The bioinspired design of a reagent allows the functionalization of Cα-H of α,β-unsaturated carbonyl compounds via the Baylis-Hillman chemistry under ambient conditions

Article abstract of DOI:10.1039/c5cc08830e

A rationally designed reagent capable of affecting alkylation at C_α of α,β-unsaturated carbonyl compounds is reported. The reaction proceeded at room temperature without any additives. The pH and H-bond formation during the reaction play a key role in the working of the reagent.

Full text of DOI:10.1039/c5cc08830e

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The bioinspired design of a reagent allows the
functionalization of Ca–H of a,b-unsaturated
carbonyl compounds via the Baylis–Hillman
chemistry under ambient conditions†
Cite this:DOI: 10.1039/c5cc08830e
Received 24th October 2015,
Accepted 11th January 2016
Palwinder Singh,* Arun Kumar, Sukhmeet Kaur, Jagroop Kaur and Harpreet Singh
DOI: 10.1039/c5cc08830e
www.rsc.org/chemcomm
A rationally designed reagent capable of affecting alkylation at Ca of
a,b-unsaturated carbonyl compounds is reported. The reaction
proceeded at room temperature without any additives. The pH and
H-bond formation during the reaction play a key role in the working of
the reagent.
Carbon–carbon bond formation is one of the fundamental
reactions in organic chemistry for which a variety of strategic
approaches have been adopted.1 In the last few decades, the
functionalization of the C–H bond of arenes with C-substituents
for preparing useful compounds has drawn great attention.2
However, the selective activation of a specific C–H bond and the
reaction conditions to tolerate the additional functionality within
the molecule pose great challenges. In continuity with the synthetic
approaches for C–C bond formation, the a,b-unsaturated carbonyl
system is another possible substrate that is part of many natural
products3 and useful synthons/compounds could be synthesized if
we achieved the C–H functionalization of this class of compounds.
Although the C–C bond formation between an a,b-unsaturated
carbonyl compound (activated alkene-nucleophile) and an aldehyde
Scheme 1 TSase catalyzed conversion of dUMP to dTMP. The part of
uracil moiety which is undergoing chemical change is shown in red.
(electrophile) is excellently accomplished through the Baylis– by the Cys residue and the resulting enolate captures a methylene
Hillman reaction,4 this synthetic approach does not cover extensively group from CH2THF – overall the a-H of the a,b-unsaturated
the alkylation/acylation reactions at Ca of the nucleophile.5 Instead, carbonyl system is replaced with the CH3 group (Scheme 1).7d,f
Funk et al. achieved the preparation of 2-alkyl/acylpropenals by Inspired by this natural endeavour and the results of our recent
thermolysis of 5-substituted-4H-1,3-dioxins.6
experiments,8 it was envisaged that reagent 1 could conveniently
When analyzing the enzymatic reactions, we found that the be used for Ca–H functionalization of a,b-unsaturated carbonyl
thymidylate synthase (TSase) catalyzed conversion of 20-deoxy- compounds (Fig. 1).
uridine-50-monophosphate (dUMP) to 20-deoxythymidine-50-mono-
We initially investigated the reaction between acrolein and
phosphate (dTMP) is an excellent example of C–H functionalization reagent 1 (Table 1) (RQCH3, the ester form was preferred to
probably involving the Baylis–Hillman chemistry.7 In this bio- avoid any interference with CysSꢀ). The progress of the reaction
chemical reaction, the a,b-unsaturated carbonyl system constituted was monitored using high resolution mass spectra besides the
by the OQC4–C5QC6 fragment of the uracil moiety is activated use of thin layer chromatography. The formation of a new
product (TLC) was observed after 30 min of the reaction at
Department of Chemistry, UGC Sponsored Centre for Advanced Studies,
pH 8.0 (25–28 1C) with the new peak in the HRMS of the
Guru Nanak Dev University, Amritsar-143005, India.
reaction mixture at m/z 485.1482 corresponding to the m/z of
E-mail: palwinder_singh_2000@yahoo.com; Fax: +91 183-2258819;
adduct 4 (calcd m/z 485.1489, [M + H]+) (Fig. S4, ESI†). We then
Tel: +91 183 2258802 ext 3495
added CH3I to the reaction mixture at pH 8.0. The formation of
† Electronic supplementary information (ESI) available: General procedure, mass
spectra, NMR spectra. See DOI: 10.1039/c5cc08830e
a new species with m/z 499.1636 was detected (Fig. S5, ESI†) but
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In order to explore the versatility of adduct 4 to react with other
electrophiles, it was treated with ethyl bromide, crotyl bromide,
benzyl bromide, allyl bromide, acetyl chloride, benzoyl chloride
and thiophene-2-carboxyl chloride. After stirring the reaction
mixture for 1 h at pH 9.5, the corresponding products 5(b–h)
were produced in moderate to high yields (Table 1, Fig. S7–S21,
ESI†). An electron-donating or -withdrawing substituent on the
benzene ring of benzyl- and benzoyl-chloride was tolerated in
this reaction. It was noticed that the steric hindrance gained
when shifting from an alkylating group to an arylating group
did not affect the yield of the arylated product.
Fig. 1 An overview of the reactions presented in this communication.
Next, we investigated the scope of this reaction with other
a,b-unsaturated carbonyl compounds under the optimized reaction
conditions (Table 2, Fig. S22–S33, ESI†). Crotonaldehyde, cinnam-
aldehyde, mesityl oxide and 4-phenylbut-3-en-2-one coupled
smoothly with reagent 1. The methylation and allylation also
proceeded with no trouble and the corresponding product 8
with anti-configuration at CQC (nOE data, ESI†) was isolated.
Probably, the discrimination between the two faces of the substrate
due to the H-bonding between the carbonyl O of the substrate and
the NH2 of the reagent was responsible for the formation of single
geometrical isomer of products 8.
Table 1 Investigation of the reaction of acrolein with reagent 1 and
further reaction of adduct 4 with various alkylating agents (R0X)
Enthused by the results of the forgoing experiments, the
cyclic substrate such as chromone was also investigated for
Table 2 Reaction of reagent 1 with a,b-unsaturated carbonyl compounds
and further reaction of adduct 7 with alkylating agents
there was no further change in the reaction even after 3 h of
stirring. We changed the pH of the reaction to 9.5. After 1 h of
stirring the reaction mixture at pH 9.5, product 5a was released
from reagent 1 (Table 1) (Fig. S6, ESI†). This result is particularly
significant because it is the first example of the TSase inspired
Baylis–Hillman reaction that proceeds under ambient conditions
without using any metal catalyst.
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Scheme 2 Alkylation of chromone and 2(5H)-furanone.
reaction with reagent 1 (Scheme 2, Fig. S34–S41, ESI†) followed
by the treatment with alkylating agents. We procured product 9
from this reaction. With enantiomerically pure (R)-1-bromoethyl
benzene and (S)-1-bromoethyl benzene, the products (ꢀ)(S)-9g
and (+)(R)-9h were obtained. The assignment of the R/S configuration
is tentative assuming the mechanism to be SN2. Further extending
the synthetic application of the reagent 1, lactone in the form
of 2(5H)-furanone was also alkylated at the C3 carbon and
compound 10, including one carrying octyl group (10j), were
obtained (Scheme 2, Fig. S42–S47, ESI†). As evidenced by the
HRMS and NMR spectra, no ring opening was observed
in the case of chromone and 2(5H)-furanone based products
9 and 10.
Mechanistically, the H-bond formation between the carbonyl
group of the substrate and the NH2 group on acridine seems to
trigger the reaction of CysSꢀ of 1 (RQCH3) at C4 of the substrate.
This was evidenced by (i) the observation that the reaction
progresses at pH 8.0, (ii) the downfield shifting of the NH2 signal
of the acridone in 1H NMR spectrum of the reaction mixture
containing reagent 1 and acrolein (the substrate) (Fig. S48, ESI†),
(iii) the downfield shift of C2 of acrolein in the 13C NMR spectrum
of the reaction mixture (Fig. S48, ESI†) and (iv) no reaction of
compound 2 (Fig. S49, ESI†) with any one of the a,b-unsaturated
carbonyl compounds studied here. The reaction of enolate 11 with
the alkylating agent (most probably through the SN2 mechanism,
ESI†) takes place at pH 8.0. The H-bond seems to play a crucial role
Scheme 3 Plausible mechanism for 1 (RQCH3) mediated Ca alkylation of
a,b-unsaturated carbonyl compounds.
In summary, we demonstrated that the Nature inspired
reagent 1 (RQCH3) provided the first example of metal free
Ca-alkylation/acylation of a,b-unsaturated carbonyl compounds.
The reaction tolerated a wide range of substitutions on the core
fragment and proceeded at room temperature in good yields.
These findings suggest the usefulness of natural synthetic
protocols for laboratory synthesis. Further synthetic applications
of this approach and kinetic studies are ongoing in our laboratory.
Financial assistance by DST and CSIR, New Delhi, is gratefully
acknowledged. AK, SK and HS thank CSIR, New Delhi, and JK
thank DST, New Delhi, for fellowship. The authors acknowledge
UGC, New Delhi, for grant under the UPE programme.
Notes and references
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product (Fig. S50, ESI†) (kinetic study will be given separately).
Since no further change was observed in the reaction mixture after
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(RQCH3) to the carboxyl group at pH 9.5 might have provided
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all in the presence of compound 3 (Fig. S49, ESI†).
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