Microwave-assisted synthesis of γ-thiolactams from ethyl isocyanoacetate

Article abstract of DOI:10.1515/hc-2018-0005

γ-Thiolactams were synthesized in good yields from ethyl isocyanoacetate through a sequential alkylation/isothiocyanation/radical cyclization under microwave irradiation.

Full text of DOI:10.1515/hc-2018-0005

Heterocycl. Commun. 2018; 24(3): 125–128
Preliminary Communication
Massimiliano Lamberto*
Microwave-assisted synthesis of γ-thiolactams
from ethyl isocyanoacetate
https://doi.org/10.1515/hc-2018-0005
We first synthesized alkenyl isocyanide 5 from
Received January 14, 2018; accepted March 6, 2018; previously
commercially available ethyl isocyanoacetate and cin-
published online April 21, 2018
namyl bromide using 2-tert-butylimino-2-diethylamino-
1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) as
Abstract: γ-Thiolactams were synthesized in good yields
a base. The use of MWs afforded the desired compound
from ethyl isocyanoacetate through a sequential alkyl-
in 10 min in 70% yield. Compound 5 was then allowed
ation/isothiocyanation/radical cyclization under micro-
to react with tert-butyl thiol under MW irradiation to give
wave irradiation.
the corresponding isothiocyanate 6 in 90% yield (Scheme
Keywords: isocyanoacetate; isothiocyanate; microwave 2). With isothiocyanate 6 in hand, it was then possible to
irradiation; radical cyclization; thiolactam.
perform the radical cyclization in the presence of tribu-
tyltin hydride which gave γ-thiolactams 7 and 8 in 78%
isolated yield [1.6:1 mixture of diastereoisomers by proton
nuclear magnetic resonance (1H NMR)]. This reaction was
also accomplished in 6 min at 140°C in the MW synthesizer.
The high yield conversion of the isocyanide to isothiocy-
anate and the radical cyclization prompted us to perform
a two-step one-pot conversion of alkenyl isocyanide 5 to
the corresponding thiolactam without isolating the isothi-
ocyanate. The reactions were performed in the same MW
vessel and gave the desired thiolactams 7 and 8 in 76%
overall yield (2:1 mixture of diastereoisomers by 1H NMR).
To further test this methodology, we then synthesized and
reacted isocyanides 9 and 12 under the above conditions
[11, 13]. Conversion of allyl isocyanide 9 directly to thiolac-
tams 10 and 11 worked well and the desired products were
obtained in high isolated yields (1:1 mixture of diastereoi-
somers by NMR). The reaction was completed in 12 min
without isolation of the isothiocyanate (Scheme 3).
Thioamides and thiolactams are important intermediates
in organic synthesis [1–3], in particular, for gaining access
to heterocycles of natural products [4–7]. Several proce-
dures have been reported for the synthesis of thiolactams
by conversion of the corresponding lactams; however,
direct preparation of these compounds is not common [8,
9]. In this communication, we present an improved strat-
egy for the synthesis of γ-thiolactams from simple iso-
cyanoacetates [10] using microwaves (MWs)-assisted flash
heating technology. In the early 1990s, Bachi reported
n-Bu3SnH mediated radical cyclization of alkenyl isothio-
cyanates to give thiolactams (Scheme 1) [8, 11]. The mecha-
nism of this reaction involves addition of organotin radical
to isothiocyanate 1 to generate a tin thioimidoyl radical
2 which undergoes 5-exo cyclization onto an alkenyl side
chain to give a tin thioimidate 3, which is spontaneously
hydrolyzed during chromatography to give thiolactam 4.
Our interest in isocyanide radical chemistry and
novel applications of MW technology to organic synthesis
[12–14] led us to investigate the feasibility of using MW-
assisted synthesis to Bachi’s approach to thiolactams. Our
synthetic strategy first entailed the synthesis of alkenyl
isothiocyanates that could be accessed by sequential reac-
tion of an isocyanoacetic acid ester with alkenyl halides,
followed by a reaction with tert-butyl mercaptan. A subse-
quent reaction with organotin reagents would give func-
tionalized thiolactams (Scheme 2).
When bis-allylated isocyanide 12 was treated with tert-
butyl thiol and n-Bu3SnH under standard MW conditions,
H
RO2C
RO2C
N
n-Bu3SnH (1.15 eq)
NCS
S
AIBN (0.15 eq), toluene
75oC, 40 min to 7 h
1
4
SiO2/H+
Mechanism:
RO2C
SSnBu3
N
C
S
RO2C
N
RO2C
N
SnBu3
SSnBu3
*Corresponding author: Massimiliano Lamberto, Department of
Chemistry and Physics, Monmouth University, West Long Branch,
NJ 07764, USA, e-mail: mlambert@monmouth.edu
2
3
Scheme 1ꢀBachi’s synthesis of thiolactams from isothiocyanates.
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126ꢀ ꢀM. Lamberto: Synthesis of γ-thiolactams
H
N
EtO2C
EtO2C
NC
EtO2C
NCS
i
ii
iii
S
EtO2C
NC
(70%)
(90%)
(78%)
Ph
Ph
Ph
5
6
7, 8
Scheme 2ꢀReagents and conditions: (i) cinnamyl bromide, BEMP, acetonitrile, MW 10 min at 110°C; (ii) t-BuSH (1.5 eq), azobisisobutyro-
nitrile (AIBN) (0.2 eq), toluene, MW 6 min at 140°C; (iii) n-Bu3SnH (1.15 eq), AIBN (0.2 eq), toluene, MW 6 min at 140°C.
Ethyl 2-isocyano-5-phenyl-pent-4-enoate (5)
H
N
EtO2C NC
EtO2C
i, ii
S
To a thick Pyrex tube were added ethyl isocyanoacetate (250 μL,
2.17 mmol), cinnamyl bromide (450 mg, 2.17 mmol), BEMP (600
μL, 2.17 mmol) and 3.0 mL of dry acetonitrile. The tube was then
flushed with nitrogen and capped. Heating was applied by means of
microwave irradiation at 110°C for 10 min. The tube was then cooled
and the solvent was removed under reduced pressure. Purification
by flash chromatography eluting with hexane/ethyl acetate (7:1)
afforded compound 5: yield 348 mg (70%); 1H NMR (CDCl3): δ 1.3 (3H,
t, Jꢀ=ꢀ7.0 Hz, CH3CH2O), 2.65–2.95 (2H, m, CHCH2), 4.3 (3H, q, Jꢀ=ꢀ7.0 Hz,
CH2O), 4.4 (1H, t, Jꢀ=ꢀ7.0 Hz, CHN) 6.1–6.25 (1H, m, CH=CHPh), 6.6 (1H,
d, Jꢀ=ꢀ16.0 Hz, PhCH=CH), 7.2–7.4 (5H, m, PhH); 13C NMR (CDCl3): 14.4,
36.8, 53.8, 57.0, 63.1, 121.9, 126.8, 128.3, 129.0, 135.7, 136.8, 161.0, 166.4;
IR (neat): νmax 2139, 1742, 1250, 1209, 1060 cm−1; GC/MS (CI): m/z 230
(79%)
10, 11
9
Scheme 3ꢀReagents and conditions: (i) t-BuSH (1.5 eq), AIBN
(0.2 eq), toluene, MW 6 min at 140°C; (ii) n-Bu3SnH (1.15 eq), AIBN
(0.2 eq), toluene, MW 6 min at 140°C.
H
EtO2C
NC
EtO2C
N
i, ii
S
(90%)
12
13, 14
+
+
(85%, [Mꢀ+ꢀH] ); 247 (47%, [Mꢀ+ꢀNH4] ). HRMS (EI). Calcd for C14H15NO2,
+
Scheme 4ꢀReagents and conditions: (i) t-BuSH (1.5 eq), AIBN (0.2
eq), toluene, MW 6 min at 140°C; (ii) n-Bu3SnH (1.15 eq), AIBN (0.2
eq), toluene, MW 6 min at 140°C.
M : m/z 229.11042. Found: m/z 229.11028.
Ethyl 2-isothiocyanato-5-phenylpent-4-enoate (6)
the corresponding thiolactams 13 and 14 were obtained in
90% yield as a 1:1 diastereomeric mixture (Scheme 4).
In conclusion, MW flash heating methodology was
successfully employed to quickly and efficiently synthe-
size γ-thiolactams in a two-step one-pot procedure in
good yields from alkenyl isocyanides that are accessible
from commercially available ethyl isocyanoacetate. This
methodology additionally provides quick access to iso-
thiocyanates from isocyanides by MW-assisted radical
reaction with tert-butyl thiol.
A thick Pyrex tube was charged with dry toluene (2.0 mL), compound
5 (176 mg, 0.769 mmol), tert-butyl thiol (112 μL, 1.0 mmol) and AIBN
(23 mg, 0.146 mmol). The tube was flushed with argon and capped.
Heating was then applied by means of microwave irradiation at 140°C
for 6 min. After cooling, the mixture was concentrated and the resi-
due was subjected to column chromatography eluting with dichloro-
methane. The isothiocyanate 6 was obtained as a brownish liquid;
yield 180 mg (90%); 1H NMR (CDCl3): δ 1.2 (3H, t, Jꢀ=ꢀ7.0 Hz, CH3CH2O),
2.7–2.9 (2H, m, CHCH2CH=CH), 4.18 (3H, q, Jꢀ=ꢀ7.0 Hz, CH3CH2O),
4.25 (1H, t, Jꢀ=ꢀ7.0 Hz, CHN) 6.0–6.1 (1H, m, CH=CHPh), 6.48 (1H, d,
Jꢀ=ꢀ14.0 Hz, PhCH), 7.1–7.3 (5H, m, PhH); 13C NMR (CDCl3): 14.3, 37.4,
59.6, 62.7, 122.4, 126.5, 127.9, 128.7, 135.4, 136.7, 168.0; IR (neat): νmax
+
2049, 1743, 1199, 1023 cm−1; GC/MS (CI): m/z 262 (66%, [Mꢀ+ꢀH] ); 279
+
+
(18%, [Mꢀ+ꢀNH4] ); HRMS (EI). Calcd for C14H15NO2S, M : m/z 261.08235.
Found m/z 261.08235.
Experimental
Flash column chromatography was performed using Sorbsil C60
(40–60 mesh silica gel). Dichloromethane and toluene were dis-
1
tilled from calcium hydride. H NMR (400 MHz) and carbon-13
Mixture of ethyl cis-4-benzyl-5-thioxopyrrolidine-2-
carboxylate (7) and ethyl trans-4-benzyl-5-thioxo-
pyrrolidine-2-carboxylate (8)
nuclear magnetic resonance (13C NMR) (100 MHz) spectra were
obtained in CDCl3 on a Bruker AVANCE III spectrometer. Infra-
red (IR) spectra were recorded on a Fourier-transform infrared
spectroscopy (FTIR) Perkin-Elmer 2000 spectrometer coupled with
an AutoIMAGE FTIR microscope. Mass spectrometry data were
obtained on a ThermoQuest gas chromatograph-mass spectrometer
configured for open access, on a Waters ZMD mass-spectrometer,
single quadrupole, liquid chromatography-mass spectrometry (LC-
MS) and a VG analytical 70-250-SE double-focusing mass spectro-
meter. MW reactions were performed on a CEM MW synthesizer.
A mixture of anhydrous toluene (2 mL), compound 6 (128 mg,
0.559 mmol), tri-n-butyltin hydride (46.2 μL, 0.166 mmol) and AIBN
(3.6 mg, 0.022 mmol) in a sealed Pyrex tube under argon atmosphere
was heated by means of MW irradiation at 140°C for 6 min. After
cooling, the solvent was removed under reduced pressure and the
residue was subjected to silica gel chromatography eluting with
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ꢂ127
hexane/ethyl acetate (7:1) to afford compounds 7 and 8 as an insepa- dry toluene in a sealed Pyrex tube under an argon atmosphere was
rable diastereomeric mixture in the ratio of 1.6:1; yield 22.6 mg (78%); microwave-irradiated at 140°C for 6 min. After cooling, the mixture in
1H NMR (CDCl3) for 7: δ 1.19 (3H, t, Jꢀ=ꢀ7.0 Hz, CH3CH2O), 1.90 (1H, dt, the tube was treated with tri-n-butyltin hydride (170 μL, 0.614 mmol)
Jꢀ=ꢀ13.0, 9.0 Hz, NCHCHH), 2.43 (1H, dt, 13.0, 8.0 Hz, NCHCHH), 2.52 and AIBN (23 mg), flushed with argon, capped and heated again at
(1H, dd, Jꢀ=ꢀ14.0, 10.5 Hz, PhCHH), 3.0 (1H, m, PhCH2CH), 3.56 (1H, 140°C for 6 min as described earlier. After removal of the solvent
dd, Jꢀ=ꢀ14.0, 4.0 Hz, PhCHH), 4.04 (1H, dd, Jꢀ=ꢀ9.0, 5.0 Hz, CHN), 4.14 under reduced pressure, the residue was subjected to silica gel chro-
1
(2H, q, Jꢀ=ꢀ7.0 Hz, CH2O), 7.82 (1H, br s, NH); H NMR (CDCl3) for 8: matography eluting with hexane/ethyl acetate (7:1). Compounds 13
δ 1.21 (3H, t, Jꢀ=ꢀ7.0 Hz, CH3CH2O), 2.15–2.30 (2H, m, NCHCHH), 2.69 and 14 were obtained as an inseparable diastereomeric mixture in
+
(1H, dd, Jꢀ=ꢀ13.5, 9.5 Hz, PhCHH), 3.07–3.15 (1H, m, PhCH2CH), 3.36 the ratio of 1:1; yield 113 mg (90%); GC/MS (EI): m/z 227 (86%, [M] ,
+
(1H, dd, Jꢀ=ꢀ13.5, 4.0 Hz, PhCHH), 4.11 (2H, q, Jꢀ=ꢀ7.0 Hz, CH2O), 4.30 154 (96%). HRMS (ESI). Calcd for C11H18NO2S, [Mꢀ+ꢀH] : m/z 228.1053.
+
(1H, t, Jꢀ=ꢀ8.0 Hz, CHN), 7.70 (1H, br s, NH); GC/MS (EI): m/z 263 (M] ), Found: m/z 228.1055.
+
+
91 (PhCH2 ). HRMS (EI). Calcd for C14H17NO2S, [M] : m/z 263.09800.
Found: m/z 263.09789.
Acknowledgments: The author would like to thank Pro-
fessor Jeremy D. Kilburn for providing useful insights and
comments that greatly assisted the research and Mon-
mouth University for funding.
Ethyl-2-isocyanopent-4-enoate (9)
A mixture of ethyl isocyanoacetate (3.0 mL, 25.8 mmol), allyl bromide
(2.21 mL, 25.8 mmol), tetra-N-butylammonium bromide (832.6 mg,
2.59 mmol), finely ground potassium carbonate (10.7 g, 77.5 mmol)
and acetonitrile (50 mL) was heated under reflux with stirring for
20 h. The mixture was then cooled, filtered and the solution was
concentrated in vacuo. The resultant brownish oil was subjected to
silica gel chromatography eluting with hexane/ethyl acetate (7:1).
Compound 9 was obtained as a yellow oil; yield 2.38 g (62%); 1H NMR
(CDCl3): 1.3 (3H, t, Jꢀ=ꢀ7.0 Hz, CH3CH2O), 2.6–2.7 (2H, m, CHCH2), 4.23
(2H, q, Jꢀ=ꢀ7.0 Hz, CH2O), 4.3 (1H, t, Jꢀ=ꢀ5.0 Hz, NCH), 5.2–5.3 (2H, m,
CH=CH2), 5.7–5.9 (1H, m, CH=CH2); 13C NMR (CDCl3): 14.1, 37.1, 56.4,
62.8, 120.6, 130.5, 160.3, 166.2; IR (neat): νmax 2145, 1753 cm−1.
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Mixture of ethyl cis-4-methyl-5-thioxo-pyrrolidine-
2-carboxylate (10) and trans-4-methyl-5-thioxo-
pyrrolidine-2-carboxylate (11)
These compounds were obtained by using the procedure described
earlier for the mixture of 7 and 8. Purification by silica gel chroma-
tography eluting with hexane/ethyl acetate (8:1) afforded compounds
10 and 11 as an inseparable 1:1 diastereomeric mixture; yield 115 mg
1
(79%); H NMR (CDCl3) for 10: δ 1.22 (3H, d, Jꢀ=ꢀ7.0 Hz, CH3CH), 1.30
(3H, t, Jꢀ=ꢀ7.0 Hz, CH3CH2O), 1.89 (1H, dt, Jꢀ=ꢀ12.0, 9.0 Hz, NCHCHH),
2.76 (1H, dt, 12.0, 8.0 Hz, NCHCHH), 2.80–2.97 (1H, m, CH3CH), 4.23
(2H, q, Jꢀ=ꢀ7.0 Hz, CH2O), 4.4 (1H, m, CHN), 8.0 (1H, br s, NH); 1H NMR
(CDCl3) for 11: δ 1.22 (3H, d, Jꢀ=ꢀ7.0 Hz, CH3CH), 1.30 (3H, t, Jꢀ=ꢀ7.0 Hz,
CH3CH2O), 2.15 (1H, dt, Jꢀ=ꢀ13.0, 7.5 Hz, CH3CHCHH), 2.54–2.62 (1H, m,
fCH3CHCHH), 2.80–2.97 (1H, m, CH3CH), 4.23 (2H, q, Jꢀ=ꢀ7.0 Hz, CH2O),
4.4 (1H, m, CHN), 8.0 (1H, br s, NH); 13C NMR (CDCl3) for the mixture:
δ 14.5, 19.2, 19.3, 35.2, 35.5, 46.7, 47.4, 60.2, 60.3, 62.4, 170.3, 170.5, 211.2;
+
GC/MS (EI) for the mixture: m/z 188, [Mꢀ+ꢀH] ; HRMS (EI) for the mix-
+
ture. Calcd for C8H13NO2S, [M] : m/z 187.06670. Found: m/z 187.06715.
Mixture of ethyl 2-allyl-cis-4-methyl-5-thioxo-pyrroli-
dine-2-carboxylate (13) and ethyl 2-allyl-trans-4-methyl-
5-thioxo-pyrrolidine-2-carboxylate (14)
A mixture of compound 12 (108 mg, 0.559 mmol), tert-butyl thiol
(81.5 μL, 0.727 mmol) and AIBN (17.5 mg, 0.111 mmol) in 2.0 mL of
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