Three-Component Ring Transformation
Subjects: Organic Chemistry
Contributors:

Nagatoshi Nishiwaki,

SONG THI LE,

Haruyasu Asahara


Submitted by:

Nagatoshi Nishiwaki

Definition
The ring transformation is a synthetic method for cyclic products including transfer of the partial
structure of a cyclic substrate to a reagent, constructing a new ring system. When one substrate andtwo reagents are used to form a cyclic structure, it is called three-component ring transformation.

1. General Concept of TCRT
1.1. Ring transformation
Ring transformation is a powerful synthetic method that accompanies “Scrap & Build” of cycliccompounds. The general concept of this method is shown in Scheme 1. When a substrate (A + B) isreacted with a reagent (C), the partial structure (A) of the substrate is transferred to the reagent toconstruct a new ring system (A + C), simultaneously eliminating the leaving group (B). This reaction
facilitates the synthesis of functionalized compounds that are not easily aﬀorded by alternative
procedures.

Scheme 1. General concept of the ring transformation.
There are four types of ring transformations, namely, Diels-Alder-type, decarboxylative, degenerate, andnucleophilic-type ring transformations, among which the last nucleophilic-type ring transformation has notbeen studied extensively as compared to the other three ring transformations [1][2][3][4][5][6]. 1-methyl3,5-dinitro-2-pyridone (1) serves as an excellent substrate for this reaction to aﬀord functionalized 4nitrophenols 3 upon treatment with enolate of 1,3-dicarbonyl compounds 2.
Table 1. Synthesis of functionalized 4-nitrophenols by ring transformation.
R1

R2OEt

COOEt

OEt

Solv.

Temp./°C

Yield/%

apyridine5091

Hbpyridine

7061MeHc

DMF

7053COOEt

Hdpyridine

11042

1.2. General concept of TCRTAlthough 1,3-dicarbonyl compounds 2 are excellent dinucleophilic reagents, only few products 3 aresynthesized because of the low diversity of the available 2. If simple ketones 4 can be used instead of 2,
the synthetic utility of the ring transformation should be improved. In such cases, it is necessary to use anitrogen source as ketone is a mononucleophilic reagent. This process is referred to as three-component
ring transformation (TCRT) (Scheme 2).

Scheme 2. The general concept of TCRT.

2. Synthesis of nitropyridines by TCRT
2.1. TCRT using ammonia as the nitrogen source
Tohda et al. reported the reaction of dinitropyridine 1 with ketones in the presence of ammonia (Table 2)[7]. When a methanol solution of pyridone 1 is heated with acetophenone 4a in the presence of larger

amounts of ammonia (140 equiv.) at 120 °C in an autoclave, TCRT proceeds to aﬀord 3-nitro-6phenylpyridine 5a in 81% yield. This reaction is applicable to other aromatic ketones 4b–e to aﬀord thecorresponding 2-(het)aryl-5-nitropyridines 5b–e, respectively. This TCRT eﬃciently proceeds under mild
conditions to aﬀord [b]-fused 5-nitropyridines 6 only when cyclohexanone is used as the reagent (Figure1).
Table 2. TCRT using dinitropyridine 1, ketones 4 and ammonia leading to nitropyridines 5.

Figure 1. Condensed nitropyridines [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23].

2.2. TCRT using ammonium acetate as the nitrogen source
TCRT using ammonia as the nitrogen source is an eﬀective approach to [b]-fused 5-nitropyridines 6.
However, when less reactive ketones such as acetophenone 4a are used, both electrophilic sites of 1 are
attacked by ammonia, which undergoes ammonolysis to consume pyridone 1 competitively. Le et al.
mitigated this problem by using a less nucleophilic ammonium acetate as a nitrogen source instead ofammonia. Even when either electron-rich or -poor ketones 4a–e are used, TCRT eﬃciently proceeds under
mild reaction conditions leading to nitropyridines 5a–e, respectively [24].
Table 3. TCRT with other aromatic ketones 5.

This protocol is applicable to a,b-unsaturated ketones [25], cycloalkanones [26], and aldehydes [24] to aﬀord
the corresponding nitropyridines (Figure 2). For the C–C bond formation on the pyridine framework, theHeck, Suzuki, Stille, and Sonogashira reactions are commonly used. However, these methods require theuse of poisonous and expensive transition metals and a puriﬁcation step to avoid metal contamination of
the products. In addition, troublesome multistep reactions are necessary to prepare the substrates forthese reactions (2-halo-5-nitropyridines). Thus, the TCRT is a metal-free supplementary method for theabove-mentioned reactions.

Figure 2. Other types of nitropyridines.

When dinitropyridone 1 is subjected to a reaction with aliphatic ketones 7 in the presence of ammonium
acetate, two types of TCRT occur to aﬀord nitropyridines 8 and nitroanilines 9 (Table 4) [27]. Generally, 2,6disubstituted 4-nitroanilines 9 are prepared from the corresponding anilines by nitration under harshreaction conditions, wherein protection and deprotection of the amino groups are necessary [28].
Furthermore, the preparation of this compound suﬀers from limitation of Friedel–Crafts alkylation. There
are several limitations for the Friedel–Crafts alkylation, such as the following: (1) the monoalkylated
product undergoes further alkylation; (2) it is diﬃcult to introduce two diﬀerent alkyl groups; (3) primaryalkyl groups longer than the ethyl group cannot be introduced; (4) a phenyl group cannot be introduced;and (5) nitrobenzene and aniline do not facilitate the alkylation. The TCRT overcomes thesedisadvantages.
Table 4. Two kinds of TCRT using aliphatic ketones 7.
KetoneYield/%R1R2MeMeH

988’a83

13—

Hb5147—EtHc66

108i-PrHd58

031PrHe83

96Et

Etf67

24—PrPrg74

22—

C6H5Prh62

24

13C6H5C6H5i881—

3. Reaction mechanism of TCRT

Scheme 2. Plausible mechanisms of TCRT when an aliphatic ketone 7 is employed as a reagent.
A plausible mechanism for this TCRT is shown in Scheme 2. The enol form of 7 attacks the electrophilic 4position of 1, then the adduct is converted enamines 10 and 11 by ammonium ion. Attack of the aminogroup attacks at the 6-position (routes a and b) furnishes bicyclic intermediates 12 and 13, from which
nitroacetamide is eliminated to aﬀord nitropyridine 8. On the other hand, the C-attack of enamine 11 at
the 6-position (route c) leads to bicyclic intermediate 14, which aﬀords nitroaniline 9.

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Keywords
three-component ring transformation;nitropyridine;nitroaniline

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