Distal Allylic/Benzylic C–H Functionalization of Silyl Ethers Using Donor/Acceptor Rhodium(II) Carbenes

Abstract

Regio- and stereoselective distal allylic/benzylic C–H functionalization of allyl and benzyl silyl ethers was achieved using rhodium(II) carbenes derived from N-sulfonyltriazoles and aryldiazoacetates as carbene precursors. The bulky rhodium carbenes led to highly site-selective functionalization of less activated allylic and benzylic C–H bonds even in the presence of electronically preferred C–H bonds located α to oxygen. The dirhodium catalyst Rh₂(S–NTTL)₄ is the most effective chiral catalyst for triazole-derived carbene transformations, whereas Rh₂(S–TPPTTL)₄ works best for carbenes derived from aryldiazoacetates. The reactions afford a variety of δ-functionalized allyl silyl ethers with high diastereo- and enantioselectivity. The utility of the present method was demonstrated by its application to the synthesis of a 3,4-disubstituted L-proline scaffold.

Graphical Abstract

Selective C–H Functionalization: Distal selective allylic/benzylic C–H functionalization of silyl ethers were developed by means of donor/acceptor carbene intermediates. The reactions proceed with high levels of regio- and stereoselectivity. The potential of this methodology was illustrated by accessing a synthetically important heterocyclic scaffold.

C–H Functionalization is a powerful strategic concept for organic synthesis, providing the potential for unconventional retrosynthetic disconnections.^[1] In this area, donor/acceptor carbenes derived from diazo compounds have been shown to be effective reagents for various C–H functionalization reactions, offering complementary approaches to some of the classical asymmetric transformations such as the aldol reaction, Mannich reaction, Michael addition, and the Claisen rearrangement.^[2] The donor group in donor/acceptor carbenes attenuates the reactivity of the carbene, leading to a system capable of site- and stereoselective intermolecular C–H functionalization of various substrates with diverse functional groups.^[3] Despite the significant advances in the chemistry of donor/acceptor carbenes derived from diazo compounds, there is still a need for alternative precursors to broaden the scope of carbene-mediated transformations.

Recently, 4-aryl-N-sulfonyl-1,2,3-triazoles have proven to be latent donor/acceptor diazo surrogates, providing α-imino metallocarbenes of broad utility for the construction of various heterocycles.^[4] Although these reagents are competent alternatives to diazo compounds, their application in sp³ C–H functionalization reactions have been limited to compounds lacking nucleophilic heteroatoms such as alkanes, silanes, alkenes and benzene derivatives.^[5] In contrast to diazo-derived rhodium carbenes,^[6] reactions of triazoles with ethers such as tetrahydrofuran did not result in C–H functionalization α- to oxygen. Instead, the ring-expanded product 2 was generated, presumably via the intermediacy of the oxonium ylide 3, which then underwent a 2,3-sigmatropic rearrangement (Scheme 1a).^[7] One of the few examples of C–H functionalization of N-sulfonyl triazoles with substrates containing oxygen functionality is the intramolecular reactions described by Sarpong (Scheme 1b). The rhodium-catalyzed intramolecular reaction of triazole tethered benzyl ether 4a generated the cis-2,3-disubstituted tetrahydrofuran 5.^[8] The reaction with the higher homologue 4b, however, gave only a trace of the tetrahydropyran derivative 6. Instead, tetrahydrofuan 7 derived from a [1,2]-alkyl shift from the oxonium ylide 8, is preferentially formed. We have proposed that the compatibility of various functional groups during C–H functionalization by diazo-derived donor/acceptor carbenes, is because they interact with various heteroatoms reversibly.^[9] This reversibility does not seem to be as pronounced in the case of the carbenes derived from N-sulfonyltriazoles because the imino group readily engages in further reactions once ylides are formed.^[4]

Scheme 1.

Previous studies on the reactions of ethers with N-sulfonyl triazoles

In order to expand the scope of the C–H functionalization chemistry of triazole-derived carbenes, suitable substrates containing broader functionality needed to be identified that would avoid undesirable ylide chemistry. In this context, we envisioned allyl silyl ethers as suitable substrates due to the fact that the silyl groups would help protect the ether and the doubly activated C–H bond flanked between ether and olefin (proximal C–H) would be highly susceptible to C–H functionalization (Scheme 2).^[10] During the exploratory studies, we carried out a reaction of (E)-allyl silyl ether 9a (2.0 mmol) with phenyl-N-(methanesulfonyl)-1,2,3-triazole 10a (0.5 mmol) in the presence of Rh₂(S–NTTL)₄ (1 mol %) catalyst in chloroform, followed by reduction of the imine with lithium aluminum hydride. We anticipated that the silyl group would sterically protect the oxygen functionality and we would observe C–H functionalization α to oxygen to form 11a, as has previously been observed in the C–H functionalization of allyl silyl ethers with aryldiazoacetates and vinyldiazoacetates.^[10] Unexpectedly, we observed the exclusive C–H functionalization at the distal allylic site to form 12a in 72% yield, 3:1 d.r and 92% ee (Scheme 2). The unexpected transformation was intriguing because it offers a novel approach for the enantioselective synthesis of δ-functionalized allyl alcohols,^[11] and the reaction could be considered as a strategic equivalent to the classical vinylogues Michael addition of enones to nitrostyrenes.^[12] Thus, we decided to explore the scope of C–H functionalization at the distal allylic position of allyl silyl ethers using donor/acceptor carbenes derived from both triazole and diazo-derived rhodium(II)carbenes. The results of the study are described herein.

Scheme 2.

Discovery of distal allylic C–H functionalization of allyl silyl ethers

The optimization studies for the distal C–H functionalization between 9 and 10 are summarized in Table 1. We focused on the phthalimido-related catalysts because they have tended to be the most effective for enantioselective reactions of N-sulfonyltriazoles.^[4] Considerable improvement in overall yield (81%) and enantioselectivity for the major diastereomer of 11a (96% ee) was achieved on addition of 2 equiv of hexafluoroisopropanol (HFIP) as additive (Table 1, entry 2 vs entry 1). A similar enhancement was not observed using nonafluoro tert-butyl alcohol (NFTB) as additive (Table 1, entry 3). The use of 2 equiv of HFIP appeared to be the optimum amount and the reaction failed completely when it was carried out neat in HFIP. A range of other related chiral catalysts^[13] were examined in this reaction (Table 1, entries 4–8). Although several gave reasonable levels of enantioselectivity, none outperformed Rh₂(S–NTTL)₄. We did not observe the proximal allylic C–H functionalization product under any of the conditions reported in Table 1.

Table 1.

Optimization of the allylic C-H functionalization reaction^[a]

entry	Catalyst	Additive	Yield[b]	d.r. [c]	ee[d]
1	Rh2(S-NTTL)4	----	72%	3:1	92/84
2	Rh2(S-NTTL)4	HFIP	81%	3:1	96/85
3	Rh2(S-NTTL)4	NFTB	76%	3:1	95/87
4	Rh2(S-PTAD)4	HFIP	53%	2:1	80/77
5	Rh2(R-PTTL)4[e]	HFIP	64%	1.5:1	−82/−84
6	Rh2(S-NTTLCl)4	HFIP	77%	3:1	93/86
7	Rh2(S-TPPTTL)4	HFIP	<5%	nd	nd
8	Rh2(S-TCPTAD)4	HFIP	14%	1:1	89/92

^[a]Reaction conditions: 9 (2.0 mmol), 10 (0.5 mmol), [Rh] catalyst (1 mol %), 16–18 h reaction time, additive (2 equiv), LiAlH₄ (2 equiv).

^[b]combined isolated yield of 12a and 12a’

^[c]determined by crude NMR

^[d]major/minor diastereomer ee dtermined by chiral HPLC analysis of the isolated products

^[e]observed opposite enantiomers. HFIP= Hexafluoroisopropanol, NFTB = Nonafluoro-tert-butyl alcohol

With the optimized conditions in hand, we explored the substrate scope using a variety of allyl silyl ethers and N-sulfonyl-1,2,3-triazoles (Scheme 3). The first reactions explored the influence of the alkene geometry and the substitutions at the distal positions (Scheme 3a). Similar to the (E)-allyl silyl ether 9a, the reaction with the isopropyl substituted (E)-allyl silyl ether 9b gave cleanly the distal C–H functionalized product, 12b in good yield (78%) and 81% ee. In the case of the methyl substituted (E)-allyl silyl ether 9c, there was a change in the site selectivity and the proximal C–H functionalized product 13c was formed although in relatively low yield (37% yield) and moderate stereoselectvity (5:1 d.r. and 52% ee). The best result was obtained in the reaction with the (Z)-allyl silyl ether 9d, which gave exceptional stereocontrol as 12d was formed with >20:1 d.r. and 98% ee. Normally, cyclopropanation is competitive with C–H functionalization in the reactions of substrates containing cis double bonds with metal-stabilized donor/acceptor carbenes,^[14] but no cyclopropanation product was observed in this case. These exploratory studies illustrate the subtle steric and electronic factors that control the site selectivity of this chemistry. The C–H functionalization is a concerted asynchronous process that builds up positive charge at the carbon undergoing the insertion. Even though the proximal allylic site a to the silyl ether is electronically most preferred, the distal allylic sites are actually functionalized when the distal site is secondary or tertiary, as seen with 12a, 12b and 12d. When the distal site is methyl, it is no longer as electronically favored, and the reaction reverts to allylic functionalization at the proximal site, as seen with 13c.

Scheme 3.

Scope of distal allylic C–H functionalization using triazole-derived rhodium(II)carbenes.

Inspired by the excellent results observed in the formation of 12d, a series of other (Z)-allyl silyl ethers were examined. In order to explore the influence of substitution at the distal position, the reaction was carried out with propyl-substituted cis-allyl silyl ether, affording 12e in 52% yield, 18:1 d.r. and 80% ee. However, substrates containing bulkier distal substituents like iso-butyl substituted cis-allyl silyl ether yielded only trace amount of C–H functionalized-product 12f. The reaction can be extended to other aryl-substituted triazoles as illustrated in the formation of the distal C–H insertion products (12g-12i) with moderate yields and excellent levels of diastereo- and enantioselectivitiy (>20:1 d.r., 93–98% ee). The relative configuration of these compound can be readily assigned on the basis of shielding effects arising from preferred conformers of the products and literature precedents.^{[5b, 5c]} In the case of 12d, both the relative and absolute stereochemistry were unambiguously determined from the X-ray structure of its desilylated derivative. The absolute stereochemistry of the other C–H functionalization products is tentatively assigned by analogy.

Next, in order to investigate the electronic and steric effects of ether functionality, studies were carried out with different ether derivatives. Aryl ethers were compatible as seen in the formation of the distal C–H functionalized product 12j in 48% yield and 96% ee, but the diastereoselectivity was considerably lower (4:1 d.r.). In contrast, when the reaction is carried out with a substrate containing an allyl benzyl ether, the C–H functionalization product 12k was not observed, which indicates that in order to inhibit the ylide formation, the functional group on ether should be either bulky or electronically attenuating the oxygen reactivity. When the reaction was carried out with a less bulky group like trimethyl silyl (TMS) protected allyl ether, a complex reaction mixture with trace amount of C–H functionalized product 12l was observed. The bulky TBDPS group on oxygen is also compatible with this chemistry, forming 12m with excellent stereocontrol. These results support our general hypothesis that ylide formation as well as the regioselectivity are highly influenced by the steric crowding around the oxygen.^[10b]

With the success of distal allylic C–H functionalization using triazole-derived carbenes, we then sought to investigate the similar reactions with diazo-derived carbenes. In the early studies with Rh₂(S-DOSP)₄ as catalyst, the diazo-derived donor/acceptor carbenes inserted into the C–H bond which is between oxygen and benzylic/allylic (proximal C-H) position.^{[10, 15]} Recently, our group developed a new generation of bulky dirhodium tetracarboxylate catalysts capable of functionalizing electronically less preferred C–H bonds over more feasible ones.^{[2a, 13, 16]} Thus, we envisioned that the reaction of allyl silyl ethers with an appropriate dirhodium carbene system derived from diazo compounds may also lead to selective C–H functionalization at the distal position. The results for the series of phthalimido-related catalysts and the early generation catalyst Rh₂(S-DOSP)₄ is summarized in Table 2, using trans-allyl silyl ether 9a and aryldiazoacetate 14a as the model system. The Rh₂(S–NTTL)₄ catalyst, which is the most effective for triazole mediated C–H functionalization, was not as effective in the present case, generating both the distal and the proximal C–H functionalization products 15a and 16a with poor regioselectivity and no diastereoselectivity for 15a (Table 2, entry 1). Other catalysts such as Rh₂(R–DOSP)₄, Rh₂(S–TCPTAD)₄ and Rh₂(R–PTAD)₄ also gave poor regioselectivity and/or stereoselectivities (Table 2 entries 2–4).^[17] Rh₂(S–TPPTTL)₄ (Table 2, entry 6) proved to be the best catalyst to generate 15a in terms of regioselectivity (93:7 r.r.), and diastereoselectivity (9:1 d.r.). The use of HFIP as an additive did not enhance regio- and diastereoselectvity of the reaction in this case (Table 2, entry 7).

Table 2.

Optimization of the allylic C-H functionalization Reaction^[a]

entry	Catalyst	Temp(°C)	Yield[b]	r.r. [c] (15a:16a)	d.r.[c] (15a)
1	Rh2(S-NTTL)4	rt	98%	78:22	1:1
2	Rh2(R-DOSP)4	rt	41%	67:33	3:1
3	Rh2(S-TCPTAD)4	rt	97%	29:71	1:1
4	Rh2(R-PTAD)4	rt	93%	64:36	1:2
5	Rh2(S-TPPTTL)4	rt	99%	92:8	7:1
6	Rh2(S-TPPTTL)4	−20	99%	93:7	9:1
7	Rh2(S-TPPTTL)4 and HFIP additive[d]	−20	99%	92:8	7.3:1

^[a]Reaction conditions: 9a (0.8 mmol), 14a (0.2 mmol), [Rh] catalyst (1 mol %), 3 h reaction time.

^[b]combined ¹H-NMR yield of 15a and 16a.

^[c]determined from crude ¹H-NMR

^[d]using 2.0 equiv of additive.

Having established Rh₂(S–TPPTTL)₄ as the optimum catalyst for the formation of 15a, the study was expanded to other allyl ethers and aryldiazoacetates (Scheme 4). Once again, the structure of the allyl silyl ether had a major influence on the site- and stereoselectivity but the trends were not the same as had been seen with the N-sulfonyltriazoles (Scheme 4a). An isopropyl group at the terminus gave the distal C–H functionalization product 15b in moderate yield (36%) but very high enantiocontrol (98% ee). Poor regio- and diastereocontrol was observed with the methyl substituted (E)-allyl silyl ether 9c and the ethyl substituted (Z)-allyl silyl ether 9d. Thus in the case of the aryldiazoacetate reactions, (E)-allyl silyl ether 9a is the best substrate.

Scheme 4.

Scope of distal allylic C–H functionalization with aryldiazoacetates. ^[a]Yield, d.r. and r.r for 16c and 15d were determined from crude ¹H-NMR

Due to the promising results with (E)-allyl silyl ether 9a, its reactions with a series of aryldiazoacetates were examined (Scheme 4b). Replacing the trichloroethoxycarbonyl (Troc) group with a trifluoroethoxycarbonyl group gave 15e with excellent enantioselectivity (99% ee) but low diastereoselectivity (3.5:1 dr). A range of trichloroethyl aryldiazoactetaes effectively formed the distal C–H functionalization products 15f-j but there were some subtle differences in the overall selectivity. When the C–H functionalization reaction was carried out with meta substituted (F, OMe) aryldiazoacetates, the reaction gave 15h (10:1 d.r, 95% ee), 15i (19:1 d.r, 94% ee) with excellent selectivities. However, the reaction with the 3,5-dibromoaryldiazoacetate gave 15j with poor selectivity (3:1 d.r., 89:11 rr and 55% ee), possibly due to steric hindrance between one of the meta bromine groups of the aryldiazoacetate with the TPPTTL ligands. Certain heterocycles are also compatible with the chemistry as long as the heteroatom is reasonably shielded as illustrated with the formation of the pyridyl derivative 15k.

The absolute and relative configuration of 15k was determined by X-ray crystallographic analysis of its corresponding carboxylic acid.^[17] The absolute and relative configuration of C-H functionalization products 15a-15j are tentatively assigned by analogy to 15k and related reactions in the literature.^{[16, 18]}

Analogous to the C–H functionalization of allyl silyl ethers, we were interested to investigate selectivity for functionalization at distal benzylic C–H bonds^[15] with triazole and diazo-derived carbenes (Scheme 5). The reaction of para-ethyl and isopropyl substituted benzyl ethers 17a and 17b with triazole 10a, using Rh₂(S-NTTL)₄ as catalyst led to C–H functionalization at the distal benzylic position to give 18a (4:1 d.r., >99% ee) and 18b (74% ee) respectively. The reaction with para-methyl substituted benzyl ether 17c gave trace amount of C–H functionalized product 18c. The Rh₂(S-TPPTTL)₄-catalyzed reactions of the aryldiazoactetate 14a with all three substrates resulted in functionalization at the distal benzylic position to form 19a–c but the reaction to form the primary C–H insertion product 19c was less effective (32%, 66% ee) than the other two. These results, once again illustrate how the steric influence can dominate over the electronic preference in the reactions of donor/acceptor carbenes.

Scheme 5.

Scope of distal benzylic C–H functionalization using diazo derived rhodium(II)carbenes

To challenge the site-selectivity of the developed conditions for distal allylic C–H functionalization, we examined the reaction using N-sulfonyl triazole 10a and homo allyl silyl ether 20 which contains two allylic and one α-to oxygen C–H bonds (Scheme 6). Even so, using Rh₂(S-NTTL)₄ conditions, selective transformation could be achieved at distal C–H position to give 21 with 68% yield, >20:1 dr and 95% ee. Similarly, allyl silyl ether 22 which contains two allylic, one benzylic and one β– to silicon C–H bonds gave distal C–H functionalized product 23 in 42% yield, >20:1 dr and 98% ee. Next, we were interested to investigate the compatibility of diazo system with allyl benzyl ether 24 which was not a suitable substrate for the C–H functionalization using triazole derived carbenes. Reaction of allyl benzyl ether 24 with aryldiazoacetate 14a under Rh₂(S-TPPTTL)₄ conditions led to distal C–H functionalization to give 25 with 49% yield, 9:1 d.r and 99% ee. Possibly, the distinctive catalyst pocket within the dirhodium catalyst is likely to be a major factor to influence the selectivity for distal allylic C–H functionalization among other active C–H bonds.^[16]

Scheme 6.

Distal allylic C–H functionalization of potentially challenging substrates

Finally, we demonstrated the synthetic utility of the obtained C–H functionalized products by synthesizing the 3,4-disubstituted L-proline framework which is a basic scaffold found in biologically active compounds such as phenylkainic acid (Scheme 7).^[19] The C–H functionalization of 9d was carried out in 5 mmol scale of triazole 10a (1.12 g) gave 12d in 46% yield and without loss of stereo- and regioselectivity. Deprotection of silyl group on 12d led to allyl alcohol 26. Subjecting alcohol 26 in palladium-catalyzed conditions afforded annulated compound 27 which on further treating under ruthenium catalyzed conditions gave the 3,4-disubstituted L-proline 28.^[20]

Scheme 7.

Applications of C–H functionalized allyl silyl ethers

In conclusion, we have developed a method for distal allylic/benzylic C–H functionalization of silyl ethers using triazole and diazo derived rhodium(II) carbenes. The present study reveals that by using a suitable rhodium carbene system, regioselectivity can be completely switched from the electronically most preferred allylic C–H bond to the less preferred C–H bond during C–H functionalization. The Rh₂(S–NTTL)₄ catalyst is suitable for triazole-derived carbene transfer reaction and the Rh₂(S–TPPTTL)₄ catalyst is ideal for diazo-derived carbenes for distal allylic C–H functionalization to afford excellent selectivities. Furthermore, we have demonstrated the application of the C–H functionalized products for the synthesis of 3,4-disubstituted L-proline scaffold.