Trimethylsilyl-Protected Alkynes as Selective Cross Coupling Partners in Ti-Catalyzed [2+2+1] Pyrrole Synthesis

Abstract

Trimethylsilyl (TMS)-protected alkynes serve as selective alkyne cross coupling partners in Ti-catalyzed [2+2+1] pyrrole synthesis. Reactions of TMS-protected alkynes with internal alkynes and azobenzene catalyzed by Ti imido catalysts yield pentasubstituted 2-TMS-pyrroles with greater than 90% selectivity over the other 9 possible pyrrole products. The steric and electronic effects of the TMS group have both been identified to play key roles in this highly selective pyrrole synthesis. This strategy provides a convenient methodology to synthesize multisubstituted pyrroles as well as an entrypoint into further pyrrole diversification through facile modification of the resulting 2-silylpyrrole products, as demonstrated through a short formal synthesis of the marine natural product Lamellarin R.

E Pluribus Unum

Trialkylsilyl-protected alkynes enable highly chemo- and regioselective reactions in Ti-catalyzed [2+2+1] multicomponent pyrrole synthesis. The resulting pentasubstituted 2-SiR₃ pyrroles are formed with up to 99% selectivity over the other 9 possible pyrrole products.

Pyrroles are molecules of interest in a variety of fields, including pharmaceuticals,^[1] natural products,^[2] dyes^[3] and materials.^[4] Even though there are many well-developed methods for the synthesis of pyrroles, the efficient synthesis of multisubstituted pyrroles is still challenging. For example the Paal-Knorr condensation of primary amines with 1,4-diketones and related cyclization reactions require extensive preconstruction of the carbon backbone and often have limited substitution patterns.^{[1, 5]} Multicomponent reactions that can circumvent complex precursor synthesis typically require very specific functional groups or substitution patterns.^[6] For example, many formal [3+2], [2+2+1], and related multicomponent cycloadditions necessitate electron-withdrawing substituents on the pyrrole,^[6–7] or are limited to the synthesis of mono-, di-, or trisubstituted pyrrole products.^{[6a, 8]}

Recently, we demonstrated an atom economical method to synthesize pentasubstituted pyrroles from simple alkynes and azobenzene via a Ti-catalyzed formal [2+2+1] reaction (Figure 1, top).^[9] However, our initial report was limited to the homocoupling of alkynes, and unsymmetric alkynes yielded poor, substrate-controlled regioselectivity. Regioselectivity in other intermolecular [2+2+1] reactions such as the Pauson-Khand reaction is often difficult to achieve in the absence of clear stereoelectronic differentiation of alkyne substituents, and remains a siginficant synthetic challenge.^[10] In an effort to design more useful and practical pyrrole syntheses, we have explored several routes to the chemo- and regioselective heterocoupling of alkynes in the [2+2+1] reaction to yield highly substituted pyrroles. Herein, we report that silyl-protected alkynes serve as excellent heterocoupling partners, yielding pentasubstituted N-aryl pyrroles in high chemo- and regioselectivity (Figure 1, bottom). This reaction provides a versatile and simple platform for the construction of highly substituted pyrroles, as well as an entrypoint into further pyrrole diversification through facile modification of the resulting 2-silylpyrrole products.

Figure 1.

General equations of Ti-catalyzed pyrrole formation.

In the course of our studies, we have found that TMS-phenylacetylene (1a) is incapable of productive [2+2+1] reactivity. Attempted hydroamination of 1a with [(py₂TiCl₂NPh]₂ and PhNH₂, which should proceed through [2+2] cycloaddition of the alkyne to the Ti=NPh imido, resulted in no product formation indicating that 1a is incapable of facile [2+2] addition with simple Ti imido halides (Figure 2, top). Thus, we hypothesized that they may be suitable cross-coupling partners with other alkynes that are capable of [2+2] cycloaddition. To test this hypothesis, we ran the reaction of 1a with 1-phenyl-1-propyne (2a), and found that it gave remarkably chemo- and regioselective cross coupling of the two alkyne partners (Figure 2, bottom). This model reaction was optimized to achieve the highest yield of the crossover pyrrole and its overall selectivity among all homocoupled and crossover products (Table S1). Selectivies are fairly good with a 1:1 ratio of 1a:2a, but we chose to use 2 equivalents of 1a in order to simplify byproduct separation.

Figure 2.

Failed [2+2] cycloaddition of 1a (top) led to the exploration of its use as a partner in selective heterocoupling reactions (bottom).

Under the optimized reaction conditions, the substrate scope was investigated. First, a suite of TMS-protected aryl alkynes was reacted with 2a (Table 1). All pyrroles were isolated after hydrolysis of the TMS group, giving 3aa-3ra as the major regioisomer in almost all cases. Most aryl TMS acetylenes give exceptionally high yields and selectivies, typically above 90%. There is no electronic effect on yield or selectivity (3aa-3fa, 3ja-3la), while sterically encumbered substrates such as 1i are more difficult to insert, leading to more homocoupling of 2a and slightly lowered yield/selectivity of the desired 3ia. The reaction shows reasonably broad functional group tolerance, including aryl halides (3ca, 3da) and some Lewis basic groups (3ea-3ga; 3la, 3ma′), although aryl nitriles and carbonyl derivatives arrest catalysis (See SI).

Table 1.

Scope of coupling partners with 1-phenyl-1-propyne (2a)^a

^a0.5 mmol (1.1 eq) 1-phenyl-1-propyne (2a), 1.0 mmol 1 (2.2 eq.), 0.225 mmol PhNNPh (0.5 eq.) and 0.025 mmol [py₂Cl₂TiNPh]₂ (0.05 eq.)) in 2.5 mL CF₃Ph heated for 3 hours. Reactions were quenched with 2M HCl in MeOH to remove the silyl group.

^bIsolated yield of 3 based on PhNNPh.

^cSelectivity against all possible pyrroles;

^d1.5 h.

^e1 equiv. of 1.

^f4 h.

^g24 h.

^h5 h.

In addition to aryl alkynes, TMS-protected alkyl alkynes (3na-3pa) all perform well in highly cross selective pyrrole formation (3na-3op), although sterically encumbered tert-butyl groups (3qa) do not participate in catalysis and yield only homocoupled 2a. Notably, conjugated enynes (3pa) are tolerated in catalysis, providing an additional functional handle on the resulting pyrrole. TMS₂C₂ (1r) is also a competent cross coupling partner, yielding 3aa on workup.

Other silyl groups are also competent for heterocoupling. Silyloxy groups (1t) effectively yield cross product 3oa. The slightly larger TBDMS-protected alkyne 1u also couples effectively to form 3aa upon workup, but the very bulky TIPS-protected alkyne 1v fails to engage in cross coupling. The TBDMS group provides a more stable silylpyrrole than the TMS group, while the Si(OMe)₃ group provides additional synthetic versatility^[11] in Hiyama-type couplings.^[12]

The origins of regio- and chemoselectivity in these heterocoupling reactions are derived mainly from electronic factors of both alkyne partners (Figure 3). Regioselectivity in [2+2] cycloaddition of phenylpropyne derivatives with Ti=NPh is driven primarily by the electronics of the metallacyclic transition state (Figure 3, TS1) where the δ⁺ is better stabilized by CH₃. This electronically-driven regioselectivity is also seen in py₃TiCl₂(NPh)-catalyzed hydroamination, where N,1-diphenylpropan-2-imine is the sole product resulting from metallacycle INT1.^[13]

Figure 3.

General mechanism and proposed origins of selectivity in cross-selective [2+2+1] pyrrole synthesis.

Chemoselectivity of alkyne insertion into the Ti-C bond of the azametallacyclobutadiene intermediate INT1 is driven by alkyne coordination to Ti. Electron-rich alkynes are better ligands to Ti^IV Lewis acids, and as such the electron-rich TMS-alkynes effectively outcompete other alkynes in binding and subsequently inserting into the metallacycle via TS2 (Figure 3). This can be observed in reactions of the series of para-substituted phenylpropynes (Table 2, 3ab-3ae) where alkynes with more electron-donating groups competed more effectively with TMSCCR, resulting in more homocoupled arylpropyne products and thus overall lower selectivity. Further evidence for alkyne electronics/binding driving 2^nd insertion selectivity can be seen in the competition experiment where the more electron rich p-substituted TMS aryl alkyne 1f outcompetes the electron deficient alkyne 1b by 2:1 (Figure 4). Regioselectivity of TMS-alkyne insertion is likely driven by the α-silyl effect, where the α-SiMe₃ moiety stabilizes δ⁻ buildup during insertion (Figure 3, TS2), favoring the metallacycle that places SiMe₃ on the α-C. Similar effects have been observed in the hydroboration of silyl alkynes^[14] and the reactivity of group 4 metal alkyne complexes.^[15]

Table 2.

Scope of coupling partners with 1a and 1o.^a

^a0.5 mmol (1.1 eq) 2, 1.0 mmol 1a or 1n (2.2 eq.), 0.225 mmol PhNNPh (0.5 eq.) and 0.025 mmol [py₂Cl₂TiNPh]₂ (0.05 eq.)) in 2.5 mL CF₃Ph heated for 1.5 or 3 hours.

^bIsolated yield of 3 based on PhNNPh. GC yields in parenthesis.

^cSelectivity against all possible pyrroles.

^d48 h.

^e24 h.

^f6 h.

^g(THF)₃I₂TiNPh (10 mol %) used as catalyst.

^h4 h.

Figure 4.

Competition between electronically differentiated TMS-protected alkynes favors reaction of electron rich alkynes.

Directing group effects are observable in reactions with (2-methoxy)phenyl-TMS-acetylene (1g) and pyridin-2-yl-TMS-acetylene (1m). 1g gives significant amounts of the 3ga′ regioisomer, and for 1m, 3ma′ is almost exclusively formed, likely because coordination of the TMS alkyne to Ti via the OMe or 2-pyridyl groups would enforce the opposite insertion of the TMS-alkyne into the azametallacyclobutene [2+2] intermediate. (Figure 5). Interestingly, the thiophenyl derivative 1l does not show a directing effect, presumably due to the hard/soft Ti/S mismatch making thiophenes weaker donors to Ti.

Figure 5.

Lewis basic groups change the selectivity of 2^nd alkyne insertion through directing effects.

Next, different [2+2] alkyne partners were tested with 1a and 1o (Table 2). Unlike modifications to the TMS-protected alkynes, electronic and steric modification of the [2+2] alkyne partner alters the reaction selectivity. For example, electron-donating phenylpropyne derivatives (3ad, 3od, 3ae, 3oe). decrease the yield and chemoselectivity of second insertion, resulting from an increase in the formation of homocoupled arylpropyne pyrroles. This highlights the importance of alkyne precoordination during the alkyne 1,2 insertion step, where now the electron-donating arylpropyne can more effectively compete with the electron-rich TMS-protected alkynes. Consistent with this, reaction of 2-methoxyphenyl propyne (2f), which can precoordinate to Ti through the ether moiety, leads predominantly to homocoupling of 2f instead of heterocoupled 3af. Ortho-steric hindrance on aryl propynes (3ag-3ai, 3og-3oi) significantly lessens conversion and regioselectivity of [2+2] cycloaddition. Prolonged reaction time does not increase conversion, indicating catalyst death in these cases.

Differing aromatic substituents (3ai, 3oi, 3ak, 3ok) are also tolerated, although now pyridine substitution (3al and 3ol) completely inhibits catalysis through coordination to Ti. Longer alkyl substituents (3am, 3om) also work well, but bulkier isopropyl substituents (3an, 3on) do not undergo facile [2+2] cycloaddition. Reactions of unactivated dialkyl/diaryl internal alkynes (3ao-3ar, 3oo-3or) require the more Lewis acidic (THF)₃I₂TiNPh. However, alkynes with little electronic differentiation, like 4-methyl-2-pentyne (3ar, 3or), yield products of unselective [2+2] cycloaddition, and bulky internal alkynes (3as, 3os) are unreactive.

The advantage of the silyl directing group is its ability to be functionalized after reaction. Although poor partners for cross coupling reactions, 2-TMS pyrroles can undergo facile electrophilic aromatic substitution. For example, NBS substitution of the TMS group yields bromopyrroles in high yield, which provides a versatile handle for further pyrrole functionalization (Figure 6, top).

Figure 6.

Further elaboration of TMS pyrroles. Top: bromination of 2-TMS-pyrroles. Bottom: formal synthesis of lamellarin R.

Furthermore, this alkyne heterocoupling strategy can provide facile access to the pyrrole core of lamellarins, a class of marine natural products. We have completed a short formal synthesis of lamellarin R. In situ benzylic oxidation of 6wd with 2-iodoxybenzoic acid (IBX) (6wd was generated from the [2+2+1] coupling of 1w, 2d and 4,4′-azodianisole) yields 7wd, which can then be deprotected by tetrabutylammonium fluoride and water to the aldehyde 8wd, intersecting a previous synthesis reported by Jia^[16] (Figure 6, bottom).

In summary, we have found that the we can exploit the electronic properties of silyl-substituted alkynes to perform highly chemo- and regioselective [2+2+1] heterocouplings to form pyrroles. The products, 2-silyl-pyrroles, can be further functionalized and provide access to a large range of tetra- and pentasubstituted pyrroles, yielding diverse N-arylated pyrroles that map onto several natural product cores. Going forward, we plan on exploiting this and related types of electronic control to further advance chemo- regioselective Ti-catalyzed oxidative amination reactions beyond pyrrole synthesis.