DOI: 10.1002/chem.201403294
Communication
& Synthetic Methods
Taming the Carboxyl Group for Directed Carbometalation: Observations on the Use of Anions, Dianions and Ester Enolates Sandy Desrat, Philip J. Gray, Matthew R. Penny, and William B. Motherwell*[a] Dedicated to the pioneering spirit of Professors Jean Normant and Alex Alexakis
Abstract: Carboxylate anions, dianions and ester enolates provide simultaneous protection and activation for directed carbometalation reactions. Advantage can be taken of the bis-carbanionic character of the intermediate for further controlled C C bond forming reactions.
Carbon–carbon bond forming reactions leading to the construction of a regio- and stereodefined alkene unit[1] are recognised to be an absolutely vital component in the armoury of the synthetic organic chemist. Within this area, following on from the pioneering studies of Normant, Alexakis and coworkers,[2] the wide ranging potential of heteroatom directed carbometalation[3] of an alkyne[4] or an allene[5] has burgeoned in recent years and provides an extremely powerful strategy. The elegant studies of Marek[6] on directed carbocupration for example, provide a perfect illustration that advantage can be taken, not only of the vinylic carbon–metal bond formed in the initial carbometalation step, but also of the heteroatom directing group, to forge additional carbon–carbon bonds. In similar fashion, with the objective of gaining increased efficiency and versatility in carbon–carbon bond formation, we were particularly intrigued by the possibility that, through the simple expedient of enolate anion formation, it would be possible to use the oxygen atom of a carbonyl group as the directing heteroatom. Such a selection leads to concomitant protection of the carbonyl group against nucleophilic attack by main group organometallic reagents together with formation of one of the preeminent cornerstones for carbon–carbon bond formation in organic synthesis. To the best of our knowledge, an enolate “protection–activation” strategy has not been employed in directed carbometalation. We were nevertheless encouraged by the seminal observation of Normant, Alexakis and Villieras that carbocupration could be directed by selection of the (Z)-enol ether geometry of 1-methoxybut-1-ene-3-yne.[7]
Scheme 1. Enolate directed carbometalation.
The foregoing concept is illustrated in more detail in Scheme 1 using the simple allenic ester 1 a, which was selected as a suitable substrate for an initial study involving directed carbocupration via 3 using either of the two oxygen atoms in the derived ester enolate 2. An additional feature of considerable interest was that the resultant heterobimetallic intermediate 4 would possess bis-carbanionic character and could therefore react, either as an ester enolate and/or as a vinyl cuprate, in subsequent reactions with selected electrophiles to furnish polyfunctionalised alkenes 5. In the first instance, we elected to examine the behaviour of the lithium ester enolate of ethyl penta-3,4-dienoate[8] 1 a in a stoichiometric carbocupration reaction using the protocol developed by Normant,[9] which involves mixing copper(I) iodide with one equivalent of Grignard reagent in diethyl ether at 30 8C for 1 h. Examination of the results in Table 1 for
[a] Dr. S. Desrat, Dr. P. J. Gray, Dr. M. R. Penny, Prof. Dr. W. B. Motherwell Department of Chemistry University College London 20 Gordon Street, London WC1H 0AJ (United Kingdom) Tel: + (44) 2076797524 E-mail: [email protected]
Entry
R
Product
Yield [%][a]
(E)/(Z) ratio[b]
1 2 3 4
iPr Et nBu Ph
6 7 8 9
81 93 56 52
80:20 90:10 75:25 30:70
[a] Yield of the isolated products based on starting material 1 a. [b] Determined by 1H NMR spectroscopic analysis of the crude reaction product.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403294. Chem. Eur. J. 2014, 20, 8918 – 8922
Table 1. Carbocupration of 1 a using a stoichiometric amount of organocopper reagent.
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Communication a series of organocopper reagents reveals that the Table 2. Reactivity of the bis-carbanionic intermediate towards electrophiles to form addition step is highly regioselective and that prepapolyfunctionalised alkenes 7–7 c. ratively useful yields can be obtained, especially when the aggregated nature of the two reacting components is considered. It should also be noted that the stereoselectivity can be strongly influenced by the nature of the organocopper reagent selected, as emphasised by the dramatic reversal between the Entry E + Equiv Product Yield [%][a] (E)/(Z) ratio[b] alkyl (entries 1–3) and aryl substituents (entry 4). Our attention was then directed towards the excit1 H2O excess 7 93 90:10 ing possibility of exploiting the bis-carbanionic character of the carbometalated intermediate 4. In order to achieve chemoselective reactions, it is of course 2 DCl excess 7 a 96 90:10 mandatory that the rates of reaction of the “ester enolate component” and the “organocopper component” in the complex heterobimetallic intermediate 3 3 equiv 7 b 44 10:90 are sufficiently different for a given electrophile. Initially, as demonstrated by the isolation of the dideuterio compound 7 a in high yield through addition of 1.1 equiv 7 c 21 90:10 4 DCl at the end of the reaction (Table 2, entry 2) it was possible to confirm the dianionic character of 4. Gratifyingly, selective alkylation at the organocopper site [a] Yield of the isolated products based on starting material 1 a. [b] Determined by could also be achieved and the monoalkylated prod1 H NMR spectroscopic analysis of the crude reaction product. uct 7 b was isolated in moderate yield, even when using three equivalents of allyl bromide as electrophile (Table 2, entry 3). By way of contrast, a preliminary experiment involving the addition of one molar equivaTable 3. Copper-mediated carbomagnesiation of 1 a directed by an enolent of an aldehyde to the reaction mixture led to selective late. trapping of the ester enolate, thus forming the alcohols 7 c (d.r. 1:1) albeit in low yield (Table 2, entry 4) together with the untrapped carbometallated product 7 as the major component. A contemporaneous study of copper-catalysed carbomagnesiation that involves the intermediacy of a more basic homocuprate species (R2CuM) also revealed several features of interEntry R Product Yield [%][a] (E)/(Z) ratio[b] est. Thus, careful optimisation of the reaction conditions 1 iPr 6 69 100:0 showed that preformation of the ester enolate is essential for 2 Et 7 71 100:0 the reaction otherwise addition of the Grignard reagent on the 3 Ph 9 79 100:0 carbonyl occurred. It also established that premixing 0.1 equiv4 Cy 10 67 100:0 alents of CuI and 1.1 equivalents of Grignard reagent at 20 8C [a] Yield of the isolated products based on starting material 1 a. [b] Deterin Et2O for 2 h prior to the addition of the ester enolate gave mined by 1H NMR spectroscopic analysis of the crude reaction product. the best results. Notably, and in contrast to the stoichiometric carbocupration reaction, the product alkenes 6, 7, 9 and 10, could be isolated in improved yield irrespective of the Grignard reagent employed, and with a stereospecific preference for formation of the (E) isomer (Table 3). Encouraged by this improvement in the stereoselectivity, the reactivity of the Grignard intermediate was then probed by treatment of the reaction mixture with DCl in D2O (Scheme 2). This experiment led to complete deuterium incorporation of the enolate position a but only 50 % of deuterium incorporaScheme 2. Trapping of the reactive species generated by copper mediated tion at the vinylic Grignard site g. This result suggested that carbomagnesiation of 1 a via an enolate. only one of the two ester enolate isomers of the highly basic Grignard intermediate 4, was protonated in situ by the di-isopropylamine generated from the use of LDA in the first step. to the carbometalation step, and led to complete deuterium This hypothesis was simply proven by removal of the di-isoproincorporation at both sites. In terms of practical utility howevpylamine under high vacuum after reaction with LDA and prior er, such additional experimental manipulations were not desirChem. Eur. J. 2014, 20, 8918 – 8922
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Communication able, with the deuterated alkene 9 a being isolated in only 22 % yield. As a logical consequence of the fact that the ester unit has two environmentally different oxygen atoms capable of directing carbometalation, we then explored the behavior of the symmetrical dilithio dianion of the carboxylic acid 1. As shown in Table 4, using the conditions optimised for the ester enolate, the carbometallated product was obtained with good (E)/(Z)
Table 5. Copper mediated carbomagnesiation of 1 directed by a carboxylate.
Table 4. Copper mediated carbomagnesiation of 1 directed by a dianion.
Entry
R
Product
Yield [%][a]
(E)/(Z) ratio[b]
1 2 3 4 5 6 7
Et nPentyl iPr Cy tBu Ph 1-Me-1-propenyl
11 a 11 b 11 c 11 d 11 e 11 f 11 g
70 78 95 96 61 74 88
90:10 90:10 95:5 95:5 95:5 90:10 95:5
[a] Yield of the isolated products based on starting material 1. [b] Determined by 1H NMR spectroscopic analysis of the crude reaction product. Entry
R
Product
Yield [%][a]
(E)/(Z) ratio[b]
1 2 3 4 5
Et nPentyl iPr Cy tBu
11 a 11 b 11 c 11 d 11 e
38 40 35 34 34
90:10 90:10 95:5 95:5 95:5
[a] Yield of the isolated products based on starting material 1. [b] Determined by 1H NMR spectroscopic analysis of the crude reaction product.
selectivity. Yields however were moderate, and substrate conversions above 50 % proved to be problematic, irrespective of the Grignard reagent employed. Even although the use of the carboxylate anion might be considered as the simplest form of protection against nucleophilic attack for a carboxylic acid, it has been well known for over a century that their reaction with main group organometallics is a very well established method for conversion to ketones.[10] We reasoned nevertheless that a copper-catalysed carbomagnesiation reaction using the allenic carboxylate as substrate would be the preferred pathway. Examination of the results for a selection of Grignard reagents illustrates that the desired alkenes 11 were formed with good (E)/(Z) selectivity and in very good yield (Table 5). From a practical standpoint, the reaction is very easy to perform since prior low temperature formation of the organocopper species is not required, and, unlike the dianion directed reaction above, complete conversion of starting material is observed. Since further functionalisation of the carbometallated intermediate 4 was a major focus of interest, a copper mediated carbomagnesiation reaction directed by the carboxylate of 1 was then treated with DCl. To our initial surprise, no deuterium incorporation was observed in the g position, and the adeuterated compound 15 was isolated in excellent yield 94 % and with a stereoselectivity of 95:5 in favour of the (E) isomer (Scheme 3). A plausible mechanistic rationale for this regiospecificity is shown in Scheme 3. Thus, the initial homocuprate generated in situ reacts with the magnesium carboxylate 1 b to give organocopper intermediate 12, which then undergoes transmetalChem. Eur. J. 2014, 20, 8918 – 8922
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Scheme 3. Proposed mechanism of the copper mediated carbomagnesiation of 1 followed by trapping of the magnesium enolate 14 by DCl.
lation with the Grignard reagent to regenerate the homocuprate and form the vinylic Grignard 13. This intermediate is a sufficiently strong base to form the dianion of the carboxylic acid 14, which was then trapped by addition of DCl. As emphasised by the wide range of electrophiles in Table 6, advantage can be taken of this dianion intermediate 14 for further carbon–carbon bond formation in an experimentally convenient one pot sequence. Thus, a-alkylation with iodomethane (entry 1) and formation of b-hydroxy carboxylic acids from a range of aldehydes and ketones (entries 3–8) all proceeded in excellent yield, save for the use of paraformaldehyde (entry 2). The tolerance of halogen functionality in the reactions of a-halo ketones (entries 9–11) is also noteworthy. The selection of an epoxide as an electrophile leading to a g-lactone (entries 12–14) is however eroded by competing rearrangement of the epoxide to a carbonyl compound. The foregoing preliminary results have hopefully illustrated that the simple concept of anionic protection of the carbonyl group also leads to concomitant efficiency in directed carbometalation and versatility in controlling further selective carbon–carbon bond forming reactions. Given the current wealth of metals that can be used in directed carbometalation, and the protocols available for regio- and stereospecific eno-
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Communication Table 6. Reactivity of the intermediate generated by copper mediated carbomagnesiation of 1 towards electrophiles to form polyfunctionalised alkenes.
Yield [%][a]
Entry
E+
Equiv
1
MeI
3 equiv
16 a
82
2
p-formaldehyde
8 equiv
16 b
49
3
3 equiv
16 c
95 (syn/anti 45:55)
4
3 equiv
16 d
95 (syn/anti 45:55)
5
3 equiv
16 e
85 (syn/anti 45:55)
6
3 equiv
16 f
87
7
3 equiv
16 g
89
8
3 equiv
16 h
92
9
3 equiv
16 i
85
10
3 equiv
16 j
85 (2 dia 50:50)
11
3 equiv
16 k
77 (2 dia 55:45)
12
5 equiv
16 l
49
16 m
33 (syn/anti 45:55)
Chem. Eur. J. 2014, 20, 8918 – 8922
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Products
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Communication Table 6. (Continued)
Entry
E+
13
14
Equiv
Yield [%][a]
Products
5 equiv
5 equiv
16 n
50 (2 dia 60:40)
16 f
40
16 o
54 (2 dia 60:40)
[a] Yield of the isolated products based on starting material 1.
late generation, application of this “protect and direct” strategy to the ketonic carbonyl group should prove to be a very fruitful area for future research. Keywords: allene · carbometalation · copper · enolate · Grignard reagent [1] For reviews, see: a) Preparation of Alkenes (Ed: J. M. J. Williams), Oxford University Press, Oxford, 1996; b) A. B. Flynn, W. W. Ogilvie, Chem. Rev. 2007, 107, 4698. [2] For a review see: J. F. Normant, A. Alexakis, Synthesis 1981, 841. [3] For reviews, see inter alia: a) J. V. N. Vara Prasad, C. N. Pillai, J. Organomet. Chem. 1983, 259, 1; b) B. Breit, Y. Schmidt, Chem. Rev. 2008, 108, 2928; c) A. G. Fallis, P. Forgione, Tetrahedron 2001, 57, 5899. [4] For reviews, see: a) A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307; b) A. G. Fallis, P. Forgione, Tetrahedron 2001, 57, 5899; c) A. Basheer, I. Marek, Beilstein J. Org. Chem. 2010, 6, 77; d) E. Erdik, Tetrahedron 1984, 40, 641. For recent examples of carbometalation of alkynes, see: e) X. Zhang, Z. Lu, C. Fu, S. Ma, Org. Biomol. Chem. 2009, 7, 3258; f) S. J. Aves, K. G. Pike, D. R. Spring, Synlett 2010, 2839; g) A. Unsinn, C. Dunst, P. Knochel, Beilstein J. Org. Chem. 2012, 8, 2202.
Chem. Eur. J. 2014, 20, 8918 – 8922
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[5] For recent reviews on the chemistry of allenes, see: a) Modern Allene Chemistry (Eds: N. Krause, A. S. K. Hashmi), Wiley-VCH, Weinheim, 2004; b) S. Ma, Chem. Rev. 2005, 105, 2829. For some recent examples of carbometalation of allenes, see:c) S. Araki, H. Usui, M. Kato, Y. Butsugan, J. Am. Chem. Soc. 1996, 118, 4699; d) T. Nishikawa, H. Shinokubo, K. Oshima, Org. Lett. 2003, 5, 4623; e) Z. Lu, S. Ma, Adv. Synth. Catal. 2007, 349, 1225; f) Y. Yoshida, K. Murakami, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2010, 132, 8878; g) S. Li, B. Miao, W. Yuan, S. Ma, Org. Lett. 2013, 15, 977. [6] a) A. Levin, A. Basheer, I. Marek, Synlett 2010, 329; b) Y. Minko, M. Pasco, L. Lercher, M. Botoshansky, I. Marek, Nature 2012, 490, 522; c) Y. Minko, M. Pasco, H. Chechik, I. Marek, Beilstein J. Org. Chem. 2013, 9, 526. [7] A. Alexakis, J. F. Normant, J. Villieras, J. Organomet. Chem. 1975, 96, 471. [8] For preparation of the b-allenyl ester 1 a, see: a) A. Dˇurisˇ, D. M. Barber, H. J. Sanganee, D. J. Dixon, Chem. Commun. 2013, 49, 2777; b) K. Kimura, S. Tanaka, Y. Tamaru, Bull. Chem. Soc. Jpn. 1995, 68, 1689. [9] J. F. Normant, Pure Appl. Chem. 1978, 50, 709. [10] a) I. Salkind, T. Beburischwili, Ber. Dtsch. Chem. Ges. 1909, 42, 4500; b) M. J. Jorgenson in Organic Reactions (Ed.: W. G. Dauben) 1970, 18, 1, John Wiley & Sons. Received: April 29, 2014 Published online on June 24, 2014
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Communication
& Synthetic Methods
Taming the Carboxyl Group for Directed Carbometalation: Observations on the Use of Anions, Dianions and Ester Enolates Sandy Desrat, Philip J. Gray, Matthew R. Penny, and William B. Motherwell*[a] Dedicated to the pioneering spirit of Professors Jean Normant and Alex Alexakis
Abstract: Carboxylate anions, dianions and ester enolates provide simultaneous protection and activation for directed carbometalation reactions. Advantage can be taken of the bis-carbanionic character of the intermediate for further controlled C C bond forming reactions.
Carbon–carbon bond forming reactions leading to the construction of a regio- and stereodefined alkene unit[1] are recognised to be an absolutely vital component in the armoury of the synthetic organic chemist. Within this area, following on from the pioneering studies of Normant, Alexakis and coworkers,[2] the wide ranging potential of heteroatom directed carbometalation[3] of an alkyne[4] or an allene[5] has burgeoned in recent years and provides an extremely powerful strategy. The elegant studies of Marek[6] on directed carbocupration for example, provide a perfect illustration that advantage can be taken, not only of the vinylic carbon–metal bond formed in the initial carbometalation step, but also of the heteroatom directing group, to forge additional carbon–carbon bonds. In similar fashion, with the objective of gaining increased efficiency and versatility in carbon–carbon bond formation, we were particularly intrigued by the possibility that, through the simple expedient of enolate anion formation, it would be possible to use the oxygen atom of a carbonyl group as the directing heteroatom. Such a selection leads to concomitant protection of the carbonyl group against nucleophilic attack by main group organometallic reagents together with formation of one of the preeminent cornerstones for carbon–carbon bond formation in organic synthesis. To the best of our knowledge, an enolate “protection–activation” strategy has not been employed in directed carbometalation. We were nevertheless encouraged by the seminal observation of Normant, Alexakis and Villieras that carbocupration could be directed by selection of the (Z)-enol ether geometry of 1-methoxybut-1-ene-3-yne.[7]
Scheme 1. Enolate directed carbometalation.
The foregoing concept is illustrated in more detail in Scheme 1 using the simple allenic ester 1 a, which was selected as a suitable substrate for an initial study involving directed carbocupration via 3 using either of the two oxygen atoms in the derived ester enolate 2. An additional feature of considerable interest was that the resultant heterobimetallic intermediate 4 would possess bis-carbanionic character and could therefore react, either as an ester enolate and/or as a vinyl cuprate, in subsequent reactions with selected electrophiles to furnish polyfunctionalised alkenes 5. In the first instance, we elected to examine the behaviour of the lithium ester enolate of ethyl penta-3,4-dienoate[8] 1 a in a stoichiometric carbocupration reaction using the protocol developed by Normant,[9] which involves mixing copper(I) iodide with one equivalent of Grignard reagent in diethyl ether at 30 8C for 1 h. Examination of the results in Table 1 for
[a] Dr. S. Desrat, Dr. P. J. Gray, Dr. M. R. Penny, Prof. Dr. W. B. Motherwell Department of Chemistry University College London 20 Gordon Street, London WC1H 0AJ (United Kingdom) Tel: + (44) 2076797524 E-mail: [email protected]
Entry
R
Product
Yield [%][a]
(E)/(Z) ratio[b]
1 2 3 4
iPr Et nBu Ph
6 7 8 9
81 93 56 52
80:20 90:10 75:25 30:70
[a] Yield of the isolated products based on starting material 1 a. [b] Determined by 1H NMR spectroscopic analysis of the crude reaction product.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403294. Chem. Eur. J. 2014, 20, 8918 – 8922
Table 1. Carbocupration of 1 a using a stoichiometric amount of organocopper reagent.
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Communication a series of organocopper reagents reveals that the Table 2. Reactivity of the bis-carbanionic intermediate towards electrophiles to form addition step is highly regioselective and that prepapolyfunctionalised alkenes 7–7 c. ratively useful yields can be obtained, especially when the aggregated nature of the two reacting components is considered. It should also be noted that the stereoselectivity can be strongly influenced by the nature of the organocopper reagent selected, as emphasised by the dramatic reversal between the Entry E + Equiv Product Yield [%][a] (E)/(Z) ratio[b] alkyl (entries 1–3) and aryl substituents (entry 4). Our attention was then directed towards the excit1 H2O excess 7 93 90:10 ing possibility of exploiting the bis-carbanionic character of the carbometalated intermediate 4. In order to achieve chemoselective reactions, it is of course 2 DCl excess 7 a 96 90:10 mandatory that the rates of reaction of the “ester enolate component” and the “organocopper component” in the complex heterobimetallic intermediate 3 3 equiv 7 b 44 10:90 are sufficiently different for a given electrophile. Initially, as demonstrated by the isolation of the dideuterio compound 7 a in high yield through addition of 1.1 equiv 7 c 21 90:10 4 DCl at the end of the reaction (Table 2, entry 2) it was possible to confirm the dianionic character of 4. Gratifyingly, selective alkylation at the organocopper site [a] Yield of the isolated products based on starting material 1 a. [b] Determined by could also be achieved and the monoalkylated prod1 H NMR spectroscopic analysis of the crude reaction product. uct 7 b was isolated in moderate yield, even when using three equivalents of allyl bromide as electrophile (Table 2, entry 3). By way of contrast, a preliminary experiment involving the addition of one molar equivaTable 3. Copper-mediated carbomagnesiation of 1 a directed by an enolent of an aldehyde to the reaction mixture led to selective late. trapping of the ester enolate, thus forming the alcohols 7 c (d.r. 1:1) albeit in low yield (Table 2, entry 4) together with the untrapped carbometallated product 7 as the major component. A contemporaneous study of copper-catalysed carbomagnesiation that involves the intermediacy of a more basic homocuprate species (R2CuM) also revealed several features of interEntry R Product Yield [%][a] (E)/(Z) ratio[b] est. Thus, careful optimisation of the reaction conditions 1 iPr 6 69 100:0 showed that preformation of the ester enolate is essential for 2 Et 7 71 100:0 the reaction otherwise addition of the Grignard reagent on the 3 Ph 9 79 100:0 carbonyl occurred. It also established that premixing 0.1 equiv4 Cy 10 67 100:0 alents of CuI and 1.1 equivalents of Grignard reagent at 20 8C [a] Yield of the isolated products based on starting material 1 a. [b] Deterin Et2O for 2 h prior to the addition of the ester enolate gave mined by 1H NMR spectroscopic analysis of the crude reaction product. the best results. Notably, and in contrast to the stoichiometric carbocupration reaction, the product alkenes 6, 7, 9 and 10, could be isolated in improved yield irrespective of the Grignard reagent employed, and with a stereospecific preference for formation of the (E) isomer (Table 3). Encouraged by this improvement in the stereoselectivity, the reactivity of the Grignard intermediate was then probed by treatment of the reaction mixture with DCl in D2O (Scheme 2). This experiment led to complete deuterium incorporation of the enolate position a but only 50 % of deuterium incorporaScheme 2. Trapping of the reactive species generated by copper mediated tion at the vinylic Grignard site g. This result suggested that carbomagnesiation of 1 a via an enolate. only one of the two ester enolate isomers of the highly basic Grignard intermediate 4, was protonated in situ by the di-isopropylamine generated from the use of LDA in the first step. to the carbometalation step, and led to complete deuterium This hypothesis was simply proven by removal of the di-isoproincorporation at both sites. In terms of practical utility howevpylamine under high vacuum after reaction with LDA and prior er, such additional experimental manipulations were not desirChem. Eur. J. 2014, 20, 8918 – 8922
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2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication able, with the deuterated alkene 9 a being isolated in only 22 % yield. As a logical consequence of the fact that the ester unit has two environmentally different oxygen atoms capable of directing carbometalation, we then explored the behavior of the symmetrical dilithio dianion of the carboxylic acid 1. As shown in Table 4, using the conditions optimised for the ester enolate, the carbometallated product was obtained with good (E)/(Z)
Table 5. Copper mediated carbomagnesiation of 1 directed by a carboxylate.
Table 4. Copper mediated carbomagnesiation of 1 directed by a dianion.
Entry
R
Product
Yield [%][a]
(E)/(Z) ratio[b]
1 2 3 4 5 6 7
Et nPentyl iPr Cy tBu Ph 1-Me-1-propenyl
11 a 11 b 11 c 11 d 11 e 11 f 11 g
70 78 95 96 61 74 88
90:10 90:10 95:5 95:5 95:5 90:10 95:5
[a] Yield of the isolated products based on starting material 1. [b] Determined by 1H NMR spectroscopic analysis of the crude reaction product. Entry
R
Product
Yield [%][a]
(E)/(Z) ratio[b]
1 2 3 4 5
Et nPentyl iPr Cy tBu
11 a 11 b 11 c 11 d 11 e
38 40 35 34 34
90:10 90:10 95:5 95:5 95:5
[a] Yield of the isolated products based on starting material 1. [b] Determined by 1H NMR spectroscopic analysis of the crude reaction product.
selectivity. Yields however were moderate, and substrate conversions above 50 % proved to be problematic, irrespective of the Grignard reagent employed. Even although the use of the carboxylate anion might be considered as the simplest form of protection against nucleophilic attack for a carboxylic acid, it has been well known for over a century that their reaction with main group organometallics is a very well established method for conversion to ketones.[10] We reasoned nevertheless that a copper-catalysed carbomagnesiation reaction using the allenic carboxylate as substrate would be the preferred pathway. Examination of the results for a selection of Grignard reagents illustrates that the desired alkenes 11 were formed with good (E)/(Z) selectivity and in very good yield (Table 5). From a practical standpoint, the reaction is very easy to perform since prior low temperature formation of the organocopper species is not required, and, unlike the dianion directed reaction above, complete conversion of starting material is observed. Since further functionalisation of the carbometallated intermediate 4 was a major focus of interest, a copper mediated carbomagnesiation reaction directed by the carboxylate of 1 was then treated with DCl. To our initial surprise, no deuterium incorporation was observed in the g position, and the adeuterated compound 15 was isolated in excellent yield 94 % and with a stereoselectivity of 95:5 in favour of the (E) isomer (Scheme 3). A plausible mechanistic rationale for this regiospecificity is shown in Scheme 3. Thus, the initial homocuprate generated in situ reacts with the magnesium carboxylate 1 b to give organocopper intermediate 12, which then undergoes transmetalChem. Eur. J. 2014, 20, 8918 – 8922
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Scheme 3. Proposed mechanism of the copper mediated carbomagnesiation of 1 followed by trapping of the magnesium enolate 14 by DCl.
lation with the Grignard reagent to regenerate the homocuprate and form the vinylic Grignard 13. This intermediate is a sufficiently strong base to form the dianion of the carboxylic acid 14, which was then trapped by addition of DCl. As emphasised by the wide range of electrophiles in Table 6, advantage can be taken of this dianion intermediate 14 for further carbon–carbon bond formation in an experimentally convenient one pot sequence. Thus, a-alkylation with iodomethane (entry 1) and formation of b-hydroxy carboxylic acids from a range of aldehydes and ketones (entries 3–8) all proceeded in excellent yield, save for the use of paraformaldehyde (entry 2). The tolerance of halogen functionality in the reactions of a-halo ketones (entries 9–11) is also noteworthy. The selection of an epoxide as an electrophile leading to a g-lactone (entries 12–14) is however eroded by competing rearrangement of the epoxide to a carbonyl compound. The foregoing preliminary results have hopefully illustrated that the simple concept of anionic protection of the carbonyl group also leads to concomitant efficiency in directed carbometalation and versatility in controlling further selective carbon–carbon bond forming reactions. Given the current wealth of metals that can be used in directed carbometalation, and the protocols available for regio- and stereospecific eno-
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Communication Table 6. Reactivity of the intermediate generated by copper mediated carbomagnesiation of 1 towards electrophiles to form polyfunctionalised alkenes.
Yield [%][a]
Entry
E+
Equiv
1
MeI
3 equiv
16 a
82
2
p-formaldehyde
8 equiv
16 b
49
3
3 equiv
16 c
95 (syn/anti 45:55)
4
3 equiv
16 d
95 (syn/anti 45:55)
5
3 equiv
16 e
85 (syn/anti 45:55)
6
3 equiv
16 f
87
7
3 equiv
16 g
89
8
3 equiv
16 h
92
9
3 equiv
16 i
85
10
3 equiv
16 j
85 (2 dia 50:50)
11
3 equiv
16 k
77 (2 dia 55:45)
12
5 equiv
16 l
49
16 m
33 (syn/anti 45:55)
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Products
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Communication Table 6. (Continued)
Entry
E+
13
14
Equiv
Yield [%][a]
Products
5 equiv
5 equiv
16 n
50 (2 dia 60:40)
16 f
40
16 o
54 (2 dia 60:40)
[a] Yield of the isolated products based on starting material 1.
late generation, application of this “protect and direct” strategy to the ketonic carbonyl group should prove to be a very fruitful area for future research. Keywords: allene · carbometalation · copper · enolate · Grignard reagent [1] For reviews, see: a) Preparation of Alkenes (Ed: J. M. J. Williams), Oxford University Press, Oxford, 1996; b) A. B. Flynn, W. W. Ogilvie, Chem. Rev. 2007, 107, 4698. [2] For a review see: J. F. Normant, A. Alexakis, Synthesis 1981, 841. [3] For reviews, see inter alia: a) J. V. N. Vara Prasad, C. N. Pillai, J. Organomet. Chem. 1983, 259, 1; b) B. Breit, Y. Schmidt, Chem. Rev. 2008, 108, 2928; c) A. G. Fallis, P. Forgione, Tetrahedron 2001, 57, 5899. [4] For reviews, see: a) A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307; b) A. G. Fallis, P. Forgione, Tetrahedron 2001, 57, 5899; c) A. Basheer, I. Marek, Beilstein J. Org. Chem. 2010, 6, 77; d) E. Erdik, Tetrahedron 1984, 40, 641. For recent examples of carbometalation of alkynes, see: e) X. Zhang, Z. Lu, C. Fu, S. Ma, Org. Biomol. Chem. 2009, 7, 3258; f) S. J. Aves, K. G. Pike, D. R. Spring, Synlett 2010, 2839; g) A. Unsinn, C. Dunst, P. Knochel, Beilstein J. Org. Chem. 2012, 8, 2202.
Chem. Eur. J. 2014, 20, 8918 – 8922
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[5] For recent reviews on the chemistry of allenes, see: a) Modern Allene Chemistry (Eds: N. Krause, A. S. K. Hashmi), Wiley-VCH, Weinheim, 2004; b) S. Ma, Chem. Rev. 2005, 105, 2829. For some recent examples of carbometalation of allenes, see:c) S. Araki, H. Usui, M. Kato, Y. Butsugan, J. Am. Chem. Soc. 1996, 118, 4699; d) T. Nishikawa, H. Shinokubo, K. Oshima, Org. Lett. 2003, 5, 4623; e) Z. Lu, S. Ma, Adv. Synth. Catal. 2007, 349, 1225; f) Y. Yoshida, K. Murakami, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2010, 132, 8878; g) S. Li, B. Miao, W. Yuan, S. Ma, Org. Lett. 2013, 15, 977. [6] a) A. Levin, A. Basheer, I. Marek, Synlett 2010, 329; b) Y. Minko, M. Pasco, L. Lercher, M. Botoshansky, I. Marek, Nature 2012, 490, 522; c) Y. Minko, M. Pasco, H. Chechik, I. Marek, Beilstein J. Org. Chem. 2013, 9, 526. [7] A. Alexakis, J. F. Normant, J. Villieras, J. Organomet. Chem. 1975, 96, 471. [8] For preparation of the b-allenyl ester 1 a, see: a) A. Dˇurisˇ, D. M. Barber, H. J. Sanganee, D. J. Dixon, Chem. Commun. 2013, 49, 2777; b) K. Kimura, S. Tanaka, Y. Tamaru, Bull. Chem. Soc. Jpn. 1995, 68, 1689. [9] J. F. Normant, Pure Appl. Chem. 1978, 50, 709. [10] a) I. Salkind, T. Beburischwili, Ber. Dtsch. Chem. Ges. 1909, 42, 4500; b) M. J. Jorgenson in Organic Reactions (Ed.: W. G. Dauben) 1970, 18, 1, John Wiley & Sons. Received: April 29, 2014 Published online on June 24, 2014
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