Diastereoselective Aziridination of 2-B(pin) Substituted Allylic Alcohols: An Efficient Approach to Novel Organoboron Compounds

Abstract

We report that 2-B(pin)-substituted allylic alcohols are good substrates for diastereoselective aziridinations in the presence of PhI(OAc)₂ and N-aminophthalimide. Under the aziridination conditions, the valuable B–C bond remains intact, affording a variety of novel boron-substituted aziridines in good yields and excellent diastereoselectivities. Oxidation of the aziridine B–C bond enables generation of syn-1,3-aminohydroxy-2-ketones with high diastereoselectivity.

The increasing utility of organoboron compounds as building blocks for the construction of complex molecules has attracted much attention.^1,2 Despite their utility, a serious limitation in the application of organoboron compounds is the high reactivity of B–C bonds. Thus, the vast majority of substrates containing B–C bonds undergo reaction at the boron center, as observed in catalytic cross-coupling processes³ and oxidative transformations.⁴ In this context, only a handful of efficient protocols involving epoxidation⁵ or cyclopropanation^6a of the double bond in vinylboronates have been reported. Even with impressive recent progress, the need to develop new transformations in which organoboron substrates retain their B–C bonds represents a considerable challenge.

We initially explored the oxidation of B(pin)-substituted allylic alcohols with TBHP and observed clean formation of the expected α-hydroxy ketones (Scheme 1, left).⁴ To expand the range of transformations that can be performed on vinylboronate esters,^5,6 we diverted the reaction of TBHP with 2-B(pin)-substituted allylic alcohols from oxidation of the B–C bond to the epoxidation of the C=C bond (Scheme 1, right). This chemoselective epoxidation of 2-B(pin)-substituted allylic alcohols is catalyzed by OV(acac)₂⁷ and generates the product with excellent diastereoselectivity (>20:1). Subsequent oxidation of the B–C bond in the presence of NaOH and H₂O₂ led to formation of the anti-2-keto-1,3-diols in good yields (55–96%).^5f This method represents a new synthesis of synthetically important keto diols.⁸

Scheme 1.

Control of chemoselectivity in oxidation of B(pin)-substituted allylic alcohols

In considering other types of oxidations that could be performed in the presence of the vinyl boronate ester, we were attracted to aziridination. Aziridines are important structural components present in many biologically active natural products and are useful synthetic intermediates.⁹ Herein we describe the highly diastereoselective aziridination of B(pin)-substituted allylic alcohols.

For any synthetic method to be useful, the substrates must be readily accessible. The B(pin)-substituted allylic alcohols were prepared as previously reported in one pot using our stereodefined 1-alkenyl-1,1-heterobimetallic reagents.^4b,5e,6 Thus, hydroboration of air-stable alkynyldioxaborolanes with dicyclohexylborane and selective B to Zn transmetalation of the vinyl-BCy₂ moiety generates the heterobimetallic intermediate. Addition of the Zn–C bond to aldehydes followed by quenching furnished (E)-2-B(pin)-substituted allylic alcohols 1a–1l in 61–88% yield (Table 1). It is noteworthy that 2-B(pin)- substituted allylic alcohols can be prepared on gram scale.^5e

Table 1.

One-pot synthesis of 2-B(pin) allylic alcohols via 1-alkenyl-1,1-heterobimetallic intermediates

entry	R	R′	allylic alcohol	yield (%)a
1	n-Bu	Ph	1a	70
2	i-Bu	Ph	1b	76
3	Bn	Ph	1c	68
4	Cy	Ph	1d	69
5	i-Pr	Ph	1e	81
6	Ph(Me)CH2-	Ph	1f	62a
7	i-Pr	4-C6H4-OMe	1g	88
8	i-Pr	4-C6H4-Cl	1h	81
9	Cy	n-Bu	1i	85
10	i-Pr	n-Bu	1j	77
11	PhCH3(CH)-	n-Bu	1k	61b
12	Bn	Cyclohexenyl	1l	79

^aIsolated yield.

^bdr = 7:1 (determined by ¹H NMR of crude reaction mixture), diastereomers separated by column chromatography and the major used in subsequent reactions.

Inspired by the seminal work of Che and Yudin describing a novel nitrene equivalent for aziridination of olefins,¹⁰ we investigated the reaction of B(pin)-substituted allylic alcohol 1a with N-aminophthalimide as the nitrogen source mediated by the strong oxidant PhI(OAc)₂ (Table 2).¹¹ Aziridination product 2a was not observed using PhI(OAc)₂ in CH₂Cl₂.¹² Instead a diastereomeric mixture of 3a was formed, presumably via aziridine ring opening promoted by the AcOH generated during the nitrene formation (entry 1).¹³ When excess K₂CO₃ was employed, however, aziridine 2a was isolated in 46% yield with an encouraging diastereoselectivity (dr = 5:1, entry 2). Changing the solvent to toluene or CH₃CN led to complex mixtures (entries 3 and 4). Other additives or bases resulted in comparable diastereocontrol to K₂CO₃ ¹⁴ and reduced yields (38–45%, entries 5–7) due to formation of byproduct 3a. Surprisingly, changing the addition order by adding PhI(OAc)₂ last, aziridine 2a could be isolated in 62% yield with good diastereomeric ratio (dr = 7:1) and only trace amounts of 3a (2a/3a ≥ 95:5, entry 8).

Table 2.

Optimization of the reaction conditions^a

entry	solvent	additive	2a/3ab	dr (2a)b	yield (%)c
1	CH2Cl2	none	< 5:95	--	--
2	CH2Cl2	K2CO3	83:17	5:1	46
3	Toluened	K2CO3	complex mixture
4	CH3CN	K2CO3	complex mixture
5	CH2Cl2	MS 4Å	70:30	10:1	38
6	CH2Cl2	Cs2CO3	94:6	2:1	42
7	CH2Cl2	MgO	70:30	7:1	45
8e	CH2Cl2	K2CO3	> 95:5	7:1	62

^aUnless otherwise noted, all the reactions were performed by adding PhI(OAc)₂ to a suspension of 1a, N-aminophthalimide and the additive.

^bDetermined by ¹H NMR of the crude reaction mixture.

^cIsolated yield.

^d12 h.

^eAllylic alcohol 1a was added the last.

The substrate scope of this method was next examined. As shown in Table 3, a wide range of B(pin)-substituted allylic alcohols was evaluated under the optimized conditions, providing the corresponding B(pin)-substituted aziridines 2b–l in good yields (59–78%) with high levels of diastereoselectivity (typically ≥15:1). Because these products are prone to decompose in the presence of trace acid or Lewis acidic silica gel, their isolation was performed by passing a solution of the aziridine through a small pad of deactivated silica gel. The reaction proceeded smoothly with styryl substrates bearing different alkyl substituents on the carbinol¹⁵ to afford products 2a–f (entries 1–6). Although the presence of an i-Bu group resulted in the formation of 2b with moderate stereoselectivity (dr = 4:1, entry 2), excellent levels of diastereocontrol (dr ≥ 15:1) and yield (63–78%) were attained for other aliphatic substrates with either linear or branched chains (entries 3–6). Moreover, the method was successful with B(pin)-substituted allylic alcohols bearing 4-methoxy or 4-chloro substituents on the styryl moiety (1g–h). These substrates provided the desired products in 69–75% yield with excellent diastereoselectivity (dr > 20:1, entries 7–8). Likewise, substrates bearing alkyl groups on the vinyl moiety (1i–k) participated in the aziridination reaction to yield the corresponding adducts as single diastereomers (entries 9–11). Reaction with the challenging dienyl substrate 1l occurred in good yield and diastereoselectivity (68%, dr = 15:1) with complete chemoselectivity in favor of aziridination at the allylic position (entry 12). This result suggests that these reactions are both accelerated and directed by the adjacent hydroxyl group.¹⁶

Table 3.

Diastereoselective aziridination of B(pin)-substituted allylic alcohols

entry	substrate	product	drb	yield (%)c
1	1a	2a	7:1	62
2	1b	2b	4:1d	59
3	1c	2c	15:1	63
4	1d	2d	>20:1	76
5	1e	2e	>20:1	78
6	1f	2f	>20:1	71
7	1g	2g	>20:1	69
8	1h	2h	>20:1	75
9	1i	2i	>20:1	65
10	1j	2j	>20:1	72
11	1k	2k	>20:1	70
12	1l	2l	15:1	68

^aAll the reactions were carried out by adding PhI(OAc)₂ to a suspension of 1, N-aminophthalimide and K₂CO₃.

^bDetermined by ¹H NMR from the crude reaction mixture.

^cIsolated yield.

^dChanging the addition order led to similar results

To confirm the stereochemistry of the aziridination and subsequent oxidation, X-ray diffraction analysis of product 2g was carried out. The structure (Figure 1) clearly shows the relative syn stereochemistry between the aziridine ring and the hydroxy group.¹⁷ The diastereoselection observed herein is consistent with other aziridinations of allylic alcohols that give rise to A^1,2 strain in one of the diastereomeric transition states.¹⁸

Figure 1.

Crystal X-ray structure of aziridine 2g.

The B(pin)-substituted hydroxyaziridines were next evaluated as synthetic intermediates. We envisioned that further oxidation of the boronate ester would enable generation of valuable 1,3-aminohydroxy-2-ketones.¹⁹ Preliminary studies on the oxidation of the B–C bond under mild conditions (NaBO₃·H₂O in THF/water at rt for 30 min) afforded the corresponding products 4j and 4l in moderate yields (53–62%, Scheme 2a). In addition, the tandem aziridination/B–C bond oxidation was studied to circumvent isolation of the B(pin)-substituted aziridine. Thus, after the completion of the aziridination, removal of the solvent and subsequent addition of NaBO₃·H₂O in THF/water led to products 4i and 4j in 49–51% over two steps (Scheme 2b). Interestingly, the desired syn-aminohydroxyketones were formed as single diastereomers in both cases, suggesting that epimerization of the α-C–H’s did not occur under the basic reaction conditions. The syn relative stereochemistry of the amino and hydroxy groups was established by single X-ray diffraction analysis of 4i (Figure 2).

Scheme 2.

Synthesis of 1,3-aminohydroxy-2-ketones.

Figure 2.

Crystal X-ray structure of 1,3-aminohydroxy-2-ketones 4i.

In summary, we have demonstrated that B(pin)-substituted allylic alcohols are very good substrates for aziridination reaction in the presence of hypervalent iodine PhI(OAc)₂ and N-aminophthalimide. This reaction gives rise to novel syn-B(pin)-substituted hydroxyaziridines in good yields (59–78%) and with high levels of diastereocontrol (typically ≥ 15:1). In addition, preliminary results demonstrate that the aziridination can be followed by oxidation of the B–C bond, delivering syn-1,3-aminohydroxy-2-ketones with excellent diastereoselectivity (dr >20:1). Significantly, these studies indicate that the oxidation-sensitive 3-coordinate B(pin) group is sufficiently stable to withstand the oxidant PhI(OAc)₂ and the aziridination agent. Thus, this study illustrates a surprising change in chemoselectivity.