Homo- A nd Heteroannulation of sp3 C-H Bonds in Acetophenones for Divergent Synthesis of Thienothiazoles

Article abstract of DOI:10.1021/acs.orglett.9b03414

A synthesis of fused thieno[3,2-d]thiazoles via direct functionalization of C(sp³)-H bonds in acetophenones was reported. The transformation is divergent to afford either 2-phenylbenzo[4,5]thieno[3,2-d]thiazoles or benzo[4,5]thieno[3,2-d]thiazo

Full text of DOI:10.1021/acs.orglett.9b03414

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Homo- and Heteroannulation of sp3 C−H Bonds in Acetophenones
for Divergent Synthesis of Thienothiazoles
Phuc H. Pham,† Khang X. Nguyen,† Hoai T. B. Pham,†,‡ Tung T. Nguyen,*,†
and Nam T. S. Phan*,†
†Faculty of Chemical Engineering, HCMC University of Technology, VNU-HCM, 268 Ly Thuong Kiet, District 10, Ho Chi Minh
City, Vietnam
‡Department of Chemistry, University of Colorado Denver, Denver, Colorado 80204, United States
S
* Supporting Information
ABSTRACT: A synthesis of fused thieno[3,2-d]thiazoles via
direct functionalization of C(sp3)−H bonds in acetophenones
was reported. The transformation is divergent to afford either
2-phenylbenzo[4,5]thieno[3,2-d]thiazoles or benzo[4,5]-
thieno[3,2-d]thiazol-2-yl(phenyl)methanones. Cross-coupling
of acetophenones with C−H bonds in phenylacetic acids,
methylazaarenes, and aldehydes was also feasible. Excellent
tolerance of functionalities was observed. Our method marks a
rare functionalization of C(sp3)−H bonds in acetophenones
to obtain heterocycles in the absence of prefunctionalized
oxime esters.
unctionalization of sp3 C−H bonds α to an aldehyde or
the synthetic schemes, since prefunctionalization of starting
1
Fketone group is a fundamental target in organic synthesis. materials is thwarted. Our aim is to synthesize thiazoles or
isosteres from acetophenones, elemental sulfur, and a nitrogen
source since sulfur-mediated activation of α C−H bonds in
ketones is known.5
The successes often require the use of strong bases and/or
relatively scarce second- or third-row transition metals. Oxime
functionality is possibly considered as a masked carbonyl, thus
able to help activate the sp3 C−H bonds under relatively
milder conditions.2 Notably, early examples of ketoxime-
assisted, C−H functionalization focused on the synthesis of N-
heterocycles using copper catalysis. Incorporation of nitrogen
atoms in oxime carboxylates into pyridines, pyrroles, and other
isosteric, fused heterocycles is favorable due to the formation
of an active imine catalyzed by a decomposition of the high
valent copper-imine intermediate.2a A diastereoselective
coupling of oxime acetates and electrophilic ketones has
been reported.2g Transition metal catalyzed, directed cleavage
of sp2 C−H bonds in carbonyl compounds is well
precedented.3 Meanwhile, oxime-assisted activation of α
C(sp3)−H bonds for synthesis of heterocycles with two
heteroatoms is much less developed. Only a few methods for
functionalization of α C−H bonds in ketoxime carboxylates
with elemental sulfur to afford S,N-heterocycles is known.4
Deng and co-workers described a copper-catalyzed annulation
of acetophenone oximes, benzaldehydes, and elemental sulfur
to derive thienothiazoles.4a If oxime acetates of 1-tetralones
were used, benzothiazoles were obtained, presumably after
oxidative aromatization.4b The scope of the substrates that
could couple with oximes was later expanded to phenyl-
acetylenes and picolines.4c,d Despite certain advancements,
most of the known examples require the two-step preparation
of oxime carboxylates. Perhaps it would be more beneficial if
ketones are directly used. The approach somewhat shortens
Thiophenes and thiazoles are ubiquitously found in a wide
range of biologically active natural products, pharmaceutical
molecules, agricultural chemicals, and functional organic
materials.6 More importantly, thiophene-fused heteroaromatic
systems have many important applications in material science
and engineering (Scheme 1). We report herein the
homocoupling of acetophenones in the presence of urea and
elemental sulfur to afford fused thieno[3,2-d]thiazoles that
have conventionally required multistep synthesis. Attempts to
couple acetophenones with C−H bonds in phenylacetic acids,
2-alkylazaarenes, or aromatic aldehydes were also successful.
Our method potentially serves as a general example for metal-
free functionalization of sp3 C−H bonds α to ketones without
the use of functionalized oxime carboxylates.
Our investigation started with a coupling of acetophenone
(1a), elemental sulfur, and urea. Based on previous studies,4,5
DMSO solvent was chosen for the reaction. A roughly 80%
yield of two products in a 6:1 molar ratio was detected (Table
1, entry 1). The major product, 2-phenylbenzo[4,5]thieno[3,2-
d]thiazole (2a), was possibly formed through a decarbox-
ylation. In the presence of organic bases, the product
distribution was changed. The best yield of the minor product,
2-benzoyl thienothiazole 3a, was obtained if a catalytic amount
Received: September 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03414
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthesis of Thiophene-Fused Heterocycles
Scheme 2. Synthesis of 2-Arylbenzo[4,5]-thieno-[3,2-d]-
a
thiazoles
a
Acetophenones (0.2 mmol), urea (0.6 mmol), sulfur (0.31 mmol, 32
g/mol), DMSO (0.2 mL), pyridine (0.05 mL), 120 °C. Yields are
isolated yields. Please see the Supporting Information for details.
Isolated as a regioisomer mixture at C3 and C3′. Isolated as a 8:1
a
b
c
Table 1. Optimization of Reaction Conditions
regioisomeric product.
Scheme 3. Synthesis of Benzo[4,5]thieno[3,2-d]thiazol-2-
a
yl(phenyl)-methanones
yield of
yield of
entry
solvent
DMSO
DMSO
DMSO
DMSO
DMSO
additive
2a, %
3a, %
b
1
−
68
58
47
36
83
94
11
30
9
15
6
b
2
DABCO
piperidine
N-methylpiperazine
b
3
b
4
c
5
−
−
d
6
DMSO−
trace
pyridine
e
7
DMSO−H2O
DMSO−H2O
DABCO
trace
25
86
37
f
8
−
a
Acetophenone 1a (0.2 mmol), additive (0.02 mmol), 120 °C under
air for 12 h. Yields are GC yields using diphenyl ether as the internal
b
standard. Please see Supporting Information for details. Urea (0.8
c
mmol), sulfur (0.4 mmol), DMSO (0.2 mL). Urea (0.6 mmol),
d
sulfur (0.25 mmol). Urea (0.6 mmol), sulfur (0.32 mmol), DMSO/
pyridine (v/v 4:1, total 0.25 mL), 2.5 h. Urea (0.15 mmol), sulfur
(0.7 mmol), DMSO/H2O (v/v 20:1, total 1.05 mL). Urea (0.6
e
f
a
mmol), sulfur (0.25 mmol), DMSO/H2O (v/v 2:1, total 0.3 mL).
Abbreviation: DABCO = 1,4-diazabicyclo[2.2.2]octane.
Acetophenones (0.2 mmol), urea (0.15 mmol), sulfur (0.7 mmol, 32
g/mol), DABCO (0.1 mmol), DMSO (1 mL), H2O (0.05 mL), 120
°C. Yields are isolated yields. Isolated as a regioisomeric product.
b
of DABCO was added (entry 2). Running the reaction in the
presence of secondary amines gave sluggish mixtures (entries 3
and 4). Decreasing the amount of urea and sulfur afforded a
better yield of product 2a (entry 5). Using cosolvents also
impacted the yields of products. Full conversion of
acetophenone to the product 2a was obtained if a 4:1 solvent
mixture of DMSO/pyridine was used (entry 6). On the other
hand, the reaction proceeded to afford an 86% yield of 3a in
wet DMSO and catalytic DABCO (entry 7). Lastly, omitting
DABCO gave a 1:1 molar ratio of the products, proving the
importance of the base with regard to diversifying the reaction
pathways (entry 8).
The reaction scope with respect to the synthesis of 2-aryl
thienothiazoles is presented in Scheme 2. The conditions were
compatible with many functionalities such as methoxy (2c,
2m), methylthio (2d), halogen (2e, 2f, and 2h), trifluor-
omethyl (2g), and protected phenol (2j, 2p, 2t) groups.
Similar to the copper-catalyzed system,4a meta-substituted
B
DOI: 10.1021/acs.orglett.9b03414
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Coupling of Acetophenone and Methylazaarenes,
Phenylacetic Acids, and Aromatic Aldehydes
Scheme 5. Mechanistic Considerations and Possible
Mechanism
a
a
a
Method A: Acetophenone (0.1 mmol), 2- or 4-methylazaarenes (0.2
mmol), urea (0.15 mmol), sulfur (0.3 mmol, 32 g/mol), NaOAc (0.1
mmol), DMSO (1 mL), 120 °C for 12 h. Method B: Acetophenone
(0.4 mmol), phenylacetic acids (0.2 mmol), NH4OAc (0.4 mmol),
sulfur (0.7 mmol, 32 g/mol), DABCO (0.2 mmol), DMSO (1 mL),
120 °C for 12 h. Method C: Acetophenone (0.2 mmol), urea (0.2
mmol), DMSO (0.5 mL), 80 °C for 0.5 h, then aldehyde (0.1 mmol),
sulfur (0.5 mmol, 32 g/mol), 120 °C for 12 h. Yields are isolated
b
yields. Please see the Supporting Information for details. 4-
Ethylpyridine was used. Method C was used to afford the product.
a
c
Condition A: acetophenone (0.2 mmol), urea (3 equiv), sulfur (0.15
equiv), DMSO/pyridine (v/v 4:1), 120 °C. Condition B:
acetophenone (0.2 mmol), urea (0.75 equiv), sulfur (3.5 equiv),
DABCO (0.5 equiv), DMSO/H2O (v/v 20:1), 120 °C.
acetophenones afforded the regioisomeric products (2k−2m,
2q). Substituents ortho to the ketone group apart from the
bromo group successfully coupled with elemental sulfur and
urea (2r, 2s, 2t). Nucleophilic substitution of sulfur possibly
occurred,7 thus yielding a monobromo derivative of 2-
phenylbenzo[4,5]thieno[3,2-d]thiazole when 2′-bromo-
acetophenone was used (2q). The reaction of thiophenyl-
and pyridyl-methyl ketones gave tetraheterocyclic products in
moderate to good yields (2u and 2v).
Synthesis of benzo[4,5]thieno[3,2-d]thiazol-2-yl(phenyl)-
methanone was next studied. The scope of the acetophenones
is described in Scheme 3. Notably, 50 mol % of DABCO was
used to completely convert all of the acetophenones. Good
yields of the products were obtained regardless of electronic
properties of acetophenones. Functional groups such as
halogens (3e, 3f, 3h), trifluoromethyl (3g), and protected
alcohol (3q) were tolerant of reaction conditions. meta-
Substituted acetophenones were competent substrates (3m,
3o, 3p). However, reactions of 2-acetylaryl halides failed to
yield the 2-benzoyl thienothiazoles.8 The homocoupling of 2′-
bromoacetophenone, elemental sulfur, and urea afforded a
debrominative product in low yield (3q). Heteroaryl ketones
were capable of furnishing the products in good yields (3u and
3v). It should be noted that the transformations were easy to
scale up while still furnishing the thienothiazoles in good
yields.8
4. Moderate to good yields of 2-hetarylbenzo[4,5]thieno[3,2-
d]thiazoles were obtained if 2-picoline and isosteres were used.
2,6-Lutidine coupled with acetophenone to afford a single
isomer derived from monofunctionalization (4d). Functional-
ization of sp3 C−H bonds in 4-ethylpyridine occurred with a
loss of alkyl carbon. The conditions were compatible to
convert 2-methylbenzoxazole, which was unactive in the
presence of strong base,4d to the product (4g). Methylene
C−H bonds in phenylacetic acids could also be used to couple
with acetophenone. Reactions required ammonium acetate as
the nitrogen source, affording the thienothiazoles in moderate
yields (5a−5c). Using modified reaction conditions, attempts
to couple acetophenones and aromatic aldehydes were
successful (5a and 5e).
Some experiments related to mechanistic consideration are
shown in Scheme 5. Adding a radical quencher such as
TEMPO to the reaction mixtures decreased the yields. During
the reaction courses, some intermediates could be detected,
such as a dithiazole thione 4, 3-aminobenzothiophene 5, and
its imine derivatives. Since 4 was inactive to couple with
acetophenone 1a under the standard conditions, this adduct
was more likely a resting state than an intermediate of the
transformation.4c Meanwhile, the reaction of 5 and 1a afforded
the products in high yield, somewhat showing that the adduct
was possibly a key intermediate.8 Based on the results in hand,
a proposed mechanism is presented in Scheme 5. We
hypothesized that 5 was formed through an aromatic radical
cyclization of acetophenone 1a. Thus, different regioselectiv-
ities were observed with regard to electron-withdrawing or
It is perhaps more general if our methods are applied for
cross-coupling of sp3 C−H bonds. Previous studies reported
examples for using elemental sulfur to functionalize sp3 C−H
bonds in phenylacetic acids and 2-/4-methylazaarenes.4d To
our delight, coupling of acetophenones and activated C−H
bonds is possible. The scope of substrates is shown in Scheme
C
DOI: 10.1021/acs.orglett.9b03414
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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electron-donating substituents at the meta position of
acetophenone. Condensation of 3-aminobenzothiophene 5
with the second acetophenone molecule produced an imine,
followed by Willgerodt−Kindler type sulfuration and oxidation
to afford an iminoyl phenylacetic acid intermediate 6.
Decarboxylation of 6 afforded the product 2a. On the other
hand, “wet” DMSO facilitated the hydrolysis of the imino
ethanethial intermediate I, which was involved in the
formation of 3-aminobenzothiophene. Imine condensation of
the hydrolysis product and 5 yielded the intermediate 7. The
presence of a hindered amine as DABCO facilitated the
Baylis−Hillman type sulfuration, followed by cyclization and
oxidation to furnish 2-benzoyl thienothiazole 3a.
In conclusion, we have developed a new metal-free synthesis
of fused thieno[3,2-d]thiazoles using the three-component
reaction between acetophenones, urea, and elemental sulfur.
The conditions could be divergent to obtain either 2-
phenylbenzo[4,5]thieno[3,2-d]thiazoles or benzo[4,5]thieno-
[3,2-d]thiazol-2-yl(phenyl)methanones. Cross-coupling of α
C−H bonds in acetophenones with other activated sp3 C−H
bonds in phenylacetic acids and 2-methylazaarenes was also
feasible. Reactions were compatible with many functionalities
such as halogens, methylthio, trifluoromethyl, and protected
alcohol groups. Attempts to expand the scope of the
transformation with regard to reagents for C−H/C−H cross-
coupling are ongoing.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03414.
(3) Selected examples: (a) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.;
Murai, S. A Ruthenium-Catalyzed Reaction of Aromatic Ketones with
Arylboronates: A New Method for the Arylation of Aromatic
Compounds via C−H Bond Cleavage. J. Am. Chem. Soc. 2003, 125,
1698. (b) Zhou, B.; Hu, Y.; Liu, T.; Wang, C. Aromatic C-H addition
of ketones to imines enabled by manganese catalysis. Nat. Commun.
2017, 8, 1169. (c) Kimura, N.; Kochi, T.; Kakiuchi, F. Iron-Catalyzed
Regioselective Anti-Markovnikov Addition of C−H Bonds in
Aromatic Ketones to Alkenes. J. Am. Chem. Soc. 2017, 139, 14849.
(d) Padala, K.; Jeganmohan, M. Ruthenium-Catalyzed Ortho-
Alkenylation of Aromatic Ketones with Alkenes by C−H Bond
Activation. Org. Lett. 2011, 13, 6144.
Details of optimization studies, general procedures, and
characterization data of unknown compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: tungtn@hcmut.edu.vn.
*E-mail: ptsnam@hcmut.edu.vn.
ORCID
(4) (a) Huang, H.; Xu, Z.; Ji, X.; Li, B.; Deng, G.-J. Thiophene-
Fused Heteroaromatic Systems Enabled by Internal Oxidant-Induced
Cascade Bis-Heteroannulation. Org. Lett. 2018, 20, 4917. (b) Xu, Z.;
Huang, H.; Chen, H.; Deng, G.-J. Catalyst- and Additive-Free
Annulation/Aromatization Leading to Benzothiazoles and Naphtho-
thiazoles. Org. Chem. Front. 2019, 6, 3060. (c) Zhou, P.; Huang, Y.;
Wu, W.; Yu, W.; Li, J.; Zhu, Z.; Jiang, H. Direct Access to Bis-S-
heterocycles via Copper-Catalyzed Three Component Tandem
Cyclization using S8 as a Sulfur Source. Org. Biomol. Chem. 2019,
17, 3424. (d) Huang, Y.; Wang, Q.; Xu, Z.; Deng, G.-J. Tri-Functional
Elemental Sulfur Enabling Bis-Heteroannulation of Methyl Ketoximes
with Methyl N-Heteroarenes. Adv. Synth. Catal. 2019, 361, 591.
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rebuild: New Strategy for Fully α-Heterofunctionalization of
Acetophenones. Green Chem. 2017, 19, 5371. (b) Liao, Y.; Peng,
Y.; Qi, H.; Deng, G.-J.; Gong, H.; Li, C.-J. Palladium-Catalyzed
Benzothieno[2,3-B]Indole Formation via Dehydrative−Dehydrogen-
ative Double C−H Sulfuration using Sulfur Powder, Indoles and
Cyclohexanones. Chem. Commun. 2015, 51, 1031.
Phuc H. Pham: 0000-0002-7086-6948
Khang X. Nguyen: 0000-0003-3336-1390
Tung T. Nguyen: 0000-0002-0912-9981
Nam T. S. Phan: 0000-0002-5928-7638
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank The Vietnam National UniversityHo Chi Minh
City (VNU-HCM) for financial support via project No.
NCM2019-20-01.
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E
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Org. Lett. XXXX, XXX, XXX−XXX