CH 3 CH=CHCH=CHCH 2 OH meta-Cl-ArCH=CHCH 2 OH
2.3 Rearrangements of tetronates without a cinnamyl residue and spirocyclopropane trapping reactions
2.3.4 Trapping of spirocyclopropane intermediates
Despite numerous attempts with various solvents and reaction temperatures the elusive spirocyclopropanes 211 could not be isolated. Spirocyclopropanes have been proposed as intermediates for abnormal Claisen rearrangements before[90,188-191], however to our knowledge no conclusive proof has ever been documented. Since we have already reacted stable spirocyclopropanes before with amines (Section 2.1.5.2) we speculated that it should be possible to trap the spirocyclopropane intermediate generated from 121m. If, as we believed the spirocyclopropane was the intermediate generated on route to the abnormal product, then a large excess of an amine could possibly react with the intermediate 211 before it rearranged to 213. Not only would such a reaction prove the intermediacy of [2,3]-sigmatropic rearrangements but would also open synthetic routes to functionalised 3-alkyltetronic acids 214 with alkyl instead of aryl residues at Cβ on the side chain.
O O
O O
O
O Toluene,
sealed tube, ∆
RNH2 O
O
OH HN R
121m 211a 214
Figure 8: X-Ray structure for compound 212c. Hydrogen atoms are omitted.
Other rearrangements of tetronates and spirocyclopropane trapping reactions 6 8
From Section 2.1.5.2 we knew that butyl amine reacted with 119a to give 144b in 67% yield.
When a mixture of 121m was heated in a sealed tube to 160oC with 5 equivalents of butyl amine for 16h the expected tetronic acid 214a was not obtained. Instead a single compound was isolated with a molecular mass ion that corresponded to 121m plus butyl amine. This told us that butyl amine had indeed reacted with 121m. Initially we proposed stucture 215 and all experimental data seemed to confirm such a structure.
O
Tetronic acids almost always exist in the enol form, however we suspected that since the reaction had been performed using a large excess of basic amine that the basic nature of the solution had converted the enol to the keto form. Another explanation that we had proposed was that the amino group existed as a H-bridge with the keto oxygen, which lead to greater thermodynamic stability than the enol form. 3-Alkyl tetronic acids have been converted as a bimolecular reaction with amines into butenolides[192]. Compound 215 should be amenable to such a reaction by acid catalyst azeotropic heating in a suitable solvent to give 217. However refluxing 215 for 24h in a Dean-Stark apparatus using toluene as a solvent gave only the quantitative amounts of starting material.
Attempts to induce the enol form, thus generating 214, by refluxing 215 in first methanol followed by chloroform solutions containg p-toluenesulphonic acid gave no result. Clearly there was a problem with the proposed structure 215. Reaction of 121a with allyl amine furtuitously gave a white crystalline solid; from which it was possible to grow suitable crystals for X-ray analysis.
X-ray single crystal structure analysis (Figure 9) shows that we had rather synthesised a 3,4,5-trisubstituted butyrolactam. The NMR spectra of these 3,4,5-3,4,5-trisubstituted butyrolactams would be almost identical to that of structure 215, thus explaining the initial confusion in the identity of compounds 218. The all-trans configuration of the residues at C-3, C-4 and C-5 fits with the vicinal coupling constants of 3J(3-H/4-H) = 10.04 Hz and 3J(4-H/5-H) = 8.45 Hz. Similar values were found for other derivatives. Figure 10 shows the proton and carbon NMR spectra of 218a.
Obviously, at elevated temperatures an excess of the polar amine opens the intermediate cyclopropane ring with a considerably weakened, if not entirely broken, C-C bond and a good deal of carbenium ion character of the more highly substituted atom C-2’. A fascinating
Figure 10a : 1H NMR for 218a-ααααα:
Figure 9: X-Ray structure for compound 218a-ααααα. Hydrogen atoms are omitted.
4-CH3
4-H NCHH
5-H
NCHH 3-H
CH=CH2
CH=CH2 OH Ph
O N
O HO
1 2
3 4
5
7 0
Figure 10c HMQC NMR for compound 218a.
Other rearrangements of tetronates and spirocyclopropane trapping reactions
Figure 10b: 13C-NMR for compound 218a:
O N
O HO
1 2
3 4 5
1' 2' 3'
4-CH3 C-4’, C-6’
C-5’
C-3’, C-7’
NCH2
C-4 C-3
C-5 C-2’
CH=CH2
Ph CH=CH2 Ph-ipso C-1’ C-2
intramolecular lactone to lactam reaction then proceeds. The breaking of the C-C bond could explain why a trans-cis 218βββββ configuration was observed in some cases. For example the “all trans” isomer for 218ααααα was recovered in 73% yield with a further 23% recovered which contained an approximate 1:1 mixture of isomers. One isomer contained the all trans configuration 218a-ααααα with the other isomer 218a-βββββ having a cis relationship between C-3 and C-4 (3JHH = 8.01 Hz) with a trans configuration between C-4 and C-5 (3JHH = 9.51 Hz) 218a-βββββ. This is in contrast to the syn-selective ring opening of 119 with amines in DCM or chloroform at ambient temperatures or slightly above to give 149.
218 X R1 R3 R4 Yield[a]
Table 14: Formation of butyrolactams 218 from 121 and a primary amine
[a] Combined yield of all isomers
[b] 73% α recovered pure,
[h] Isomer β recovered only
218ααααα 218βββββ
Other rearrangements of tetronates and spirocyclopropane trapping reactions 7 2
Although two diastereoisomers were identified for 218a, the predominant isomer, as with all other examples, is the all-trans configuration 218a-ααααα. The overall yield for 218a was 94%
which is truly remarkable for a Domino two step rearrangement-nucleophilic addition, internal trans-esterification reaction. Considering that the highest yield obtained for the single step conversion of 121a to 119 was only 73% under the reaction conditions used to synthesis 218.
Clearly this is a highly efficient reaction, it is reasonable to assume that 119a and the more elusive cyclopropanes 211 react immediately with the large excess of amine before side products or decomposition can occur. The yields for compounds 218h-i were much higher than we originally expected with 84% obtained for 218i. In hindsight this is unsurprising as compounds 210, 211 and 212 are all expected to exist as an equilibrium mixture under the reaction conditions; therefore as 211 reacts with the amine more of 211 is generated from the reservoirs of 210 and 212.
This reaction appears to tolerate a wide variety of amines with even the complex methyl (2R)-2-amino-4-methylpentanoate giving very high yields, albeit with a mixture of up to 4 diastereoisomers. Unfortunately when 121q was reacted in toluene with allyl amine or butyl amine the result was complete decomposition. This could be possible through an attack of the carbenium ion at the C-5 position with expulsion of the phenyl group followed by uncontrolled rearrangements.
O O
O CH2=CHCH2NH2
Toluene, 160oC, sealed bomb tube
121q 219
O N
O HO
As a final proof for the reaction sequence we have proposed, a solution of 144d was heated in a sealed tube to 160oC for 16h using toluene as a solvent. TLC and GC analysis of the reaction mixture showed only the presence of compound 218a. No other compounds could be detected in the reaction mixture.
O O
OH
HN Toluene, sealed tube 160oC, 16h, ~100%
O N
O HO
144d 218a
Compound 121o gave a more complicated set of results when heated with an excess of butyl amine. This time the elusive spirocyclopropane contains a methyl and ethyl group attached to the cyclopropane ring. Clearly C-1’ and C-2’ occupy almost identical chemical enviroments and unsurprisingly the nucleophilic butyl amine attacked both positions. A total of four isomers were recovered, the two trans (3-H and 4-H) structures were present as a mixture as were the two cis (3-H and 4-H) diastereoisomers. No information could be determined for the stereochemistry between 4-H and 5-H due to the complexity of the NMR signals. No attempt was made to further purify these compounds by chiral HPLC. The structures and stereochemistry was determined by 1H coupling constants and confirmed by COSY, HMQC and NOESY
The reaction of 121m with N,N-dimethylamine using the same reaction conditions as before for spirocyclopropane trapping reactions, led to 222. The structure was confirmed by X-ray single crystal structure analysis (Figure 11). 222 must have arisen due to the presence of water in the toluene solvent. The water therefore attacked the intermediate cyclopropane much faster than the secondary amine.
O O
O O
O
OH H2O, toluene OH
160oC, sealed glass tube
121m 222
O O
O O
O
O
Bu H2N Toluene
170oC
O N
O HO
220α 220β
O N
O 92% HO
121o
O N
O HO
O N
O HO
221α 221β
Other rearrangements of tetronates and spirocyclopropane trapping reactions 7 4
Figure 11: X-Ray structure for compound 222. Hydrogen atoms are omitted.
The formation of 222 from 121m with water would suggest that the elusive spirocyclopropanes could theoretically also be trapped using alcohols, without the subsequent lactone to lactam conversion step.When a mixture of 121m and five equivalents of ethanol were heated together in a sealed glass tube under nitrogen, to 165oC for 16h, the corresponding (3’-ethoxybut-2’-yl)-tetronic acid 223b was obtained in an excellent 92% yield (Figure 12). The use of methanol also gave an excellent yield of 88%. It should be mentioned that reaction of 121q under these conditions with methanol led to complete decomposition as with reaction with the amines.
From these results we can be certain that abnormal Claisen rearrangements of allyl tetronates proceed through cyclopropane intermediates. It is therefore reasonable to assume that all abnormal Claisen rearrangements proceed through spirocyclopropane intermediates and can in theory be trapped using suitable trapping reagents.
O O
O O
O
OH ROH, Toluene, 16h O R
160oC, sealed glass tube
121m 223
223 a b
R Me Et
Yield
92%
88%
1' 2'
3' 4'
Figure 12a:1H-NMR of compound 223b:, # = CDCl3.
Figure 12b:13C-NMR of compound 223b: # = CDCl3. O
O
OH O
1' 2'
1 2
3 4
OH
1’-CH OCH2
1’-CH3 2’-CH3
CH2CH3
1’-CH3 CH2CH3 2’-CH
C-1’
cyc-hexane OCH2
C-2’
C-5 C-2 C-3
C-4
7 6
Reaction of 121m with propanol did not lead to 223. Instead we were surprised to find 212a.
Even if propanol was too weak of a nucleophile to react with the intermediate spirocyclopropane we would have expected it to rearrange through the full sequence to compound 213. One possible explanation for this observation is that propanol interacts through hydrogen bonding with the hydroxy group in 212a thus confering stability to 212a and making the [1,3], [1,5]-H-shifts thermodynamically unfavourable. 212a has also recently been prepared in our group using microwave irradiation.[241]
O O
O
propanol, toluene 165oC, 65%
O O
OH
121m 212a