Indium-Employed One-Pot Sequential Double Nucleophilic Attack on a Symmetrical Dicarboxaldehyde

Abstract

A novel concept of one-pot sequential double nucleophilic attacks using two different nucleophiles to a molecule having identical functionalities was established via an indium-employed ­allylation strategy involving an HOAc quenching after the first ­allylation.

allylation - Barbier type reaction - homoallylic alcohol - indium - one-pot reaction - terminal selectivity

References

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5

The reaction was sluggish and even dropwise addition of prenyl bromide did not furnish good results.

6a Nair V. Ros S. Jayan CN. Viji S. Synthesis  2003,  2542 

6b

Perhaps the success for the mono allylation (Table [1] ) could be due to the relatively low reactivity of allyl chloride as well as dilute reaction medium; however, in the case of prenyl halides, both prenyl chloride and bromide seem to be less reactive towards indium to form the respective allylicindium.

6c

From the results presented in Table [1] (entries 5, 6 as well as 8, 9) addition of NaI enhances the yield of products 5a-c, and it reveals that halide exchange (Cl^-/Br^- of allyl/prenyl halide into the corresponding allyl/prenyl iodide) takes place.

7

It is well known that halide exchange is very fast, but we observed the slow and gradual conversion of allyl chloride into allyl iodide under the conditions as monitored by the ¹H NMR spectrum at regular intervals over 24 h by shaking NaI with allyl chloride in DMF-d ₇.

8

Mono prenylation of aliphatic dialdehyde such as glutaraldehyde (50% aq solution) was established, however, cyclic product 6-(1,1-dimethylallyl)tetrahydropyran-2-ol was obtained. Double allylation of aliphatic dialdehydes will be revealed in full account elsewhere.

9

We performed the quenching with other protic sources such as H₂O and aq HCl; however, in these conditions we observed the formation of mixtures of allylation products.

10

When acetic acid was added immediately after the addition of indium in the first step, this experiment revealed the formation of a bis-prenylation product as well as 7a.

11

General Procedure for the Double Nucleophilic Allylation. To a DMF (7 mL) solution containing the dicarboxaldehyde 4 (0.2 g), NaI (1.6 equiv) were added prenyl bromide (1.6 equiv) and indium powder (1 equiv). The reaction mixture was stirred for 1 h at r.t.; then HOAc (0.6 mL) was added and the stirring was continued for 30-45 min. After this period, to the above reaction mixture were added NaI (1.65 equiv), allyl bromide (1.65 equiv), indium powder (1 equiv) and stirred for further 2-3 h. Followed by this period, the reaction mixture was treated with H₂O and extracted with Et₂O, followed by concentration to afford a crude reaction mixture. The obtained mixture was subjected to column chromatographic purification to furnish the pure products. All new compounds exhibited spectral data consistent with their structures. Representative spectroscopic data of 1-[4-(1-hydroxybut-3-enyl)-phenyl]-2,2-dimethylbut-3-en-1-ol (7a). IR:(neat): 3398, 2978, 1639, 1415, 1052, 914 cm^-1. ¹H NMR (270 MHz, CDCl₃): δ = 7.22 (4 H, s, arom-CH), 5.87 (1 H, dd, J ₁ = 18.0 Hz, J ₂ = 10.5 Hz, =CH), 5.80-5.68 (1 H, m), 5.13-4.99 (4 H, m), 4.65 (1 H, t, J = 6.5 Hz, HOCH), 4.36 (1 H, s, HOCH), 2.50 (2 H, br s, OH), 2.45 (2 H, t, J = 6.8 Hz), 0.97 (3 H, s, CH ₃), 0.92 (3 H, s, CH ₃). ¹³C NMR (67.9 MHz, CDCl₃):
δ = 144.84 (=CH), 142.78 (quart-C), 139.88 (quart-C), 134.34 (=CH), 127.62 (=CH), 124.80 (=CH), 118.02 (=CH₂), 113.59 (=CH₂), 80.31 (HOCH), 73.00 (HOCH), 43.63 (CH₂), 42.07 (quart-C), 24.30 (CH₃), 21.10 (CH₃). MS (CI): m/z (%) = 247 (1) [M⁺ + 1], 229 (84), 211 (14), 187 (6), 159 (100), 131 (2). HRMS (CI): m/z calcd for C₁₆H₂₃O₂: 247.1698. Found: 247.1693 [M⁺ + 1].