Abstract:A convenient synthesis of γ‐spirolactams in only two steps was developed. Birch reduction of benzoic acids and immediate alkylation with chloroacetonitrile afforded cyclohexadienes in high yields. The products could be isolated by crystallization on a large scale in analytically pure form. Subsequent hydrogenation with platinum(IV) oxide as the catalyst reduced the nitrile functionality and the double bonds in the same step with excellent stereoselectivity. The relative configurations were determined unequivoc… Show more
“…Although the Birch reduction is known since more than half a century, [1,2] we published reactions in the presence of chloroacetonitrile, a commercially available and inexpensive reagent, [20] for simple benzoic acids very recently [13] . Herein, we applied such optimized reaction conditions with no co‐solvent and high concentrations for the regioisomeric dimethyl benzoic acids ( 1 e – g ) for the first time (Table 1, entries 1–3).…”
Section: Resultsmentioning
confidence: 99%
“…Furthermore, their ability to form hydrogen bridges has been applied in enantioselective reactions [16] . On the other hand, the synthesis of spiro compounds requires usually many steps, [17–19] in contrast, our method offered an easy entry by Birch reduction [13] …”
Section: Introductionmentioning
confidence: 99%
“…Later on, we developed a two‐step substitution of aromatic carboxylic acids, [11] which was extended by Studer for palladium‐catalyzed functionalizations [12] . Very recently, we described first Birch reductions in the presence of chloroacetonitrile in a communication (Scheme 1a) [13] …”
A convenient method for the synthesis of γ‐spirolactams in only three steps is described. Birch reduction of inexpensive and commercially available aromatic carboxylic acids in the presence of chloroacetonitrile affords nitriles in moderate to good yields. Suitable precursors are methyl‐substituted benzoic acids, naphthoic, and anthroic acid. Subsequent catalytic hydrogenation proceeds smoothly with PtO2 or Raney Ni as catalysts and lactams are isolated in excellent yields and stereoselectivities. Thus, up to 3 new stereogenic centers can be constructed as sole diastereomers from achiral benzoic acids. Furthermore, it is possible to control the degree of saturation at different pressures, affording products with 0, 1, or 2 double bonds. Overall, more than 15 new γ‐spirolactams have been synthesized in analytically pure form.
“…Although the Birch reduction is known since more than half a century, [1,2] we published reactions in the presence of chloroacetonitrile, a commercially available and inexpensive reagent, [20] for simple benzoic acids very recently [13] . Herein, we applied such optimized reaction conditions with no co‐solvent and high concentrations for the regioisomeric dimethyl benzoic acids ( 1 e – g ) for the first time (Table 1, entries 1–3).…”
Section: Resultsmentioning
confidence: 99%
“…Furthermore, their ability to form hydrogen bridges has been applied in enantioselective reactions [16] . On the other hand, the synthesis of spiro compounds requires usually many steps, [17–19] in contrast, our method offered an easy entry by Birch reduction [13] …”
Section: Introductionmentioning
confidence: 99%
“…Later on, we developed a two‐step substitution of aromatic carboxylic acids, [11] which was extended by Studer for palladium‐catalyzed functionalizations [12] . Very recently, we described first Birch reductions in the presence of chloroacetonitrile in a communication (Scheme 1a) [13] …”
A convenient method for the synthesis of γ‐spirolactams in only three steps is described. Birch reduction of inexpensive and commercially available aromatic carboxylic acids in the presence of chloroacetonitrile affords nitriles in moderate to good yields. Suitable precursors are methyl‐substituted benzoic acids, naphthoic, and anthroic acid. Subsequent catalytic hydrogenation proceeds smoothly with PtO2 or Raney Ni as catalysts and lactams are isolated in excellent yields and stereoselectivities. Thus, up to 3 new stereogenic centers can be constructed as sole diastereomers from achiral benzoic acids. Furthermore, it is possible to control the degree of saturation at different pressures, affording products with 0, 1, or 2 double bonds. Overall, more than 15 new γ‐spirolactams have been synthesized in analytically pure form.
“…During the synthesis of γ-spirolactams 1 , we obtained different regio- and stereoisomers, some configurations have been already established in our previous studies [7]. However, in the 8-methyl derivatives 1b cis and trans isomers have been isolated, with functional groups too far away from each other to apply NOE NMR experiments for structure elucidation.…”
Section: Introductionmentioning
confidence: 99%
“…Very recently, we developed an easy entry to such compounds by Birch reduction of the corresponding benzoic acids 2 (R = H, Me) and subsequent alkylation and hydrogenation (Fig. 1) [7]. Fig.…”
The title compounds, 2-azaspiro[4.5]deca-1-one, C
9
H
15
NO, (
1a
),
cis
-8-methyl-2-azaspiro[4.5]deca-1-one, C
10
H
17
NO, (
1b
), and
trans
-8-methyl-2-azaspiro[4.5]deca-1-one, C
10
H
17
NO, (
1c
), were synthesized from benzoic acids
2
in only 3 steps in high yields. Crystallization from
n
-hexane afforded single crystals, suitable for X-ray diffraction. Thus, the configurations, conformations, and interesting crystal packing effects have been determined unequivocally. The bicyclic skeleton consists of a lactam ring, attached by a spiro junction to a cyclohexane ring. The lactam ring adopts an envelope conformation and the cyclohexane ring has a chair conformation. The main difference between compound
1b
and compound
1c
is the position of the carbonyl group on the 2-pyrrolidine ring with respect to the methyl group on the 8-position of the cyclohexane ring, which is
cis
(
1b
) or
trans
(
1c
). A remarkable feature of all three compounds is the existence of a mirror plane within the molecule. Given that all compounds crystallize in centrosymmetric space groups, the packing always contains interesting enantiomer-like pairs. Finally, the structures are stabilized by intermolecular N–H···O hydrogen bonds.
Electronic supplementary material
The online version of this article (10.1186/s13065-019-0586-7) contains supplementary material, which is available to authorized users.
Birch reductions are well‐known transformations of arenes, applied for large scale synthesis of 1,4‐cyclohexadienes. Herein, we describe first reactions of benzoic acids in the presence of carbonyl compounds, affording aldol products in moderate to high yields. Alkyl aldehydes give the expected nonconjugated dienes by reaction at the α‐position. Interestingly, the intermediately formed enolate attacks aryl aldehydes and ketones from its γ‐position, which can be explained by steric hindrance. This opens the door for the one‐pot synthesis of 1,3‐cyclohexadienes, which are not accessible by classical Birch reductions. Our method is applicable to benzoic, m‐ and p‐toluic acid and various carbonyl compounds, and more than 25 new products were isolated in up to 93% yield. Prochiral aryl aldehydes afford diastereomeric mixtures in ratios of about 4:1, but in the cyclohexadiene ring only trans isomers are formed with high selectivity. Finally, the 1,3‐cyclohexadienes are suitable precursors for further transformations, which we have demonstrated in first examples. Thus, aromatization affords products of a formal meta selective Friedel‐Crafts alkylation, and four new stereocenters were generated by cycloaddition of singlet oxygen with excellent selectivity.
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