, such as the palladium-catalyzed
ARO reactions of organoboronic acids,2 the nickel-catalyzed
conjugate addition of terminal alkynes,3 the copper-cata-
lyzed ARO reactions of Grignard reagents4 and aluminum
reagents,5 the rhodium-catalyzed ARO reactions of phenol,6
and various metal-catalyzed ARO reactions of dialkylzincs.7
Those reactions provide potential promising methods to
form carbon-nitrogen bonds through the addition of nitro-
gen-based nucleophiles to the azabicyclic alkenes, offering
facile and efficient synthetic routes to 1,2-trans-diamino
derivatives. Compounds possessing a 1,2-trans-diamino
skeleton have many potential applications in both chemistry
and medicine.8 In addition, the catalytic addition of amines
to unsaturated bonds has attracted great attention in organic
synthesis because of its high atom efficiency.9 Recently,
ARO of oxa- and azabicyclic alkenes with nitrogen-based
nucleophiles catalyzed by rhodium and iridium com-
plexes has been reported by Lautens et al.10a-e and our
laboratory,10f-k respectively. Herein, we report the exten-
sion of this method to asymmetric ring-opening reactions of the
less reactive azabicyclic alkenes 1a-c with primary aromatic
amines to afford the corresponding cyclohexyl 1,2-trans-
diamine derivatives in good to excellent enantioselectivities in
the presence of iridium catalysts.
*To whom correspondence should be addressed. E-mail: yangdq@scnu.
edu.cn (D.Y.); yuhualong68@hotmail.com (Y.L.). Tel: þ86 20 39310068.
Fax: þ86 20 85210087.
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pubs.acs.org/Organometallics
Published on Web 10/25/2010
2010 American Chemical Society

Article
Organometallics, Vol. 29, No. 22, 2010 5937
Table 1. Identification of the Optimal Chiral Ligand for Iridium-Catalyzed Asymmetric Ring-Opening of N-Boc-Azabenzonorbornadiene
1a with Anilinea
entry
ligand (amt (mol %))
amt of [Ir(COD)Cl]2 (mol %)
time (h)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
DPPF (5)
2.5
1.0
1.5
2.0
2.5
4.0
1.0
1.0
20
24
24
18
16
12
24
60
71
55
70
62
72
76
43
8
(S)-BINAP (2)
(S)-BINAP (3)
(S)-BINAP (4)
(S)-BINAP (5)
(S)-BINAP (8)
(S)-p-Tol-BINAP (2)
(R)-(S)-PPF-PtBu2 (2)
78
79
69
75
72
72
52
a The reaction was carried out with 1a (0.21 mmol) and 3.0 equiv of aniline (0.63 mmol) in THF (2.0 mL) at 80 °C (oil bath temperature). b Isolated
yield after silica gel column chromatography. c Determined by HPLC with a Chiralcel AD-H colum.
Results and Discussion
have been widely used in the ring-opening reaction.13 Among
the chiral ligands we tested, (S)-BINAP gave the highest ee value
(Table 1, entries 2 and 3), while (S)-p-Tol-BINAP gave a slightly
lower ee value with poor yield (Table 1, entry 7). Poor
enantioselectivity and low yield (Table 1, entry 8) were
observed with (R)-(S)-PPF-PtBu2 in the iridium-catalyzed
reaction. This suggested that (R)-(S)-PPF-PtBu2 was not
an ideal ligand, although it performed well in the rhodium-
catalyzed ARO reactions, in which the reactions offered
excellent enantioselectivities.14
Among the chiral ligands we had tested, (S)-BINAP and
(S)-p-Tol-BINAP were found to give better yields and
reasonable enantioselectivities(Table 1, entries 2-7). More-
over, in the case of (S)-BINAP, the enantioselectivitiy was
found to be slightly higher than for (S)-p-Tol-BINAP (79% ee
vs 72% ee). Therefore, we chose (S)-BINAP as the ligand for
this ring-opening reaction (Table 1, entry 3).
It was found that the enantioselectivities of the ring-opening
reaction of 1a were influenced by the amount of catalyst
loading. For example, when 4 mol % of [Ir(COD)Cl]2 was
used, the reaction gave product 2a in 72% ee with a low yield
after 12 h (Table 1, entry 6). When 2.5 mol % Ir catalyst was
used, the yield of ring-opening product was also low (Table 1,
entry 5). The best result was obtained with 1.5 mol % of
[Ir(COD)Cl]2 (Table 1, entry 3).
The solvents used in the ARO reaction were found to be
crucial. We screened several common used solvents (Table 2,
entries 1-6 and 8). Among the screened solvents, THF gave
68% yield and 85% enantioselectivity (Table 2, entry 9),
while in DME, dioxane, and THP the enantioselectivities were
79%, 43%, and 79% ee, respectively (Table 2, entries 4-6). The
reactions in CH2Cl2 and CH3CN gave higher ee values but
N-Boc-azabenzonorbornadiene (1a) was prepared through
the cycloaddition of benzyne with commercially available
N-Boc pyrrole on the basis of the literature method.10a,c
Benzyne could be generated in situ from anthranilic acid and
isoamyl nitrite, and the N-substituted group in 1a could be
easily replaced by other groups in one step. For example,
treating 1a in CH2Cl2 with Et3N and tetramethylsilane
(TMSI) followed by CH3OH and sulfonyl chloride or acetyl
chloride gave the corresponding N-sulfonyl-substituted (1b) or
acetyl-substituted (1c) derivatives.
Rhodium catalysts have been demonstrated to offer high
regio- and enantioselectivities in ARO reactions of azabicyclic
alkenes with terminal alkynes,3 amines,10a,11 and arylboronic
acids.12 Moreover, rhodium and iridium have similar chemical
properties. It was expected that the iridium-catalyzed ARO
reactions of azabicyclic alkenes with amine nucleophiles would
proceed through a mechanism similar to that of rhodium-
catalyzed ARO reactions.10d
To validate the catalytic activity of the iridium complex,
1,10-bis(diphenylphosphino)ferrocene (DPPF), a cheaper achiral
ligand, was selected to screen the ARO reaction of 1a with
aniline nucleophile. The desired product 2a was obtained in
moderate yield (71%) (Table 1, entry 1). Encouraged by these
results, we then used other chiral diphosphine ligands which
(11) Cho, Y.-H.; Fayol, A.; Lautens, M. Tetrahedron: Asymmetry
2006, 17, 416–427.
(12) Murakami, M.; Igawa, H. Chem. Commun. 2002, 4, 390–391.
(13) (a) Li, L.-P.; Rayabarapu, D. K.; Nandi, M.; Cheng, C.-H. Org.
Lett. 2003, 5, 1621–1624. (b) Feng, C.-C.; Nandi, M.; Sambaiah, T.; Cheng,
C.-H. J. Org. Chem. 1999, 64, 3538–3543. (c) Nakamura, M.; Matsuo, K.;
Inoue, T.; Nakamura, E. Org. Lett. 2003, 5, 1373–1375. (d) Millward, D. B.;
Sammis, G.; Waymouth, R. M. J. Org. Chem. 2000, 65, 3902–3909.
(e) Lautens, M.; Renaud, J.-L.; Hiebert, S. J. Am. Chem. Soc. 2000, 122,
1804–1805.
(14) Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki, A. Org.
Lett. 2002, 4, 1311–1314.

5938 Organometallics, Vol. 29, No. 22, 2010
Yang et al.
Table 3. Iridium-Catalyzed Asymmetric Ring Opening of
N-Boc-azabenzonorbornadiene (1a) with Primary Aromatic Aminesa
Table 2. Condition Screening for the Iridium-Catalyzed Asym-
metric Ring Opening of N-Boc-azabenzonorbornadiene (1a) with
Anilinea
entry
solvent
additiveb
time (h)
yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
CH2Cl2
CH3CN
toluene
dioxane
DME
THP
24
24
24
24
24
24
48
24
24
12
24
24
24
24
24
23
35
trace
25
42
70
n.r.
49
68
54
5
86
90
43
79
79
THFe
THF
78
85
82
13
77
80
81
90
9
THFf
THFg
THF
THF
THF
10
11
12
13
14
14
NH4F
NH4Cl
NH4Br
NH4I
10
3
15
54
THF
THF
Bu4NI
a The reaction was carried out with 1a (0.21 mmol) and 3.0 equiv of
aniline (0.63 mmol) in solvent (2.0 mL) at 80 °C (oil bath temperature) in
the presence of [Ir(COD)Cl]2 (1.5 mol %) and (S)-BINAP (3.0 mol %).
b Isolated yield after silica gel column chromatography. c 1.0 equiv of
additive. d Determined by HPLC with a Chiralcel AD-H column. e Oil
bath temperature was room temperature. f Oil bath temperature was
100 °C. g Oil bath temperature was 120 °C.
a The reaction was carried out with 1a (0.21 mmol) and 3.0 equiv of
amine (0.63 mmol) in THF (2.0 mL) at 100 °C (oil bath temperature) in
the presence of [Ir(COD)Cl]2 (1.5 mol %) and (S)-BINAP (3.0 mol %).
b Isolated yield after silica gel column chromatography. c Determined by
HPLC with a chiral stationary column: (Chiralcel AD-H column for 2a,b,
Chiralcel OD-H column for 2f-k).
lower yields than those in THF (Table 2, entries 1 and 2). On
the basis of these observations, THF was found to be the
optimal solvent. From Table 2, it can be seen that the
reaction temperature had great influence on the reaction.
At room temperature (Table 2, entry 7), the reaction did
not give any ring-opening product, while the best result
was obtained at 100 °C (Table 2, entry 9). In addition, we
investigated the effect of ammonium halides as additives in
this ring-opening reaction (Table 2, entries 11-14). We
found that the halide ions played an important role in this
iridium-catalyzed ring-opening reaction, in which the
reactivity and enantioselectivity could be significantly
improved by choosing a suitable halide ion. The best
result was obtained with Bu4NI as additive. In the pres-
ence of Bu4NI, reactions underwent smoothly, the yield
was improved to 54%, and the enantioselectivity was up
to 90% ee (Table 2, entry 14). However, the yield was poor
with low enantioselectivity when NH4F was used (Table 2,
entry 11). With a series of ammonium halides, an inter-
esting trend was observed. The reaction enantioselectivi-
ties increased in the order F < Cl < Br < I. The halide
effect may derive from removing the chloride ligand from
the coordination sphere of the iridium and replacing it
with iodide prior to the addition of nucleophiles. Experimental
evidence supported the hypothesis that the halide additives
were acting at the iridium metal (Table 2, entries 11-14).
Table 3 gives the results obtained for the reactions of
several nucleophiles with 1a, which were carried out in the
presence of an iridium/(S)-BINAP catalyst (1.5 mol % of Ir).
Despite different steric and electronic effects of the nucleophiles,
the enantioselectivities of the reactions were found to be more
than 70% ee with good yields (up to 87%; Table 3, entry 10).
However, in the case of o- and m-bromoaniline, no ring-opening
products were found, even after prolonged reaction times
(Table 3, entries 3 and 4), which is probably due to steric
hindrance and electron-withdrawing effects, which would
reduce the reactivity of the -NH2 group of the nucleo-
phile. On the other hand, p-CH3 or OCH3 on the aniline
are electron-donating groups which enhanced the reactivi-
ties of the NH2 group of the nucleophiles. As a result,
good yield and enantioselectivity were obtained (Table 3,
entries 7-10).
It is also worth noting that 2,4-dimethoxyaniline reacted
with 1a to give the expected product with good yield and
enantioselectivity (Table 3, entry 10), whereas the reaction of
1a with 2,4-dibromoaniline did not produce the desired
product (Table 3, entry 5), presumably due to the electronic
effect of nucleophiles.
To further explore the reaction scope, we used several
substrates of N-substituted azabenzonorbornadienes,
including N-Ts-azabenzonorbornadiene (1b) and N-
Ac-azabenzonorbornadiene (1c), to perform the ring-opening
reactions (Tables 4 and 5). The asymmetric ring-opening
reactions of N-Ts-azabenzonorbornadiene (1b) with primary
aromatic amines were also investigated. Nucleophiles g-j,
having substituents (CH3, OCH3, and CH2CH3) on the ani-
line, gave the corresponding products 3g-j in moderate to
good yields (56-96%) with high to excelllent enantio-
selectivities (up to 97% ee) (Table 4, entries 7-10). How-
ever, in the case of 2,4-dibromoaniline as a nucleophile for

Article
Organometallics, Vol. 29, No. 22, 2010 5939
Table 4. Iridium-Catalyzed Asymmetric Ring Opening of N-
Ts-azabenzonorbornadiene (1b) with Primary Aromatic Aminesa
Table 5. Iridium-Catalyzed Asymmetric Ring Opening of N-
Ac-azabenzonorbornadiene (1c) with Primary Aromatic Amines a
a The reaction was carried out with 1c (0.21 mmol) and 3.0 equiv of
amine (0.63 mmol) in THF (2.0 mL) at 100 °C (oil bath temperature) in
the presence of [Ir(COD)Cl]2 (1.5 mol %) and (S)-BINAP (3.0 mol %).
b Isolated yield after silica gel column chromatography. c Determined by
HPLC with a chiral stationary column: (Chiralcel AD-H column for 4j,
k, Chiralcel OD-H column for 4a,b,f,g,i).
a The reaction was carried out with 1b (0.21 mmol) and 3.0 equiv of
amine (0.63 mmol) in THF (2.0 mL) at 100 °C (oil bath temperature) in
the presence of [Ir(COD)Cl]2 (1.5 mol %) and (S)-BINAP (3.0 mol %).
b Isolated yield after silica gel column chromatography. c Determined by
HPLC with a chiral stationary column: (Chiralcel AD-H column for 3a,
b,d,h,j,k, Chiralcel OD-H column for 3c,e-g,i).
this reaction, the ee value was decreased to 11% (Table 4,
entry 5). As shown in Table 4, the presence of electron-
withdrawing groups in the nucleophiles was not favorable
to enantioselectivities. Interestingly, the reaction using
1-aminonaphthalene resulted in good yield and high en-
antioselectivity (Table 4, entry 11).
The ring-opening reaction of N-Ac-azabenzonorborna-
diene (1c) was also investigated. In comparison to N-
Boc-azabenzonorbornadiene (1a), N-Ac-azabenzonorborna-
diene (1c) had lower steric hindrance on the substrate.
The results of the asymmetric ring-opening reactions with
primary aromatic amines are summarized in Table 5. Overall,
N-Ac-azabenzonorbornadiene (1c) showed good reactivity.
Unfortunately, it offered products with very poor enantioselec-
tivity. Presumably, the steric effect of the activating group on
nitrogen had a strong impact on the enantioselectivity of the
substrate ring-opening (Table 5, entries 1-7).
The absolute configuration of ring-opened product 2b was
analyzed by X-ray crystallography. Single crystals were
obtained by slow evaporation of the solvent from its solu-
tions in dichloromethane, petroleum ether, and ethyl acetate.
It was assigned a 1R,2R configuration with the groups of
HNBoc and 4-bromoaniline in a trans relationship (Figure 1).
On the basis of our observations and findings, we 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-Boc-azabenzonorborna-
diene (1a) then reversibly coordinate to the iridium center of
Figure 1. ORTEP plot for 2b.
the catalyst to give the intermediate B. Oxidative insertion of
the iridium into the C-N bond of B forms C. Then, attack of
the primary aromatic amine nucleophiles along with config-
urational inversion occurs in an SN2 displacement of the
iridium catalyst. The trans-1,2-diamino product 2 is subse-
quently released, and A is regenerated.
Conclusions
In summary, we have investigated a novel iridium-
catalyzed ring-opening reaction of azabicyclic alkenes with
primary aromatic amines, which afforded the expected
products in good yields with excellent enantioselectivities.
The key step in this approach was the iridium-catalyzed
ARO of azabenzonorbornadienes, which establishes the
diaminotetralin core, the regiochemistry, and the relative

5940 Organometallics, Vol. 29, No. 22, 2010
Scheme 1. Proposed Mechanism of the Ring-Opening Reaction
Yang et al.
and absolute stereochemistry of the diamine moiety simul-
taneously. This highly atom-economical reaction offers
a convenient method for the synthesis of functionalized
1,2-trans-diamino derivatives. Moreover, it was observed
that both the substituted groups on nitrogen of the azabicyclic
alkenes and the electronic effect of nucleophiles were
found to have remarkable impact on the enantioselectivity
of the ring-opening reaction. The results show that the
nature of the chiral ligand strongly influences the reactiv-
ity of the catalyst. Furthermore, it was also observed that the
chiral ligands play an important role in regulating the enantio-
selectivities in the ARO reaction. Studies on an asymmetric
conversion of the iridium-catalyzed reaction with other nucleo-
philes are currently under investigation in our laboratory.
Rf = 0.33 on silica gel (1/10 ethyl acetate/petroleum ether, v/v).
Mp: 84-86 °C. The ee was determined to be 86% using HPLC
analysis on a Chiralcel AD-H column (90/10 hexane/2-propanol,
v/v, 0.5 mL/min, λ 254 nm); Retention times were 15.4 min
(major) and 24.4 min (minor). [R]20 = -157.4° (c = 1.00,
D
CHCl3). IR (KBr, cm-1): 3404 (w), 2977 (w), 1704 (s), 1594 (s),
1496 (s), 1367 (m), 1319 (m), 1248 (m), 1168 (s), 814 (m),
1
782 (m). H NMR (400 MHz, CDCl3): δ 7.33-7.13 (m, 6H),
6.72 (d, J = 6.0 Hz, 3H), 6.56 (d, J = 9.6 Hz, 1H), 6.09 (dd, J =
4.4, Hz, 5.2 Hz, 1H), 5.05 (t, J = 7.2 Hz, 1H), 4.75 (d, J =
8.4 Hz, 1H), 4.28 (s 1H), 3.86 (s, 1H), 1.47 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ 155.9, 146.8, 134.0, 132.5, 129.4, 128.6,
128.5, 128.2, 127.9, 126.9, 117.5, 113.2, 79.8, 53.5, 52.4, 28.4.
MS (ESI): calcd m/z for C21H24N2O2 (Mþ) 336.18, found
359.26 (M þ Na)þ. Anal. Calcd for C21H24N2O2: C, 74.97;
H, 7.19; N, 8.33. Found: C, 74.62; H, 7.51; N, 8.46.
The ARO reactions of N-Boc-azabenzonorbornadiene (1a),
N-Ts-azabenzonorbornadiene (1b), and N-Ac-azabenzonor-
bornadiene (1c) with primary aromatic amines are the same as
the above representative procedure. See the Supporting Infor-
mation for details of the syntheses of the new compounds 2a-k,
3a-k, and 4a-k.
Experimental Section
General Procedure for the Asymmetric Ring Opening of N-
Boc-azabenzonorbornadiene (1a) with Primary Aromatic Amines.
A 5.0 mL round-bottomed flask fitted with a reflux condenser
was flame-dried under a stream of nitrogen and cooled to room
temperature. [Ir(COD)Cl]2 (2.1 mg, 1.5 mol %) and (S)-BINAP
(3.9 mg, 3 mol %) were simultaneously added, followed by
addition of anhydrous THF (2.0 mL). After the mixture was
stirred for about 10 min, N-Boc-azabenzonorbornadiene (1a)
(48.6 mg, 0.2 mmol) was added and the mixture was heated to
reflux. On the first sign of reflux, nucleophile (3 equiv with
regard to 1a) was added. Then the temperature was continu-
ously increased to 100 °C until the reaction was complete, as
judged by thin-layer chromatography. The solvent was removed in
vacuo, and the crude mixture was purified by column chromatog-
raphy (silica gel: 200-300 mesh) to give the target product.
Acknowledgment. We are grateful to the National
Natural Science Foundation of China (Nos. 20772036
and 20802021) and the Natural Science Foundation of
Guangdong Province (No.8251063101000002) for finan-
cial support.
Supporting Information Available: Text, figures, and tables
giving experimental procedures and full characterization data
for all new compounds, including optical rotations, IR, 1H and
13C NMR, MS, elemental analyses, and X-ray structure data for
compound 2b. This material is available free of charge via the
Internet at http://pubs.acs.org.
(1R,2R)-[2-(Phenylamino)-1,2-dihydronaphthalen-1-yl]carbamic
Acid tert-Butyl Ester (2a). Following the above general
procedure, 2a was obtained as a white solid (47.7 mg, 71%).