Aqueous Compatible Protocol to Both Alkyl and Aryl Thioamide Synthesis

Article abstract of DOI:10.1021/acs.orglett.5b03541

An efficient aqueous synthesis of thioamides through aldehydes, sodium sulfide, and N-substituted formamides has been developed. Both alkyl and aryl aldehydes are amenable to this protocol. N-Substituted formamides are essential for this transformation. Readily available inorganic salt (sodium sulfide) serves as the sulfur source in water, which makes this method much more practical and efficient. Furthermore, the late-stage modification of bioactive molecules and derivatives through this protocol has been established.

Full text of DOI:10.1021/acs.orglett.5b03541

Letter
pubs.acs.org/OrgLett
Aqueous Compatible Protocol to Both Alkyl and Aryl Thioamide
Synthesis
Jianpeng Wei,† Yiming Li,† and Xuefeng Jiang*,†,‡
†Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal University,
Shanghai 200062, P. R. China
‡Beijing National Laboratory for Molecular Sciences (BNLMS), Beijing 100190, P. R. China
S
* Supporting Information
ABSTRACT: An efficient aqueous synthesis of thioamides through aldehydes, sodium sulfide, and N-substituted formamides
has been developed. Both alkyl and aryl aldehydes are amenable to this protocol. N-Substituted formamides are essential for this
transformation. Readily available inorganic salt (sodium sulfide) serves as the sulfur source in water, which makes this method
much more practical and efficient. Furthermore, the late-stage modification of bioactive molecules and derivatives through this
protocol has been established.
hioamides are prevalent organic motifs found in vital
biological and pharmaceutical molecules, such as closthioa-
Scheme 1. Synthetic Methods for Thioamide
T
mide,1a hydroxymethyl thiolactam cyclothialidine,1b and N-
cyclohexylethyl-ETAsV,1c etc. (Figure 1). Meanwhile, as
Figure 1. Representative bioactive thioamide scaffolds.
(Scheme 1, eq 1b). Moreover, Willgerodt−Kindler reaction7 is
another alternative means to reach thioamides, starting from aryl
aldehydes or aryl alkyl ketones. However, only aryl/benzyl
thioamides can be afforded even under harsh conditions.7c
Recently, several excellent approaches have been exploited by the
Nguyen,8a,d Singh,8e and Jiang8f groups (Scheme 1, eq 2) that
improve the approaches for the synthesis of thioamides by
significant building blocks,2 they are widely applied to
construction of many important sulfur-containing heterocycles,3
such as thiazolins,3a,e thiazolinones,3b thiazoles,3c−e tetrazoles,3f
etc. Conventionally, Lawesson’s reagent and its analogues are
applied to the synthesis of thioamides (Scheme 1, eq 1a).4
Similarly, sulfur−phosphorus-type reagents are also used to
afford the thioamides through carboxylic acids5a or nitriles.5b,c
Practically, isothiocyanates are employed for preparing thio-
amides thesis efficiently under Friedel−Crafts conditions6
Received: December 14, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03541
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
altering different types of starting materials. Therefore, the
establishment of an effective, practical, and green strategy,9
particularly for alkyl thioamides formation, remains highly
desirable. Based on the development of sulfur atom transfer
reactions in our laboratory,10 we herein report a new aqueous
three-component synthesis of thioamides involving alkyl and aryl
aldehydes, sodium sulfide (Na2S·9H2O), and N-substituted
formamides (Scheme 1, eq 3).
Table 2. Scope of Alkyl Thioamides
We commenced our study by investigating 3-phenylpropanal
and N-formylmorpholine in the presence of sodium sulfide. With
the assistance of benzoyl peroxide (BPO), the desired product
was found in 33% yield (Table 1, entry 1). Then, cosolvents were
Table 1. Optimization of Reaction Conditions
a
b
c
Isolated yields. N-Formylmorpholine (2 equiv) was used. Morpho-
line was used instead of N-formylmorpholine. BPO = benzoyl
peroxide; DMSO = dimethyl sulfoxide; NMP = 1-methylpyrrolidin-
2-one; BQ = benzoquinone.
a
Conditions A: alkyl aldehyde (0.3 mmol), Na2S·9H2O (1.05 mmol),
K2S2O8 (0.54 mmol), N-substituted formamide (1.5 mmol), pyridine
b
c
tested to improve the solubility, in which pyridine performed the
best in 42% yield (Table 1, entry 2−5). When the amounts of
Na2S·9H2O and BPO were reduced, the yield increased to 56%
(Table 1, entry 6). There was no higher transformation when the
amount of N-formylmorpholine (Table 1, entry 7) was reduced.
Different oxidants were estimated (Table 1, entry 8−10), in
which potassium persulfate (K2S2O8) was found to be the best
choice giving 74% yield. The yield was further promoted to 83%
by adjusting the amount of K2S2O8 to 1.8 equiv (Table 1, entry
11, conditions A). Remarkably, only a trace amount of product
could be detected when morpholine was used instead of N-
formylmorpholine (entry 14).
The readily oxidized alkyl aldehydes, which are big challenges
in thioamide synthesis, were widely investigated under
conditions A (Table 2). Different formamides and corresponding
amines were surveyed under the same conditions. As shown in
Table 2, a wide array of primary aldehydes worked well with N-
substituted formamides to afford the corresponding thioamides
in moderate to excellent yields (2a−g). Notably, a sensitive
hydroxyl group could be tolerated in this transformation (2e).
Moreover, the secondary aldehydes worked commendably under
these conditions (2h−m). The structure was further confirmed
by X-ray analysis of 2h.11 It is worth noting that naturally
occurring aldehydes and cholesterol derivative with carbon−
carbon double bonds could realize the late-stage modification12
through this transformation, such as citronellal (2e, 2f), lily
aldehyde (2j, 2k, 2l), melonal (2m), and cholesterol derivative
(2n), which offered a convenient method for drugs and bioactive
(1.5 mmol), H2O (0.5 M), 100 °C, isolated yields. 60 °C. H2O/
glycol = 1/1 (0.3 M).
molecule modification. These results show the excellent
substrate compatibility between alkyl aldehydes and formamides.
After the generalities of alkyl aldehydes were studied, aryl
aldehydes were further investigated (Table 3). In general, aryl
aldehydes could be assembled with both primary formamides
(3a−c) and secondary formamides (3d−h) to afford the desired
products in moderate to excellent yields. Delightedly, the
formamides containing sensitive hydroxyl (3i) and allylic groups
(3j) could afford the thioamides in 74% and 75% yields.
Meanwhile, aryl aldehydes substituted with electron-rich,
-neutral, and -deficient groups (3k−v) all could afford
thioamides in 52%−95% yields. The structure was further
confirmed by X-ray crystallographic analysis of 3v.13 Thioamide
with a strong electron-rich group could be obtained as well in
excellent yield through this transformation (3r). Moreover, this
method could also be applied to condensed groups, and
heterocycles, such as naphthalene (3w), thiophene (3x), pyridine
(3y), benzofuran (3z), benzothiophene (3aa), and N-
benzylindole (3ab) could be afforded in excellent yields.
Remarkably, bis(carbothioamide) (3ac) could be obtained
through double thioamidation. 4-Hydroxybenzaldehyde (3ad),
salicylaldehyde (3ae), and estrone derivative (3af) containing a
free phenolic hydroxyl group could afford the desired thioamides
B
DOI: 10.1021/acs.orglett.5b03541
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Scope of Aryl Thioamides
Scheme 2. Control Experiments
(Scheme 2, entry 1). Sodium formate was further added,
affording the similar result (Scheme 2, entry 2). But when
sodium dihydrogen phosphate was added to the system, 3j was
obtained in 71% yield (Scheme 2, entry 3), indicating that
hydrogen sulfide generated from sodium sulfide assisting the
transformation. To furtherly verify the hypothesis, triethylam-
monium hydrogen sulfide was examined in the system (Scheme
2, entry 4 and 5), which demonstrated that imine was activated
by hydrogen sulfide and then attacked by sodium sulfide.
On the basis of the above results, the possible mechanism is
proposed in Scheme 3. Amine release was achieved with the help
Scheme 3. Proposed Mechanism
a
b
Conditions A, isolated yields. Conditions B: aldehyde (0.5 mmol),
Na2S·9H2O (1.75 mmol), BPO (1.25 mmol), DMF (2.5 mmol), H2O
c
d
(1 M), 100 °C. Conditions B in 60 °C. Aldehyde (0.5 mmol), Na2S·
9H2O (3.5 mmol), BPO (2.5 mmol), DMF (5 mmol), H2O (0.5 M),
e
60 °C. Aldehyde (0.5 mmol),Na2S·9H2O (3.5 mmol), BPO (2.5
f
mmol), DMF (5 mmol), H2O (0.5 M), 100 °C. Aldehyde (0.3
mmol), Na2S·9H2O (2.1 mmol), K2S2O8 (1.08 mmol), DMF (3
g
mmol), pyridine (3 mmol), H2O (0.3 M), 100 °C. H2O/glycol = 1/1
(0.3 M).
of sodium sulfide (SI, part III), accompanied by sodium formate
and hydrogen sulfide.15 Imine A was formed with aldehyde16 and
then activated by hydrogen sulfide, forming iminium hydrogen
sulfide B. Sulfide B was attacked by sulfur anion, and
intermediate C was immediately formed, which was further
oxidized by potassium persulfate to afford the desired thioamide.
In summary, we have developed an efficient aqueous method
for the synthesis of thioamides involving aldehydes, sodium
sulfide, and N-substituted formamides. Both alkyl and aryl
aldehydes are amenable to this protocol with great functional
group toleration. N-Substituted formamides are superior to the
corresponding amines due to the slow release of hydrogen sulfide
through the hydrolysis of formamide by sodium sulfide. Readily
available inorganic salt (sodium sulfide) serves as sulfur source in
water, which makes it more practical and efficient. Further
studies on synthetic applications are ongoing in our laboratory.
in excellent yields as well. These results show great substrate
compatibility.
In order to gain mechanistic insight into this protocol, radical
trapping reagent TEMPO was introduced to the reaction system,
in which the formation of desired product 3h was sharply
suppressed (Scheme 2, eq 4). Furthermore, radical clock
reactions were examined through designed 4a and 4b with
benzaldehyde under the standard conditions.14 However,
thioamides (4aa and 4bb) were obtained instead of cyclization
products, which excluded the radical pathway to a large extent
(Scheme 2, eq 5 and 6). Imine intermediate was another
possibility,8c which was formed from aldehyde and amine. Then
N-benzylideneprop-2-en-1-amine (4c) was subjected to the
standard conditions with only 10% of product formation
C
DOI: 10.1021/acs.orglett.5b03541
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03541.
■
S
Experimental procedure, NMR spectra, and X-ray and
analytical data for all new compounds (PDF)
X-ray data for 2h (CIF)
X-ray data for 3v (CIF)
́
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Szczodrowska, B. Bull. Soc. Chim. Belg. 1987, 96, 449. (e) Jagodzinski,
T. Synthesis 1988, 1988, 717. (f) Varun, B. V.; Sood, A.; Prabhu, K. R.
RSC Adv. 2014, 4, 60798.
AUTHOR INFORMATION
Corresponding Author
■
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*E-mail: xfjiang@chem.ecnu.edu.cn.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support was provided by NBRPC (973 Program,
2015CB856600), NSFC (21472050, 21272075), NCET
(120178), DFMEC (20130076110023), Fok Ying Tung
Education Foundation (141011), the program for Shanghai
Rising Star (15QA1401800), Professor of Special Appointment
(Eastern Scholar) at Shanghai Institutions of Higher Learning,
and the Changjiang Scholar and Innovative Research Team in
University.
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DOI: 10.1021/acs.orglett.5b03541
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