Catalytic enantioselective addition of terminal 1,3-diynes to N-sulfonyl aldimines: Access to chiral diynylated carbinamines

Article abstract of DOI:10.1039/c2cc37290h

An efficient method for the asymmetric synthesis of chiral diynylated carbinamines is described. The direct catalytic enantioselective addition of terminal 1,3-diynes to N-sulfonyl aldimines proceeded smoothly under mild reaction conditions to produce diy

Full text of DOI:10.1039/c2cc37290h

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COMMUNICATION
Catalytic enantioselective addition of terminal 1,3-diynes to N-sulfonyl
aldimines: access to chiral diynylated carbinaminesw
Tian-Lin Liu,a Heng-Xia Zhang,a Yan Zheng,a Qingwei Yaob and Jun-An Ma*a
Received 6th October 2012, Accepted 30th October 2012
DOI: 10.1039/c2cc37290h
An efficient method for the asymmetric synthesis of chiral
diynylated carbinamines is described. The direct catalytic
enantioselective addition of terminal 1,3-diynes to N-sulfonyl
aldimines proceeded smoothly under mild reaction conditions to
produce diynylated carbinamines in up to 98% yield and
99% ee.
Table 1 Optimization of reaction conditionsa
Chiral propargyl amines are potentially intriguing blocks for
the synthesis of many natural products and compounds of
pharmaceutical significance.1 The asymmetric alkynylation of
imines provides the most direct access to these important
synthetic intermediates.2 Since the pioneering work of both
Li’s and Knochel’s groups on the catalytic asymmetric addition
of terminal alkynes to imines and their analogues,3 significant
progress has been made in the development of highly selective
and efficient catalytic systems for these synthetically useful
transformations.4 However, little attention has been paid to
exploring 1,3-diynes as viable nucleophilic substrates in the
asymmetric addition reaction of imines.5 Such studies would
be of immense benefit for expanding the scope of application of
this reaction to the synthesis of chiral diynylated carbinamines.6
Herein we report the results of our preliminary investigation of
enantioselective diynylation of aldimines by using various
terminal 1,3-diynes. We demonstrate that, in the presence of
binol-type ligands, the present transformation provides a facile
route to chiral diynylated carbinamines in high yield (up to
98%) and excellent enantioselectivity (up to 99% ee).
Entry
Ligand (mol%)
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
L1 (20)
L2 (20)
L3 (20)
L4 (20)
L5 (20)
L6 (20)
L7 (20)
L8 (20)
L9 (20)
L10 (20)
L8 (20)
L8 (20)
L8 (20)
L8 (15)
L8 (20)
L8 (20)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Et2O
DCM
DCE
DCE
DCE
DCE
77
81
87
74
80
67
82
90
81
80
82
88
94
88
85
96
8
72
87
15
25
31
40
92
56
58
89
91
93
85
90
94
9
10
11
12
13
14
15d
16e
a
Reactions were conducted with 1 equiv. of 1a, 2.2 equiv. of 2a,
2 equiv. of Me2Zn (1.2 M in toluene), and the ligand in solvent at
In an initial investigation, we conducted the model reaction of
N-tosyl benzaldimine 1a with diynylzinc generated in situ from
phenylbuta-1,3-diyne 2a and Me2Zn, by employing (S)-1,10-bi-2-
naphthol (binol) as the chiral ligand to afford the desired adduct
3aa in 77% yield but with poor enantioselectivity (8% ee) (entry 1,
Table 1). Subsequent screening with a series of binol-type ligands
containing various groups at the 3,30-positions of the binaphthol
backbone (entries 2–10) revealed the bulky ligand L8 to be
optimal, delivering adduct 3aa in 90% yield with high enantio-
selecitivity (92% ee), whereas the use of more bulky ligands L9
b
room temperature. Yield of isolated products. The ee values were
d
determined by HPLC analysis on a chiral stationary phase. Reaction
c
e
temperature: 10 1C. Reaction time: 6 h.
and L10 resulted in a substantial decrease in enantioselectivity
(entries 9 and 10 vs. 8). A comparison of the results obtained in
different solvents showed that this asymmetric addition is not
sensitive to the solvent used (entries 8 and 11–13). Given the
poor solubility of N-sulfonyl aldimines in toluene and ether, we
chose dichloroethane (DCE) as the reaction solvent. Decreasing
the amount of ligand to 15 mol% resulted in a decrease in both
the yield and the ee value of the product (entry 14). Further
optimization by changing the temperature and the reaction time
(entries 15 and 16) revealed that the best results were obtained
when 20 mol% of ligand L8 was used at room temperature for
6 hours (96% yield, 94% ee).
a Department of Chemistry, Tianjin University, Tianjin 300072, China.
E-mail: majun_an68@tju.edu.cn; Fax: +86-22-2740-3475
b Sphinx Scientific Laboratory Corporation, Sycamore, IL 60178,
USA
w Electronic supplementary information (ESI) available. CCDC
870991. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2cc37290h
c
12234 Chem. Commun., 2012, 48, 12234–12236
This journal is The Royal Society of Chemistry 2012

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Table 2 Enantioselective addition of phenylbuta-1,3-diyne 2a to
various N-sulfonyl aldimines 1a
Table 3 Enantioselective addition of various 1,3-diynes 2 to N-
tosylaldimine 1aa
Time 3: Yieldb eec
Entry 2: R3
Time (h) 3: Yieldb (%) eec (%)
Entry 1: R1, R2
(h)
(%)
(%)
1
2b: 4-Fluorophenyl
16
4
3ab: 92
3ac: 95
3ad: 97
3ae: 95
3af: 98
3ag: 90
3ah: 88
3ai: 93
3aj: 97
3ak: 95
3al: 90
3am: 94
90
95
1
1a: Phenyl, 4-tolyl
6
5
8
4
8
4
6
16
16
16
8
3aa: 96
3ba: 89
3ca: 93
3da: 91
3ea: 93
3fa: 90
3ga: 93
3ha: 91
3ia: 90
3ja: 91
3ka: 94
3la: 93
3ma: 93
3na: 90
3oa: 95
3pa: 93
3qa: 91
3ra: 74
3sa: 74
94
97
91
98
98
96
94
94
95
92
90
91
92
96
91
90
90
61
63
2
3
4
5
6
7
8
9
2c: 4-Chlorophenyl
2d: 4-Bromophenyl
2e: 4-Methylphenyl
2f: 4-Methoxyphenyl
2g: 2-Methoxyphenyl
2h: 2-Chlorophenyl
2i: 3-Methoxyphenyl
2j: 1-Cyclohexenyl
2k: Triisopropylsilyl
2l: TMSO(CH3)2CH
2m: C6H4CH2CH2
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18d
19d
1b: 4-Fluorophenyl, 4-tolyl
1c: 4-Chlorophenyl, 4-tolyl
1d: 4-Bromophenyl, 4-tolyl
1e: 4-Methylphenyl, 4-tolyl
1f: 4-Methoxyphenyl, 4-tolyl
1g: 3-Methoxyphenyl, 4-tolyl
1h: 2-Chlorophenyl, 4-tolyl
1i: 2-Bromophenyl, 4-tolyl
1j: 2-Allylphenyl, 4-tolyl
4
5
90
93
3
4
97
93
16
16
6
24
3
90
88
95
93
92
>99
10
11
12
1k: 3,4-Dichlorophenyl, 4-tolyl
8
1l: 2,4,6-Trimethoxyphenyl, 4-tolyl 12
a
General reaction conditions: 1/2a/Me2Zn/L8 = 1.0 : 2.2 : 2.0 : 0.2
b
in DCE at room temperature for the stated time. Yield of isolated
1m: 2-Naphthyl, 4-tolyl
1n: 2-Furyl, 4-tolyl
1o: Cinnamyl, 4-tolyl
1p: Phenyl, cyclopropyl
1q: Phenyl, 1-allylcyclopropyl
1r: CF3, 4-tolyl
16
5
4
8
8
c
products. The ee values were determined by HPLC analysis on a
chiral stationary phase.
8
8
various positions of the phenyl ring were well tolerated. One of
the diynylated carbinamines (3ad) was crystallized from
CH2Cl2–hexane, and its absolute configuration was determined
to be S from single-crystal X-ray structural analysis (Fig. 1).8
It is noteworthy that 1-cyclohexenyl- and triisopropylsilyl-
substituted buta-1,3-diynes (2j and 2k) also gave the adducts
(3aj and 3ak) in excellent yields and enantioselectivities (entries 9
and 10). Additionally, the reaction worked well with alkyl-
substituted 1,3-diynes such as 2l and 2m to afford the desired
products (3al in 90% yield and 92% ee, and 3am in 94% yield
and 99% ee) (entries 11 and 12).
1s: CH3(CH2)2, 4-tolyl
a
General reaction conditions: 1/2a/Me2Zn/L8 = 1.0 : 2.2 : 2.0 : 0.2
b
in DCE at room temperature for the stated time. Yield of isolated
c
products. The ee values were determined by HPLC analysis on a
d
chiral stationary phase. Ligand L10 was used.
With the optimal conditions established, the scope of the
reaction was then probed. As highlighted in Table 2, a wide
range of functional groups, including electron-neutral, -with-
drawing, and -donating groups on the aromatic rings of
N-tosyl benzaldimines can be tolerated (Table 2, entries
1–12). In all cases, high yields (90–96%) and excellent ee
values (90–98%) were obtained. The reaction worked well
with N-tosyl-2-naphthaldimine 1m to afford the adduct 3ma in
93% yield with 92% ee (entry 13). Other aromatic imine
derivatives such as N-tosyl-2-furaldimine 1n also worked well,
furnishing the corresponding product 3na in high yield and
enantioselectivity (entry 14). It was worth noting that N-tosyl
cinnamaldimine 1o gave the 1,2-adduct 3oa in 95% yield
with 91% ee (entry 15). To further define the scope of our
methodology, the addition reactions of different N-sulfonyl-
substituted benzaldimines such as 1p and 1q were also tested
(entries 16 and 17). The desired adducts 3pa and 2qa were
obtained in high yields and enantioselectivities. In addition, we
investigated the addition reaction with alkyl-substituted imines.
These substrates were found to give good yields and moderate
ee values. For example, in the presence of more bulky ligand
L10, N-tosyl-2,2,2-trifluoroacetaldimines 1r and 1s provided the
adducts 3ra and 3sa in good yields with 61% ee and 63% ee,
respectively (entries 18 and 19).7
Adducts 3 are versatile synthetic intermediates and can be
readily transformed into functionalized amine derivatives that
are otherwise difficult to access. For example, direct hydro-
genation of 3aa in the presence of 10% Pd/C in ethanol
provided the secondary N-tosyl carbinamine 4, in almost
quantitative yield without any erosion of its enantiopurity,
which can be conveniently converted to the corresponding free
amine 5 by reductive cleavage with SmI2 (Scheme 1).9
Reduction of 3aa with LiAlH4 delivered the (E)-1, 3-enynyl-
substituted carbinamine 6 in 85% yield with 94% ee.10
In summary, we have developed an efficient catalytic asymmetric
diynylation of N-sulfonyl aldimines by using chiral binol-type
ligands. The addition reaction proceeded smoothly under mild
conditions for a broad variety of N-sulfonyl aldimines and terminal
1,3-diynes, affording the desired products in good to excellent
yields (74–98%) and enantioselectivities (up to 99% ee). Further
This protocol can also be readily extended to the use of
other 1,3-diynes. As shown in Table 3, a series of representative
substituted phenylbuta-1,3-diynes (2b–i) were shown to undergo
the addition transformation with consistently high yields and
enantioselectivities (entries 1–8). Both electron-withdrawing
(F, Cl, Br) and electron-donating (Me, OMe) substituents at
Fig. 1 X-ray crystal structure of the diynylated adduct 3ad
(ORTEP).
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 12234–12236 12235

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Scheme 1 Further synthetic transformations of the diynylated
adduct 3aa.
extension of this diynylation addition to other substrates is ongoing
in our laboratory.
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7 The ligand effect on the addition of phenylbuta-1,3-diyne to N-tosyl
2,2,2-trifluoroacetaldimine to afford the adduct: L8 (64% yield, 35% ee),
L9 (77% yield, 43% ee), and L10 (74% yield, 61% ee).
This work was supported financially by NSFC (No.
20902067 and 20972110).
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8 CCDC 870991 (3ad)w.
9 Unfortunately, due to the presence of the conjugated diyne and
enyne moieties in compounds 3aa and 6, all attempts to remove the
N–Ts group under reductive conditions failed to give the free
amines. For similar observations, see ref. 4k.
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c
12236 Chem. Commun., 2012, 48, 12234–12236
This journal is The Royal Society of Chemistry 2012