Base-catalysed [3 + 2] cycloaddition of propargylamines and aldehydes to substituted furans

Article abstract of DOI:10.1039/c7gc03618c

A base-catalysed [3 + 2] cycloaddition reaction of propargylamines and aldehydes for the regiospecific synthesis of substituted furans under metal-free conditions is developed. Propargylamines are used as allenyl anion equivalents and applied in [3 + 2] cycloaddition reactions with aldehydes. Various substituted furans are provided up to 91% yield for 28 examples.

Full text of DOI:10.1039/c7gc03618c

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Base-Catalysed [3+2] Cycloaddition of Propargylamines and
Aldehydes to Substituted Furans
Received 00th January 20xx,
Accepted 00th January 20xx
Jinhai Shen,* Jing Zhao, Bing Hu, Yangxin Chen, Longqiao Wu, Qihua You and Li Zhao
DOI: 10.1039/x0xx00000x
www.rsc.org/
a) Wan's work:
A base-catalysed [3+2] cycloaddition reaction of propargylamines
and aldehydes for the regiospecific synthesis of substituted furans
under metal-free conditions is developed. The propargylamines
are used as allenyl anion equivalents and applied in [3+2]
cycloaddition reactions with aldehydes. Various substituted furans
are provided in up to 91% yield for 28 examples.
R4
R1
LiHMDS (2 equiv)
PMDTA (2.4 equiv)
Ar
R2
HN
R3
N
+
R3
N
R2
THF, -78 °C to rt
R1
R4
b) This work:
R1 CHO
R3
R1
Substituted furans are key structural motifs existing in a broad
spectrum of biologically active natural products1 and
important pharmaceuticals.2 They also have extensive
applications as versatile synthons3 and are widely used in
material science.4 Accordingly, the development of efficient
approaches to functionalized furans has received considerable
attention. In addition to traditional methods,5 the transition-
metal-mediated synthesis of furans has become popular.6
Among them, the [3+2] cycloaddition reactions7 are still
limited to some specific substrates such as azides, nitrones,
azomethine ylides, nitrile imines, and nitrile oxides. Moreover,
the expensive and complicate transition metal catalysts cause
not only higher cost, but also potential contamination of the
products that is particularly significant in the pharmaceutical
industry. Therefore, transition-metal-free synthesis of
functionalized furans under mild conditions remains highly
desirable.
N
TBAOH ( 20 mol%)
DMSO, rt, 2 h
+
R2
R2
O
R3
Scheme 1. [3+2] Cycloaddition using propargylamines as allene
precursors.
transition-metal-free conditions, the generation of allene from
propargylamine remains rare. Only in 2013, Wan group
reported a LiHMDS (bis(trimethylsilyl)amide)-promoted [3+2]
cycloaddition of propargylamines with imines for the synthesis
of tetrasubstituted pyrroles under transition-metal-free
conditions (Scheme 1, a).11 In this reaction, the base-promoted
direct deprotonation of the preformed propargylamines
generates the allenyl anions. However, the requirement of
stoichiometric organolithium reagents and rigorous conditions
o
(-78 C) are undesirable for large-scale applications. In recent
years, aldehydes have acted as versatile electrophiles in the
anion-catalysed addition of activated allenes under mild
conditions.12 In our continuing interest in metal-free
heterocycle synthesis,13 herein we report a base-catalysed
[3+2] cycloaddition reaction of propargylamines with
aldehydes for the regiospecific synthesis of substituted furans
under metal-free conditions (Scheme 1, b). In this reaction,
only 0.2 equiv of tetrabutylammonium hydroxide (TBAOH) was
used as a catalyst, and the reaction was carried out under
ambient temperature, both of which are eco-friendly.
Recently, considerable interest has been focused on the
Mannich-type three-component coupling of an aldehyde, an
alkyne, and an amine (A3-coupling), which has emerged as an
efficient and general synthetic approach toward
propargylamines.8 A3-coupling-derived propargylamines are
highly useful building blocks and have been abundantly used
as precursors for the synthesis of heterocyclic compounds.9 In
particularly, the transition-metal-mediated hydride shifting
(1,5-H shift) of propargylamines along with the elimination of
amines lead to the generation of allenes.10 However, under
We began our investigation using the cyclization of
benzaldehyde 1a with 2-(1,3-diphenylprop-2-yn-1-yl)-1,2,3,4-
tetrahydroisoquinoline 2a as the model reaction to optimize
various reaction parameters (Table 1). To our delight, the
desired product 2,3,5-triphenylfuran 3aa was isolated in a 57%
yield when the mixture of 1a and 2a in DMSO was treated with
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Table 1. Optimization of reaction conditions.a
Ph
R1
TBAOH (20 mol%)
N
CHO
+
R1
DMSO, rt, 2 h
open flask
Ph
Ph
Ph
O
Ph
1
2a
3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
Ph
O
O
Entry
1
Base (equiv)
KOtBu (1)
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yield (%)b
57
Ph
Cl
Me
O
Me
3aa, 78%
3ba, 74%
3ca, 62%
Ph
3da, 73%
Ph
Ph
Ph
2
Cs2CO3 (1)
KOH (1)
22
3
47
Ph
Ph
O
Ph
O
O
O
Br
O
Br
4
NaOH (1)
43
3ea, 70%
3fa, 64%
3ga, 76%
3ha, 84%
5
NaOtBu (1)
53
Ph Ph
Ph
Ph
Ph
6
CsOH (1)
58
Ph
Ph
O
O
Ph
Ph
Ph
O
7
TBAOH c (1)
TBAOH d (1)
TBAOH d (1)
TBAOH d (1)
TBAOH d (1)
TBAOH d (1)
TBAOH d (1)
TBAOH d (0.2)
TBAOH d (0.1)
no
67
O
Ph
O
S
N
3ia, 73%
3ja, 78%
3kb, 35%a
3la, 35%
8
78
Scheme 2. Substrate scope of aldehydes. a2.5 Equiv of 2b was
used instead of 2a
9
54
.
10
11
12
13
14
15
16
17 e
18 f
19g
20h
NMP
61
CH3CN
toluene
H2O
trace
N.R.
N.R.
78
were also tested. When other tertiary propargylamines 2b-2d
were subjected to the TBAOH-catalyzed [3+2] cycloaddition
with benzaldehyde 1a, the desired product 3aa could also be
successfully attained, albeit in decreased yields. The
superiority of 2a may be due to the assistance of the
deprotonation at benzylic position,14 which was followed by a
1,3-H shift to give the propargyl anion (see Scheme 4).
Secondary propargylamines 2e, however, failed to give the
targeted product. The base-mediated derect deprotonation of
sp3 C–H bond adjacent to nitrogen in secondary amines still
remians challenging.15
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
68
N.R.
74
TBAOH d (0.2)
TBAOH d (0.2)
TBAOH d (0.2)
TBAOH d (0.2)
63
48
tarce
With the optimized reaction conditions in hand (entry 14,
Table 1), we first investigated the scope of aldehydes (Scheme
2). To our delight, a remarkably broad range of benzaldehydes
were tolerated. Propargylamine 2a could react efficiently with
benzaldehydes bearing either electron-donating or electron-
withdrawing groups, and gave the desired products in good
aReaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), base (x
equiv), in 1 mL solvent under air atmosphere for 2 h. bIsolated
yields (3aa
-3fa, 62-78% yield ). Halogens, including Cl and Br,
c
d
were well-tolerated (3da
−
3fa, 64−73% yield), which makes this
yields. N.R. = No Reaction. 10% in water (w/w). 25% in methanol
(w/w). eUsing 2b instead of 2a. Using 2c instead of 2a. gUsing 2d
f
transformation particularly attractive for increasing the
molecular complexity by transition-metal-catalyzed coupling
reactions. Compared the yield of 3ea with the yield of 3fa (70%
vs 64%), we found that the steric hindrance did not influence
this reaction obviously. Fused aryl and heteroaryl aldehydes
were also suitable substrates, and provided the corresponding
instead of 2a. hUsing 2e instead of 2a. DMSO = dimethylsulfoxide.
DMF = N,N-dimethylformamide. NMP = N-methyl-2-pyrrolidone.
KOtBu for 2 h (entry 1). In the presence of a medium-strength
base, such Cs2CO3, the efficiency was affected (22%, entry 2).
Other strong bases, including KOH, NaOH, NaOtBu, CsOH and
TBAOH, provided 3aa in acceptable yields (entries 3-8). A 67%
yield was obtained when TBAOH (10% in water) was employed
(entry 7). Using TBAOH (25% in methanol) increased the yield
of 3aa to 78% (entry 8). The solvent screening experiments
were subsequently carried out and DMSO was proved to be
the best choice (entries 9-13). Decreasing the loading of
TBAOH to 0.2 equiv did not derease the yield of product, a 78%
yield of product still could be provided (entry 14). Notably, a
respectable 68% yield of 3aa was achieved using 0.1 equiv of
TBAOH(entry 15). Other A3-coupling-derived propargylamines
furan products (3ga
-3ja) in 73-84% yields. Notably, double
[3+2] cycloaddition
of propargylamines 2b with
isophthalaldehyde 1k afford the bis-furan product 3kb in a 35%
yield. Alkenyl aldehyde, such as cinnamaldehyde, could also
participate in this reaction, albeit giving a lower yield of
product
(3la, 35% yield). Aliphatic aldehydes (such as
phenylacetaldehyde and n-hexaldehyde), however, failed to
afford any furan product.
Subsequently, we further investigated the scope of
tetrahydroisoquinoline(THIQ)-derived
When R1 and R2 were aryls, propargylamines
A3-propargylamines.
with both
2
2 | J. Name., 2012, 00, 1-3
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Scheme 4. Plausible reaction mechanism.
The intramolecular 5-endo-dig cyclization of
formation of the cyclized intermediate . Protonation of
gave intermediate . Finally, the elimination of amine from
C results in the
D
D
E
E
yields the desired furan product 3.
Conclusions
In conclusion, an efficient base-catalysed [3+2] cycloaddition
reaction of propargylamines and aldehydes for the
regiospecific synthesis of substituted furans under metal-free
conditions has been developed. This protocol use the
propargylamines as allenyl anion equivalents, and only 0.2
equiv TBAOH was required as a catalyst. Metal-free and high
efficiency make this reaction possess extensive synthesis
applications, especially in the pharmaceutical industry.
Scheme 3. Substrate scope of propargylamines.
electro-withdrawing and electro-donating groups, such as
methyl, methoxy, and fluoro, afforded the corresponding
furans in appreciable yields (3af
Halogens were also tolerated, and the halogenated furan
products were provided in good to excellent yields (3ag 3ai
and 3aq 3as, 60-91% yields). When fused aryl and heteroaryl
propargylamines were used, the corresponding products were
furnished efficiently (3aj 3am and 3t, 60-80% yields). It is
-3ag and 3ao-3aq, 59-83%).
Conflicts of interest
-
-
There are no conflicts to declare.
-
worth mentioning that 2,2':5',2''-terfuran 3hk could be easily
prepared form furan-2-carbaldehyde 1h and propargylamines
2k in a 72% yield. When R1 was an alkenyl group, the reaction
efficiency was affected (3an, 22% yield). However, when R1 or
R2 was an alkyl group, no desired product was formed.
Acknowledgements
We gratefully acknowledge the financial support of Scientific
Research Foundation of Xiamen Huaxia University (1003), Out-
standing Youth Scientific Research Cultivation Plan in Fujian
Province University (2017), Fujian Education and Scientific Re-
search Project for Young and Middle-aged Teachers
(JAT170820). We thank Professor Xiuling Cui from Huaqiao
University for the help with compound characterization.
To prove the practicality of this base-catalysed [3+2]
cycloaddition reaction,
a gram-scale synthesis of 2,3,5-
triphenylfuran 3aa was performed. When 0.53g of
benzaldehyde 1a (5 mmol) and 1.62g of 2-(1,3-diphenylprop-2-
yn-1-yl)-1,2,3,4-tetrahydroisoquinoline 2a (5 mmol) were
loaded, 1.02 g of 2,3,5-triphenylfuran 3aa was obtained in a 69%
yield (eq 1).
Notes and references
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2
3
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TBAOH (20 mol%)
N
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Ph
Ph
(1)
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previous reports,11-12,16 a tentative reaction mechanism was
proposed, as depicted in Scheme 4. Initially, propargylamine
undergoes a TBAOH-initiated deprotonation at the propargylic
position to give propargyl anion , and then the propargyl-
allenyl equilibrium17 produces allenyl anion
. Subsequently,
allenyl anion reacts with aldehyde to form intermediate
2
A
B
B
1
C.
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R3
R1
N
R1 CHO
base
DMSO, rt
+
R2
R2
O
R3
Metal-free
Mild conditions
Complete regioselectivity
28 examples
up to 91% yield
A base-catalyzed [3+2] cycloaddition reaction using propargylamines as
allenyl anion equivalents for the regiospecific synthesis of substituted
furans under metal-free conditions is developed.