Rh₂(II)-Catalyzed Nitro-group Migration Reactions: Selective Synthesis of 3-Nitroindoles from β-Nitro Styryl Azides

Abstract

Rhodium carboxylate complexes (1 mol %) catalyze the migration of electron withdrawing groups to selectively produce 3-substituted indoles from β-substituted styryl azides. The relative order of migratorial aptitude for this transformation is ester ≪ amide < H < sulfonyl < benzoyl ≪ nitro.

Reactions that involve a selective migration event can convert simple, readily accessible starting materials into complex functionalized products. While selective 1,2-shifts of alkyl-, aryl-, or other electron-releasing groups are well established in organic synthesis,¹ the migration of strong electron-withdrawing groups are underdeveloped² and have the potential to be powerful synthetic tools for constructing important biologically active small molecules.^3–5 While nitro group migrations have been observed in isolated cases,⁶ these transformations have not been harnessed for the regioselective synthesis of nitro-substituted N-heterocycles. Styryl azides are established as useful indole precursors,⁷ and our group has previously reported that Rh₂(II) octanoate catalyzes a phenyl group migration to transform β,β-diphenylstyryl azide into 2,3-diphenylindole.^2b When the styryl azide contains a β-hydrogen, a C–H amination reaction occurs: thermolysis of β-nitro-substituted 1 was reported by Gribble and co-workers to produce 2-nitroindole 2 as the major product (eq 1).⁸ Herein, we report that Rh₂(II) carboxylates promote a fundamental change in the reactivity of 1 to form 3-nitroindole as the exclusive product thereby providing a new synthetic method for N-heterocycle formation.

(1)

A variety of transition metal complexes were examined to catalyze the formation of nitroindole from stryryl azide 1, which was synthesized in three steps from 2-nitrobenzaldehyde (Table 1).⁹ To our surprise, exposure of azide 1 to Rh₂(II)-carboxylates (5 mol %) formed 3-nitroindole as the only product.¹⁰ Minimal optimization was required to identify the optimal conditions for this transformation: 1 mol % of Rh₂(esp)₂ ¹¹ in toluene cleanly converted 1 to 3 in >95% isolated yield with no observable 2-nitroindole byproduct. Other Rh₂(II)-carboxylates were found to be nearly as efficient (cf. entries 3 and 4),¹² except for Rh₂OAc₄, which was unreactive. In addition to these complexes, examination of a series of known N-atom transfer catalysts identified only RuCl₃•hydrate¹³ to be competent, although less efficient than Rh₂(esp)₂ (entry 5). Other transition metal complexes, including CoTPP and [Ir(cod)OMe]₂ (entries 6 and 7)¹⁴ afforded <10% of 2 and 3, whereas Cu- or Fe salts failed to react with the styryl azide.^15,16

Table 1.

Optimization of Reaction Conditions.

entry	Catalyst	conv., %a	yield, %a	2:3
1	none	0	0	n.a.
2	Rh2(esp)2a	99	95	0:100
3	Rh2(O2CC7H15)4	95	89	0:100
4	Rh2(O2CC3F7)4	97	90	1:99
5c	RuCl3•nOH2	89	67	1:99
6	CoTPP	17	7	43:57
7	[Ir(cod)OMe]2	29	trace	100:0

^aAs determined using ¹H NMR spectroscopy.

^besp = α,α,α',α'-tetramethyl-1,3-benzenedipropionate.

^cReaction performed without the addition of MS in 1,2-dimethoxyethane.

Using our optimized conditions, the scope of the rhodium(II)-catalyzed formation of nitroindoles from β-nitro-substituted styryl azides 4 was examined (Table 2). A series of 3-nitroindoles were produced selectively from substrates bearing a range of R¹-, R²-, or R³ substituents (entries 1 – 9). The catalyst loading could be reduced when the reaction scale was increased: 2 mmol of styryl azide 4c required only 0.1 mol % of Rh₂(esp)₂ to be converted to indole 5c. Only when an R⁴-substituent was introduced to azide 4 did 2-nitroindole formation become a competitive process (entries 10 – 14). While a mixture of indoles 5 and 6 were obtained for aryl-, methyl- and methoxy R⁴-groups, exposure of azide 4n bearing a strong ortho-electron-withdrawing group (R⁴ = CF₃) to reaction conditions afforded only 2-nitroindole 6n.

Table 2.

Scope of Rh(II)-Catalyzed NO₂ Migratorial Reactions.

entry	4	R1	R2	R3	R4	yield, %a	5:6b
1	a	H	H	OMe	H	91	>95:5
2	b	H	H	Cl	H	79	>95:5
3c	c	H	H	CF3	H	96	>95:5
4	d	H	H	CO2Me	H	>95	>95:5
5	e	H	Br	H	H	87	>95:5
6	f	H	Cl	H	H	90	>95:5
7	g	H	CO2Me	H	H	>95	>95:5
8	h	H	OCH2O		H	93	>95:5
9	i	Cl	H	H	H	>95	>95:5
10	j	H	H	CH=CHCH=CH		94	49:51
11	k	H	H	H	OMe	>95	26:74
12	l	H	H	H	Me	97	30:70
13	m	Br	H	H	Br	71	8:92
14	n	H	H	H	CF3	99	>5:95

^aIsolated yield after SiO₂ chromatography.

^bAs determined using ¹H NMR spectroscopy.

^c2 mmol scale using 0.1 mol% Rh₂(esp)₂.

Styryl azides bearing electron-withdrawing groups at the β-position were investigated to determine if NO₂-migration was a general phenomenon (Table 3). Aryl- and alkyl ketones migrated to provide only 3-substituted indoles (entries 1 – 3). In contrast, a mixture of indoles 8d and 9d was obtained from Weinreb amide 7d, and only the 2-carboxylate indole 9e was observed when isopropyl ester 7e was subjected to reaction conditions. These results show that migrations of amides and esters are less facile than ketones or nitro groups and suggest that stronger electron-withdrawing groups are more prone to migrate.¹⁷ Accordingly, sulfones were anticipated to migrate, and styryl azides 7f – 7h were converted to a 9:1 ratio in favor of 3-sulfonylindole 8 irrespective of the electronic environment of the sulfonyl group. In ortho-methoxy-substituted azide 7i, the migration of the sulfonyl group was inhibited affording only 2-sulfonylindole 9i. Together with 4j – 4n, these results suggest that migration can be suppressed with an additional ortho-substituent.

Table 3.

Scope of Migrating Group in Rh(II)-Catalyzed Migrations.

entry	7	Styryl azide	Major indole	yield, %a	8:9
1	a			93	>95:5
2	b			66	>95:5
3	c			65	>95:5
4	d			94	23:77
5	e			>95	<5:95
6	f			>95	89:11
7	g			78b	89:11
8	h			>95	90:10
9	i			>95	<5:95

^aIsolated yield after SiO₂ chromatography.

^b3 mol % Rh₂(esp)₂ used.

To further examine the propensity for a group to migrate, several β-substituted styryl azides were submitted to reaction conditions and their products were compared (Table 4). In our first report,^7b no alkyl- or aryl group migration was observed for styryl azides with β-hydrogen substituents (entry 1). Our subsequent study revealed that aryl groups migrate in preference to alkyl groups (entry 2).^12a Azides 10d – 10f were constructed for an intramolecular competition between migrating groups (entries 3 and 4). Exposure of 10d and 10e to reaction conditions revealed that no phenyl group migration occurred in the presence of either a β-sulfone or β-amide. The reaction of azide 10f provided only 12f, the product of nitro migration; no benzoyl group migration was observed.

Table 4.

Intramolecular Competition Experiments to Compare Migration Preference.

entry	10	Styryl azide	mol %	Product	yield, %a
1b	a		5		R = n-hex 68
	b				R = Ph 95
2c	c		5		>95
3	d		5		49d
4	e		5		91
5	f		1		40d

^aIsolated yield after SiO₂ chromatography.

^bref. 7b.

^cref. 12a.

^dRemaining material was oligomeric decomposition.

Our results enable the construction of a scale for the migration of different β-substituents (eq 2). Styryl azide 10c reveals that aryl group migration is preferred over an alkyl shift.^12a Neither group, however, will migrate in the presence of a β-hydrogen.^7b Consequently, we rank their migratorial aptitude behind hydrogen. While hydrogen migration is preferred over amide migration in 7d, azide 10e revealed that when the β-hydrogen is replaced with a phenyl group, only amide migration is seen. Therefore amides are placed ahead of aryl groups but behind hydrogen. The difference in reactivity between 7a–c (only 3-carbonylindole) and 7f–h (90:10 favoring 3-sulfonylindole) suggests that sulfones should be positioned in between hydrogen and ketones. Finally, because only nitro group migration was seen for 10f, we rank it ahead of ketones. The propensity for these electron-withdrawing groups to migrate, however, hinges on the absence of a second ortho-electron withdrawing substituent on the aryl azide.

(2)

While a number of mechanisms could explain the reactivity patterns we observed, we propose that migration occurs from a common catalytic intermediate 14 (Scheme 1). Coordination of the Rh₂(II)-carboxylate to the α- or γ-nitrogen atom followed loss of N₂ forms rhodium nitrene 13.^18,19 A 4π-electron-5-atom electrocyclization establishes the C–N bond and generates a carbocation on C3 in 14.²⁰ From this intermediate, several different pathways could produce the desired migration. Examination of 15, a resonance structure of 14, reveals that a [1,5] sigmatropic shift could occur to form the C3–N bond in 16.^2a,b Alternatively, the shift could occur stepwise. Homolysis of the C–O bond in 14 forms diradical 17. The mesomer 18 places the radical at C3 which could recombine to form the C–N bond in 16. A similar diradical mechanism was proposed for the rearrangement of sulfinate ions²¹ and nitro groups in electrophilic aromatic substitution.²² Tautomerization of 16 would form the 3-substituted indole.

Scheme 1.

Potential Mechanism for NO₂ Migration.

Several experiments were performed to test our mechanistic hypothesis (Scheme 2). A double crossover experiment between styryl azides 1-¹⁵N and 4a produced only indoles 3-¹⁵N and 5a to reveal that no solvent-separated reactive intermediates were formed in the catalytic cycle. As predicted by our previous mechanistic study,²¹ styryl azide 4k reacted 2.1 times faster than 1. This result confirms that the reaction can be accelerated when an electron-donating group is positioned to assist in N₂ loss—supporting that C–N bond formation occurs via an electrocyclization.

Scheme 2.

Double Crossover- and Relative Rate Experiments.

In conclusion, we have demonstrated that rhodium(II) carboxylate complexes catalyze the migration of electron-withdrawing groups to enable the selective formation of 3-substituted indoles from β-substituted styryl azides. Our data allowed for the construction of a scale, which categorizes the aptitude of migration for a range of functional groups. Future experiments will be centered on clarifying the mechanism of this reaction as well as exploiting these reactivity trends to produce complex, functionalized N-heterocycles from simple, readily accessible styryl azides.