Non-Racemic 3°-Carbamines from the Asymmetric Allylboration of N-Trimethylsilyl Ketimines with B-Allyl-10-phenyl-9-borabicyclo[3.3.2]decanes

Abstract

The simple and efficient asymmetric synthesis of 3°-carbamines 7 from N-TMS enamines (3) and either enantiomeric form of B-allyl-10-(phenyl)-9-borabicyclo[3.3.2]decane (1) is reported. The high reactivity (<1 h, −78 °C) and enantioselectivity (60– 98% ee) of these substrates can be attributed to the fact that the complexation of 3 with 1 facilitates its isomerization to the corresponding syn-N-TMS ketimine complex from which allylation can occur. In addition to providing the homoallylic amines 7 with predictable stereochemistry, the procedure also permits the efficient recovery of the chiral boron moiety (50–65%) as air-stable crystalline pseudoephedrine complexes 8 which are directly converted back to 1 with allylmagnesium bromide in ether (98%).

The synthesis of non-racemic 3°-carbamines from the asymmetric allylation of achiral ketimines represents an important synthetic challenge. These amines can be prepared through the asymmetric addition of Grignard and organolithium reagents to unsymmetrical chiral N-sulfinyl ketimines.¹ The asymmetric allylsilylation of ketone-derived N-benzoylhydrazones was also demonstrated to provide these non-racemic 3°-carbamines after the SmI2-mediated reduction of the resulting homopropargylic hydrazines.² While no analogous asymmetric allylboration process is known for achiral ketimines or related compounds, new allylboranes and processes have been recently reported for the asymmetric allylboration of ketones.³ Among these, the B-allyl-10-phenyl-9-borabicyclo[3.3.2]decanes (9-BBDs) (1) contain a nearly ideal chiral pocket for the highly enantioselective allylation of methyl ketones.^3a In the present study, we wish to report the asymmetric allylboration of N-TMS ketimines 2 generated in situ from the reaction of N-TMS enamines 3 with 1. The new process can be viewed as occurring through an initial complex 4 followed by isomerization to 5, allylation giving 6 which provides the desired 3°-carbamines 7 after a pseudoephedrine (PE) workup (Scheme 1).

Scheme 1.

Clearly, 3 is not an obvious choice as a substrate for the allylboration process. In fact, our plan was to follow an earlier protocol which was successful for the allylboration of N-H aldimines derived from the borane-mediated methanolysis of their N-TMS precursors.⁴ Since the allylboration of the aldimines with the BBD systems does not occur until the N-TMS derivatives are converted to their N-H counterparts,^4e we anticipated that similar behavior, namely that 1 would smoothly allylate the N-H ketimines derived from 2 in a predictable manner (c.f., 9, 10).⁵ Mixtures of the anti-N-TMS ketimines (a-2) and 3 were prepared through the Rochow protocol⁶ from nitriles and LiMe followed by TMSCl (75–95%). These mixtures are thermally unstable and heating usually increases the amount of 3 and also gives rise to minor amounts of the syn-ketimine s-2 (Table 1).

Table 1.

N-TMS ketimines and enamines from nitriles

R	series	a-2:3a	s-2:a-2:3b
Ph	a	94:6	16:22:62
2-MeOC6H4	b	70:30	4:4:92
4-MeOC6H4	c	40:60	5:48:47
t-Bu	d	80:20	-
c-Hx	e	60:40	-
4-BrC6H4	f	45:55	15:35:50
4-MeC6H4	g	74:26	5:36:59
3-Py	h	60:40	4:9:87
4-Me2NC6H4	i	81:19	-
4-ClC6H4	j	60:40	10:26:64
2-thienyl	k	87:13	0:70:30

^aThe a-2:3 ratios were estimated from the ¹³C NMR analysis of the peak areas for the TMS signals. Other characteristic signals for these tautomers were also observed in each case.

^bThe a-2:3 mixtures were heated at reflux temperature (24–72 h) and the ratios of s-2, a-2 and 3 were estimated as above (see SI).

Treatment of a-2a:3a (90:10) with a 1:1 mixture of 1 and MeOH at −78 °C results in the clean formation of the desired N-boryl homoallylic amine (¹¹B NMR δ 51). An oxidative work-up provided 7aR in 80% yield and 52% ee. The R configuration of 7aR is consistent with the allylboration of PhCOMe with 1 (i.e., R, 96% ee).^3a The lesser ee for a-2a:3a vs PhCOMe parallels a similar pattern observed in the allylboration of N-H aldimines vs aldehydes with B-allyl-10-TMS-9-BBD.^4e Our models for the key pre-transition states for these two processes are illustrated above (c.f., 9 and 10).

Seeking a more selective reaction protocol, we prepared (±)-BEt-10-Ph-9-BBD (11) as a non-reacting model for 1. Its complexation with PhMeC=NH (4 equiv) was examined by ¹¹B NMR revealing that 11 (δ83) was completely converted to its imine complex (δ 1). Unexpectedly, we also noted that 11 is partially complexed (¹¹B NMR δ −1, ~5%) with the excess 90:10 a-2a:3a mixture at −78 °C even before the addition of MeOH. Moreover, using 4 equiv of the 16:22:62 s-2:a-2:3 mixture increases the complexation with 11 to ~90%.

This suggested that a-2:3 mixtures may undergo allylboration with 1 even without converting the N-TMS to the corresponding N-H ketimine. The allylboration process was examined with (−)-1R at −78 °C employing a 94:6 a-2a:3a mixture (2 equiv) with the finding that the addition was complete in 16 h. Significantly, the homoallylic amine 7a was formed in 92% ee and with the opposite S absolute configuration from that obtained from PhMeC=NH! Moreover, under these same conditions, the 16:22:62 s-2:a-2:3 mixture (2 equiv) also gave 7aS, again in 92% ee, with the reaction being complete in <1 h. This reactivity is consistent with the general process illustrated in Scheme 1 wherein 3 initially forming a complex with 1 which rapidly isomerizes to the reacting 5 complex which leads to 6 and ultimately to 7. Clearly, 5 could also form directly from s-2, but even in cases where this isomer is not present, rapid allylboration occurs provided ample 3 is present to react with 1 as illustrated in Scheme 1. Moreover, to gain additional support for our view of the process, the anti aldimine PhHC=NTMS (2 equiv) was found to partially complex 1 (~20% at −78 °C), but not its 10-TMS counterpart. However this aldimine, despite its being less substituted than a-2a, does not undergo allylboration with either 1 or its 10-TMS counterpart even after one week at 25 °C. These aldimines simply do not have access to their syn isomers because the enamine-based process is not an option for them.

We carried out the allylboration of the 2/3 mixtures (≥2 equiv of 2/3) for 1 h at −78 °C with 1 to ultimately produce 8 (48–65%) and the desired 3°-carbamine 7 (50–82%) in high ee (60–98%) (Table 2). The complex 8 is easily recycled back to 1 (98%) with allylmagnesium bromide in ether.

Table 2.

Asymmetric allylboration of N-TMS ketimines with 1

3	1	8a	yield of 7b (%)	% ee (abs. config.)c
a	R	63	75	92 (S)
b	R	52	58	94 (S)
c	R	48	55	92 (S)
d	R	58	50	98 (S)
e	S	64	66	70 (R)
f	S	61	65	70 (R)
g	S	65	67	84 (R)
h	R	50	71	60 (S)
i	R	-	82	94 (S)
j	S	60	74	64 (R)
k	S	65	80	60 (R)

^aYield of crystalline (+)-8R from (−)-1R or (−)-8S from (+)-1S reactions.

^bIsolated yield based upon 1.

^cThe product ee’s were determined by ³¹P NMR analysis of their Alexakis thiophosphoric triamides.⁷ The absolute configurations of 7 were based upon the known rotation of 7a.^1a,²

As can be noted from these results, higher ee’s for 7 are generally observed for aryl derivatives with electron-donating groups in the aromatic ring. Sterically biased examples (e.g., 3d) also provide excellent substrates for this process. For the 4-BrC₆H₄ (f) series, we also prepared the mixture of N-triethylsilyl (TES) ketimine and its enamine (81:19). This also underwent allylboration with (+)-1S (1 h, −78 °C) to give 7fR (60%) in somewhat lower ee (50%) than was observed with 3f (70% ee).

Simple MM calculations⁸ suggest that 3 strongly prefers (a series, ~5 kcal/mol) to complex (−)-1R trans to the 10-Ph group (i.e., 4). Tautomerism leads either to 5 or its rotomer 12.

We view the larger TES vs TMS group as increasing the relative amount of the minor 7fS enantiomer through this “upside-down” isomer which avoids TMS-Ph repulsions. Moreover, through the addition of EtMgBr to PhCN followed by TMSCl, we prepared the N-TMS propiophenone enamines 3l as an 83:17 Z/E mixture free of either ketimine tautomer. This mixture reacts rapidly with (+)-1S (1 h, −78 °C) to give 7lR (67%) in 65% ee.⁹ Thus, with the larger Et vs Me inward group, repulsions between the BBD ring and this group apparently also increase the amount of 7 originating from this “upside-down” pathway thereby lowering the product ee.

Clearly the carbamines 7 are rare with only 7a being known in non-racemic form.^1a,2 With their ready availability through the present methodology, we chose to further demonstrate their utility through their conversion to the corresponding β³,³-amino acids and β-amino aldehydes.^1a Thus, acetylation of 7b gives 13b (80%) whose ozonolysis (CH₂Cl₂, −78 °C) affords 14b (90%) and 15b (57%) with oxidative (H₂O₂) and reductive (Me₂S) work-ups, respectively.

The asymmetric allylboration of ketimines with the BBD reagent 1 has been accomplished in a unique manner utilizing their N-TMS enamines 3 to access the requisite syn-ketimine-allylborane complexes 5. The reagents 1 are readily prepared in either enantiomeric form and are easily recycled providing the 3°-carbamines 7 in high ee (60–98%). With the N-TMS substitution being readily hydrolyzed during work-up, this new method has the advantage of producing the free 3°-carbamines 7 for subsequent conversions.

Supplementary Material

1si20060531_03. Supporting Information Available.

Experimental procedures, analytical data and selected spectra for 1–3, 7–8, 13f, 14f, 15g and derivatives and X-ray data for (+)-8R. (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.