Metal-Catalyzed [1,2]-Alkyl Shift in Allenyl Ketones: Synthesis of Multisubstituted Furans

Cycloisomerization of allenyl ketones is an efficient approach for the assembly of the furan ring, an important heterocyclic unit.^[1] This transformation in the presence of transition-metal catalysts was first reported by Marshall et al.^[2] and later by Hashmi et al.^[3] for the synthesis of furans [G = H, Eq. (1)]. Recently, we have developed a set of transition-metal-catalyzed cascade transformations of allenyl ketones involving 1,2-migration of various groups (G = SR,^[4] Hal,^[5] OP(O)(OR)₂, OC(O)R, OSO₂R^[6]) to produce up to tetrasubstituted furans [Eq. (1)]. Herein, we wish to report a novel metal-catalyzed [1,2]-alkyl shift in allenyl ketones as a key step in the formation of up to fully carbon-substituted furans [Eq. (1)].

(1)

Recently, we reported the Au-catalyzed regiodivergent synthesis of halofurans.^[5] It was found that in the presence of Au^I catalysts clean hydrogen migration from 1 occurs to form 2 [Eq. (2)]. The absence of H/D-scrambling, in contrast to that observed in the Cu/base-assisted synthesis of pyrroles,^[7] supported the clean [1,2]-hydrogen shift to the carbenoid center in intermediate i.^[5]

(2)

It occurred to us that 1,2-migration of an alkyl/aryl group by this mechanism is also feasible,^[8–11] which may allow for the assembly of fully carbon-substituted furans. To this end, we have tested the possible cycloisomerization of allene 3 to give furan 4 in the presence of different catalysts (Table 1). We have found that employment of Au^I and Au^III halides gave low yields of furan 4 (Table 1, entries 1 and 2). Gratifyingly, switching to cationic Au^I complexes led to formation of 4k in nearly quantitative yield (Table 1, entries 3 and 4). In analogy to gold halides, Pt^II, Pt^IV, and Pd^II salts were inefficient in this reaction (Table 1, entries 5–7). Use of Cu^I halides resulted in no reaction (Table 1, entry 8), while employment of cationic Ag^I, Cu^I, and Cu^II salts produced 4 in moderate to high yields (Table 1, entries 9–13). Encouraged by these results, we also tested main-group metals in this reaction. Surprisingly, Al, Si, Sn, and In triflates provided moderate to excellent yields of desired furan 4 (Table 1, entries 14, 16–19). Although [Au(PPh₃)]OTf, AgOTf, In(OTf)₃, Sn(OTf)₂, and TIPSOTf were nearly equally efficient in the cascade cycloisomerization of 3 to give 4, In(OTf)₃ appeared to be a more general catalyst with respect to the substrate scope.^[12]

Table 1.

Optimization of reaction conditions.^a

Entry	Catalystb	mol%	Solvent	T [°C]	Yield [%]c
1	AuBr3	5	toluened	100	23
2	AuI	5	toluened	100	traces
3	[Au(PPh3)]OTf	1	toluened	100	100 (89)
4	[Au(PPh3)]OTf	5	CH2Cl2e	RT	99
5	PtCl2	5	toluenef	100	21
6	PtCl4	5	toluenef	100	21
7	[PdCl2(PhCN)2]	5	toluenef	100	35
8	CuX (X = Cl, Br, I)	5	toluenef	100	0
9	CuOTf·PhH	5	toluenef	100	42
10	Cu(OTf)2	5	tolueneg	100	95
11	AgPF6	5	tolueneg	100	47
12	AgOTf	5	tolueneg	100	(80)
13	AgOTf	20	CH2Cl2e	RT	70 (62)
14	Al(OTf)3	5	tolueneg	100	64
15	Zn(OTf)2	5	tolueneg	100	39
16	TMSOTf	20	CH2Cl2e	RT	82 (62)
17	In(OTf)3	5	tolueneg	100	91 (81)
18	Sn(OTf)2	5	tolueneg	100	97 (81)
19	TIPSOTf	5	tolueneg	100	100 (81)
20	TMSNTf2	5	tolueneg	100	72

^aEntries 1–4: Ar = p-Br-C₆H₄; entries 5–20: Ar = Ph.

^bTf = trifluoromethanesulfonyl, TIPS = triisopropylsilyl, TMS = trimethylsilyl.

^cYield determined from NMR spectrum; yield of isolated product in parentheses.

^d0.05 M, solution of 3.

^e0.02 M solution of 3.

^f1 M solution of 3.

^g0.1 M solution of 3.

Next, cycloisomerization of differently substituted allenyl ketones 3a–m was examined under the optimized conditions (Table 2). Thus, cycloisomerization of 4,4-diphenyl-substituted allenyl ketones 3b–d proceeded smoothly to provide good to high yields of furans 4b–d (Table 2, entries 2–4). Selective migration of the phenyl over the methyl group occurred in allenyl ketone 3e to give 4e in 72% yield (Table 2, entry 5). Not surprisingly, cycloisomerization of allenyl ketone 3i, possessing two methyl groups, provided the corresponding furan 4i in low yield only (Table 2, entry 8). In contrast to the disfavored methyl-group migration in Table 2, entry 5, migration of the ethyl group competed with the phenyl group in 3f, which resulted in formation of a 2.3:1 mixture of regioisomeric furans 4f and 4g, respectively (Table 2, entry 6). Cyclopentylidene allenyl ketone 3h underwent smooth cyclization with ring expansion^[13] to give fused furan 4h in 75% yield (Table 2, entry 7). It was also demonstrated that a variety of functional groups such as methoxy (Table 2, entry 9), bromo (Table 2, entry 10), nitro (Table 2, entry 11), and cyano (Table 2, entry 12) were perfectly tolerated under these reaction conditions.

Table 2.

Lewis acid catalyzed synthesis of furans.

Entry	Allenyl ketone		Furan		Yield [%]a
1		3a		4a	81b
2		3b		4b	64c
3		3c		4c	90
4		3d		4d	79d
5		3e		4e	72 (52)e,f
6		3f		4f	88g
				4g	(76)h,f,i
7		3h		4h	75
8		3i		4i	10f
9		3j		4j	62
10		3k		4k	93 (89)h
11		3l		4l	85b
12		3m		4m	94b

^aYield of isolated product; 0.25–0.8-mmol scale, In(OTf)₃ was used unless otherwise mentioned.

^b5 mol% Sn(OTf)₂ was used.

^c10 mol% In(OTf)₃ was used.

^d20 mol% AgOTf/p-xylene, 140°C, 1 h.

^e2 mol% [Au(PPh₃)]OTf was used.

^fYield determined from NMR spectrum.

^g2.3:1 mixture of 4 f:4g by ¹H NMR spectroscopy.

^h1 mol% [Au(PPh₃)]OTf was used.

ⁱ2.2:1 mixture of 4 f:4g by ¹H NMR spectroscopy.

In addition, we have shown that trisubstituted furan 4b can be obtained directly from alkynyl ketone 5b [Eq. (3)]. However, the yield for this one-pot transformation was somewhat lower than that for cycloisomerization of allene 3b (Table 2, entry 2).

(3)

We propose the following mechanism for the cascade transformation of allenyl ketone 3 into furan 4 (Scheme 1). Cycloisomerization in the presence of oxophilic Lewis acids, such as In, Sn, and Si triflates, follows path A, according to which, the Lewis acid activates the enone moiety (see 6) to form vinyl cation 7.^[14] [1,2]-Alkyl shift in 7 produces the regioisomeric vinyl cation 8,^[15] which, upon cyclization, transforms into furan 4 and regenerates the Lewis acid catalyst. Alternatively, π-philic catalysts, such as Ag^I, Cu^I, and Au^I salts, activate the carbon–carbon double bond of allene (see 9) and trigger nucleophilic attack of a carbonyl oxygen lone pair at the terminal carbon of the allene moiety to form cyclic oxonium intermediate 10.^[2c,5] [1,5]-Alkyl shift^[16] (Scheme 1, path B) to form 11 with subsequent elimination of metal gives 4. The involvement of an electrophilic mechanism (Scheme 1, paths A and B) is supported by the data presented in Table 2. Thus, the migratory aptitude of a phenyl vs. that of a methyl group (> 100:1) is in good agreement with that reported in the literature for rearrangements of cations.^[17] Although a mechanism involving [1,2]-alkyl shift in the carbenoid intermediate 12^[5,8] (Scheme 1, path C) cannot be completely ruled out at this point, it is considered to be less likely.^[18,19]

Scheme 1.

Proposed mechanisms for the synthesis of furans 4.

In summary, we have developed a novel metal-catalyzed method for the synthesis of furans, which proceeds by an unprecedented [1,2]-alkyl shift in allenyl ketones. This method allows for efficient synthesis of up to fully carbon-substituted and fused furans.