Direct Construction of Quaternary Carbons from Tertiary Alcohols via Photoredox-Catalyzed Fragmentation of tert-Alkyl N-Phthalimidoyl Oxalates

Abstract

A convenient method for the direct construction of quaternary carbons from tertiary alcohols by visible-light photoredox coupling of tert-alkyl N-phthalimidoyl oxalate intermediates with electron- deficient alkenes is reported.

Forming sterically demanding quaternary carbons by the reaction of nucleophilic carbon radicals with electron-deficient alkenes is attractive for several reasons: the forming bond is unusually long in calculated transition structures (2.2–2.5 Å);¹ the rates of addition of tertiary radicals to electron-deficient alkenes are faster than those of Me, primary and secondary radicals;² and stereoselectivity in the addition of tertiary radicals to prochiral alkenes is typically larger than that of primary or secondary radicals.^2a,3,4, Although these appealing features have been recognized for many years,^2a,5 this method is not mentioned in a recent comprehensive survey of methods to construct quaternary carbons.⁶ The considerable potential such bond constructions hold was suggested in our recent formal total synthesis of (−)- aplyviolene, wherein the stereoselective coupling of a tertiary carbon radical, generated by visible-light photoredox decarboxylative fragmentation of N- (acyloxy)phthalimide 1, to α-chlorocyclopentenone 2 was the central step (eq 1).^7a This result represented the first utilization of such substrates in a C–C bondforming reaction since their initial disclosure by Okada.⁸ We surmise that the reason tertiary carbon radicals have not heretofore played a significant role in assembling quaternary carbons is the lack of convenient methods for generating these intermediates from widely available tertiary alcohols.⁴ Further-more, despite the pronounced advancement of visible- light photoredox-catalyzed transformations in recent years, methods that generate tertiary carbon radicals remain largely unexplored.^7b,9 In this communication, we report such a method.

(1)

The method we developed was inspired by Barton’s pioneering introduction of tert-alkyl N-hydroxypyridine- 2-thionyl oxalates for generating carbon radicals from alcohols.¹⁰ Although Barton oxalate intermediates can be formed from tertiary alcohols, the instability of these intermediates, which prevents their isolation, and their light sensitivity are likely responsible for their limited use in the formation of quaternary carbons.^11–15 Anticipating that related tert-alkyl N-phthalimidoyl oxalates would be more convenient precursors of tertiary carbon radicals, we initially explored conditions to access these compounds.

After examining several potential methods for preparing these mixed oxalate diesters, we found that tertiary alcohols smoothly underwent acylation with chloro N-phthalimidoyl oxalate (4, generated in situ from oxalyl chloride and N-hydroxyphthalimide) at room temperature in the presence of Et₃N and catalytic DMAP to afford tert-alkyl N-phthalimidoyl oxalates in high yields (5→6, Figure 1). In contrast to N- (acyloxy)phthalimides, which are generally quite stable to aqueous workup and silica gel chromatography, oxalates 6 proved to be much more sensitive. However, we found that the byproducts of their synthesis typically could be removed by simple filtration to furnish the desired product in acceptable purity. tert-Alkyl N-phthalimidoyl oxalates 6a–6k are stable to ambient light and can be easily prepared on multigram scale. Confirmation that this sequence did provide the previously unknown alkyl N-phthalimidoyl oxalates was secured by single-crystal X-ray analysis of oxalate diester 6j.

Figure 1. Synthesis of tert-alkyl N-phthalimidoyl oxalates.

^aIsolated yield, ^bPhth = N-phthalimido

With a general route to tert-alkyl N-phthalimidoyl oxalates in hand, we examined the coupling of oxalate 6a with methyl vinyl ketone. Employing conditions similar to those used in our earlier studies with N-(acyloxy)phthalimides⁷ resulted largely in decomposition of the oxalate, furnishing coupled product 7a in only small amounts (Table 1, entry 1). Omission of i-Pr₂NEt provided an improvement in yield (entry 2), reflecting the instability of 6a to the presence of this amine. The use of i-Pr₂NEt•HBF₄ resulted in improved yields of 7a (entries 3–9). Whereas using an excess or equal amount of methyl vinyl ketone relative to 6a proved detrimental (entries 1–5),¹⁶ optimal yields were obtained when oxalate 6a was present in slight excess (entries 6–10). It was also found that a 1:1 THF-CH₂Cl₂ solvent mixture was superior to either CH₂Cl₂ or THF alone (entries 8 and 9). The i- Pr₂NEt•HBF₄ additive was found to be beneficial even under optimized conditions, as its omission led to lower product yields (entry 10). Finally, [Ru(bpy)₃](BF₄)₂ or the commercially available [Ru(bpy)₃](PF₆)₂ performed comparably in the reaction (entries 8 and 9). Under the optimized reaction conditions, the coupling of oxalate 6a with methyl vinyl ketone gave ketone product 7a in 82% yield.

Table 1.

Optimization for the coupling of 6a with methyl vinyl ketone.

Entry	oxalate equiv	MVK equiv	Hantzsch ester equiv	additive equiv	solventa	X	Yield (%)b,c
1	1.0	1.5	1.0	i-Pr2NEt (2.2)	CH2Cl2	BF4	16b
2	1.0	1.5	1.0	none	CH2Cl2	BF4	36b
3	1.0	1.5	1.0	i-Pr2NEt•HBF4 (2.2)	CH2Cl2	BF4	40b
4	1.0	5.0	1.0	i-Pr2NEt•HBF4 (2.2)	CH2Cl2	BF4	22b
5	1.0	1.0	1.0	i-Pr2NEt•HBF4 (2.2)	CH2Cl2	BF4	56b
6	1.5	1.0	1.5	i-Pr2NEt•HBF4 (2.2)	CH2Cl2	BF4	77b
7	1.5	1.0	1.5	i-Pr2NEt•HBF4 (1.0)	CH2Cl2	BF4	82b
8	1.5	1.0	1.5	i-Pr2NEt•HBF4 (1.0)	THF/CH2Cl2a	BF4	92b
9	1.5	1.0	1.5	i-Pr2NEt•HBF4 (1.0)	THF/CH2Cl2a	PF6	92b 82c
10	1.5	1.0	1.5	none	THF/CH2Cl2a	PF6	65c

^a1:1 mixture of THF-CH₂Cl₂; Hantzsch ester = diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.

^bYield determined by ¹H NMR,

^cIsolated yield after silica gel chromatography.

The results of our initial survey of the scope of the coupling of tert-alkyl N-phthalimidoyl oxalates with methyl vinyl ketone are summarized in Table 2. In most cases, yields of the coupled products were excellent, ranging from 68–85% (entries 1–7). Chiral oxalates 6c, 6d and 6e coupled with high diastereoselectivity (>20:1) from the sterically most accessible face (entries 3, 4 and 5). The coupling of the estrone- derived precursor 6e is significant as it demonstrates the construction of vicinal-quaternary carbon centers (entry 5). Two nitrogen-containing heterocyclic substrates were also investigated (entries 7 and 8). Piperidinone-derived 6h furnished coupled product 7h in 82% yield, whereas the coupling of indole-containing oxalate 6i proceeded in diminished yield. As expected from our exploratory studies, carrying out the coupling of 6d and 6e with equal equivalents of the oxalate precursor and me- thyl vinyl ketone gave the coupled products in somewhat diminished yields (4 and 5). The reaction of adamantyl oxalate 6j led to the expected product 7j in low yield, with the major product deriving from coupling of the intermediate alkoxycarbonyl radical with methyl vinyl ketone (entry 9). To no surprise, homoallylic oxalate 6k coupled with methyl vinyl ketone to give butyrolactone 7k (entry 7).^15a,17

Table 2.

Coupling of tert-alkyl N-phthalimidoyl oxalates with methyl vinyl ketone.

Entry	Oxalate	Product	Yield (%)b,c
1	6a	7a	82b
2	6b	7b	85b
3	6c	7c	82b
4	6d	7d	85b 63c
5	6e	7e	68b 43c
6	6f R = TBS 6g R = PMB	7f	81b
		7g	78b
7	6h	7h	82b
8	6i	7i	36b
9	6j	7j	22b
		8j	65b
10	6k	7k	43b

^a1:1 mixture of THF:CH₂Cl₂,

^bIsolated yield after silica gel chromatography (average of two experiments),

^cIsolated yield after silica gel chromatography with 1:1 ratio of oxalate precursor to acceptor,

^dPhth = N-phthalimido

The scope of this new coupling reaction with respect to the conjugate acceptor is summarized in Table 3. Acceptors possessing a terminal double bond generally performed best in the reaction, with acrylonitrile, phenyl vinyl sulfone, and methyl acrylate providing the coupled products in excellent yield (entries 1–3); the yield was somewhat lower with dimethyl acrylamide (entry 4). Dimethyl fumarate also served as an excellent coupling partner producing 9e in 85% yield (entry 5).

Table 3.

Coupling of 6a with various acceptors.

Entry	Acceptor	Product	Yield (%)b
1		9a	92b
2		9b	89b
3		9c	84b
4		9d	64b
5		9e	85b
6		9f	54b
7		9g	52b
8		9h	72b
9		9i	62b

^a1:1 mixture of THF:CH₂Cl₂,

^bIsolated yield after silica gel chromatography (average of two experiments)

Cyclic acceptors could be utilized also, although the yields of coupled products were slightly lower (entries 6–9). Use of a butenolide acceptor (entry 8) furnished the desired product in 72% yield, with addition occurring exclusively from the face opposite the methoxy substiuent.¹⁸ Finally, the activated trisubstituted acceptor 2-carbomethoxycyclopen-2- ene-1-one coupled with tert-alkyl N-phthalimidoyl oxalate 6a to afford trans product 9i in 62% yield (entry 9).

A plausible mechanism for the visible-light photoredox coupling reported herein is outlined in Scheme 1. As proposed by Okada⁸ for the fragmentation of N-(acyloxy)phthalimides, single-electron transfer from Ru(bpy)₃⁺ to the tert-alkyl N-phthalimidoyl oxalate, followed by homolytic cleavage of the N–O bond and subsequent decarboxylation generates alkoxycarbonyl radical 12. A second slower decarboxylation leads to the formation of tertiary radical 13,^10,19 which after addition to an electron- deficient alkene provides α-acyl radical 14. Hydrogen atom abstraction from Hantzsch ester radical cation 10b would furnish the final product (14→7). An alternative pathway (not shown), involving reduction of α-acyl radical 14 to the corresponding enolate and subsequent protonation, could also lead to the formation of 7. While the presence of Hantzsch ester 10a is necessary to realize catalytic turnover, the role of the ammonium additive is not fully understood at this time. However, it could potentially serve to protonate intermediate radical anion 11 and also act as a source of BF₄⁻ to undergo anion exchange with [Ru(bpy)₃](PF₆)₂ leading to the formation of the more soluble [Ru(bpy)₃](BF₄)₂ complex.

Scheme 1.

In conclusion, we have developed a convenient method for the direct construction of quaternary carbons from tertiary alcohols by visible-light photoredox coupling of tert-alkyl N-phthalimidoyl oxalate intermediates with electron-deficient alkenes. In three examples, in which the intermediate tertiary carbon radical is chiral and sterically biased, diastereoselection in forming the new quaternary carbon stereocenter was excellent. Additional synthetic applications of tert-alkyl N-phthalimidoyl oxalates, as well as mechanistic studies of their reactivity in photoredox-mediated processes, are currently under investigation and will be reported in due course.