A Robust, Eco-Friendly Access to Secondary Thioamides through the Addition of Organolithium Reagents to Isothiocyanates in Cyclopentyl Methyl Ether (CPME)

Article abstract of DOI:10.1002/chem.201504247

The nucleophilic addition of widely available and variously functionalized organolithium reagents to isothiocyanates represents a straightforward, high-yielding, one-pot method to access secondary thioamides. The simple reaction conditions required and the broad scope (>50 cases examples) makes it a robust and reliable method to access both simple and complex thioamides, including enantiopure ones. Noxious and unpleasant-smelling sulfurating agents, usually employed in the literature established methods, are avoided during the whole synthetic procedure thus, rendering the protocol highly attractive, also for sustainability aspects.

Full text of DOI:10.1002/chem.201504247

DOI: 10.1002/chem.201504247
Communication
&
Synthetic Methods
A Robust, Eco-Friendly Access to Secondary Thioamides through
the Addition of Organolithium Reagents to Isothiocyanates in
Cyclopentyl Methyl Ether (CPME)
Vittorio Pace,*[a] Laura Castoldi,[a] Serena Monticelli,[a] Sandra Safranek,[a] Alexander Roller,[b]
Thierry Langer,[a] and Wolfgang Holzer[a]
Dedicated to Professor Norbert De Kimpe on the occasion of his retirement
Compared to the extensive studies available on amide-link syn-
Abstract: The nucleophilic addition of widely available
theses, conceptual approaches towards thioamides are rather
and variously functionalized organolithium reagents to
limited.[5] In fact, despite the huge, non-discussed importance,
isothiocyanates represents a straightforward, high-yield-
the most common methods for the synthesis of thioamides
ing, one-pot method to access secondary thioamides. The
still relies on thionation (direct or by previous electrophilic acti-
simple reaction conditions required and the broad scope
vation)[6] of carboxamides with sulfurating agents, such as the
(>50 cases examples) makes it a robust and reliable
Lawesson’s reagent (Scheme 1a).[7] The effectiveness of these
method to access both simple and complex thioamides,
including enantiopure ones. Noxious and unpleasant-
smelling sulfurating agents, usually employed in the litera-
ture established methods, are avoided during the whole
synthetic procedure thus, rendering the protocol highly
attractive, also for sustainability aspects.
Thioamides constitute a pivotal class of organic molecules, the
chemo-, physico- and biological properties of which differ sub-
stantially from their corresponding oxoamide analogues.[1] The
pronounced resonance stabilization in the thioamide moiety
arising from the donation from the nonbonding nitrogen lone
pair is increased by the high polarizability of the sulfur atom.[2]
Unlike other thiocarbonyl derivatives, they present attractive
features, such as stability, crystallizability, and the absence of
unpleasant smells; thus, the combination of the chemical reac-
tivity and the physical properties renders them highly valuable
scaffolds across the chemical sciences.[3] Among the most strik-
Scheme 1. Conceptually distinct approaches towards thioamides.
ing advantages of using thioamides (in place of oxoamides),
the feasibility of nucleophilic additions of reducing agents or
organometallics to the electrophilic carbon (by the straightfor-
ward transformation into thioiminium salts) plays a prominent
role, as showcased in elegant works by Murai and co-workers.[4]
procedures is highly dependent on the harsh reaction condi-
tions employed; in particular, the use of high-boiling-point sol-
vents or even carcinogenic ones, such as hexamethylphosphor-
amide (HMPA), are frequently required to solubilize the sulfur
source or to promote these long-time requiring reactions. Tedi-
ous work-up techniques and purifications, the persistent and
powerful malodour together with the high toxicity of the re-
agents and chemoselectivity issues, severely limit the synthetic
appeal of such non-uniformly high-yielding and expensive ap-
proaches. Sulfur incorporation through different techniques,
such as the Willgerodt–Kindler reaction,[8] decarboxylative thio-
amidation,[9] and multicomponent reactions,[10] are often
plagued by analogous drawbacks or by a limited functional-
group tolerance.
[a] Dr. V. Pace, L. Castoldi,+ S. Monticelli,+ S. Safranek, Prof. Dr. T. Langer,
Prof. Dr. W. Holzer
Department of Pharmaceutical Chemistry
University of Vienna
Althanstrasse, 14 1090, Vienna (Austria)
E-mail: vittorio.pace@univie.ac.at
[b] A. Roller
Institute of Inorganic Chemistry
University of Vienna
Währingerstrasse 42 1090, Vienna (Austria)
[+] Both authors contributed equally to this work
In this scenario, an alternative approach involving the addi-
tion of a carbon nucleophile to an extremely electrophilic iso-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504247.
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thiocyanate can be envisaged. Although firstly illustrated by
Worrall[11] and Gilman[12] in 1920s, the addition of organometal-
lics to these electrophiles has not emerged as the method of
choice for the synthesis of thioamides; unfortunately applica-
tions in organic synthesis are rare, thus obscuring the synthetic
potential of the methodology.[13]
Increasing the temperature up to 238C (rt, entry 11), resulted
in a lower efficiency, thus revealing 08C as the optimal temper-
ature.
Once the optimal conditions for accessing thioamides from
isothiocyanates and organolithium reagents were established,
we next focused on the scope of the method. As presented in
Scheme 2, the reaction of variously functionalized commercial-
ly available isothiocyanates with organolithium reagents af-
forded a wide range of thioamides (4–31) in very high yields
after simple purification by recrystallization from CPME, thus
Considering the wide availability of both isothiocyanates
and methods to prepare organolithium reagents (configura-
tionally stable),[14] herein we report a robust protocol to pre-
pare a broad series of thioamides, including enantiopure ones,
through a simple nucleophilic addition (Scheme 1b). Key fea-
tures of the method are: 1) uniform efficiency under mild con-
ditions, and high yields regardless of the nature of the two re-
acting partners used; 2) obtainment of the desired thioamides
as the exclusive reaction products, thus simplifying the work-
up and purification procedures; 3) absence of unpleasant
odors during the whole reaction process; 4) use of cyclopentyl
methyl ether[15] as the ideal reaction medium; and 5) retention
of optical purity when chiral isothiocyanates and/or organo-
lithium reagents are used.
Our investigations commenced by selecting the highly steri-
cally hindered 1-adamantyl isothiocyanate 1 (Table 1) as the
model substrate. Upon the addition of MeLi (2 equiv) in THF at
08C, the desired thioamide 2 was formed in a satisfactory iso-
lated yield of 71% after a simple recrystallization (entry 1).
Lowering the loading of the nucleophile to 1.5 or 1.0 equiva-
lents decreased the yields, thus suggesting 2 equivalents as
the ideal amount of the reactant (entries 1–3). Switching to
a more apolar media, such as 2-MeTHF[16] and toluene (en-
tries 4 and 5), benefited the reaction compared to polar sol-
vents (entries 9 and 10). A further improvement and the best
result was achieved by running the reaction in cyclopentyl
methyl ether (CPME; entry 6),[15] which is an attractive alterna-
tive to classical ethereal solvents, such as THF and 1,4-dioxane.
Table 1. Model reaction optimization.[a]
Entry
MeLi
Solvent[b]
T [8C]/t [h]
Isolated
[equiv]
yield [%]
1
2
3
4
5
6
7
8
2.0
1.5
1.0
2.0
2.0
2.0
1.5
1.0
2.0
2.0
2.0
THF
THF
THF
2-MeTHF
toluene
CPME
CPME
CPME
1,4-dioxane
Et2O
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
rt/1
71
65
59
88
91
98
92
84
75
81
85
9
10
11
CPME
[a] See Experimental Section in the Supporting Information for details.
[b] THF=tetrahydrofuran, 2-MeTHF=2-methyltetrahydrofuran, and
CPME=cyclopentyl methyl ether.
Scheme 2. Use of commercially available organolithium reagents in the syn-
theses of thioamides.
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simplifying significantly the overall procedure. The observed
reactivity is quite general, allowing the combination of reac-
tions of both aliphatic and aromatic isothiocyanates with both
types of organolithium reagents (combinations A–D). The
steric hindrance on both sides of the reaction partners was
perfectly tolerated and allowed to prepare sterically demand-
ing thioamides (4, 5, 12–15, 24, 25, and 28–30) in excellent
yields. Analogously, (hetero)aromatic isothiocyanates contain-
ing different electron-donating or -withdrawing substituents
were also viable and gave the corresponding products (16, 17,
and 31). Allylic moieties (9 and 19) or heteroaromatic nuclei
(11, 19, 23, and 26) as substituents on the carbon-bearing iso-
thiocyanates did not affect the feasibility of the process. The
employment of a substituted alkyllithium (19) or heteroaryl-
lithium (20, 22, 23, 25, 27, 28, 30, and 31) species proceeded
equally well. No enolization processes were detected during
the addition of lithium reagents to isothiocyanates bearing
acidic a-protons (10).
ed thioamide 37 in high yield. Analogously, 2-lithiopyridine,
which was obtained from the metalation of 2-bromopyridine,
afforded compound 38 in 79% isolated yield. Of particular in-
terest is the possibility to generate the highly sterically de-
manding 2,4,6-triisopropylphenyllithium, which was able to
attack not only the simple phenylisothiocyanate yielding 39,
but also the 1-adamantyl congener, affording the thioamide
40, which had not been previously reported. To the best of our
knowledge, the latter represents one of the most bulky exam-
ples of thiocarbonyls known. The ease of addition was also evi-
denced by using sp3 lithium species as the corresponding cy-
clopropyl, cyclobutyl or cyclohexyl derivatives (41–45). It is
worth remarking the independence of the effectiveness from
the nature of both organolithium reagents and isothiocyanates
employed. This is evidently a big advantage compared to pro-
cedures based on thionation methods, the effectiveness of
which is also influenced by the not always smooth availability
of the starting amides.
The wide availability of established methods to generate or-
ganolithium reagents permits further expansion of the versatili-
ty of the protocol.[17] As such, we employed two common ac-
cesses to such reagents, namely deprotonation and lithium–
halogen exchange (Scheme 3). Triphenylmethane (32), a thioa-
cetal (33), thioanisole (34), furan (35), or an enolate (36) served
as excellent pronucleophiles regardless of the electronic and/
or steric features on the isothiocyanate. A lithium–halogen ex-
change method was employed to generate sp2 organolithium
reagents; thus, the obtained styryllithium was smoothly added
to a furyl-containing isothiocyanate to give the a,b-unsaturat-
Optically active isothiocyanates underwent the addition of
highly basic alkyl- or aryllithium reagents in excellent yields
without loss of the chirality (Scheme 4, 46–49).[18] Importantly,
chiral lithiated species performed equally well in the nucleo-
philic addition, as showcased by the use of N-Boc-substituted
pyrrolidine[19] in the formation of 50–53, as well as Hoppe’s
carbamate (54),[20] which resulted in the isolation of compound
Scheme 3. Use of organolithium reagents, generated by deprotonation or
Scheme 4. Addition to enantiopure isothiocyanates and employment of
lithium–halogen exchange methods.
enantioenriched organolithium reagents.
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55. In both cases, the enantiopure a-oxo and a-amino func-
tionalized carbanions were generated by (À)-sparteine-assisted
deprotonation in CPME (98:2 to 99:1 e.r.).[21] The opposite
enantiomers (51 and 53) could be prepared in analogous ex-
cellent enantiopurity by switching to (+)-sparteine. Finally, the
addition of the generated chiral organolithium to an optically
active isothiocyanate proceeded with an excellent diastereose-
lectivity (52 and 53). X-ray crystallography analyses of 50, 52,
53, and 55 (Figure 1 and the Supporting Information) deter-
mined the absolute configuration of the newly formed
carbon–carbon bond.
ty of the isothiocyanate is also manifested in the chemoselec-
tive reaction with
a
mixed lithium–copper reagent
[(nBu)2CuLi].[23] This so-called Gilman reagent, presenting evi-
dently a tamed nucleophilicity compared to a classical organo-
lithium, is able to attack the isothiocyanate exclusively, regard-
less of the concomitant presence of an ester (59), providing
the methoxycarbonyl-substituted thioamide (60).
In conclusion, we have reported a robust, highly efficient
access to variously functionalized secondary thioamides
through the addition of widely available or prepared organo-
lithium reagents to isothiocyanates. The method is character-
ized by an excellent versatility, which renders it applicable to
the synthesis of thioamides ranging from the simplest to steri-
cally hindered and complex ones. Preservation of the enantio-
purity when using chiral isothiocyanates or organolithium re-
agents further showcases its potential. A complete avoidance
of noxious and unpleasant-smelling conventional thionating
agents together with conducting the reaction in CPME maxi-
mizes the eco-compatibility of this otherwise limited synthetic
process.
Acknowledgements
Figure 1. Molecular structures of 52 and 55 drawn with 50% displacement
ellipsoids. According to the resulting chiral space group P212121 for both, C1
can be determined in R conformation (Flack52 =À0.012(11),
The University of Vienna is gratefully acknowledged for gener-
ous financial support. L.C. and S.M. thank the University of
Vienna for Uni:docs doctoral grants. V.P. acknowledges the Fac-
ulty of Life Sciences of the University of Vienna for the 2015
Young Investigator Award.
Flack55 =0.003(2)). Details about X-ray structure analysis[24] and further results
for 50 and 53 can be found in the Supporting Information.
It should be highlighted how this protocol shows superior
performances in terms of both synthetic economy and efficien-
cy compared to previously reported preparations of 2-substi-
tuted pyrrolidinyl thioamides, which are organocatalyst precur-
sors. In fact, Lawesson’s reagent mediated thionation of the
corresponding oxoamides occurred with uniformly lower yields
and in the case of compound 51 with dramatic erosion of the
enantiopurity down to 26% ee.[22]
Keywords: isothiocyanates · lithiation · nucleophilic addition ·
one-pot synthesis · thioamides
´
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Received: October 22, 2015
Published online on November 20, 2015
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