Iridium-catalyzed asymmetric ring-opening reactions of N-boc- azabenzonorbornadiene with secondary amine nucleophiles

Article abstract of DOI:10.1021/ol801768e

(Equation Presented) Iridium-catalyzed asymmetric ring-opening reactions of N-Boc-azabenzonorbornadiene with a number of secondary amines has been developed for the first time. The reaction gave 1,2-trans-diamine derivatives in moderate to good yields wit

Full text of DOI:10.1021/ol801768e

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4723-4726
Iridium-Catalyzed Asymmetric
Ring-Opening Reactions of
N-Boc-azabenzonorbornadiene with
Secondary Amine Nucleophiles
Dingqiao Yang,* Yuhua Long, Huan Wang, and Zhenming Zhang
School of Chemistry and EnVironment, South China Normal UniVersity,
Guangzhou 510006, China
yangdq@scnu.edu.cn
Received June 17, 2008
ABSTRACT
Iridium-catalyzed asymmetric ring-opening reactions of N-Boc-azabenzonorbornadiene with a number of secondary amines has been developed
for the first time. The reaction gave 1,2-trans-diamine derivatives in moderate to good yields with high enantioselectivity in the presence of
2.5 mol % of [Ir(COD)Cl]2 and 5 mol % of (S)-BINAP. The trans-configuration of the 1,2-diamino products was confirmed by X-ray crystallography.
Transition-metal-catalyzed asymmetric ring-opening of het-
erobicyclic alkenes is one of the most powerful tools for the
synthesis of optically active compounds. Iridium-catalyzed
allylic substitution reaction is an efficient protocol; it has
emerged as an effective approach to the construction of
carbon-carbon bonds and carbon-heteroatom bonds, which
provides a feasible way to generate useful multifunctional
chiral building blocks.1 As a result, two new chiral centers
can be established by desymmetrization of a meso-bicyclic
alkene in a single step.2
Recently, Cu-catalyzed, highly enantioselective conjugate
addition and allylic alkylation reactions with Grignard
reagents were developed by Feringa3 and Alexakis,4 respec-
tively.
To the best of our knowledge, asymmetric ring-opening
of N-substituted azabenzonorbornadienes is currently focused
on Rh and Pd catalysts. For example, Lautens and co-
workers5 and Carretero and co-workers6 have extensively
investigated the Pd-catalyzed asymmetric ring-opening of
N-substituted azabenzonorbornadienes with organozinc re-
agents.
(1) For reviews, see: (a) Nomura, N.; Komiyama, S.; Kasugai, H.; Saba,
M. J. Am. Chem. Soc. 2008, 130, 812–814. (b) Alexakis, A.; Hajjaji, S. E.;
Polet, D.; Rathgeb, X. Org. Lett. 2007, 9, 3393–3395. (c) Polet, D.; Alexakis,
A. Org. Lett. 2005, 7, 1621–1624. (d) Kanayama, T.; Yoshida, K.; Miyabe,
H.; Kimachi, T.; Takemoto, Y. J. Org. Chem. 2003, 68, 6197–6201. (e)
Woodward, S. Angew. Chem., Int. Ed. 2005, 42, 5560–5562. (f) Hayashi,
T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829–2844. (g) Lautens, M.;
Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48–58.
In addition, Lautens and co-workers7 also explored the
Rh-catalyzed asymmetric ring-opening of N-Boc-azaben-
zonorbornadienes with amine nucleophiles.
(2) (a) Ward, R. S. Chem. Soc. ReV. 1990, 19, 1–19. (b) Magnuson,
S. R. Tetrahedron 1995, 51, 2167–2213. (c) Lautens, M.; Fagnou, K.;
Taylor, M.; Rovis, T. J. Organomet. Chem. 2001, 624, 259–270. (d) Lautens,
M.; Rovis, T. J. Org. Chem. 1997, 62, 5246–5247.
(5) Lautens, M.; Hiebert, S.; Renaud, J. L. Org. Lett. 2000, 2, 1971–
1973.
(3) (a) Lopez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L.
J. Am. Chem. Soc. 2004, 126, 12784–12785. (b) Lopez, F.; Van Zijl, A. W.;
Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2006, 409–411.
(4) (a) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew. Chem., Int.
Ed. 2004, 43, 2426–2428. (b) Falciola, C. A.; Tissot-Croset, K.; Alexakis,
A. Angew. Chem., Int. Ed. 2006, 45, 5995–5998.
(6) Cabrera, S.; Arrayas, R. G.; Alonso, I.; Carretero, J. C. J. Am. Chem.
Soc. 2005, 127, 17938–17947.
(7) (a) Cho, Y. H.; Zunic, V.; Senboku, H.; Olsen, M.; Lautens, M.
J. Am. Chem. Soc. 2006, 128, 6837–6846. (b) Cho, Y. H.; Fayol, A.;
Lautens, M. Tetrahedron: Asymmetry 2006, 17, 416–427.
10.1021/ol801768e CCC: $40.75
Published on Web 10/04/2008
2008 American Chemical Society

However, the ring-opening of N-substituted azabenzonor-
bornadiene using other transition-metal catalysts remains
unknown. Herein, we report the first iridium-catalyzed
asymmetric ring-opening of N-Boc-aza-benzonorbornadiene
with N-substituted piperazine nucleophiles. Compared with
previous methods, this method has several advantages: the
catalyst [Ir(COD)Cl]2 is easy to make and the BINAP ligand
is commercially available at low cost. Both catalyst and
ligand are air-stable, which would remarkably simplify the
synthetic procedure. This new method also offers potentially
useful synthetic routes to trans-1,2-diamines which are the
scaffolds for chiral ligands8 and valuable intermediates for
total synthesis of bioactive compounds.9
N-Boc-azabenzonorbornadiene 1 and [Ir(COD)Cl]2 were
prepared according to the reported procedure.10,11 We first
chose an achiral 1,1′-bis(diphenylphosphino)ferrocene (DPPF)
ligand to validate the catalytic activity of the iridium
complex.
In the initial attempts, N-phenylpiperazine was used as a
nucleophile. When it reacted with N-Boc-azabenzonorbor-
nadiene 1 (0.21 mmol) in THP (2 mL) at 100 °C in the
presense of 2.5 mol % of [Ir(COD)Cl]2 and 5 mol % of
DPPF, the corresponding product 2a was obtained in a high
yield of 78% after 6 h (Table 1, entry 1). This result
PPF-PtBu2 was not an ideal ligand, which prompted us to
screen other ligands. Among several chiral ligands we had
tested, (S)-BINAP13 and (S)-p-Tol-BINAP were found to
give better yields and reasonable enantioselectivity (Table
1, entries 3 and 4). Moreover, in the case of (S)-BINAP, the
enantioselectivity is slightly higher (79% vs 70% ee);
therefore, we decided to use (S)-BINAP as a ligand.
We further found that the use of 2.5 mol % of [Ir-
(COD)Cl]2 and 5 mol % of (S)-BINAP was needed to ensure
both high yield and enantioselectivity (Table 2, entry 1).
Table 2. Condition Screening for Iridium-Catalyzed Asymmetric
Ring-Opening Reactions of N-Boc-Azabenzonorbornadiene 1
with N-Phenylpiperazinea
entry solvent T (°C) additive time (h) yieldb (%) eec (%)
1
THPg
THFh
THP
100
100
100
100
100
100
100
100
100
25
8
24
8
76
36
77
78
35
31
21
26
70
79
72
72
70
45
68
10
50
75
2d
3e
4f
5
THP
8
toluene
CH3CN
DME
DMF
dioxane
THP
THP
THP
THP
THP
24
24
24
24
8
12
48
8
24
24
24
24
6
7
8
9
10
11
12
13
14
15
16
n.r
80
18
79
nr
10
24
48
70
67
Table 1. Identification of Optimal Chiral Ligand for
Iridium-Catalyzed Asymmetric Ring-Opening of
N-Boc-azabenzonorbornadiene 1 with N-Phenylpiperazine
120
100
100
100
100
NH4F
NH4Cl
NH4Br
NH4I
21
43
68
THP
THP
a The reaction was carried out with 1 (0.21 mmol) and 3.0 equiv of
N-phenylpiperazine (0.63 mmol) in solvent (2.0 mL) in the presence of
[Ir(COD)Cl]2 (2.5 mol %) and (S)-BINAP (5.0 mol %). b Isolated yield
after silica gel column chromatography. c Determined by HPLC with a
Chiralcel AD column. d [Ir(COD)Cl]2: 1.0 mol %, (S)-BINAP: 2.0 mol %.
e [Ir(COD)Cl]2: 3.5 mol %, (S)-BINAP: 7.0 mol %. f [Ir(COD)Cl]2: 5.0 mol
%, (S)-BINAP: 10.0 mol %. g THP is tetrahydropyran. h THF is
tetrahydrofuran.
Slightly higher yields but lower enantioselectivities were
observed when more catalyst was loaded (Table 2, entries 3
and 4), and lower catalyst loading (1.0 mol %) resulted in a
considerable decrease in yield (Table 2, entry 2).
entry
ligand
DPPF
time (h)
yielda (%)
eeb (%)
Next, we screened the impact of solvents (Table 2, entries
5-9). Among the solvent systems tested, tetrahydropyran
(THP) was found to be optimal to give the best yield and
enantioselectivity for 2a. Temperature was found to play an
important role in the reaction. At room temperature, there
was no reaction (Table 2, entry 10). The best results were
obtained at 100 °C (Table 2, entry 1). At 80 °C, a sluggish
reaction was observed with poor yield (Table 2, entry 11).
At higher temperature, such as 120 °C, it was found that the
reaction gave a better yield but with worse enantioselectivity
(Table 2, entry 12).
1
2
3
4
6
24
8
78
23
76
75
0
58
79
70
(R,S)-PPF-Pt-Bu2
(S)-BINAP
(S)-p-Tol-BINAP
8
a Isolated yield after silica gel column chromatography. b Determined
by HPLC with a Chiralcel AD column. c Solvent is tetrahydropyran.
encouraged us to screen other chiral phosphine ligands so
as to optimize the reaction conditions. Ferrocenyl diphos-
phine ligand, (R,S)-PPF-PtBu2,12 was first attempted.
Unfortunately, the desired product, 2a, was obtained in
low yield (23%) with reasonable enantioselectivity (58% ee)
after 24 h (Table 1, entry 2). This result suggested (R,S)-
Lautens and Fagnou14 found that the halide ions might
play an important role in transition-metal catalysis, in which
the reactivity and enantioselectivity could be significantly
improved by choosing a suitable halide ion. Inspired by those
4724
Org. Lett., Vol. 10, No. 21, 2008

findings, we attempted to use ammonium halides (NH4X, X
) F, Cl, Br, I) as additives15 (1 equiv to 1) (Table 2, entries
13-16).
However, in our hands, we found that the halide ions were
not necessary and that the reaction worked even better
without them.
Table 4. Scope of Ring-Opening Reactions of
N-Boc-azabenzonorbornadiene 1 with Disubstituted
N-Phenylpiperazines and Other Types of Substituted
Piperazinesa
Based on those observations, we decided to expand the
reaction to a number of substituted N-phenylpiperazines
(Table 3), which consistently showed satisfactory yields and
enantioselectivities.
entry
R
time (h) product yieldb (%) eec (%)
1
2
3
4
5
6
7
8
9
10
3,4-Cl2C6H3
2,4-F2C6H3
3,4-Me2C6H3
2,5-Me2C6H3
2,4-Me2C6H3
2,3-Me2C6H3
CHPh2
CH2Ph
CO2Et
furoyl
8
10
12
12
12
18
12
48
24
48
2p
2q
2r
2s
84
78
76
68
72
65
83
61
73
67
79
73
73
74
75
84
77
84
73
61
Table 3. Scope of Ring-Opening Reactions of
N-Boc-azabenzonorbornadiene 1 with Substituted
N-Phenylpiperazinesa
2t
2u
2v
2w
2x
2y
a The reaction was carried out with 1 (0.21 mmol) and 3.0 equiv of
substituted piperazine (0.63 mmol) in THP (2 mL) at 100 °C in the presence
of [Ir(COD)Cl]2 (2.5 mol %) and (S)-BINAP (5.0 mol %). b Isolated yield
after silica gel column chromatography. c Determined by HPLC with a
Chiralcel AD column.
entry
R
time (h)
product
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
p-OMe
p-Me
p-F
6
8
8
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
86
77
79
82
67
73
61
72
59
65
69
55
75
70
87
83
77
79
75
80
65
81
82
81
76
78
78
82
p-Cl
8
p-COMe
p-CF3
p-NO2
o-OMe
o-Me
24
24
24
12
24
18
18
48
12
12
The crystal structure of 2w, obtained by solvent-evapora-
tion from its solution in dichloromethane and petroleum
ether, confirmed its 1,2-trans configuration, i.e, (1R,2R)16 as
shown in Figure 1. It is obvious that the reaction favors the
formation of trans-1,2-diamino products.
9
10
11
12
13
14
o-F
o-Cl
o-CN
m-Me
m- CF3
a The reaction was carried out with 1 (0.21 mmol) and 3.0 equiv of
substituted N-phenylpiperazine (0.63 mmol) in THP (2 mL) at 100 °C in
the presence of [Ir(COD)Cl]2 (2.5 mol %) and (S)-BINAP (5.0 mol %).
b Isolated yield after silica gel column chromatography. c Determined by
HPLC with a Chiralcel AD column.
The results (Table 3) also demonstrated that the functional
groups on the phenyl ring of nucleophiles had less impact
on both yields and enantioselectivies. However, it was
observed that electron-rich functional groups on the phe-
nylpiperazines are more reactive than those of electron-
deficient ones. For example, the reaction of N-Boc-
azabenzonorbornadiene 1 with 4-methoxyphenylpiperazine
offered much higher yield in a shorter time compared to that
of 4-nitrophenylpiperazine (Table 4, entries 1 and 7).
Moreover, we observed that substituted groups at the
ortho-position of the phenyl ring gave poorer yields (Table
4, entries 8-12) than those of meta- and para-substituted
N-phenylpiperazines, probably due to steric hindrance.
We further extended our reactions to the phenylpiperazines
with two substituents on the phenyl ring as well as other
types of substituted piperazines (Table 4).
Figure 1. ORTEP plot for 2w.
To further investigate the scope of this new catalyst
system, ring-opening reactions of N-Boc-azabenzonorbor-
nadienes with compounds such as substituted N-methyla-
niline as nucleophiles were investigated. The optimized
conditions in this reaction were used to study the catalytic
asymmetric ring-opening of 1 in the presence of 1.5 mol %
of [Ir(COD)Cl]2 and 3.0 mol % of (S)-BINAP in THF with
the results summarized in Table 5. Remarkably, it was found
that the reactivity and enantioselectivity are both lower than
that of N-substituted piperazines nucleophiles. This happens
because of the p-π conjugation of the nitrogen lone pair with
These ring-opening reactions all proceeded smoothly with
high yields and enantioselectivities.
Org. Lett., Vol. 10, No. 21, 2008
4725

formed. The nitrogen atom and the double bond of N-Boc-
azabenzonorbornadiene 1 are then reversibly coordinated to
the iridium center of the catalyst to give the intermediate B.
Insertion of the iridium into the C-N bond of B forms
C.
Table 5. Asymmetric Ring-Opening Reactions of
N-Boc-azabenzonorbornadiene 1 with Substituted
N-Methylanilines
Nucleophilic attack with configuration inversion is pro-
posed to occur in an SN2′ displacement of the iridium
catalyst. The trans-1,2-diamino product 2 was subsequently
released, and the iridium complex A was regenerated.
In summary, we have successfully developed the first
enantioselective iridium-catalyzed ring-opening reactions of
N-Boc-azabenzonorbornadiene with a number of secondary
amine nucleophiles. It provides an efficient and practical
access to the optically active 1,2-diimine derivatives in
moderate to good yields with high enantioselectivities. The
new method is significant in terms of the low cost for the
ligands and facile manipulation compared to literature close
precedents. An investigation on the biological and pharma-
ceutical activities of the products is in progress. Studies on
further expansion of the scope and synthetic utility of this
Ir-catalyzed method are also being pursued in our laboratory.
entry
R
time (h)
product
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
H
48
48
48
48
48
48
48
48
3a
3b
3c
3d
3e
3f
56
48
56
59
24
29
48
nr
80
49
85
55
51
65
42
3-Cl
3-Me
4-Cl
4-F
4-Br
4-OMe
4-NO2
3g
3h
a The reaction was carried out with 1 (0.21 mmol) and 3.0-5.0 equiv
of N-methylanilines in THF (2.0 mL) at 80 °C 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
Chiralcel AD column.
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (No.20772036) and the Natural
Science Foundation of Guangdong Province (No.8251063101-
000002 and No.7005804) for financial support.
the electron cloud of the benzene ring for substituted
N-methylaniline and decreases the ability of nucleophiles.
For example, electron-withdrawing substituted groups on the
benzene ring of N-methylanilines decreased the ability of
nucleophiles and gave low yields and enantioselectivities
(Table 5, entries 2, 4-6, and 8).
Supporting Information Available: Experimental pro-
cedures and full characterization data for all new products
including optical rotations, IR, 1H NMR and 13C NMR, MS,
elemental analysis, and X-ray structure data for compound
2w. This material is available free of charge via the Internet
at http://pubs.acs.org.
Based on our studies, a working hypothesis is shown in
Scheme 1.17 The chiral dimeric iridium complex A is first
OL801768E
(8) (a) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem.
ReV. 2000, 100, 2159–2232. (b) Trost, B. M.; Van Vranken, D. L.; Bingel,
C. J. Am. Chem. Soc. 1992, 114, 9327–9343. (c) Jacobsen, E. N.; Zhang,
W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991, 113,
7063–7064. (d) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N.
J. Am. Chem. Soc. 1990, 112, 2801–2803.
Scheme 1. Working Hypothesis for the Asymmetric
Ring-Opening of N-Boc-azabenzonorbornadiene 1 with
Secondary Amine Nucleophiles
(9) (a) Alexander van Vliet, L.; Tepper, P. G.; Dijkstra, D.; Damsma,
G.; Wikstrom, H.; Pugsley, T. A.; Akunne, H. C.; Heffner, T. G.; Glase,
S. A.; Wise, L. D. J. Med. Chem. 1996, 39, 4233–4237. (b) Degnan, A. P.;
Meyers, A. I. J. Org. Chem. 2000, 65, 3503–3512. (c) Marquet, A. Pure
Appl. Chem. 1993, 65, 1249–1252. (d) Hettinger, T. P.; Craig, L. C.
Biochemistry 1970, 9, 1224–1232. (e) Umezawa, H.; Maeda, K.; Takeuchi,
T.; Okami, Y. J. Antibiot. Ser. A 1996, 19, 200–209.
(10) Lautens, M.; Fagnou, K.; Zunic, V. Org. Lett. 2002, 4, 3465–3468.
(11) Van der Ent, A.; Onderdelinden, A. L. Inorg. Synth. 1973, 14, 92–
95.
(12) (a) Blaser, H. U.; Buser, H. -P.; Hausel, R.; Jalett, H. -P.; Spindler,
F. J. Organomet. Chem. 2001, 621, 34–38. (b) Nishibayashi, Y.; Singh,
J. D.; Arikawa, Y.; Uemura, S.; Hidai, M. J. Organomet. Chem. 1997, 531,
13–18.
(13) (a) Shibata, T.; Toshida, N.; Yamasaki, M.; Maekawa, S.; Takagi,
K. Tetrahedron 2005, 61, 9974–9979. (b) Makino, K.; Hiroki, Y.; Hamada,
Y. J. Am. Chem. Soc. 2005, 127, 5784–5785. (c) Shibata, T.; Takagi, K.
J. Am. Chem. Soc. 2000, 122, 9852–9853.
(14) (a) Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26–
47. (b) Lautens, M.; Fagnou, K. J. Am. Chem. Soc. 2001, 123, 7170–7171.
(15) (a) Leong, P.; Lautens, M. J. Org. Chem. 2004, 69, 2194–2196.
(b) Lautens, M.; Fagnou, K.; Yang, D. -Q. J. Am. Chem. Soc. 2003, 125,
14884–14892.
(16) See the Supporting Information.
(17) Lautens, M.; Fagnou, K. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5455–5460.
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