Highly selective 4-alkynoic acids synthesis via iron-mediated complete inversion of stereogenic carbon centers

Abstract

An Fe-catalyzed highly regio- and diastereoselective reaction of 4-ethynyloxetan-2-ones with different Grignard reagents affording alkynes 3 in good yields with absolute configuration of the β-carbon atom completely inverted has been developed. The optically active acids may be easily converted to esters, which may easily undergo desilylation and highly diastereoselective allenylation to afford optically active 4,5-allenoates with two chiral centers and one axial allene chirality.

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Introduction

As is well known, the stereoselectivity in the reaction of a chiral carbon center bearing a leaving group such as halide, tosylate, or tosylamide with a hard carbon nucleophile, such as Grignard reagents, lithium reagents, or lithium cuprates, is a basic topic of current interest with either high stereoselectivity for inversion or partial racemization.^1–9 Although iron compounds or complexes have been recently reported to be very efficient catalysts for many organic transformations,¹⁰ the FeCl₃-catalyzed reactions of ArMgX with optically active alkyl bromides proceed with complete racemization.¹¹ Surprisingly, such reactions with the more readily available yet stable acetates are quite limited (Scheme 1).¹²

Scheme 1 Inversion of a chiral carbon center.

On the other hand, in 2000, Nelson et al. reported the Cu(I)-catalyzed S_N2′ type coupling reaction of 4-(trimethylsilylethynyl) oxetan-2-one 1 with alkyl Grignard reagents for the synthesis of β-allenoic acid derivatives 2 together with the formation of γ-propargylic acids 3 as the minor products (eqn (1));^13–15 Fürstner et al. reported the Fe(acac)₃-catalyzed reaction of Grignard reagents with 1-alkynyl epoxides affording 2,3-allenols¹⁶ and the [Fe(MgX)₂]_n-catalyzed coupling reaction of primary propargylic bromides with Grignard reagents affording alkynes.^17–19 Herein, we wish to report the highly regio- and stereo-selective Fe-catalyzed reaction of 4-(trimethylsilylethynyl)oxetan-2-one 1 with Grignard reagents affording 4-alkynoic acids 3 with absolute configuration of the chiral center being completely inverted.

Results and discussion

During the study of the reaction of cis-3-methyl-4-(trimethylsilylethynyl)oxetan-2-one 1a with 3 equiv. of MeMgCl, it was observed that the reaction catalyzed by 10 mol% of Fe(acac)₃ at −78 °C afforded 2,3-dimethyl-5-(trimethylsilyl)pent-4-ynoic acid 3a as the major product with a selectivity of 3a/2a = 97/3 and dr value of 3a being about 100/0 as judged by the ¹H NMR analysis of the crude reaction mixture (entry 1, Table 1). Other solvents such as Et₂O and toluene led to a lower yield and selectivity (entries 2 and 3, Table 1). FeCl₃·6H₂O demonstrated a similar results and the loading of catalyst could be reduced to 5 mol% (entries 6 and 7, Table 1). Anhydrous FeCl₃ catalyzed this transformation affording 3a in 61% yield together with 2a in 3% yield (entry 8, Table 1). Iron salt is vital to the coupling reaction: neither 3a nor 2a was provided from the blank test and the control experiment with CuCl as catalyst (entries 9 and 10, Table 1).

Table 1 Effects of catalyst and solvent on the coupling of MeMgCl with 1a^a

Entry	Cat. (mol%)	Solvent	Yield of 3a^b (%)	3a/2a
a The reaction was conducted using 0.2 mmol of 1a, 3 equiv. of MeMgCl, and the indicated amount of the corresponding catalyst in 3 mL of solvent. b NMR yield. c The reaction time was 1.0 h. d 1 mmol of 1a was applied and the reaction time was 1 h. e Recovery: 80%. f Recovery: 77%.
1	Fe(acac)3 (10)	THF	86	97/3
2	Fe(acac)3 (10)	Et2O	79	95/5
3	Fe(acac)3 (10)	Toluene	77	95/5
4	Fe(acac)2 (10)	THF	87	97/3
5^c	FeCl2 (10)	THF	87	98/2
6	FeCl3·6H2O (10)	THF	83	96/4
7^d	FeCl3·6H2O (5)	THF	88	98/2
8	FeCl3 (10)	THF	61	95/5
9^e	CuCl (10)	THF	0	—
10^f	—	THF	0	—

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The structure, as well as the relative configurations of the two chiral centers of 3a, was unambiguously established by its single crystal X-ray diffraction analysis (Fig. 1),²⁰ which clearly indicated that the in situ generated metallic reagent undergoes an S_N2 substitution reaction at the β-position of 4-(trimethylsilylethynyl)oxetan-2-one affording 4-alkynoic acid 3 with the configuration of this carbon center inverted.

Fig. 1 ORTEP representation of the product 3a.

Under this set of optimized reaction conditions, the scope and the limitations of this reaction were explored. The reaction of 1b with MeMgCl afforded 2,3-dimethyl-5-(trimethylsilyl)pent-4-ynoic acid 3b with a yield of 84% and a selectivity of 97/3 (entry 1, Table 2). Aryl Grignard reagents could also be used in the reaction providing the corresponding products 3 in 73–89% yield with a regioselectivity of 93/7–97/3 (entries 2 and 5–8, Table 2). Different alkyl or allyl substituents could be introduced into the 2-position of the products in yields of 78%–87% with excellent ratios of 97/3–99/1 of 3/2 (entries 3 and 9–11, Table 2).

Table 2 Substrate scope of the FeCl₃·6H₂O-catalyzed coupling reactions of racemic 1 with Grignard reagents^a

Entry	R^1	R^2	Yield of 3 (%)	3/2
a The reaction was conducted using 1 mmol of 1, 3 equiv. of Grignard reagents, and 5 mol% of FeCl3·6H2O in 5 mL of THF. b 0.4 mmol of 1a was applied. c The reaction time was 1.5 h. d 0.5 mmol of 1d was applied. e TES was used instead of TMS.
1	H (1b)	Me	84 (3b)	97/3
2	H (1b)	Ph	80 (3c)	94/6
3	Me (1a)	Me	84 (3a)	98/2
4^b	Me (1a)	Ph	88 (3d)	96/4
5	Me (1a)	p-MeC6H4	78 (3e)	95/5
6	Me (1a)	m-MeC6H4	79 (3f)	93/7
7	Me (1a)	p-MeOC6H4	73 (3g)	95/5
8	Me (1a)	2-Thienyl	89 (3h)	97/3
9^c	CH2CH2Cl (1c)	Me	78 (3i)	97/3
10^d	Allyl (1d)	Me	87 (3j)	99/1
11^c^,^e	n-C3H7 (1e)	Me	77 (3k)	98/2

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Based on these observations, we were anxious to see whether various optically active substrates 1 may be applied to this Fe-catalyzed coupling reaction. Interestingly, when optically active 4-(trimethylsilylethynyl)oxetan-2-ones were treated with different Grignard reagents, the corresponding optically active 4-alkynoic acids 3 were formed without any racemization (Table 3). Furthermore, we may easily conduct the reaction of 0.8976 g of (2R,3R)-1g and 0.8934 g of (2S,3S)-1g affording 0.9015 g of (2R,3S)-3m and 0.8967 g of (2S,3R)-3m in excellent yield and selectivity (entries 7 and 8, Table 3).

Table 3 Substrate scope of the diastereoselective transformation of β-lactones 1 to 4-alkynoic acids 3^a

Entry	1	R^2	Yield of 3 (%) (ee%)	3/2
	R^1 (ee%)
a The reaction was conducted using 1 mmol of 1, 3 equiv. of Grignard reagents, and 5 mol% of FeCl3·6H2O in 5 mL of THF. b The reaction time was 2 h. c TBS was used instead of TMS and 4 mmol of the 1g were applied.
1	(S,S)-1a Me (98)	Me	81 (99) (S,R)-3a	98/2
2	(S,S)-1a Me (98)	Ph	77 (98) (S,R)-3d	95/5
3^b	(S,S)-1a Me (98)	PMP	72 (97) (S,R)-3g	95/5
4	(R,R)-1d allyl(99)	Me	81 (98) (R,S)-3j	99/1
5	(S,S)-1f^nPr (97)	Me	74 (97) (S,R)-3l	98/2
6	(R,R)-1f^nPr (>99)	Me	73 (>99) (R,S)-3l	97/3
7^c	(S,S)-1g Me(>99)	Me	94 (99) (S,R)-3m	98/2
8^c	(R,R)-1g Me(>99)	Me	94 (98) (R,S)-3m	99/1

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However, the reaction of FeCl₃·6H₂O-catalyzed coupling of 1b bearing just one chiral center with n-C₄H₉MgCl afforded a complex mixture (entry 1, Table 4) while a ratio of 75/25 of 3/2 was observed when Fe(acac)₃ was used instead of FeCl₃·6H₂O (entry 2, Table 4). Et₂O appeared better than THF (entry 3, Table 4) and the addition of 1 equiv. of NaI, added as ligand, also helped (entry 4, Table 4). By comparing the results with these shown in Table 3, we reasoned that water from FeCl₃·6H₂O may have a unique role. In fact, the addition of 0.3 equiv. of H₂O did further improve the regioselectivity of this coupling reaction using Fe(acac)₃ as the catalyst (entries 4 and 5, Table 4). The reactions of 1b with n-C₄H₉MgCl and n-C₅H₁₁MgCl afforded the corresponding products 3n and 3o in 71% and 69% yields with an excellent ratio of 94/6 of 3/2 (entries 5 and 6, Table 4).

Table 4 Fe(acac)₃-catalyzed coupling reactions of 1b with alkyl Grignard reagents^a

Entry	R^2MgCl	Solvent	Additive	Yield of 3^b (%)	3/2
a The reaction was conducted using 0.2 mmol of 1b, 3.5 equiv. of the Grignard reagent, 5 mol% of Fe(acac)3, 1 equiv. of NaI (if required), 0.3 equiv. H2O (if required), 2 mL of solvent. b Isolated yield of 3. c FeCl3·6H2O was applied. d 1 mmol of 1b was applied.
1^c	n-C4H9	THF	—	Complex mixture
2	n-C4H9	THF	—	60 (3n)	75/25
3	n-C4H9	Et2O	—	70 (3n)	89/11
4	n-C4H9	Et2O	NaI	64 (3n)	91/9
5^d	n-C4H9	Et2O	NaI–H2O	71 (3n)	94/6
6^d	n-C5H11	Et2O	NaI–H2O	69 (3o)	94/6

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Furthermore, we conducted the S_N2 substitution reaction of (R)-1b with a single chiral center with n-C₄H₉MgCl affording (S)-3n without any racemization in 68% yield with a ratio of 94/6 of (S)-3n/(R_a)-2n (eqn (3)).

These “inverted” observations led to the conclusion that the mechanism is different from the reported one under Fe-catalysis with the coordination-directed direct delivery of the R group¹⁶ from the in situ generated highly reduced iron–magnesium cluster reagent.¹⁷ We believed that the attack of the R² from in situ generated highly reduced iron–magnesium cluster reagent R²–M at the 4-position of 4-(trimethylsilyl)ethynyloxetan-2-one (2S,3S)-1 may be mediated by the Lewis acidic species in the solution coordinating with the oxygen atom to afford (2S,3R)-3. The steric effect of the trimethylsilylacetylenyl group is beneficial to this transformation. The configuration of the chiral center in the products (2S,3R)-3 followed the Walden inversion which shows that the coupling reaction proceeds via an S_N2 mechanism with complete inversion of the carbon center (Scheme 2).²¹

Scheme 2 Rationale for the inverted absolute configuration.

It is well established that the extra C–C triple bond in the products is synthetically very useful in organic synthesis, undergoing many reactions²² such as highly stereoselective ionic additions, semi-hydrogenation, complete hydrogenation, and manipulation based on the terminal acidic C–H bond. In addition to these known protocols, here, (2S,3R)-5-(t-butyldimethylsilyl)-2,3-dimethylpent-4-ynoic acid (2S,3R)-3m was converted to the benzyl ester easily, which was followed by desilylation by treating with TBAF. This terminal alkynoic acid ester may undergo an enantioselective allenylation of terminal alkyne reaction (EATA) with (R)- or (S)-diphenylprolinol and CyCHO²³ providing (S_a,2S,3S)-benzyl-6-cyclohexyl-2,3-dimethylhexa-4,5-dienoate (S_a,2S,3S)-5 or (R_a,2S,3S)-benzyl-6-cyclohexyl-2,3-dimethylhexa-4,5-dienoate (R_a,2S,3S)-5 in excellent de and ee (Scheme 3). The absolute configuration of the allene unit has been assigned based on our previous report.²³ Likewise, its enantiomers (S_a,2R,3R)-5 and (R_a,2R,3R)-5 could be prepared similarly by using (2R,3S)-5-(t-butyldimethylsilyl)-2,3-dimethylpent-4-ynoic acid (2R,3S)-3m as the starting material.

Scheme 3 Synthesis of four diastereoisomers of 5 with two asymmetric carbon centers and one axially chiral allene. (a) 1.5 equiv. BnBr, 3 equiv. NaHCO₃, DMF, 30 °C, 16 h. (b) i. 1 equiv. TBAF, THF, rt, 2 h; ii: 1.8 equiv. CyCHO, 0.8 equiv. ZnBr₂, 1.25 equiv. (R)-diphenylprolinol, toluene, 120 °C, 24 h. (c) i. 1 equiv. TBAF, THF, rt, 2 h; ii. 1.8 equiv. CyCHO, 0.8 equiv. ZnBr₂, 1.25 equiv. (S)-diphenylprolinol, toluene, 120 °C, 24 h.

In addition, (2S,3R)-4m may undergo a desilylation reaction followed by a Sonogashira coupling²⁴ with PhI to afford (2S,3R)-benzyl 2,3-dimethyl-5-phenylpent-4-ynoate (2S,3R)-6, which further extends the potential of this reaction by introducing an extra substituent at this location (eqn (4)).

In summary, we have achieved an Fe-catalyzed highly regio- and stereoselective coupling reaction of 4-ethynyl-oxetan-2-ones with different Grignard reagents affording 4-alkynoic acids in good yields with the absolute configuration of the β-carbon atom completely inverted. The optically active acids may be easily esterified, which may be followed by desilylation to unveil the attractive terminal C–C triple bond for arylation or enantioselective allenylation (EATA) to afford optically active 4,5-allenoates with defined advanced steric nature. Although the mechanism, especially the real nature of the in situ generated metallic species and the role of NaI as well as water, is far from clear, due to the easy availability of the Fe-catalyst and optically active starting materials,²⁵ high regio- and stereo-selectivity, and potential of the products, this reaction will be useful in organic synthesis involving multiple chiralities. Further studies including the effect of water in this area are ongoing in our laboratory.

Experimental

1. Fe-catalyzed S_N2 coupling reaction of Grignard reagent with 1. Synthesis of 2,3-dimethyl-5-(trimethylsilyl)pent-4-ynoic acid 3a

Typical procedure. To a mixture of FeCl₃·6H₂O (13.7 mg, 0.05 mmol), 1a (183.0 mg, 1 mmol), and THF (5 mL) was added dropwise a solution of MeMgCl (1 mL, 3 M in THF, 3 mmol) at − 78 °C within 3 min under N₂ atmosphere. After being stirred at −78 °C for 1 h, the reaction mixture was quenched with EtOH (0.5 mL), and then acidified with 5% HCl (aq.) to pH = 1. The resulting mixture was extracted with ether (15 mL × 3), washed with brine, filtered, and evaporated. The ratio of 3a/2a (= 98/2) was determined by ¹H NMR analysis of the crude reaction mixture before separation. The residue was purified by flash chromatography on silica gel (eluent: petroleum ether–ethyl acetate = 10 : 1–2 : 1 to afford 3a (167.3 mg, 84%): Solid: m.p. 67.3–68.4 °C (hexane–ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 10.54 (brs, 1 H, COOH), 2.83 (pentet, J = 7.2 Hz, 1 H, CH), 2.42 (pentet, J = 7.2 Hz, 1 H, CH), 1.32 (d, J = 6.9 Hz, 3 H, CH₃), 1.22 (d, J = 6.9 Hz, 3 H, CH₃), 0.14 (s, 9 H, 3 × CH₃Si); ¹³C NMR (CDCl₃, 75 MHz) δ 181.6, 108.0, 86.6, 45.1, 30.0, 19.4, 14.8, 0.1; IR (neat, cm⁻¹) 2977, 2938, 2899, 2169, 1712, 1460, 1427, 1373, 1268, 1245, 1212, 1088; MS (EI) m/z (%) 198 (M⁺, 0.23), 183 ((M − CH₃)⁺, 20.67), 75 (100); Elemental analysis calcd for C₁₀H₁₈O₂Si: C, 60.56, H, 9.15, found: C, 60.40, H, 8.95%.

2. Desilylation and enantioselective allenylation of 4m. Synthesis of (S_a,2S,3S)-benzyl 6-cyclohexyl-2,3-dimethylhexa-4,5-dienoate (S_a,2S,3S)-5

Typical procedure. To a solution of (2S,3R)-4m (164.5 mg, 0.50 mmol) in THF (3 mL) was added TBAF (0.5 mL, 1 M in THF, 0.5 mmol). After stirring for 2 h at rt, the resulting solution was quenched with water (5 mL), extracted with ether (15 mL × 3), washed with brine, dried over Na₂SO₄, filtered, and evaporated. The residue was purified by flash chromatography on silica gel (eluent: petroleum ether–ethyl ether = 60 : 1) to afford (2S,3R)-benzyl 2,3-dimethylpent-4-ynoate (2S,3R)-4o, which was used directly in the next step.

To a reaction tube was added ZnBr₂ (90.3 g, 0.40 mmol). This reaction tube was then dried under vacuum with a heating gun. (R)-Diphenylprolinol (156.4 mg, 0.62 mmol), CyCHO (101.2 mg, 0.90 mmol)/toluene (1 mL), and (2S,3R)-benzyl 2,3-dimethylpent-4-ynoate (2S,3R)-4o/toluene (2 mL) were then added sequentially under a N₂ atmosphere. The reaction tube was then placed in a pre-heated oil bath at 120 °C. After the reaction was complete as monitored by TLC, the reaction mixture was cooled to rt and the crude reaction mixture was filtered through a short pad of silica gel (2 cm) eluted with ether. After evaporation, the residue was purified by flash chromatography on silica gel (petroleum ether–ethyl ether = 80 : 1) to afford (S_a,2S,3S)-5 (88.5 mg, 57%, 99% ee: HPLC conditions: OJ-H column, rate = 0.7 mL min⁻¹, eluent: hexane–i-PrOH = 400 : 1, λ = 214 nm, t_R 14.8 min (minor), 15.8 min (major)): Liquid; [α]²⁰_D = +11.6 (c = 1.82, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 7.40–7.30 (m, 5 H, ArH), 5.19–5.00 (m, 4 H, CH₂ + 2 × CH=), 2.58–2.35 (m, 2 H, 2 × CH), 2.01–1.85 (m, 1 H, CH), 1.80–1.56 (m, 5 H, 5 protons of Cy), 1.35–0.95 (m, 11 H, 5 protons of Cy + 2 × CH₃); ¹³C NMR (CDCl₃, 75 MHz) δ 202.4, 175.6, 136.0, 128.5, 128.1, 98.2, 94.2, 66.0, 45.5, 37.1, 36.6, 33.04, 33.00, 26.1, 26.0, 18.4, 14.1; IR (neat, cm⁻¹) 2966, 2925, 2851, 1959, 1735, 1498, 1449, 1379, 1345, 1254, 1219, 1158; MS (EI) m/z (%) 312 (M⁺, 1.10), 165 (100), 91 (100), 69 (100); HRMS calcd for C₂₁H₂₈O₂ (M⁺): 312.2089, found: 312.2092.

Acknowledgements

Financial support from the National Basic Research Program of China (2011CB808700) and National Natural Science Foundation of China (21232006) is greatly appreciated. S. Ma is a Qiu Shi Adjunct Professor at Zhejiang University. We thank Miss Qiong Yu in this group for reproducing the preparation of 3d, (2S,3R)-3l, and 3o.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and detailed characterization data for all new compounds. CCDC 940135. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3qo00066d

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