Iridium-Catalyzed Cycloisomerization of Alkynoic Acids: Synthesis of Unsaturated Lactones

Article abstract of DOI:10.1002/adsc.201901322

The iridium-catalyzed cycloisomerization of various alkynoic acids was successfully developed, and a series of five-, six-, and especially seven-membered unsaturated lactones were constructed with moderate yields and excellent regioselectivities (up to 68

Full text of DOI:10.1002/adsc.201901322

Title: Iridium-Catalyzed Cycloisomerization of Alkynoic Acids:
Synthesis of Unsaturated Lactones
Authors: Yi Huang, Xianghe Zhang, Xiu-Qin Dong, and Xumu Zhang
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10.1002/adsc.201901322
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iridium-Catalyzed Cycloisomerization of Alkynoic Acids:
Synthesis of Unsaturated Lactones
Yi Huang,† Xianghe Zhang,† Xiu-Qin Dong,*† Xumu Zhang‡,†
† Key Laboratory of Biomedical Polymers, Engineering Research Center of Organosilicon Compounds & Materials,
Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei, 430072, P. R.
China.
‡ Department of Chemistry, Southern University of Science and Technology, Shenzhen Grubbs Institute, Shenzhen,
Guangdong, 518055, P. R. China.
E-mail address: xiuqindong@whu.edu.cn.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The iridium-catalyzed cycloisomerization of
various alkynoic acids was successfully developed, and a
series of five-, six-, and especially seven-membered
unsaturated lactones were constructed with moderate yields
and excellent regioselectivities (up to 68% yield, >99:1 rr).
In addition, the indole compound can be easily prepared
with 75% yield through this efficient synthetic
methodology. Moreover, a plausible mechanism for this Ir-
catalyzed cycloisomerization of alkynoic acids was
proposed.
Keywords: cycloisomerization, alkynoic acids, unsaturated
Figure 1. Examples of natural products and biologically
lactones, regioselectivity, indole.
active molecules containing lactone motifs.
(N-heterocyclic carbenes),[3f] bromolactonization of
long-chain olefinic acids promoted by sulfur-based
zwitterionic organocatalyst,[8] intermolecular [6+2]
The lactones and their derivatives have been
cyclization of amphoteric molecules with siloxy
identified as an important kind of heterocyclic motifs,
alkynes,[9] oxtene ring-opening reaction,[10] borylated
which are widely distributed in many natural products
lactones
from
esters
with
electrophilic
and biologically active molecules.[1] For example, γ-
Rubromycin shows the activity against the reverse
transcriptase of human immunodeficiency virus-1 and
telomerase, which is overproduced in cancer cells
(Figure 1).[1d-e] Purpuromycin is a potential topical
agent for the treatment of vaginal infections.[1f] The
natural product thunberginol F and its derivatives
exhibit anti-allergic and anti-microbial effects.[1g-h]
The steroid cattienoid B displays cytotoxicity against
KB (a human epidermal carcinoma) cells, which is
isolated from fruiting bodies of Tomophagus
cattienensis.[1i] In addition, these special skeletons are
useful and versatile building blocks, and key
intermediates in the field of organic synthesis.[2]
oxyboration,[11] and intramolecular addition of
carboxylic acids or esters to alkynes or alkenes
promoted by transition metal, organic acids or
bases.[3a-e, 3g, 4, 5, 6a, 12-14] Among these synthetic routes
to lactones, the cycloisomerization of alkynoic acids
is a straightforward and attractive synthetic method to
access lactones with great atom economy.[14] These
cycloisomerization reactions have been extensively
investigated by Pd,[3b, 3e, 4a, 5a, 14a-f, 14h-k] Rh,[3a, 5b] Ru,[4b]
Pt[14g] and Au[3d, 3g-i, 4c, 5c] catalytic systems. And they
were mainly focused on the preparation of five- and
six-membered lactones, the synthesis of seven-
membered lactones is very challenging and less
studied, which were always listed as one to three
examples with poor to moderate yields. Among these
research work, only Porcel’s group[5c] and
Bourissou’s group[14g] concentrated on the
construction of seven-membered lactones through the
cycloisomerization of alkynoic acids promoted by Au
and Pt catalytic system with moderate to high yields
Owing to the great importance of these
intriguing structures, much attention was paid to
exploring synthetic methods, and tremendous
progress have been achieved over the last decades.
Many synthetic methodologies were well established
to prepare lactones,[3-14] such as oxidative cyclization
reaction of alkynylbenzaldehydes catalyzed by NHC
1
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10.1002/adsc.201901322
Advanced Synthesis & Catalysis
(Scheme 1). To the best of our knowledge, there was
this
transformation.
Poor
reactivities
and
rare
exploration
about
Ir-catalyzed
regioselectivities were obtained with Bisbi, Tribi and
Tetrabi as the ligands (7%-15% conversions, 2%-3%
yields, 50:50-17:83 rr, Table 1, entries 1-3). The
electron-deficient ligands bisphosphoramidite L1,
triphosphoramidite L2 and tetraphosphoramidite L3
did not work in this reaction, and no conversion was
observed (Table 1, entries 4-6). Although the highly
electron-rich ligand Ph-BPE provided poor reactivity,
good regioselectivity was obtained (31% conversion,
24% yield, 85:15 rr, Table 1, entry 7). The reaction
solvents always have great influence on the reactivity
and selectivity. This [Rh(COD)Cl]2/Ph-BPE-
catalyzed cycloisomerization was then carried out in
different solvents. Poor results obtained in DCM and
toluene (17%-28% conversions, 11%-22% yields,
63:37-79:21 rr, Table 1, entries 8-9). No reaction was
detected in THF, 1,4-dioxane and CHCl3 (Table 1,
entries 10-12). To our delight, excellent
regioselectivity was observed in MeCN, albeit with
low yield and moderate conversion (52% conversion,
19% yield, >99:1 rr, Table 1, entry 13). The reactivity
was improved greatly with [Ir(COD)Cl]2 as metal
precursor, and the regioselectivity was not affected
(96% conversion, 42% yield, >99:1 rr, Table 1, entry
14).
cycloisomerization of alkynoic acids to construct
lactones, only one example was involved with 4-
pentynoic acid as the substrate catalyzed by Ir/NCN
pincer
conversions.[15] It was until now that there is nearly
no investigation about Ir-catalyzed
ligand
complexes
with
moderate
cycloisomerization of alkynoic acids to prepare
seven-membered lactones. Based on our interest in
this cycloisomerization, great efforts were made to
realize Ir-catalyzed cycloisomerization of alkynoic
acids for the synthesis of a series of five-, six-, and
especially seven-membered unsaturated lactones with
moderate yields and excellent regioselectivities
(Scheme 1, see also Supporting Information).
In order to achieve full conversion and higher
yield, the [Ir(COD)Cl]2/Ph-BPE catalytic system was
continued to be investigated in various solvents.
Good to excellent conversions, poor to moderate
yields and excellent regioselectivities were provided
in MeCN, MeOH and TFE (85%->99% conversions,
30%-50% yields, >99:1 rr, Table 2, entries 1-2, 7).
i
Poor conversions were obtained in EtOH, PrOH,
THF and toluene (Table 2, entries 3-6). It is possible
that the polymerization of substrate 1a,
intermolecular addition, polymerization of vinyl
lactone product 2a, which may lead to the undesirable
yield of this reaction. When the reaction temperature
was decreased to 65 °C, it may be helpful to this
cycloisomerization, and moderate yield can be
obtained (54% yield, Table 2, entry 8). In addition,
we found that this transformation can be finished
within 18 h (Table 2, entry 10). Furthermore, 61%
isolated yield can be afforded when the reaction was
carried out with 0.3 mmol scale (Table 2, entry 11).
Scheme 1. The construction of seven-membered
unsaturated
lactones
and
derivatives
through
cycloisomerization of alkynoic acids and derivatives.
The initial research for the cycloisomerization of
alkynoic acids was started with 2-(but-3-yn-1-
yl)benzoic acid 1a as model substrate to investigate
phosphine ligands (Figure 2) in the presence of
[Rh(COD)Cl]2 at 70 oC in DCE for 16 h. As shown in
Table 1, a series of phosphine ligands were applied in
Table 1. Screening ligands and solvents for Rh-catalyzed cycloisomerization of 2-(but-3-yn-1-yl)benzoic acid (1a). [a]
entry
ligand
Bisbi
Tribi
Tetrabi
L1
solvent
DCE
DCE
DCE
DCE
conv. (%) [b]
rr (2a:2a’) [b]
30:70
yield (%) [c]
1
2
3
4
13
15
7
2
3
17:83
50:50
2
NR
NA
NA
2
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10.1002/adsc.201901322
Advanced Synthesis & Catalysis
5
L2
DCE
DCE
NR
NR
31
NA
NA
NA
NA
24
6
L3
7
Ph-BPE
Ph-BPE
Ph-BPE
Ph-BPE
Ph-BPE
Ph-BPE
Ph-BPE
Ph-BPE
DCE
85:15
79:21
63:37
NA
8
DCM
28
22
9
toluene
THF
17
11
10
11
12
13
14 [d]
NR
NR
NR
52
NA
NA
NA
19
1,4-dioxane
CHCl3
MeCN
MeCN
NA
NA
>99:1
>99:1
96
42
[a] Unless otherwise mentioned, all reactions were carried out with the ratio of [Rh(COD)Cl]2/ligand/1a (0.2 mmol) of
o
2.5/5.0/100 in 2.0 mL DCE at 70 C for 16 h. DCE is 1, 2-dichloroethane, THF is tetrahydrofuran. NR is no reaction, NA
is not available.
[b] The conversion and regioselectivity were determined by 1H NMR analysis.
[c] The yield is 1H NMR yield with CH2Br2 as internal standard.
[d] [Ir(COD)Cl]2 was used as metal precursor, 24 h.
With the optimized reaction conditions in
hand, we then focused on the investigation of the
substrate scope study for this cycloisomerization.
As shown in Table 3, a variety of alkynoic acids
could participate in this reaction smoothly, and
the corresponding desired products seven-
membered vinyl lactones were formed with
moderate yields and excellent regioselectivities.
The substrates (1b-1d) with electron-withdrawing
group or electron-donating group on the phenyl
ring were tolerated well, affording the products
(
2b-2d
)
with 48%-68% yields and >99:1
regioselectivity. The naphthyl substituted
substrate 1e also worked well to prepare product
2e with moderate yield and excellent
regioselectivity (52% yield, >99:1 rr). To our
surprise, the substrate with dialkynoic acid 1f can
be proceeded to provide the corresponding
desired product 2f with 29% yield. The seven-
membered nitrogen-containing heterocyclic vinyl
Figure 2. The structure of phosphine ligands.
Table 2. Screening solvents for the Ir-catalyzed cycloisomerization of 2-(but-3-yn-1-yl)benzoic acid (1a).[a]
entry
solvent
MeCN
MeOH
EtOH
T (°C)
70
Time (h)
24
conv. (%) [b]
rr (2a:2a’) [b]
>99:1
yield (%) [c]
1
2
3
4
5
6
96
85
57
5
42
30
13
1
70
24
>99:1
70
24
>99:1
iPrOH
70
24
>99:1
THF
70
24
10
18
98:2
3
toluene
70
24
>99:1
5
3
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10.1002/adsc.201901322
Advanced Synthesis & Catalysis
7
TFE
TFE
TFE
TFE
TFE
70
65
60
65
65
24
24
24
18
18
>99
>99
>99
>99
>99
>99:1
50
54
40
54
61
8
>99:1
>99:1
>99:1
>99:1
9
10
11 [d]
[a] Unless otherwise mentioned, all reactions were carried out with ratio of [Ir(COD)Cl]2/(S,S)-Ph-BPE/1a (0.2 mmol) of
2.5/5.0/100 in 2.0 mL solvent at 70 oC for 24 h.
[b] The conversion and regioselectivity were determined by 1H NMR analysis.
[c] The yield is 1H NMR yield with CH2Br2 as internal standard.
[d] 0.3 mmol substrate 1a, 5 mol% catalyst, 3.0 mL TFE, isolated yield.
lactone 2g can be prepared through this
cycloisomerization with moderate conversion.
And the five-membered vinyl lactone 2h was
afforded with 53% yield and >99:1
regioselectivity. However, it is difficult and
challenging to access eight-membered vinyl
lactone 2i through this reaction, very poor
conversion was provided. In addition, more
flexible substrate hept-6-ynoic acid 1j was
applied into this cycloisomerization, but mess
reaction system was observed.
results. Moreover, the indole compound 2m was
easily constructed through this cycloisomerization
with 75% yield, which provided an efficient synthetic
method to prepare indole (Scheme 2b). In addition, it
is very challenging to produce seven or eight-
membered lactams through the metal-catalyzed
cycloisomerization of alkynyl amides.[16] The alkynyl
amide substrate 2-(but-3-yn-1-yl)-N-tosylbenzamide
1n was then examined in this Ir-catalyzed
cycloisomerization, the desired product seven-
membered unsaturated lactam 2n could be obtained
but with 18% yield (Scheme 2c).
Table 3. Substrate scope study for Ir-catalyzed
cycloisomerization of alkynoic acids. [a]
Scheme 2. Synthesis of unsaturated lactones, indole and
lactam.
The synthetic application potentiality of this Ir-
catalyzed cycloisomerization methodology was
demonstrated by the gram-scale transformation. The
Ir-catalyzed cycloisomerization of model substrate 2-
(but-3-yn-1-yl)benzoic acid 1a with gram scale was
proceeded smoothly to provide the desired product 2a
with >99% conversion, 45% yield and >99:1
regioselectivity (Scheme 3a). In addition, Ir-catalyzed
cycloisomerization of 1a can be performed efficiently
under microwave irradiation condition, and 60%
yield and >99:1 regioselectivity were obtained
(Scheme 3b). This cycloisomerization of 2-(but-3-yn-
[a] Unless otherwise mentioned, all reactions were carried
out with the ratio of [Ir(COD)Cl]2/(S,S)-Ph-BPE/substrate
o
1 (0.3 mmol) of 2.5/5.0/100 in 3.0 mL TFE at 65 C for 18
h. The conversion and regioselectivity were determined by
1H NMR analysis. The yield is isolated yield.
As shown in Scheme 2a, the disubstituted
alkynoic acids substrates were further investigated in
this catalytic system, the six-membered unsaturated
lactones 2k and 2l were obtained with moderate
4
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10.1002/adsc.201901322
Advanced Synthesis & Catalysis
1-yl)benzoic acid 1a also can be proceeded in the
presence of water (Scheme 3c). Moreover, the
cycloisomerization product 2a was easily hydrolyzed
in acid or alkalinous reaction condition, which
generated 2-(3-oxobutyl)benzoic acid
moderate yields (Scheme 3d).
3
with
Scheme 4. Deuterium-labeling experiment and proposed
catalytic cycle.
In summary, we successfully developed Ir-
catalyzed cycloisomerization of various alkynoic
acids to prepare a series of five-, six-, and especially
seven-membered unsaturated lactones with moderate
yields and excellent regioselectivities (up to 68%
yield, >99:1 rr). Moreover, the indole compound can
be easily available through this efficient synthetic
methodology. In addition, a plausible mechanism for
this Ir-catalyzed cycloisomerization methodology
were proposed according to the reaction results.
Scheme 3. Ir-catalyzed cycloisomerization of 1a and
hydrolysis of product 2a.
In order to get insight into a reasonable reaction
mechanism, the deuterium-labeling experiment was
conducted. As shown in Scheme 4a, the model
substrate 2-(but-3-yn-1-yl)benzoic acid 1a went
Experimental Section
General procedure for Ir-catalyzed cycloisomerization
of alkynoic acids: In an argon-filled glove-box, a solution
of [Ir(COD)Cl]2 (5.0 mg, 2.5 mol%) and (S,S)-Ph-BPE (7.6
mg, 5 mol%) in 3 mL anhydrous TFE (trifluoroethanol)
was stirred at rt for 2.0 h and then transferred into the
sealed tube which was charged with 0.3 mmol substrate
alkynoic acids 1. The vials were taken out of glove-box
through
Ir-catalyzed
cycloisomerization
in
CF3CH2OD, and the deuterium product 2a-D was
obtained containing partial deuteration on the
hydrogen atoms of the vinyl group with full
conversion, >99:1 rr and 60% yield. Based on the
experimental observation and literature results,[4c, 14h,
o
and placed in the preheated 65 C oil bath and stirred at
this temperature for 18 h. The reaction mixture was
subjected to a short celite column on silica gel to remove
1
14k, 17]
the metal complex. The product was analyzed by H NMR
a plausible reaction mechanism is proposed in
spectra for conversion-determination with CH2Br2 as
internal standard and subsequent purification by flash
column chromatography using PE/EA (20: 1) to provide
the desired product.
Scheme 4b. Initially, the substrate alkynoic acid A
could be went through partial deuterium exchange in
the presence of CF3CH2OD and iridium catalyst,
which indicated that this deuteration process may be
reversible. And then it was coordinated with Ir-
catalyst species to activate the triple bond, which
went through cyclization and delivered intermediate
Acknowledgements
We are grateful for financial support from the National
Natural Science Foundation of China (Grant No. 21432007,
21502145), Wuhan Morning Light Plan of Youth Science and
Technology (Grant No. 2017050304010307), the Fundamental
Research Funds for and the Central Universities (Grant No.
2042018kf0202), Shenzhen Nobel Prize Scientists Laboratory
Project (Grant No. C17783101), Science and Technology
C. The intermediate
C
was protonated by
CF3CH2OH/CF3CH2OD to deliver the final desired
product D, and to regenerate the Ir-catalyst species,
which was involved in the next catalytic cycle.
5
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10.1002/adsc.201901322
Advanced Synthesis & Catalysis
Innovation
Committee
of
Shenzhen
(Grant
No.
[4] For some examples for the cycloisomerizations
leading to δ-lactones, see: a) H. Sashida, A.
Kawamukai, Synthesis, 1999, 1999, 1145; b) M.
Jiménez-Tenorio, M. C. Puerta, P. Valerga, F. J.
Moreno-Dorado, F. M. Guerra, G. M. Massanet,
Chem. Commun., 2001, 2324; c) E. Marchal, P.
Uriac, B. Legouin, L. Toupet, P. van de Weghe,
Tetrahedron 2007, 63, 9979.
KQTD20150717103157174, JSGG 20170821140353405 and
JSGG 20160608140847864). The Program of Introducing
Talents of Discipline to Universities of China (111 Project) is
also appreciated.
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COMMUNICATION
Iridium-Catalyzed Cycloisomerization of Alkynoic
Acids: Synthesis of Unsaturated Lactones
Adv. Synth. Catal. 2019, Volume, Page – Page
Yi Huang,† Xianghe Zhang,† Xiu-Qin Dong,*†
Xumu Zhang‡,†
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