Mild-condition synthesis of allenes from alkynes and aldehydes mediated by tetrahydroisoquinoline (THIQ)

Article abstract of DOI:10.1021/jo4018183

A practical 1,2,3,4-tetrahydroisoquinoline (THIQ)-mediated synthesis of 1,3-disubstituted allenes from terminal alkynes and aldehydes under mild conditions in the presence of CuBr first and then ZnI₂ was reported. This telescoped allene synthes

Full text of DOI:10.1021/jo4018183

Article
pubs.acs.org/joc
Mild-Condition Synthesis of Allenes from Alkynes and Aldehydes
Mediated by Tetrahydroisoquinoline (THIQ)
Guo-Jie Jiang,† Qin-Heng Zheng,† Meng Dou, Lian-Gang Zhuo, Wei Meng, and Zhi-Xiang Yu*
Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering,
College of Chemistry, Peking University, Beijing 100871, China
S
* Supporting Information
ABSTRACT: A practical 1,2,3,4-tetrahydroisoquinoline (THIQ)-mediated synthesis of 1,3-disubstituted allenes from terminal
alkynes and aldehydes under mild conditions in the presence of CuBr first and then ZnI2 was reported. This telescoped allene
synthesis reaction includes three consecutive steps and two reactions: first, a room-temperature CuBr-catalyzed synthesis of
propargylamines, exo-yne-THIQs, from terminal alkynes, aldehydes, and THIQ, then filtration of the CuBr catalyst, and finally
the ZnI2-mediated allene synthesis from the generated exo-yne-THIQs under mild conditions (either at room temperature or
heating at 50 or 75 °C). A wide range of aliphatic or aromatic aldehydes and terminal alkynes are tolerated, affording the allene
products in up to 92% yield. Especially, temperature-sensitive aldehydes can be used in the reaction system. Preliminary
exploration of the asymmetric allene synthesis has also been conducted, and a moderate enantioselectivity has been achieved.
Finally, the relative reactivities of several secondary amines were compared with THIQ, showing that THIQ is the best of these
amines in the synthesis of allenes under mild reaction conditions.
́
the original and modified Crabbe homologation is that the
INTRODUCTION
■
reaction is restricted to paraformaldehyde, and no allene was
formed when other aldehydes were used. Recently, Ma and co-
workers have reported a breakthrough, achieving a one-pot
synthesis of 1,3-disubstituted allenes from terminal alkynes, normal
aldehydes, and morpholine in the presence of ZnI2 at high
temperature (reaction b, Scheme 1).8,9 Later on, Ma and
Periasamy’s groups independently developed the asymmetric
versions of this reaction by using either chiral ligands or chiral
secondary amines (reactions c−e, Scheme 1).10 Meanwhile, Che
and co-workers have also reported a two-step process for the
synthesis of axially chiral allenes at 40 °C, including first gold(III)
salen complex-catalyzed synthesis of chiral propargylamines via a
three-component coupling reaction of terminal alkynes, aldehydes,
and amines, and then gold- or silver-mediated highly
enantioselective synthesis of chiral allenes (reaction f, Scheme 1).11
We were especially attracted by the allene synthesis developed
by Ma and Periasamy because of their efficient synthesis of allenes
in one pot and the use of cheap mediators. However, these
synthetic methods require very high temperature (some reactions
Allenes are very useful building blocks and functional groups
that are widely applied for many transformations in organic
synthesis.1,2 Allene moieties have also been found in natural
products, pharmaceuticals, and molecular materials.3 Because of
these, developing efficient reactions for the synthesis of allenes
from simple and readily available organic compounds is very
important. Until now numerous synthetic methodologies have
been developed to access allenes.4,5 One of the methods that
are appealing to synthetic chemists for the synthesis of allenes is
the secondary amine-mediated allene synthesis from alkynes and
aldehydes in the presence of metal promoters (Scheme 1).6−11
́
This transformation was originally reported by Crabbe and co-
workers for the generation of monosubstituted allenes by a three-
component reaction of terminal alkynes, paraformaldehyde, and
diisopropylamine in the presence of substoichiometric CuBr
(reaction a, Scheme 1).6 Reaction a is now recognized as Crabbe
homologation, and several modifications have been reported.7
́
́
Ma has significantly improved the Crabbe homologation reaction
by replacing both CuBr and diisopropylamine by CuI and
dicyclohexylamine respectively, showing that the reaction yield
can be improved dramatically and many functional groups can be
tolerated in this new protocol.7d However, a limitation in both
Received: August 17, 2013
© XXXX American Chemical Society
A
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Scheme 1. Previous Reports on the Secondary Amine-Mediated Allene Synthesis
Scheme 2. Mechanism for the Allene Synthesis Proposed by Ma
were carried out at 130 °C), and we believe that this can limit the
use of these methods in organic synthesis. For instance, some
aldehydes or alkynes are not stable at high temperature, and
consequently they cannot be used for the synthesis of allenes using
Ma and Periasamy’s methods. This could become a serious
problem for multistep synthesis if any precursor for the three-
component allene synthesis is sensitive to high temperature
because of the lability of specific functional groups. Moreover, high
temperature could be detrimental to the reaction yield. Also for
achieving asymmetric synthesis of allenes, high temperature may
result in low enantioselectivity because the energy difference
between two transition states leading to enantiomers becomes
smaller at higher temperature. In addition, racemization of the
generated allenes could take place in the reaction system, further
diminishing the enantioselectivity. Actually when we applied Ma’s
protocol in synthesizing allenes using temperature-sensitive
substrates, we did not get the desired products.12 Therefore,
developing allene synthesis under milder conditions is highly
desired.
The proposed mechanism by Ma for the allene synthesis is
shown in Scheme 2.8 The whole procedure involves two parts:
the generation of the propargylamine intermediate 1 via the
nucleophilic attack of the 1-alkynyl zinc species to the iminium
ion formed in situ from an aldehyde and morpholine,13,14 and
the ZnI2-mediated formation of allene 2 through [1,5]-hydride
transfer15,16 and β-elimination.
Since there were already some reports on the generation of
propargylamines from terminal alkynes, aldehydes, and
secondary amines (A3 reactions) carried out at room
temperature,17 we hypothesized that the [1,5]-hydride transfer
process in Ma and Periasamy’s protocols could be the rate-
determining step in the allene synthesis and this step might
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Scheme 3. (U)B3LYP/6-31G(d) Computed C−H Bond Dissociation Energies (BDEs)
Scheme 4. Target Allene Synthesis of the Present Investigation
require high temperature. We envisioned that if a secondary
amine with a benzylic H atom adjacent to the reactive N atom
can be used, the [1,5]-hydride transfer could become easier
because of the weaker benzylic C−H bond. Once this step
becomes easier, the allene synthesis could be carried out at
lower temperature. We computed the C−H bond dissociation
energies (BDE) of several secondary amines, finding that the
benzylic C−H bond adjacent to the reactive N atom in the
commercially available 1,2,3,4-tetrahydroisoquinoline (THIQ)
is the weakest among the C−H bonds in all calculated
secondary amines (Scheme 3).18,19 Therefore, we hypothesized
that the allene synthesis mediated by THIQ could be achieved
under mild conditions through room-temperature formation of
propargylamines (exo-yne-THIQs) and [1,5]-hydride transfer
also at room temperature or under mild conditions (Scheme 4).
This hypothesis was encouraged by the discovery of Helaja,
who showed that exo-yne-THIQs can give allenes using Au
catalysts.20 However, only very special exo-yne-THIQs (enyne-
THIQs) had been investigated by Helaja and co-workers, and
the reported yields of allenes were not satisfactory. Because of
this, we wanted to test whether cheap promoters such as ZnX2 can
convert exo-yne-THIQs to allenes under mild conditions. In
addition, exo-yne-THIQs used by Helaja were not synthesized by
the A3 reaction.21 Therefore, realization of the hypothesized allene
synthesis using THIQ as the mediator will provide a general and
efficient strategy to achieve allene synthesis from common
aldehydes and alkynes, via either a stepwise fashion or a one-pot
fashion. Here we report our development of THIQ-mediated
synthesis of 1,3-disubstituted allenes from terminal alkynes and
aldehydes under mild conditions.
1-decyne 3a with 1.8 equiv of benzaldehyde 4a, 1.4 equiv of
THIQ, and 0.8 equiv of ZnI2 in toluene at 65 °C did not give
any allene product at all (eq 2). We reasoned that the in situ
generated water, originating from the formation of iminium ion
between aldehyde and amine, might affect the reaction at low
temperature, while it could be excluded from the reaction
mixture at 130 °C in Ma’s protocol. Therefore, a portion of 4 Å
molecular sieves (MS) was added to the reaction system. In this
case, the reaction took place smoothly, affording allene 2aa in
30% yield at 65 °C (eq 3). Since there were still lots of starting
materials left in the reaction system, further efforts on the
optimization of the reaction conditions were pursued.
Unfortunately, it was found that the reaction yield did not
increase significantly. We then decided to optimize the
formation of the propargylamine intermediate exo-yne-THIQ
and the [1,5]-hydride transfer process separately. Once both
steps were optimized, we could then combine them together to
get one-pot synthesis of allene.
Stimulated by previous studies of A3 reactions,17 first of all,
we screened the reaction conditions for the formation of 5aa
(Table 1). A series of copper salts, zinc triflate, and gold
tribromide were tested (entries 1−7). Usage of CuCl gave the
propargylamine intermediate exo-yne-THIQ in 71% yield
together with a coupling product of 1-decyne 3a in 23% yield
(entry 1). Astonishingly, a side endo-yne-THIQ product 5aa′,
which was not reported so far to our knowledge, can be
obtained when CuBr was employed (entry 2). Side product
5aa′ could be furnished as the major product triggered by CuI
as the catalyst (entry 3). Some other catalysts gave low
conversion with poor chemoselectivity (entries 4 and 7), while
CuCN, Zn(OTf)2 led to nothing (entries 5 and 6). To get rid
RESULTS AND DISCUSSION
■
1. Reaction Optimization of Allene Synthesis Medi-
ated by THIQ. We initially carried out the allene synthesis
using 1-decyne 3a, benzaldehyde 4a, THIQ, and ZnI2 in
toluene under Ma’s reaction conditions8 at 130 °C (eq 1). To
our delight, a 44% yield could be reached within 7 h, although it
was lower than that using morpholine as the secondary amine
in Ma’s standard conditions. The dimeric coupling product
(3a−3a, structure is given in Table 1) of 1-decyne 3a was also
obtained using THIQ, and then a test was conducted to
determine whether a lower temperature could promote this
allene synthesis. It was found that the reaction of 1.0 equiv of
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a
Table 1. Optimization of the Formation of Propargylamine Intermediate exo-Yne-THIQ
b
yield (%)
c
entry
catalyst (X mol %)
ratio (3a/4a/THIQ)
5aa + 5aa′ (ratio)
3a−3a
1
2
3
4
5
6
CuCl (10)
CuBr (10)
CuI (10)
1/1.2/1.2
1/1.2/1.2
1/1.2/1.2
1/1.2/1.2
1/1.2/1.2
1/1.2/1.2
1/1.2/1.2
1/1.8/1.4
1/1.2/1.2
71 (1/0)
80 (6/1)
96 (0/1)
12 (2/1)
NR
23
14
0
CuOTf (10)
CuCN (10)
Zn(OTf)2 (10)
AuBr3 (10)
CuBr (10)
CuBr (20)
66
NR
NR
7
NR
d
7
42 (1/1.2)
86 (4.4/1)
8
trace
3
9
87 (1/0)
a
b
c
The reactions were carried out on 0.5 mmol scale in 2.0 mL of toluene using 300 mg of 4 Å MS. Isolated yield. The value in the parentheses is the
ratio of isomers 5aa and 5aa′ determined by 1H NMR. This is the second example of Au(III)-catalyzed Glaser coupling in homogeneous system.23
d
of the coupling product 3a−3a, an increased equivalent of 4a
and THIQ was also tested, finding that a combined reaction
yield of 86% and a ratio of 4.4/1 for two yne-THIQs can be
obtained (entry 8). As 5aa′ cannot give the final allene product,
then we concentrated here on finding the optimal conditions
for the formation of 5aa. Study of the scope of the formation of
5aa′ will be reported in another paper.22 Fortunately, it
indicated that with 20 mol % of CuBr as the catalyst, the
reaction of 1-decyne with 1.2 equiv of benzaldehyde, 1.2 equiv
of THIQ in toluene at room temperature afforded the desired
product 5aa in 87% yield (entry 9).
toluene at 65 °C, the reaction finished in 4 h and afforded the
allene product 2aa in 83% yield (entry 1). To our delight, the
reaction could be carried out at room temperature, even though
it gave the allene in a lower yield (39%) and with a longer
reaction time (entry 2). As the starting materials were not
totally consumed after 12 h, we increased the amount of ZnI2
(entries 3−5). When 1.5 equiv of ZnI2 was used, the
propargylamine 5aa was almost fully converted to the allene
product 2aa in 88% yield (entry 4). Further increasing the
amount of ZnI2 to 1.8 equiv did not shorten the reaction time
but decreased the reaction yield (entry 5), maybe because of
the lability of the generated allene under these reaction
conditions. When ZnI2 was changed to ZnBr2, the reaction
yield decreased sharply (entry 6). We also tested Che’s system
using KAuCl4 or AgNO3 as promoter,11b,c but the allene
product was isolated in only 20 and 23% yields, respectively
(entries 7 and 8). Therefore, for the transformation from 5aa to
2aa, the best reaction conditions include using 1.5 equiv of ZnI2
as promoter, toluene as solvent, and carrying out the reaction at
room temperature for 12 h (entry 4). Here we want to point
out that after the reaction, we could not isolate the byproduct
3,4-dihydroisoquinoline. This could be attributed to the lability
of 3,4-dihydroisoquinoline in the present reaction system.24
The successes of room-temperature synthesis of exo-yne-
THIQ 5aa and its easy transformation to the allene product 2aa
promoted us to combine these two steps in one pot using both
CuBr and ZnI2 as the mediators. Unfortunately, all endeavors
to this aim failed because these two reaction systems were not
compatible to each other. Therefore, we decided to use a three-
step procedure, which was developed by Ma in the asymmetric
synthesis of allenes (reaction c, Scheme 1).10a We carried out
the propargylamine synthesis and [1,5]-hydride transfer process
separately, and the two procedures were connected by a simple
filtration through a short pad of silica gel to remove Cu(I)
catalyst from the first step. After screening the reaction
conditions (Table 3), we were happy to find that the best
We then screened the reaction conditions to obtain a mild-
condition [1,5]-hydride transfer reaction from exo-yne-THIQ
5aa (Table 2). When we subjected 5aa to 0.8 equiv of ZnI2 in
Table 2. Optimization of the [1,5]-Hydride Transfer
a
Reaction
b
entry
promoter
equiv
T (°C)
time (h)
yield (%)
1
2
3
4
5
6
ZnI2
0.8
0.8
1.0
1.5
1.8
1.5
0.1
0.5
65
rt
4
83
39
45
88
72
51
20
23
ZnI2
12
12
12
12
12
24
24
ZnI2
rt
ZnI2
rt
ZnI2
rt
ZnBr2
KAuCl4
AgNO3
rt
c
7
c
40
40
8
a
The reactions were carried out on 0.5 mmol scale in 2.5 mL of
b
c
toluene unless specified. Isolated yield. The reactions were carried
out on 0.1 mmol scale in 2.0 mL of CH3CN.
D
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a
3. Preliminary Test of Asymmetric Allene Synthesis
Mediated by THIQ and Its Analogues. After the successful
development of THIQ-mediated synthesis of 1,3-disubstituted
allenes under mild conditions, we then explored its asymmetric
version. We added chiral ligands to the reaction system in the
first step of the standard three-step procedure, but we found
that either the reaction systems became complex or no reaction
took place at all (Scheme 5).
Table 3. Screening of the Reaction Conditions
We then explored the asymmetric allene synthesis by using
chiral THIQ derivatives, readily prepared from naturally
abundant phenylalanine derivatives (Scheme 6). It was found
that 6a, 6c, and 6d25b cannot mediate the allene synthesis.
Fortunately, 6b25a gave a moderate yield (53%) and ee value
(65%) of the chiral allene R-2aa (its absolute chirality was
assigned on the basis of previous studies).10b If we purified the
exo-yne-THIQ 7 from the first step of A3 reaction and then
subjected the purified 7 to allene synthesis, the final reaction
yield (68%) and ee (72%) value of obtained allene R-2aa can
be improved. The chirality transfer from pure exo-yne-THIQ 7
(75% ee from the first step A3 reaction using 6b) to allene R-
2aa (72% ee) was satisfactory, but this was decreased by 10% in
the three-step sequence (from 75 to 65% ee), suggesting that
possibly some side products from the A3 step were detrimental
to [1,5]-hydride transfer step if the used exo-yne-THIQ 7 was
not purified.
4b
THIQ
CuBr
4 Å MS
(mg)
yields (2ab,
b
entry (equiv)
(equiv)
(mol %)
3a−3a) (%)
1
2
3
4
5
6
7
1.2
1.8
1.8
1.5
1.8
1.8
1.8
1.2
1.8
1.8
1.5
1.8
1.8
1.4
20
20
20
20
15
10
15
300
300
150
150
150
150
150
50, 9
58, 5
64, trace
52, 5
70, trace
67, 6
73, trace
a
The reactions were carried out on 0.5 mmol scale in 2.0 mL of
toluene for the first step and 2.5 mL of toluene for the third step.
b
Because of the fact that 2ab and 3a−3a have the same Rf, the mixture
of 2ab and 3a−3a was separated by column chromatography, and the
1
separate yields were determined by H NMR.
conditions for allene synthesis are those given in entry 7 of
Table 3.
4. Comparison of Reactivities of THIQ and Other
Amines in Allene Synthesis. Finally, we tested whether
other secondary amines can also mediate the allene synthesis
under mild conditions, which have not been investigated by Ma
and Periasamy previously (Table 5). When we treated different
amines with the similar conditions used for THIQ-mediated
allene synthesis, we found that, in all cases, the propargylamine
intermediates can be generated in the presence of CuBr at
room temperature, with good or poor yield. However, the
reaction conditions of the ZnI2-mediated transformations from
the propargylamine intermediates to the allene products varied
and depended on amine substrates. For morpholine or
dibenzylamine, no allene product was observed when the
reaction mixture of the first step (after removal of Cu(I) with
filtration) was treated with 1.5 equiv of ZnI2 at room
temperature. Only when the reaction temperature was increased
to 50 °C, allene 2aa was isolated in 20 and 52% total yields,
respectively (entries 2 and 5). When pyrrolidine and diethyl-
amine were used as the secondary amines in the allene synthesis,
the ZnI2-mediated transformations from the propargylamine
intermediates to the allene product could take place at room
temperature, but affording allene 2aa in low yields, 13 or 36%,
respectively (entries 3 and 4). When isoindoline was used to
mediate the allene synthesis, only a trace amount of the allene
product was observed (entry 6). This may be due to the lability
of isoindoline and the corresponding propargylamine inter-
mediate. The above comparison shows that THIQ is the best to
mediate the allene synthesis under mild reaction conditions.
When we carried out the synthesis of allene in a stepwise fashion
by isolating the A3 products first and then running ZnI2-mediated
allene synthesis separately, THIQ still had the best performance.
2. Scope of Allene Synthesis Mediated by THIQ. We
then investigated the scope of the reaction (Table 4). In the
presence of THIQ, CuBr, and then ZnI2, 1-decyne reacted with
various substituted benzaldehydes 4 at room tempersature to
give the corresponding allenes 2 in good to excellent yields
(60−92%), not influenced by the substitution patterns and the
electronic natures of the substituents (entries 2−8). The
heterocyclic aryl-substituted aldehyde can also be used in the
reaction, but heating at 50 °C was required in the third step to
give product 2ci in 51% yield (entry 9). To our delight, the
temperature-sensitive aldehydes, such as trans-cinnamaldehyde
and trans-3-cyclopropylacrylaldehyde, which were not suitable
substrates by using Ma’s method at 130 °C, can be subjected to
our reaction system when these reactions were carried out at 50
or 75 °C for the [1,5]-hydride transfer step, giving the desired
products 2bj and 2bk in 33 and 24% yields, respectively
(entries 10 and 11).12 The relative lower yields may be due to
the lability of the generated allenes under the reaction
conditions (highly polar and inseparable mixture was observed
in the reaction systems). The aliphatic cyclohexanecarbox-
aldehyde, valeraldehyde, and isobutyraldehyde are less reactive
compared with aromatic aldehydes because their reactions with
4-phenyl-1-butyne to afford allenes 2bl, 2bm, and 2bn had to
be conducted at 50 °C for the [1,5]-hydride transfer step,
instead of room temperature (entries 12−14).
In addition to 1-decyne, the used alkynes can have different
substituents (for example, phenyl, chloro, cyano, and vinyl
groups, entries 15−18). Furthermore, the low-boiling 1-
heptyne and aromatic phenylacetylene can also react with
benzaldehyde to give allenes 2fa and 2ga in 76 and 70% yields,
respectively (entries 19 and 20). To further demonstrate the
practicality of this methodology in synthesizing 1,3-disubsti-
tuted allenes, the reaction of 1-decyne, benzaldehyde, and
THIQ was conducted on a scale of 10 mmol, and allene 2aa
was obtained in a slightly higher yield, 67% (entry 1). We also
tried to use this method to synthesize terminal allenes using
paraformaldehyde. Unfortunately, only a trace amount of the
allene product was observed.
CONCLUSION
■
In summary, we have developed a practical 1,2,3,4-tetrahy-
droisoquinoline (THIQ)-mediated synthesis of 1,3-disubsti-
tuted allenes from terminal alkynes and aldehydes under mild
conditions in the presence of CuBr first and then ZnI2. This
telescoped allene synthesis has wide scope, including several
E
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ab
,
Table 4. Scope of the Allene Synthesis
a
The reactions were carried out on 0.5 mmol scale in 2.0 mL of toluene using 150 mg of 4 Å MS for the first step and 2.5 mL of toluene for the third
b
step. For a comparative purpose, a list of selected examples including the results of the THIQ method with previous ones from Ma and Periasamy
groups was given in Table S1 of the Supporting Information, which shows that the present method gives reaction yields usually comparable to those
c
d
obtained by Periasamy’s method but are higher than those obtained by Ma’s method. Isolated yield. The value in the parentheses is the yield when
e
the reaction was conducted on a 10 mmol scale using 3.0 g of 4 Å MS. We found that the reactions under Ma’s standard conditions at 130 °C using
THIQ gave lower yields (44 and 16% for entries 1 and 7, respectively), suggesting that THIQ-mediated allene synthesis is not good at high
f
g
temperature. The yield is much higher than that using Ma’s protocol. Cyp = Cyclopropyl.
Scheme 5. Preliminary Exploration of Asymmetric Allene Synthesis Using Chiral Ligands
F
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Scheme 6. Preliminary Exploration of Asymmetric Allene Synthesis Using Chiral THIQ Derivatives
a
Yield and ee values in parentheses were obtained when the exo-yne-THIQ from the A3 reaction was purified first and then subjected this
b
intermediate to ZnI2-mediated allene synthesis. “No reaction” means that the first A3 reaction did not take place.
washed with PE/EA (10/1), and the combined filtrate was concentrated.
The crude product was purified by flash column chromatography on silica
gel (eluted with PE/EA = 50/1) to afford propargylamine 5aa (141.3 mg,
examples using unprecedented labile substrates, and good to
excellent yields. A promising asymmetric allene synthesis with
moderate enatioselectivity was also achieved by using a chiral
THIQ derivative readily prepared from naturally abundant
phenylalanine. Finally, we compared the reactivities of selected
secondary amines with THIQ, showing the obvious advantage
of THIQ as the mediator in allene synthesis. Further study of
using DFT calculations to understand how different sub-
stituents affect the [1,5]-hydride transfer and β-elimination
processes is ongoing and will be disclosed in due course.
1
87%). Pale yellow oil: TLC Rf = 0.71 (PE/EA = 20/1); H NMR
(400 MHz, CDCl3) δ 7.65 (d, J = 7.4 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H),
7.28 (t, J = 7.3 Hz, 1H), 7.12−7.06 (m, 3H), 7.01−6.97 (m, 1H), 4.81 (s,
1H), 3.76 (d, J = 16.8 Hz, 1H), 3.72 (d, J = 15.2 Hz, 1H), 2.96−2.83 (m,
2H), 2.82−2.68 (m, 2H), 2.31 (td, J = 7.0, and 2.0 Hz, 2H), 1.63−1.50
(m, 2H), 1.48−1.37 (m, 2H), 1.33−1.20 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 139.0, 135.5, 134.5, 128.7, 128.5, 128.1,
127.5, 126.7, 125.9, 125.5, 88.9, 75.3, 61.2, 52.1, 47.1, 31.9, 29.7, 29.3, 29.1,
29.0, 22.7, 18.8, 14.1; IR (neat) 2925, 2854, 1491, 1449, 1141 cm−1;
HRMS (ESI) calcd for C26H34N (M + H)+ 360.26858, found 360.26810.
Synthesis of 2-Benzyl-1-(dec-1-yn-1-yl)-1,2,3,4-tetrahydroi-
soquinoline (5aa′). To a flame-dried pear-shaped flask (10 mL) was
added CuI (9.5 mg, 0.05 mmol) and newly activated 4 Å molecular sieves
(300 mg) inside a glovebox. Toluene (2 mL) was then added under
nitrogen atmosphere outside of the glovebox, followed by benzaldehyde
4a (65.5 mg, 0.617 mmol), THIQ (80.4 mg, 0.604 mmol), and 1-decyne
3a (70.5 mg, 0.510 mmol). The reaction mixture was stirred at room
temperature (25 °C) for 12 h. After completion of the reaction, the
mixture was filtered through a thin pad of silica gel. The filter cake was
washed with PE/EA (10/1), and the combined filtrate was concentrated.
The crude product was purified by flash column chromatography on silica
gel (eluted with PE/EA = 50/1) to afford propargylamine 5aa′ (176.2
EXPERIMENTAL SECTION
■
General Information. Toluene was dried over Na before use. The
reaction course was followed by TLC. For chromatographic purifications,
200−300 mesh silica gel was employed. H NMR (400 MHz) and 13C
1
NMR (100 MHz) spectra were recorded in parts per million using
tetramethylsilane (TMS) as the internal standard. IR spectra were reported
in wavenumbers (cm−1). HRMS were performed under ESI ionization tech-
nique using FT-ICR analyzer. PE = petroleum ether, EA = ethyl acetate.
Experimental Notes. The commercially available ZnI2 was used in
the synthesis. But sometimes the purchased ZnI2 was not pure, and the
reaction yield of allene synthesis was low at room temperature. In this
case, sublimed ZnI2 can be used to reproduce the reaction yield
reported in Table 2. Also the first step of formation of exo-yne-THIQs
is sensitive to air and must be conducted under N2 or Ar atmosphere.
The ZnI2-mediated synthesis of allene is also sensitive to moisture. We
also found that the reported reaction can be performed under N2
atmosphere, and there is no need to use glovebox (in our lab, CuBr
and ZnI2 purchased were stored in the glovebox, so we measured these
reagents within the glovebox).
Synthesis of 2-(1-Phenylundec-2-ynyl)-1,2,3,4-tetrahydroi-
soquinoline (5aa). To a flame-dried pear-shaped flask (10 mL) was
added CuBr (14.4 mg, 0.1 mmol) and newly activated 4 Å molecular
sieves (300 mg) inside a glovebox. Toluene (2 mL) was then added under
nitrogen atmosphere outside of the glovebox, followed by benzaldehyde
4a (55.4 mg, 0.522 mmol), THIQ (71.1 mg, 0.534 mmol), and 1-decyne
3a (61.0 mg, 0.441 mmol). The reaction mixture was stirred at room
temperature (25 °C) for 12 h. After completion of the reaction, the
mixture was filtered through a thin pad of silica gel. The filter cake was
1
mg, 96%). Pale yellow oil: TLC Rf = 0.60 (PE/EA = 20/1); H NMR
(400 MHz, CDCl3) δ 7.43 (d, J = 7.1 Hz, 2H), 7.32 (t, J = 7.3 Hz, 2H),
7.27 (d, J = 7.2 Hz, 1H), 7.21−7.17 (m, 1H), 7.15−7.11 (m, 2H), 7.11−
7.05 (m, 1H), 4.55 (s, 1H), 3.89 (d, J = 13.1 Hz, 1H), 3.80 (d, J = 13.1
Hz, 1H), 3.06−2.88 (m, 2H), 2.82−2.65 (m, 2H), 2.23 (td, J = 7.0, and
2.0 Hz, 2H), 1.58−1.48 (m, 2H), 1.47−1.36 (m, 2H), 1.34−1.19 (m,
8H), 0.88 (t, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 138.6,
136.4, 133.9, 129.2, 128.9, 128.2, 127.7, 127.1, 126.7, 125.7, 87.2, 77.9,
59.5, 54.1, 45.6, 31.9, 29.3, 29.11, 29.06, 29.00, 28.9, 22.7, 18.9, 14.1; IR
(neat) 2929, 2858, 1499, 1458, 1138 cm−1; HRMS (ESI) calcd for
C26H34N (M + H)+ 360.26858, found 360.26874.
General Procedure for THIQ-Mediated Synthesis of 1,3-
Disubstituted Allenes from Terminal Alkynes and Aldehydes.
To a flame-dried pear-shaped flask (10 mL) was added CuBr (10.8 mg,
0.075 mmol) and newly activated 4 Å molecular sieves (150 mg) inside
G
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a
Table 5. Comparison of the Reactivities of THIQ and Other Secondary Amines in Allene Synthesis
a
The reactions were carried out on 0.5 mmol scale in 2.0 mL of toluene using 150 mg of 4 Å MS for the first step and 2.5 mL of toluene for the third
b
step. Yields in the parentheses are results of the first step of A3 coupling and the second step of [1,5]-hydride transfer of purified propargyl amines,
respectively, which are both carried out at room temperature. Yields with star marks were carried out at 50 °C, and in these cases, room temperature
c
d
reactions are not satisfactory. Isolated yield using the three-step procedure. No allene product was observed when the temperature was lowered to
room temperature.
a glovebox. Toluene (2 mL) was then added under nitrogen atmosphere
outside of the glovebox, followed by aldehyde 4 (0.9 mmol), THIQ (93.2
mg, 0.7 mmol), and terminal alkyne 3 (0.5 mmol). The reaction mixture
was stirred at room temperature (25 °C) for 12 h. After completion of the
reaction, the mixture was filtered through a thin pad of silica gel. The filter
cake was washed with PE/EA, and the combined filtrate was
concentrated. The crude product was used in the next step without
further treatment. To another flame-dried pear-shaped flask (10 mL) was
added ZnI2 (239.4 mg, 0.75 mmol) inside a glovebox, and then the flask
was taken out. The above crude product was dissolved in toluene
(2.5 mL) and transferred to the flask via a syringe under nitrogen
atmosphere. After stirring at the indicated temperature for the indicated
reaction time (at room temperature for 12 h, or at 50 °C for 4 h, or at
75 °C for 5 h; see these in Table 4), the reaction was stopped, the
reaction mixture was filtered through a thin pad of silica gel, and the filter
cake was washed with PE (except for the synthesis of allene 2da, where
PE/EA = 10/1 was used as the eluting solvent). After evaporation, the
residue was purified by flash column chromatography on silica gel (eluted
with PE/EA = 10/1 for allene 2da and PE for other allenes) to afford the
corresponding allene product 2. Also this procedure was applied for the
three-step synthesis of allene shown in Table 5, except that THIQ was
replaced by the corresponding secondary amines.
(110.8 mg, 0.922 mmol), and THIQ (91.1 mg, 0.684 mmol) were
converted to the allene product 2ad (114.8 mg, 92% yield). Colorless oil:
TLC Rf = 0.93 (PE); 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 7.5 Hz,
1H), 7.20−7.03 (m, 3H), 6.33−6.27 (m, 1H), 5.56−5.48 (m, 1H), 2.36 (s,
3H), 2.16−2.08 (m, 2H), 1.54−1.43 (m, 2H), 1.40−1.19 (m, 10H), 0.88
(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 205.9, 134. 8, 133.3,
130.4, 127.0, 126.5, 126.0, 94.2, 91.7, 31.9, 29.4, 29.3, 29.2, 28.9, 22.7, 19.8,
14.1; IR (neat) 2925, 2854, 1465, 1262 cm−1; HRMS (ESI) calcd for
C18H27 (M + H)+ 243.21073, found 243.21071.
trans-1-Cyclopropyl-7-phenylhepta-1,3,4-triene (2bk). Following
the general procedure above, 4-phenyl-1-butyne (65.0 mg, 0.5 mmol),
trans-3-cyclopropylacrylaldehyde (86.0 mg, 0.9 mmol), and THIQ
(93.2 mg, 0.7 mmol) were converted to the allene product 2bk
1
(25.0 mg, 24% yield). Colorless oil: TLC Rf = 0.81 (PE); H NMR
(400 MHz, C6D6; the singlet peak at 7.15 was used as the standard) δ
7.20−7.11 (m, 2H), 7.10−7.01 (m, 3H), 5.99 (dd, J = 14.8 and 10.6
Hz, 1H), 5.91−5.82 (m, 1H), 5.28 (q, J = 5.9 Hz, 1H), 4.97 (dd, J =
15.0 and 8.8 Hz, 1H), 2.61 (t, J = 7.6 Hz, 2H), 2.28−2.17 (m, 2H),
1.24−1.13 (m, 1H), 0.53−0.42 (m, 2H), 0.24−0.15 (m, 2H); 13C
NMR (100 MHz, C6D6; the triplet peaks at 128.0 were used as the
standard) δ 206.7, 141.9, 136.1, 128.8, 128.6, 126.1, 123.9, 95.2, 92.0,
35.6, 31.0, 14.4, 7.3; IR (neat) 2934, 2858, 1944, 1497, 1454 cm−1;
HRMS (ESI) calcd for C16H19 (M + H)+ 211.14813, found 211.14823.
General Procedure for Attempts of Asymmetric Allene
Synthesis Using Chiral Ligands. Similar to the general procedure
for THIQ-mediated allene synthesis, terminal alkyne and aldehyde
were converted into 1,3-disubstituted allene via a three-step sequence.
Corresponding chiral ligand (0.083 mmol) was added into the flask
The structures of allene molecules 2aa,8 2ab,10b 2ac,10b 2ae,10b 2af,10b
2ag,8 2bh,10b 2ci,10b 2bj,26 2bl,27 2bm,27 2bn,28 2ba,10b 2ca,10b 2da,10b
2ea,11c 2fa,10b 2ga11b and R-2aa,10b which were confirmed by 1H and 13
C
NMR spectra, are consistent with those reported previously.
1-(2-Methylphenyl)undeca-1,2-diene (2ad). Following the general
procedure above, 1-decyne (71.4 mg, 0.516 mmol), 2-methylbenzaldehyde
H
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Article
inside a glovebox prior to the addition of substrates. Reactions were
monitored by TLC.
were converted to propargyl amine product 8c (818.3 mg, 56% yield).
Yellow oil: TLC Rf = 0.60 (PE/EA = 10/1); H NMR (400 MHz,
1
CDCl3) δ 7.62 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.24 (t, J =
7.2 Hz, 1H), 4.80 (s, 1H), 2.60−2.49 (m, 2H), 2.49−2.38 (m, 2H),
2.30 (td, J = 6.9, and 1.9 Hz, 2H), 1.62−1.51 (m, 2H), 1.50−1.40 (m,
2H), 1.38−1.23 (m, 8H), 1.03 (t, J = 7.1 Hz, 6H), 0.88 (t, J = 6.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 140.6, 128.4, 127.9, 127.0, 87.5,
76.0, 56.5, 44.5, 31.9, 29.3, 29.14, 29.11, 28.9, 22.7, 18.8, 14.1, 13.6; IR
(neat) 2929, 2856, 1450, 1382, 1196 cm−1; HRMS (ESI) calcd for
C21H34N (M + H)+ 300.26858, found 300.26820.
N,N-Dibenzyl-1-phenylundec-2-yn-1-amine (8d). Similar to the
synthesis of 5aa, under 25 °C, dibenzylamine (1.1934 g, 6.05 mmol),
benzaldehyde (505.5 mg, 4.76 mmol), and 1-decyne (827.5 mg, 5.99
mmol) were converted to propargyl amine product 8d (1.4137 g, 70%
yield). Colorless oil: TLC Rf = 0.21 (PE); 1H NMR (400 MHz, CDCl3)
δ 7.67 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 7.4 Hz, 4H), 7.34−7.25 (m, 6H),
7.20 (q, J = 7.0 Hz, 3H), 4.69 (s, 1H), 3.70 (d, J = 13.5 Hz, 2H), 3.44 (d,
J = 13.5 Hz, 2H), 2.42 (td, J = 6.9, and 2.0 Hz, 2H), 1.71−1.62 (m, 2H),
1.60−1.50 (m, 2H), 1.43−1.25 (m, 8H), 0.89 (t, J = 6.9 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 140.03, 139.96, 129.0, 128.44, 128.35, 128.1,
127.4, 127.0, 88.9, 74.9, 55.8, 54.7, 32.0, 29.5, 29.4, 29.3, 29.2, 22.9, 19.0,
14.3; IR (neat) 2928, 2853, 1494, 1452, 1117 cm−1; HRMS (ESI) calcd
for C31H38N (M + H)+ 424.29988, found 424.30106.
2-(1-Phenylundec-2-yn-1-yl)isoindoline (8e). Similar to the syn-
thesis of 5aa, under 25 °C, isoindoline (718.5 g, 6.03 mmol),
benzaldehyde (530.1 mg, 4.99 mmol), and 1-decyne (830.9 mg, 6.01
mmol) were converted to propargyl amine product 8e (510.6 mg, 30%
yield). Dark red oil: TLC Rf = 0.64 (PE/EA = 10/1); 1H NMR
(400 MHz, CDCl3) δ 7.67−7.61 (m, 2H), 7.39−7.32 (m, 2H), 7.31−7.26
(m, 1H), 7.15 (s, 4H), 4.91 (s, 1H), 4.05 (d, J = 11.2 Hz, 2H), 3.97 (d, J
= 11.1 Hz, 2H), 2.27 (td, J = 7.0, and 2.0 Hz, 2H), 1.57−1.48 (m, 2H),
1.43−1.34 (m, 2H), 1.31−1.19 (m, 8H), 0.87 (t, J = 6.9 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 140.0, 139.6, 128.23, 128.21, 127.5, 126.6,
122.4, 89.5, 76.3, 58.3, 55.3, 31.8, 29.2, 29.1, 29.0, 28.9, 22.7, 18.8, 14.1; IR
(neat) 2928, 2854, 1465, 1343, 1272 cm−1; HRMS (ESI) calcd for
C25H32N (M + H)+ 346.25293, found 346.25385.
General Procedure for Attempts of Asymmetric Allene
Synthesis Using Chiral THIQs. Similar to the general procedure for
THIQ-mediated allene synthesis, terminal alkyne and aldehyde were
converted into 1,3-disubstituted allene via a three-step sequence. The
first and third steps were carried out at 50 °C instead of room
temperature for 12 h. Reactions were monitored by TLC.
Synthesis of Allene R-2aa10b in One Pot via a Three-Step
Sequence. Following the general procedure for allene synthesis,
THIQ-ester 6b (264.3 mg, 0.6 mmol), benzaldehyde 4a (87.5 mg,
0.8 mmol), and 1-decyne 3a (53.6 mg, 0.4 mmol) were finally converted
into allene product 2aa (47.2 mg, 0.2 mmol, 53%). The ee value of allene
was determined by HPLC using an OD-H chiral column with hexane
25
as eluent. The ee value turned out to be 65%. [α]D −150.2 (c = 0.50,
CHCl3).
Stepwise Synthesis of Allene R-2aa: Synthesis of exo-Yne-
THIQ 7 and Subsequent Chiral Allene Synthesis Using Chiral
THIQ 6b. Similar to the synthesis of exo-yne-THIQ 5aa, THIQ-ester
6b (114.7 mg, 0.6 mmol), benzaldehyde 4a (53.0 mg, 0.5 mmol), and
1-decyne 3a (83.0 mg, 0.6 mmol) were converted into exo-yne-THIQ 7
(186.7 mg, 0.447 mmol, 89%). Purification was by silica gel, PE/EA =
100/1. The ee value of 7 was determined by HPLC using an AD-H chiral
column with 99/1 hexane/iPrOH as eluent. The measured ee value was
75% according to the HPLC profile (the absolute configuration of the
stereogenic center was not determined). Subsequently, 7 (108.4 mg,
0.260 mmol) was applied to the general procedure for the allene synthesis
from exo-yne-THIQ; allene 2aa (45.3 mg, 0.198 mmol, 76%) was
obtained. The measured ee value was 72%.
(3S)-Methyl 2-(1-phenylundec-2-yn-1-yl)-1,2,3,4-tetrahydroiso-
quinoline-3-carboxylate (7). Colorless oil: TLC Rf = 0.40 (PE/EA
= 30/1); 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.3 Hz, 2H), 7.34
(t, J = 7.3 Hz, 2H), 7.30−7.24 (m, 1H), 7.11−7.02 (m, 3H), 6.88 (d,
J = 6.6 Hz, 1H), 5.01 (s, 1H), 4.12 (t, J = 5.7 Hz, 1H), 3.73 (s, 2H),
3.72 (s, 3H), 3.25−3.10 (m, 2H), 2.25 (td, J = 7.0, 2.0 Hz, 2H), 1.58−
1.46 (m, 2H), 1.44−1.34 (m, 2H), 1.34−1.18 (m, 8H), 0.87 (t, J =
6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.7, 139.4, 134.7,
132.4, 128.5, 128.3, 128.1, 127.7, 126.4, 126.1, 126.0, 89.3, 75.9, 58.8,
58.7, 51.7, 48.0, 33.0, 31.9, 29.3, 29.1, 28.94, 28.90, 22.7, 18.9, 14.2; IR
(neat) 2927, 2854, 1742, 1451, 1195, 1173 cm−1; HRMS (ESI) calcd
for C28H36NO2 (M + H)+ 418.27406, found 418.27404.
Synthesis of 8a−8e followed the similar procedure of synthesis of 5aa
4-(1-Phenylundec-2-yn-1-yl)morpholine (8a). Similar to the syn-
thesis of 5aa, under 50 °C, morpholine (110.7 mg, 1.27 mmol),
benzaldehyde (113.5 mg, 1.07 mmol), and 1-decyne (175.2 mg, 1.27
mmol) were converted to propargyl amine product 8a (88.3 mg, 26%
yield). Colorless oil: TLC Rf = 0.30 (PE/EA = 10/1); 1H NMR
(400 MHz, CDCl3) δ 7.56 (d, J = 7.2 Hz, 2H), 7.36−7.30 (m, 2H),
7.29−7.24 (m, 1H), 4.52 (s, 1H), 3.75−3.63 (m, 4H), 2.59−2.46 (m,
4H), 2.31 (td, J = 6.9, and 1.8 Hz, 2H), 1.63−1.52 (m, 2H), 1.49−1.38
(m, 2H), 1.37−1.21 (m, 8H), 0.88 (t, J = 6.7 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 138.5, 128.6, 128.1, 127.5, 88.8, 75.4, 67.2, 61.7,
49.8, 31.8, 29.2, 29.1, 29.04, 28.97, 22.7, 18.8, 14.1; IR (neat) 2926,
2854, 1451, 1321, 1117 cm−1; HRMS (ESI) calcd for C21H32NO (M +
H)+ 314.24784, found 314.24723.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C spectra for all products, HPLC analysis
profile of R-2aa, 7, comparison of different allene synthesis
methods, and computational details. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yuzx@pku.edu.cn.
■
Author Contributions
†G.-J. Jiang and Q.-H. Zheng contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
1-(1-Phenylundec-2-yn-1-yl)pyrrolidine (8b). Similar to the syn-
thesis of 5aa, under 25 °C, pyrrolidine (267.7 mg, 3.76 mmol), benz-
aldehyde (393.2 mg, 3.71 mmol), and 1-decyne (416.7 mg, 3.01 mmol)
were converted to propargyl amine product 8b (850.3 mg, 95% yield).
We are indebted to the generous financial support from the
Natural Science Foundation of China (21072013) and the
National Basic Research Program of China-973 Program
(2010CB833203). We thank Prof. Shengming Ma and his
students at Shanghai Institute of Organic Chemistry and East
China Normal University for providing us several key
references. Also Prof. Ma and his students repeated the
synthesis of 2aa, finding that the THIQ-mediated allene
synthesis with all commercially available ZnI2 may be realized at
temperature higher than 80 °C, but at low temperature, the
yield was very low. This key observation prompted us to
investigate further, and we finally found that sublimed ZnI2 can
achieve the synthesis of 2aa at room temperature with good
1
Colorless oil: TLC Rf = 0.16 (PE/EA = 10/1); H NMR (400 MHz,
CDCl3) δ 7.48−7.41 (m, 2H), 7.26−7.20 (m, 2H), 7.19−7.14 (m, 1H),
4.53 (s, 1H), 2.57−2.46 (m, 4H), 2.19 (td, J = 7.0, and 2.1 Hz, 2H), 1.72−
1.63 (m, 4H), 1.52−1.42 (m, 2H), 1.40−1.30 (m, 2H), 1.29−1.12 (m, 8H),
0.80 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 140.2, 128.2,
128.1, 127.3, 87.1, 77.018, 58.8, 50.2, 31.9, 29.3, 29.1, 29.0, 28.9, 23.5, 22.7,
18.8, 14.1; IR (neat) 2928, 2856, 1451, 1268, 1136, 1030 cm−1; HRMS
(ESI) calcd for C21H32N (M + H)+ 298.25293, found 298.25224.
N,N-Diethyl-1-phenylundec-2-yn-1-amine (8c). Similar to the
synthesis of 5aa, under 25 °C, diethylamine (487.1 mg, 6.66 mmol),
benzaldehyde (514.6 mg, 4.85 mmol), and 1-decyne (805.3 mg, 5.82 mmol)
I
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Article
Soc. 2009, 131, 12910. (l) Zhao, X.; Zhong, Z.; Peng, P.; Zhang, W.;
Wang, J. Chem. Commun. 2009, 2535. (m) Bolte, B.; Odabachian, Y.;
Gagosz, F. J. Am. Chem. Soc. 2010, 132, 7294. (n) Xiao, Q.; Xia, Y.; Li,
H.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2011, 50, 1114.
(o) Hossain, M. L.; Ye, F.; Zhang, Y.; Wang, J. J. Org. Chem. 2013, 78,
1236. (p) Hashimoto, T.; Sakata, K.; Tamakuni, F.; Dutton, M. J.;
Maruoka, K. Nat. Chem. 2013, 5, 240.
reaction yield. We thank Prof. Ma for this great help also. We
also thank Dr. Lei Jiao and Prof. Thorsten Bach from
Technische Universitat Munchen, Mr. Zhe Dong and Prof.
̈
̈
Guangbin Dong from University of Texas, Austin, and Mr.
Yaocheng Shi from Peking University, for repeating the
experiment of the synthesis of 2aa. We are grateful to Prof.
Zuqiang Bian of Peking University for helping us get sublimed
ZnI2.
(6) (a) Rona, P.; Crabbe,
(b) Dollat, J.-M.; Luche, J.-L.; Crabbe,
1977, 761. (c) Crabbe, P.; Fillion, H.; Andre,
Soc., Chem. Commun. 1979, 859. (d) Crabbe,
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