A stereoselective thiocyanate conjugate addition to electron deficient alkynes and concomitant cyclization to N,S-heterocycles

Article abstract of DOI:10.1039/c7cc06081e

A regio- and stereoselective thiocyanate addition to ynones is achieved using KSCN in AcOH at 70 °C. The reaction is extendable to ynals, ynesulfones, ynoic acids and ynoates. Adducts from ynones were readily transformed into thiazine-2-thione derivatives under slightly modified reaction conditions. In contrast, thiocyanated adducts from ynamides underwent an in situ decyanative amido cyclization towards isothiazolones. None of these events needed any transition metal or catalyst, attaining a high synthetic value.

Full text of DOI:10.1039/c7cc06081e

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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A Stereoselective Thiocyanate Conjugate Addition to
Electron Deficient Alkynes and Concomitant Cyclization
to N, S-Heterocycles
Received 00th January 20xx,
Accepted 00th January 20xx
Vikas Dwivedia,‡, Manda Rajesha,‡, Ravi Kumar,a,b Ruchir Kantc and Maddi Sridhar Reddy*,a,b,d
DOI: 10.1039/x0xx00000x
www.rsc.org/
A regio- and stereoselective thiocyanate addition to ynones is resultant 3-thiocyanato-α,β-unsaturated carbonyl could be
o
achieved using KSCN in AcOH at 70 C. The reaction is extendable cyclised in situ via a second thiocyanation with a slight increase
to ynal, ynesulfone, ynoic acid and ynoate. The adduct from of temperature and time. Pleasingly, this double C-S bond
ynones were readily transformed to thiazine-2-thione derivatives formation event also does not require support of any
under slightly modified reaction conditions. In contrast, catalyst/transition metal. Ynamides in contrast underwent a
thiocyanated adducts from ynamides underwent an in situ decyanative amido cyclization subsequent to the thiocyanate
decyanative amido cyclization towards isothiazolones. None of addition to deliver isothiazolones under similar conditions.
these events needed any transition metal or catalyst attaining a
FG
high synthetic value.
M
R1
A
R
R1
Hydrofunctionalization of alkynes1-2 is a remarkable strategy to
access a variety of highly substituted/functionalized olefins
with very high regio and stereo selection (Scheme 1A)1. This
has uncovered the ways to solve several long lasting problems
in selective synthesis of olefins through conventional methods.
The strategy is highly reliable because the starting materials
required are readily accessible alkynes and the criteria
necessary is usually a simple electronic or steric bias. Few
recent breakthroughs reveal that a coordinating group in a
nearby region also can help the event occur in a highly
selective manner. Using the high intrinsic electronic bias,
electron withdrawing group (EWG) tethered alkynes can be
selectively functionalized through conjugate addition2.
Although ubiquitous on conjugated olefins, this addition is
hardly explored on EWG-tethered alkynes. We recently
reported a catalyst-free azide addition to ynones2b where the
resultant vinyl azide underwent an in situ denitrogenative
cyclization to yield isooxazoles (Scheme 1B). As another similar
example, and as part of our ongoing program of uncovering
the novel activities of functionalized alkynes,1g,1k-l,2b,3 we report
herein a thiocyanate conjugate addition of ynones under
R
FG-H/X
H
FG-H/X =R
,
, RNH2, RB(OR)2, B2(OR)4, HCN
R
KSCN, RCOOH, R-X, RSiX, RSeX, RSnX, X2, RSO2X
E
Nu
R1
-
+
N
B
our previous work
O
O
N N2
R2
TMSN3
R1
R2
O
M
-SCN
S
Nu
E
R1
N
R2
O
S
N
N
S
R1
R2
KSCN
R1
R
R2
R2
isolable
C
this work
NC
NH
R
S
R1 = -NHR
S
R2
O
O
Scheme 1. Hydrofunctionalization/addition of alkynes
.
Insertion of sulfur can result in a dramatic change in both the
physical characteristics and the biological properties of
molecules. As a result, apart from being prevalent in nature,
organosulfur compounds are commonly found in
pharmaceuticals, agrochemicals and material science.4 The
sources of sulfur being used to achieve such targets usually
elemental sulfur (S8), thiols, thioacetates, thiocyanates or
thioureas.5 Out of these, thiocyanates prove to be more
promising as they can be further modified6 due to presence of
active CN group on sulfur. Jiang et al. have recently reported
an elegant silver catalyzed hydrothiocyanation of
catalyst/metal free conditions (Scheme 1C). Showing
a
hitherto uncovered derivatization of thiocyanate group, the
a.Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, BS-
10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India.
b.Academy of Scientific and Innovative Research, New Delhi 110001, India.
c.
MSB Division, CSIR-Central Drug Research Institute, Jankipuram extension,
Sitapur Road, Lucknow 226031, India.
d.MCB Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
E-mail: msreddy@iict.res.in
†Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
‡ Contributed equally
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bromoalkynes using KSCN as thio source.7 We herein show this the ynone (1b-f) did not affect the reaction and thus afforded
thiocyanation on electron-deficient alkynes and various the corresponding hydrothiocyanated products 2b-f in 76-90%
concomitant cyclizations all under the metal/catalyst free yields. Electron-rich substitution on the alkyne terminus (1g
conditions
)
.
promoted the reaction (92% of 2g) whereas the same on keto
We commenced our optimization studies with the addition of terminal (1h-j) led to slight erosion of the yields (72-77%).
KSCN to ynone 1a in the presence of AgOAc (Table-1). No
O
O
SCN
R2
reaction was observed at room temperature in AcOH (entry 1).
o
When the same reaction contents were heated to 70 C, the
KSCN (1.5 equiv)
AcOH, 70 oC, 30 min
R1
R1
R2
2a-2ccb
substrate was totally consumed in 1h. Pleasingly, the desired
product 2a was obtained in 60% yield but with a surprising
formation of thiazine-2-thione 3a in 20% as a byproduct (entry
2). We reasoned that 3a was formed from 2a through the
reaction with another molecule of KSCN (Vide Infra,
mechanism). This was proved through a separate conversion
of 2a to 3a in similar conditions (conditions mentioned in entry
9). This unprecedented derivatization of thiocyanate and the
medicinally unexplored new dithio heterocycle 3a prompted
us to explore separate conditions for the exclusive formation
of both the products. Other catalysts like AgOTf, Ag2O and
Cu(OTf)2 were neither selective nor as productive (entries 3-5).
Surprisingly, the exclusion of the catalyst and reduction of the
reaction time to 30 min cleanly converted the substrate to
thiocyanate addition adduct 2a in 89% yield (entry 6). No
double thiocyanation/cyclization adduct 3a was observed.
Very pleasingly, increase of quantity of KSCN and elevation of
temperature slowly converted 2a to 3a (entries 7-9). Thus, use
1a-1cc
O
SCN
Ph
, X = H, 89%
2a
O
O
SCN
2b, X = 4-Et, 84%
2c, X = 4-tBu, 87%
2d, X = 4-Ph, 76%
2e, X = 3-Me 90%
Ph
2f, 82%
Me
SCN
X
O
SCN
RO
Ph
OR = 4-OMe, 77%
2i, OR = 3,4-di-OMe, 72%
2j, OR = 3,4-OCH2O-, 76%
Ph
Ph
2g, 92%
2h,
OMe
F
O
SCN
O
SCN
O
SCN F
Ph
2k, 74%
Ph
2l, 84%
2m, 72%
Br
F
O
SCN
Cl
Ph
o
2n, 80%
of 3 equiv of KSCN at 100 C for 4 h cleanly afforded 3a as a
single product in 85% yield. Change of solvent from AcOH to
DMSO, dioxane, DCE, EtOH or H2O was found to be either
inappropriate or totally unproductive (entries 10-14). AcOH
was thus identified as the only appropriate solvent.
O
SCN
2k:CCDC No.1556460
SCN
O
SCN
Ph
O
Ph
, 82%
2w, 91%
S
2v
O
Ph
O
SCN
O
SCN
X
2o, X = 4-Br, 76%
2p, X = 4-CF3, 71%
2q, X = -CN, 73%
2r, X = -NO2, 69%
2s, X = -CHO, 65%
Ph
Ph
2x, 86%
S
2y, 88%
2z, R= cyclohexyl, 80%
2aa, R= n-propyl, 83%
O
SCN
, R= n-hexyl, 85%
2bb
R
Ph
2t
, X = -COMe, 68%
2u, X = -CO2Me, 66%
a1a (0.5 mmol), KSCN (0.75 mmol) in 4 mL AcOH under air.
bIsolated yield.
Scheme 2. Thiocyanate conjugate addition to ynones.
All halo groups survived in the reaction irrespective of their
position, and the substrates possessing them reacted as good
as electronically neutral substrates. Thus, 1k-p afforded 2k-p in
71-84% yields. Pleasingly, highly reactive functional groups like
formyl, acetyl, ester and cyano comfortably survived in the
reaction (2q-u). Electron-poor substrates were found to be
relatively less productive. In contrast, the heteroaryl
substitution on either end of ynone (1v-x) showed excellent
reactivity to afford the products (2v-x) in 82-91% yields.
Further, enynone 1y selectively reacted to give 2y with olefin
group intact. Expanding the scope, Thus, the alkyl-substituted
Table 1: Optimization studies
.
With separate optimized conditions in hand for both addition
and cyclized adducts, we investigated the scope of the
selective thiocyanate addition to ynone as shown in Scheme-2.
Alkyl/phenyl substitution on the phenyl ring on either end of
ynones (1z, 1aa-bb) were also proved to be equally effective
substrates for this metal-free thiocyanate addition and
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transformed to the corresponding thiocyano enones 2z
,
2aa
-
bb Thus alkyl-phenyl ynones were initially transformed to the
corresponding thiazine-2-thione 3a-e in excellent yields of 73-
85%. Alkoxy- and halophenyl ynones also smoothly passed
through the reaction to afford 3f-l in practical yields (58-74%).
Further, ynones with tifluoromethyl, ester, naphthyl and
heteroaryl groups were also proved to be suitable substrates
for the reaction showing its generality (3m-r in 49-69% yields).
were obtained in 80-85% yields.
In contrast to all the above alkynes with various EWG,
ynamides under similar conditions afforded isothiazolones, an
underexplored N,S-heterocycle,8 (Scheme 5) via thiocyanation
followed by decyanative intramolecular amido cyclization.
Amide being ready and appropriate intramolecular nucleophile
might have quickly interfered the double thiocyanate addition
and led to this new adduct formation. The reaction was
consistent with all the substrates 4a-e that we used and
afforded the new N, S-heterocycles 5a-e in excellent yields (72-
85%).
Scheme 3. Thiocyanation of EWG tethered alkynes.
Our focus next turned to investigating other potential
activating groups on the alkyne that could allow this metal-
free thiocyanation (Scheme-3). Pleasingly, ynal 1cc underwent
the addition smoothly to afford thiocyano enal 2cc in 74%
yield. Ynoic acid 1dd was found to react equally well where as
the ynoate 1ee underwent hydrolysis after intended addition
(
2dd). Delightedly, extending the reaction scope further,
sulfonyl acetylene 1ff also smoothly participated in this
selective hydrothiocyanation to give 2ff in 77% yield.
Scheme 5
. Isothiazolones from ynamides.
Finally, as part of derivatization, a dethiocarbonylative ring
contraction of 3 (3a) using iodine in MeOH was achieved
(Scheme 6) to get the another N,S-heterocycle isothiazole 69 in
74% yield.
Scheme 6. Isothiazole from thiazene-2-thione.
A proposed mechanism for the tandem thiocyanate conjugate
addition and thiocyanative/decyanative cyclization is depicted
in Scheme 7. Accordingly, the nucleophilic addition of
thiocyanate occurs with the help of AcOH catalysis (to give
from and from ) and the stereoselection is a result of
orienting large groups trans to one another (thermodynamic
control). In the case of , the second thiocyanate attacks on
2
1
C
4
Scheme 4. Thiazine-2-thione from ynones.
2
With these exciting results, we next moved on to evaluate the
generality of the tandem thiocyanate addition and
electrophilic CN group of vinyl thiocyanate and the incipient
imide anion adds on the nearby carbonyl group. Finally,
concomitant thiocyanative cyclization (1 to 3, Scheme 4).
expulsion of KOCN revealed the desired thiazine-2-thione
3. In
Almost all the substrates used for hydrothiocyanation cleanly
underwent this tandem transformation to afford the desired
thiazine-2-thione using 3 equiv of KSCN at 100 oC for 4-6 h.
case of C, the ready amide nucleophile in close premises
cyclizes on to thiocyanate to afford
group.
5
by expelling the cyanide
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Scheme 7. Proposed mechanism.
In summary, we have shown a catalyst-free thiocyanate
conjugate addition to ynones, ynal, ynoic acid, ynoate and
ynesulfone. Derivatising the thus synthesized thiocyanoenone,
a concomitant second thiocyanation followed by cyclization
was achieved to access thiazine-2-thiones with
increase of time and temperature. Ynamides in contrast
underwent quick decyanative cyclization after
a mere
a
hydrothiocyanation to afford isothiazolones. The excellent
regio- and stereoselectivity, broad scope, and high synthetic
yields are some of the noteworthy features of the present
method.
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