Nucleophilic capture of the imino-quinone methide type intermediates generated from 2-aminothiazol-5-yl carbinols

Article abstract of DOI:10.1021/ol902023g

Generation of imino-quinone methide type intermediates from 2-aminothiazole-5-carbinols using alkylsulfonic acids in nitromethane followed by trapping with a wide range of nucleophiles effects C-C, C-O, C-N, C-S, and C-P bond formation

Full text of DOI:10.1021/ol902023g

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5154-5157
Nucleophilic Capture of the
Imino-Quinone Methide Type
Intermediates Generated from
2-Aminothiazol-5-yl Carbinols
Mark G. Saulnier,*,† Marco Dodier,† David B. Frennesson,† David R. Langley,‡
and Dolatrai M. Vyas†
Department of DiscoVery Chemistry and Department of Computer-Assisted Drug
Design, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, Connecticut 06492
mark.saulnier@bms.com
Received August 31, 2009
ABSTRACT
Generation of imino-quinone methide type intermediates from 2-aminothiazole-5-carbinols using alkylsulfonic acids in nitromethane followed
by trapping with a wide range of nucleophiles effects C-C, C-O, C-N, C-S, and C-P bond formation.
Quinone methides (QM) have long been known to play key
roles in the mechanism of action of many antitumor agents
and natural products such as mitomycin C, adriamycin, and
etoposide.1 The potential toxicity of such intermediates is
perhaps most well-known for the over-the-counter analgesic
acetaminophen, which is metabolized in the liver to give an
N-acyl-p-imino-quinone species that can covalently bind with
proteins and nucleic acids.2 Generation of QM species by
bioreduction is utilized for release of drugs in the context of
targeting.3 Quinone methides also serve as useful intermedi-
ates in organic synthesis.4 For example, in the field of
anthracycline antibiotics, Angle reports the isolation of an
ortho-quinone methide (o-QM) which undergoes addition
reactions with amines, alcohols, thiols, and DNA bases.5
Brown demonstrates that 5-hydroxyflavinoids are suitable
substrates for acid-catalyzed solvolysis to an o-QM inter-
mediate which is trapped by sodium benzenesulfinate to give
a sulfone.6 Furthermore, Borchardt describes the trimethyl-
silane reduction of an o-QM intermediate formed from
2-hydroxy benzyl alcohols in the presence of trifluoroacetic
acid.7 Gardner’s work illustrates one of the first examples
of C-C bond formation with an o-QM under basic condi-
tions using sodium cyanide and diethyl malonate as the
C-nucleophiles.8 Macor reports the direct displacement of
OH by amine and sulfonamide nucleophiles in hydroxy-
methylimidazoles.9 Most recently, Martin reveals the trapping
of carbocations stabilized by electron-rich aromatic rings with
† Department of Discovery Chemistry.
‡ Department of Computer-Assisted Drug Design.
(1) (a) Li, V. S.; Choi, D.; Tang, M. S.; Kohn, H. J. Am. Chem. Soc.
1996, 118, 3765. (b) Gaudiano, G.; Resing, K.; Koch, T. H. J. Am. Chem.
Soc. 1994, 116, 6537. (c) Saulnier, M. G.; Vyas, D. M.; Langley, D. R.;
Doyle, T. W.; Rose, W. C.; Crosswell, A. R.; Long, B. H. J. Med. Chem.
1989, 32, 1418.
(5) (a) Angle, S. R.; Yang, W. J. J. Am. Chem. Soc. 1990, 112, 4524.
(b) Angle, S. R.; Rainier, J. D.; Woytowicz, C. J. Org. Chem. 1997, 62,
5884.
(6) Attwod, M. R.; Brown, B. R.; Lisseter, S. G.; Torrero, C. L.; Weaver,
P. M. J. Chem. Soc., Chem. Commun. 1984, 177.
(7) Borchardt, R. T.; Sinhababu, A. K. Synth. Commun. 1983, 13, 677.
(8) (a) Gardner, P. D.; Rafsanjani, H. S.; Rand, L. J. Am. Chem. Soc.
1959, 81, 3364. (b) Merijan, A.; Gardner, P. D. J. Org. Chem. 1965, 30,
3965.
(2) (a) Borne, R. F. Principles of Medicinal Chemistry, 4th ed.; Foye,
W. O., Lemke, T. L., Williams, D. A., Eds.; Williams and Wilkins:
Baltimore, MD, 1995; pp 544-545.
(3) Tanabe, K.; Zhang, Z.; Ito, T.; Hatta, H.; Nishimoto, S. Org. Biomol.
Chem. 2007, 5, 3745.
(4) For a recent review, see: Van De Water, R. W.; Pettus, T. R. R.
Tetrahedron 2002, 58, 5367.
(9) Macor, J. E.; Cornelius, L. A. M.; Roberge, J. Y. Tetrahedron Lett.
2000, 41, 2777.
10.1021/ol902023g CCC: $40.75
Published on Web 10/14/2009
 2009 American Chemical Society

π-C-nucleophiles such as silyl ketene acetals.10 Martin’s
work employs heterocyclic carbinol substrates such as
indol-2-yl and indol-3-yl, as well as pyrrol-2-yl, furan-
2-yl, and thiophen-2-yl carbinols which undergo Lewis
acid catalyzed conversion to a heteroaryl-stabilized car-
bonium ion (Scheme 1).
nucleophile, ethanol, as the solvent. Therefore, we explored
the use of 2 equiv of an alcohol and 3 equiv of MSA using
typical solvents without much success until nitromethane
was employed. Under these conditions, 1 and 2-(4-bromo-
phenyl)ethanol give ether 4 in 70% yield (Scheme 3).12
Scheme 3. Ether Formation from 1 under Acidic Conditions
Scheme 1.
Martin Reaction of Indol-3-yl Carbinols9
The methanesulfonic acid/nitromethane conditions shown
in Scheme 3 facilitate the use of a wide variety of nucleo-
philes. In addition to primary alcohols (i.e., 4), secondary
alcohols, anilines, sulfonamides, amides, lactams, carbamates,
ureas, sulfinic acids, phosphites, and some NH-heterocycles
also serve as suitable nucleophiles to capture intermediate
2, as shown by the products 5-16 in Table 1. In some cases,
Herein, we now report a simple procedure for the
generation and nucleophilic capture of imino-quinone
methide type intermediates derived from 2-aminothiazole-
5-carbinols that accommodates a wide variety of nucleophiles
to effect C-C, C-O, C-N, C-S, and C-P bond formation.
During the course of a medicinal chemistry program, we
required a versatile route to a series of C-5-substituted
2-aminothiazole analogues. The most direct precursor in this
context is 2-aminothiazol-5-yl carbinol (1). However, we
were unsuccessful in attempts to utilize 1 under Mitsunobu
conditions or by conversion to its mesylate or halogen
derivatives. Perhaps, this is not surprising given that the
2-amino group in 1 is unprotected. However, we then
reasoned that under acidic conditions solvolysis of 1 to its
imino-quinone methide type (I-QM) intermediate 2 should
take place: Indeed, 1 is converted quantitatively (by LCMS)
to its ethyl ether 3 with 3 equiv of methanesulfonic acid
(MSA) in ethanol solvent at 80 °C for 2 h (Scheme 2). Ether
3 is isolated by preparative HPLC in 80% yield.11
Table 1. Products from Solvolysis of 1 with Nucleophilesa
Scheme 2. Solvolysis of 2-Aminothiazol-5-yl Carbinol
a All reactions are performed with 0.2-0.3 mmol of 1, 2 equiv of
nucleophile, and 3 equiv of MSA in nitromethane at 80 °C for 6-18 h
unless otherwise noted. b With 3 equiv of MSA and 3 equiv of nucleophile.
c With 3 equiv of MSA and 6 equiv of nucleophile. d With 3 equiv of sodium
p-fluorobenzenesulfinate and 7 equiv of TfOH. e With 3 equiv of TfOH
and 3 equiv of nucleophile.
The formation of ether 3 implicates the generation and
nucleophilic capture of I-QM intermediate 2. However, the
potential synthetic utility of 2 is limited by the use of the
(10) Fu, T.; Bonaparte, A.; Martin, S. F. Tetrahedron Lett. 2009, 50,
3253.
(11) All yields is this paper refer to products purified by preparative
reverse phase HPLC in 1 to 2 runs using a Phenomenex Luna 30 × 100
mm column with a linear gradient of solvent A (10% methanol/90% water
with 0.1% TFA) and solvent B (90% methanol/10% water with 0.1% TFA)
over 10 min with peak detection at 254 nM. Product fractions are then
applied to a 1 g Waters Oasis MCX cation exchange cartridge using slight
vacuum, washed with methanol, and then product is eluted off the cartridge
with 15 mL of 2 M ammonia in methanol. Evaporation gives the pure
product. It should be noted that this method is designed for rapid parallel
synthesis, but there may be 10-30% material lost from this process as
demonstrated by control runs.
trifluoromethanesulfonic acid (TfOH) gives better results than
MSA. This may be due to the better solubility that TfOH
affords in some cases and/or the presence of a basic atom in
the nucleophile (vide infra). The successful use of amides
and lactams is notable in that no O-alkylated products are
observed: It is likely that the formation of such O-alkylated
species is reversible under these reaction conditions.
Org. Lett., Vol. 11, No. 22, 2009
5155

Aromatic and heteroaromatic rings also trap intermediate
2 to give products of C-C bond formation, as exemplified
in Table 2. Anisole and various phenols predominantly
chemoselectivity of intermediate 2 dependent upon the ratio
of acid to nucleophile used (Scheme 4). Reaction of 1 with
2 equiv of 25 and 3 equiv of trifluoromethanesulfonic acid
Table 2. C-C Bond Formation with Aromatic Nucleophilesa
Scheme 4. N-Alkylation-Induced Ring-Opening Reaction with 1
at 80 °C for 5 h gives the expected product 26 via substitution
para to the phenol, but in only 17% isolated yield. In an
effort to improve this yield, the reaction was repeated using
5 equiv of trifluoromethanesulfonic acid and 9 equiv of
phenol 25. Under these conditions, compound 27, the product
of an N-alkylation-induced ring-opening reaction, is obtained
in 42% yield. A possible mechanism for this result is shown
in Scheme 4, wherein the I-QM intermediate 2 initially
Scheme 5. Attempted Trapping of I-QM Species 40
a All reactions are performed with 0.2-0.3 mmol of 1, 2 equiv of ArH,
and 3 equiv of MSA in nitromethane at 80 °C for 6-12 h unless otherwise
noted. b With 4 equiv of TfOH and 3 equiv of nucleophile at 80 °C for 5 h.
undergo para-substitution.13 In the case of 4-chlorophenol
(entry 3), the yield is less than 25% with MSA, but a much
improved result (77% yield) is obtained by the use of the
stronger TfOH. Trapping of I-QM intermediate 2 by 1 and/
or conversion to its labile nitromethane adduct can sometimes
occur if the nucleophile is sufficiently less reactive.
attacks the isoxazolyl nitrogen atom. Apparently, when there
is more acid present than reagent 25, this same nitrogen atom
is sufficiently protonated such that intermediate 2 can attack
para to the phenol to give 26.
In addition to parent 1, (2-(p-tolylamino)thiazol-5-yl)-
carbinol (28) also serves as a suitable substrate for this acid-
induced solvolysis chemistry. For example, 28 is prepared
via SNAr reaction of 2-chlorothiazol-5-yl carbinol and then
is converted to representative products, as shown in Table
3. In the case of ether 34, the use of additional acid (7 equiv)
is required due to the neutralizing effect of the basic amino
group.
We then decided to explore chemoselectivity differences
between the various nucleophiles accommodated by this
chemistry. Primary amides react preferentially to secondary
amides as shown by a competition experiment with 28 and
3 equiv each of benzamide, N-methylbenzamide, and TfOH;
In the example of the reaction with 2-(isooxazol-5-
yl)phenol (25), we discovered an interesting switch in the
(12) Representative procedure follows: A mixture of 1 (25.0 mg, 0.19
mmol) and 4-chlorophenol (78 mg, 0.60 mmol) in nitromethane (3 mL) is
sonicated briefly, then treated with neat TfOH (69 µlit, 0.78 mmol). The
resulting solution is heated at 80 °C for 5 h, cooled to -20 C, and quenched
with a cold solution of 7 M NH3 in MeOH. The solvent is evaporated, the
residue dissolved in MeOH (1.8 mL) and purified in one run by preparative
HPLC as described in ref 11 to give 35.5 mg of 19 (77%): 1H NMR (DMSO-
d6) δ 9.79 (s, 1H), 7.08-7.05 (m, 2H), 6.81 (d, 1H, J ) 9.1 Hz), 6.68 (s,
1 H), 6.66 (br s, 2H), 3.79 (s, 2H); HRMS calcd for C10H10ON2ClS 241.0197
(M + H+), obs 241.0197.
(13) Very small amounts of ortho-substitution products are also likely
formed but are not isolated.
5156
Org. Lett., Vol. 11, No. 22, 2009

Table 3. Preparation and Reaction of (2-(p-Tolylamino)thiazol-
Table 4. Chemoselectivity of 28 with Bifunctional Nucleophiles
5-yl)carbinol with Nucleophilesa
a With 0.3-0.4 mmol of 28, 3 equiv of nucleophile, and 3 equiv of
TfOH at 80 °C in nitromethane for 2-3 h. b With 0.4 mmol of 28, 3 equiv
of MSA, and 5 equiv of 5-chlorooxindole at 80 °C for 3 h.
Interestingly, these same nitromethane/TfOH conditions serve
as an excellent method for an otherwise difficult SNAr
reaction of p-toluidine with 2-bromothiazole ester 41 to
assemble the requisite 2-aminothiazole ester 42 in 72%
yield.14 Treating 39 with 3 equiv of MSA in nitromethane
in the presence of 4-chlorophenol at rt for 30 min gives only
the olefin 43 in 69% yield.11 Further heating the reaction at
80-100 °C for 16-20 h does not lead to any incorporation
of the phenol as nucleophile, vis-a`-vis 19. It is likely that
the initially generated intermediate I-QM 40 rapidly tau-
tomerizes to the isomeric olefin 43, therefore precluding its
nucleophilic capture. Further exploration of other heterocyclic
systems suitable for the generation and nucleophilic capture
of related I-QM intermediates would provide an opportunity
for expansion of the scope of the chemistry described herein.
a All reactions are performed with 0.3 mmol of 28, 2 equiv of
nucleophile, and 3 equiv of TfOH at 80 °C for 6-18 h in nitromethane
unless otherwise noted. b With 3 equiv of MSA and 3 equiv of benzyl
alcohol. c With 3 equiv of TfOH and 5 equiv of nucleophile. d With 7 equiv
of TfOH and 3 equiv of amino-alcohol.
A 4:1 mixture favoring amide product 30 over the corre-
sponding N-methyl amide is isolated in 69% combined yield.
The products shown in Table 4 are examples wherein
carbinol 28 is combined with nucleophiles bearing more than
one potential site of reaction. Whereas alcohols containing
an aromatic ring give ethers vis-a`-vis electrophilic attack on
the aromatic ring (compounds 4, 5, 29, vide supra), the
chemoselectivity is completely switched when the aromatic
ring contains a strong electron-donating group. Thus, phenol
alcohol 36 is formed exclusively in the reaction of 28 with
4-(2-hydroxyethyl)phenol. The reaction of the sulfonamide
group in the presence of an amide is preferred (compound
37), and C-C bond formation takes place at C-3 when
5-chlorooxindole is used as the nucleophile (compound 38).
In an endeavor to increase the stability of imino-quinone
methide (I-QM) 2, we envisioned tertiary alcohol 39 as
precursor to the corresponding I-QM 40 (Scheme 5).
Acknowledgment. We thank Dr. Yingzi Wang of our
DAS group for NMR support.
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL902023G
(14) The use of acid catalysis for weakly basic amines in SNAr reactions
is known. For example, the combination of trifluoroacetic acid in trifluo-
roethanol facilitates SNAr displacement of fluorine and chlorine from
pyrimidine and purine substrates with weakly basic substituted anilines.
See: Whitfield, H. J.; Griffin, R. J.; Hardcastle, I. R.; Henderson, A.;
Meneyrol, J.; Mesguiche, V.; Sayle, K. L.; Golding, B. T. J. Chem. Soc.,
Chem. Commun. 2003, 2802.
Org. Lett., Vol. 11, No. 22, 2009
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