Dehydrative Fragmentation of 5-Hydroxyalkyl-1H-tetrazoles: A Mild Route to Alkylidenecarbenes

Abstract

The development of a mild, base-free method for the generation of alkylidenecarbenes is reported. Treatment of 5-hydroxyalkyl-1 H-tetrazoles with carbodiimides generates products arising from the 1,2-rearrangement or [1,5]-C-H bond insertion of a putative alkylidenecarbene. Formation of this divalent intermediate is proposed to occur by way of a tetraazafulvene, which undergoes extrusion of two moles of dinitrogen. Details of this methodology, its applicationtothesynthesisofcombretastatinA-4andanimprovedrouteto5-hydroxyalkyl-1 H-tetrazolesare described.

1H-Tetrazoles have long been recognized as metabolically stable bioisosteres of the carboxylate group for which reason they have found widespread application in medicinal chemistry.¹ Our interest in these nitrogen-rich heterocycles, however, stems from their chemical instability^2,3 and attendant potential as precursors of alkylidenecarbenes: transient, electron deficient species, which undergo a number of synthetically valuable reactions, including [1,2]-rearrangement, ylide formation, alkene cyclopropanation and [1,5]-C-H bond insertion.⁴ Over the last decade, we have studied the latter transformation as a means to access O- and N-heterocycles and natural products that encompass these ring systems.⁵

Synthetic potential notwithstanding, the practical value of alkylidenecarbenes remains limited by a deficiency of methods for their generation under non-basic conditions.⁶ Although a number of noteworthy solutions to this issue have been reported, including the thermolysis of epoxyaziridinyl imines⁷ and addition of “soft” nucleophiles to alkynyl(phenyl)iodonium salts,⁸ the continued development of new methods appears to be warranted. In this context, we were intrigued by a rarely cited report from Behringer regarding the thermolysis and rearrangement of 5-hydroxy(diarylmethyl)-1H-tetrazoles and related derivatives 1 to form diarylalkynes 4 (Scheme 1).⁹ In this case, dehydration of 1 (X = OH) was proposed to generate unstable tetraazafulvene intermediate 2 which undergoes conversion to the observed products through extrusion of two moles of dinitrogen and rearrangement of the resulting alkylidenecarbene 3.^10,11

Scheme 1.

In this communication we report on our investigation of this unusual tetrazole reactivity manifold and the development of conditions that trigger the dehydration and fragmentation of 5-hydroalkyl-1H-tetrazoles to form alkylidenecarbenes under exceptionally mild conditions. In addition to employing this methodology in the preparation of alkynes, diynes, triynes and 5-membered hetero/carbocycles, its application to the stereoselective total synthesis of combretastatin A4 (18) is also described.

Our study commenced with the development of a general method for the preparation of 5-hydroalkyl-1H-tetrazoles 7 (Table 1). While potentially available from cyanohydrins via cycloaddition with azide,¹² we sought to establish a more flexible route to these substrates that avoided the direct use of cyanide and azide-based reagents.¹³ In this regard, we opted to adapt a two-step protocol reported by Satoh involving the addition of 1-benzyl-5-tetrazoyllithium to carbonyl electrophiles and subsequent de-N-benzylation.^14,15 Thus, treatment of ketones, ynones and an aldehyde 6 with 1-allyl-5-tetrazoyllithium (5)¹⁶ in THF at low temperature provided the desired alcohols 7 in excellent yield (Table 1).

Table 1.

Preparation of 5-hydroalkyl-1H-tetrazoles 8.

entry	R1	R2	7 (yield %)a	8 (yield %)b
1		Ph	7a, 90	8a, 99
2		Ph	7b, 87	8b, 99
3		Ph	7c, 93	8c, 98
4		Ph	7d, 99	8d, 99
5		Ph	7e, 90	8e, 99
6		Ph	7f, 96	8f, 99
7		Ph	7g, 92	8g, 32c
8	n-Pentyl	Ph	7h, 83	8h, 76c
9		Ph	7i, 99	8i, 99
10		H	7j, 78	8j, 89
11		Ph	7k, 99	8k, 99
12			7l, 70	8l, 50c

^aUnless otherwise noted, isolated yield, after purification by flash chromatography on silica gel.

^bUnless otherwise noted, yield after aqueous workup; no further purification required.

^cIsolated yield, after purification by back extraction.

Efficient, direct de-N-allylation of the addition products 7 was now accomplished under Yamamoto’s conditions,¹⁷ by treatment with a combination of catalytic NiCl₂(dppe) and tert-BuMgCl in CH₂Cl₂ (Table 1). The ease with which the N-allyl groups are removed from 7 is notable, as cleavage of N-benzyl protecting groups from this type of substrate has previously proved problematic.^14a

Turning our attention to the generation of alkylidenecarbenes 9, we now opted to examine carbodiimide dehydrating agents as a means to access the putative tetraazafulvene intermediate since Behringer noted a single example of the use of DDC in mediating the decomposition of 1. Gratifyingly, treatment of 8a with a range of carbodiimides, including DCC, EDC and most conveniently, diisopropylcarbodiimide (DIC) smoothly provided diphenylacetylene (10a) in excellent yield (Figure 1). In all cases but 8f and 8l, decomposition occurred at room temperate over the course of 24 h.

Figure 1.

Dehydrative fragmentation of of 5-hydroalkyl-1H-tetrazoles: alkylidenecarbene 1,2-rearrangement. ^aUnless otherwise noted, isolated yield, after purification by flash chromatography on silica gel. ^bReaction conducted in 1,2-dichloroethane at reflux: 10f (5 min); 10l (1 h). ^cEDC used in place of DIC for ease of purification.

That the onset of these reactions is accompanied by the generation of nitrogen gas appears to be consistent with the proposed mechanism. Encouragingly, this process displays considerable scope and offers access to symmetrical and non-symmetrical alkynes (10a–j) as well as diynes (10k) and triynes (10l) in yields which compare favorably with the 1,2-rearrangement of other precursors, including 1,1-dihaloalkenes.¹⁸ In addition to product 10c, dehydration of o-anisole derivative 8c also yielded traces (3%) of 3-phenylbenzofuran (11), which is believed to arise from carbene 9c through competitive oxonium ylide formation and de-O-alkylation at the o-MeO substituent.¹⁹ That pyridines are known to undergo ring opening in the presence of carbodiimides may account for the inefficiency observed during the formation of product 10g.²⁰

Given the success of the [1,2]-rearrangement process, we next sought to expand our methodology to include the [1,5]-C-H insertion manifold. In this case, substrates were purposely chosen with substituents known to have low migratory apptitude.²¹ The requisite tetrazoles 12 (Figure 2) were prepared from the corresponding methyl ketones through the two-step sequence previously described. In all cases, the overall yield of these substrates compared favorably with those noted in Table 1.

Figure 2.

Dehydrative fragmentation of 5-hydroalkyl-1H-tetrazoles: alkylidenecarbene [1,5]-C-H bond insertion. ^aFor details of the preparation of substrates 12a–f, see Supporting Information. ^bIsolated yields, after purification by flash chromatography on silica gel. ^cDCC used in place of DIC ^dIsolated as an inseparable 5:4 mixture of [1,5]-C-H insertion and 1,2-rearrangement products.

While attempts to effect the decomposition of 12 at room temperature in the presence of DIC or DCC failed, conducting this reaction in 1,2-dichloroethane at reflux (84 °C) rapidily generated the desired insertion products 13 in reasonable yield. Significantly, the efficiency of these cyclizations compare favorably with that of other intramolecular alkylidenecarbene C-H insertion reactions.²² While the low yield of cyclopentene 13a arises, in part, from the volatility of this product, it may also reflect the increased bond dissociation energy of the target C-H bond in this system relative to the other substrates in which the presence of an adjoining heteroatom favors C-H insertion.²³ Unexpectedly, the formation of 4-azaspiro[2.4]heptane 13f was accompanied by a significant amount of [1,2]-rearrangement.

Having established the viability of our methodology in [1,5]-C-H insertions, we turned our attention to its application to natural product synthesis. The dried stem wood of the South African bush willow tree Combretum caffrum harbors several biologically active stilbenoid phenols now commonly known as combretastatins. First isolated by Pettit in 1989,²⁴ combretastatin A4 (18) competitively binds the colchicine site of tubulin and is an exceptionally potent inhibitor of microtubule assembly and cellular mitosis. Its selectivity for proliferating endothelial cells and suppression of tumor angiogenesis places 18 and its numerous synthetic analogs²⁵ in an emerging class of anti-cancer drugs referred to as vascular disrupting agents.²⁶

Our route to combretastatin A4 (18) commenced from isovanillin derivative 14,²⁷ which underwent addition of 3,4,5-trimethoxyphenyllithium²⁸ to generate the corresponding benzhydryl alcohol in excellent yield (93%). Treatment of this compound with 2-iodoxybenzoic acid (IBX) in DMSO then provided ketone 15. After tetrazole addition and de-N-allylation, treatment of 16 with DIC led to the formation of 17 in good overall yield. Low temperature treatment of this alkyne with Bu₂Ti(Oi-Pr)₂, generated in situ by treatment of Ti(Oi-Pr)₄ with n-BuLi (2 equiv), and protolytic workup, exclusively provided the Z-stilbene.²⁹ Diastereoselectivity in this case arises through stereospecifc diprotonation of the 3-membered titanacyle formed by epimetalation of alkyne 17.³⁰ Finally, acid hydrolysis of the MEM ether afforded combretastatin A4 (18) with an overall yield of 38% from isovanillin. Spectral data collected for synthetic 18 were found to be in complete agreement with those reported by Pettit for the natural product.³¹

In summary, we have developed a new method for the generation of alkylidenecarbenes involving the dehydration and fragmentation of 5-hydroalkyl-1H-tetrazoles under exceptionally mild conditions. This methodology displays wide substrate scope and can be utilized for the synthesis of alkynes, diynes and triynes through the 1,2-rearrangement of the intermediate carbene, or 5-membered carbocycles and heterocycles via [1,5]-C-H bond insertion. This chemistry was also succesfully utilized in a highly stereoselective total synthesis of combretastatin A4 (18), which was accomplished in 8 steps from isovanillin with an overall yield of 38%.

Scheme 2.