Silver catalyzed proto- and sila-Nakamura-type α-vinylation of silyl enol ethers with dichloroacetylene. Divergent formation of stereochemically pure tri- and tetrasubstituted olefins.

Abstract

The silver-catalyzed reaction of silyl enol ethers with dichloroacetylene (DCA) is described. When DCA was used as a solution in diethyl ether, we found that the silyl group was transferred to the vinyl group, resulting in stereochemically pure tetrasubstituted olefins. However, when DCA was used as a solution in the more polar acetonitrile, protonation was the major pathway, and trisubstituted olefins were the dominant products.

Graphical Abstract

Tri- and tetrasubstituted alkenes are ubiquitous structures in organic chemistry, thus a significant amount of research has gone into developing synthetic routes towards alkenes. However, the stereocontrolled synthesis of multi-substituted alkenes remains a significant challenge in organic synthesis.¹ Traditional methods of olefin syntheses, including Wittig,² Julia,³ and Peterson olefinations,⁴ require prefunctionalized reagents, produce significant amounts of byproducts, and often lead to mixtures of isomers. More recent approaches minimize preactivation by “building out” from suitable C₂ building blocks, either via the hydro- and carbometalation of alkynes⁵ or via the synthesis of stereodefined vinyl halides and vinyl silanes that can be sequentially functionalized via transition metal cross-coupling reactions.⁶

Organ⁷ and others⁸ have developed modular syntheses of polysubstituted olefins from commercially available or easily accessible 1,1- and 1,2-dihaloalkenes. Trichloroethylene has also been identified as an inexpensive and useful C₂ building block for constructing polysubstituted olefins. Trichloroethylene can be converted into dichloroacetylene (DCA) in situ, and reacted with alcohols and amines to generate dichlorovinyl ethers and amides that could be further elaborated via palladium-catalyzed cross coupling reactions.⁹

We imagined that if DCA could be engaged in cycloaddition chemistry, we could access a wide variety of dichlorinated (hetero)cycles. The electron-rich Danishefsky’s diene has been frequently used in the synthesis of oxygen-substituted six-membered rings via Diels-Alder cycloadditions with olefins.¹⁰ Hilt and co-workers have described a series of cobalt-catalyzed reactions of simple 1,3-butadienes¹¹ and mono-O-functionalized 1,3-butadienes¹² with alkynes that yielded six-membered Diels-Alder adducts as either the 1,4-hexadiene or benzene, depending on the location of the oxygen substituent (Scheme 1, A). We therefore sought to develop an analogous benzannulation reaction of dichloroacetylene (DCA) via a Diels-Alder cycloaddition with Danishefsky’s and related dienes to synthesize substituted o-dichlorobenzenes (Scheme 1, B). However, while we were only able to detect a trace amount of the targeted dichlorobenzene derivative by GC-MS, we were pleased to observe the addition of the enol ether across DCA to yield tri- and tetrasubstituted olefins 3a and 3b.

Scheme 1.

A. Hilt’s cobalt catalyzed reaction of O-functionalized dienes with alkynes. B. Observed reactivity of Danishefsky’s diene 1a and dichloroacetylene 2 C. Other reactions of electrophiles and nucleophiles with alkynes.

DCA has been previously shown to react with lithium enolates only under strongly basic conditions.¹³ An alternate approach to the reaction of enolates with alkynes is the Nakamura reaction (Scheme 1, C, right). This process however, is also very limited as it requires a highly activated carbonyl compounds and monosubstituted alkynes.¹⁴ Other methods of synthesizing α– vinyl carbonyl compounds include palladium¹⁵ or base¹⁶ catalyzed cross-coupling with vinyl electrophiles. Dihalosilylolefins are highly useful synthetic intermediates, generally prepared by the addition of dihalides¹⁷ to or dihalide equivalents¹⁸ to silylacetylenes (Scheme 1, C, left).

Our serendipitous discovery that silyl enol ethers added across DCA in the presence of a catalyst to generate β,γ-unsaturated ketones both with and without silyl transfer inspired us to develop conditions that could selectively generate either protonated or silylated dichloroalkenes. We began our optimization process by evaluating the performance of several Lewis acids in the reaction between the silyl enol ether of acetophenone, 1b, and DCA 2 (Table 1). For the convenience and safety of using DCA,¹⁹ we prepared DCA as an ether solution (~1 M), which can be stored in a freezer for one week.²⁰ To our surprise, the copper complex that we discovered the reaction with failed to catalyze the reaction between 1b and 2 (Entry 1). Extensive screening of more than 40 catalysts (see Electronic Supporting Information (ESI) for additional details) revealed that copper triflate (Entry 2) and silver triflate (Entry 3) both led to moderate isolated yields for the product 3a (30% and 28% yield, respectively) after 24 hours; most of the screened catalysts were ineffective, and only unreacted 1b and/or acetophenone 5 could be detected. When copper triflate was employed as the catalyst, increasing the reaction time from 24 to 48 hours was ineffective (Entry 4); this is attributed to the rapid copper catalyzed decomposition of silyl enol ether 1b. However, when silver triflate was employed as the catalyst, decomposition of 1b was slower, and thus increasing the reaction time from 24 to 48 hours improved the isolated yield of 3b from 28% to 40% (Entry 3 versus 5) as determined by ¹H NMR analysis. We also detected a third byproduct, 3b´, by ¹H NMR spectroscopy.²¹

Table 1.

Selected optimization experiments between silyl enol ether 1a and dichloroacetylene 2.

Entry	[M] (10 mol%)	Solventb	Additive	T (°C)	3b:4b:5	3b:3b’	yield (%)c
1d	Cu(MeCN)4PF6	-	-	50			0
2d	Cu(OTf)2	-	-	50			(30)
3d	AgOTf	-	-	50			(28)
4	Cu(OTf)2	-	-	50	1:0:2.4	1:0.1	25
5	AgOTf	-	-	50	1:0:1.3	1:0.2	40
6	AgOTf	toluene	-	50	1:0:3.6	1:0.6	17
7	AgOTf	hexane	-	50	1:0:3.6	1:0.9	10
8	AgOTf	DCM	-	50	1:0.05:1.5	1:0.3	30
9	AgOTf	MeCN	-	50	1:3.1:3.5	1:0.4	15
10	AgOTf	DMF	-	50	0:0:1	-	0
11	AgOTf	-	TMSCle	50	1:0:1	1:0	50
12	AgOTf	-	-	80	1:0:0.3	1:0.1	70 (69)
13	AgOTf	-	TMSCle	80	1:0:0.4	1:0	71 (67)
14	AgOTf	-	TMSCIe MeCNf	80	1:0.22:0.22		70
➩15	AgOTf	-	TMSCle, MeCNg	80	1:0:0.25	1:0	80(75)
➩16	AgOTf	MeCNh	-	80	1:3.6:0.07	1:0	62i

^aUsing 0.2 mmol 1a and 1 mL DCA solution in ether (1 M).

^b“-” Represents using only ether as a solvent; otherwise, a 1:1 solvent:ether mixture was used.

^c1H NMR yield using CH₂Br₂ as an internal standard; isolated yield of 3b indicated in brackets.

^dReaction time was 24 h.

^eUsing an additional 0.68 equiv TMSCl.

^fUsing 0.5 mL MeCN.

^gUsing 0.1 mL MeCN.

^hDCA 2 was prepared in a solution of MeCN.

ⁱIsolated yield of 4a.

Continuing with silver triflate as our optimum catalyst, we turned to screening other reaction variables. Changing the solvent to a mixture of diethyl ether with other solvents did not improve the yield (see ESI for additional solvent screening details). The application of nonpolar solvents, such as toluene (Entry 6) and hexane (Entry 7), gave only 17% and 10% conversion to 3b, and increased production of 3b´. A slightly more polar solvent, CH₂Cl₂, gave a better result (30% yield of 3b and comparable production of 3b´, entry 8). More polar solvents, such as MeCN (Entry 9) and DMF (Entry 10), were much less effective. In most of the screening conditions, acetophenone 5 was the major component in the crude reaction mixture, which was presumably produced via the decomposition of silyl enol ether 1b.

As changing the solvent led to no improvement in the conversion to 3b, we next screened several additives to evaluate their effectiveness in both reducing the decomposition of 1b and the formation of 3b´ (see ESI for additional details). When substoichiometric amounts of exogenous TMSCl were used as an additive,²² the yield of product 3b was increased to 50% (Entry 11). More significantly, 3b´ was no longer detected by ¹H NMR analysis. Because acetophenone 5 was still observed as the major byproduct, we next decreased the reaction temperature in an attempt to slow decomposition of 1b; however, no improvement in the yield of 3b was observed (see ESI for details). We reasoned that if the decomposition of 1b to 5 was faster than addition across DCA (2), increasing the reaction temperature could favor the formation of 3b. Indeed, increasing the reaction temperature to 80 °C, led to 69% isolated yield of 3b, and reduction in the formation of 5 (Entry 12); however, small amounts of 3b´ were formed. Applying exogenous TMSCl as an additive to the higher temperature conditions both reduced decomposition of 1b and prevented the formation of 3b´ (Entry 13 versus entries 11 and 12).

As a final attempt to decrease the decomposition of 1b, we considered mixed solvent systems. While the polar solvent MeCN gave the greatest yield of protonated 4b, the use of MeCN also led to decreased formation of 5 (Entry 9 vs entries 6–8). Via a detailed screening of MeCN as a co-solvent (see ESI for additional details), we found that adding 10% MeCN gave the best isolated yield of 3b when used in conjunction with TMSCl at 80 °C (Entry 15; optimized Conditions A). Finally, using DCA (2) as a solution in MeCN at 80 °C led to the greatest conversion to trisubstituted olefin 4b (Entry 16; optimized Conditions B). All screening reactions and subsequent studies on the scope of the reaction were performed on a 0.2 mmol scale, though we found that we could increase the scale to 0.5 mmol and 1 mmol, with little effect on the yield, and could decrease the catalyst loading to 5 mol% with only a small decrease in the isolated yield of 3b. However, in consideration of the safety issue of DCA at high temperature, we did not pursue increasing the scale of the reaction further.

The addition of nucleophiles across DCA is well-known to produce trans-dichloroolefins.^{9c, 13d} However, to unambiguously confirm the geometry of the olefin, we treated products 3b and 4b with 2,4-dinitrophenylhydrazine (DNP); the derivatives 3b-DNP and 4b-DNP were crystalline, and we confirmed the anti-geometry by single crystal X-ray diffraction (Fig. 1). The geometry of other adducts 3 and 4 were assigned by analogy.

Figure 1.

Thermal ellipsoid representations, 50 % probability, of the 2,4-dinitrophenylhydrazine adducts of 3b and 4b. Most protons omitted for clarity.

With these optimized conditions in hand, we investigated the scope of this catalytic Nakamura-type reaction under both Conditions A and B (Table 2). We found that the addition of the silyl enol ethers 1 across DCA 2 generally proceeded smoothly, and the tetrasubstituted olefins 3 were isolated in moderate yields.²³ The products bearing electron-rich groups (3c, 3d, 3e) were generally isolated in higher yields than those containing electron-withdrawing groups (3f, 3g, 3h). The α-tetralone derived substrate 3i was isolated in moderate yield, as were alkyl methyl ketone based substrates 3j and 3k. The application of Conditions B were somewhat less general. α-Vinylated acetophenone derivatives with electron-donating groups (4c, 4d, 4e) were isolated in good yields, as was the p-chloro analogue 4f. While the p-bromo compound was observed via crude ¹H NMR spectroscopy, we were unable to isolate 4g due to decomposition during column chromatography. Similarly, tetralone adduct 4i appeared to have formed via ¹H NMR analysis of the crude material, but was unstable and decomposed upon column chromatography. We were unable to confirm formation of either m-trifluoromethyl acetophenone adduct 4h or t-butyl methyl ketone derivative 4j, though adamantyl derivative 4k was isolated in good yield.

Table 2.

Substrate scope for the addition of silyl enol ethers 1c-1k to dichloroacetylene 2 under Conditions A to give tetrasubstituted olefins 3c-3k or trisubstituted olefins 4c-4f, 4k under Conditions B.^a,b

^aUsing 0.2 mmol scale for the reaction.

^bYields of isolated, analytically pure material.

^c0.67 equiv of TMSCl was added.

^dProduct was identified by ¹H NMR analysis of the crude reaction mixture, but decomposed upon column chromatography.

^eProduct not identified by ¹H NMR analysis of the crude reaction mixture.

Interestingly, we observed partial C(sp²)-H silylation when some silyl enol ethers were exposed to the silver catalyst and DCA (Scheme 2). Tetrasubstituted olefins 3l and 3l’ were isolated in 42% and 30% yields, respectively. The thiophene based silyl enol ether 1m led to tetrasubstituted olefins 3m and 3m’, in 50% and 14% isolated yields. The mechanism for the formation of 3l’ and 3m’ is unclear at this point. Typical C-H silylation reactions occur from hydrosilanes,²⁴ and the regioselectivity is surprising, given that carbonyl groups typically direct silylation to occur ortho to themselves.²⁵ While detailed studies to elucidate the mechanism are warranted, it appears that under the standard conditions, an unknown reactive silyl source is being formed in situ, as exposing a ketone to the silver catalyst and chlorotrimethylsilane did not lead to C-H silylation (Scheme 2, equation A, bottom).

Scheme 2.

C(sp²)-H silylation was observed in the reaction of p-fluoroacetophenone (A) and 3-thiophene (B) derived silyl enol ethers with DCA.

Finally, we varied both the substituents on the silyl enol ether and the exogenous silyl source to study their influence on the reaction outcome under Conditions A (Scheme 3). The parent trimethylsilyl enol ether gave the adduct 3b-TMS in 75% yield. The slightly more bulky triethylsilyl 1b-TES yielded the tetrasubstituted olefin 3b-TES in 43% yield. The very bulky tert-butyldimethylsilyl enol ether 1b-TBS was unreactive under the standard conditions, but the dimethylphenylsilyl enol ether 1b-DMPS led to tetrasubstituted olefin 3b-DMPS in 39% yield. Most interestingly, when we exposed trimethylsilyl enol ether 1b-TMS to the silver catalyst, DCA, and chlorotriethylsilane, the TMS group was preferentially incorporated into the olefin over TES, giving more than twice 3b-TMS over 3b-TES (Scheme 3, equation B). This further supports our supposition that the silyl enol ether is a reactive silyl source under these conditions.

Scheme 3.

Varying internal (A) and exogenous (B) [Si] source. (C) Simplified proposed mechanism.

As a simple mechanistic picture, it seems likely that the π bond in DCA is activated by silver triflate,²⁶ followed by attack of the silyl enol ether to form a putative vinylsilver species with an anti-geometry.²⁷ We postulate that in a non-polar solvent, the disassociated silyl group from the silyl enol ether remains closely associated with the organosilver species, and quenches it to yield the tetrasubstituted olefin 3. However, in a polar solvent, the ion pair can separate, and the vinylsilver complex is quenched by adventitious water to give the trisubstituted olefins 4. The observed reactivity is unique to that of DCA, as other alkynes, including methyl propiolate, dimethyl acetylenedicarboxylate, and phenylacetylene remain unreactive under these conditions.

In conclusion, we report here a Nakamura-type reaction between silyl enol ethers and DCA, which can generate either tri- or tetrasubstituted olefins, controlled by a simple switch of the solvent. Both sets of products contain highly functionalizable handles, and are useful building blocks to form more complex olefin compounds. Furthermore, we have discovered interesting silyl transfer processes, for which the mechanisms are a current line of investigation and will be reported in due course.

Highlights:

• Silver catalyzed activation of dichloroacetylene towards addition

• Highly trans selective addition of enol ether across dichloroacetylene

• Silyl versus proton transfer controlled via solvent

• Highly functionalized tri- and tetrasubstituted alkenes selectively obtained

• Unusual C-H silylation observed in select cases