Synthesis of Unique Scaffolds via Diels-Alder Cycloadditions of Tetrasubstituted Cyclohexadienes

Abstract

Diels-Alder cycloadditions of highly substituted cyclohexadienes derived from rhodium-mediated [2+2+2] cyclizations are reported. Reactive heterodienophiles, including singlet oxygen (¹O₂), 4-substituted-1,2,4-triazoline- 3,5-diones (TADs), and aryl- and acylnitroso compounds were employed, yielding novel heterocyclic products.

Reactivity in Diels-Alder (DA) cycloadditions of cyclohexadienes is strongly influenced by steric constraints, often requiring forceful conditions or catalysis to promote the desired annulation.^1,2 Unactivated, highly substituted cyclohexadienes, which can be accessed via transition metal-catalyzed [2+2+2] cyclizations, are relatively unreactive in intermolecular cycloadditions.^2b,3

Previously, we reported the rhodium-mediated intramolecular [2+2+2] cyclizations of tethered diyneenone substrates to produce cyclohexadiene systems which were subsequently aromatized with DDQ, giving highly substituted benzene rings.⁴ Other groups have also reported the use of [2+2+2] cyclizations to generate cyclohexadienes with quaternized allylic centers which cannot aromatize.⁵ We became interested in the reactivity of these highly substituted, electronically unactivated diene systems in DA cycloadditions, particularly with heterodienophiles, as this would allow the creation of unique, densely functionalized scaffolds.

The preparation of three model substrates 4a–c was straightforward employing methodology we previously reported (Scheme 1).⁴ Diynyl esters 1a and 1b, prepared from sequential S_N2 displacements of 1,4-dibromobutyne,^4,6 were subjected to Weinreb amidations, followed by isopropenyl Grignard additions to give enediynes 3a and 3b. The desired [2+2+2] cyclizations were achieved under Rh(I)-catalyzed, microwave-promoted conditions to give racemic cyclohexadienes 4a and 4b in 90% and 91% yields, respectively.⁴ Pyrrolidine substrate 4c was easily prepared from [2+2+2] cyclization of diyne 5⁷ with excess methyl methacrylate 6.^5b

Scheme 1.

Synthesis of Model Cyclohexadiene Substrates.

With the tetrasubstituted cyclohexadienes in hand, we turned to the cycloadditions of highly substituted cyclohexadiene 4a. We began with singlet oxygen (¹O₂), generated in situ via photochemical excitation,⁸ or degradation of the 1:1 ozone:(PhO)₃P adduct.⁹ Successful cycloaddition of 4a with ¹O₂ would produce an endoperoxide, an intriguing class of compounds that display antimalarial and other therapeutic properties.¹⁰

Both methods of ¹O₂ generation produced endoperoxide cycloadduct 7a in modest yield (Table 1).¹¹ The high diastereoselectivity was unexpected considering the small size and limited steric bias of the dienophile.¹² The relative configuration was determined by NOE studies,¹³ with the major stereoisomer resulting from ¹O₂ addition to the face opposite the angular methyl group. Although the ozone-phosphite adduct reaction underwent complete conversion (entry 1), several other products were also formed. These by-products were reduced by lowering the amount of (PhO)₃P used and ensuring all exogenous ozone was purged (entry 3). The photochemical reaction was limited by low conversion of 4a even after extended reaction times (entry 4), though the yield and dr remained comparable to the ozone-phosphite procedure.

Table 1.

Cycloaddition of ¹O₂ with Cyclohexadiene 4a.

entry	conditionsa [equiv (PhO)3P]	yield (%)b	drc
1	A [10]	25	17:1
2	A [5]	21	>20:1
3	A [2]	36	>20:1
4	B	37 (30)d	13:1

^aConditions: A: (PhO)₃P, O₃, DCM, −70 – 0 °C, 1.5 h; B: Rose Bengal (1 mol %), O₂ (1 atm), hν, EtOH, 0 – 10 °C, 7 h.

^bIsolated yields.

^cDetermined by NMR.

^dPercentage of (±)-4a recovered.

The singlet oxygen cycloaddition was then extended to cyclohexadienes 4b and 4c (Table 2, entries 1 and 2), yielding endoperoxides 7b and 7c. The high diastereoselectivity of 7c likely results from the unfavorable electronic repulsion that would exist between the angular ester group and the approaching oxygen dienophile in leading to the other diastereomer. Aromatizable cyclohexadiene 4d⁴ (entry 3) could also be trapped with ¹O₂ at low temperature, yielding diastereomeric endoperoxides 7d and 7e in a 4:3 ratio.¹⁴ The low selectivity was attributed to the equatorial orientation of the ester group in 4d, which reduces competition between addition to the two faces of the diene.

Table 2.

Cycloaddition of Dienes 4b–d with ¹O₂.^a

entry	substrate	product	yield (%)b	drc
1	(±)-4b		40	10:1
2	(±)-4c		48	>20:1
3

^aConditions: (PhO)₃P (2 equiv), O₃, −70 – 0 °C, 1.5 h.

^bIsolated yield.

^cDetermined by NMR.

With these promising results in hand, reactive nitrogen-containing heterodienophiles were screened with cyclohexadiene 4c, which is easily prepared in large quantities. These included 1,2,4-triazoline-1,4-diones (TADs) 9 (Table 3, entries 1 and 2),¹⁵ arylnitroso 10 (entries 3–6),^16,17 and acylnitroso compounds 11 (entries 7–9), which are generated in situ by hydroxamic acid oxidation¹⁸ and have been extensively used by Miller and co-workers to prepare a variety of biologically active compounds.18a–c,e

Table 3.

Dienophile Screening with Cyclohexadiene 4c.

entry	dienophile	conditionsa	product	yield (%)b	isomer ratioc
1	9a R = Me	A	(±)-8a	74	>20:1d
2	9b R = Ph	A	(±)-8b	69	>20:1d
3	10a X1 = H	B	(±)-8c	82	15:1
	X2 = H
4	10b X1 = Br	B	(±)-8d	87	6:1
	X2 = H
5	10c X1 = H	B	(±)-8e	52	3.5:1e
	X2 = Br				(10:1)d
6	10d X1 = Cl	B	(±)-8f	73	5:1
	X2 = H
7		C	(±)-8g	70	8:1
8	11b R = BnO	D	(±)-8h	72	17:1
9	11c R = tBuO	D	(±)-8i	64	10:1

^aConditions: A: 9a–b (1.1 equiv), DCM, 0 °C; B: 10a–d (2.0 equiv), DCM, 0 °C; C: 11a (1.5 equiv), NaIO₄ (1.6 equiv), BnEt₃NCl (1.6 equiv), DCM, 0 °C; D: 11b–c (1.5 equiv), Bu₄NIO₄ (1.5 equiv), DCM, 0 °C.

^bIsolated yield.

^cDetermined by NMR, identity of minor product unknown unless otherwise noted.

^dDiastereomeric ratio.

^eRegioisomeric ratio.

The resulting racemic heterocyclic cycloadducts 8a–i were produced in yields ranging from 64–87% and isomeric ratios of up to >20:1 (Table 3). The diastereoselectivities of the cycloadditions were analogous to those of ¹O₂ additions, in which the major diastereomer resulted from dienophile addition to the face away from the ester group. This was supported by NOE studies¹³ and, for the triazoline dienophiles, confirmed by X-ray crystal structure analysis of PTAD cycloadduct 8b (Figure 1). The p-substituted arylnitroso compounds 10a,b,d and acylnitroso precursors 11a–c exhibited good regioselectivity in favor of the bulkier N-substituted group adding remote to the ester-containing quaternary center.¹⁹ Introduction of an ortho bromine substituent (10c, Table 3, entry 5) reduced both the reactivity and regioselectivity.

Figure 1.

ORTEP Diagram of Cycloadduct (±)-8b.

While acylnitroso adducts 8g–i are stable in solution for several days, arylnitroso adducts 8c,d,f undergo 10–25% cycloreversion to 4c within 24 h in CDCl₃.²⁰ In order to address this instability, reductive cleavage of the N-O bond of 8g with Zn/AcOH²¹ was carried out (Scheme 2, eq 1), producing amidoalcohol 12a in excellent yield. The comparatively electron rich N-O bond of arylnitroso cycloadduct 8c was resistant to these and other reductive conditions, including SmI₂,²² Na/SiO₂,²³ and Pd/C-H₂ (1 atm),²⁴ leading only to recovery of a mixture of cycloadduct and cycloreversion product 4c. By increasing the H₂ pressure to 40 bar using an H-Cube^® hydrogenation reactor, the desired N-O cleavage was achieved for 8c and 8f, yielding stable aminoalcohols 12b and 12c, respectively (Scheme 2, eq 2). Aryl bromide cycloadducts 8d and 8e underwent dehalogenation in addition to N-O bond cleavage under these conditions, yielding only 12b.

Scheme 2.

N-O Bond Cleavage of Nitroso Cycloadducts.

The reactivity of racemic tricyclic cyclohexadienes with select heterodienophiles from Table 3 was also investigated (Scheme 3 and Scheme 4). Substrates 4a and 4b underwent cycloadditions with TADs 9a and 9b (Scheme 3, eq 1), providing four novel heterocyclic cycloadducts, 13a–14b, in good to excellent yields and high diastereoselectivities. Aromatizable cyclohexadienes 4d–g were also successfully trapped with 9a and 9b, yielding cycloadducts 15a–18a and 15b–18b, respectively, also in good yields and diastereoselectivities (Scheme 3, eq 2).

Scheme 3.

Cycloadditions of Cyclohexadienes 4a,b,d–g with TADs 9a and 9b.a

^aSee Supporting Information for complete reaction details and compound characterization.

Scheme 4.

Acylnitroso Cycloadditions of Cyclohexadienes 4a,b,d.a

^aSee Supporting Information for complete reaction details and compound characterization.

Acylnitroso dienophiles also underwent cycloadditions with 4a and 4b (Scheme 4, eqs 1 and 2). Subsequent N-O cleavage of the pyridinyl-containing cycloadducts yielded amidoalcohols 13c and 14c. (Scheme 4, eq 1). Low regio-and diastereoselectivities were observed in the analogous cycloaddition of aromatizable cyclohexadiene 4d with 11a (Scheme 4, eq 3), similar to what was observed for the cycloaddition of 4d with ¹O₂.

Overall, the regio- and diastereoselectivities of all cycloadducts derived from tricyclic cyclohexadienes were consistent with previous observations. For nonaromatizable tricyclic dienes 4a and 4b (Scheme 3, eq 1 and Scheme 4, eqs 1 and 2), major products resulted from approach of the dienophile from the face opposite the angular methyl group with the more sterically demanding N-substituted portion of the unsymmetrical acylnitroso dienophiles adding away from the Me-bearing quaternary center. Aromatizable cyclohexadienes 4d–g (Scheme 3, eq 2) formed TAD cycloadducts in which the dienophile added to the face opposite the ethyl ester.

In conclusion, cycloadditions of highly substituted, unactivated cyclohexadienes were achieved using several classes of heterodienophiles under mild conditions. The substrates are easily prepared by Rh(I)-catalyzed [2+2+2] cyclizations previously reported.⁴ The resulting novel heterocyclic cycloadducts were generally isolated in good yields and high selectivities. Future work is focused on diversification of the cycloadducts. Development of an asymmetric version of the [2+2+2] cyclization as well as studies to better understand the origin of selectivity in these cycloadditions are also being investigated and will be reported in due course.