==== Front
Beilstein J Org Chem
Beilstein J Org Chem
Beilstein Journal of Organic Chemistry
1860-5397
Beilstein-Institut Trakehner Str. 7-9, 60487 Frankfurt am Main, Germany

10.3762/bjoc.19.74
Full Research Paper
Chemistry
Organic Chemistry
Synthesis of tetrahydrofuro[3,2-c]pyridines via Pictet–Spengler reaction
Mendogralo Elena Y https://orcid.org/0000-0003-3721-8516
zelina.e@psu.ru
1
Uchuskin Maxim G https://orcid.org/0000-0001-9008-7610
1
Baxendale Ian Associate Editor
1 Perm State University, Bukireva st. 15, Perm, 614990, Russian Federation https://ror.org/029njb796 https://www.isni.org/isni/000000012230939X
2023
30 6 2023
19 991997
10.3762/bjoc.19.745 4 2023
20 6 2023
Copyright © 2023, Mendogralo and Uchuskin
2023
Mendogralo and Uchuskin
https://creativecommons.org/licenses/by/4.0/ This is an open access article licensed under the terms of the Beilstein-Institut Open Access License Agreement (https://www.beilstein-journals.org/bjoc/terms/terms), which is identical to the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0). The reuse of material under this license requires that the author(s), source and license are credited. Third-party material in this article could be subject to other licenses (typically indicated in the credit line), and in this case, users are required to obtain permission from the license holder to reuse the material.
A semi-one-pot method for the synthesis of 4-substituted tetrahydrofuro[3,2-c]pyridines by the Pictet–Spengler reaction was developed. The method is based on the condensation of easily accessibly 2-(5-methylfuran-2-yl)ethanamine with commercially available aromatic aldehydes followed by acid-catalyzed Pictet–Spengler cyclization. Using this approach, we synthesized a range of 4-substituted tetrahydrofuro[3,2-c]pyridines in reasonable yields. The reactivity of some of the products was investigated and selected synthetic transformations of the obtained tetrahydrofuro[3,2-c]pyridines were shown.

acid hydrolysis
1,4-diketone
tetrahydrofuro[3,2-c]pyridines
Paal–Knorr reaction
Pictet–Spengler reaction
Russian Science Foundation http://dx.doi.org/10.13039/501100006769 21-73-10063 We thank the Russian Science Foundation (grant 21-73-10063) for support of this work.All costs related to the publication of this open access article were entirely funded by the Beilstein-Institut.
==== Body
pmcIntroduction

Hydrogenated furo[3,2-c]pyridines represent an important class of heterocyclic compounds, which skeleton is the key frame of many bioactive and natural compounds. For example, tetrahydrofuro[3,2-c]pyridine A demonstrates excellent in vitro JAK2 inhibitory activity superior to tofacitinib (Figure 1) [1]. Furan B is a potent κ-opioid receptor agonist and exhibits excellent antinociceptive activity [2]. Lactam C possesses potent antituberculosis activity and excellent selectivity to Mycobacterium tuberculosis strain H37Rv [3]. Araliopsine (D) was isolated from the fruits of Zanthoxylum simulans [4]. Benzofuran E is a potent and relatively selective α2-adrenoceptor antagonist [5].

Figure 1 Examples of natural and bioactive hydrogenated furo[3,2-c]pyridines.

Despite the simplicity of the tetrahydrofuro[3,2-c]pyridine core, only limited approaches for the synthesis of this subclass of heterocycles using furan derivatives as starting compounds have been described [6–8]. The first group of methods is based on the use of 3-substituted furans. For example, the intramolecular Friedel–Crafts alkylation reaction (Scheme 1a) of alcohols [9–11], alkenes [12] or acetylenes [13] affords the desired tetrahydrofuro[3,2-c]pyridines. A related method is based on a Au(I)-catalyzed domino sequence dearomatization/ipso-cyclization/Michael-type Friedel–Crafts alkylation (Scheme 1b) [14–16]. Unfortunately, approaches including the intramolecular alkylation of 3-substituted furans are underinvestigated as these substrates are usually hard to reach and the resulting benzyl carbocation is often prone to undergo rearrangement to a more stable benzhydryl-type cation resulting in the formation of isomeric products.

Scheme 1 The described approaches to tetrahydrofuro[3,2-c]pyridines and our work.

In an alternative group of methods, more accessible 2-substituted furans are used as starting compounds. For example, a construction of tetrahydrofuro[3,2-c]pyridines based on the Pictet–Spengler reaction [17–18] was described (Scheme 1c). The most studied variation of this cyclization is based on the generation of an acyliminium cation from the corresponding alcohols [19–23] or alkenes [24–29], subsequent attack of furan ring and the formation of annulated tetrahydrofuro[3,2-c]pyridines. Moreover, multistep cascade processes with the simultaneous construction of several cores were described, where the key step is the generation of an acyliminium cation and the Pictet–Spengler cyclization [30–32], including solid-phase synthesis [33–35]. Another route for the construction of tetrahydrofuro[3,2-c]pyridines is based on a Bischler–Napieralski cyclocondensation followed by the C=N bond reduction (Scheme 1d) [36–39]. Despite the simplicity of the latter approach and availability of 2-(furan-2-yl)ethanamine, the instability of intermediate dihydrofuro[3,2-c]pyridines, substantial tarring of reaction mixtures in acidic conditions and a limited number of cyclization examples might constrain its wide application.

Diverse bioactivities and prevalence of hydrogenated furo[3,2-c]pyridines in nature prompted us to develop an approach to substituted tetrahydrofuro[3,2-c]pyridines. From the analysis of the literature data [2,40–43], we suggested that the interaction of furanic amines with various aldehydes in an acidic media should be accompanied by the formation of the corresponding imine, the generation of the iminium cation, and subsequent Pictet–Spengler cyclization to form the key tetrahydrofuro[3,2-c]pyridines. For this method to be effective, the following requirements must be met: 1) the starting compounds must be commercially or readily available; 2) the resulting iminium cation should be stable enough for a smooth cyclization; 3) side processes and tarring of the reaction mixture should be minimized; 4) the possibility for the synthesis of a wide range of desired products should be realized. We have found that all requirements are met for the reaction of 2-(5-methylfuran-2-yl)ethanamine with a set of aromatic aldehydes. Herein, we report the results of our study of this tandem reaction.

Results and Discussion

Initially, we synthesized the key imine 3a by refluxing a solution of the starting 2-(5-methylfuran-2-yl)ethylamine (1a) and commercially available benzaldehyde (2a) in absolute CH3CN for one hour in a quantitative yield. To our delight, when 2 equiv of HCl were subsequently added to the solution of imine 3a at 50 °C, the formation of the desired 2-methyl-4-phenyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine (4a) was observed in 26% yield (Table 1, entry 1). It should be noted that most part of the product 4a was formed as the hydrochloride salt that was converted to the free base by the treatment with an aqueous solution of NaOH overnight (see Supporting Information File 1 for full experimental data). The yield of the desired product 4a raised significantly when the reaction time was increased (Table 1, entry 2). At the same time, increasing the reaction temperature leads to the formation of the desired product 4a with moderate yield (Table 1, entries 3 and 4). Next, we found that TsOH as a catalyst and several studied solvents (toluene, 1,4-dioxane, AcOH) are inefficient (Table 1, entries 5–10). Finally, we settled on the mixture of acetic and hydrochloric acid previously well-proven for furan chemistry [44–48]. Under these conditions at room temperature for 1 hour, the product yield was 18% (Table 1, entry 11). An increase of the reaction time up to 48 h leads to a significant increase of the yield (Table 1, entries 12 and 13). To reduce the reaction time, we increased the temperature (70 °C) and achieved a comparable result in 3.5 hours (Table 1, entry 14). Moreover, we found that the short-term treatment with aq NaOH solution at rt and at 50 °C overnight were less effective than the treatment with aq NaOH at rt overnight (Table 1, entries 15 and 16). Finally, we found that the optimal reaction time was 5 hours. The yield of the desired product 4a in this case was 67% (Table 1, entry 18). With a shorter time, a slightly reduced reaction yield of 4a was observed, while at longer heating the reaction mixture underwent abundant tarring (Table 1, entries 17 and 19). The treatment of the reaction mixture after the reaction with an aqueous solution of NaHCO3 turned out to be less effective (Table 1, entry 20). It should be noted that 3-(2-oxopropyl)-2-phenylpiperidin-4-one (5a), which is a product of further acid hydrolysis of 4a was observed in most cases in trace amounts; an exception is entry 18 (Table 1), in which the 1,4-diketone 5a was isolated in 10% yield.

Table 1 Optimization of reaction conditionsa.

	
	
Entry	Solvent	Time, h	T, °С	Acid, equiv	Yield of 4a, %b	
	
1	CH3CN	1.5	50	HCl (2.0)	26	
2	CH3CN	5.5	50	HCl (1.0)	53	
3	CH3CN	4.5	82	HCl (1.5)	32	
4	CH3CN	24	82	HCl (1.5)	29	
5	CH3CN	30	70	TsOH (2.0)	11	
6	toluene	2	70	HCl (1.0)	58	
7	toluene	2	110	HCl (1.0)	25	
8	1,4-dioxane	2	70	HCl (1.0)	8	
9	AcOH	24	50	TsOH (3.0)	13	
10	AcOH	48	118	TsOH (4.0)	ND	
11	AcOH	2	rt	HCl (1.0)	18	
12	AcOH	24	rt	HCl (2.0)	31	
13	AcOH	48	rt	HCl (2.0)	47	
14	AcOH	3.5	70	HCl (2.0)	48	
15c	AcOH	3.5	70	HCl (2.0)	41	
16d	AcOH	3.5	70	HCl (2.0)	33	
17	AcOH	1	70	HCl (2.0)	52	
18 e	AcOH	5	70	HCl (2.0)	67	
19	AcOH	6.5	70	HCl (2.5)	38	
20f	AcOH	5	70	HCl (2.0)	50	
aAll reactions were performed at a 1 mmol scale of 1a. The reaction mixture was treated with aq NaOH at rt overnight; bisolated yield; ctreatment of the reaction mixture with aq NaOH at rt for 2 h; dtreatment of the reaction mixture with aq NaOH at 50 °C overnight; e3-(2-oxopropyl)piperidin-4-one (5a) was isolated with 10% yield; ftreatment of the reaction mixture with aq NaHCO3 at rt overnight.

With the optimized reaction conditions in hand, we investigated the scope of the developed tetrahydrofuro[3,2-c]pyridine synthesis. We found that a wide range of substituents at the aromatic cores was tolerant to the reaction conditions, and the yields of the desired products 4 remain moderate to good (Scheme 2). In particular, the use of starting benzaldehydes 2 containing electron-donating groups leads to the desired products 4e–g,i–k in much higher yields than with substrate 4d containing a strong electron-withdrawing group. The product 4n with the nitro group in the para-position of starting benzaldehyde 2n was formed in only trace amounts. A similar result was also observed in the case of isonicotinaldehyde (2m). These results were associated with an insufficient stabilization of the generated iminium cation due to the presence of a strong electron-withdrawing nitro group (for 3n), and due to the fact that the electron deficiency of the pyridine ring is strongly manifested in an acidic media (for 3m). In addition, the disadvantages of the developed method include the impossibility of using aliphatic aldehydes (for example, 2-phenylacetaldehyde (2o)), that is also explained by an insufficient stabilization of the resulting cation and the impossibility of cyclization. We also did not detect the formation of the target product when 1H-pyrrole-2-carbaldehyde (2p) was used. In this case, we observed abundant tarring and decomposition of the reaction mixture, which is probably due to the acidophobic nature of monosubstituted pyrroles. Surprisingly, the reaction of 4-(methylthio)benzaldehyde (2h) with 2-(5-methylfuran-2-yl)ethylamine (1a) under the optimized reaction conditions, in addition to the desired tetrahydrofuro[3,2-c]pyridine (4h), led to the major formation of the corresponding 1,4-diketone 5h.

Scheme 2 The synthesis of tetrahydrofuro[3,2-c]pyridines 4. Conditions: athe reaction was performed at 1 mmol scale of 1a; bthe reaction was performed at 2 mmol scale of 1a; cthe corresponding 3-(2-oxopropyl)piperidin-4-one was isolated with 20% yield; dORTEP diagram with ellipsoid contour probability level of 50%; edetected by GC–MS.

This unexpected formation of 3-(2-oxopropyl)piperidin-4-one (5h) led us to the idea that the tandem sequence Pictet–Spengler cyclization/furan acid hydrolysis could be a convenient tool for the synthesis of substituted 3-(2-oxopropyl)piperidin-4-ones 5. Using tetrahydrofuro[3,2-c]pyridine 4a as the model compound, we studied the effect of various Brønsted acids, temperature, concentrations, and the nature of the solvent on the efficiency of the reaction. In most cases, we observed the abundant tarring of the reaction mixture and we could not achieve the full conversion of the starting tetrahydrofuro[3,2-c]pyridine 4a in any experiment. The best results were achieved when HCl in 1,4-dioxane was used (Scheme 3). However, upon isolation and purification of the desired product by column chromatography, as well as upon recrystallization from ethyl acetate, 1,4-diketone 5а undergoes Paal–Knorr cyclization with the formation of the starting tetrahydrofuro[3,2-c]pyridine 4а, which ultimately leads to mixtures of compounds 4а and 5а with different ratios. The reversibility of the acid hydrolysis is quite typical for furans and is more pronounced for di- and polysubstituted furans, due to the higher stability of the latter [49–51].

Scheme 3 The acid-catalyzed reversible transformation of tetrahydrofuro[3,2-c]pyridine 4a and 3-(2-oxopropyl)piperidin-4-one 5a. The product yield was determined by GC–MS using an internal standard.

3-(2-Oxopropyl)piperidin-4-one 5a could be involved into the Paal–Knorr pyrrole synthesis in a one-pot manner. Thus, without isolation of the intermediate 3-(2-oxopropyl)piperidin-4-one 5a, the reaction mixture after acid hydrolysis was treated with aniline and the desired tetrahydro-1H-pyrrolo[3,2-с]pyridine 6а was isolated in 19% yield only (Scheme 4).

Scheme 4 Synthesis of tetrahydropyrrolo[3,2-c]pyridine 6a.

Finally, we studied some reactions of the obtained tetrahydrofuro[3,2-c]pyridine 4a. We showed that the N-acetyl-protected tetrahydrofuro[3,2-c]pyridine 4q could be obtained by treating the starting tetrahydrofuro[3,2-c]pyridine 4a with acetyl chloride while the N-methylated tetrahydrofuro[3,2-c]pyridine 4r can be formed via subsequent treatment of 4a with NaH and methyl iodide (Scheme 5).

Scheme 5 Reactivity of tetrahydrofuro[3,2-c]pyridine 4a.

Conclusion

In conclusion, we have developed a semi-one-pot method for the synthesis of 2,3-annulated furans based on the Pictet–Spengler reaction. This method provides a shortcut to 4-substituted tetrahydrofuro[3,2-c]pyridines in reasonable yields starting from readily available 2-(5-methylfuran-2-yl)ethylamine and aromatic aldehydes. The use of starting benzaldehydes containing electron-donating groups leads to the desired products in much higher yields than with aldehydes containing electron-withdrawing moieties. The availability of the starting materials, mild reaction conditions, and reasonable yields are some of the attractive features of the developed method. In addition, we have also demonstrated some transformations of the products into functionalized derivatives.

Supporting Information

File 1 Experimental procedures, characterization data, copies of 1H and 13C NMR spectra, HRMS of new compounds, and X-ray crystallography data.

File 2 Crystallographic information file for compound 4a.

The authors are grateful to Dr. Maksim V. Dmitriev (Perm State University) for performing the X-ray analysis.
==== Refs
1 Wang Y Huang W Xin M Chen P Gui L Zhao X Zhu X Luo H Cong X Wang J Bioorg Med Chem 2019 27 2592 2597 10.1016/j.bmc.2019.03.048 30926315
2 Naylor A Judd D B Scopes D I C Hayes A G Birch P J J Med Chem 1994 37 2138 2144 10.1021/jm00040a004 8035420
3 Zhang W Liu L-l Lun S Wang S-S Xiao S Gunosewoyo H Yang F Tang J Bishai W R Yu L-F Eur J Med Chem 2021 213 113202 10.1016/j.ejmech.2021.113202 33516983
4 Chang Z Q Liu F Wang S L Zhao T Z Wang M T Yaoxue Xuebao 1981 16 394 396
5 Van der Mey M Windhorst A D Klok R P Herscheid J D M Kennis L E Bischoff F Bakker M Langlois X Heylen L Jurzak M Bioorg Med Chem 2006 14 4526 4534 10.1016/j.bmc.2006.02.029 16517171
6 Nagai Y Uno H Umemoto S Chem Pharm Bull 1977 25 1911 1922 10.1248/cpb.25.1911
7 Imanishi T Yagi N Hanaoka M Tetrahedron Lett 1981 22 667 670 10.1016/s0040-4039(01)92518-3
8 Imanishi T Yagi N Hanaoka M Chem Pharm Bull 1983 31 1243 1253 10.1248/cpb.31.1243
9 Schneider C S Pook K H J Chem Soc, Perkin Trans 1 1986 877 883 10.1039/p19860000877
10 Schafroth M A Rummelt S M Sarlah D Carreira E M Org Lett 2017 19 3235 3238 10.1021/acs.orglett.7b01346 28573860
11 Davies S G Fletcher A M Holder K E Roberts P M Thomson J E Zimmer D Heterocycles 2019 99 919 941 10.3987/com-18-s(f)59
12 Fuchs J R Funk R L Org Lett 2001 3 3349 3351 10.1021/ol016592n 11594831
13 Sun Y-W Tang X-Y Shi M Chem Commun 2015 51 73 13937 13940 10.1039/c5cc05808b
14 Baba T Oka J Noguchi K Tanaka K Eur J Org Chem 2015 4374 4382 10.1002/ejoc.201500486
15 He Y Li Z Robeyns K Van Meervelt L Van der Eycken E V Angew Chem, Int Ed 2018 57 1 272 276 10.1002/anie.201710592
16 He Y Wu D Li Z Robeyns K Van Meervelt L Van der Eycken E V Org Biomol Chem 2019 17 25 6284 6292 10.1039/c9ob01299k 31194210
17 Calcaterra A Mangiardi L Delle Monache G Quaglio D Balducci S Berardozzi S Iazzetti A Franzini R Botta B Ghirga F Molecules 2020 25 2 414 10.3390/molecules25020414 31963860
18 Gholamzadeh P Adv Heterocycl Chem 2019 127 153 226 10.1016/bs.aihch.2018.09.002
19 Kano S Yuasa Y Yokomatsu T Shibuya S Heterocycles 1984 21 701 10.3987/s-1984-02-0701
20 Tanis S P Deaton M V Dixon L A McMills M C Raggon J W Collins M A J Org Chem 1998 63 6914 6928 10.1021/jo980718l 11672313
21 Gao S Tu Y Q Hu X Wang S Hua R Jiang Y Zhao Y Fan X Zhang S Org Lett 2006 8 2373 2376 10.1021/ol0607185 16706529
22 Shengule S R Ryder G Willis A C Pyne S G Tetrahedron 2012 68 10280 10285 10.1016/j.tet.2012.10.014
23 Metz A E Ramalingam K Kozlowski M C Tetrahedron Lett 2015 56 5180 5184 10.1016/j.tetlet.2015.07.058 26321769
24 Lee H I Cassidy M P Rashatasakhon P Padwa A Org Lett 2003 5 5067 5070 10.1021/ol036106r 14682766
25 Padwa A Lee H I Rashatasakhon P Rose M J Org Chem 2004 69 8209 8218 10.1021/jo048647f 15549789
26 Cassidy M P Özdemir A D Padwa A Org Lett 2005 7 7 1339 1342 10.1021/ol0501323 15787501
27 Rose M D Cassidy M P Rashatasakhon P Padwa A J Org Chem 2007 72 538 549 10.1021/jo0619783 17221972
28 Ascic E Jensen J F Nielsen T E Angew Chem, Int Ed 2011 50 5188 5191 10.1002/anie.201100417
29 Jebali K Planchat A Amri H Mathé-Allainmat M Lebreton J Synthesis 2016 48 1502 1517 10.1055/s-0035-1561398
30 Zhang W Franzén J Adv Synth Catal 2010 352 499 518 10.1002/adsc.200900686
31 Patil N T Shinde V S Sridhar B Angew Chem, Int Ed 2013 52 2251 2255 10.1002/anie.201208738
32 Petersen R Le Quement S T Nielsen T E Angew Chem, Int Ed 2014 53 44 11778 11782 10.1002/anie.201405747
33 Nielsen T E Meldal M J Org Chem 2004 69 3765 3773 10.1021/jo049918p 15153007
34 Diness F Beyer J Meldal M Chem – Eur J 2006 12 8056 8066 10.1002/chem.200600138 16881029
35 Komnatnyy V V Givskov M Nielsen T E Chem – Eur J 2012 18 16793 16800 10.1002/chem.201202745 23132763
36 Herz W Tocker S J Am Chem Soc 1955 77 3554 3556 10.1021/ja01618a038
37 Sano T Toda J Shoda M Yamamoto R Ando H Isobe K Hosoi S Tsuda Y Chem Pharm Bull 1992 40 3145 3156 10.1248/cpb.40.3145
38 Tamayo N A Bo Y Gore V Ma V Nishimura N Tang P Deng H Klionsky L Lehto S G Wang W J Med Chem 2012 55 1593 1611 10.1021/jm2013634 22329507
39 Kreituss I Chen K-Y Eitel S H Adam J-M Wuitschik G Fettes A Bode J W Angew Chem, Int Ed 2016 55 4 1553 1556 10.1002/anie.201509256
40 Wang Y Huang W Xin M Chen P Gui L Zhao X Tang F Wang J Liu F Bioorg Med Chem 2017 25 1 75 83 10.1016/j.bmc.2016.10.011 27771180
41 Lepovitz L T Martin S F Tetrahedron 2019 75 130637 10.1016/j.tet.2019.130637
42 Tan Q Yang Z Jiang D Cheng Y Yang J Xi S Zhang M Angew Chem, Int Ed 2019 58 6420 6424 10.1002/anie.201902155
43 García-Muñoz M J Foubelo F Yus M J Org Chem 2016 81 21 10214 10226 10.1021/acs.joc.6b01047 27332863
44 Butin A V Uchuskin M G Pilipenko A S Tsiunchik F A Cheshkov D A Trushkov I V Eur J Org Chem 2010 920 926 10.1002/ejoc.200901241
45 Butin A V Nevolina T A Shcherbinin V A Uchuskin M G Serdyuk O V Trushkov I V Synthesis 2010 2969 2978 10.1055/s-0030-1258165
46 Uchuskin M G Molodtsova N V Lysenko S A Strel'nikov V N Trushkov I V Butin A V Eur J Org Chem 2014 2508 2515 10.1002/ejoc.201301762
47 Merkushev A A Strel'nikov V N Uchuskin M G Trushkov I V Tetrahedron 2017 73 6523 6529 10.1016/j.tet.2017.09.043
48 Zelina E Y Nevolina T A Sorotskaja L N Skvortsov D A Trushkov I V Uchuskin M G J Org Chem 2018 83 11747 11757 10.1021/acs.joc.8b01669 30148633
49 Lutz R E Welstead W J J Am Chem Soc 1963 85 755 761 10.1021/ja00889a023
50 Popp F D Schleigh W R Katz L E J Chem Soc C 1968 2253 2257 10.1039/j39680002253
51 Grochowski M R Yang W Sen A Chem – Eur J 2012 18 12363 12371 10.1002/chem.201201522 22915231