Stereoselective [2,3]-Sigmatropic Rearrangements of Unstabilized Nitrogen Ylides

Abstract

The steric course of the [2,3]-rearrangement of several unstabilized nitrogen ylides has been investigated. The reactions proceed cleanly through an anti transition state, affording modest to good yields of a single diastereomer of the product. In two examples containing an N-cinnamyl group, a competing [1,2]-rearrangement affords a minor product.

Electrophilic substitution reactions of α-alkoxy- and α-aminoorganolithium compounds (Eq 1) have been extensively studied, and constitute an important class of synthetic methods, with hundreds of applications reported so far.^1,2 A second class of carbon-carbon bond forming reactions utilizing these reactive intermediates is sigmatropic rearrangements.^3,4 In 1978, Still and Mitra reported the first example of a [2,3]-rearrangement of an organolithium generated by tin-lithium exchange,⁵ which was later shown to be invertive at the lithium-bearing carbon (Eq 2).^6–8

(1)

(2)

The nitrogen (aza) analog of the Still-Wittig [2,3]-rearrangement (Eq 3) is less facile, due primarily to the lower stability of the lithium amide compared to the lithium alkoxide product of the oxygen version.^3,4,9,10 Once generated, the N-allyl α-aminoorganolithium often follows competing [1,2]- and [2,3]-rearrangement pathways (Eq 3).^11–13 Quaternization of the nitrogen (Eq 4) with a trimethylsilyl group,¹⁴ boron trifluoride,¹⁵ or an alkyl group^13,16 accelerates the concerted [2,3]-rearrangement over the radical-mediated [1,2]-rearrangement of the ylides. The steric course of the anionic and ylide aza-[2,3]-rearrangements is invertive if the metal bearing carbon is stereogenic (Eqs 3 and 5),¹³ but the stereoselectivity at the migration terminus of nitrogen ylides has only been explored in stabilized ylides such as the enolate shown in Eq 4. In most cases, the diastereoselectivity is modest,^16–18 with only a few examples of high selectivity in auxiliary mediated processes.^19,20 We now report the results of our studies on the diastereoselectivity at the migration terminus of the [2,3]-rearrangement of several unstabilized, lithionitrogen ylides (Eq 5), in which we find that the rearrangement is highly stereoselective. Note: Strictly speaking, the ylide is the zwitterion having a positive nitrogen and a negative carbon. Since the anionic carbon is stereogenic, we draw the carbon-lithium ion pair as a bond.

(3)

(4)

(5)

Stannane 1 is a challenging test of the methodology for two reasons. Firstly, stannane 1 fails to undergo tin-lithium exchange, so it was of interest to determine whether quaternization of the nitrogen would facilitate the exchange. Secondly, we wanted to evaluate the diastereoselectivity of the [2,3]-rearrangement in the context of acyclic stereoselection. To test the first point, 1 was simply quaternized with methyl iodide. Treatment of the methiodide salt with butyllithium in THF at −78 °C for 1 h, quenching with methanol, and silica gel chromatography afforded a 69% yield of tetrabutyltin, indicating that transmetalation to the ylide is facile in this system. Quaternization of racemic 1 with E-crotyl bromide, and E- and Z-cinnamyl bromide affords ammonium salts 2a–c, as shown in Scheme 1. For some compounds, anion exchange from halide to hexafluorophosphate facilitated handling, provided a salt that was less hygroscopic, and increased solubility in organic solvents (see Supporting Information).

Scheme 1.

As illustrated in Scheme 2, stannylammonium ions 2a–c were treated with butyllithium in THF at −60 °C to effect transmetalation and stirred at that temperature for 20–24 h. After workup and column chromatography, amines 5a–c were obtained in the yields shown in Table 1, entries 1–3.

Scheme 2.

Table 1.

Rearrangements of ylides (Stannane + BuLi, −60 °C, unless otherwise noted).

Entry	Ylide	R1	R2	X−	Product(s)	Yield
1	2a	Me	H	I−	5a	57%
2	2b	Ph	H	PF6−	5b	54%
3	2c	H	Ph	PF6−	5c	29%
4	10a	Me	H	PF6−	12a	60%
5*	10b	Ph	H	Br−	12b+14b (4:1)	55%
6*	10c	H	Ph	Br−	12c+14c (9:1)	35%

^*T = −83 °C; MeLi instead of BuLi for transmetalation.

Of interest in these rearrangements is the possibility of two transition state conformers, syn and anti 4a–c, which would afford diasteromeric products 5 or 6, and possibly [1,2]-rearrangement product 7. In all cases, only one diastereomer was isolated. Independent synthesis of 5b and 5c established the relative configurations (see Supporting Information). It appears that the [2,3]-rearrangement prefers the anti transition state 4, independent of alkene geometry, even though anti 4c having a Z double bond appears somewhat more congested. The lower yield from the Z-cinnamyl intermediate 3c may indicate that steric crowding in the anti transition state slows the rearrangement, allowing pathways toward nonproductive decomposition to become more competitive; in this case, there were numerous unidentified polar byproducts. It is noteworthy that under these conditions, none of the [1,2]-products 7a-c were detected.

If R² and R³ in Eq 5 are different, then the nitrogen is a stereocenter and the stereoselectivity of the rearrangement will rely on the stereoselective quaternization of the nitrogen. To probe the diastereoselectivity of the rearrangement in cyclic systems, we chose racemic N-methyl-2-(tributylstannyl)-piperidine, 8. Based on precedent from a single example in an earlier report,¹³ we anticipated that alkylation of 8 would occur trans to the tin.

In the event, alkylation of 8 with E-crotyl bromide and with E- and Z-cinnamyl bromide afforded ammonium ions 9a–c, with 90–94% diastereoselectivity, as indicated by integration of the N-methyl peaks in the NMR (Scheme 3). Again, exchange of the halide anion for PF₆⁻ often facilitated handling of the salt, increased its solubility in organic solvents, and made it less hygroscopic.

Scheme 3.

Transmetalation of 9a–c afforded ylides 10a–c, and ultimately their rearrangement products, as summarized in Table 1, entries 4–6, and illustrated in Scheme 4. The E-crotyl ylide 10a rearranged to a mixture of isomers, of which piperidine 12a was the major (92%) component. The isomers were not obtained in sufficient quantity to identify; one may be the [1,2]-product 14a, while others are diastereomers that could have arisen from transition structure syn-11, or from minor contaminants of cis alkene ylide (10, R²=Me, R¹=H). Trans-cinnamyl ylide 10b afforded a 3.6:1mixture of [2,3]-product 12b and [1,2]-product 14b, while cis-cinnamyl ylide 10c afforded a 6.9:1 mixture of [2,3]-product 12c and [1,2]-product 14c. None of the diastereomeric products 13b–c were detected by GC-MS, and the structure of 12b was confirmed by independent synthesis (See Supporting Information). To further confirm these assignments, stannane 8 was transmetalated with BuLi at −78 °C in THF, and alkylated with trans cinnamyl bromide according to our established procedure.²¹ Analysis of the product mixture revealed a mixture of S_N2 product 14b, along with S_N2′ products 12b and 13b. In the [2,3]-rearrangement of 10b–c, the extra stabilization afforded by the phenyl group probably facilitates homolytic cleavage of the allylic C–N bond to produce 14b–c after radical recombination. In summary, nitrogen ylides 3a–c and 10a–c rearrange preferentially through transition structures anti-4 and anti-11, creating two adjacent stereocenters with a high degree of stereoselectivity. Further applications of the [2,3]-rearrangement of unstabilized nitrogen ylides are under active investigation and will be reported in due course.

Scheme 4.

Supplementary Material

1File001. Supporting Information Available.

Full experimental details, independent syntheses of 5b, 5c, and 12b, characterization data and NMR spectra for all new compounds. This information is available via the internet at pubs.acs.org.