A Simple Procedure for the Synthesis of β-Hydroxyallenamides via Homoallenylation of Aldehydes

Abstract

A simple one-pot synthesis of β-hydroxyallenamides is reported. This procedure entails chemo- and regioselective hydroboration of 3-en-1-ynyl-sulfonylamides with Cy₂BH followed by homoallenylation of aldehydes to yield β-hydroxyallenamides (up to 94% yield and >20:1 dr). Controlled synthesis of up to three continuous stereochemical elements was realized. Density functional theory (DFT) calculations suggest a concerted Zimmerman-Traxler chair-like transition state. Initial results suggest that enantio- and diastereoselective synthesis of β-hydroxyallenamides with optically active hydroboration reagents is viable.

Graphical abstract

Carbonyl allylations and related transformations are among the most important and widely utilized carbon–carbon bond forming reactions.^[1] Although many metal allyls have been introduced for carbonyl additions, boron allyls are the most prominent because of their ease of preparation and predictable stereochemical outcomes. Despite significant progress,^[2] the vast majority of boron allylation reactions deliver only the parent allyl or crotyl groups.^[2c] The use of more functionalized allylating reagents is complicated by their challenging syntheses and propensity to undergo isomerization reactions.^[2e] These limitations are also found in the homoallenylation and dienylation of aldehydes.^[3]

Boron-substituted 1,3-dienes represent versatile and synthetically valuable reagents in organic synthesis.^[4] Thus, several methods for the synthesis of 2-boryl 1,3-dienes have been developed.^[5] In the realm of homoallenylation reactions,^[6] beautiful enantioselective boron-based methods have been developed by the Soderquist^[7] and Yu^[8] groups (Scheme 1A and B) involving the generation of enantioenriched allylating agents via transmetallation pathways. The drawback of these approaches, however, is the lengthy synthesis of the dienylboranes, which cannot be prepared by direct hydroboration. Szabo and coworkers prepared allenylation reagents through catalytic diboration of propargylic epoxides and demonstrated their application to the tandem allylboration/allenylboration of aldehydes (Scheme 1C).^[9]

Scheme 1.

Homoallenylation prior art and proposed work.

With the goal of accessing more functionalized homoallenylation reagents, we focused on methods that would enable the introduction of amino groups (Scheme 1D). Nitrogen is present in most biologically active compounds and medications.^[10] Furthermore, allenamides^[11] have garnered considerable attention from the chemistry community^[12] as versatile intermediates in synthesis. Herein we disclose a straightforward approach to amino-substituted dienylboranes and demonstrate their application to the highly diastereoselective homoallenylation of aldehydes. Initial results suggest that an enantioselective version is also viable.

The highly selective reagents in Scheme 1A and 1B were prepared by transmetallation. The most practical method to generate boron-carbon bonds, however, is via simple hydroboration. Key to the use of hydroboration approaches to generate allenylating reagents is 1) inverting the regioselectivity of the hydroboration of 1,3-enynes and 2) disfavoring 1,3-borotropic rearrangements. With this in mind, we hypothesized that generation of 1-substituted 2-boryl diene intermediates could be accomplished by the chemo- and regioselective hydroboration of substituted 1,3-enynamides (Scheme 1D). Witulsky, Hoffman and our group previously demonstrated hydroboration of N-sulfonyl ynamides resulted in placement of the boron distal to the amino group with excellent regioselectivity.^[13] The chemoselectivity of hydroboration of 1,3-enynamides, however, has been rarely explored.^[14],[15]

Our initial studies of the chemo- and regioselective hydroboration of enynamide 1a were performed with Cy₂BH in CDCl₃ at room temperature (Scheme 2). We were pleased to find that the hydroboration of the enynamide occurred faster than reaction at the double bond (as judged by ¹H NMR) and the reaction was complete in 5 min.^[16] It is noteworthy that the intermediate 3a, derived from a 1,3-borotropic rearrangement, was not observed by ¹H NMR.^[17] To probe the stereochemistry of the hydroboration, protodeboration of 2-dicylcohexylboryl-diene 2a with acetic acid generated the cis stereoisomer 4a (J = 7.5 Hz, see the Supporting Information for the in-situ NMR experiments).

Scheme 2.

Chemo- and regioselective hydroboration of 1a with Cy₂BH

With an understanding of the chemo- and regioselective hydroboration of 1,3-enynamide 1a, we initiated the tandem hydroboration/homoallenylation of benzaldehyde to optimize the reaction parameters. As outlined in Table 1, we began by examining various solvents. The procedure involved addition of the 1,3-enynamide 1b to a heterogeneous solution of Cy₂BH under a nitrogen atmosphere at 0 °C. After addition, the reaction mixture was remove from the ice bath and stirred for 10 min. Benzaldehyde was then added and the solution stirred for an additional 120 min. A basic oxidative work-up (NaOH, H₂O₂) was followed by isolation on deactivated silica gel to provide hydroxyallenamide 5a. With use of 2 equiv of benzaldehyde, consumption of 2-boryl 1,3-dienes was not complete in CH₂Cl₂, diethyl ether, or THF. The diastereoselectivities of hydroxyallenamide 5a, however, were excellent (>20:1 dr, entries 1–3). Using Et₂BH instead of Cy₂BH led to similar levels of diastereoselectivity in THF but in slightly diminished yield (>20:1 dr, 51%, entry 4). Hydroboration of 1b with Cy₂BH in hexanes was very slow because of the poor solubility of 1b in non-polor solvents (entry 5). We proceeded to change the limiting reagent to benzaldehyde, because the decomposition product tosylbenzylamine was observed by ¹H NMR and TLC of unpurified reaction mixtures, suggesting hydrolysis of ynamide 1b. With 1:1:1 ratio of 1b, Cy₂BH and benzaldehyde, the yield did not improve significantly (62%, entry 6). Using 1.2 equiv of both ynamide 1b and Cy₂BH resulted in good yield and excellent diastereoselectivity in THF (80%, >20:1 dr, entry 7). Finally, 1.3 equiv of both ynamide 1b and Cy₂BH in THF provided β-hydroxyallenamide 5a in 92% isolated yield with >20:1 dr (entry 8). The stereochemistry of the β-hydroxyallenamide 5a was established by X-ray structure analysis (see Supporting Information).^[18]

Table 1.

Optimization of homoallenylation.

entry	1ab	Cy2BHb	PhCHOb	solvent	time (min)	yield (%)c
1	1.0	1.0	2.0	CH2Cl2	120	50
2	1.0	1.0	2.0	ether	120	54
3	1.0	1.0	2.0	THF	120	60
4	1.0	1.0	2.0	THF	120	51d
5	1.0	1.0	2.0	hexanes	120	–e
6	1.0	1.0	1.0	THF	10	62
7	1.2	1.2	1.0	THF	10	80
8	1.3	1.3	1.0	THF	10	92

^adiastereomeric ratio (dr) was determined by analysis of ¹H NMR spectra of unpurified reaction mixtures.

^bmmol.

^cisolated yield.

^dEt₂BH instead of Cy₂BH.

^e1b was insoluble.

Employing the optimized conditions in Table 1 (entry 8), a series of aromatic and aliphatic aldehydes were investigated in the one-pot hydroboration-homoallenylation procedure. First, we performed a gram scale reaction of benzaldehyde (5 mmol), providing 5a with 80% isolated yield (Table 2, 1.68 g). Electron-neutral, electron-rich and electron-poor benzaldehyde derivatives with ortho or para substitution were good substrates for the homoallenylation (5a–f, 72–93%, Table 2). Heteroaryl aldehydes including 2-thiophenyl, 2-furyl, 3-furyl, and 2-pyridyl aldehydes also reacted readily to give products (5g–j) in excellent yields (85–94%) with high levels of diastereoselectivity (>20:1). Aliphatic and conjugated aldehydes reacted to give the products 5k–m in 89–92% yield and excellent diastereoselectivity (>20:1).

Table 2.

Substrate scope.^[a,b,c]

R	cmpd	yield (%)	R	cmpd	yield (%)
Ph[d]	5a	95	2-furyl	5h	94
4-C6C4-Me	5b	90	3-furyl	5i	92
4-C6C4-Cl	5c	93	2-py	5j	85
4-C6C4-OMe	5d	72	n-Bu	5k	92
2-C6C4-OMe	5e	93	i-Bu	5l	89
1-Naphthyl	5f	90	1-cyclohexenyl	5m	89
2-thienyl	5g	89

^aConditions: 1a (0.13 mmol), Cy₂BH (0.13 mmol), and aldehydes (0.1 mmol) in THF (0.1 M for aldehyde).

^bIsolated yields.

^cdiastereomeric ratios of all reactions are >20:1.

^d5 mmol of PhCHO was used, 1.68 g 5a, 80% yield.

Intrigued by the high diastereoselectivity in homoallenylation, we then explored utility of our reaction with substituted enynamides. At the outset, we were concerned about the syn/anti selectivity of α-substituted allyl boron reagents. The substituted dienyl nucleophiles would result in three adjacent stereogenic elements, including the axially chiral allenamide. Nonetheless, the methyl-substituted enynamide 1a was subjected to the optimized conditions (Scheme 3). We were pleased to observe that the hydroboration of 1a followed by homoallenylaton of benzaldehyde afforded 5n (>15:1 dr) in 80% isolated yield.

Scheme 3.

Homoallenylation for three continuous stereocenters.

To probe the origin of the observed diastereoselectivity, we performed DFT calculations on the relevant transition states and intermediates leading to the homoallenylation products. We modeled the reaction using the methylsulfonyl (vs tosylsulfonyl) and used a methyl group as model for the alkyl-derived aldehydes (R=CH₃; Table 2) to lower computational costs. Extensive conformational searches were performed but only the lowest energy transition states are discussed herein, computed at the M062X-6-31G(d)^[19] level of theory in THF (CPCM^[20]) as implemented in GAUSSIAN09.^[21] This method has previously been used to explain the selectivity in related systems and other organic processes.^[22] The major diastereomer (6a-(2R*,5S*)) arises from a Zimmerman-Traxler transition state, which favors the alkyl (Me) substituent in the equatorial position (6a-chair-eq) with an overall energy barrier of 11.2 kcal/mol leading to the observed product (Figure 1). Notably, the corresponding chair-like transition state with the alkyl group in an axial position (6a-chair-ax), which would lead to the opposite diastereomer, is greater than 5 kcal/mol higher in energy, presumably due to severe 1,3-diaxial interactions with one of the boron methyl groups. Rather, the formation of the minor diastereomer was calculated to proceed via a boat-like transition state (6a-boat-eq) with an overall energy barrier of 15.7 kcal/mol.

Figure 1.

Relative free energy barriers (∆G in kcal/mol) computed at the M06-2X/6-31G(d) in THF (CPCM solvation model).

Closer inspection of the two lowest energy transition states (Figure 2, 6a-chair-eq and 6a-boat-eq) reveals significant conjugation in the amine-diene-system and has the Ms moiety syn to the vinyl-CH, which avoids steric interactions with the alkyl group of the amine. In both of these transition states, the methyl of the aldehyde avoids severe 1,3-diaxial interactions.

Figure 2.

Lowest energy TS leading to the observed diastereomers with alkyl-derived aldehydes computed using M06-2X/6-31G(d) in THF (CPCM solvation model). Selected distances are in Ångstroms.

Similarly, with the aryl-derived aldehydes the major diastereomer arises from a chair-like transition state while the minor diastereomer, again, arises from the boat-like TS (see Supporting Information). Importantly, this model predicts that the substituted amino-dienes should proceed with high selectivity. For example, a methyl-substituted amino-diene is predicted to proceed to the major diastereomer via a chair-like transition state with similar diastereomeric ratio as the unsubstituted substrates over the three stereochemical elements (see Supporting Information).

While significant efforts have been devoted toward the development of new methods to access chiral allenes, the asymmetric synthesis of allenamides has been limited to chirality transfer reactions of enantioenriched starting materials, which include allenyl halides,^[23] propargyl amides,^[24] propargyl sulfides,^[25] propargyl phosphorimidates,^[26] and esters.^[27] Therefore, a strong demand remains for the development of asymmetric syntheses of enantiomerically enriched allenamides from prochiral starting materials. We therefore performed the hydroboration with (−)-Ipc₂BH, which is readily accessible via Brown’s method.^[28] We were pleased to observe that treatment of enynamide 1b with (−)-Ipc₂BH at −40 °C for 2 h, then warming of the solution to −20 °C over 2 h (condition A), followed by treatment of the resulting 1-amido-2-boryldiene intermediate with benzaldehyde at −78 °C for 5 h provided moderate yields (7–55%) with high diastereoselectivities (>20:1) and good to excellent enantioselectivities (67–91% ee) (Table 3, entries 1–4). Assuming that slow hydroboration at low temperature was responsible for moderate yields, we performed the initial hydroboration at 0 °C then warmed the solution to rt for 40 min followed by cooling to −78 °C and addition of 1.0 equiv of benzaldehyde. Improved yields were obtained (69–75%) with 88–90% ee (entries 5–7). Therefore, increased amounts of 1b and (−)-Ipc₂BH were employed to push the reactions toward completion, resulting in higher yields (76–85%, entries 8–9). Finally, using 2.6 equiv of 1b and (−)-Ipc₂BH with 1 equiv of benzaldehyde in diethyl ether afforded 85% yield with >20:1 diastereoselectivity and 90% ee (entry 9).

Table 3.

Optimization of enantio- and diastereoselective homoallenylation.^[a]

entry	1b : (−)-Ipc2BH : PhCHO	Cond.[b]	Time (h)	solvent	Yield (%)[c]	ee[d]
1	1.3 : 1.3 : 1.0	A	5	CH2Cl2	7	67
2	1.3 : 1.3 : 1.0	A	5	toluene	55	84
3	1.3 : 1.3 : 1.0	A	5	THF	46	80
4	1.3 : 1.3 : 1.0	A	5	Et2O	48	91
5	1.3 : 1.3 : 1.0	B	8	Et2O	69	90
6	1.3 : 1.3 : 1.0	B	8	toluene[e]	75	88
7	1.3 : 1.3 : 1.0	B	8	THF[e]	72	88
8	2.0 : 2.0 : 1.0	B	3.5	Et2O	76	87
9	2.6 : 2.6 : 1.0	B	3.5	Et2O	85	90

^adiastereomeric ratio (dr) was determined by analysis of ¹H NMR spectra of unpurified reaction mixtures.

^bconditions A: −40 °C for 2 h followed by warming to −20 °C over 2 h; conditions B: addition of 1b at 0 °C followed by warming to rt over 40 min.

^cisolated yield.

^denantiomeric excess (ee) was determined by chiral SFC analysis.

^e10% diethyl ether was used.

In summary, we have developed a practical and scalable method for the highly diastereoselective homoallenylation of aldehydes to afford β-hydroxyallenamides. Chemo- and regioselective hydroboration of 3-en-1-ynamides affords 2-boryl dienyl amides. The homoallenylation proceeds under mild conditions with excellent diastereoselectivity (>20:1) and good to excellent yields (72–94%). Reactions with a substituted enynamide generated product with three contiguous stereogenic elements with high dr. Theoretical calculations support the relative stereochemistry of possible diastereomers, for which the homoallenyl group is transferred through a Zimmerman-Traxler transition state. Preliminary results indicate this approach is amenable to the asymmetric synthesis of β-hydroxyallenamides using (−)-Ipc₂BH. We expect that this straightforward and highly diastereoselective method will be useful in the synthesis of diversely functionalized amino-containing products.

Experimental Section

Synthesis and Characterization of β-Hydroxyallenamides 5 via the Homoallenylation of Aldehydes

General Procedure A

Cy₂BH (46.3 mg, 0.26 mmol) was weighed into a 10 mL microwave vial containing a stir bar in a glove box. THF (2 mL) was added to the vial to form a white suspension. The flask was capped with a rubber septum and removed from the glove box. The reaction vial was put under a positive pressure of nitrogen and placed in a 0 °C ice bath. The white suspension was stirred for 5 min. N-Benzyl-N-(but-3-en-1-yn-1-yl)-4-methylbenzenesulfonamide 1b (81.0 mg, 0.26 mmol) was added to the white heterogeneous solution under positive pressure of nitrogen. The ice bath was removed and the reaction mixture was stirred for 10 min at room temperature, during which time the solution became homogeneous. Aldehyde (0.2 mmol) was added dropwise via a microliter syringe, the mixture was stirred for an additional 10 min, and the vial was placed in an ice bath. After stirring for 3 min in the ice bath, saturated aqueous NaHCO₃ (0.5 mL) or aqueous NaOH (0.5 mL, 2 M) was added followed by slow addition of 30% H₂O₂ (1.0 mL). The reaction mixture was stirred vigorously for 5 h at room temperature. Brine (5 mL) was added, the solution mixed and poured into a separatory funnel. The organic layer was separated and the aqueous layer was extracted with Et₂O or EtOAc (3 × 5 mL). The combined organic solution was dried over MgSO₄, filtered, and concentrated under reduced pressure. The ratio of diastereomers was determined by ¹H NMR spectra of unpurified reaction products. The crude product was purified by flash column chromatography on silica gel to afford 5.

Enantioselective Synthesis of N-Benzyl-N-((2S,5S)-5-hydroxy-5-phenylpenta-1,2-dien-1-yl)-4-methylbenzenesulfonamide ((+)-5a)

(−)-Ipc₂BH^[28] (149 mg, 0.52 mmol) was weighed into a 10 mL round bottom flask with a stir bar in a glove box. The flask was capped with a rubber septum, removed from the glove box. The flask was put under a positive pressure of nitrogen and placed in a 0 °C ice bath. Diethyl ether (2.0 mL) was added via a syringe to the flask and the white suspension was cooled to 0 °C in an ice bath for 5 min. N-Benzyl-N-(but-3-en-1-yn-1-yl)-4-methylbenzenesulfonamide 1b (161.9 mg, 0.52 mmol) was added in one portion under positive pressure of nitrogen. The flask was removed from the ice bath, allowed to warm to room temperature and stirred for 40 min. When hydroboration was completed, the solution became colorless and homogeneous. The flask then was cooled to −78 °C in a dry ice/acetone bath and stirred for 5 min. Benzaldehyde (20.3 μL, 0.2 mmol) was added dropwise at −78 °C to the reaction mixture via a microliter syringe. The reaction mixture was stirred at −78 °C for 3.5 h until TLC showed complete consumption of benzaldehyde. MeOH (0.1 mL) was then added dropwise via a syringe at −78 °C and the reaction mixture was placed in an ice bath and stirred for 10 min. Next, saturated aqueous NaHCO₃ (0.5 mL) or aqueous NaOH (0.5 mL, 2M) was added followed by slow addition of 30% aqueous H₂O₂ (1.0 mL). The reaction mixture was stirred for 10 min in the 0 °C ice bath and the ice bath was removed. The reaction mixture was stirred vigorously for 5 h at room temperature. Brine (5 mL) was added, the combined layers were poured into a separatory funnel, the organic layer was separated and the aqueous layer was extracted with Et₂O (3 × 10 mL). The combined organic solution was dried over MgSO₄, filtered, and concentrated under reduced pressure. The ratio of diastereomers was determined by ¹H NMR spectra of unpurified reaction products. The crude product was purified by flash column chromatography on silica gel to afford (+)-5a as a colorless oil (71.3 mg, 85% yield, 90% ee). [α]_D^22.4 = 47.6° (c =0.333, CHCl₃).