A Strecker approach to 2-substituted ethyl 5-aminothiazole-4-carboxylates

Article abstract of DOI:10.1016/j.tetlet.2015.12.069

A general approach to 2-substituted ethyl 5-aminothiazole-4-carboxylates is reported herein. Both aliphatic and aromatic thioamides undergo 1,2-addition to ethyl glyoxylate to give hemiaminals which, when treated with acetyl chloride, undergo elimination

Full text of DOI:10.1016/j.tetlet.2015.12.069

Accepted Manuscript
A Strecker approach to 2-substituted ethyl 5-aminothiazole-4-carboxylates
Ken Cheng, Andrew McClory, Whitney Walker, Jie Xu, Haiming Zhang, Remy
Angelaud, Francis Gosselin
PII:
S0040-4039(15)30484-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.069
TETL 47116
Reference:
Tetrahedron Letters
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Accepted Date:
3 December 2015
18 December 2015
Please cite this article as: Cheng, K., McClory, A., Walker, W., Xu, J., Zhang, H., Angelaud, R., Gosselin, F., A
Strecker approach to 2-substituted ethyl 5-aminothiazole-4-carboxylates, Tetrahedron Letters (2015), doi: http://
dx.doi.org/10.1016/j.tetlet.2015.12.069
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A Strecker approach to 2-substituted ethyl 5-
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Ken Cheng, Andrew McClory,* Whitney Walker, Jie Xu, Haiming Zhang, Remy Angelaud, and Francis
Gosselin

1
Tetrahedron Letters
A Strecker approach to 2-substituted ethyl 5-aminothiazole-4-carboxylates
Ken Cheng, Andrew McClory, Whitney Walker, Jie Xu, Haiming Zhang, Remy Angelaud, and Francis
Gosselin
Small Molecule Process Chemistry, Genentech, A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A general approach to 2-substituted ethyl 5-aminothiazole-4-carboxylates is reported herein.
Both aliphatic and aromatic thioamides undergo 1,2-addition to ethyl glyoxylate to give
hemiaminals which, when treated with acetyl chloride, undergo elimination to the corresponding
imines. Upon exposure to aqueous sodium cyanide the imines undergo a Strecker addition-
cyclization reaction to provide the target heterocycles in modest to good yields over the 3-step
process.
Available online
Keywords:
Thiazole
2015 Elsevier Ltd. All rights reserved.
Strecker
Convergent
Thioamide
Cyanide
The thiazole ring is present in a large number of natural
products and pharmaceutically active molecules. Certain
thiazole-containing compounds have been found to display a
range of important biological activities (Figure 1), including
antitumor (tiazofurin, 1), antibiotic (sulfathiazole, 2), antifungal
(abafungin, 3), and antiviral (ritonavir, 4).1
Figure 2. 2-Substituted 5-aminothiazole-4-carboxylic acids
The literature preparation of ethyl 5-amino-4-carboxylates
involves a three-step sequence (Scheme 1).4g,6 Commercially
available oxime 6 is reduced to amine 7, which is then acetylated
with an acid chloride (e.g. benzoyl chloride) to give the
corresponding amide 8. Thioamide formation then yields 9,
which undergoes in situ ring-closure and tautomerization to
produce the thiazole product 10 in 10% yield over 3 steps
(average 47% yield per step).
Figure 1. Selected biologically active thiazoles
Given this wide array of important biological activity, the
efficient synthesis of substituted thiazoles remains an important
endeavor for synthetic chemistry. In the context of a development
program in our laboratories, we were confronted with the need to
prepare 2-substituted 5-aminothiazole-4-carboxylic acids
5
(Figure 2), a starting material that has been used to prepare
inhibitors of MAP kinase,2 glycogen phosphorylase,3 PIM
kinase,4 and Janus kinase.5
Scheme 1. Literature approach to ethyl 5-amino-2-
phenylthiazole-4-carboxylate (10)
———
 Corresponding author. Tel.: +1-650-225-7605; e-mail: mcclory.andrew@gene.com

2
Tetrahedron Letters
The above method was found to be difficult to scale up due to
pyridine nitrogen in the acetylation step (entry 7). Alkyl-
substituted thioamides were examined next, and were found to
also participate in the 3-step thiazole-forming process. Linear
alkyl (entry 8), branched alkyl (entry 9), and cyclopropyl groups
(entry 10) performed similarly, producing the thiazole products
in modest yields (20-26%). The higher yield obtained for the t-
butyl group (entry 11, 52% yield) may be reflective of steric
crowding near the thiocarbonyl functionality which could block
access to this reactive center, thus favoring productive
nucleophilic attack at the imine center.
the use of Lawesson’s reagent (waste generation) and pyridine,
the poor conversion7 and tedious column purification in the final
step, and the low overall yield. It was reasoned that producing
thioamide intermediate 9 under milder conditions should enable a
more efficient ring-closing event to form 10. Thus an alternative
disconnection was envisaged in which 9 would be produced
through addition of cyanide to activated imine 11 (Scheme 2).
This activated imine8 could potentially be formed by dehydration
of hemiaminal 12, which in turn could possibly be accessed
through a simple carbonyl addition of thioamide 14 to ethyl
glyoxylate (13).
Table 1. Scope of thioamides in 5-aminothiazole formation
Thioamide
entrya
1
Thiazole Product
Yield (%)c
45
Substrate
2b
49
35
Scheme 2. Retrosynthetic analysis of ethyl 5-amino-2-
phenylthiazole-4-carboxylate (10)
3
4
Following initial small-scale optimization experiments, it was
found that heating thioamide 13 with 200 mol% ethyl glyoxylate9
in toluene furnished the corresponding 1,2-addition product 12
(Scheme 3). Exposure of the crude hemiaminal to pyridine and
acetyl chloride10 enabled elimination to the corresponding imine
intermediate 11. Addition of the crude imine solution to warm
aqueous sodium cyanide,11 followed by extractive workup,
column chromatography, and crystallization12 furnished thiazole
10 in 40% yield over 3 steps on 20 g scale (average 74% yield
per step).13 Both the conversion and crude HPLC purity for the
first 2 steps were >90%, while the final step gave complete
conversion but afforded a mixture containing several unidentified
side products in addition to the major product 10.
46
28
22
0
5
6
7
8
9
26
20
23
52
10
11
Scheme 3. Strecker synthesis of ethyl 5-amino-2-
phenylthiazole-4-carboxylate (10)
aReactions carried out on 30 mmol scale utilizing conditions shown in
Scheme 3. bCarried out on 58 mmol scale. cIsolated yield after column
chromatography and crystallization.
With this encouraging result in hand the scope of the
thioamide substrate was examined on gram-scale (Table 1). In
terms of aromatic groups it was found that electron-withdrawing
(o-fluoro and o,o-difluoro, entries 1 and 2, 45% yield and 49%
yield) and weakly electron-donating (o-methyl and o,o-dimethyl,
entries 3 and 4, 35% yield and 46% yield) substituents led to
similar isolated yields when compared to the parent phenyl
system (Scheme 3, 40% yield). However, both a strongly
electron-withdrawing (p-CF3, entry 5, 28% yield) and electron-
donating (p-OMe, entry 6, 22% yield) substituent led to
It was surmised that the scope of the 3-step transformation
could be further extended if ethyl glyoxylate were replaced with
a different electrophilic aldehyde.14 This was indeed found to be
the case: employing phenylglyoxal monohydrate (37) furnished a
thiazole with a ketone group in the 3-position (eq 1, 25% yield,
Scheme 4), while use of trifluoroacetaldehyde monohydrate (39)
afforded a thiazole bearing a trifluoromethyl substituent (eq 2,
33% yield).
diminished isolated yields.
A
heterocyclic group (3-
methylpyridine-2-carbothioamide, 27) functioned well in the
thioamide addition step, but ultimately afforded multiple
unidentifiable side products in the final reaction mixture,
presumably due to the competing nucleophilic nature of the

3
Scheme 4. Alternative aldehyde partners
The product ethyl 5-aminothiazole-4-carboxylates possess a
useful juxtaposition of amine and ester groups which could be
exploited in further chemoselective transformations (Scheme 5).
For example, the amine group of thiazole 18 could be replaced
with either a bromide group or a hydride using diazotization
conditions, affording derivatives 41 (62% yield) and 42 (49%
yield), respectively. The amine group was nucleophilic enough to
participate in both amide formation and reductive amination15
reactions to furnish 43 (75% yield) and 44 (84% yield),
respectively. Finally, the ester group could be readily saponified
to the corresponding carboxylic acid, providing 45 in 95% yield.
Scheme 5. Selected transformations of ethyl 5-aminothiazole-
4-carboxylate 18. (a) isoamyl nitrite, CuBr2, CH3CN, 65 ºC;
(b) isoamyl nitrite, CH3CN, 65 ºC; (c) PhCOCl, i-Pr2NEt,
THF, 60 ºC; (d) p-anisaldehyde, TFA, NaBH(OAc)3, THF, 25
ºC; (e) NaOH, H2O, 70 ºC.
In summary, a 3-step sequence has been discovered to convert
thioamides and ethyl glyoxylate to 5-aminothiazole-4-
carboxylate products. The process is marked by: (a) improved
yields relative to the existing routes; (b) the practicality of a
telescoped 3-step process that obviates the use of Lawesson’s
reagent; (c) generation of a variety of alkyl and aryl substituents
at the 2-position of the thiazole; and (d) a range of orthogonal
synthetic transformations available to the products.
Supplementary data
Acknowledgments
Supplementary data (full experimental details, compound
characterization, and selected spectra for key compounds)
associated with this article can be found, in the online version,
at http://XXXXX.
The authors thank Christine Gu (Genentech, Inc.) for
obtaining the HRMS data.
see: Shimada, K.; Aikawa, K.; Fujita, T.; Sato, M.; Goto, K.;
Aoyagi, S.; Takikawa, Y.; Kabuto, C. Bull. Chem. Soc. Jpn.
2001, 74, 511˗525.
1
Reviews: (a) De Souza, M. V. N. J. Sulfur Chem. 2005, 26,
429˗449. (b) Davyt, D.; Serra, G. Mar Drugs 2010, 8,
2755˗2780.
9
Use of 1.5 equivalents ethyl glyoxylate led to incomplete
conversion.
2
Michelotti, E. L. et al. PCT Int. Appl., 2010019930, 18 Feb
10
Using a stronger base (triethylamine) led to fragmentation
2010.
of the hemiaminal back to the thioamide starting material.
3 Evans, K. et al. PCT Int. Appl., 2006052722, 18 May 2006.
11
Use of less than 5 equiv of sodium cyanide resulted in a
4
(a) Burger, M. et al. PCT Int. Appl., 2009109576, 11 Sep
lower yield and a greater amount of unidentified side
products. Potassium cyanide and sodium cyanide were found
to function equally well.
2009. (b) Burger, M. et al. U.S. Pat. Appl. Publ.,
20100216839, 26 Aug 2010. (c) Burger, M. et al. PCT Int.
Appl., 2012004217, 12 Jan 2012. (d) Burger, M. et al. U.S.
Pat. Appl. Publ., 20120225061, 06 Sep 2012. (e) Burger,
Matthew et al. PCT Int. Appl., 2014033631, 06 Mar 2014. (f)
Ge, Yu et al. PCT Int. Appl., 2013020371, 14 Feb 2013. (g)
Burch, J. et al. U.S. Pat. Appl. Publ., 20140088117, 27 Mar
2014.
12
HPLC mass assay showed 12% loss of product to the
mother liquor.
13
Representative procedure: To
a
suspension of
benzothioamide (14, 20.0 g, 146 mmol, 1.00 equiv) in toluene
(146 mL) was added ethyl glyoxylate solution (50 wt% in
toluene, 57.7 mL, 292 mmol, 2.00 equiv). The mixture was
heated to 60 °C, held for 1 h, then cooled to 25 °C and
concentrated in vacuo. The resulting crude hemiaminal
intermediate was dissolved in CH3CN (200 mL), and pyridine
(58.9 mL, 730 mmol, 5.00 equiv) was added. The solution
was cooled to 0 °C and acetyl chloride (20.8 mL, 292 mmol,
2.00 equiv) was added over 20 min while maintaining the
temperature below 10 °C. The mixture was warmed to 25 °C
over 30 min and then held for 1 h. The resulting solution of
crude imine intermediate was transferred over 15 min to a 50
°C solution of sodium cyanide (35.72 g, 730 mmol, 5.00
equiv) in H2O (200 mL). [CAUTION: use base scrubber]. The
mixture was stirred for 15 min at 50 °C, then cooled to 25 °C
and isopropyl acetate (250 mL) was added, followed by H2O
(250 mL). The mixture was filtered through Celite and then
5
Machacek, M. R. et al. PCT Int. Appl., 2010011375, 28 Jan
2010.
6
(a) Ashwell, S. et al. PCT Int. Appl., 2005066163, 21 Jul
2005. (b) Wang, X. et al. U.S. Pat. Appl. Publ., 20110059961,
10 Mar 2011. (c) Wang, X. et al. PCT Int. Appl., 2011124580,
13 Oct 2011. (d) Bleicher, K. et al. PCT Int. Appl.,
2011154327, 15 Dec 2011. (e) Hodges, A. J. et al. U.S. Pat.
Appl. Publ., 20130079321, 28 Mar 2013.
7
Golankiewicz, B.; Januszczyk, P. Tetrahedron 1985, 41,
5989˗5994.
8
At the outset, it was not clear that such a 1,3-thiaza-1,3-
butadiene would in fact be stable enough to generate in the
absence of the cyanide nucleophile. For an alternative method
of forming such unstable species, and their in situ reactions,

4
Tetrahedron
the phases were separated. The aqueous layer was washed
with isopropyl acetate (100 mL). The combined organic
extracts were washed with half-saturated aqueous NH4Cl (150
mL), brine (75 mL), dried over anhydrous MgSO4, and
filtered. Celite (60.0 g) was added to the filtrate, which was
then concentrated in vacuo and purified by flash
chromatography (dichloromethane/methanol 100:0 → 98:2) to
provide a brown solid. The crude product was dissolved in
refluxing EtOH (50 mL), cooled to 25 °C over 2 h, and then
H2O (25 mL) was added over 15 min. The slurry was held for
2 h and then the resulting crystals were filtered, washed with
EtOH/H2O (67:33, 20 mL), and dried in vacuo under N2 purge
at 60 °C to furnish 10 as pale yellow crystals. Yield: 14.4 g
1
(40%). MP: 137.7–138.3 °C. H NMR (400 MHz, CDCl3): δ
(ppm) 7.83 – 7.75 (m, 2H), 7.44 – 7.31 (m, 3H), 6.10 (s, 2H),
4.42 (q, J=7.1 Hz, 2H), 1.44 (t, J=7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 164.82, 159.61, 149.44, 133.23, 129.43,
128.76, 126.08, 122.64, 60.68, 14.57. HRMS. Calcd. For
C12H12N2O2S: 249.0692; Found [M+H]+: 249.0694.
14
Use of benzaldehyde led to the corresponding aminal
product, which did not participate in the subsequent
elimination or Strecker steps.
15
Chen, L.; Li, Z. M.; Zhou, J.; Song, H. R.; Xu, B. L.
Chinese Chem Lett. 2012, 23, 695˗698.