Consecutive three- and four-component coupling-Bagley-Bohlmann-Rahtz syntheses of tri- and tetrasubstituted pyridines

1 Introduction

The synthesis of pyridines [1, 2] and their derivatization is an ongoing important topic in synthetic chemistry. In addition numerous compounds containing the pyridine core exhibit highly interesting properties. Besides their application as building blocks in synthesis [3–8], supramolecular and coordination chemistry [9–16], and as functional constituents in materials science [17–22] many derivatives have raised particular interest due to their high biological activity [23–35].

Today pyridines are commonly found in drugs and agrochemicals. In particular, they are important active ingredients in herbicides, fungicides and insecticides [36–39], and furthermore in several potent pharmaceuticals against, e.g. asthma, inflammation and coronary diseases (Scheme 1) [40]. Therefore, the development of novel syntheses of substituted pyridines is particularly important [41, 42].

Scheme 1:

Examples of biological active compounds containing a pyridine core.

Pyridines can be accessed either by ring functionalization and transformation or by de novo syntheses [43, 44]. Among de novo pyridine formations one-pot multicomponent syntheses by Tschitschibabin [45] (name spelled as in the original publication [45]; engl. Chichibabin) and Hantzsch [46] have become most attractive (Scheme 2). However, a major drawback of the Tschitschibabin pyridine synthesis lies in the high pressure which leads to the formation of many byproducts. Although the Hantzsch (dihydro)pyridine synthesis has become a useful tool for the synthesis of many pyridines, among them the dihydropyridine Nifedipine, a powerful medication in the treatment of coronary diseases [47, 48], the downside of this one-pot process are the necessity of an oxidation step to the pyridine target and the inherent low degree of diversity.

Scheme 2:

Classical pseudo four-component syntheses of pyridines by Tschitschibabin (top) and Hantzsch (bottom).

For overcoming these limitations, a couple of years ago we have disclosed versatile three- and four-component syntheses of unsymmetrically substituted [49, 50] and anellated pyridines [51, 52] initiated by a Pd/Cu-catalyzed coupling-isomerization domino reaction [53–56]. Interestingly, already in 1957, Bohlmann and Rahtz reported a two-step pyridine synthesis by cyclization of an alkynone with an enamine (Scheme 3) [57].

The amino-butadienone intermediate had to be isolated and the employed high temperatures for the cyclocondensation step made the original protocol less attractive for application until Bagley and coworkers used the Bohlmann-Rahtz synthesis in 1998 as an elegant key step in the synthesis of promothiocin A for quickly establishing the 2,3,6-trisubstituted pyridine core (Scheme 4) [58–60].

Scheme 3:

Bohlmann-Rahtz pyridine synthesis.

Scheme 4:

Bohlmann-Rahtz pyridine synthesis as a key step in the synthesis of promothiocin A.

Later, Bagley’s group undertook major efforts to develop general two-component processes that circumvent the isolation of the amino-butadienone intermediate by adjusting the reaction conditions, using microwave irradiation, Brønsted or Lewis acid catalysis as well as ethanol as a favorable solvent in the cyclization step (Scheme 5) [61–63].

Scheme 5:

Bagley’s one-pot Bohlmann-Rahtz pyridine synthesis.

Another major achievement was the in-situ generation of the enamine by reaction of a β-ketoester with an ammonia source furnishing a three-component variation of the Bohlmann-Rahtz pyridine synthesis (Scheme 6) [64–66].

Scheme 6:

Bagley’s three-component Bohlmann-Rahtz pyridine synthesis.

Having expanded the cross-coupling avenue to Michael systems to catalytic ynone formation as an entry to consecutive multicomponent syntheses of heterocycles [67–70], we became interested in developing a coupling-Bagley-Bohlmann-Rahtz (cBBR) pyridine synthesis initiated by catalytic ynone generation. Here, we report studies on consecutive three- and four-component pyridine syntheses via the Bagley-Bohlmann-Rahtz avenue.

2 Results and discussion

Starting from the outset of modified Sonogashira coupling as an entry to ynone formation from acid chlorides and terminal alkynes [71, 72], we first set out to probe the reaction conditions of the three-component process with 2-thienoyl chloride (1a), 1-hexyne (2a), and ethyl 3-aminocrotonate (3) as a model system to give ethyl 2-methyl-4-n-butyl-6-(thiophen-2-yl)pyridine-3-carboxylate (4a) (Scheme 7, Table 1).

Scheme 7:

Optimization of the three-component cBBR synthesis of pyridine 4a.

With a reaction temperature of 100°C for the Bagley-Bohlmann-Rahtz (BBR) step, a reaction time of 3 h was not sufficient (Table 1, entry 1) and full conversion was achieved after 24 h (Table 1, entry 2). Increasing ethyl-3-aminocrotonate (3) from 1 to 2 equivalents caused a significant loss in yield of pyridine 4a (Table 1, entry 5). A further increase of the reaction temperature, for instance by microwave irradiation, either gave substantially lower yield or increased decomposition (Table 1, entries 6, 9, 11, and 14). Interestingly, the absence of acetic acid led to considerably longer reaction times to achieve full conversion (Table 1, entry 8). Unfortunately, Bagley’s best original conditions only furnished 24% of compound 4a (Table 1, entry 3). Neither 1,4-dioxane, toluene or acetonitrile as solvents (Table 1, entries 3, 4, 9–14) nor the employment of different Brønsted or Lewis acids, such as PTSA (Table 1, entries 13 and 14), amberlyst 15 (Table 1, entry 12), zinc bromide or boron trifluoride etherate (Table 1, entries 10, 11) gave satisfying yields. In summary, the conditions of entry 2 employing THF as a solvent and addition of 17.5 equivalents of acetic acid for the BBR step performed at 100°C for 24 h turned out to give the highest yields of model compound 4a.

With these conditions in hand, the stage was set to probe the scope at two points of diversity, namely from the acid chloride 1 and the alkyne 2, while ethyl 3-aminocrotonate (3) was kept constant as a substrate in this study. Upon coupling acid chloride 1 and alkyne 2 in the presence of catalytic amounts of Pd(PPh₃)₂Cl₂ and CuI and triethylamine as a base, the formed ynone was subsequently reacted with ethyl 3-aminocrotonate (3a) and acetic acid in the same reaction vessel at 100°C for 24 h to give after purification 3-ethoxycarbonyl 2-methylpyridines 4 in low to moderate yields in the sense of a consecutive three-component coupling-BBR sequence (Scheme 8, Table 2). The structures of all compounds were unambiguously assigned by extensive ¹H and ¹³C NMR and IR spectroscopy, mass spectrometry and combustion analysis or HRMS.

The isolated yields of this novel one-pot sequence fall in a range between 19–55%. Taking into account that three new bonds are being formed, the yield per bond forming step counts to 57–82%.

Scheme 8:

Three-component cBBR synthesis of 3-ethoxycarbonyl 2-methylpyridines 4.

Table 2:

Consecutive three-component cBBR synthesis of 3-ethoxycarbonyl-2-methylpyridines 4.

Entry	Acid chloride 1	Alkyne 2	3-Ethoxycarbonyl-2-methylpyridine 4 (%)a
1	R1 = 2-thienyl (1a)	R2 = n-butyl (2a)
2	R1 = p-MeOC6H4 (1b)	2a
3	R1 = p-ClC6H4 (1c)	2a
4	R1 = p-O2NC6H4 (1d)	2a
5	1a	R2 = Ph (2b)
6	R1 = p-MeC6H4 (1e)	2b
7	1c	2b
8	R1 = o-FC6H4 (1f)	2b
9	1a	R2 = H (2c)b
10	1b	2c
11	1c	2c
12	1d	2c
13	1e	2c
14	1f	2c
15	R1 = Ph (1g)	2c

^aIsolated yield after flash chromatography; ^bthe employed alkyne 2c is (trimethylsilyl)acetylene.

In general, the yields for the trisubstituted pyridines 4 (Table 2, entries 9–15) are higher than for the tetrasubstituted derivatives (Table 2, entries 1–8). The variation of electron withdrawing and electron donating groups in the acid chloride 1 is generally possible and these polar functional groups are tolerated. As previously reported for other one-pot synthesis initiated by catalytic ynone formation [67–70], when (trimethylsilyl)acetylene is employed as alkyne the silyl group is concomitantly cleaved upon Michael addition/cyclocondensation and, therefore, trisubstituted pyridines are the obvious reaction products. For the synthesis of tetrasubstituted pyridines n-butyl and phenyl substituents as representatives of alkyl and aryl substitution are introduced in the 4-position of the pyridines 4.

Furthermore, we became interested in probing Bagley’s three-component Bohlmann-Rahtz pyridine synthesis, i.e. the in-situ formation of ethyl 3-aminocrotonate (3) by condensation of ethyl acetoacetate and an ammonia source after the cross-coupling step, and developing it into a four-component cBBR pyridine synthesis. Therefore, we chose the previous model system (Scheme 7), however, now employing ethyl acetoacetate (5) and ammonium acetate as third and fourth components for finding the optimal conditions for the formation of model pyridine 4a (Scheme 9, Table 3).

Scheme 9:

Optimization of the four-component cBBR synthesis of pyridine 4a.

Without the addition of a cosolvent and an acid the BBR step took 74 h to full conversion of the intermediate alkynone at 100°C and only 24% of product 4a could be isolated (Table 3, entry 1). Ethanol as a cosolvent and increasing the reaction time from 24 to 74 h (Table 3, entries 2 and 3) led to an increase in the yield of pyridine 4a. However, upon reducing the amount of ammonium acetate to one equivalent caused a significant drop in yield (Table 3, entry 4). Surprisingly, the increase in ethyl acetoacetate to two equivalents had a detrimental effect on the yield (Table 3, entry 5). Expectedly, the addition of acetic acid as a cocatalyst (Table 3, entries 6–11) caused an increase in the yield of the desired product, indicating the crucial importance of buffered conditions. In this optimization series the highest yield could be obtained with equimolar amounts of two equivalents of ammonium acetate and acetic acid, respectively, at 100°C for 24 h (Table 3, entry 8). Excessive acetic acid (Table 3, entries 10 and 13), unbalanced amounts of ethyl acetoacetate as well as omitting ethanol as a cosolvent (Table 3, entries 13–16) and lower reaction temperatures (Table 3, entry 9) always causes a drop in yield. It is also noteworthy to mention that the stronger acid PTSA is not an effective catalyst (Table 3, entry 12) and 2-methoxyethanol and tert-butanol turned out to be poor cosolvents in the BBR step, even at elevated reaction temperatures (Table 3, entries 17 and 18) and toluene did not reach yields comparable to those in ethanol (Table 3, entry 19). Dielectric heating with or without ethanol as a cosolvent in the BBR step only gave poor yields of the desired product (Table 3, entries 20 and 21). The more basic ammonium carbonate as an ammonia source did not prove to be as suitable as ammonium acetate (Table 3, entry 22) and the more acidic ammonium chloride turned out to be detrimental (Table 3, entries 23 and 24). In summary, the conditions of entry 8 employing equimolar amounts of ammonium acetate and acetic acid and ethanol as a cosolvent for the BBR step performed at 100°C for 24 h turned out to give the highest yields of model compound 4a. These conditions were employed to the one-pot four-component synthesis of three selected examples furnishing the desired 3-ethoxycarbonyl-2-methylpyridines 4a, 4i, and 4j in low to moderate yields (Scheme 10). Interestingly, the comparison of the yields of the four-component process reveals that they are equal (compound 4a), lower (compound 4i), or higher (compound 4j) than the corresponding three-component reaction (Table 2, entries 1, 9, and 10). However, taking into account that four new bonds are being formed in this novel consecutive four-component process the yield per bond forming step counts to 68–83%, the sequence can be considered to be quite efficient.

Scheme 10:

Four-component cBBR synthesis of selected 3-ethoxycarbonyl-2-methylpyridines 4 (^a(trimethylsilyl)acetylene (2c) was employed as an alkyne).

In conclusion we could expand the two- and three-component Bagley variation of the Bohlmann-Rahtz pyridine synthesis into three- and four-component cBBR sequences in a one-pot fashion furnishing the targeted 3-ethoxycarbonyl-2-methylpyridines in modest to moderate yields, however, with high average bond forming yields. This novel process not only tolerates various electronic modulations in the 4- and 6-positions of the pyridyl core as introduced in the initial coupling step. In particular, the extension from the three- to the four-component process indicated that the in-situ formation of the relevant 3-aminocrotonate is delicate and only narrow variations in the solvents, catalysts, ammonia sources, and stoichiometries are permitted. Further studies directed to expand the coupling-cyclization concept to the formation of other six-membered hetero- and carbocycles are currently underway.

3 Experimental details

Supporting information

¹H, ¹³C, and 13-DEPT-135 NMR spectra of 3-ethoxycarbonyl-2-methylpyridines 4 are given as Supporting Information available online (DOI: 10.1515/znb-2016-0046).