Divergent synthesis of N-heterocyclic 1,6-enynes through a zinc-catalyzed decarboxylative A3 reaction

Article abstract of DOI:10.1039/c9cc06985b

A zinc-catalyzed decarboxylative A³ reaction of cyclic amino acids, α,β-unsaturated aldehydes and terminal alkynes has been developed. A series of functionalized N-heterocyclic 1,6-enynes have been successfully obtained with excellent regioselectivities through this novel approach. In addition, the utility of this straightforward process is demonstrated by the preparation of a polycyclic nitrogen-containing heterocyclic compound.

Full text of DOI:10.1039/c9cc06985b

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Divergent synthesis of N-heterocyclic 1,6-enynes
3
through a zinc-catalyzed decarboxylative A
Cite this: Chem. Commun., 2019,
5, 14170
reaction†
5
Received 7th September 2019,
Accepted 30th October 2019
a
a
a
b
a
Zhuo-Ya Mao, Yi-Wen Liu, Rui-Jun Ma, Jian-Liang Ye,
Chang-Mei Si,
a
c
Bang-Guo Wei * and Guo-Qiang Lin
DOI: 10.1039/c9cc06985b
rsc.li/chemcomm
3
A zinc-catalyzed decarboxylative A reaction of cyclic amino acids, group provides a distinct pathway to amine a-alkynylation using the
3
a,b-unsaturated aldehydes and terminal alkynes has been developed. same starting materials as the typical A process. The isomerization
A series of functionalized N-heterocyclic 1,6-enynes have been of an iminium cation via an azomethine ylide is the key in the
3
9c
successfully obtained with excellent regioselectivities through this redox-A reaction. Very recently, Liu reported a series of tunable
novel approach. In addition, the utility of this straightforward process is iminium ions generated from 4-trifluoromethyl-p-quinols and
demonstrated by the preparation of a polycyclic nitrogen-containing cyclic amines via redox-neutral isomerization (Fig. 1c).
3
10a
heterocyclic compound.
The decarboxylative A reaction established by Li
and
1
0b
Seidel independently provided an alternative route to amine
The discovery of an efficient methodology for constructing C–C a-alkynylation using amino acids, alkynes and an appropriate
bonds is one of the most important tasks in modern organic
1
synthesis. As a prime instance, the effective C–C cross-coupling
at the a-position of nitrogen is a very important approach for the
synthesis of nitrogen-containing building blocks in synthetic
and pharmaceutical chemistry, because it serves as a substructure
for numerous biologically relevant alkaloids and pharmaceutical
2
agents. In particular, the N-heterocyclic 1,6-enyne scaffold also
3
serves as a flexible synthetic precursor in synthetic chemistry.
Recently, great progress was achieved in the synthesis of
N-heterocyclic 1,6-enynes through a transition-metal catalyzed
4
process. Typical examples include Cu-catalyzed addition of
alkynyls to N-allyliminium ion intermediates, which were in situ
generated from allyl amines and aldehydes. The transformation
3
went through an A type reaction (alkyne aldehyde amine
5
coupling reaction) and the metal-catalyzed redox CDC (cross-
dehydrogenative coupling reaction) process of propargylic
6
amines and terminal alkynes. In the field of a-alkynylation
3
of nitrogen compounds, the A (alkyne aldehyde amine coupling)
7
,9,10
3
reaction
is the most widely used reaction. The typical A
7
8
reaction is an effective method to synthesize propargylamines
3
9
(
Fig. 1a). The redox-A reaction (Fig. 1b) developed by the Seidel
a
b
c
Department of Natural Medicine, School of Pharmacy, Fudan University,
26 Zhangheng Road, Shanghai, 201203, China. E-mail: bgwei1974@fudan.edu.cn
8
College of Chemistry and Chemical Engineering and the Key Laboratory for
Chemical Biology of Fujian Province, Xiamen University, Xiamen 361005, China
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
3
45 Lingling Road, Shanghai 200032, China
†
Electronic supplementary information (ESI) available: Experimental procedure,
3
characterization of all new compounds. See DOI: 10.1039/c9cc06985b
Fig. 1 Models of A type reactions.
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1
5
16
3
aldehyde in the presence of a copper catalyst (Fig. 1d). It is In addition, the reactions with Ni(OTf)
2
,
In(OTf)
and NiCl
2
worth mentioning that this process could be accelerated by did not work at all (Table 1, entries 5–7).
employing electron-deficient aldehydes and aromatic aldehydes
were required in this case.
Considering Zn(II) or Cd(II) salts could activate the terminal
6b,c
alkyne in the CDC reaction, Zn(OTf) and ZnF were examined,
2
2
As a continuation of our interest in the synthesis of nitrogen- and the results showed that ZnF could catalyze this decarboxylative
2
1
1
3
containing building blocks for natural products, we recently A reaction, producing 5 rather than the a-alkynylation product 4aa
reported the synthesis of functional pyrrolizidine derivatives (Table 1, entry 9). Interestingly, when ZnCl
17
2
was used, the desired
through a conjugated azomethine ylide involved 1,3-dipolar 4aa was obtained. Although the yield of 4aa was only 20%, the
11b
cycloaddition reaction. We envisioned that the metal-catalyzed regioselectivity was excellent (4aa :5 4 20 : 1) (Table 1, entry 10).
addition of alkynyls to N-allyliminium ions, derived from Delightfully, the yield of 4aa was improved to 59% along with high
conjugated azomethine ylides, would be a direct approach to regioselectivity (4aa :5 4 20 : 1) when ZnBr was employed (Table 1,
2
3
N-heterocyclic 1,6-enynes (Fig. 1e). To the best of our knowl- entry 11). However, ZnI failed to promote this decarboxylative A
2
edge, the nucleophilic addition of N-allyliminium ions which reaction (Table 1, entry 12). A similar result has been reported by Yu
3
are generated from conjugated azomethine ylides is very in the Cu-catalyzed A reaction for C1-alkynylation of THIQs, in
1
2
13
difficult, due to the competitive 1,3-dipolar cycloaddition
which the regioselectivity of the reaction was tuned by using
1
4
or 1,5-electrocyclization (6p-electrocylization) of the conjugated different copper catalysts. When CuBr was used, the exo-yne-
azomethine ylide. We herein present our studies on such a zinc- THIQ was the major product; however, CuI yields endo-yne-
catalyzed nucleophilic addition of N-allyliminium ions through a THIQ as a major product.
1
8
3
decarboxylative A process to N-heterocyclic 1,6-enynes.
Next, we turned our attention to investigate the substrate
3
3
Our investigation started with a decarboxylative A process scope and limitation of the decarboxylative A reaction. First,
of proline 1a, cinnamaldehyde 2a and phenylacetylene 3a. First, different substituted arylethynes 3a–g were surveyed under the
3
we pursued the decarboxylative A reaction of proline 1a, optimal conditions, as summarized in Table 2. In general, the
cinnamaldehyde 2a, and phenylacetylene 3a using the known reactions with phenylacetylene 3a and substituted phenylacety-
10a
procedure. Disappointingly, when the reaction was refluxed in lenes 3b–g proceeded smoothly in moderate yields with high
toluene in the presence of a catalytic amount of copper(I) iodide regioselectivities (420 : 1) (4aa–4af), except for 1-ethyl-4-ethynyl-
(CuI), the mixture turned complicated, without forming any desired benzene (4ag, 35% yield). Various a,b-unsaturated aldehydes 2b–f
product 4aa (Table 1, entry 1). When the cinnamaldehyde was were also screened, and the reactions could tolerate different
added slowly over 12 h, the desired 4aa was produced in 23% yield substitutions, smoothly leading to the desired products in
(
Table 1, entry 2). For reactions using CuBr or CuCl as the catalyst, moderate yields and with excellent regioselectivities (4ah–4al).
2
the results turned out to be fruitless (Table 1, entries 3 and 4). It is worth mentioning that dec-2-enal and acrylaldehyde could
also produce the desired a-alkynylation products 4ak and 4al in
6
2% and 54% yields, respectively. The combination of different
a,b,c,d
Table 1 Screening of optimal reaction conditions
substituted phenylacetylenes and substituted a,b-unsaturated
aldehydes was also examined, and the desired products were
obtained in moderate yields and with excellent regioselectivities
(
1
4am–4ao). The replacement with piperidine-2-carboxylic acid
b was investigated for this decarboxylative A reaction. The
3
results showed that most of the substituted arylethynes could
generate the desired a-alkynylation products 4ba–4bf in moderate
yields and with excellent regioselectivities (420 : 1), with yields
varying slightly for different substituted a,b-unsaturated aldehydes
a
b
c
(
4bg–4bh). Acrylaldehyde also worked in this case to afford the
desired product 4bi in 37% yield with an excellent regioselectivity
420 : 1). Other types of aldehydes were also tested. When benz-
Entry
Metal
Yield /%
4aa/5
d
1
CuI
CuI
CuBr
—
—
20 : 1
—
—
—
—
—
—
1 : 20
20 : 1
20 : 1
—
(
2
3
4
5
6
7
8
9
23
Trace
—
aldehyde was used, the desired product can be obtained in 51%
yield with a favorable 3 : 1 ratio of regioisomers. Meanwhile,
CuCl
Ni(OTf)
In(OTf)
NiCl
Zn(OTf)
ZnF
ZnCl
ZnBr
ZnI
2
2
—
—
—
—
47
20
59
—
3
19a
hexaldehyde gives the typical A product in 67% yield.
3
6,10
2
Based on the previous related works,
a possible mechanism
2
is proposed for the decarboxylative three component coupling
reaction (Fig. 2). First, the proline 1a was condensed with an
aldehyde to produce oxazolidin-5-one 6, which was easily decarboxy-
2
1
1
1
0
1
2
2
2
2
10
lated to give the conjugated azomethine ylide 7. Then, the
a
The reactions were performed with proline 1a (1.5 mmol), cinnamaldehyde terminal alkyne 3 was added to 7 in the presence of ZnBr to
2
2
a (1.0 mmol) and phenylacetylene 3a (1.5 mmol) in toluene (5 ml) with
generate the product 4. To further explore the regioselectivity of the
reaction, DFT calculations were performed at the B3LYP/6-31G*
level and the results show that the energy of 8b, the located
metal salt (0.2 mmol) at 120 1C for 12 h. The cinnamaldehyde was slowly
b
c
1
added over 12 h. Isolated yield. Ratio was determined by H NMR of the
crude product. The cinnamaldehyde was added at one time.
d
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a,b
Table 2 Substrate scope of the decarboxylative A reaction
Fig. 2 Possible mechanism for the decarboxylative three component
coupling reaction.
Scheme 1 Transformation of the N-heterocyclic 1,6-enyne to a poly-
cyclic nitrogen-containing heterocycle.
Pd(OAc)
in 84% yield.
2 3
and ( p-MePh) P at 60 1C for 6 h to give pyrrolizidine 11
2
3
a
The reactions were performed with amino acids 1 (1.5 mmol),
a,b-unsaturated aldehyde 2 (1.0 mmol) and terminal alkyne 3 (1.5 mmol)
In summary, we established a novel and efficient approach
in toluene (5 ml) with ZnBr (0.2 mmol) at 120 1C for 12 h. The a,b-
unsaturated aldehyde 2 was added over 12 h. Isolated yield.
2
for highly regioselective synthesis of functionalized N-heterocyclic
b
3
1
,6-enynes through a zinc(II)-catalyzed decarboxylative A process
of cyclic amino acids 1a–b, a,b-unsaturated aldehydes 2a–f and
terminal alkynes 3a–g. A series of functionalized N-heterocyclic 1,6-
enynes were successfully obtained with excellent regioselectivities.
Moreover, this approach was applied to synthesize the polycyclic
nitrogen-containing heterocyclic compound 10 through a one-pot
rearrangement process.
À1
transition state of addition to endo iminium, is ca. 7.08 kacl mol
lower than that of the exo addition transition state 8a. Therefore, the
1
9
major product is 4.
Considering the important use of N-heterocyclic 1,6-enynes
in organic synthesis, we focused on their transformation to
2
0
polycyclic nitrogen-containing heterocyclic compounds.
Thus, treatment of 4bf with iodomethane (MeI) in acetonitrile
smoothly gave iodide salt 9 in quantitative yield without
purification. Then, 9 was stirred in an ethanolic solution of
KOH to successfully obtain the desired 10 in 70% yield through
2
1
the intramolecular rearrangement process (Scheme 1).
Another transformation is the preparation of pyrrolizidine
skeletons, which are common structural units in many bioactive
2
2
alkaloids, azasugars and pharmaceutical agents. As shown
Scheme 2 Transformation of the N-heterocyclic 1,6-enyne to a pyrroli-
in Scheme 2, 4aa was stirred in toluene in the presence of zidine skeleton.
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We thank the National Natural Science Foundation of China
21772027) and the Open Research Fund Program of Beijing Key
Lab of Plant Resource Research and Development, BTBU (no.
PRRD-2018-ZD1) for their financial support. The authors also
thank Dr Han-Qing Dong (Arvinas, Inc.) for helpful suggestions.
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