Key words copper catalysis - asymmetric synthesis - allenols - propargylic alcohols - aldehydes
Due to their unique structural properties, reactivities, and potential applications
in medicine, allenes have attracted much attention from organic chemists, materials
scientists, and pharmacists over the last few decades.[1 ]
[2 ] A particular challenge in allene chemistry is to construct axially chiral allenes
efficiently.[3 ] Several strategies have been applied to achieve this goal.[4,5 ]
In 2012, our group reported a two-step approach for the synthesis of optically active
allenes from propargylic alcohols and aldehydes in which a catalytic amount of CuBr
and a chiral 4-[1-(2-diphenylphosphanyl)naphthyl]-N -(1-phenylethyl)phthalazin-1-amine (N -PINAP) ligand[6 ] are responsible for the highly enantioselective formation of a propargylic amine.
After filtration to remove Cu(I), we used ZnI2 (0.45 equiv) and NaI (0.5 equiv) to convert the optically active propargylic amine
into an allene through a stereodefined anti -1,5-hydride shift (Scheme [1 ]).[5a ] Later, we observed that CdI2 works in harmony with CuBr to realize this transformation without filtration (Scheme
[1 ]).[5b ] However, both methods required a rather high loading of metal salts to promote the
formation of allenes from the optically active propargylic amines generated in situ.
Moreover, the stepwise addition of chemicals is not operationally friendly. Therefore,
approaches to the enantioselective allenylation of terminal alkynes (EATA) that use
a chiral catalyst operating in both steps are highly desired. Here, we report the
realization of such a concept (Scheme [1 ]).
Scheme 1 Enantioselective catalytic allenylation of terminal alkynes with aldehydes
On the basis of our previous observation that the dialkylamine played a vital role
in the CuI-catalyzed synthesis of allenes from terminal alkynes and aldehydes,[7 ] we reasoned that long-chain dialkylamines or structurally similar cyclic amines
might be viable reactants for an enantioselective reactions of this type. After preliminary
screening of a series of dialkylamines and cyclic amines, we were glad to find that
the commercially available cyclic amine azocane was the most effective reactant in
this EATA reaction (Table [1 ])[8 ]. When the reaction was carried out with propargylic alcohol (1a ), 1.6 equivalents of cyclohexanal (2a ), and 1.4 equiv of azocane with 10 mol% of CuI and 10 mol% of (R ,Sa
)-N -PINAP as the catalyst system at room temperature for 0.5 hours and then at 130 °C
for five hours, the desired allenol (S )-3aa was formed in 76% yield and 86% ee (entry 7). Although a series of dialkylamines
reacted smoothly to produce the corresponding propargylic amines, the second step
to form the allene was not efficient (entries 1–3). In comparison, for cyclic amines,
the second step became much easier on increasing the ring size from five to eight
(entries 4–7). However, the yield of (S
a )-3aa decreased to 37% for azonane (entry 8), which was attributed to the fact that azonane
is more similar to an open-chain dialkylamine.
Table 1 Amines Screened and Preliminary Resultsa
Entry
R, R
Timeb (h)
Yieldc (%) of (Sa
)-3aa
Yieldc (%) of (Sa
)-4aa
eed (%) of (Sa
)-3aa
1
i -Bu, i -Bu
24
6
78
–e
2
Bu, Bu
22
14
82
–e
3
(±)-CH2 CH(Et)Bu, CH2 CH(Et)Bu
18
4
76
–e
4
–(CH2 )4 –
1
0
54
–e
5
–(CH2 )5 –
2
10
84
76
6
–(CH2 )6 –
1
35
52
76
7
–(CH2 )7 –
0.5
76
12
86
8
–(CH2 )8 –
1
37
65
88
a The reaction was carried out on a 0.2 mmol scale in 1,4-dioxane (1.6 mL).
b Reaction time for the first step.
c Determined by 1 H NMR analysis with CH2 Br2 as the internal standard.
d Determined by chiral HPLC analysis of the isolated product.
e Not determined.
Encouraged by these preliminary results, we started to optimize the reaction conditions
for the highly stereoselective formation of allene (S )-3aa . Surprisingly, we observed that the metal/ligand ratio had an obvious effect on the
enantioselectivity.[9 ] When the metal/ligand ratio was adjusted from 10:10 to 10:2.5, the ee value of (S )-3aa increased from 86% to 90% (Table [2 ], entries 1–4); however, a further reduction in the ratio of ligand led to a lower
ee (entry 5). Increasing the ratio of CuI made no difference to the yield or the ee
(entry 6). Furthermore, when the reaction temperature for the second step was lowered
to 120 °C, the ee value slightly increased, but the yield of (S )-3aa dropped to 59% (entry 7). When the reaction time for the second step was extended
from 8 to 12 hours, the yield of (R )-4aa dropped from 6% to 4%, and the yield of (S )-3aa increased from 76% to 79%; however, the ee for (S )-3aa dropped from 90% to 87% (entry 8). After solvent screening, it was observed that
1,4-dioxane still provided the best yield and ee (entries 9–13). Thus, the optimized
reaction conditions were as follows: a mixture of CuI (10 mol%), (R ,Sa
)-N -PINAP (2.5 mol%), propargylic alcohol (1a ), aldehyde 2a (1.6 equiv), and azocane (1.4 equiv) was stirred at room temperature in toluene until
the first step was complete (as monitored by TLC), and then the reaction tube was
directly placed in an oil bath at 130 °C for the second step (entry 4).
Table 2 Optimization of the Reaction Conditionsa
Entry
x/y (mol%)
Solvent
t2 (h)
Yieldb (%) of (S )-3aa
Yieldb (%) of (R )-4aa
eec (%) of (S )-3aa
1
10/10
1,4-dioxane
5
76
12
86
2
10/5
1,4-dioxane
8
77
6
89
3
10/3.3
1,4-dioxane
8
76
6
89
4
10/2.5
1,4-dioxane
8
76
6
90
5
10/1.5
1,4-dioxane
8
76
7
87
6
12.5/2.5
1,4-dioxane
8
77
7
90
7d
10/2.5
1,4-dioxane
8
59
22
91
8
10/2.5
1,4-dioxane
12
79
4
87
9
10/2.5
toluene
8
62
8
85
10
10/2.5
THF
8
79
12
68
11
10/2.5
MTBE
8
38
54
87
12
10/2.5
DCE
8
21
60
67
13
10/2.5
PhCF3
8
4
78
–e
a The reaction was carried out on a 0.2 mmol scale in 1.6 mL of solvent.
b Determined by 1 H NMR analysis with CH2 Br2 as the internal standard.
c Determined by chiral HPLC analysis of the isolated product.
d The second-step reaction was carried out at 120 °C.
e Not determined.
The reaction was easily conducted on a 1 mmol scale (Table [3 ], entry 1). When (R ,R
a )-N -PINAP was employed (Condition B), the enantiomer (R )-3aa was produced in a slightly higher ee (Table [3 ], entry 2). With the optimized conditions in hand, we started to investigate the
scope of the reaction.[10 ] In general, both cyclic and acyclic tertiary propargylic alcohols 1a –d reacted with secondary alkyl aldehydes 2a –d to give the corresponding allenols (S )-3aa to (R )-3dc in 40–73% yields and in 81–95% ee (entries 1–8). The enantioselectivity was sensitive
to the R3 group of the aldehyde: increasing the steric bulk of the R3 group was beneficial to the enantiocontrol of the reaction (entries 7 and 8). The
linear alkyl aldehyde 2e also gave the corresponding allenol (S )-3ce in 53% yield, albeit with only 63% ee (entry 9). The first step of the reaction of
aromatic aldehyde 2f proved sluggish, and allene (S )-3af was obtained in 66% yield and with 65% ee (entry 10).
Table 3 The Scope of the CuI/N -PINAP-catalyzed EATA Reactiona
entry
R1 , R2 (1 )
R3 (2)
Condition
Yield (%) of 3
eeb (%) of 3
1
–(CH2 )5 – (1a )
Cy (2a )
A
72 [(S )-3aa ]
90
2
–(CH2 )5 – (1a )
Cy (2a )
B
73 [(R )-3aa ]
91
3
–(CH2 )5 – (1a )
i -Pr (2b )
A
54 [(S )-3ab ]
92
4
–(CH2 )4 – (1b )
i -Pr (2b )
B
45 [(R )-3bb ]
95
5
Me, Me (1c )
Cy (2a )
B
65 [(R )-3ca ]
84
6
Me, Me (1c )
CHEt2 (2c )
A
50 [(S )-3cc ]
90
7
Et, Et (1d )
cyclopentyl(2d )
B
54 [(R )-3dd ]
81
8c
Et, Et (1d )
CHEt2 (2c )
B
40 [(R )-3dc ]
93
9
Me, Me (1c )
(CH2 )6 Me (2e )
A
53 [(S )-3ce ]
63
10d
–(CH2 )5 – (1a )
Ph (2f )
A
66 [(S )-3af ]
65
a Condition A : 1 (1 mmol), 2 (1.6 equiv), azocane (1.4 equiv), CuI (10 mol%), (R,Sa
)-N -PINAP (2.5 mol%), 1,4-dioxane (8 mL), r.t., 1 h, then 130 °C, 8 h; Condition B : As Condition A, but with ligand (R,Ra
)-N -PINAP (2.5 mol%). The reaction was carried out on a 1 mmol scale in 1,4-dioxane (8
mL).
b Determined by chiral HPLC analysis.
c The reaction time for the first step was 24 h.
d The reaction time for the first step was 48 h.
For the primary propargylic alcohol 1e and the secondary propargylic alcohol 1f , chiral α-allenols (S )-3ea and (S
a , S )-3fa were obtained in 52 and 69% yield, respectively; however, the ee values decreased
to 60% and 41%, respectively (Scheme [2 ]).
Scheme 2 EATA Reaction with alkyne 1d and 1e
The absolute configurations of the allenols were assigned by comparison with authentic
samples prepared by following the protocol described in a previous report[5 ] and by applying the Lowe–Brewster rule.[11 ] A plausible model is proposed to predict the absolute configuration of the allenols
(Scheme [3 ]). First, the chiral alkynyl copper species (R ,S
a )-5 , generated in situ, reacts with the iminonium intermediate 6 , also generated in situ from the aldehyde and azocane, to form the corresponding
propargylic amine (R )-4 enantioselectively.[6 ] Subsequently Cu(I) coordinates to the C≡C triple bond with the assistance of the
proximal hydroxy group to form complex 7 , which undergoes highly stereoselective anti -1,5-hydride transfer and anti -β-elimination to afford the corresponding allenol (S )-3 .
Scheme 3 Proposed mechanism and prediction of the absolute configuration of the allenols
In summary, we have developed a catalytic EATA reaction to synthesize optically active
tertiary α-allenols from common tertiary propargylic alcohols and aldehydes by using
only 10 mol% of CuI and 2.5 mol% of N -PINAP ligand. The medium-sized cyclic amine azocane plays an important role in determining
both the yield and enantioselectivity of this transformation. Another crucial factor
affecting the stereoselectivity of the reaction is the metal/ligand ratio; however,
it should be noted that the results for secondary terminal propargylic alcohols or
normal terminal alkynes and aromatic/linear aliphatic aldehydes are still disappointing.
Further studies, including the design of new ligands for such transformations, are
being conducted in our laboratory.
