A Unified Approach for Divergent Synthesis of Heterocycles via TMSOTf-Catalyzed Formal [3+2] Cycloaddition of Electron-Rich Alkynes

Article abstract of DOI:10.1002/adsc.202100769

We present a synthetic protocol for the construction of polysubstituted five-membered heterocycles via TMSOTf-catalyzed formal [3+2] cycloaddition of electron-rich alkynes, which features free from any metal, atom economy and water as the main by-product. Furthermore, alkenyl ether adduct has been verified as the key intermediate. Notably, by utilizing this approach, we can synthesize a broad range of polysubstituted furans, thiophenes and pyrroles, and extend this transformation to deliver fused-polyheterocycles. This reaction can be achieved on a gram scale and the corresponding products are intermediates for producing diverse potentially useful scaffolds. (Figure presented.).

Full text of DOI:10.1002/adsc.202100769

RESEARCH ARTICLE
doi.org/10.1002/adsc.202100769
A Unified Approach for Divergent Synthesis of Heterocycles via
TMSOTf-Catalyzed Formal [3+2] Cycloaddition of Electron-
Rich Alkynes
Ping Chen,a Wei Cao,a Xiangqian Li,a and Dayong Shia, b,*
a
State Key Laboratory of Microbial Technology
and Marine Biotechnology Research Center, Shandong University
72 Binhai Road, Qingdao 266237, Shandong, People’s Republic of China
E-mail: shidayong@sdu.edu.cn
b
Laboratory for Marine Biology and Biotechnology
Pilot National Laboratory for Marine Science and Technology
168 Wenhai Road, Qingdao 266237, Shandong, People’s Republic of China
Manuscript received: June 21, 2021; Revised manuscript received: August 24, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100769
Abstract: We present a synthetic protocol for the construction of polysubstituted five-membered heterocycles
via TMSOTf-catalyzed formal [3+2] cycloaddition of electron-rich alkynes, which features free from any
metal, atom economy and water as the main by-product. Furthermore, alkenyl ether adduct has been verified
as the key intermediate. Notably, by utilizing this approach, we can synthesize a broad range of polysubstituted
furans, thiophenes and pyrroles, and extend this transformation to deliver fused-polyheterocycles. This reaction
can be achieved on a gram scale and the corresponding products are intermediates for producing diverse
potentially useful scaffolds.
Keywords: π-rich alkynes; cycloaddition; heterocycles; TMSOTf; modularity
Introduction
protocols have been successively reported for synthesis
of these π-rich heterocycles (Figure 2b).[11–14] Inspired
π-Rich heterocycles are a type of structurally diverse by these elegant previous works and as a continuation
skeleton in natural products, pharmaceuticals and of our interest in the chemistry of electron-rich
bioactive molecules, such as pukalide and nitrofural
(Figure 1).[1]
During the past few decades, extensive efforts have
been devoted to the synthesis of these compounds.[2–9]
Traditional approaches mainly include venerable Ge-
wald-type[3] and Paal-Knorr-type[4] reactions based on
α-cyanoester and 1,4-dicarbonyl analogs, respectively
(Figure 2a-1). Besides, Csp2À Y bond (Y=O, N, S, Se)
formation of arenes has also been intensively
investigated,[5–9] such as metal-catalyzed Buchwald-
Hartwig,[6] Ullmann-Goldberg[7] and Chan-Lam[8] type
CÀ Y coupling reactions, and direct CÀ H functionaliza-
tion of arenes in the presence of oxidants (Figure 2a-
2).[9]
It is worth noting that Pennanen achieved a
convenient preparation of the furan derivatives in
Figure 1. Natural Products and Bioactive Molecules bearing π-
Rich Heterocycles.
moderate yields using labile ynamines and acyloins as
the starting materials in 1977.[10] Afterwards, more
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Table 1. Screening of Optimal Reaction Conditions.[a]
Entry[a]
Catalyst
Solvent
Time[h]
3l (%)[b]
1
2
3
4
5
6
7
8
B(C6F5)3
AgOTf
In(OTf)3
TfOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
THF
12 h
12 h
5 h
5 min
5 min
1 h
trace
trace
67
74
85
66
N.D
67
80
76
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
12 h
toluene
DCE
10 min
5 min
5 min
5 min
10 min
1 h
9
10[c]
11[d]
12[e]
13[f]
14[g]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
84
71
79
78
Figure 2. Strategies to Access π-Rich Heterocycles.
15 min
[a] Reaction conditions: ynamide 1a (0.2 mmol), 2l (1.2 equiv.),
catalyst (10 mol%), solvent (2.0 mL), ambient temperature,
Ar, unless otherwise noted.
alkynes.[11–15] Herein, we envision a complementary
process for the divergent synthesis of heterocycles via
TMSOTf-catalyzed formal [3+2] cycloaddition of
electron-rich alkynes. Moreover, the water is the main
by-product and this transformation proceeds smoothly
within 30 min (Figure 2c).
[b] Isolated yields.
[c] 1.1 equiv. of 2l.
[d] 1.4 equiv. of 2l.
[e] 0.05 equiv. of TMSOTf.
[f]
°
0 C.
[g] Under Air.
[h] Reaction times were determined when the alkynes were
completely consumption. N.D=not detected.
Results and Discussion
The initial investigations were commenced with
ynamide 1a and benzoin 2l as the representative
substrates. At the outset, a range of Lewis and
Brønsted acids, such as B(C6F5)3, AgOTf, In(OTf)3, desired multisubstituted furans (3a–i) in excellent
TfOH, TMSOTf, were evaluated for this transforma- yields. Moreover, substrates (3j–k) containing
tion in CH2Cl2 at ambient temperature under Ar naphthalene and benzofuran were obtained in 91% and
atmosphere (Table 1, entries 1–5). To our delight, 87%, respectively. Of note, tetrasubstituted furans (3l–
TMSOTf exhibited superior efficiency, yielding the p) also could be isolated in good yield. Moreover, 4-
product 3l in 85% yield (Table 1, entry 5), and the hydroxy-2-butanone was also tested under standard
structure of 3l was confirmed by single-crystal X-ray reaction conditions, yielding the desired product 3q in
diffraction analysis. Subsequently, various solvents 52% yield.
were surveyed, but the majority of them were not
Next, we extended this transformation to deliver
effective in promoting this transformation (Table 1, functionalized fused furan derivatives with “natural
entries 6–9). Examining different ratios of two starting product-like” skeletons (i.e., (�)-Laevigatin). To in-
materials did not enhance the transformation (Table 1, troduce structural diversity around the furan ring, a
entries 10–11). Further evaluation of other reaction wide array of cyclic ketones were used in this strategy,
parameters including the catalytic amount of TMSOTf and the corresponding tricyclic-fused furans (3r–y)
and temperature also did not result in further improve- were obtained in 73–93% yields. Additionally, me-
ment (Table 1, entry 12–13). In addition, the yield dium-sized cyclic ketones were also successfully
decreased slightly when the reaction was conducted engaged in this approach, delivering the six, eight and
under air (Table 1, entry 14).
twelved-membered furan fused heterocycles (3z–ab)
With the optimized conditions for the π-rich hetero- with good efficiency. To our delight, multi-substituted
cycles synthesis established, a variety of α-hydroxy thiophenes and pyrroles (3ac–af) could also be
ketone analogs were first evaluated (Table 2). Both achieved under standard conditions in serviceable
electron-donating and electron-withdrawing substitu- yields.
tions at the para position of the aryl ring (R1) could be
Subsequently, we focused our efforts on investigat-
well tolerated in this transformation to afford the ing the ability of electron-rich alkynes to participate in
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Table 2. Substrate Scope of Ketones Bearing Different Nucleophilic Groups (XH=OH, SH, MsNH).
[a] Reaction conditions: ynamide 1a (0.2 mmol), 2 (0.24 mmol), TMSOTf (10 mol%), CH2Cl2 (2.0 mL), ambie temperature, Ar,
unless otherwise noted.
[b] 12 h.
this protocol. As summarized in Table 3, an assortment diverse substitutions (Boc, ethyl sulfonyl, cyclopropyl
of ynamides containing both electron-withdrawing sulfonyl, and p-toluenesulfonyl) and (Bn, p-Me-Ph,
(CF3, NO2, Br, and Cl) and electron-donating (Et, and Me) on the nitrogen proceeded smoothly, affording
OMe, and H) functional groups on the aryl moiety the expected furans (4k–q) in moderate to high yields.
(R1), were well adapted to this transformation (4a–g).
Remarkably, other N-protecting groups of ynamides
Likewise, thiophene substituted furan (4h) was also (i.e., oxazolidinones and (À )-camphorsultam) were
obtained in 83% yield under standard conditions. In also compatible in this process to yield the correspond-
contrast, ynamides possessing cyclopropyl and ester ing furans (4r–u) in moderate yields, due to steric
groups could be converted into the corresponding hindrance. In addition, the (+)-dehydroabietylamine-
products (4i–j) in 69% and 51% yields, respectively. derived ynamide could engage in this transformation to
Subsequently, the reactions of ynamides bearing furnish the desired product (4v) in 79% yield. It was
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Table 3. Substrate Scope of Electron-Rich Alkynes.
[a] Reaction conditions: electron-rich alkynes 1 (0.2 mmol), 2a (0.24 mmol), TMSOTf (10 mol%), CH2Cl2 (2.0 mL), ambient
temperature, Ar, unless otherwise noted.
[b] 12 h.
noteworthy that thioalkyne and selenoalkyne were also
suitable in this process to deliver the desired products
(4w–x) in 71% and 34% yields, respectively. However,
this strategy was not applicable to terminal ynamide
1y and alkylynamide 1z–aa, which would be con-
verted into esters (4y–z) and quinoline derivative 4aa
in moderate yields under standard conditions, respec-
tively. The structure of 4aa was confirmed by single-
crystal X-ray diffraction analysis.
2-Amido-furans are very useful building blocks that
allow rapid further functionalization. We performed a
gram-scale reaction between ynamide 1a and 2-
hydroxyacetophenone 2a to obtain the corresponding
product 3a in a high yield (1.29 g, 78.9%). To
substantiate the synthetic potential of this strategy, we
also carried out several chemical transformations
(Scheme 1). In this context, bromide 5a can be
Scheme 1. Gram-Scale Reaction and Chemodivergent Trans-
accessed with 1.2 equiv. of N-bromosuccinmide (NBS)
formations.
in 81% yield. Of note, furan 3a could be converted
into the diaryl maleimide 5b using 2.6 equiv. of NBS.
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In addition, treatment of furan 3a with PIFA afforded Encouragingly, the hydrothiolation of ynamide 1a
furan-2(5H)-one 5c in 83% yield. Subsequently, Ms proceeded smoothly using 2-mercapto-1-phenyletha-
could be removed with TfOH, giving the correspond- none 2ac in 5 min, giving desired intermediate 3ac’
ing product 5d smoothly. The solution of 3a in THF and product 3ac in 56% and 10% yields, respectively
was irradiated at 254 nm under an argon atmosphere to (Scheme 2c). Subsequently, when the reaction time
yield the annulation product 5e. Finally, we made increased to 12 hours, the thiophene 3ac was obtained
efforts to examine the cycloaddition of 3a and in 81% yield along with concomitant a trace amount of
(trimethylsilyl)phenyl triflate, the rearrangement prod- 3ac’, suggesting that alkenyl sulfide 3ac’ was prob-
uct 5f was obtained in 77% yield.
ably the key intermediate.
To gain further insight into the mechanism of this
On the basis of the above experimental observations
protocol, we envisioned the possibility of trapping the and pilot studies upon ynamides,[12] a plausible mecha-
key intermediate. Firstly, the ynamide 1a and 2- nism has been depicted in Scheme 3 taking substrates
hydroxyacetophenone 2a were used as the starting 1a and 2l as an example under standard conditions.
materials. The desired compound 3a’ was not detected Initially, TMSOTf could be transformed into TfOH by
under standard conditions within 1 min. Perhaps the reacting with a trace amount of water in the reaction
labile intermediate 3a’ was stantaneously converted system. Ynamide 1a is activated by TfOH to afford a
into furan 3a (Scheme 2a). Notably, the ynamide 1a transient activated keteniminium ion A whose trapping
was replaced with 1q, yielding the lactone 4q’ as the with a hydroxy group of 2l would yield an enamide B.
main byproduct, which could not be converted from Further intramolecular nucleophilic attack toward the
furan 4q under standard conditions (Scheme 2b). acid-activated carbonyl to afford an iminium ion D.
Subsequently, enamide-iminium tautomerism occurs to
generate an intermediate enamide E, which would be
rapidly converted into the desired product 3l via acid-
catalyzed dehydration.
Conclusion
In summary, we have developed a method to acquire
various highly substituted π-rich heterocycles and
fused-polycyclic derivatives in moderate to good
yields. Hallmarks of this process are broad substrate
scope and atom economy and water as the main by-
product. The mechanism investigation verify that these
processes may undergo an acid-catalyzed syn-addition/
cyclization/aromatization cascade. Overall, this strat-
egy paves the way for a variety of other privileged
heterocycles, and the subsequent research findings will
be reported in due course.
Experimental Section
Scheme 2. Control Experiments.
General Procedure for the Synthesis of π-Rich
Heterocycles 3/4
To a solution of the alkyne 1 (0.2 mmol), ketone 2 (0.24 mmol)
in CH2Cl2 (2.0 mL) was added TMSOTf (10 mol%) dropwise at
room temperature under Ar. Then, the mixture was stirred at
room temperature until the TLC indicated the consumption of
the starting material. At this point, saturated sodium bicarbonate
solution (2.0 mL) was added, and then extracted with EtOAc
three times. The combined organic layers were washed with
brine and dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by flash
chromatography to give the desired product 3/4.
Scheme 3. Plausible Reaction Mechanism.
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N. A. White, R. Y. Liu, S. L. Buchwald, J. Am. Chem.
Soc. 2018, 140, 4721–4725.
Acknowledgements
This work was supported by the Funded by National Program
for Support of the National Natural Science Foundation of
China (81803344). Top-notch Young Professionals, Fund of
Taishan scholar project, Shandong Provincial Natural Science
Foundation for Distinguished Young Scholars (JQ201722),
Qingdao Science and Technology Benefit People Demonstration
Guide Special Project (20-3-4-20-nsh), the Fundamental
Research Funds of Shandong University. Thank Haiyan Sui and
Xiaoju Li from Shandong University Core Facilities for Life
and Environmental Sciences for their help with the NMR.
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RESEARCH ARTICLE
A Unified Approach for Divergent Synthesis of Heterocycles
via TMSOTf-Catalyzed Formal [3+2] Cycloaddition of
Electron-Rich Alkynes
Adv. Synth. Catal. 2021, 363, 1–7
P. Chen, W. Cao, X. Li, D. Shi*