Enantioselective intramolecular propargylic amination using chiral copper-pybox complexes as catalysts

Article abstract of DOI:10.1039/c4cc01676a

Intramolecular propargylic amination of propargylic acetates bearing an amino group at the suitable position in the presence of chiral copper-pybox complexes proceeds enantioselectively to give optically active 1-ethynyl-isoindolines (up to 98% ee). The method described in this communication provides a useful synthetic approach to the enantioselective preparation of nitrogen containing heterocyclic compounds with an ethynyl group at the α-position. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01676a

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Enantioselective intramolecular propargylic
amination using chiral copper–pybox complexes
as catalysts†
Cite this: Chem. Commun., 2014,
50, 7874
Received 5th March 2014,
Accepted 22nd May 2014
Masashi Shibata, Kazunari Nakajima and Yoshiaki Nishibayashi*
DOI: 10.1039/c4cc01676a
www.rsc.org/chemcomm
Intramolecular propargylic amination of propargylic acetates bearing an
amino group at the suitable position in the presence of chiral copper–
pybox complexes proceeds enantioselectively to give optically active
1-ethynyl-isoindolines (up to 98% ee). The method described in this
communication provides a useful synthetic approach to the enantio-
selective preparation of nitrogen containing heterocyclic compounds
with an ethynyl group at the a-position.
Heterocycles containing a nitrogen atom, such as pyrrolidines,
tetrahydroquinolines and isoindolines, and their derivatives are
widely found in many natural products and biologically active
compounds.1 In addition to classical synthetic approaches to obtain
these heterocycles, a variety of preparative methods catalyzed by
transition metal complexes have been reported including their
asymmetric version for the optically active heterocycles.1,2
Scheme 1
good to high yields with up to 98% ee. Preliminary results are
In continuation of our study on the development of transition described here.
metal-catalyzed propargylic substitution reactions of propargylic
We have designed 1-phenylpropargylic acetates bearing an
alcohol derivatives with various nucleophiles including their enantio- aminomethyl group at the ortho-position of the benzene ring 1,
selective versions,3,4 we have recently disclosed the copper-catalyzed which were prepared via four steps from 2-bromobenzaldehyde,
propargylic amination of propargylic esters with amines via copper– as shown in Scheme 2. After the protection of the original
allenylidene complexes as key reactive intermediates.5–7 In our reac- formyl group in 2-bromobenzaldehyde, the introduction of
tion system, (R)-Cl-MeO-biphep was found to work as an effective another formyl group and sequential ethynylation of the formyl
ligand toward the propargylic amination with secondary amines such group gave 1-(2-formylphenyl)prop-2-yn-1-yl acetate in a good
as N-methylaniline (Scheme 1(a)),5 in contrast to van Maarseveen’s yield. Then, reductive amination with various aniline derivatives
reaction system, where the propargylic amination with primary led to the formation of 1 in high yields.
amines was achieved by using diPh-pybox as a chiral ligand
Treatment of 1-(2-((phenylamino)methyl)phenyl)prop-2-yn-
(Scheme 1(b)).6 Based on these research backgrounds, we envisaged 1-yl acetate (1a) in methanol at room temperature for 14 h in
the application of this reaction system to the preparation of hetero-
cycles containing a nitrogen atom via an intramolecular cyclization of
propargylic esters bearing an amine moiety at a suitable position. In
fact, we have succeeded in obtaining chiral 1-ethynyl-isoindolines in
Institute of Engineering Innovation, School of Engineering, The University of Tokyo,
Yayoi, Bunkyo-ku, Tokyo, 113-8656, Japan. E-mail: ynishiba@sogo.t.u-tokyo.ac.jp;
Fax: +81 3 5841-1175
† Electronic supplementary information (ESI) available. CCDC 989441. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
Scheme 2
c4cc01676a
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Table 1 Intramolecular propargylic amination of 1a in the presence of
chiral copper complexesa
when the cyclic amination was carried out at a lower reaction
temperature by using L4 and L5 as chiral ligands. The highest
enantioselectivity was achieved at 0 1C and ꢁ10 1C by using L4
(Table 1, entries 12 and 13). A slightly lower enantioselectivity was
observed in the reaction at 0 1C by using L5 as a chiral ligand
(Table 1, entry 14).
Intramolecular cyclic amination of various propargylic acetates
bearing an aminomethyl group was investigated by using L4 and L5
as chiral ligands. Typical results are shown in Table 2. The presence
of a substituent such as a methyl, fluoro, or bromo group at the para-
position of the benzene ring in the amino group decreased the
reactivity, a longer reaction time (20–30 h) being necessary to obtain
the corresponding 1-ethynyl-isoindolines in high yields with a high
enantioselectivity (Table 2, entries 1–6). The highest enantioselectivity
was achieved in the reaction of 1d as a substrate by using L5 (Table 2,
entry 8). After one recrystallization of crude cyclic product, the
enantiomerically pure 2d was isolated and its absolute configuration
(1R) was determined by X-ray analysis (Fig. 1).13
Next, we investigated the nature of substituents on the
aromatic scaffold linking the propargylic acetate. Typical
results are shown in Scheme 3. The introduction of a fluoro
group at the 5-position and two methoxy groups at the 4- and
5-positions substantially increased the enantioselectivity under
Entry
Ligand
Time (h)
Yield of 2ab (%)
eec (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L4
L4
L5
14
4
20
4
4
4
8
20
4
4
4
17
19
2
57d
55d
17d
89
85
82
80
56
50
80
83
81
87
25
49
82
34
87
87
91
9
10
11
12e
13f
14e
23
20d
93
8
20
8
93
90
a
Reactions of 1a (0.2 mmol) in the presence of CuOTfꢀ1/2(C6H6)
(0.01 mmol), ligand (0.02 mmol), and iPr2NEt (0.24 mmol) were carried out
in MeOH at room temperature. b Isolated yield. c Determination by HPLC.
d The opposite absolute configuration (1S) was found. e At 0 1C. f At ꢁ10 1C.
the presence of 5 mol% of CuOTfꢀ1/2(C6H6) and 10 mol% of the same reaction conditions.
(R)-Cl-MeO-biphep8 (L1) gave 1-ethynyl-2-phenylisoindoline (2a)
As described in our previous work, the intermolecular
in 17% yield with 57% ee (Table 1, entry 1). Typical results are propargylic amination proceeded via copper–allenylidene
shown in Table 1. The use of related diphosphines such as complex (I),5,6,14 which was generated from the copper–pybox
(R)-binap9 (L2) and (R)-segphos10 (L3) as chiral ligands afforded only complex with the propargylic acetate. At present, we consider
low yields of 2a (Table 1, entries 2 and 3). When pyboxs were used as
chiral ligands under the same reaction conditions, the intra-
molecular amination proceeded smoothly to give 2a in good to high
yields with a high enantioselectivity. The use of a larger amount
Table 2 Intramolecular propargylic amination of 1 in the presence of
chiral copper complexesa
(2 equiv. to Cu atom) of pyboxs slightly increased the enantio-
selectivity in all cases. (S)-Me-pybox11 (L4) was found to work as an
effective chiral ligand to achieve the highest enantioselectivity, i.e.
89% ee (Table 1, entry 4) although the use of related pyboxs such as
i
Ph-pybox11 (L5), Pr-pybox11 (L6), and Bn-pybox11 (L7) gave high
Entry 1, Ar
Ligand Time (h) Yield of 2b (%) eec (%)
enantioselectivities (85% ee, 82% ee, and 80% ee, respectively)
(Table 1, entries 5–7). Other pyboxs such as tBu-pybox11 (L8),
indan-pybox11 (L9), and diPh-pybox6 (L10) did not work as effective
ligands, with only low to moderate enantioselectivities (56% ee, 50%
ee, and 23% ee, respectively) (Table 1, entries 8–10). When a
bis(oxazoline) ligand12 (L11) was used as a chiral ligand, the amina-
tion did not occur smoothly, affording 2a with only a low enantios-
electivity (Table 1, entry 11). A higher enantioselectivity was observed
1
2
3
4
5
6
7
8
1a, C6H5
1a, C6H5
1b, 4-MeC6H4 L4
L4
L5
8
8
87
91
79
70
79
77
89
89
93
90
92
92
95
88
93
96
20
20
30
30
30
30
1b, 4-MeC6H4 L5
1c, 4-FC6H4
1c, 4-FC6H4
1d, 4-BrC6H4
1d, 4-BrC6H4
L4
L5
L4
L5
a
Reactions of 1 (0.2 mmol) in the presence of CuOTfꢀ1/2(C6H6)
(0.01 mmol), L4 or L5 (0.02 mmol), and iPr2NEt (0.24 mmol) were
carried out in MeOH at 0 1C. Isolated yield. Determination by HPLC.
b
c
Fig. 1 Ortep drawing of optically active 2d.
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place with only a low enantioselectivity. This low selectivity was
not surprising based on the results found by van Maarseveen and
co-workers for the intermolecular amination with primary aniline
by using Ph-pybox.6
In summary, we have disclosed the copper-catalyzed intra-
molecular propargylic amination of propargylic acetates bear-
ing an amine moiety at a suitable position to give optically
active 1-ethynyl-isoindolines. In the present reaction system,
copper–pybox complexes have been found to work as effective
catalysts toward the propargylic amination (up to 98% ee). We
believe that the present method provides a useful synthetic
approach to the enantioselective preparation of optically active
nitrogen containing heterocyclic compounds with an ethynyl
group at the a-position with a high enantioselectivity as an
application of the copper-catalyzed propargylic amination.
Further studies on the transition metal-catalyzed propargylic
substitution reactions are currently in progress.
Scheme 3
Fig. 2 Copper–allenylidene complex as a key reactive intermediate.
Notes and references
1 For reviews, see: (a) M. Chrzanowska and M. D. Rozwadowska,
Chem. Rev., 2004, 104, 3341; (b) Y.-G. Zhou, Acc. Chem. Res., 2007,
40, 1357; (c) S. Anas and H. B. Kagan, Tetrahedron: Asymmetry, 2009,
20, 2193; (d) M. Ahamed and M. H. Todd, Eur. J. Org. Chem., 2010,
that the intramolecular amination also proceeds via a similar
reaction pathway. The absolute configuration at the propargylic
position in 2 indicates that the intramolecular attack of an
amino group on the cationic g-carbon in I occurs from the Si
face (Fig. 2).
´
5935; (e) V. Sridharan, P. A. Suryavanshi and J. C. Menendez, Chem.
Rev., 2011, 111, 7157.
The successful results of the intramolecular cyclic amina-
tion prompted us to investigate double propargylic amination
including sequential inter- and intra-molecular amination
(Scheme 4). The reaction of 1,10-(1,2-phenylene)-bis(prop-2-
yne-1,1-diyl) diacetate (3) with aniline in methanol at room
temperature in the presence of 5 mol% of CuOTfꢀ1/2(C6H6) and
10 mol% of L5 proceeded smoothly to give 1,3-di(ethynyl)-2-
phenylisoindoline (4a) in 70% yield as a mixture of two diaster-
eoisomers (meso-isomer/DL-isomer = 5/1) (Scheme 4(a)). The
minor DL-isomer was obtained with 75% ee. On the other hand,
the reaction of 3 with N,N0-diphenylethane-1,2-diamine under the
same reaction conditions afforded 1,6-diethynyl-2,5-diphenyl-
1,2,3,4,5,6-hexahydrobenzo[ f ][1,4]diazocine (4b) in 68% yield as
a mixture of two diastereoisomers (meso-isomer/DL-isomer = 8/1)
(Scheme 4(b)). The minor DL-isomer was obtained with 66% ee.
The low selective formation of DL-isomers in the both reaction
systems indicates that the first intermolecular amination of 3 took
2 For enantioselective synthesis of isoindolines, see: (a) Y. Sato,
T. Nishimata and M. Mori, J. Org. Chem., 1994, 59, 6133;
(b) Y. Sato, T. Nishimata and M. Mori, Heterocycles, 1997, 44, 443;
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´
´
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4 For recent reviews by other research groups, see: (a) R. J. Detz,
H. Hiemstra and J. H. van Maarseveen, Eur. J. Org. Chem., 2009,
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5 For our recent papers of enantioselective propargylic amination,
see: (a) G. Hattori, H. Matsuzawa, Y. Miyake and Y. Nishibayashi,
Angew. Chem., Int. Ed., 2008, 47, 3781; (b) G. Hattori, A. Yoshida,
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by van Maarseveen and co-workers, see: (a) R. J. Detz,
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Chem., Int. Ed., 2008, 47, 3777; (b) R. J. Detz, Z. Abiri, R. le Griel,
H. Hiemstra and J. H. van Maarseveen, Chem. – Eur. J., 2011, 17, 5921.
7 For recent papers of enantioselective propargylic amination
reported by other research groups, see: (a) C. Zhang, Y.-H. Wang,
X.-H. Hu, Z. Zheng, J. Xu and X.-P. Hu, Adv. Synth. Catal., 2012,
354, 2854; (b) T. Mino, H. Taguchi, M. Hashimoto and M. Sakamoto,
Tetrahedron: Asymmetry, 2013, 24, 1520.
8 (R)-Cl-MeO-biphep = (R)-5,50-dichloro-6,60-dimethoxy-2,20-bis(diphenyl-
phosphino)-1,10-biphenyl: (a) R. R. Huddleston, H.-Y. Jang and
M. J. Krische, J. Am. Chem. Soc., 2003, 125, 11488; (b) H.-Y. Jang,
F. W. Hughes, H. Gong, J. Zhang, J. S. Brodbelt and M. J. Krische, J. Am.
Chem. Soc., 2005, 127, 6174; (c) J. U. Rhee and M. J. Krische, J. Am.
Scheme 4
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Chem. Soc., 2006, 128, 10674; (d) E. Skucas, J. R. Kong and M. J. Krische, 12 For a recent review on bis(oxazoline) ligands, see: G. Desimoni,
J. Am. Chem. Soc., 2007, 129, 7242. G. Faita and K. A. Jørgensen, Chem. Rev., 2006, 106, 3561.
9 (R)-binap = (R)-2,20-bis(diphenylphosphino)-1,10-binaphthyl: R. Noyori 13 See ESI† for Experimental details.
and H. Takaya, Acc. Chem. Res., 1990, 23, 345 and references therein.
10 (R)-segphos = (R)-5,50-bis(diphenylphosphino)-4,40-bi-1,3-benzodioxole:
H. Shimizu, I. Nagasaki, K. Matsumura, N. Sayo and T. Saito, Acc. Chem.
Res., 2007, 40, 1385 and references therein.
11 pybox = Pyridine-2,6-bis(oxazolines): G. Desimoni, G. Faita and
P. Quadrelli, Chem. Rev., 2003, 103, 3119.
14 (a) The copper–allenylidene complexes have not yet been isolated and
characterized until now although silver- and gold–allenylidene com-
plexes have already been reported by Bertrand and Hashmi, respec-
tively; (b) M. Asay, B. Donnadieu, W. W. Schoeller and G. Bertrand,
Angew. Chem., Int. Ed., 2009, 48, 4796; (c) M. M. Hansmann,
F. Rominger and A. S. K. Hashmi, Chem. Sci., 2013, 4, 1552.
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