Evaluation of Baylis-Hillman Routes to 3-(Aminomethyl)coumarin Derivatives

Article abstract of DOI:10.1080/00397911.2013.803575

The relative merits of two different Baylis-Hillman approaches toward the preparation of coumarin derivatives, containing peptide-like side chains, have been explored. In one approach, use of methyl acrylate as the activated alkene requires a protecting group strategy, an approach that is not necessary when using tert-butyl acrylate. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.803575

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Evaluation of Baylis-Hillman Routes to 3-
(Aminomethyl)coumarin Derivatives
Idris Olasupo a , Nathan R. Rose a c , Rosalyn Klein a , Luqman A. Adams b , Oluwole B.
Familoni b & Perry T. Kaye a
a Department of Chemistry and Centre for Chemico- and Biomedicinal Research , Rhodes
University , Grahamstown , South Africa
b Department of Chemistry , University of Lagos , Nigeria
c Department of Biochemistry , University of Oxford , Oxford , UK
Accepted author version posted online: 27 Aug 2013.
To cite this article: Synthetic Communications (2013): Evaluation of Baylis-Hillman Routes to 3-(Aminomethyl)coumarin
Derivatives, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI: 10.1080/00397911.2013.803575
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Evaluation of Baylis-Hillman routes to 3-(aminomethyl)coumarin derivatives
Idris Olasupo1, Nathan R. Rose1,3, Rosalyn Klein1, Luqman A. Adams2, Oluwole B.
Familoni2, Perry T. Kaye1,
1Department of Chemistry and Centre for Chemico- and Biomedicinal Research, Rhodes
University, Grahamstown, South Africa 2Department of Chemistry, University of Lagos,
Nigeria 3Department of Biochemistry, University of Oxford, Oxford, UK
, E-mail: P.Kaye@ru.ac.za
Abstract
The relative merits of two different Baylis-Hillman approaches towards the
preparation of coumarin derivatives, containing peptide-like side-chains, have been
explored. In one approach, use of methyl acrylate as the activated alkene requires a
protecting group strategy an approach which is not necessary when using tert-butyl
acrylate.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
KEYWORDS: Baylis-Hillman, aza-Michael, 3-(aminomethyl)coumarins
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INTRODUCTION
The coumarin motif is often associated with pharmacological activity[1] and is present in
phenprocoumon 1,[2] a competitive HIV-1 protease inhibitor, and in the anti-coagulant,
Warfarin 2,[3] which has shown weak activity against HIV-1 protease. In research on
applications of Baylis-Hillman methodology in the construction of benzannulated
heterocycles, we reported the formation of complex mixtures of coumarin and chromene
derivatives from the 1,4-diazabicyclo[2.2.2]octane (DABCO)-catalysed reactions of
salicylaldehyde with methyl acrylate.[4,5] Chemoselective access to chromenes was
achieved by using activated alkenes which precluded nucleophilic acyl substitution.[6]
Access to the coumarin analogues, on the other hand, initially required the application of
protection strategies.[7] Subsequently, however, it was found that use of tert-butyl acrylate
as the activated alkene permitted isolation of the corresponding o-hydroxybenzaldehyde-
derived Baylis-Hillman adducts and, importantly, their chemoselective cyclisation to
coumarin derivatives.[8]
Structures 1-3
In applications of this chemistry, we have been exploring the preparation of potential,
coumarin-based HIV-1 protease inhibitors and coumarin-AZT conjugates (e.g.,
compound 3)[9] as dual-action HIV-1 protease and reverse transcriptase inhibitors.
Nagesam et al.[10] have reported the synthesis of antibacterial 4,6-dimethyl-3-
(aminomethyl)coumarins from 3-(chloromethyl)-4,6-dimethylcoumarin, while Savel’ev
et al.[11] have applied Mannich chemistry to access 4-substituted 3-(pyrrolidinomethyl)-
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and 3-(piperidinomethyl)coumarins, which exhibit weak psychotropic activity. A search
of the literature has, surprisingly, revealed only one example of a 3-
(aminomethyl)coumarin in which the coumarin moiety is unsubstituted at position 4; it
was prepared by Sokolov et al.[12] using a very different pathway. 4-Chloro-, 4-hydroxy-
and 4-methyl analogues were reported in the same paper as possible water-soluble
luminophores and laser dyes. We now describe the preparation of a series of 3-
(aminomethyl)coumarins, unsubstituted at position 4, using two different Baylis-Hillman-
based strategies.
DISCUSSION
As outlined in Scheme 1 (ROUTE I), reaction of the o-hydroxybenzaldehydes 4a-d with
benzyl bromide in the presence of K2CO3 and NaI afforded the corresponding O-
benzylated derivatives 5a-d in moderate to good yield (57-76%). DABCO-catalysed
reaction of the protected o-hydroxybenzaldehydes 5a-d with methyl acrylate in CHCl3
gave the Baylis-Hillman adducts 6a-d in good yield (73-85%). These adducts were then
subjected to aza-Michael addition of S-benzylcysteamine hydrochloride to afford
mixtures of the distereomeric products 7a-d in 62-93% yield, preparative layer
chromatography (PLC) permitting isolation of individual diastereomers for
characterisation. Treatment of the diastereomeric conjugate addition products 7a-d with a
mixture of conc. HCl, AcOH and Ac2O led, via tandem deprotection, cyclisation and
dehydration to the desired achiral 3-substituted coumarins 8a-d in disappointingly low
yields (11-27%) following PLC. The deprotection step may well involve the formation of
an o-quinone methide intermediate.
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DABCO-catalysed reaction of the unprotected o-hydroxybenzaldehydes 4a-e with tert-
butyl acrylate (ROUTE II), on the other hand, provided access to the stable Baylis-
Hillman adducts 9a-e, which we have previously isolated in yields of 36 – 66%.[8,9] These
reactions tend to be very slow, and the formation of the adducts 9a-c was confirmed by
1H NMR analysis of the crude products, which were used without further purification in
the next step of the synthesis. The adducts 9d and 9e, however, precipitated out of the
reaction solution and were simply washed with chloroform prior to use. Reaction of the
Baylis-Hillman adducts 9a-e with conc. HCl in refluxing AcOH facilitated cyclisation via
nucleophilic acyl substitution and dehydration to give the 3-(chloromethyl)coumarins
10a-e, which we have previously obtained in yields of 79 – 94%.[8] Although there is
room for improvement in the yields for the Baylis-Hillman step, the second step
involving cyclization to the coumarins appears to proceed virtually quantitatively. Unlike
their methyl ester analogues the tert-butyl ester Baylis-Hillman adducts 9a-e do not
cyclise spontaneously, and coumarin formation follows treatment with HCl. The 3-
(chloromethyl)coumarins 10a-e were reacted with the commercially available
hydrochloride salts of glycine ethyl ester, L-serine ethyl ester and S-benzylcysteamine
using Proton Sponge® [1,8-bis(dimethylamino)-naphthalene] to effect in situ
neutralization and release of the nucleophilic amino groups (Scheme 1). Proton Sponge®
was finally used to neutralise the amine hydrochlorides after various attempts using
NaHCO3 or NaOH had proved to be impractical; this base has found use in
phosphorylation reactions[14] but not, to our knowledge, for the neutralistion of
problematic amine hydrochlorides. Flash chromatography or HPLC of the crude products
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yielded both the monocoumarinated (8d-j) and the dicoumarinated (11d-i) amino
products, all of which are new compounds.[16] Although the isolated yields varied,
competing attack at either C-4 or C-2 of the coumarin nucleus was not observed in any of
these reactions. Isolation of the L-serine derivative 8j in excellent (92%) yield after radial
chromatography is significant given our interest in accessing peptidomimetic coumarin
derivatives as potential HIV-1 protease inhibitors.
In rationalising the observed regioselectivity of nucleophilic attack on the 3-
(chloromethyl)coumarins 10, the electrophilicity of three centres needs to be considered
(C-1’, C-2 and C-4; Scheme 2). Thus, suitable nucleophiles might be expected, a priori,
to attack: - i) the lactone carbonyl carbon (C-2), leading to acyl substitution and ring-
opening; ii) the vinylic centre (C-4), leading to conjugate addition or SN’ displacement of
chloride; and/or iii) the exocyclic 3-chloromethyl carbon (C-1’), resulting in nucleophilic
substitution. We have previously observed[15] that nitrogen and carbon nucleophiles
appear to attack these systems exclusively at the exocyclic centre (C-1’) – a pattern which
is also apparent in the present study. The electrophilicity of the 3-chloromethyl carbon is
further evidenced by the isolation, in most cases, of the tertiary amine products 11,
arising from nucleophilic attack by the relatively hindered secondary amines 8 on a
second 3-(chloromethyl)coumarin molecule. It may be argued that nucleophilic attack on
the 3-(chloromethyl)coumarins 10a-e (with displacement of Cl-) should be favoured at
the exocyclic electrophilic centre (Path B; Scheme 2) since an SN process would not
compromise the overall aromaticity of the coumarin nucleus. Attack at either C-4 [via
conjugate addition or an SN’ process (Path A)] or at C-2 to afford a tetrahedral
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intermediate (Path C) would interrupt conjugation in the heterocylic moiety and, hence,
its overall aromaticity, thus destabilizing the respective transition state complexes.
CONCLUSIONS
Access to eleven novel 3-(aminomethyl)coumarin derivatives 8 and, in most cases, their
bis-coumarin analogues 11 has been successfully achieved using two different Baylis-
Hillman approaches. Subject to optimization of the initial reaction with tert-butyl
acrylate, Route II would appear to be the approach of choice for the construction of more
complex peptidomimetic analogues.
EXPERIMENTAL
NMR spectra were recorded on Bruker 400 MHz AVANCE or Bruker 600 MHz Biospin
spectrometers and were referenced using solvent signals (δH: 7.26 ppm for residual
CHCl3; δC: 77.0 ppm for CDCl3). High-resolution mass spectra were recorded at the
University of Witwatersrand or the University of Stellenbosch. Melting points were
determined using a hot-stage apparatus and are uncorrected. The general synthetic
procedures are detailed below. Analytical data for other new compounds obtained in this
study are provided in the Supplementary Information, available online.
General procedures for known compounds, 5a-d and 6a-d,[7] 9a-e[9] and 10a-e[8,13] have
been reported elsewhere.
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The general procedure for the preparation of the aza-Michael addition products 7a-d is
illustrated by the following example.
A mixture of methyl 3-(2-benzyloxyphenyl)-3-hydroxy-2-methylenepropanoate 6a (0.30
g, 1.0 mmol), S-benzylcysteamine hydrochloride (0.61 g, 3.0 mmol), sodium acetate
(0.25 g, 3.0 mmol) and TBAB (0.64 g, 2.0 mmol) in dry MeOH (5.0 ml) was stirred in a
stoppered flask for 10 d. The mixture was concentrated in vacuo to give a brown oil,
which was purified by PLC [on silica; elution with EtOAc-hexane (1:2)] to afford the two
diastereomeric methyl 3-(2-benzyloxyphenyl)-2-[(benzylthio)-ethylamino)methyl]-3-
hydroxy-propanoate products 7a1 and 7a2 (0.43 g, 93.1%); further PLC afforded the pure
diastereomers.
Diastereomer 7a1 as a yellow oil (176 mg, 37.9%) (Found M+: 465.198166. C27H31NO4S
requires M, 465.197381); δH (400 MHz; CDCl3) 2.46 (1H, dd, J 4.8Hz and 8.4Hz, 3’-
CHA), 2.50 - 2.54 (2H, m, 5’-CH2), 2.61 - 2.68 (2H, m, 4’-CH2), 3.09 (2H, d, J 9.2Hz, 2-
CH and 3’-CHB), 3.71 (2H, s, 6’-CH2), 3.76 (3H, s, 1’-OCH3), 5.12 (2H, s, OCH2Ph),
5.75 (1H, s, CHOH), 6.94 (1H, d, J 8.4Hz, Ar-H), 7.04 (1H, t, J 7.2Hz, Ar-H), 7.24 - 7.34
(7H, series of overlapping multiplets, Ar-H), 7.38 (2H, t, J 7.2Hz, Ar-H) 7.48 (2H, d, J
7.6Hz, Ar-H) 7.58 (1H, d, J 7.6Hz, Ar-H); δC (100 MHz; CDCl3) 31.0 (5’-CH2), 36.1 (6’-
CH2), 46.5 (3’-CH2), 47.4 (2-CH), 48.4 (4’-CH2), 51.9 (1’-OCH3), 69.6 (3-CHOH), 71.7
(OCH2Ph), 111.4, 120.8, 126.7, 127.0, 127.1 127.7, 128.1, 128.4, 128.7, 131.6, 136.9,
138.2 and 154.5 (Ar-C) and 174.0 (C=O); m/z 465 (M+ 46%) and 91 (100).
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Diastereomer 7a2 as a yellow oil (114 mg, 24.6%) (Found M+: 465.194878. C27H31NO4S
requires M, 465.197381); δH (400 MHz; CDCl3) 2.47 (2H, t, J 6.4Hz, 5’-CH2), 2.60 -
2.70 (2H, m, 4’-CH2), 2.80 (1H, q, J 6.0Hz, 3’-CHA), 2.90 (2H, dd, J 4.8Hz and 12.0Hz,
3’-CHB and NH ), 3.15 (1H, d, J 6.0Hz, 2-CH), 3.51 (3H, s, 1’-OCH3), 3.67 (2H, s, 6’-
CH2), 5.10 (2H, d, J 2.8Hz, OCH2Ph), 5.32 (1H, d, J 4.8Hz, CHOH), 6.93 (1H, d, J
8.0Hz, Ar-H), 6.98 (1H, t, J 7.6Hz, Ar-H), 7.21 - 7.41 (12H, series of overlapping
multiplets, Ar-H), δC (100 MHz; CDCl3) 31.2 (5’-CH2), 36.1 (6’-CH2), 48.2 (4’-CH2),
49.4 (3’-CH2), 50.2 (2-CH), 51.4 (1’-OCH3), 70.1 (OCH2Ph), 70.6 (3-CHOH), 111.5,
120.9, 127.0, 127.2 128.0, 128.4, 128.5, 128.6, 128.8, 130.3, 136.8, 138.3 and 155.0 (Ar-
C) and 174.0 (C=O); m/z 465 (M+ 30%) and 148 (100).
The general procedure (Route I) for the preparation of the coumarin derivatives 8a-d is
illustrated by the following example.
Conc. HCl (2.0 ml) was added to a solution of the diastereomeric methyl 3-(2-
benzyloxyphenyl)-2-[(benzylthio)ethylamino)methyl]-3-hydroxypropanoates 7a1 and 7a2
(0.10 g, 0.2 mmol) in a mixture of AcOH (1.0 ml) and Ac2O (1.0 ml). The mixture was
boiled under reflux for 2h, allowed to cool to room temperature and then poured into ice-
cooled water (5.0 ml). Stirring for ca. 30 min gave a precipitate, which was filtered off
and washed with hexane. The products were separated by PLC [on silica gel, elution with
ethyl acetate-hexane (1:2)] to afford 3-[(benzylthio)ethylamino)-methyl]coumarin 8a as a
brown oil (13 mg, 20%) (Found M+1: 326.1221. C19H20NO2S requires MH+, 326.1215);
δH (400 MHz; CDCl3) 2.72 (2H, t, J 6.8Hz, 3’-CH2), 2.84 (2H, t, J 6.4Hz, 2’-CH2), 3.72
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(2H, s, 4’-CH2), 3.79 (2H, s, 1’-CH2), 7.17 (1H, t, J 7.6Hz, Ar-H), 7.27-7.35 (6H, series
of multiplets, Ar-H) 7.51 (2H, d, J 8.4Hz, Ar-H) and 7.86 (1H, s, 4-CH); δC (100 MHz;
CDCl3) 30.6 (3’-CH2), 36.3 (4’-CH2), 47.4 (2’-CH2), 48.0 (1’-CH2), 116.6, 119.0,
124.3,[16] 124.6, 127.1, 128.0, 128.6, 128.8, 131.6, 138.1 (Ar-C), 141.1 (4-CH), 153.3
(Ar-C) and 161.5 (C=O); m/z 326 (M+1 100).
The general procedure (Route II) for the preparation of the 3-(aminomethyl)coumarin
derivatives 8 and 11 is illustrated by the following example.
3-(Chloromethyl)coumarin 10e (97 mg, 0.5 mmol), glycine ethyl ester hydrochloride
(209 mg, 1.5 mmol) and Proton Sponge® (343 mg, 3.2 mmol) were dissolved in a
mixture of THF (8 mL) and H2O (2 mL). The mixture was sealed in a reaction tube and
stirred for 7 d. Extraction with EtOAc (10 mL), drying (MgSO4), and subsequent
removal of the solvent in vacuo yielded the crude product (205 mg), which was purified
by flash chromatography [on silica gel; elution with hexane:EtOAc (2:1)] to afford two
fractions.
Fraction 1: Ethyl N-[(2H-1-benzopyran-2-on-3-yl)methyl]glycinate 8e as a brown oil (59
mg, 45%) (Found M+: 261.10049. C14H15O4N requires M, 261.10011); max (thin
film)/cm-1 3343 (NH), 1722 (C=O) and 1609 cm (C=C)
H (400 MHz, C6D6) 0.92 (3H,
t, J = 7.1 Hz, CH2CH3), 3.13 (2H, s, CH2NH), 3.53 (2H, d, J = 1.3 Hz, NHCH2), 3.91
(2H, q, J = 7.1 Hz, CH2CH3), 6.72 (1H, m, Ar-H), 6.81 (1H, m Ar-H), 6.91 (2H, m Ar-H)
and 7.15 (1H, s, 4-H); C (100 MHz, C6D6) 14.2 (CH2CH3), 48.4 (CH2N), 50.7 (CH2N),
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60.5 (CH2CH3), 116.4, 119.7, 123.8, 127.5, 128.2, 130.5, 137.5 and 153.6 (Ar-C and
C=C), 160.5 (coumaryl C=O) and 171.9 (glycinate C=O).
Fraction 2: Ethyl N,N-bis[(2H-1-benzopyran-2-on-3-yl)methyl]glycinate 11e as beige
crystals (34 mg, 32%), m.p. 133-134 oC (Found M+: 419.13656. C24H21O6N requires M,
419.13689); max (nujol)/cm-1 1727 (C=O) and 1698 (C=O); H (400 MHz, C6D6) 0.93
(3H, t, J = 7.1 Hz, CH2CH3), 3.28 (2H, s, NHCH2C=O), 3.69 (4H, s, 2 x CH2NH), 3.92
(2H, q, J = 7.1 Hz, OCH2CH3), 6.79 (2H, dt, J = 1.1, 7.6 Hz, Ar-H), 6.91-7.01 (6H, series
of multiplets, Ar-H) and 7.35 (2H, s, 2 x 4-H); C (100 MHz, C6D6) 14.2 (OCH2CH3),
53.7 (2 x CH2N), 55.1 (C=OCH2N), 60.5 (OCH2CH3), 116.6, 118.0, 121.0, 127.5, 130.2,
133.6, 138.6, 152.5, (Ar-C and C=C), 160.0 (coumaryl C=O) and 170.1 (glycinate C=O).
ACKNOWLEDGEMENTS
The authors thank the National Research Foundation (NRF; Grant no. 62273), the
Medical Research Council of South Africa (MRC) and Rhodes University for financial
support. Any opinion, findings and conclusions or recommendations expressed in this
material are those of the authors and therefore the NRF does not accept any liability in
regard thereto.
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Scheme 1. Routes to 3-(aminomethyl)coumarin derivatives.
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Scheme 2. Summary of possible nucleophilic attack pathways.
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