Trimethylsilyldiazomethane: A Useful Reagent for Generating Alkylidene

Carbenes and Its Application to Organic Synthesis

Takayuki Shioiri and Toyohiko Aoyama

Faculty of Pharmaceutical Sciences, Nagoya City University

Abstract: The lithium salt of trimethylsilyldiazomethane (TMSC(Li)N2) smoothly reacts

with alkyl aryl ketones and aldehydes to give the corresponding homologous alkynes via

alkylidene carbene intermediates. In the case of aliphatic ketones, the resulting alkylidene

carbenes can be trapped by an amine to afford enamines which are efficiently converted to

the homologous aldehydes. TMSC(Li)N2 can also be effectively used for the preparation of

heterocycles such as 2,3-dihydrofurans, cyclohepta[b]pyrrol-2-ones, and 3-pyrrolines from

the corresponding ƒÀ-siloxyketones, N-methylanilides of oc-keto acids, N,N-dialkylamides of

a-keto acids, and N,N-disubstituted a-amino ketones, respectively.

1. Introduction

One of the most urgent tasks facing synthetic organic chemists today is the development of readily

accessible organic synthetic methodology that is environmentally safe. Our interest in trimethylsilyl-

diazomethane (TMSCHN2) as a synthetic reagent originated from the hazardous nature of diazomethane

though the latter has been widely used in various organic synthesis. TMSCHN2 is stable and safe in

contrast to labile and explosive diazomethane. The stability of TMSCHN2 is due to the pƒÎ-dƒÎ resonance

contributing to stabilization of its ground state. However, its utilization in organic synthesis had never

been explored up to the time we launched our investigation of this compound in the late 1970's . We have well proven that TMSCHN2 is a user-friendly reagent and a stable and safe substitute for hazardous

diazomethane in various organic synthesis (ref. 1). TMSCHN2 is very useful as a reagent for the

introduction of a C-1 unit and can be used as a [C-N-N] synthon for the preparation of various azoles .As a C-1 unit introducing reagent, TMSCHN2 and its lithium salt (TMSC(Li)N2)

, easily prepared bylithiation of TMSCHN2, generally behave in a similar way to diazomethane. On the other hand , they f

unction as [C-N-N] azole synthons in an analogous, but not the same fashion as diazomethane . The usefulness of TMSCHN2 in organic synthesis hitherto uncovered is summarized in Figures 1-4 , most of which has been explored by our group.

Recently, we have found that TMSC(Li)N2 is also useful as a reagent for generating alkylidene

carbenes from various carbonyl compounds. This paper deals with our results on the synthetic

applications of TMSC(Li)N2 as an alkylidene carbene generator.

2. Synthetic Applications of Lithium Trimethylsilyldiazomethane as an Alkylidene

Carbene Generator

The reaction of TMSC(Li)N2 with carbonyl compounds smoothly proceeds to generate alkylidene

carbenes which undergo various types of reactions to give the homologous alkynes, aldehydes, and h

eterocycles depending upon the substrates used.

2.1. Preparation of Alkynes

In 1973, Colvin and Hamill reported that TMSC(Li)N2 reacted with ketones (1), such as b

enzophenone and benzil, to give the corresponding homologous alkynes (4) via the Colvin

918 ( 44 ) J . Synth . Org . Chem . , Jpn

Fig. 1 Me3SiCHN2 as a C1-unit introducing reagent

Fig. 2 Me3SiC(Li)N2 as a Crunit introducing reagent

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Fig. 3 Me3SiCHN2 as a 1C-N-N] synthon

Fig. 4 Me3SiC(Li)N2 as a [C-N-N] synthon

920 ( 46 ) J . Synth . Org . Chem . , Jpn .

rearrangement, as shown in Scheme 1 (ref. 2, 3). The mechanism for this interesting reaction (ref. 2, 4)involves nucleophilic attack at the carbonyl carbon atom of 1 by TMSC(Li)N,) to give the α-

diazoalkoxide (2). Subsequent elimination of TMSOLi followed by expulsion of nitrogen from 2 gives the alkylidene carbene intermediate (3) which then undergoes rearrangement to provide the homologous alkyne (4). Under the same reaction conditions (Et20, 0°C, 2 h), however, ketones (1) bearing an enolizable a-proton (e.g., acetophenone) and aldehydes (e.g., benzaldehyde) failed to give appreciableamounts of the corresponding alkynes. On the other hand, Sch011kopf and Scholz found that α-

diazoalcohols (5) derived trom 1 including enolizable ketones and aldehydes could be prepared in good yields when the nucleophilic addition of TMSC(Li)N2 was conducted in THF at -78°C. These experiments have suggested that the conditions used for the reaction play a critical role. Wereinvestigated this reaction and found that upon treatment of 1 and TMSC(Li)N2 in THF at -78℃

followed by heating under reflux conditions, alkyl aryl ketones and aldehydes were cleanly converted to the corresponding homologous alkynes (4) (ref. 5, 6).

2 3

5 4

The usefulness of the reaction is well illustrated in Table 1. Various aromatic and heteroaromaticketones (1) smoothly react with TMSC(Li)N2 to give 4 in good yields (runs 1-9 in Table 1). The α,β-

unsaturated ketone also undergoes the reaction to attord the ene-yne product (run 10). Untortunately, the

Scheme 1

Table 1. Preparation of Homologous Alkynes (4) from Alkyl Aryl Ketones and Aldehydes (1)

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reaction with aliphatic ketones gives a complex mixture and no alkynes are obtained. In the cases of

aldehydes, aliphatic as well as aromatic aldehydes are smoothly converted to the terminal alkynes (runs

12•`16). Interestingly, the reaction with N-tert-butoxycarbonyl-L-prolinal proceeds with retention of

configuration (run 16).

In a similar way, thioketones (6) also react with TMSC(Li)N2 to give the alkynes (4) though the

yields are moderate (ref. 7).

2.2. Preparation of Aldehydes

As described above, aliphatic ketones (1) also react with TMSC(Li)N2, but the products are a complex mixture. This result seems to be due to the relatively low migratory aptitude of the alkyl group on the alkylidene carbene intermediate (3). However, when the reaction is conducted in the presence of excess diisopropylamine, the resulting 3 can be trapped as the enamines (7) (ref. 8, 9). The enamines (7) thus obtained easily undergo hydrolysis by treatment with silica gel to afford the homologous aldehydes (8).

Table 2. Preparation of Homologous Aldehydes (8) from Aliphatic Ketones (1)

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The results are summarized in Table 2 . Various ketones including normal alkyl. alicvclic .unsaturated, and heterocyclic ketones are smoothly converted to the corresponding homologous

aidenydes in good to moderate yields. It is interesting to note that the reaction of 2-undecannne with TMSC(Li)N2 in the absence of an amine has been reported to give the cyclopentene derivative resulting

from intramolecular 1,5 C-H insertion of 3 (ref. 4), while the reaction in the presence of an amine gives 2-methylundecanal (run 4 in Table 2). Other ketones bearing a hydrogen at they-position of the carbonvl group, sucn as ,b-u-isopropylidenedioxy-2-hexanone and 4-(4-dimethylaminophenv1)-2-hexanone_nave also been reported to undergo a similar reaction to give the corresponding cyclonentenes . respectively (ret. 4, 10).

2.3. Preparation of 5-Trimethylsilyl-2,3-dihydrofurans

Alkylidene carhenes generated from the reaction of TMSC(Li)N1 with ketones easily inserted intn tne N-H bond of an amine giving enamines , as described in section 2.2. This result indicates that 2.3-dihydroturans can be obtained by intramolecular insertion of alkvlidene carhenes to the 0 -14 &Ind if

Ketones substituted with the hydroxy group at the ƒÀ-position of the carbonvl function are used as

substrates. In fact, treatment of TMSC(Li)N2 with the ƒÀ-hydroxyketone (9) gives the 2 _3-dihydmfnran

(1U) though the yield is low, as shown in Scheme 2 (ref. 11). However. renlacement of the hviimyvgroup of 9 with the trimethylsiloxy group leads to a significant improvemenfof the yield_ Thus: the

β- trimetnyislioxy Ketones (11) smoothly react with TMSC(Li)N, to give the corresnondino 5-tnmethylsily1-2,3-dihydrofurans (12) in high to moderate yields . In some cases_ the alkvnes (111 areobtained as by-products.

910

11 12 13

Table 3. Preparation of 5-Trimethylsilyl-2 ,3-dihydrofurans (12) from f3-Trimethylsiloxyketones (11)

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The scope of the new preparation of 5-trimethylsilyl-2,3-dihydrofurans is summarized in Table 3. Various I3-trimethylsiloxyketones (11) are smoothly converted to the corresponding di-, tri-, and tetrasubstituted 2,3-dihydrofurans (12) (runs 1-8 in Table 3). The aromatic ketones also react with TMSC(Li)N2 to give the desired 2,3-dihydrofurans (12), but the major products are the alkynes (13) (runs 9, 10). In the case of the reaction with the aldehyde, the alkyne (13) was the only isolable product and no 2,3-dihydrofuran could be detected (run 11).

The mechanism of the reaction will be as shown in Scheme 3: the reaction of TMSC(Li)N2 with 11 first gives the alkylidene carbene intermediate (14). Subsequent cyclization of 14 affords the oxonium ylide (15), which is then rearranged to 12 (path a). However, when the R1 group on 11 has a higher migratory aptitude, rearrangement of 14 competes with the oxonium ylide formation and a mixture of 12 and 13 is formed (path b).

1114 15

13 12

The trimethylsilyl group of 12 can be easily removed with tetra-n-butylammonium fluoride in THE to give the 2,3-dihydrofuran (16), as shown in Scheme 4. In addition, the dihydrofurans (12) are

efficiently converted to the furans (17) in high yields by oxidation with Mn02 (CMD, chemical manganese dioxide) (ref. 12).

16

17

2.4. Preparation of Cyclohepta[b]pyrrol-2-ones

It has been reported that the potassium salt of diethyl diazomethylphosphonate (DAMP, (EtO)2P(0)CHN2) reacts with N-methylanilides of pyruvic acid (18) to give the cyclohepta[b]pyrrol-2-

ones (20) via the alkylidene carbene intermediate (19) (path a), as shown in Scheme 5 (ref. 13). This method involving the construction of a seven-membered ring by expansion of an aromatic ring is very unique, but excess DAMP is required for completion of the reaction and yet the yields are moderate.

Scheme 3

Scheme 4

924 ( 50 ) J. Synth. Org . Chem .,

However, when TMSC(Li)N2 is used in place of DAMP, the reaction smoothly proceeds to give 20 (ref. 14). In some cases, the 2-oxo-3-pyrrolines (21) are formed as by-products (path b). The results are summarized in Table 4. Various N-methylanilides of oc-keto acids (18) undergo the reaction with TMSC(Li)N2 to afford 20. The reaction with TMSC(Li)N2 is much more efficient than that with DAMP. Substituents on the benzene ring of 18 exert no influence on the yield of 20.

18

19

21 20

2.5. Preparation of 2-0xo-3-pyrrolines and 3-Pyrrolines

In some cases of our cyclohepta[b]pyrrol-2-one synthesis, small amounts of 2-oxo-3- pyrrolines (21) (1,5 C-H insertion products) areformedas by-products. We thought that 2-oxo-3- pyrrolines could be exclusively obtained if N,N-dialkylamides of a-keto acids were used as substrates. In fact, treatment of TMSC(Li)N2 with 1-(a-oxopropionyl)piperidine(22a) in Et20 under the same

Scheme 5

Table 4. Preparation of Cyclohepta[b]pyrrol-2-ones (20) from N-Methylanilides of a-Keto Acids (18)

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reaction conditions for the preparation of 20 gives the desired 3(5H)-indolizinone (23a) though the yield is only 13%. However, changing the reaction solvent to THE and addition of magnesium bromide (MgBr2) as an additive lead to a significant improvement of the yield. Thus, the reaction of TMSC(Li)N2 with 22 smoothly proceeds to give the corresponding 2-oxo-3-pyrrolines (23) as sole isolable products, as shown in Table 5 (ref. 15). Although an analogous reaction with DAMP has been reported (ref. 16), the product is a mixture of 23 and considerable amounts of N,N-dialkyl-2-butynamides, the latter of which are formed by migration of the carbamoyl group in the alkylidene carbene intermediates. Furthermore, two equivalents of DAMP are required to conduct the reaction smoothly. Thus, the reaction with TMSC(Li)N2 is much more efficient than that with DAMP.

2223

N,N-Disubstituted a-amino ketones (24) also undergo the analogous reaction with TMSC(Li)N2 to afford the 3-pyrrolines (25) in good yields (ref. 15). In this case, the reaction smoothly proceeds in the absence of MgBr2. The results are summarized in Table 6. It should be noted that the reaction with the anilides (18) gives the cyclohepta[b]pyrrol-2-ones (20), as described in section 2.4., while the reaction with the aniline derivatives (24a, b) gives the 3-pyrrolines (25a, b) only. The 3-pyrrolines (25) obtained are easily converted to the pyrroles (26) by oxidation with CMD, as shown in Table 6.

2425 26

Table 5. Preparation of 2-0xo-3-pyrrolines (23) from N,N-Dialkylamides of a-Keto Acids (22)

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3 . Conclusion

Trimethylsilyldiazomethane (TMSCHN2) has now been fully proven to be a user-friendly , stable, and safe substitute for hazardous diazomethane. In addition to its utilization as a C-1 unit introducing reagent and a [C-N-N]azole synthon, we have been able to widen the scope of its utility in organic synthesis as an alkylidene carbene generator from various carbonyl compounds . This account has described our results in this area, which are summarized in Figure 5.

Table 6. Preparation of 3-Pyrrolines (25) and Pyrroles (26) from N,N-Disubstituted a-Amino Ketones (24)

Fig. 5 Me3SiC(Li)N2 as an alkylidene carbene generator

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We believe that TMSCHN2 still possesses latent properties which could be applied to organic synthesis and investigation along this line will be undertaken in the near future.

Acknowledgments: We would like to thank all of our co-workers whose names appear in the references for their dedication, intellectual contribution, and hard work. Our work was partially supported by Grants-in-Aid from the Ministry of Education, Science, Sports and Culture, Japan.

References and Notes

(1) For reviews, see (a) Shioiri, T.; Aoyama, T. J. Synth. Org. Chem. Japan 1986, 44, 149. (b) Aoyama, T. Yakugaku Zasshi 1991, 111, 570. (c) Anderson, R.; Anderson, S. B. Advances in Silicon Chemistry Vol. 1, Larson, G. L. (ed.), JAI Press, Greenwich CT, 1991, p. 303. (d) Shioiri, T.; Aoyama, T. Advances in The Use of Synthons in Organic Chemistry Vol. 1, Dondoni, A. (ed.), JAI Press Ltd., London, 1993, p.51. (e) Shioiri, T.; Aoyama, T. Encyclopedia of Reagents for Organic Synthesis Vol. 7, Paquette, L. A. (ed.), John Wiley & Sons, Chichester, 1995, p. 5248.

(2) (a) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Chem. Commun. 1973, 151. (b) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Perkin Trans I 1977, 869.

(3) We would like to propose that this 1,2-rearrangement is named the Colvin rearrangement in view of Colvin's pioneering work.

(4) (a) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem. Commun. 1992, 721. (b) Ohira, S.; Moritani, M.; Ida, T.; Yamato, M. J. Chem. Soc., Chem. Commun . 1993, 1299.

(5) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett, 1994, 107. (6) While our work was in progress, Ohira and co-workers reported that the reaction of decanal with

TMSC(Li)N2 gave 1-undecyne, see ref. 4. (7) Shioiri, T.; Iwamoto, Y.; Aoyama, T. Heterocycles, 1987, 26, 1467. (8) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett, 1994, 109. (9) Analogous reaction with the potassium salt of dimethyl diazomethylphosphonate has been reported.

See (a) Gilbert, J. C.; Weerasooriya, U. Tetrahedon Lett. 1980, 21, 2041. (b) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1983, 48, 448.

(10) Taber, D. F.; Meagley, R. P. Tetrahedron Lett. 1994, 43, 7909. (11) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett, 1994, 461. (12) Chemical manganese dioxide (CMD) used here has been produced for battery manufacture by Chuo

Denki Corp., Japan. It is available from ITE Sample Office (Japan), 39-2 Youke Ukino, Chiaki-cho, Ichinomiya, Aichi 492, Japan (Fax +81-586-81-1988).

(13) Gilbert, J. C.; Blackburn, B. K. J. Org. Chem. 1986, 51, 4087. (14) Ogawa, H.; Aoyama, T.; Shioiri, T. Synlett, 1994, 757. (15) Ogawa, H.; Aoyama, T.; Shioiri, T. Heterocyclecs, 1996, 42, 75. (16) Gilbert, J. C.; Blackburn, B. K. J. Org. Chem. 1986, 51, 3656.

(Received June 19, 1996)

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