Phosphine-Catalyzed [4 + 2] Annulation: Synthesis of Cyclohexenes

Abstract

Phosphine-catalyzed [4 + 2] annulations of α-alkylallenoates with activated olefins allow the efficient syntheses of cyclohexenes. Hexamethylphosphorous triamide (HMPT)-catalyzed [4 + 2] annulations of α-alkylallenoates with arylidenemalononitriles provided highly functionalized 5,5-dicyano-4,6-disubstituted cyclohex-1-enecarboxylates in excellent yields (77–98%) and moderate to high diastereoselectivities (1:2–12:1). Remarkably, the corresponding triarylphosphine-catalyzed [4 + 2] annulations of α-methylallenoate with arylidenemalononitriles manifested a polarity inversion of the 1,4-dipole synthon, providing 4,4-dicyano-5-substituted cyclohex-1-enecarboxylates in excellent yields (80–93%). The polarity inversion of α-alkylallenoates from one 1,4-dipole to another under phosphine catalysis presumably resulted from a change in the balance of the equilibrium between the phosphonium dienolate and the vinylogous phosphonium ylide intermediate.

The construction of suitably functionalized cyclohexene frameworks plays a central role in many natural product synthesis.¹ Although the Diels–Alder reaction is among the most powerful tools for generating such carbocycles,² it is often difficult to form systems that are highly congested or possess substituent arrays that are incompatible with the reaction.³ A number of alternative methods for synthesizing cyclohexenes have arisen from catalytic approaches, such as the phosphine-catalyzed Rauhut–Currier reaction,⁴ transition metal-catalyzed ring-closing metathesis (RCM),⁵ and cycloisomerization reactions.⁶ In contradistinction to the widespread use of these intramolecular processes, intermolecular counterparts for catalytic cyclohexene synthesis are less well developed.⁷

Nucleophilic phosphine catalysis has emerged recently as an efficient means of generating carbo- and heterocycles.⁸ In particular, Lu's [3+2] cycloaddition⁹ to form cyclopentenes from allenoates and alkenes under phosphine catalysis has been applied in the syntheses of several natural products.¹⁰ Nevertheless, phosphine catalysis has not been utilized previously for the formation of cyclohexenes. Building upon our phosphine-catalyzed [4 + 2] annulation for the synthesis of tetrahydropyridines,¹¹ we reasoned that it might be possible to formulate an all-carbon variant of this strategy. Herein, we disclose the facile synthesis of cyclohexenes 3 and 4 via phosphine-catalyzed [4 + 2] annulations between allenoates 1 and activated olefins 2 (eq 1).

(1)

We initiated our investigation by seeking a viable phosphine catalyst for the [4 + 2] annulation of the allenoate 1a and benzylidenemalononitrile 2a to provide the cyclohexene 3a (Table 1). The optimal conditions for tetrahydropyridine synthesis (20 mol% PBu₃, CH₂Cl₂, rt) were ineffective for the formation of the cyclohexene (entry 1).¹² Further examination revealed that hexamethylphosphorous triamide (HMPT) catalyzed the [4 + 2] reaction in benzene under reflux to provide 3a in 98% yield (entry 2). Interestingly, use of the less-nucleophilic¹³ PPh₃ induced preferable formation of the regioisomeric cyclohexene 4a (entry 5). Among the triarylphosphines tested, we found that the more electron deficient the aryl groups, the greater the amount of 4a obtained (entries 3–7). Using tris(p-chlorophenyl)phosphine, we obtained isomer 4a exclusively (entry 7). Therefore, allenoate 1a serves as dipole A under the influence of HMPT and as inverted dipole B under triarylphosphine catalysis (eq 1).

Table 1.

Survey of phosphine catalysts for [4 + 2] annulation of allenoate 1a and alkene 2a^a

entry	phosphine	3a:4ab	% yieldc
1d	PBu3	NA	NR
2	P(NMe2)3	100:0	98
3	P(4-MeOC6H4)3	33:67	96
4	P(4-Me2NC6H4)Ph2	32:68	95
5	PPh3	26:74	93
6	P(4-FC6H4)3	8:92	98
7e	P(4-ClC6H4)3	0:100	93

^aReaction conditions: 1a (1.2–1.4 mmol), 2a (1 mmol), and the phosphine (20 mol%) were heated under reflux in benzene (10 mL) for 14 h.

^bDetermined through NMR spectroscopic analyses.

^cIsolated yields.

^dReference 12.

^eThis transformation required a reaction time of 120 h.

Success at identifying phosphine catalysts for the efficient syntheses of both isomers of the cyclohexenes prompted us to probe the generality of the reaction using other activated olefins (Table 2). In the presence of HMPT, the allenoate 1a reacted with both electron-deficient and -rich arylidenes to provide the cyclohexenes 3a–3c in high yields (Table 2, entries 1–3). With tris(p-fluorophenyl)phosphine, the regioisomeric cyclohexenes 4a–c were obtained with high efficiency (entries 4–6). Notably, these conditions also worked well for activated heteroarylidenes, furnishing the cyclohexenes 4d–f (entries 7–9).

Table 2.

Survey of alkenes for [4 + 2] annulation with allenoate 1a^a

entry	R1	phosphine	product	% yieldb
1	Ph (2a)	P(NMe2)3	3a	98
2	4-MeOC6H4 (2b)	P(NMe2)3	3b	94
3	4-BrC6H4 (2c)	P(NMe2)3	3c	86
4	Ph (2a)	P(4-FC6H4)3	4a	93
5	4-MeOC6H4 (2b)	P(4-FC6H4)3	4b	90
6	4-BrC6H4 (2c)	P(4-FC6H4)3	4c	85
7	2-furyl (2d)	P(4-FC6H4)3	4d	88
8	3-pyridyl (2e)	P(4-FC6H4)3	4e	80
9	N-Me-2-indolyl (2f)	P(4-FC6H4)3	4f c	91

^aReaction conditions: 1a (1.2 mmol), 2 (1 mmol), and the phosphine (20 mol%) were heated under reflux in benzene (10 mL) for 14 h.

^bIsolated yields.

^cConfirmed through single-crystal X-ray analysis.

The intriguing reversal of regioselectivity can be rationalized as indicated in Scheme 1. Under HMPT catalysis, the β-phosphonium dienolate intermediate 5, formed through conjugate addition of the phosphine to the allenoate 1a, adds to 2a at the γ carbon atom to give adduct 6. Zwitterion 6 converts into the allylic phosphonium intermediate 7 through proton transfer.^11a Conjugate addition of the malononitrile anion in 7 and subsequent β-elimination of HMPT provide the cyclohexene 3a. On the other hand, the phosphonium dienolate-to-phosphorous ylide equilibrium (5 ⇆ 8) favors the ylide when a more-electron-withdrawing triarylphosphine is used.¹⁴ The vinylogous ylide 8 adds conjugatively to olefin 2a to give the adduct 9. Consecutive proton transfers provide the deconjugated enoate 10, which allows 6-endo cyclization to generate the cyclic ylide 11. Finally, 1,2-proton transfer and subsequent β-expulsion of the phosphine catalyst furnish the cyclohexene 4a.

Scheme 1.

Mechanistic proposal for the formation of cyclohexenes 3a and 4a with polarity inversion of the 1,4-dipole synthon 1a

The reaction tolerated a wide range of allenylic β′ substituents on the allenoate 1, including aryl, ester, alkyl, and vinyl moieties, to provide the cyclohexenes 3 in excellent isolated yields (Table 3). For these β′-substituted allenoates 1, only 3 was formed, independent of the phosphine employed, presumably because of steric hindrance and the resulting diminished reactivity at the allenylic carbon atom. Good diastereoselectivities resulted when using α-benzylallenoates (entries 1–3), except when the benzyl group incorporated an ortho substituent (entry 4).¹⁵ The reactions of α-alkylallenoates occurred with improved diastereoselectivities upon increasing the size of the allenylic substituent (entries 5–7), although α-isobutylallenoate 1k manifested a unique preference for the trans isomer (entry 8). The diastereoselectivity was highest for the reactions of α-allylallenoates (entries 9 and 10).

Table 3.

Survey of allenoates 1 for [4 + 2] annulations with the alkene 2a^a

entry	R	product	T (°C)	cis:transb	% yieldc
1	Ph (1d)	3dd	45	82:18	93
2	p-BrC6H4 (1e)	3e	45	84:16	96
3	m-MeOC6H4 (1f)	3f	45	78:22	92
4	o-MeC6H4 (1g)	3g	45	64:36	90
5	CO2Et (1h)	3h	rt	66:33	96
6	Me (1i)	3i	88	80:20	95
7	Et (1j)	3j	88	92:8	98
8	i-Pr (1k)	3k	88	34:66	77
9	CH=CH2 (1l)	3l	45	91:9	94
10	CH=CHPh (1m)	3m	45	91:9	93

^aReaction conditions: 1 (1.2–1.4 mmol), 2a (1 mmol), and HMPT (20 mol%) were stirred in benzene (10 mL) for 14 h at the designated temperature.

^bDetermined through NMR spectroscopic analysis and comparison with the spectra of cis-3d, for which a single-crystal X-ray structure was obtained.

^cIsolated yield.

^dConfirmed through single-crystal X-ray crystallographic analysis.

Scheme 2 demonstrates the potential utility of this [4 + 2] annulation for the synthesis of biologically active natural products: rapid entry into the tetracyclic framework 12 of nodulisporic acids¹⁶ via the Houben–Hoesch reaction of 4f.

Scheme 2.

One application of the allene–alkene [4 + 2] annulation^a

^a (a) Conc. HCl/EtOAc (10:1), cat. H₂SO₄. (b) EtOH, cat. H₂SO₄, 85% isolated yield over two steps.

In summary, we have developed novel phosphine-catalyzed [4 + 2] annulation processes that enable regio-differentiating syntheses of cyclohexenes. In these all-carbon [4 + 2] annulations, simply switching the catalyst from HMPT to a triarylphosphine changes the reactivity of the α-alkylallenoate from that of a 1,4-dipole A to an inverted dipole B. These highly efficient and regioselective processes serve as rapid conduits toward the scaffolds of many natural products. Our future efforts will focus on developing asymmetric variants of these reactions and applying them to the construction of other biologically significant natural products.

Supplementary Material

1si20070712_09. Supporting Information Available.

Representative experimental procedures and spectral data for all new compounds (PDF). Crystallographic data for 3d, 4f, and 12 (CIF). This information is available free of charge via the Internet at http://pubs.acs.org.