Modular synthesis of pyrrolo[2,1-b]thiazoles and related monocyclic pyrrolo structures

Article abstract of DOI:10.1002/jhet.550

A modular synthesis of selectively-substituted pyrrolo[2,1-b]thiazoles (Δ⁶ isomeric form) has been implemented, involving a distinctive bicyclization reaction of a mucobromic acid derivative followed by a Suzuki-Miyaura coupling. A novel proces

Full text of DOI:10.1002/jhet.550

286
Modular Synthesis of Pyrrolo[2,1-b]thiazoles and Related
Monocyclic Pyrrolo Structures
Vol 48
Emma E. O’Dwyer, Nessa S. Mullane, and Timothy P. Smyth*
Department of Chemical and Environmental Sciences, University of Limerick, National
Technological Park, County Limerick, Ireland
*E-mail: timothy.smyth@ul.ie
Received March 11, 2010
DOI 10.1002/jhet.550
Published online 19 November 2010 in Wiley Online Library (wileyonlinelibrary.com).
A modular synthesis of selectively-substituted pyrrolo[2,1-b]thiazoles (D6 isomeric form) has been
implemented, involving a distinctive bicyclization reaction of a mucobromic acid derivative followed by
a Suzuki-Miyaura coupling. A novel process of D6 to D7 isomerization of the pyrrolothiazole structure
was uncovered that appears to involve a 1,4-addition-1,2-elimination mechanism. Preparation of 1,5-
dihydropyrrol-2-one structures, selectively substituted at the 3- and 4-positions, was also achieved using
the mucobromic acid synthon in a reductive amination process.
J. Heterocyclic Chem., 48, 286 (2011).
INTRODUCTION
reoisomer of the bicyclic product was formed. [8] The
bicyclic structure 3 was converted to its benzhydryl
ester 4 to facilitate its purification and for optimal for-
mation of the subsequent Suzuki-Miyaura products 5a–f.
The R0 substituents (aryl, heteroaryl, and alkenyl groups)
were introduced by a Suzuki-Miyaura coupling [9] using
commercially available boronic acids or boronic acid
pinacol esters.
Pyrrolo[2,1-b]thiazole and 1,5-dihydropyrrol-2-one
structures are important synthetic targets given the range
of biological and other properties that they show [1,2].
As part of our research on development of serine prote-
ase inhibitors a modular synthesis of the above struc-
tures was required that allowed for ready variation of
the substituent groups R, R0, and R00. Herein we report
on a modular synthesis based on mucobromic acid,
which is a cheap multifunctional building block [3–5].
A mechanism for the bicyclization with D-penicill-
amine is given in Scheme 2 together with data (this
work) on the relative thermodynamic stability of the dia-
stereomeric products B and B0: the stereochemical out-
come appears to be controlled by an unfavorable endo-
cyclic interaction between the 3-carboxyl group and the
c-lactam carbonyl that occurs in B0 but not in B. The
facile formation of structure type B, involving H2O as a
leaving group in a weakly acidic aqueous medium at
ambient temperature, attests to the strong thermody-
namic driving force for cyclization of structure type A.
During the synthetic work, it was found that the bicycli-
zation reaction did not proceed well where the halogen
of muco structure 2 was replaced by nonelectron-with-
drawing groups. The reaction rate and yield of the
bicyclization was much lower (27–32%) when cysteine
was used in place of penicillamine [10]. This difference
may be as a result of a faster thiazolidine ring formation
step with penicillamine due to a gem-dimethyl effect
RESULTS AND DISCUSSION
The first step in the modular synthesis (Scheme 1)
was introduction of substituent R via a 1,4-addition-
elimination reaction on the anionic ring-opened form of
mucobromic acid. Thiols and phenols are suitable for
this reaction as the corresponding thiolate and phenoxide
nucleophiles are readily formed in aqueous base [6] here
ethyl and isopropyl mercaptan as well as 3-chloro and
3-nitrophenol were used. Formation of the pyrrolo[2,1-
b]thiazole structure was achieved by a bicyclization
reaction of the muco derivative with D-penicillamine.
This type of reaction was first reported by Wasserman
et al. [7] and was later exploited by Moore and Arnold,
who verified by X-ray crystallography that a single ste-
C
V
2010 HeteroCorporation

March 2011 Modular Synthesis of Pyrrolo[2,1-b]thiazoles and Related Monocyclic Pyrrolo Structures
287
Scheme 1. (i) KOHaq, (ii) RSH or ArOH, KOHaq, (iii) HClaq, (iv) D-penicillamine, EtOH/H2O 1:1, HOAc (1.2 equiv.), (v) Diphenyldiazomethane,
(vi) Suzuki-Miyaura coupling, (vii) AlCl3 in CH2Cl2/EtNO2, ꢀ80ꢁC, 1 h.
[11], making the bicyclization path dominant over com-
peting side reactions.
tion—here again the facile ring closure, involving water
as a leaving group in a weakly acidic medium at ambi-
ent temperature, indicates the strong thermodynamic
driving force for the formation of the unsaturated c-lac-
tam unit. In the reductive amination step with 2a, a
small amount of the desbromo reduction product was
formed, which was removed prior to the coupling step.
Isomerisation of D6 to the D7 isomer. In previous
work, we had found that, in at least one case, the D7
isomer was thermodynamically more stable than the D6
isomer. Thus, in the rearrangement reaction of a modi-
fied penicillin with MeOH/Et3N (Scheme 4), the
Muco synthons 2a and 2d were also used to prepare a
set of 1,5-dihydropyrrol-2-ones (8a–c, Scheme 3) by
reductive amination followed by Suzuki-Miyaura cou-
pling. (R)-phenylglycine methyl ester was used for the
preparation of 7a and 2-(3,4-dimethoxyphenyl)ethyl-
amine was used for 8b and 8c. This reaction occurs via
imine formation with the neutral ring-opened form of
the mucoderivative, which is present in very low equi-
librium concentration with the ring-closed form [5].
Hydride addition to the imine leads directly to cycliza-
Scheme 2. Mechanism of the bicyclization reaction between D-penicillamine and a mucohalic acid.
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E. E. O’Dwyer, N. S. Mullane, and T. P. Smyth
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Scheme 3. (i) Reductive amination; (ii) Suzuki-Miyaura coupling
quantitatively isolated product was the D7 pyrrolothia-
zole 10, which must have been derived from the ini-
tially-formed D6 isomer 9 [12]. The most likely isomeri-
zation mechanism under those reaction conditions is via
deprotonation of the bridgehead hydrogen H-8. This pro-
cess was found to lack general applicability. In this
work, an alternative isomerization process was uncov-
rose to 41% when phosphate buffer/20% DMSO was
used. Two further freeze-drying cycles from H2O to
maximize removal of DMSO did not alter the composi-
tion, however, on standing for several days at 4ꢁC the
1
solid material—a DMSO solvate by its H NMR spec-
trum—was found to contain, largely, the D7 isomers but
no 6d. The new structures did not correspond to the c-
lactam ring-opened form of 6d. In previous work, we
had shown that a signature of such ring-opened struc-
tures is the significant upfield shift of the resonance of a
gem-dimethyl group [12], which was absent here, and in
addition, 6d was found to remain unchanged after 20 h
at 21ꢁC in D2O buffer (50 mM phosphate, pH 7.2). The
new resonances were consistent with two D7 diastereom-
ers (6-R and 6-S epimers) derived from the 6d salt: two
new sets of resonances were clearly observed for the ar-
omatic hydrogens and for H-3, and the new resonances
for the methylene hydrogens of the ethylsulfanyl unit at
1
ered with the carboxylate salt of 6d. The H NMR spec-
trum of 6d in D2O buffer (50 mM phosphate, pH 7.2)
containing 10% DMSO-d6 indicated the presence of
ꢂ1% each of two structures, which were not present in
1
the free acid 6d in CDCl3. Unexpectedly, the H NMR
spectrum (D2O) of the solids recovered after freeze-dry-
ing showed the presence of ꢂ10% of each of the new
structures with the remainder being, largely, unreacted
6d. Indeed, the material recovered after freeze-drying
twice from phosphate buffer/10%DMSO contained
ꢂ30% of each of the new structures (Fig. 1); this value
Scheme 4. Mechanisms of D6 to D7 isomerization of selected pyrrolo-thiazole structures. Top route: Deprotonation of bridgehead hydrogen H-8: (i)
CH3OH/NEt3; Lower route: 1,4 addition-1,2 elimination, (ii) aqueous phosphate buffer/20% DMSO (with freeze-drying), Ar ¼ p-nitrophenyl, Nu
¼ nucleophile-cum-leaving group.
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Figure 1. Top: 1H NMR spectrum of the p-nitrophenyl derivative 6d in D2O phosphate buffer/10%DMSO-d6. Bottom: 1H NMR spectrum in D2O
of the material recovered after two stages of freeze-drying from phosphate buffer/10% DMSO showing ꢂ30% of each of the D7 isomers. * ¼ sol-
vent impurities, ** ¼ DMSO-d6. Note that a small displacement of chemical shift values is observed between D2O buffer/10% DMSO-d6 and pure
D2O as solvent.
2.45 ppm were characteristic of those of a dialkyl sul-
fide such as diethyl sulfide. The initial observation in
the D2O buffer system showed a diminution in the in-
tensity of the H-8 resonance of 6d without the obvious
appearance of a new peak indicating deuterium incorpo-
ration in the new structures. High-resolution mass
Figure 2. A portion of the 1H NMR spectrum in CDCl3 of the recovered free acids (crude) of each D7 isomer of 6d. (Bottom): before exchange
with D2O; (Top): after partial exchange with D2O.
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E. E. O’Dwyer, N. S. Mullane, and T. P. Smyth
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and concentrated by rotary evaporation to leave a brown (2a and
2b) or orange (2c) to bright orange (2d) oil.
4-Bromo-3-ethylsulfanyl-5-hydroxy-5H-furan-2-one (2a). 568
spectral analysis of this sample gave peaks at 393.0573
and at 394.0641, which correspond respectively, to the
molecular weights of the D6 isomer (calcd. 393.0579)
and of the D7 isomer containing one deuterium (calcd.
394.0642). The crude free acids of the D7 isomers were
recovered from an acidified aqueous solution (pH 3.5)
of the solids by extraction with dichloromethane. The
1H NMR spectrum (Fig. 2) of these clearly showed sin-
glets, ꢂ40:60, respectively, for each H-3 at 4.47 and
4.51, and at 4.55 and 4.58 ppm for each H-6; these lat-
ter hydrogens were characterized by being exchanged
for deuterium on addition of D2O. The enhancing effect
of divalent sulfur on the kinetic acidity of a-hydrogens
is well established [13].
1
mg, 2.38 mmol, 61%; H NMR (270 MHz, CDCl3) d 1.32 (t,
3H, J ¼ 7 0.42 Hz, CH3ACH2), 3.23 (dq, 1H, J ¼ 13.5, 7.42
Hz, CH3CH2AS (diastereotopic)) overlapping with 3.29 (dq,
1H, J ¼ 13.5, 7.42 Hz, CH3CH2BS (diastereotopic)), 5.97 (s,
1H, H-5); 13C NMR (67.5 MHz, CDCl3, DEPT) d15.49
(CH3CH2S), 25.01 (CH3CH2), 97.70 (CH(OH)O), 131.11,
139.27 (C-3, C-4), 166.53 (C¼¼O); ESI-HRMS for
C6H7O3SBr: [M ꢀ H]ꢀ calcd: 236.9221, found: 236.9256 and
238.9241. This material was used directly in the bicyclization
reaction (see below) without further purification.
4-Bromo-5-hydroxy-3-isopropylsulfanyl-5H-furan-2-one
(2b). (754 mg, 2.98 mmol, 50%); 1H NMR (270 MHz,
CDCl3) d1.32 (d, 6H, J ¼ 6.93 Hz (CH3)2CHS, diastereotopic
methyl groups with coincident chemical shifts), 4.22 (sept, 1H,
J ¼ 6.68 Hz, (CH3)2CHS), 6.00 (s, 1H H-5); 13C NMR (67.93
MHz, CDCl3, DEPT) d 23.59, 23.96 ((CH3)2CHS (diastereo-
topic methyl groups)), 35.82 ((CH3)2CHS), 97.82 (CH(OH)O),
131.43, 141.27 (C-3, C-4), 166.83 (C¼¼O); EI-HRMS for
C7H9O3SBr: [M]þ calcd: 251.9459, found: 251.9456 and
253.9453. This material was used directly in the bicyclization
reaction (see below) without further purification.
4-Bromo-3-(3-chlorophenoxy)-5H-furan-2-one (2c). Purification
by silica gel column chromatography using 1:1 dichlorome-
thane/hexane containing 5% acetic acid, followed by washing
with water to remove acetic acid, gave 2c as a colorless gum
(590 mg, 1.93 mmol, 50%); 1H NMR (270 MHz, CDCl3) d
6.10 (s, 1H, H-5), 6.96 (ddd, 1H, J ¼ 8.18, 2.47, 0.99 Hz,
ArH), 7.07 (app t, 1H, J ¼ 2.23 Hz, ArH), 7.17 (ddd, 1H, J ¼
7.92, 1.98, 0.99 Hz, ArH), 7.28 (t, 1H, J ¼ 8.16 Hz, ArH);
13C NMR (67.93 MHz, CDCl3, DEPT) d 96.24 (CH(OH)O),
115.93, 118.15, 123.02 (C-3/C-4), 125.07, 130.42, 134.90 (C-
3/C-4), 142.34, 154.26 (ArC), 164.52 (C¼¼O); ESI-HRMS for
C10H6O4BrCl: [M þ Na]þ calcd: 326.9036, found: 326.9046
and 328.9040.
The most likely mechanism of isomerization is via 1,4-
addition-1,2-elimination as shown in Scheme 4, with
phosphate dianion as the nucleophile-cum-leaving group.
For an example of a reaction where phosphate di-anion
has been shown to act as a nucleophile-cum-leaving group
see [14]. The finding that a similar isomerization occurred
with the phenyl derivative 6a but not with the N,N-di-
methyl derivative 6e supports a 1,4 addition step. In the
freeze-drying process water is removed faster than
DMSO so that the frozen solution becomes enriched in
DMSO, which may enhance the activity of the buffer
nucleophiles [15] this may also be the case with the solid
DMSO solvate. Isomerization of the earlier-stage synthon
3a was unsuccessful under these conditions.
CONCLUSIONS
A concise modular synthesis of selectively-substituted
pyrrolo[2,1-b]thiazoles (D6 isomeric form) has been
implemented, involving a distinctive bicyclization step
with a mucobromic acid derivative. A novel process of
D6 to D7 isomerization of these pyrrolothiazoles was
uncovered that appears to involve a 1,4-addition-1,2-
elimination mechanism, which is accelerated by repeated
freeze-drying from a phosphate buffer/DMSO mixture.
The synthesis of related monocyclic 3,4-disubstituted
1,5-dihydropyrrol-2-ones was also elaborated by reduc-
tive amination of the mucobromic acid derivative.
4-Bromo-3-(3-nitrophenoxy)-5H-furan-2-one (2d). Purification
by silica gel column chromatography using 1:1 dichlorome-
thane/hexane containing 5% acetic acid, followed by washing
with water to remove acetic acid, gave 2d as a pale yellow gum
(637 mg, 2.02 mmol, 52%); 1H NMR (270 MHz, CDCl3) d 6.17
(s, 1H, H-5), 7.44 (ddd, 1H, J ¼ 8.16, 2.47, 1.24 Hz, ArH), 7.56
(t, 1H, J ¼ 8.16 Hz, ArH), 7.88 (app t, 1H, J ¼ 1.98 Hz, ArH),
8.05 (ddd, 1H, J ¼ 8.16, 1.98, 0.99 Hz, ArH); 13C NMR (67.93
MHz, CDCl3, DEPT) d 96.26 (CH(OH)O), 112.75, 119.81,
124.0, 124.54 (C-3/C-4), 130.63, 142.36 (C-3/C-4), 148.87,
154.39 (ArC), 163.61 (C¼¼O); ESI-HRMS for C10H6O6Br: [M
þ H]þ calcd: 337.9276, found: 337.9290 and 339.9274.
Bicyclization–general procedure. To a solution of D-peni-
cillamine (315 mg, 2.11 mmol) and sodium chloride (144 mg) in
water (3 mL) containing acetic acid (144 lL, 2.52 mmol) was
added a solution of the required muco derivative 2a-2c (1.92
mmol) in ethanol (3 mL). The mixture was stirred at room tem-
perature overnight and was then extracted with dichloromethane
(10 mL). The organic layer was dried, filtered and concentrated
by rotary evaporation to yield the free acid as a yellow solid.
(3S,7aR)-7-Bromo-6-ethylsulfanyl-2,2-dimethyl-5-oxo-2,3,5,7a-
tetrahydro-pyrrolo[2,1-b] thiazole-3-carboxylic acid (3a). A yel-
low solid (459 mg, 1.31 mmol, 68%); 1H NMR (270 MHz,
CDCl3) d 1.30 (t, 3H, J ¼ 7.42 Hz, CH3CH2S), 1.59 (s, 3H,
a-CH3), 1.62 (s, 3H, b-CH3), 3.14 (dq, 1H, J ¼ 13.5, 7.42 Hz,
EXPERIMENTAL
1,4-Addition-elimination–general procedure. To a solution
of mucobromic acid (1.00 g, 3.88 mmol) in water (4 mL) con-
taining potassium hydroxide (256 mg, 4.56 mmol) was added
the required alkyl mercaptan (5.82 mmol), or substituted phenol
(4.27 mmol), in water (3.5 mL) containing potassium hydroxide
(392 mg, 5.82 mmol). The mixture was allowed to stir at room
temperature for 3 h. The pH was lowered to <2 using 1M HCl
and extracted with dichloromethane (2 ꢃ 10 mL). The organic
extracts were combined, dried over magnesium sulfate, filtered,
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CH3CH2AS (diastereotopic)) overlapping with 3.25 (dq, 1H, J
¼ 13.5, 7.42 Hz, CH3CH2BS (diastereotopic)), 4.66 (s, 1H, H-
3), 5.87 (s, 1H, H-8). This material was converted into its
benzhydryl ester (see below) without further purification.
(3S,7aR)-7-Bromo-6-isopropylsulfanyl-2,2-dimethyl-5-oxo-
2,3,5,7a-tetrahydro-pyrrolo [2,1-b]thiazole-3-carboxylic acid
139.09, 140.92 (ArC, C-6, C-7), 167.48, 169.67 (2ꢃ C¼¼O);
ESI-HRMS for C25H26NO3S2Br: [M þ H]þ calcd: 532.0616,
found: 532.0595 and 534.0617.
(3S,7aR)-7-Bromo-6-(3-chlorophenoxy)-2,2-dimethyl-5-oxo-
2,3,5,7a-tetrahydro-pyrrolo[2,1-b]thiazole-3-carboxylic acid
benzhydryl ester (4c). Purification using 1:1 dichloromethane/
hexane gave 4c as a pale yellow solid (535 mg, 0.92 mmol,
1
(3b). A yellow solid (458 mg, 1.25 mmol, 65%); H NMR (270
1
MHz, CDCl3) d 1.30 (d, 3H, J ¼ 6.68 Hz, (CH3A)2CHS (dia-
stereotopic)) overlapping with 1.31 (d, 3H, J ¼ 6.68 Hz,
(CH3B)2CHS (diastereotopic)), 1.58 (s, 3H, a-CH3), 1.62 (s, 3H,
b-CH3), 4.09 (sept, 1H, J ¼ 6.68 Hz, (CH3)2CHS), 4.68 (s, 1H,
H-3), 5.90 (s, 1H, H-8). This material was converted into its
benzhydryl ester (see below) without further purification.
63%); H NMR (270 MHz, CDCl3) d 1.28 (s, 3H, a-CH3), 1.53
(s, 3H, b-CH3), 4.76 (s, 1H, H-3), 5.95 (s, 1H, H-8), 6.92 (dd,
1H, J ¼ 8.16, 2.47 Hz, HArCl), 6.98 (s, 1H, CHPh2), 7.05 (app
t, 1H, J ¼ 2.23 Hz, HArCl), 7.11 (dd, 1H, J ¼ 8.16, 2.23 Hz,
HArCl), 7.25 (t, 1H, J ¼ 8.16 Hz, HArCl), 7.29–7.38 (m, 10H,
ArH); 13C NMR (67.93 MHz, CDCl3, DEPT) d 26.23 (a-CH3),
32.06 (b-CH3), 60.80, 68.39, 69.10 (C-2, C-3, C-8), 78.68
(CHPh2), 115.32, 117.79, 122.42, 124.49, 126.94, 127.77,
128.19, 128.47, 128.60, 128.65, 130.38, 135.06, 139.97, 139.03,
144.31, 155.33 (ArC, C-6, C-7), 165.92, 167.33 (2ꢃ C¼¼O);
ESI-HRMS for C28H23NO4SClBr: [M þ Na]þ calcd: 606.0117,
found: 606.0129 and 608.0104.
Reductive Amination–General Procedure. (R)-(4-Bromo-
3-ethylsulfanyl-2-oxo-2,5-dihydropyrrol-1-yl)-phenylacetic acid
methyl ester (7a). To a stirred solution of 2a (412 mg, 1.72
mmol) and phenyl glycine methyl ester hydrochloride (416
mg, 2.06 mmol) in chloroform (5 mL) was gradually added so-
dium triacetoxyborohydride (547 mg, 2.58 mmol). The solu-
tion color lightened during addition from dark to pale yellow.
After stirring for 10 min at room temperature the mixture was
diluted with chloroform (10 mL) and washed twice with DIW
(10 mL). The organic extracts were combined, dried, filtered,
and concentrated by rotary evaporation to leave a yellow solid.
Purification by silica gel column chromatography using 1:1
hexane/ethylacetate gave 7a as a pale yellow glassy solid (238
mg, 0.643 mmol, 35%); 1H NMR (270 MHz, CDCl3) d 1.28
(t, J ¼ 7.42 Hz, 3H, (CH3CH2S), 3.15 (dq, 1H, J ¼ 13.50,
7.42 Hz, CH3CH2AS(diastereotopic)) overlapping with 3.21
(dq, 1H, J ¼ 13.50, 7.42 Hz, CH3CH2BS(diastereotopic)), 3.58
(d, J ¼ 18.80 Hz, 1H, H-5A), 3.79 (s, 3H, OCH3), 4.44 (d, J
¼ 18.80 Hz, 1H, H-5B), 6.06 (s, 1H, CHC(O)), 7.23–7.44 (m,
5H, ArH); 13C NMR (67.93 MHz, CDCl3, DEPT) d 15.47
(CH3CH2S), 25.22 (CH3CH2S), 52.58, 54.08, 57.82 (C-5,
OCH3, NCH(Ph)), 128.47, 129.01, 129.23, 131.56, 133.57,
134.63, 140.52 (ArC, C-3, C-4), 167.13, 170.47 (2ꢃ C¼¼O);
ESI-HRMS for C15H16BrNO3S: [M þ H]þ calcd: 370.0113,
found: 370.0103 and 372.0041.
(R)-(3-Ethylsulfanyl-2-oxo-2,5-dihydropyrrol-1-yl)-phenylace-
tic acid methyl ester (desbromo structure). An off-white solid;
1H NMR (270 MHz, CDCl3) d 1.34 (t, 3H, J ¼ 7.42 Hz,
CH3CH2S), 2.89 (q, 2H, J ¼ 7.42 Hz, CH3CH2S (diastereotopic
methylene hydrogens with coincident chemical shifts), 3.51 (dd,
1H, J ¼ 19.55, 2.47 Hz, H-5A), 3.77 (s, 3H, OCH3), 4.35 (dd, 1H,
J ¼ 19.55, 2.47 Hz, H-5B), 6.12 (s, 1H, CHC(O)), 6.51 (t, 1H, J ¼
2.47, H-4), 7.20–7.39 (m, 5H, ArH); ESI-HRMS for
C15H17NO3S: [M]þ calcd: 291.0929, found: 291.0927.
4-Bromo-3-(3-nitrophenoxy)-1-phenethyl-1,5-dihydropyrrol-
2-one (7b). Prepared as for 7a but using 2d with 2-(3,4-dime-
thoxyphenyl)ethylamine hydrochloride, in dichloroethane with a
12 h reaction time; purification by silica gel column chromatog-
raphy using ethylacetate/hexane 1:1 then 3:1 gave 7b as a yel-
low oil (239 mg, 0.516 mmol, 30%); 1H NMR (270 MHz,
CDCl3) d 2.89 (t, 2H, J ¼ 7.17 Hz, NCH2CH2), 3.71 (t, 2H, J
¼ 7.17 Hz, NCH2CH2), 3.86 (s, 3H, OCH3), 3.88 (s, 3H,
(3S,7aR)-7-Bromo-6-(3-chlorophenoxy)-2,2-dimethyl-5-oxo-
2,3,5,7a-tetrahydro-pyrrolo[2,1-b]thiazole-3-carboxylic acid
1
(3c). A pale yellow oil (611 mg, 1.46 mmol, 76%); H NMR
(270 MHz, CDCl3) d 1.66 (s, 6H, a-CH3, b-CH3), 4.62 (s, 1H,
H-3), 5.96 (s, 1H, H-8), 6.93 (ddd, 1H, J ¼ 7.92, 2.47, 0.99
Hz, HArCl), 7.05 (app t, 1H, J ¼ 2.24 Hz, HArCl), 7.11 (ddd,
1H, J ¼ 7.92, 2.47, 0.99 Hz, HArCl), 7.25 (t, 1H, J ¼ 7.92
Hz, HArCl). This material was converted into its benzhydryl
ester (see below) without further purification.
Benzyhydryl ester formation–general procedure. To the
required pyrrolothiazole acid 3a-3c in dichloromethane at
room temperature was added dropwise a solution of diphenyl-
diazomethane (ꢂ0.65M) in dichloromethane (prepared by oxi-
dation of benzophenone hydrazone with activated MnO2) until
a pale pink color persisted and the evolution of nitrogen gas
was no longer observable (2–3 h). The solution was concen-
trated by rotary evaporation to yield a yellow solid, which was
purified by silica gel column chromatography as indicated
below.
(3S,7aR)-7-Bromo-6-ethylsulfanyl-2,2-dimethyl-5-oxo-2,3,5,7a-
tetrahydro-pyrrolo[2,1-b] thiazole-3-carboxylic acid benzhydryl
ester (4a). Purification using 3:1 dichloromethane/hexane gave
4a as a pale yellow solid (438 mg, 0.84 mmol, 49%); 1H
NMR (270 MHz, CDCl3) d 1.27 (s, 3H, a-CH3), 1.29 (t, J ¼
7.42 Hz, 3H, CH3CH2S), 1.50 (s, 3H, b-CH3), 3.13 (dq, 1H, J
¼ 13.50, 7.42 Hz, CH3CH2AS (diastereotopic)) overlapping
with 3.25 (dq, 1H, J ¼ 13.50, 7.72 Hz, CH3CH2BS (diastereo-
topic)), 4.79 (s, 1H, H-3), 5.89 (s, 1H, H-8), 6.98 (s, 1H,
CH(Ph)2), 7.26–7.39 (m, 10H, ArH); 13C NMR (67.93 MHz,
CDCl3, DEPT) d15.62 (CH3CH2S), 25.03 (a-CH3), 26.11
(CH3CH2S), 32.13 (b-CH3), 60.70, 68.76, 72.26 (C-2, C-3, C-
8), 78.48 (CH(Ph)2), 126.92, 127.73, 128.12, 128.39, 128.55,
128.59, 132.58, 138.97, 139.05, 139.09 (ArC, C-6, C-7),
167.49, 169.53 (2ꢃ C¼¼O); ESI-HRMS for C24H24NO3Br: [M
þ Na]þ calcd: 540.0283, found: 540.0291 and 542.0333.
(3S,7aR)-7-Bromo-6-isopropylsulfanyl-2,2-dimethyl-5-oxo-
2,3,5,7a-tetrahydro-pyrrolo [2,1-b]thiazole-3-carboxylic acid
benzhydryl ester (4b). Purification using 3:1 dichloromethane/
hexane gave 4b as a yellowish solid (488 mg, 0.92 mmol,
1
33%); H NMR (270 MHz, CDCl3) d 1.27 (s, 3H, a-CH3) over-
lapping with 1.28 (d, 3H, J ¼ 6.93 Hz, (CH3A)2CHS (diastereo-
topic)) overlapping with 1.30 (d, 3H, J ¼ 6.93 Hz, (CH3B)2CHS
(diastereotopic)), 1.49 (s, 3H, b-CH3), 4.13 (sept, 1H, J ¼ 6.80
Hz, (CH3)2CHS), 4.81 (s, 1H, H-3), 5.92 (s, 1H, H-8), 6.98 (s,
1H, CH(Ph)2), 7.30–7.37 (m, 10H, ArH); 13C NMR (67.93
MHz, CDCl3, DEPT) d 23.19, 24.27 ((CH3)2CHS (diastereotopic
methyl groups)), 26.10 (a-CH3), 32.22 ((CH3)2CH), 35.63 (b-
CH3), 60.71, 68.77, 72.32 (C-2, C-3, C-8), 78.47 (CH-Ar2),
126.92, 127.69, 128.11, 128.38, 128.54, 128.58, 132.90, 139.05,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

292
E. E. O’Dwyer, N. S. Mullane, and T. P. Smyth
Vol 48
OCH3), 3.91 (s, 2H, CH2NC(O)), 6.73–6.86 (m, 3H, HAr(-
OCH3)2), 7.305 (ddd, 1H, J ¼ 8.16, 2.47, 0.99 Hz, HArNO2),
7.50 (t, 1H, J ¼ 8.16 Hz, HArNO2), 7.80 (app t, 1H, J ¼ 2.47
Hz, HArNO2), 7.98 (ddd, 1H, J ¼ 8.16, 2.23, 0.99 Hz,
HArNO2); 13C NMR (67.93 MHz, CDCl3, DEPT) d 34.12
(NCH2CH2), 44.56, 52.98 (NCH2CH2, CH2NC(O); 55.90 (2 ꢃ
OCH3), 111.43, 111.64, 117.71, 114.89, 118.58, 120.61, 123.21,
130.20, 130.38, 144.72, 147.92, 148.95, 149.14, 155.67 (ArC,
C-3, C-4), 162.97 (C¼¼O); ESI-HRMS for C20H19N2O6Br: [M
þ H]þ calcd: 463.0505, found: 463.0490 and 465.0471.
low solid (317 mg, 0.556 mmol, 60%); 1H NMR (270 MHz,
CDCl3) d 1.25 (d, 3H, J ¼ 6.80 Hz, (CH3A)2CHS(diastereo-
topic) overlapping with 1.25 (s, 3H, a-CH3) overlapping with
1.27 (d, 3H, J ¼ 6.80 Hz (CH3B)2CHS (diastereotopic)), 1.49 (s,
3H, b-CH3), 3.57 (d, 2H, J ¼ 6.93 Hz, ArCH2CH¼¼CH), 3.88
(sept, 1H, J ¼ 6.68 Hz, (CH3)2CHS), 4.73 (s, 1H, H-3), 5.93 (s,
1H, H-8), 6.15 (dt, 1H, J ¼ 15.83, 7.17 Hz, ArCH2CH¼¼CH),
6.72 (d, 1H, J ¼ 15.83 Hz, ArCH2CH¼¼CH), 6.96 (s, 1H,
CH(Ph)2), 7.15–7.38 (m, 15H, ArH); ESI-HRMS for
C34H35NO3S2: [M þ H]þ1 calcd: 570.2137, found: 570.2133.
(3S,7aR)-6-Ethylsulfanyl-2,2-dimethyl-7-(4-nitrophenyl)-5-oxo-
Suzuki-Miyaura Coupling–general Procedure. To a solution of
the required benzhydryl ester 4a–4c, or the muco derivatives 7a
and 7b, (0.498 mmol) in degassed 1:1 toluene/water (4 mL each)
was added the required boronic acid (0.747 mmol), cesium fluoride
(151 mg, 0.996 mmol), PdCl2(PPh3)2 (8.74 mg, 0.01245 mmol),
and benzyldimethylhexadecyl ammonium chloride (4.93 mg,
0.01245 mmol). The mixture was heated to reflux under N2 for 2–
48 h during which time the color changed from yellow-brown to ei-
2,3,5,7a-tetrahydro-pyrrolo[2,1-b]thiazole-3-carboxylic
acid
benzhydryl ester (5d). Twenty-four h reaction time; purifica-
tion using 3:1 dichloromethane/hexane gave 5d as a yellow
glassy solid (125 mg, 0.223 mmol, 40%); H NMR (270 MHz,
1
CDCl3) d 1.29 (t, 3H, J ¼ 7.42 Hz, CH3CH2S), 1.33 (s, 3H,
a-CH3), 1.56 (s, 3H, b-CH3), 3.23 (dq, 1H, J ¼ 13.50, 7.42
Hz, CH3CH2AS (diastereotopic)), 3.41 (dq, 1H, J ¼ 13.50,
7.42 Hz, CH3CH2BS (diastereotopic)), 4.81 (s, 1H, H-3), 6.30
(s, 1H, H-8), 7.02 (s, 1H, CH(Ph)2), 7.28–7.39 (m, 10H, ArH),
7.86 (d, 2H, J ¼ 8.91 Hz, HArNO2), 8.29 (d, 2H, J ¼ 8.91 Hz,
HArNO2); 13C NMR (67.93 MHz, CDCl3, DEPT) d 15.54
(CH3CH2S), 26.03, 26.42 (CH3CH2S, a-CH3), 31.73 (b-CH3),
61.64, 67.90, 68.47 (C-2, C-3, C-8), 78.58 (CH(Ph)2), 123.82,
126.90, 127.81, 128.16, 128.47, 128.59, 128.62, 128.84, 131.56,
137.78, 139.06, 139.11, 147.73, 149.86 (ArC, C-6, C-7), 167.72,
170.83 (2 ꢃ C¼¼O); ESI-HRMS for C30H28N2O5S2: [M ꢀ H]ꢀ
calcd: 559.1361, found: 559.1378.
1
ther pink or brown; reaction progress was monitored by H NMR
spectroscopy. The mixture was allowed to cool to room tempera-
ture, quenched with 0.5M HCl (50 mL) and diluted with toluene
(20 mL) and separated. The aqueous layer was re-extracted with
toluene (20 mL), the organic extracts were combined, washed with
DIW (30 mL), dried, filtered, and concentrated by rotary evapora-
tion to yield a red orange gel, which was purified by silica gel col-
umn chromatography as indicated below.
(3S,7aR)-6-Ethylsulfanyl-2,2-dimethyl-5-oxo-7-phenyl-2,3,5,7a-
tetrahydro pyrrolo [2,1-b]thiazole-3-carboxylic acid benzhydryl
ester (5a). The reaction time is 2.5 h; purification using 3:1
dichloromethane/hexane gave 5a as a pale yellow solid (121
(3S,7aR)-7-(4-Dimethylaminophenyl)-6-ethylsulfanyl-2,2-di-
methyl-5-oxo-2,3,5,7a-tetrahydro-pyrrolo[2,1-b]thiazole-3-
carboxylic acid benzhydryl ester (5e). Two h reaction time;
purification using 3:1 hexane/ethyl acetate gave 5e as an orange-
red glassy solid (312 mg, 0.559 mmol, 67%); 1H NMR (270 MHz,
CDCl3) d 1.24 (t, 3H, J ¼ 7.42 Hz, CH3CH2S), 1.31 (s, 3H, a-
CH3), 1.51 (s, 3H, b-CH3), 3.03 (s, 6H, N(CH3)2 overlapping
with 3.04 (dq, 1H, J ¼ 13.5, 7.42 Hz, CH3CH2AS (diastereo-
topic)), 3.17 (dq, 1H, J ¼ 13.5, 7.42 Hz, CH3CH2BS (diastereo-
topic)), 4.83 (s, 1H, H-3), 6.28 (s, 1H, H-8), 6.70 (d, 2H, J ¼ 9.15
Hz, N(CH3)2ArH), 7.00 (s, 1H, CH(Ph)2), 7.29–7.42 (m, 10H,
ArH), 7.81 (d, 2H, J ¼ 9.15 Hz, N(CH3)2ArH); 13C NMR (67.93
1
mg, 0.235 mmol, 47%); H NMR (270 MHz, CDCl3) d 1.25 (t,
3H, J ¼ 7.42 Hz, CH3CH2S), 1.32 (s, 3H, a-CH3), 1.54 (s, 3H,
b-CH3), 3.12 (dq, 1H, J ¼ 13.5, 7.42 Hz, CH3CH2AS (diastereo-
topic)), 3.28 (dq, 1H, J ¼ 13.5, 7.42 Hz, CH3CH2BS (diastereo-
topic)), 4.83 (s, 1H, H-3), 6.30 (s, 1H, H-8), 7.01 (s, 1H,
CH(Ar)2), 7.25–7.48 (m, 13H, ArH), 7.70–7.80 (m, 2H, ArH);
13C NMR (67.93 MHz, CDCl3, DEPT) d 15.39 (CH3CH2S),
26.11, 26.44 (a-CH3, CH3CH2S), 31.82 (b-CH3), 61.12, 67.94,
68.81 (C-2, C-3, C-8), 78.40 (CHPh2), 126.95, 127.82, 128.09,
128.20, 128.38, 128.58, 128.60, 128.65, 130.02, 131.80, 139.23,
139.30, 154.19 (ArC, C-6, C-7), 168.02, 172.07 (2 ꢃ C¼¼O);
ESI-HRMS for C30H29NO3S2: [M þ H]þ1 calcd: 516.1667,
found: 516.1660.
MHz, CDCl3, DEPT)
d 15.25 (CH3CH2S), 26.41, 26.64
(CH3CH2S, a-CH3), 32.08 (b-CH3), 39.99 (N(CH3)2, 60.57,
67.89, 68.89 (C-2, C-3, C-8), 78.20 (CH(Ph)2), 111.32 (C-7),
119.26, 120.06, 126.94, 127.76, 127.92, 128.39, 128.52, 128.55,
129.90, 139.30, 139.37, 151.31, 156.43 (ArC, C-6, C-7), 168.25,
173.22 (2ꢃ C¼¼O); ESI-HRMS for C32H34N2O3S2: [M ꢀ H]ꢀ
calcd: 557.1933, found: 557.1906.
(3S,7aR)-6-Ethylsulfanyl-2,2-dimethyl-5-oxo-7-((E)-3-phenyl-
propenyl)-2,3,5,7a-tetrahydropyrrolo[2,1-b]thiazole-3-carbox-
ylic acid benzhydryl ester (5b). Three h reaction time; purifi-
cation using 1:1 hexane/ethyl acetate gave 5b as a pale yellow
1
solid (144 mg, 0.259 mmol, 65%); H NMR (270 MHz, CDCl3)
(3S,7aR)-6-(3-Chlorophenoxy)-7-furan-3-yl-2,2-dimethyl-5-
oxo-2,3,5,7a-tetra hydropyrrolo[2,1-b]thiazole-3-carboxylic
acid benzhydryl ester (5f). Three h reaction time; purification
using 3:1 hexane/ethylacetate gave 5f as a yellow oil (116 mg,
0.199 mmol, 40%); 1H NMR (270 MHz, CDCl3) d 1.34 (s, 3H, a-
CH3), 1.58 (s, 3H, b-CH3), 4.72 (s, 1H, H-3), 6.11 (s, 1H, H-8),
6.62 (d, 1H, J ¼ 1.73 Hz, furanyl), 6.93 (ddd, 1H, J ¼ 8.16, 2.47,
0.99 Hz, HArCl), 6.99 (s, 1H, CHPh2), 7.04–7.09 (m, 2H, HArCl),
7.22 (t, 1H, J ¼ 8.16 Hz, HArCl), 7.27–7.40 (m, 10H, ArH), 7.45
(d, 1H, J ¼ 1.73 Hz, furanyl), 7.74 (s, 1H, furanyl); 13C NMR
(67.93 MHz, CDCl3, DEPT) d 26.43 (a-CH3), 31.79 (b-CH3),
61.30, 64.97, 67.44 (C-2, C-3, C-8), 78.52 (CH(Ph)2), 108.58,
114.37, 116.84, 123.81, 126.94, 127.80, 128.14, 128.43, 128.58,
128.63, 135.04, 135.17, 138.51, 139.08, 139.17, 156.18 (ArC, C-
d 1.24 (t, 3H, J ¼ 7.42 Hz, CH3CH2S) overlapping with 1.26 (s,
3H, a-CH3), 1.50 (s, 3H, b-CH3), 3.00 (dq, 1H, J ¼ 13.5, 7.42
Hz, CH3CH2AS (diastereotopic)) overlapping with 3.11 (dq, 1H,
J ¼ 13.5, 7.42 Hz, CH3CH2BS (diastereotopic)), 3.58 (d, 2H, J
¼ 6.93 Hz, ArCH2CH ¼ CH), 4.70 (s, 1H, H-3), 5.89 (s, 1H,
H-8), 6.14 (dt, 1H, J ¼ 16.08, 6.93 Hz, ArCH2CH¼¼CHA), 6.69
(d, 1H, J ¼ 15.83 Hz, ArCH2CH¼¼CHA), 6.96 (s, 1H,
CH(Ph)2), 7.16–7.36 (m, 15H, ArH); ESI-HRMS for
C33H33NO3S2: [M þ H]þ1 calcd: 556.1980, found: 556.1969.
(3S,7aR)-6-Isopropylsulfanyl-2,2-dimethyl-5-oxo-7-((Z)-3-phe-
nylpropenyl)-2,3,5,7a-tetrahydropyrrolo[2,1-b]thiazole-3-car-
boxylic acid benzhydryl ester (5c). The reaction time is 2.5 h;
purification using 3:1 dichloromethane/hexane gave 5c as a yel-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011 Modular Synthesis of Pyrrolo[2,1-b]thiazoles and Related Monocyclic Pyrrolo Structures
293
furanyl, C-6, C-7), 167.79, 167.83 (2 ꢃ C¼¼O); ESI-HRMS for
C32H26NO5SCl: [M þ Na]þ calcd: 594.1118, found: 594.1133.
[4-(1-Benzyl-1H-pyrazol-4-yl)-3-ethylsulfanyl-2-oxo-2,5-
dihydropyrrol-1-yl]-phenylacetic acid methyl ester
(8a). Forty-eight h reaction time using the boronic acid pina-
col ester with 7a; purification using 1:1 hexane/ethylacetate
point ethyl acetate (70 mL) and 5% sodium carbonate (45 mL)
were added successively while maintaining the temperature at
ꢀ84ꢁC. The reaction mixture was allowed to warm to room
temperature at which point the aqueous layer was separated
and filtered through celite before being extracted with ethyl ac-
etate (20 mL). The aqueous portion was layered with ethyl ac-
etate (30 mL) and the pH lowered to 2.2 using 1M HCl. The
organic extract was separated and the aqueous portion
extracted with a further portion of ethyl acetate (30 mL). The
organic extracts were combined, dried, filtered, and concen-
trated by reduced pressure to yield a solid, which was further
dried under vacuum.
1
gave 8a as a brown oil (129 mg, 0.288 mmol, 45%); H NMR
(270 MHz, CDCl3) d 1.23 (t, J ¼ 7.42 Hz, 3H, CH3CH2S),
3.08 (dq, 1H, J ¼ 13.50, 7.42 Hz, CH3CH2AS (diastereotopic))
overlapping with 3.16 (dq, 1H,
J
¼
13.50, 7.42 Hz,
CH3CH2BS (diastereotopic)), 3.74 (d, 1H, J ¼ 18.06 Hz, H-
5A), 3.79 (s, 3H, OCH3), 4.61 (d, J ¼ 18.31 Hz, 1H, H-5B),
5.31 (s, 2H, PhCH2N), 6.18 (s, 1H, CHC(O)), 7.15–7.41 (m,
10H, ArH), 7.86 (s, 1H, C¼¼CHAN), 8.05 (s, 1H, CACH¼¼N);
13C NMR (67.93 MHz, CDCl3, DEPT) d 15.46 (CH3CH2S),
26.29 (CH3CH2S), 49.31, 52.41, 56.25, 57.68 (C-5, OCH3,
(Ph)CH2N) (CHC(O)), 115.62, 120.95 (C¼¼C), 127.54, 127.75,
128.24, 128.41, 128.68, 128.85, 128.96, 129.09, 129.18,
134.27, 135.71, 138.42, 145.52 (ArC, C-3, C-4, N¼¼C),
170.08, 170.89 (2 ꢃ C¼¼O); ESI-HRMS for C25H25N3O3S: [M
ꢀ H]ꢀ calcd: 448.1695, found: 448.1692.
(3S,7aR)-6-Ethylsulfanyl-2,2-dimethyl-5-oxo-7-phenyl-2,3,5,7a-
tetrahydro pyrrolo[2,1-b] thiazole-3-carboxylic acid (6a). A
pale yellow solid (166 mg, 0.475 mmol, 70%); H NMR (270
1
MHz, CDCl3) d 1.25 (t, 3H, J ¼ 7.42 Hz, CH3CH2S), 1.65 (s,
3H, a-CH3), 1.70 (s, 3H, b-CH3), 3.11 (dq, 1H, J ¼ 13.50,
7.42 Hz, CH3CH2AS (diastereotopic)) overlapping with 3.24
(dq, 1H, J ¼ 13.50, 7.42 Hz, CH3CH2BS (diastereotopic)),
4.66 (s, 1H, H-3), 6.27 (s, 1H, H-8), 7.42–7.47 ((m, 3H,
ArH)), 7.73–7.76 (m, 2H, ArH); 13C NMR (67.93 MHz,
CDCl3, DEPT) d 15.30 (CH3CH2S), 26.28, 26.80 (a-CH3,
CH3CH2S), 30.79 (b-CH3), 60.73, 68.00, 68.82 (C-2, C-3, C-
8), 127.03, 128.24, 128.66, 130 0.18, 131.53 (ArC, C-7)
154.31 (C-6), 172.36, 172.76 (2 ꢃ C¼¼O); ESI-HRMS for
C17H19NO3S2: [M ꢀ H]ꢀ calcd: 348.0728, found: 348.0733.
(3S,7aR)-6-Ethylsulfanyl-2,2-dimethyl-5-oxo-7-((Z)-3-phenyl-
propenyl)-2,3,5,7a-tetrahydropyrrolo[2,1-b]thiazole-3-car-
boxylic acid (6b). A pale yellow solid (27.2 mg, 0.0698
4-Furan-3-yl-3-(3-nitrophenoxy)-1-phenethyl-1,5-dihydropyr-
rol-2-one (8b). Three h reaction time using the boronic acid with
7b; purification using 1:3 hexane/ethylacetate gave 8b as a pale yel-
low solid (135 mg, 0.30 mmol, 60%); 1H NMR (270 MHz, CDCl3)
d 2.92 (t, 2H, J ¼ 7.42 Hz, NCH2CH2), 3.75 (t, 2H, J ¼ 7.42 Hz,
NCH2CH2), 3.85 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.90 (s, 3H,
NCH3), 4.08 (s, 2H, CH2NC(O)), 6.56 (d, 1H, J ¼ 1.98 Hz, furanyl),
6.76–6.85 (m, 3H, HAr(OCH3)2), 7.315 (ddd, 1H, J ¼ 8.41, 2.27,
0.74 Hz, HArNO2), 7.44 (d, 1H, J ¼ 1.98 Hz, furanyl), 7.49 (t, 1H, J
¼ 8.41 Hz, HArNO2), 7.70 (s, 1H, furanyl), 7.81 (app t, 1H, J ¼
2.47 Hz, HArNO2), 7.95 (ddd, 1H, J ¼ 8.41, 2.23, 0.74 Hz,
HArNO2); 13C NMR (67.93 MHz, CDCl3, DEPT) d 34.23
(NCH2CH2), 44.48, 48.59 (NCH2CH2, CH2NC(O); 55.88 (2 x
OCH3), 108.13, 111.07, 111.34, 111.69, 116.28, 118.06, 120.62,
122.60, 127.83, 130.25, 130.72, 139.28, 141.49, 144.18, 147.77,
149.05, 156.39 (ArC, C-furanyl, C-3, C-4), 164.87 (C¼¼O); ESI-
HRMS for C24H22N2O7: [M þ H]þ calcd: 451.1505, found:
451.1501.
1
mmol, 27%); H NMR (270 MHz, CDCl3) d 1.24 (t, 3H, J ¼
7.42 Hz, CH3CH2S), 1.60 (s, 3H, a-CH3), 1.62 (s, 3H, b-
CH3), 2.99 (dq, 1H, J ¼ 13.50, 7.42 Hz, CH3CH2AS (diaster-
eotopic)) overlapping with 3.07 (dq, 1H, J ¼ 13.50, 7.42 Hz,
CH3CH2BS (diastereotopic), 3.58 (d, 2H, J ¼ 6.93 Hz,
PhCH2CH¼¼CHA), 4.52 (s, 1H, H-3), 5.85 (s, 1H, H-8), 6.21
(dt, 1H, J ¼ 16.08, 6.93 Hz, PhCH2CH¼¼CH), 6.70 (d, 1H, J
¼ 16.08 Hz, PhCH2CH¼¼CH), 7.18–7.44 (m, 5H, ArH); ESI-
HRMS for C20H23NO3S2: [M ꢀ H]ꢀ calcd: 388.1041, found:
388.1039.
4-(1-Methyl-1H-pyrazol-4-yl)-3-(3-nitrophenoxy)-1-phenethyl-
1,5-dihydropyrrol-2-one (8c). Twenty-four
(3S,7aR)-6-Isopropylsulfanyl-2,2-dimethyl-5-oxo-7-((Z)-3-phe-
nyl-propenyl)-2,3,5,7a-tetrahydropyrrolo[2,1-b]thiazole-3-car-
boxylic acid (6c). A pale yellow solid (44 mg, 0.109 mmol,
19%); 1H NMR (270 MHz, CDCl3) d 1.24 (d, 3H, J ¼ 6.68
Hz, (CH3A)2CHS (diastereotopic)) overlapping with 1.26 (d,
3H, J ¼ 6.68Hz, (CH3B)2CHS (diastereotopic)), 1.59 (s, 3H,
a-CH3), 1.62 (s, 3H, b-CH3), 3.58 (d, 2H, J ¼ 6.93 Hz, Ph-
CH2CH¼¼CH), 3.82 (sept, 1H, J ¼ 6.68 Hz, (CH3)2CHS), 4.53
(s, 1H, H-3), 5.87 (s, 1H, H-8), 6.22 (dt, 1H, J ¼ 7.17, 16.08
Hz, Ph-CH2CH¼¼CH), 6.72 (d, 1H, J ¼ 15.83 Hz, Ph-
CH2CH¼¼CH), 7.17–7.36 (m, 5H, ArH); 13C NMR (67.93
MHz, CDCl3, DEPT) d 23.21, 24.06, (CH3)2CHS (diastereo-
topic methyl groups)), 26.64, 30.81, 36.77 (a-CH3, b-CH3,
(CH3)2CHS), 39.70 (ArCH2C¼¼C), 60.51, 66.74, 67.52 (C-2,
C-3, C-8), 123.03 (ArCH2CH¼¼CH), 126.44, 126.61, 128.58,
128.68, 138.35, 139.20 (ArC, C-7, ArCH2CH¼¼CH), 157.64
h reaction time
using the boronic acid pinacol ester with 7b; purification using
ethylacetate then methanol gave 8c as a pale yellow oil (173
mg, 0.373 mmol, 75%); 1H NMR (270 MHz, CDCl3) d 2.92
(t, 2H, J ¼ 7.17 Hz, NCH2CH2), 3.74 (t, 2H, J ¼ 7.17 Hz,
NCH2CH2), 3.85 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.90 (s,
3H, NCH3), 4.09 (s, 2H, CH2NC(O)), 6.76–6.84 (m, 3H,
HAr(OCH3)2), 7.31 (ddd, 1H, J ¼ 8.41, 2.27, 0.74 Hz,
HArNO2), 7.49 (t, 1H, J ¼ 8.41 Hz, HArNO2), 7.59 (s, 1H,
pyrazole), 7.60 (s, 1H, pyrazole), 7.81 (app t, 1H, J ¼ 2.47
Hz, HArNO2), 7.95 ((ddd, 1H, J ¼ 8.16, 2.23, 0.74 Hz,
HArNO2); ESI-HRMS for C24H24N4O6: [M þ H]þ calcd:
465.1774, found: 465.1785.
Benzhydryl removal–general procedure. The required
benzhydryl ester (0.6748 mmol) was dissolved in dichlorome-
thane (15 mL) and cooled under nitrogen to ꢀ84ꢁC (liquid N2/
ethylacetate slurry). A solution of aluminum trichloride (222
mg, 1.664 mmol) in nitroethane (1.39 mL) was added in one
portion to the cooled pyrrolothiazole solution at which point
the solution changed color from pale to intense yellow. The
reaction mixture was allowed to stir at ꢀ84ꢁC for 1 h at which
(C-6), 171.97, 173.18 (2
ꢃ
C¼¼O); ESI-HRMS for
C21H25NO3S2: [M ꢀ H]ꢀ calcd: 402.1198, found: 402.1190.
(3S,7aR)-6-Ethylsulfanyl-2,2-dimethyl-7-(4-nitrophenyl)-5oxo-
2,3,5,7a-tetrahydropyrrolo[2,1-b]thiazole-3-carboxylic
acid
1
(6d). An orange solid (48.7 mg, 0.123 mmol, 55%); H NMR
(270 MHz, CDCl3) d 1.29 (t, 3H, J ¼ 7.42 Hz, CH3CH2S),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

294
E. E. O’Dwyer, N. S. Mullane, and T. P. Smyth
Vol 48
REFERENCES AND NOTES
1.66 (s, 3H, a-CH3), 1.71 (s, 3H, b-CH3), 3.24 (dq, 1H, J ¼
13.50, 7.42 Hz, CH3CH2AS (diastereotopic)), 3.38 (dq, 1H, J
¼ 13.50, 7.42 Hz, CH3CH2BS (diastereotopic)), 4.67 (s, 1H,
H-3), 6.27 (s, 1H, H-8), 7.89 (d, 2H, J ¼ 9.15 Hz, HArNO2),
8.31 (d, 2H, J ¼ 9.15 Hz, HArNO2); 13C NMR (67.93 MHz,
CDCl3, DEPT) d 15.51 (CH3CH2S), 26.14, 26.73 (a-CH3,
CH3CH2S), 30.86 (b-CH3), 61.13, 67.92, 68.46 (C-2, C-3, C-
8), 123.86, 128.91, 131.71, 137.57, 147.85, 149.79 (ArC, C-6,
[1] Tverdokhlebov, A. V. Heterocycles 2007, 71, 761 and refer-
ences therein.
[2] (a) Yoon-Miller, S. J.; Dorward, K. M.; White, K. P.; Pel-
key, E. T. J. Heterocycl Chem 2009, 46, 447; (b) Dorward, K. M.;
Guthrie, N. J.; Pelkey, E. T. Synthesis 2007, 15, 2317.
[3] (a) Sulikowski, G. A.; Agnelli, F.; Spencer, P.; Koomen, J.
M.; Russell, D. H. Org Lett 2002, 4, 1447; (b) Sulikowski, G. A.;
Liu, W.; Agnelli, F.; Corbett, R. M.; Lou, Z.; Hershberger, S. J. Org
Lett 2002, 4, 1451.
C-7), 171.43, 171.88 (2
ꢃ
C¼¼O); ESI-HRMS for
C17H18N2O5S2: [M ꢀ H]ꢀ calcd: 393.0579, found: 393.0591.
(3S,7aR)-7-(4-Dimethylaminophenyl)-6-ethylsulfanyl-2,2-di-
methyl-5-oxo-2,3,5,7a -tetrahydropyrrolo[2,1-b]thiazole-3-car-
boxylic acid (6e). An orange-red solid (122 mg, 0.311 mmol,
[4] (a) Zhang, J.; Blazecka, P. G.; Belmont, D.; Davidson, J. G.
Org Lett 2002, 4, 4559; (b) Bellina, F.; Anselmi, C.; Martina, F.;
Rossi, R. Eur J Org Chem 2003, 2290.
1
65%); H NMR (270 MHz, CDCl3) d 1.25 (t, 3H, J ¼ 7.42 Hz,
[5] (a) Zhang, J.; Blazecka, P. G.; Davidson, J. G. Org Lett
2003, 5, 553; (b) Sarma, K. D.; Zhang, J.; Huang, Y.; Davidson, J. G.
Eur J Org Chem 2006, 3730.
CH3CH2S), 1.64 (s, 3H, a-CH3), 1.72 (s, 3H, b-CH3), 3.05 (s,
6H, N(CH3)2 overlapping with 3.04 (dq, 1H, J ¼ 13.50, 7.42
Hz, CH3CH2AS) overlapping with 3.14 (dq, 1H, J ¼ 13.50, 7.42
Hz, CH3CH2BS)), 4.57 (s, 1H, H-3), 6.20 (s, 1H, H-8), 6.72 (d,
2H, J ¼ 8.91 Hz, N(CH3)2ArH), 7.86 (d, 2H, J ¼ 8.91 Hz,
N(CH3)2ArH); 13C NMR (67.93 MHz, CDCl3, DEPT) d 15.21
(CH3CH2S), 26.61, 26.86 (a-CH3, CH3CH2S), 30.19 (b-CH3),
40.00 (N(CH3)2, 59.89, 68.09, 68.58 (C-2, C-3, C-8), 111.34,
118.95, 120.02, 130.10, 151.51, 156.76 (ArC, C-6, C-7),
170.82, 174.84 (2 ꢃ C¼¼O); ESI-HRMS for C19H24N2O3S2: [M
ꢀ H]ꢀ calcd: 391.1150, found: 391.1135.
[6] (a) Kurbangalieva, A. R.; Devyatova, N. F.; Bogdanov, A.
V.; Berdnikov, E. A.; Mannafov, T. G.; Krivolapov, D. B.; Litvinov, I.
A.; Chmutova, G. A. Phosphorus Sulfur Silicon Relat Elem 2007, 182,
¨
607; (b) Buu-Hoı, N. P.; Dufour, M.; Jacquignon, P. Bull Soc Chim Fr
1971, 8, 2999.
[7] Wasserman, H. H.; Precopio, F. M.; Liu, T.-C. J Am Chem
Soc 1952, 74, 4093.
[8] Moore, H. W.; Arnold, M. J. J Org Chem 1983, 48, 3365.
[9] (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.;
Satoh, M.; Suzuki, A. J Am Chem Soc 1989, 111, 314. (b) For the
general protocol followed here see Reference 4a above.
[10] LaLonde, R. T.; Xie, S. Chem Res Toxicol 1992, 5, 618.
[11] (a) Ingold, C. K.; Sato, S.; Thorpe, J. F. J Chem Soc 1922, 1117
and references therein; (b) Kaneti, J.; Kirby, A. J.; Koedjikov, A. H.; Pojar-
lieff, I. G. Org Biomol Chem 2004, 2, 1098 and references therein.
[12] (a) Ruddle, C. C.; Smyth, T. P. Org Biomol Chem 2007, 5,
160; (b) Ruddle, C. C.; Smyth, T. P. Chem Commun 2004, 2332.
[13] (a) Guth, J. J.; Gross, R. L.; Carson, F. W. J Org Chem
1982, 47, 2666; (b) Bordwell, F. G.; Van der Puy, M.; Vanier, N. R.
J Org Chem 1976, 41, 1885.
(3S,7aR)-6-(3-Chlorophenoxy)-7-furan-3-yl-2,2-dimethyl-5-
oxo-2,3,5,7a-tetra hydropyrrolo[2,1-b]thiazole-3-carboxylic
1
acid (6f). A pale yellow solid (64 mg, 0.154 mmol, 45%); H
NMR (270 MHz, CDCl3) d 1.66 (s, 3H, a-CH3), 1.70 (s, 3H, b-
CH3), 4.56 (s, 1H, H-3), 6.08 (s, 1H, H-8), 6.65 (d, 1H, J ¼ 1.98
Hz, furanyl), 6.94 (ddd, 1H, J ¼ 8.16, 2.23, 0.74, HArCl), 7.06–
7.11 (m, 2H, HArCl), 7.24 (t, 1H, J ¼ 8.16 Hz, HArCl), 7.48 (d,
J ¼ 1.98 Hz, furanyl), 7.78 (s, 1H, furanyl); ESI-HRMS for
C19H16NO5SCl: [M ꢀ H]ꢀ calcd: 404.0359, found: 404.0376.
Acknowledgments. E. E. O’D thanks Roche Ireland Ltd, Clare-
castle, County Clare and IRCSET for financial support through
its EMBARK initiative. N. S. Mullane thanks the Department of
Chemical and Environmental Sciences, University of Limerick
for financial support.
[14] Westwood, N. J.; Schofield, C. J.; Claridge, T. D. W.
J Chem Soc Perkin Trans 1 1997, 2725.
[15] (a) Goyal, S. S.; Hafez, A. A. R. J Agric Food Chem 1995,
43, 2641 and references therein; (b) Vajda, T. Cell Mol Life Sci
1999, 56, 398 and references therein.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet