A Bench-Stable Vilsmeier Reagent for in situ Alcohol Activation: Synthetic Application in the Synthesis of 2-Amino-2-Thiazolines

Article abstract of DOI:10.1055/s-0036-1589086

A robust, chemoselective direct condensation/cyclization of thioureas and amino alcohols is described. Employing a bench-stable Vilsmeier reagent, methoxymethylene- N, N -dimethyliminium methyl sulfate, the selective in situ activation of alcohols is achieved with high efficiency and broad functional-group tolerance. The reversible interaction of the Vilsmeier reagent with substrate was key to the success of this activation strategy.

Full text of DOI:10.1055/s-0036-1589086

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
en
M. T. Corbett, S. Caille
Letter
Synlett
A Bench-Stable Vilsmeier Reagent for in situ Alcohol Activation:
Synthetic Application in the Synthesis of 2-Amino-2-Thiazolines
Michael T. Corbett*
Seb Caille
0
0
0
0
0-
0
0
2
1-
7
0
4
4-
8
9
X
Me
OSO3Me
N
Me
OMe
(1.5 equiv)
HO
Pivotal Drug Substance Process Development, Amgen,
One Amgen Center Drive, Thousand Oaks, CA 91320, USA
mcorbe01@amgen.com
S
H
NaOAc (1.5 equiv)
Me
+
PhNCS
Me
OH
PhHN
N
H2N
DMF (0.5 M)
23 °C, 4 h
OH
This paper is dedicated to Professor Vic Snieckus in honor of his
80th birthday
93% yield
>20:1 dr
>20:1 chemoselectivity
Received: 15.06.2017
Accepted: 04.07.2017
Published online: 16.08.2017
DOI: 10.1055/s-0036-1589086; Art ID: st-2017-r0476-l
the in situ chemoselective activation of alcohols employing
a bench-stable Vilsmeier reagent to transiently generate ac-
tivated alcohol species that undergo displacement with an
endogenous nucleophile.
Abstract A robust, chemoselective direct condensation/cyclization of
thioureas and amino alcohols is described. Employing a bench-stable
Vilsmeier reagent, methoxymethylene-N,N-dimethyliminium methyl
sulfate, the selective in situ activation of alcohols is achieved with high
efficiency and broad functional-group tolerance. The reversible interac-
tion of the Vilsmeier reagent with substrate was key to the success of
this activation strategy.
(a)
Me
Me
Cl
Cl
1.
N
1
Ar
H
Ar CHO
2. H2O
Key words alcohol activation, amino alcohols, chemoselectivity, con-
densation, thiazolines, thioureas, Vilsmeier reagents
(b)
R
R
Cl
O
path a
Me
Me
N
1
H2O
Nucleophilic displacement of activated alcohols rep-
resents a fundamental yet powerful method for the con-
struction of stereogenic heteroatom–carbon bonds.1 Ex-
ploiting the abundance of alcohol functionality in synthetic
building blocks2 for the development of new synthetic
methodologies has relied heavily on identifying strategies
to overcome the latent reactivity of alcohols in SN2 reac-
tions given their poor nucleofugality.3 Traditional ap-
proaches to alcohol activation generally rely on the genera-
tion of discrete activated alcohol species (–OTf, –OMs, –OTs,
etc.) or conversion to halides (–Cl, –Br) in a prerequisite
nonstrategic step.4 Alternative metal-free methods for the
direct in situ activation of alcohols have garnered signifi-
cant interest within the synthetic community recently
through the development of catalytic Mitsunobu reactions5
and exploration of alternative activating reagents for the
transient formation of carbamates6 and oxalates.7 Despite
the limited success of these strategies, development of
methodologies enabling greater functional-group compati-
bility, chemoselectivity, and regioselectivity are paramount
for the broad adoption of these protocols in complex small-
molecule synthesis. Herein, we report a robust protocol for
OH
Cl
R
O
path b
– HCl
R
O
H
2
Nuc
R
Nuc
path c
Scheme 1 Reactivity of (chloromethylene)dimethyliminium chloride (1)
Vilsmeier reagents, such as (chloromethylene)dime-
thyliminium chloride (1), are traditionally deployed as C1
synthons in the formylation of π-nucleophiles through the
Vilsmeier–Haack reaction (Scheme 1, a).8 Given their
heightened reactivity towards pronucleophiles,9 the syn-
thetic utility of Vilsmeier salts has also been explored with-
in the context of alcohol functionalization for the prepara-
tion of chlorides and formates through the irreversible gen-
eration of imidate 2 (Scheme 1, b). Vilsmeier salts are
traditionally prepared via activation of DMF with strong de-
hydration reagents (POCl3, COCl2, SOCl2, (COCl)2, etc.) result-
ing in imidate species containing chloride counterions that
readily react with the activated alcohol 2 to afford alkyl/vi-
nyl halide products (Scheme 1, b, path a).10 Under cryogenic
conditions or in the presence of sterically encumbered al-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
M. T. Corbett, S. Caille
Letter
Synlett
cohols, hydrolysis of 2 can outcompete the rate of nucleo-
philic displacement by the counterion leading to the isola-
tion of formates (Scheme 1, b, path b).11 There is limited
precedent in the literature of prior art that has achieved the
direct displacement of the activated alcohol 2 with endoge-
nous nucleophiles due to competitive reaction of 1 with
other functionality leading to reactions suffering from poor
chemoselectivity and functional-group tolerance (Scheme
1, b, path c).12 In order to circumvent deleterious pathways
inherent to halide-derived Vilsmeier salts, we hypothesized
that employing Vilsmeier reagents bearing less reactive
counterions such as those derived from sulfates would en-
able greater chemoselectivity due to their tempered reac-
tivity relative to 1 through the generation of more benign
byproducts.
O
O
(a)
S
O
MeO
OMe
Me
Me
OSO3Me
OMe
3
Me
N
N
H
96% yield
60 °C
>2 mol scale
Me
(b)
Me
O
Me
1
N
N
Cl
HCl
+
+
+
+
R
R
R
OH
Me
O
Me
3
OSO3Me
MeOH
(c)
OH
R2
The preparation of methoxymethylene-N,N-dimethyli-
minium methyl sulfate (3) was first reported in 1963,13 but
its synthetic applications have been limited to the prepara-
tion of N,N-dimethylformamidines,14 esterification of car-
boxylic acids,15 formation of acetals,16 amongst others17
during the ensuing 50 years. Vilsmeier reagent 3 is attrac-
tive since it is a commercially available bench-stable
Vilsmeier salt, which can also be readily prepared on scale
(Scheme 2, a).18 Unlike the highly hygroscopic chloride salt
1, the sulfate salt 3 exhibits stability under ambient storage
conditions enabling it to be easily prepared and deployed in
process-scale reactions. In contrast to 1, Vilsmeier reagent 3
undergoes reaction with alcohols to liberate an equivalent
of a sulfate salt and methanol, which are less prone to par-
ticipate in deleterious pathways (Scheme 2, b). We envis-
aged the potential synthetic utility of this chemoselective
alcohol-activation strategy employing Vilsmeier reagent 3
could be effectively demonstrated in the intramolecular de-
hydrative cyclization of β-hydroxy thioureas prepared from
isothiocyanates 4 and amino alcohols 5 to afford 2-amino-
2-thiazolines 6 (Scheme 2, c). The 2-amino-2-thiazoline
framework was selected given the relative dearth of robust
procedures for their preparation6a,19 and the broad interest
in this class of heterocycles as synthetic building blocks in
the construction of biologically active molecules.20
We began our studies by exploring the condensation of
phenyl isothiocyanate (4a) and ethanolamine (5a) in the
presence of methoxymethylene-N,N-dimethyliminium
methyl sulfate (3, Table 1). Employing sodium acetate as a
base, the reaction was found to proceed efficiently in DMF
at ambient temperature affording N-phenyl-4,5-dihydro-
thiazol-2-amine (6a) in 92% assay yield (Table 1, entry 1).
EtOAc provided comparable yields to DMF in the generation
of 6a, however, the solubility of the β-hydroxy thioureas
derived from other substrates proved inhibitive of further
pursuit of this solvent (Table 1, entry 2). Other polar solvent
such as MeCN and CH2Cl2 were found to be inferior afford-
ing moderate to low yields (Table 1, entries 3 and 4). Non-
polar solvents were found to be incompatible with the reac-
OH
R2
S
N
S
3
R1HN
R1 NCS
+
R1
N
N
R2
H2N
H
H
4
5
6
Scheme 2 Reactivity of methoxymethylene-N,N-dimethyliminium
methyl sulfate (3)
tion due to poor substrate/reagent solubility (Table 1, en-
tries 5 and 6). NaOAc and iPr2NEt were found to exhibit the
highest efficacy in the parent transformation with other in-
Table 1 Optimization of Vilsmeier Salt Promoted Condensation/Cy-
clization of Phenyl Isothiocyanate 4a and Ethanolamine 5aa
3 (1.5 equiv)
HO
S
N
base (1.5 equiv)
PhNCS
PhHN
+
solvent
H2N
23 °C, 4 h
4a
5a
6a
(1.0 equiv)
(1.1 equiv)
Entry
Base
Solvent (M)
Yield (%)b
1
2
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
K2CO3
DMF (0.2)
EtOAc (0.2)
CH2Cl2 (0.2)
MeCN (0.2)
MTBE (0.2)
toluene (0.2)
DMF (0.2)
DMF (0.2)
DMF (0.2)
DMF (0.2)
DMF (0.5)
92
88
13
60
3
3
4
5
6
1
7
35
9
8
Cs2CO3
2,6-lutidine
iPr2NEt
NaOAc
9
66
77
93d
10
11c
aReactions were performed on 1 mmol scale.
bDetermined by 1H NMR analysis of the crude reaction mixture employing
benzyl benzoate as an internal standard.
cReaction performed on 20 mmol scale.
dIsolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
M. T. Corbett, S. Caille
Letter
Synlett
organic and organic bases providing reduced yields (Table 1,
entries 7–10). Optimized reaction conditions were identi-
fied employing 1.5 equivalents of 3 and NaOAc in DMF (0.5
M) at room temperature providing the 2-amino-2-thiazo-
line 6a in 93% yield (Table 1, entry 11). 22
ized aliphatic amino alcohols like tryptophanol (6j), tyrosi-
nol (6k), serinol (6l), and methioninol (6m) affording func-
tionalized products in excellent yields.
Aryl-substituted 2-amino-2-thiazolines, such as 6n, can
also be accessed in slightly reduced chemical yields. Tertia-
ry amines were also readily deployed in this reaction af-
fording 6o in 86% yield. Despite their heightened steric en-
cumbrance, secondary alcohols were also found to partici-
pate in the reaction. Phenylethanolamine reacted to provide
6p in 84% yield. Deploying poorly nucleophilic alcohols
such as 3-amino-1,1,1-trifluoropropan-2-ol, alcohol me-
tathesis with 3 is slow resulting in selective elimination of a
thioimidate providing the 2-amino-2-oxazoline 6q-O in
80% yield.23 Tertiary alcohols were found to be too sterically
encumbered to participate resulting in no isolated yield of
2-amino-2-thiazoline 6r.
With optimized reaction conditions in hand, we turned
our attention towards investigating the generality of this
protocol for the generation of functionalized 2-amino-2-
thiazolines 6 through the dehydrative cyclization of isothio-
cyanates 4 and 1,2-amino alcohols 5 (Scheme 3). The reac-
tion was found to exhibit broad functional-group tolerance
for the incorporation of a variety of alkyl (6b), aryl (6d–
h,k–q), heteroaryl (6i), and carbamate (6c) isothiocyanates
in uniformly high yields irrespective of the steric and elec-
tronic characteristics of the reactive thiourea intermedi-
ates. Similarly, the scope of variously substituted 1,2-amino
alcohols was investigated in the reaction to probe the toler-
ance of the transformation towards both primary, second-
ary, and tertiary alcohols. In addition to phenylalaninol
(6b–f) and valinol (6g–i), the reaction tolerated functional-
The utility of this process was also expanded to access
other classes of heterocycles by employing 1,3-amino alco-
hols. The condensation/cyclization of 1,3-aminopropanol
and 2-aminobenzyl alcohol proceeded smoothly affording
3 (1.5 equiv)
R4
R3
R2
R1
R4
R3
R2
R1
S
C
N
HO
S
N
NaOAc (1.5 equiv)
R5HN
+
DMF (0.5 M)
23 °C, 1–8 h
H2N
R5
4
5
6
NC
Ac
O
S
S
S
S
H
H
H
H
N
H
EtO
N
H
N
N
N
N
N
N
H
H
6b
85% yield
6c
94% yield
6d
91% yield
6e
87% yield
Br
Br
N
S
S
S
H
H
H
S
H
Me
Me
Me
N
N
N
O2N
N
N
N
N
N
H
H
H
H
Cl
Me
Me
Br
Me
6f
6g
6h
6i
90% yield
93% yield
91% yield
87% yield
F3C
OH
S
N
S
H
S
S
N
H
H
H
NH
OH
N
SMe
N
N
N
H
N
N
H
H
H
Br
6j
6k
92% yield
6l
95% yield
6m
94% yield
91% yield
H
Me
H
S
CF3
Me
S
H
S
X
S
Me
Me
N
N
H
N
N
N
N
H
N
N
H
N
N
H
H
6n
79% yield
6o
86% yield
6p
84% yield
6qa
X = S: <5% yield
X = O: 80% yield
6ra
0% yield
Scheme 3 Reaction scope with 1,2-amino alcohols. Reactions were performed on 5–20 mmol scale with 4 (1.00 equiv) and 5 (1.10 equiv) and pro-
ceeded to full conversion as adjudged by TLC. Isolated yields of analytically pure material are reported. aReaction was performed at 75 °C for 4–8 h
employing iPr2NEt (1.5 equiv) as the base.21
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
M. T. Corbett, S. Caille
Letter
Synlett
5,6-dihydro-4H-1,3-thiazin-2-amine derivatives 6s–u in
high yields (Scheme 4). The construction of these six-mem-
bered heterocycles proceeded with similar efficacy to those
obtained from the analogous 1,2-amino alcohols with no
need to either increase the reaction time/temperature or
incorporate Thorpe–Ingold effects.
confirmed our hypothesis that the activation of alcohols
proceeds in situ via the generation of a transient imidate
species 8. The reversibility of the imidate formation enables
the title transformation to proceed with high chemoselec-
tivity and suggests that the limiting step in the reaction is
the nucleophilic displacement of the imidate species.
3 (1.5 equiv)
3 (1.5 equiv)
iPr2NEt (1.5 equiv)
(a)
S
(S)
HO
(R)
(S)
S
N
NaOAc (1.5 equiv)
HO
H2N
S
C
N
+
+
PhNCS
PhHN
DMF (0.5 M)
23 °C, 4–8 h
DMF (0.5 M)
75 °C, 8 h
(S)
RHN
N
H2N
R
4a
5v
6v
4
5
6
76% yield
>20:1 dr
3 (1.5 equiv)
S
S
S
(R)
Ph
Ph
HO
Ph
Ph
(S)
S
N
NaOAc (1.5 equiv)
+
N
N
PhNCS
PhHN
N
N
N
N
H
H
H
DMF (0.5 M)
23 °C, 8 h
(S)
(S)
H2N
Br
6s
6t
82% yield
6u
86% yield
4a
5w
6w
90% yield
85% yield
>20:1 dr
Scheme 4 Reaction scope with 1,3-amino alcohols. Reactions were
performed on 8 mmol scale with 4 (1.00 equiv) and 5 (1.10 equiv) and
proceeded to full conversion as adjudged by TLC. Isolated yields of ana-
lytically pure material are reported.
(b)
D
D3C
N
OMe
CD3
MeO3SO
In order to better understand the mechanism of this
transformation, we sought to elucidate both the mechanism
by which Vilsmeier reagent 3 activates alcohols and the
mechanism by which nucleophilic displacement of the re-
sultant imidate occurs (Scheme 5). In the reaction of both
(1S,2S)-trans-2-aminocyclohexanol (5v) and (1R,2S)-(–)-2-
amino-1,2-diphenylethanol (5w) under the standard reac-
tion conditions, we obtained inversion of the alcohol ste-
reocenter affording the products 6v and 6u in >20:1 dr
(Scheme 5, a). Since the stereochemistry is inverting during
nucleophilic displacement, the reaction is proposed to pro-
ceed through a SN2-type mechanism, which is consistent
with observations in the application of Vilsmeier salts in
the Mitsunobu reaction.12a This SN2-type reaction pathway
is also consistent with experimental results that primary
alcohols react faster than more sterically encumbered sec-
ondary/tertiary alcohols 6p–r. Activation of alcohols with
Vilsmeier salt 1 is known to be an irreversible process;
however, we suspected that activation of alcohols with
Vilsmeier salt 3 would be a reversible process since the me-
tathesis of alcohols and 3 generates an equivalent of MeOH
that could undergo metathesis with the imidate intermedi-
ate to regenerate the starting material (Scheme 2, b). In or-
der to investigate this hypothesis, we prepared the DMF-d7
derivative of Vilsmeier salt 3. The reaction of 4-chloroben-
3-d7
(2.0 equiv)
D
HO
D3C
MeOH
+
N
O
DMF-d7 (2.0 M)
Cl
CD3
MeO3SO
Cl
23 °C
7
8
7:8
t = 30 min
t = 60 min
t = 18 h
5.4:1.0
4.0:1.0
2.5:1.0
Scheme 5 Mechanistic elucidation
A significant challenge for the application of in situ alco-
hol activation strategies in the construction of complex
small-molecule building blocks is the ability to selectively
activate an alcohol in the presence of other functionality
that may participate in deleterious reaction pathways in the
presence of activating reagents.6b Encouraged by the ability
to efficiently deploy amino alcohols, such as tyrosinol and
serinol, which contain other alcohol functionality in the
parent reaction, we became interested in the ability to se-
lectively activate primary alcohols in the presence of sec-
ondary alcohols. Treatment of 5x with phenyl isothiocya-
nate (4a) under the optimized reaction conditions selec-
tively led to the formation of 6x demonstrating the
potential utility of this methodology as an effective strategy
for the chemoselective functionalization of alcohols in
complex small-molecule synthesis (Scheme 6, a). Upon
generation of the intermediate β-hydroxy thiourea, metath-
esis with 3 through loss of methanol can proceed to either
form the activated primary alcohol intermediate 9 or the
activated secondary alcohol intermediate 10, which can
also interconvert through an intramolecular alcohol me-
1
zyl alcohol (7) and 3-d7 was monitored by H NMR spec-
troscopy (Scheme 5, b). It was observed that a slow equili-
bration took place – where after one hour at ambient tem-
perature there was a 4.0:1.0 ratio of 7/8, which was
accompanied by an equimolar generation of MeOH with re-
spect to 8. Allowing the mixture to age overnight, a thermo-
dynamic equilibrium of 2.5:1.0 7/8 was reached, which
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
M. T. Corbett, S. Caille
Letter
Synlett
OSO3Me
Me2N
(a)
S
H
O
S
Me
PhHN
N
Me
OH
PhHN
OH
N
H
PhNCS
6x
93% yield
>20:1 dr
4a
9
3 (1.5 equiv)
>20:1 chemoselectivity
NaOAc (1.5 equiv)
HO
+
DMF (0.5 M)
23 °C, 4 h
Me
H2N
OSO3Me
Me2N
Me
OH
5x
Me
O
S
S
H
OH
OH
PhHN
N
PhHN
N
H
6y
10
(b)
1 (1.0 equiv)
iPr2NEt (2.0 equiv)
HO
S
H
Me
+
PhNCS
Me
PhHN
N
H2N
DMF (0.5 M)
23 °C, 4 h
OH
OH
4a
5x
6x
39% yield
>20:1 dr
Scheme 6 Chemoselective primary alcohol activation
CuI (5 mol%)
1,10-phenanthroline (10 mol%)
Cs2CO3 (2.0 equiv)
R2
S
tathesis (vide supra). Since the rate of alcohol metathesis is
faster than the rate of nucleophilic displacement of the imi-
date, the selectivity of the reaction is dictated by the rates
of nucleophilic displacement. Since the primary imidate 9 is
more reactive than the sterically hindered secondary imi-
date 10, a high level of chemoselectivity can be obtained re-
sulting in the selective formation of 6x. In order to highlight
the utility of Vilsmeier reagent 3, the analogous reaction of
4a and 5x was performed employing the chloride-derived
Vilsmeier reagent 1, which led to the formation of 6x in
only 39% yield with the remaining mass balance consisting
of a complex product mixture (Scheme 6, b).
R2
S
R1
N
N
N
H
N
R1
1,2-dimethoxyethane (0.2 M)
85 °C, 1 h
Br
6
11
S
H
SMe
S
S
H
Me
N
N
N
N
N
N
Me
Br
11a
97% yield
11b
96% yield
11c
96% yield
Despite significant synthetic interest in 2-amino-2-thi-
azolines themselves, we were also interested in exploring
the utility of these substrates as building blocks for higher-
order fused heterocycles. Under copper(I) catalysis, sub-
strates bearing 2-bromophenyl substituents underwent
facile intramolecular C–N coupling to allow for the genera-
tion of fused heterocycles 11 in excellent yield (Scheme 7).
The reaction was found to work well for both five- and six-
membered fused heterocycles providing products in near
quantitative yields.24 This transformation enables the con-
struction of chiral 2,3-dihydro[1,3]thiazolo[3,2-a]benzim-
idazoles 11a and 11b in two synthetic steps from commer-
cially available isothiocyanates and amino alcohols.
Scheme 7 Copper(I)-catalyzed synthesis of fused heterocycles. Reac-
tions were performed on 3 mmol scale and proceeded to full conversion
as adjudged by TLC. Isolated yields of analytically pure material are re-
ported.
In summary, we have demonstrated a robust protocol
for the synthesis of 2-amino-2-thiazolines through a che-
moselective direct condensation/cyclization of thioureas
and amino alcohols, which was achieved through in situ ac-
tivation of alcohols employing bench-stable methoxymeth-
ylene-N,N-dimethyliminium methyl sulfate (3) under mild
reaction conditions. The ability to reversibly generate the
reactive imidate intermediate in situ was paramount to the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
M. T. Corbett, S. Caille
Letter
Synlett
high levels of functional-group tolerance and chemoselec-
tivity. Further applications of Vilsmeier reagents for in situ
activation of alcohols are also currently being explored.
(12) (a) Barrett, A. G. M.; Braddock, D. C.; James, R. A.; Koike, N.;
Procopiou, P. A. J. Org. Chem. 1998, 63, 6273. (b) Rao, M.; Yang,
M.; Kuehner, D.; Grosso, J.; Deshpande, R. P. Org. Process Res.
Dev. 2003, 7, 547. (c) Caille, S.; Cui, S.; Hwang, T.-L.; Wang, X.;
Faul, M. M. J. Org. Chem. 2009, 74, 3833.
(13) (a) Hafner, K.; Vöpel, K. H.; Ploss, G.; König, C. Justus Liebigs Ann.
Chem. 1963, 661, 52. (b) Bredereck, H.; Effenberger, F.; Simchen,
G. Chem. Ber. 1963, 96, 1350.
Acknowledgment
The authors thank Tawnya Flick for assistance in obtaining HRMS data.
(14) Li, B. L.; Ding, S. Y.; Ren, Y. F.; Wang, L. C.; Jia, Y. C.; Zhang, X. Q.;
Gu, H. M. Bull. Korean Chem. Soc. 2013, 34, 1537.
(15) Kantlehner, W.; Funke, B. Chem. Ber. 1971, 104, 3711.
(16) (a) Kantlehner, W.; Gutbrod, H.-D.; Groß, P. Liebigs Ann. Chem.
1979, 522. (b) Kantlehner, W.; Gutbrod, H.-D. Liebigs Ann. Chem.
1979, 1362.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589086.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(17) (a) Wasserman, H. H.; Ives, J. L. J. Org. Chem. 1985, 50, 3573.
(b) Jarrahpour, A.; Zarei, M. Tetrahedron 2010, 66, 5017. (c) Rai,
A.; Rai, V. K.; Singh, A. K.; Yadav, L. D. S. Eur. J. Org. Chem. 2011,
4302. (d) Yao, B.; Shen, C.; Liang, Z.; Zhang, Y. J. Org. Chem. 2014,
79, 936.
(18) Hafner, K.; Vöpel, K. H.; Ploss, G.; König, C. Org. Synth. 1967, 47,
52.
(19) (a) Klayman, D. L.; Woods, T. S. J. Org. Chem. 1975, 40, 2000.
(b) Kim, T. H.; Cha, M.-H. Tetrahedron Lett. 1999, 40, 3125.
(c) Kim, T. H.; Min, J. K.; Lee, G.-J. Tetrahedron Lett. 1999, 40,
8201.
(20) (a) Gaumont, A.-C.; Gulea, M.; Levillain, J. Chem. Rev. 2009, 109,
1371. (b) Just-Baringo, X.; Albericio, F.; Alvarez, M. Curr. Top.
Med. Chem. 2014, 14, 1244.
(21) At elevated reaction temperatures, the decomposition of 3 in
the presence of NaOAc is a competing pathway leading to the
generation of MeOAc. This deleterious pathway can be circum-
vented through the use of iPr2NEt. At ambient temperature, the
background reaction of 3 and NaOAc is nonconsequential under
the time scale of the reaction.
References and Notes
(1) (a) But, T. Y. S.; Toy, P. H. Chem. Asian J. 2007, 2, 1340.
(b) Liégault, B.; Renaud, J.-L.; Bruneau, C. Chem. Soc. Rev. 2008,
37, 290. (c) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.;
Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551. (d) Trost, B. M. Tet-
rahedron 2015, 71, 5708. (e) Butt, N. A.; Zhang, W. Chem. Soc.
Rev. 2015, 44, 7929.
(2) Henkel, T.; Brunne, R. M.; Müller, H.; Reichel, F. Angew. Chem.
Int. Ed. 1999, 38, 643.
(3) (a) Stirling, C. J. M. Acc. Chem. Res. 1979, 12, 198. (b) Jaramillo,
P.; Domingo, L. R.; Pérez, P. Chem. Phys. Lett. 2006, 420, 95.
(c) Spahlinger, G.; Jackson, J. E. Phys. Chem. Chem. Phys. 2014,
16, 24559.
(4) (a) Clarke, P. A.; Santos, S.; Martin, W. H. C. Green Chem. 2007, 9,
438. (b) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2,
167. (c) Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657.
(d) Dach, R.; Song, J. J.; Roschangar, F.; Samstag, W.; Senanayake,
C. H. Org. Process Res. Dev. 2012, 16, 1697.
(5) (a) Hirose, D.; Taniguchi, T.; Ishibashi, H. Angew. Chem. Int. Ed.
2013, 52, 4613. (b) Fletcher, S. Org. Chem. Front. 2015, 2, 739.
(c) Buonomo, J. A.; Aldrich, C. C. Angew. Chem. Int. Ed. 2015, 54,
13041. (d) Hirose, D.; Gazvoda, M.; Košmrlj, J.; Tamiguchi, T. Org.
Lett. 2016, 18, 4036.
(6) (a) Bernacki, A. L.; Zhu, L.; Hennings, D. D. Org. Lett. 2010, 12,
5526. (b) Trader, D. J.; Carlson, E. E. Mol. BioSyst. 2012, 8, 2484.
(7) (a) Nawrat, C. C.; Jamison, C. R.; Slutskyy, Y.; MacMillan, D. W.
C.; Overman, L. E. J. Am. Chem. Soc. 2015, 137, 11270. (b) Zhang,
X.; MacMillan, D. W. C. J. Am. Chem. Soc. 2016, 138, 13862.
(8) (a) Seybold, G. J. Prakt. Chem. 1996, 338, 392. (b) Jones, G.;
Stanforth, S. P. Org. React. 1997, 49, 1. (c) Jones, G.; Stanforth, S.
P. Org. React. 2000, 56, 355.
(9) Mayr, H.; Ofial, A. R. Tetrahedron Lett. 1997, 38, 3503.
(10) (a) Hanessian, S.; Plessas, N. R. Chem. Commun. 1967, 1152.
(b) Dods, R. F.; Roth, J. S. Tetrahedron Lett. 1969, 10, 165.
(c) Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 2163.
(d) Benazza, M.; Uzan, R.; Beaupère, D.; Demailly, G. Tetrahedron
Lett. 1992, 33, 4901.
(22) Representative Procedure for the Preparation of 2-Amino-2-
thiazoline 6
To a stirred solution of ethanolamine 5a (1.35 mL, 22.4 mmol,
1.10 equiv) in DMF (40.0 mL, 0.5 M) at r.t. was added phenyl iso-
thiocyanate 4a (2.40 mL, 20.0 mmol, 1.00 equiv). After stirring
for 2 min at r.t., Vilsmeier salt 3 (7.20 g, 30.0 mmol, 1.50 equiv),
and NaOAc (2.51 g, 30.6 mmol, 1.50 equiv) were added sequen-
tially. The reaction mixture was allowed to stir at r.t. until
adjudged complete by TLC, generally 4 h. The reaction was
diluted with EtOAc (120 mL) and sequentially washed with sat.
aq NaHCO3 (40 mL) and brine (40 mL). The organic layer was
dried over MgSO4, polish filtered, and concentrated under
reduced pressure. The crude residue was purified by silica gel
column chromatography (100% heptane to 80% EtOAc in
heptane gradient) to give 6a (3.31 g, 18.6 mmol, 93% yield) as a
white solid (mp 153 °C).
Analytical Data for 6a
1H NMR (400 MHz, CDCl3): δ = 7.31–7.24 (m, 2 H), 7.16–7.08 (m,
2 H), 7.04–7.01 (m, 1 H), 6.36 (br s, 1 H), 3.78 (t, J = 7.04 Hz, 2 H),
3.27 (t, J = 7.04 Hz, 2 H). 13C NMR (101 MHz, CDCl3): δ = 161.83,
147.59, 128.89, 123.10, 121.12, 50.44, 31.81. ESI-HRMS: m/z
calcd for C9H11N2S [M + H]+: 179.06349; found: 179.06375. TLC
(EtOAc/heptane, 1:1): Rf = 0.22. The spectral properties are in
agreement with those previously reported in the literature.6a
(23) See Supporting Information for further information.
(24) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133.
(11) Morita, K.; Noguchi, S.; Nishikawa, M. Chem. Pharm Bull. 1959,
7, 896.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F