Synthesis, spectroscopic characterization and chemical reactions of stable o-QM on solid phase

Article abstract of DOI:10.1039/b205793j

A novel approach towards quinone methides stabilization has been achieved by anchoring the reactive o-QM intermediate on solid phase (RTHP). The reactivity and selectivity of supported o-QM towards N and S centered nucleophiles have been explored.

Full text of DOI:10.1039/b205793j

Synthesis, spectroscopic characterization and chemical reactions of stable
o-QM on solid phase
Riccardo Zanaletti and Mauro Freccero*
Dipartimento Chimica Organica, Università di Pavia, V.le Taramelli 10, 27100 Pavia, Italy.
E-mail: freccero@chifis.unipv.it; Fax: +39 0382 507323; Tel: +39 0382 507668
Received (in Cambridge, UK) 14th June 2002, Accepted 15th July 2002
First published as an Advance Article on the web 26th July 2002
A novel approach towards quinone methides stabilization
has been achieved by anchoring the reactive o-QM inter-
mediate on solid phase (RTHP). The reactivity and selectiv-
ity of supported o-QM towards N and S centered nucleo-
philes have been explored.
0.7–1.2 mmol g21 15
) according to the standard PTSA coupling
procedure16 to afford the resin-bound ammonium salt 4
(Scheme 2). Gel-phase 13C-NMR and FT-IR (Diffuse Re-
flectance, DR) spectroscopies monitored the successful SP step.
In fact, comparison of the 13C-NMR spectra of naked DHP HM
resin and unsupported o-QM precursor (1) with that of
supported ammonium salt (4), clearly showed for the modified
resin 4 the presence of signals due to TBDMS methyl groups (d
= 23.88, 18.30 ppm) and of ammonium functional group
Quinone methides (QMs) are highly reactive intermediates,
which may act either as electrophiles1 or electron poor
heterodienes.2 In fact, QMs have been widely used in organic
synthesis, in particular for carrying out ‘reverse electron
demand’ Diels–Alder cycloadditions to give chroman deriva-
tives.3 It has been suggested that QM-like structures play a key
role as intermediates in several biological processes, including
enzyme inhibition4 and DNA cross-linking.5 Recently, a
transient QM-like structure has been proposed as covalent
trapping device applied to the development of combinatorial
antibody library,6 and supported p-QM have been generated
from pH cleavable linkers.7 Despite this wide interest, examples
of stable simple QMs, i.e. those bearing no substituents on the
exocyclic double bond or at the ortho positions to the oxygen
atom, are scarce. In fact, the parent compound, o-QM has been
detected only as intermediate in solution8,9 or stabilized in the
form of a metal p-complex.10 Recently it has been reported that
o-QMs are effective alkylating agents for amino acids,
peptides9 and nucleobases in water.11 This is a highly appealing
application, but of limited scope, since with less reactive
substrates, such as poor nucleophiles and non-electron rich
alkenes, hydration9 and polymerization processes12 are com-
petitive. Therefore, we explored a new approach to the
stabilization of unsubstituted o-QM, viz. supporting o-QM on
solid phase (SP) in order to inhibit bimolecular self-addition.
For the same reason, the structurally related o-quinodi-
methane13 has been supported on SP.14 In the event, a general
and unprecedented synthetic approach to prepare and spec-
troscopically characterize stable o-QM supported on SP was
developed. The results of the reactions of resin-bonded o-QM
towards nucleophiles, through the characterization of the
resulting alkylation adducts (both grafted on the resin and after
cleavage), offered alternative support for its formation and
reactivity. Trapping reactions through Michael addition were
performed with both N and S centered nucleophiles. The
suitability of the ammonium salt 1 as o-QM precursor was
positively tested in CH2Cl2 solution, where a completely
selective formation of 5-hydroxymethyl-o-QM (2, Scheme 1) is
triggered by fluoride anion. The protocol followed in order to
anchor precursor 1 onto SP is straightforward (Scheme 2).
Ammonium salt 1 was linked to DHP HM resin (loading
+
(CH2NMe3 ; d = 25.99, 52.93 ppm).† The modified resin 4
was then exposed to fluorine anion (n-Bu4NF in CH2Cl2 at rt) to
afford covalently linked o-QM to resin (5), within few minutes.
The presence of supported o-QM was inferred after its
generation in the absence of water or any trapping agent by
monitoring the appearance of a strong carbonyl band at
1718–1707 cm21 by FT-IR (Fig. 1a). To support the assign-
ment, the experimental IR spectra were compared to the
computed ones,17 calculated for the 4-methyl-o-QM, at B3LYP/
6-311G+(d,p) level of theory, both in gas phase (Fig. 1b) and in
benzene solution [at C-PCM-B3LYP/6-311+G(d,p) level of
theory]. Computational frequency calculation allowed the
evaluation of the effect caused by polystyrene resin bulk on the
IR spectra. Actually, the computed vibrational frequencies in
gas phase and benzene solution for the carbonyl-stretching
mode are 1722 and 1716 cm21, respectively. They are almost
identical to the IR experimental maximum absorption registered
for 5 (1718–1707 cm21). The broadening of the IR absorption
band in the experimental spectra (Fig. 1a) is due to the effect of
the resin bulk (computationally modeled by benzene as
solvent), which slightly lowers the CNO stretching frequency,
by increasing the zwitterionic character of o-QM. An aliquot of
o-QM supported on resin (5) was kept in a dry box at rt and
periodically checked for stability via FT-IR. The characteristic
strong band did not change significantly upon standing for 24
hours.‡ Despite its stability, o-QM on SP (5) displays a
remarkable reactivity toward N and S centered nucleophiles. In
fact, samples of resin 5 suspended in CH2Cl2 solutions
Scheme 1 (i) CH2NN(Me)2I, K2CO3 in CH2Cl2, 75% yield. (ii) tBuMe2SiCl,
imidazole in CH2Cl2, 0 °C, 82% yield. (iii) NaBH4, MeOH, 0 °C, 85% yield.
(iv) MeI in CH2Cl2, 0 °C, 85% yield. (v) nBu4NF, in CH2Cl2, rt. (vi) HNu
50 mM, in CH2Cl2, rt.
Scheme 2 (i) PTSA, ClCH2CH2Cl, rt. (ii) nBu4NF, in CH2Cl2, rt. (iii) HNu
50 mM, in CH2Cl2, rt. (iv) CF3COOH+H2O = 95+5.
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CHEM. COMMUN., 2002, 1908–1909
This journal is © The Royal Society of Chemistry 2002

containing octane-1-thiol, piperidine and
L
-cysteine methyl
and peptides, and to the photoreversibility of the alkylation
process,9 supported o-QM could work as a photo-removable
linker of peptides, which can be mildly generated and stored.
Therefore our approach appears promising and general for the
preparation of further unsubstituted stable QMs on solid phase,
with applications both to organic synthesis, and as anchored
trapping agents of biological nucleophiles.
ester, were converted at room temperature, within few minutes,
into alkylated adducts grafted to resin (6a–6c, respectively).
Spectroscopic analysis, after filtration and drying of the
resulting resin under vacuum, disclosed the complete depletion
of the absorption band centered at 1718–1707 cm21 (see Fig.
1c), as well as the disappearance of the 13C-NMR signals due to
the TBDMS and the alkyl ammonium group (typical of resin 4).
New signals pertaining to the nucleophile moiety (alkylated by
supported o-QM), appeared in parallel.† Assignments were
unequivocally determined by comparisons with the 13C-NMR
signals of supported ammonium salt (4) and o-QM-alkylation
adducts (3a–3c), obtained from nucleophile alkylation proc-
esses involving 2 in solution.† The above evidence shows
clearly the efficiency of nucleophiles in trapping o-QM
supported on resin. Standard cleavage15 of resins 6a–6c,
afforded 3a–3c alkylation adducts with yields from 66% to
54%. The increased stability of o-QM on resin is truly
remarkable, since o-QM can only survive for a very short period
in solution; i.e. < 10 ms in water9 and < 1 s in organic non
nucleophilic solvents (in the latter case due to dimerization–
polymerization at rt),12 while supported o-QM can be safely
stored in a dry and cool place. On the other hand, SP does not
preclude the typical reactivity/selectivity of o-QM in solution
towards nitrogen and sulfur centered nucleophiles. In fact,
similarly to free o-QM in solution, which is highly selective
toward thiols, alkylation of cysteine methyl ester, o-QM on SP
(5) attacks selectively only the SH moiety, since no N-alkylation
adduct was detected. Our results, although preliminary, repre-
sent the first report of persistent o-QM on solid phase. THP-HM
resin succeeds in stabilizing the most reactive o-QM among all
known QMs and preserving it from dimerization–polymeriza-
tion and hydration processes. It is quite evident that undesired
intra-site reactions do not plague our solid phase synthesis.
Although site–site isolation does not per se guarantee stabiliza-
tion, since cross reactivity of highly reactive species on SP has
been reported,18 lack of proximity should play an important
role. The effective stabilization of o-QM on SP is also the result
of the protection from hydration, plausibly through p-stacking
interactions, in the hydrophobic environment of the resin bulk.
Due to the o-QM reactivity and selectivity towards amino acids
Notes and references
† Selected analytical data: 1: NMR (CDCl3) dH 0.23 (s, 6H), 1.00 (s, 9H),
3.31 (s, 9H), 4.70 (s, 2H), 4.74 (s, 2H), 6.91 (d, 1H, J = 9.5 Hz), 7.37 (dd,
1H, J = 1.5, 9.5 Hz), 7.80 (d, 1H, J = 1.5 Hz). dC 23.98, 18.25, 25.91,
53.26, 63.13, 64.56, 117.35, 119.03, 134.62, 135.58, 154.39, 153.67. Anal.
Calc. for C17H32INO2Si: C, 46.68, H, 7.37, I, 29.01, N, 3.20, O, 7.32, Si,
6.42. Found: C, 46.70, H, 7.39, I, 29.06, N, 3.18, Si, 6.47%. 4: dC 23.88,
18.30, 25.99, 52.93, 64.46, 65.77. Only dC of 1 aliphatic moiety on SP are
reported. 3a: NMR (CDCl3) dH 0.90 (t, 3H, J = 7.0 Hz), 1.20–1.38 (m,
10H), 1.56 (m, 2H), 2.43 (t, 2H, J = 7.0 Hz), 3.80 (s, 2H), 4.60 (s, 2H), 6.90
(d, 1H, J = 9.0 Hz), 7.09 (s, broad, 1H), 7.21 (d, 1H, J = 9.0 Hz), 7.29 (s,
1H). dC 14.00, 22.54, 28.63, 28.89, 29.01, 29.04, 30.87, 31.69, 32.78, 64.87,
117.17, 122.55, 128.05, 129.47, 132.83, 155.07. Anal. Calc. for C16H26O2S:
C, 64.04, H, 9.28, O, 11.33 S, 11.35. Found: C, 68.07, H, 9.35, S, 11.31%.
6a: dC 14.11, 22.60, 28.75, 29.10, 29.32, 29.85, 31.08, 31.74, 32.73, 65.77.
Only dC of 3a aliphatic moiety on SP are reported. 3b: NMR (CDCl3) dH
1.51 (bm, 2H), 1.64 (m, 4H), 2.52 (bm, 4H), 3.68 (s, 2H), 4.55 (s, 2H), 5.15
(bm, 1H), 6.80 (d, 1H, J = 9.0 Hz), 7.00 (s, 1H), 7.16 (d, 1H, J = 9.0 Hz).
dC 23.76, 25.60, 53.70, 61.89, 65.00, 115.82, 121.46, 127.38, 127.52,
131.19, 157.63. Anal. Calc. for C13H19NO2: C, 70.56, H, 8.65, N, 6.33, O,
14.46, S. Found: C, 70.58, H, 8.62, N, 6.39%. 6b: dC 23.68, 25.52., 53.57,
61.79, 65.50. Only dC of 3b aliphatic moiety on SP are reported. 3c: NMR
(CDCl3) dH 2.90 (m, 2H), 3.78 (s, 3H), 3.83 (m, 1H), 4.50 (s, 2H), 6.80 (d,
1H, J = 9.0 Hz), 7.09 (d, 1H, J = 9.0 Hz), 7.21 (s, 1H). dC 32.35, 34.15,
52.65, 64.75, 65.99, 117.33, 125.47, 128.14, 130.65, 135.01, 156.00,
171.50. Anal. Calc. for C12H17NO4S: C, 53.12, H, 6.32, N, 5.16, O, 23.59,
S, 11.82. Found: C, 53.22, H, 6.21, N, 5.19, S, 11.81%. 6c: 27.55, 29.57,
51.97, 62.30, 68.06. Only dC of 3c aliphatic moiety on SP are reported.
‡ The relative intensity of the carbonyl band displayed a detectable decrease
after 2 days. o-QM on SP kept under moisturised air displayed a detectable
weakening of the characteristic band (210%) after 10 h.
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Fig. 1 IR detection of the o-QM supported on solid phase (SP). a) Difference
IR spectrum of functionalized resins 5 and 4. b) Calculated B3LYP/
6-311+G(d,p) unscaled frequencies of 4-methyl-o-QM in gas phase. c)
Difference IR spectrum of functionalized resin 6b and 4, showing the
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