Synthesis of Quaternary-Substituted Thiazolines via Halocyclization of S-Allyl Thioimidate Salts

Article abstract of DOI:10.1021/acs.joc.7b02299

An efficient synthesis of S-allyl thioimidate hydrobromide salts via coupling of thioamides with allyl bromide derivatives is described. A range of mono-, di-, and trisubstituted olefins as well as alkyl- and arylthioamides with variations in electronics are tolerated. A rapid anti-diastereoselective halocyclization of these salts provides a variety of substituted alkyl- and arylthiazolines. Initial development of an efficient enantioselective synthesis of quaternary-substituted thiazolines through the organo-catalyzed halocyclization of sulfonate thioimidate salts is also described.

Full text of DOI:10.1021/acs.joc.7b02299

Featured Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX-XXX
Synthesis of Quaternary-Substituted Thiazolines via Halocyclization
of S‑Allyl Thioimidate Salts
Patrick D. Parker, Berenice C. Lemercier,† and Joshua G. Pierce*
́
́
Department of Chemistry, College of Sciences, NC State University, Raleigh, North Carolina 27695, United States
S
* Supporting Information
ABSTRACT: An efficient synthesis of S-allyl thioimidate hydrobromide salts via coupling of thioamides with allyl bromide
derivatives is described. A range of mono-, di-, and trisubstituted olefins as well as alkyl- and arylthioamides with variations in
electronics are tolerated. A rapid anti-diastereoselective halocyclization of these salts provides a variety of substituted alkyl- and
arylthiazolines. Initial development of an efficient enantioselective synthesis of quaternary-substituted thiazolines through the
organo-catalyzed halocyclization of sulfonate thioimidate salts is also described.
INTRODUCTION
■
Nitrogen-containing heterocyclic motifs are the core structural
elements of many natural products1 and approved pharma-
ceuticals.2 Although there has been intense development of
synthetic methods for the construction of nitrogen heterocycles
since the advent of modern organic chemistry, there remains a
need for improved access to these privileged scaffolds.
2-Thiazolines are five-membered heterocycles found in many
natural products and biologically relevant compounds showcas-
ing activities such as anticancer,3 antimicrobial,1,4 antiviral,5 and
neurological properties.6 They have also been used as metal
ligands in asymmetric catalysis7 and can be found in a variety of
flavors, aromas, and luminescent compounds.8 As a result,
many methods currently exist for their synthesis.9 The most
common of these methods utilizes β-amino alcohols and β-
amino thiols (Figure 1a), but with limited commercial
availability and difficult synthetic accessibility of starting
material, these methods can take multiple steps in cases
Figure 1. Approaches for thiazoline synthesis.
where unnatural amino acids are required or quaternary
substitution is desired.10 Therefore, the development of
Finally, the copper is reductively eliminated to provide the
bromothiazoline product. Although this reaction was efficient
and diastereoselective, a straightforward method for accessing
the corresponding quaternary-substituted derivative or anti-
diastereomer (vs the alternate six-membered ring products) as
well as obtaining the thiazolines in enantioenriched form
efficient and stereoselective methods for the synthesis of
thiazolines is still an ongoing challenge.
As part of our program directed toward the development of
novel methods to construct nitrogen-containing heterocycles,11
we previously developed a syn-diastereoselective synthesis of
thiazolines through a copper-catalyzed cyclization of S-allyl
thiohydroximic acids (Figure 1b).12 The reaction is thought to
remained elusive.
proceed through an oxidative addition of copper bromide to the
nitrogen−oxygen bond of the activated substrate, followed by a
cis-iminocupration across the olefin to form the thiazoline ring.
Received: September 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b02299
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
To address these limitations, we envisioned that a
halocyclization of S-allyl thioimidates would provide access to
the anti-diastereomer, favor the 5-exo cyclization pathway, and
could potentially be rendered asymmetric (Figure 1c).
Halocyclization reactions have been described in the literature
for well over a century with the first reported bromolactoniza-
tion by Fittig in 1883.13 Lactones were the most common
heterocycles synthesized during the first century, and it was not
until the latter half of the 1900s when halocyclization reactions
were applied to the synthesis of other heterocycles. Due to side
reactions that plagued asymmetric approaches, such as olefin-
to-olefin halogen exchange,14,15 enantioselective versions of
halocyclizations did not appear in the literature until 1981 with
the first substrate-controlled iodolactonization reported by
Takano and co-workers, where proline was used as a chiral
auxiliary to provide 16% ee.16 The first reagent-controlled
halocyclization was reported by Taguchi and co-workers in
1992, which employed stoichiometric amounts of a chiral
titanium complex to obtain iodolactones in up to 64% ee,17 and
the first catalytic asymmetric reaction was reported by Wang
and co-workers in 2004, which utilized a chiral phase transfer
catalyst to provide iodolactones in up to 42% ee.18 Since 2004,
there has been a surge in the number of reported catalytic
asymmetric halocyclization reactions, and the potential for this
area of synthetic chemistry is still being revealed.15 Herein, we
have developed an efficient anti-diastereoselective halocycliza-
tion of S-allyl thioimidate salts to prepare quaternary 2-
thiazolines and have demonstrated the initial utility of these
reactions to achieve thiazoline synthesis in an asymmetric
fashion.
5); however, the yield was decreased significantly when mildly
acidic workup was employed to remove triethylamine (entry 6).
Further, the reaction yields were highly irreproducible and
resulted in no isolated thioimidate products in many cases
(entry 7).
As a result of the instability of compound 1a, we re-evaluated
our approach. Reacting thiobenzamide with 1 equiv of 3-
bromo-2-methylpropene in tetrahydrofuran at room temper-
ature provided compound 2a as the hydrobromide salt of
compound 1a (Table 2, entry 1). The reaction was significantly
Table 2. Optimization of S-Allyl Thioimidate Salt 2a
entry
X
conditions
yield of 2a (%)
a
1
2
3
4
1
1
2
3
THF (0.2 M), rt, 142 h
THF (0.2 M), 67 °C, 24 h
THF (0.5 M), 67 °C, 5 h
THF (0.2 M), 67 °C, 3 h
2a observed
a
2a observed
b
92
b
78
a
b
Observed by LC-MS; reactions did not go to completion. Isolated
yield.
faster at reflux in tetrahydrofuran, but it also did not go to
completion (entry 2). Increasing the concentration of
thioamide and employing 2 equiv of 3-bromo-2-methylpropene
provided the highest yield of 92% (entry 3), whereas increasing
the equivalents of allyl bromide to 3 decreased the yield to 78%
(entry 4). Further studies on the stability of compounds 1a and
2a were conducted, and it was found that while compound 1a
shows significant decomposition after a day at room temper-
ature, compound 2a is stable indefinitely.21 In addition, the
reaction provides high yields of 2a as a solid, and the
purification only requires filtration and trituration in ethyl
acetate.
With the optimized conditions in hand, the substrate scope
of S-allyl thioimidate formation was evaluated (Figure 2). We
began by exploring the olefin substitution on the allylic
bromides (R2−R4, 2a−2k). The reaction performed well on
various types of mono-, di-, and trialkyl-substituted olefins (2a−
2d). Electronically poor alkenes cleanly undergo reaction, albeit
with slightly lower isolated yields (2e and 2f). The reaction also
works well for vinyl halides (2g) and similarly for benzylic- and
aromatic-substituted olefins (2h−2k). We also examined the
substrate scope by exploring the nature of the thioamide (R1,
2l−2t, Figure 2). Simple alkylated thioamides (2l) and
electron-rich thioamides provide the desired product in good
yield (2m), whereas electron-poor thioamides give moderate
yields (2n). The reaction also performs well for various
halogenated and heteroaryl thiobenzamides (2o−2q) as well as
heteroaromatic thioamides such as the benzothiophenyl
thioimidate 2r. Finally, we examined the use of alkyl bromides,
providing thioimidates with remote alkenes in moderate yields
(2s and 2t).
RESULTS AND DISCUSSION
■
In order to begin studying the proposed thiazoline synthesis, a
straightforward method for preparing S-allyl thioimidates was
required. Previous methods for accessing these substrates were
scarce, and few provided detailed experimental procedures.19
We began by employing a reported procedure for S-alkyl
thioimidates for the synthesis of our desired allylic substrates.20
Reacting thiobenzamide with 3-chloro-2-methylpropene in
refluxing tetrahydrofuran with base and catalytic tetrabutylam-
monium iodide (TBAI) provided no reaction (Table 1, entries
1 and 2). Employing 3-bromo-2-methylpropene as a more
reactive electrophile also provided no reaction at room
temperature (entry 3) but yielded 16% of the thioimidate
under reflux in tetrahydrofuran (entry 4). The addition of
triethylamine as a basic additive provided higher yield (entry
Table 1. Optimization of S-Allyl Thioimidate 1a
a
entry
X
conditions
yield of 1a (%)
b
1
2
3
4
5
6
7
Cl
Cl
Br
Br
Br
Br
Br
LiHMDS, TBAI (10 mol %), 67 °C, 47 h
NaH, TBAI (10 mol %), 67 °C, 47 h
NaH (1.2 equiv), rt, 96 h
NR
bc
,
NR
NR
b
d
d
With the optimization of starting material complete, and a
panel of substrates in hand, we began our investigations into
thiazoline synthesis. Gratifyingly, treatment of thioimidate 2a
with 2 equiv of N-bromosuccinimide (NBS) in dichloro-
methane at room temperature provided 90% of thiazoline 3a
(Table 3, entry 1). The reaction became dark yellow and was
finished upon addition of NBS. Lowering the equivalents of
KHMDS, 67 °C, 44 h
16
39
Et3N, TBAI (10 mol %), rt, 47 h
Et3N, TBAI (10 mol %), 67 °C, 6 h
Et3N, TBAI (10 mol %), 67 °C, 4 h
e
2
0−55
a
b
c
Isolated yield. Observed by LC-MS. Decomposition observed.
d
e
Reactions did not go to completion. Acidic workup.
B
DOI: 10.1021/acs.joc.7b02299
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
Figure 2. S-Allyl thioimidate substrate scope.
under reverse-phase chromatography, pure thiazoline 3d and
pure thiazine 3d-1 were obtained in 12 and 45% yield,
respectively. The reaction shuts down completely in the
presence of electronically poor olefins. Compounds 3e and 3f
were not observed under the reaction conditions, which gave a
complex mixture consisting of mostly starting material after a
day.22 Further attempts to synthesize 3e, such as performing
the reaction at elevated temperatures, gave similar results. The
reaction also did not work on the vinyl-bromide-containing
substrate 2g. As in the case with substrates 2e and 2f, this
reaction gave mostly starting material after a day, and neither
thiazoline 3g nor the corresponding thiazole was observed. The
reaction works well for benzylic-substituted compounds such as
thiazoline 3h, which was synthesized in 75% yield. This is
significant as it could provide access to certain quaternary-
substituted analogues of thiazoline-containing natural products
that were previously inaccessible with current methods.10 The
cyclization also works well for other aromatic thiazolines such
as 3i and 3j, which were synthesized in 66 and 57% yield,
respectively. Finally, substrate 2k provided thiazoline 3k in 77%
yield with no formation of thiazine observed.
We also examined the substitutions on the left-hand side of
the starting material (R1, 3l−3r, Figure 3). The reaction works
for simple alkyl substrates such as thiazoline 3l, which was
synthesized in 69% yield. Electronically rich substrates such as
the p-methoxy compound 2m provided thiazoline 3m with an
excellent yield of 97%. The reaction also works well on
electronically poor substrates such as the nitro-containing
compound 2n, which provided thiazoline 3n in 81% yield.
Various halogen-substituted aromatic rings were tolerated as
well with chloro- and bromothiazolines 3o and 3p prepared in
81 and 77% yield, respectively. Heteroaryl-containing substrates
are also effective substrates. Thiazole-substituted thiazoline 3q
was synthesized in 90% yield, and benzothiophene-containing
thiazoline 3r was synthesized in 88% yield.
Table 3. Optimization of anti-Diastereoselective Thiazoline
Synthesis
a
b
entry
electrophile
Y
yield of 3a/4a (%)
1
2
3
4
NBS
NBS
NBS
NIS
2
90
90
87
1.1
1
1.1
91
a
b
Reactions were performed on 0.05 g scale at 0.05 M. Isolated yield.
NBS gave thiazoline 3a in similar 90 and 87% yields (entries 2
and 3, respectively). The reaction also works well for forming
iodinated thiazolines. Reacting 2a with 1.1 equiv of N-
iodosuccinimide (NIS) in dichloromethane gave thiazoline 4a
in 91% yield (entry 4). It should be noted, however, that
reacting compound 2a with N-chlorosuccinimide (NCS)
provided bromothiazoline 3a as the only observed product.
The observation that bromide (vs chloride) is incorporated was
surprising and becomes mechanistically important with our
investigations into asymmetric synthesis of thiazolines (vide
infra).
With the optimal conditions in hand, we investigated the
substrate scope of thiazoline formation (Figure 3). We began
by examining the substitutions on the olefin of the substrate
(R2−R4, 3a−3k). Substrates 2a and 2b provided thiazolines 3a
and 3b in 90 and 60% yield, respectively. Substrate 2c gave a
69% overall yield of a mixture of thiazoline 3c and thiazine 3c-
1. After a second purification via reverse-phase chromatog-
raphy, pure thiazoline 3c and thiazine 3c-1 were obtained in 33
and 34% yield, respectively. As in the case with substrate 2c,
thioimidate 2d gave an overall yield of 68% of a mixture of
thiazoline 3d and thiazine 3d-1. After a second purification
Finally, we examined the utility of this reaction on the
substrates that contain extended olefins (2s and 2t, Figure 2).
C
DOI: 10.1021/acs.joc.7b02299
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
Figure 3. Thiazoline substrate scope.
Homoallyl thioimidate 2s was converted to thiazine 3s with a
moderate yield of 42% and no observation of the corresponding
seven-membered thiazepine (Figure 3); however, there was no
observation of either thiazepine or an eight-membered
thiazocine in the case of substrate 2t.
Table 4. Initial Investigations into Asymmetric Synthesis of
3a
We were previously able to demonstrate the utility of these
brominated thiazolines to be displaced with various nucleo-
philes;12 however, we were unable to form a hydroxylated
thiazoline through this route. Because many thiazoline-
containing natural products have an exocyclic oxygen
functionality in this position,3−6,8 we wanted to investigate
this further. It had been reported that oxazoline-containing
neopentyl iodides could be displaced with cesium acetate.23 To
this end, iodinated thiazoline 4a was readily displaced for an
acetate to form compound 5a in 91% yield (Scheme 1).
a
b
entry
X
yield of 3a (%)
% ee
1
2
3
4
2
53
53
53
44
26
44
52
58
Scheme 1. Synthesis of Alcohol-Containing Thiazoline
10
20
50
a
b
Reactions were performed on 0.10 g scale at 0.05 M. Isolated yield.
in the measured selectivity, with the best results achieved at 50
mol % of catalyst, which gave 58% ee (entries 2−4). Although
this is clearly not an optimal catalyst loading, this reaction
provided initial promise for further optimization efforts.
Following our successes in racemic thiazoline synthesis, we
planned to investigate the potential for this reaction to be
rendered asymmetric. There have been numerous reports on
enantioselective synthesis of oxazoline rings through organo-
catalyzed halocyclization of N-allyl amides.24,25 Due to their
high analogy to thiazolines, we initially explored these methods.
When applied to the asymmetric synthesis of thiazolines,
many of the reports for chiral oxazolines gave either no product
or provided racemic thiazolines;24 however, one report by
Borhan and co-workers utilizes the quinine-based catalyst
(DHQD)2PHAL and hydantoin-based halogen electrophiles
and provided moderate yields as well as measurable selectivity
in the synthesis of thiazolines in our initial studies (Table 4).25
Under the originally reported conditions, 2 mol % of catalyst
provided 53% yield and 26% ee of thiazoline 3a (entry 1).
Gradual increases in catalyst loading provided gradual increases
One interesting outcome of the results from Table 4 is the
formation of brominated thiazoline 3a considering that the
electrophilic halogen source was a chlorinated hydantoin. The
chlorinated thiazoline was not observed, and this posed
intriguing mechanistic questions. Bromide is unlikely to
displace a neopentyl chloride at such low temperatures, and
we therefore hypothesized that the bromide of thioimidate 2a
was reacting with the chlorinating agent to form bromine
chloride as the active electrophile. Freebasing compound 2a to
compound 1a and subjecting that to the reaction conditions
with 20 mol % of catalyst provided chlorinated thiazoline 6a
with a 31% jump in enantioselectivity (Scheme 2). To further
explore this hypothesis, tetrabutylammonium bromide was
added to a solution of DCDPH, after which the solution turned
D
DOI: 10.1021/acs.joc.7b02299
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
Scheme 2. Enantioselective Synthesis of Thiazoline 6a from
Thioimidate 1a
Figure 4. Crystal structure of compound 11a.
To examine product stability, we subjected thiazoline 6a to the
reaction conditions and only recovered 24% after 23 h.
Thiazoline 6a was stirred with each individual reagent, and
decomposition was observed to be caused by the chlorinating
agent DCDPH. Furthermore, when compound 7a is added
slowly to the reaction mixture containing DCDPH, only trace
amounts of product are observed. This could be due to the
product decomposition directly as it is formed, leaving only
starting material as DCDPH disappears. Lowering the
equivalents of DCDPH to 1 equiv gave a slight increase in
yield from 37 to 43% (Table 7, entry 1). Adding DCDPH
slowly over time gave another gradual increase in yield to 52%
(Table 7, entry 2).
a deep yellow color, indicating the formation of bromine
chloride, and this resulting mixture displayed effective electro-
philic bromination reactivity.
With these results in hand, we began investigating the
synthesis of thioimidate salts that contained non-nucleophilic
counterions. Protonation of thioimidate 1a with 1 equiv of p-
toluenesulfonic acid (p-TsOH) provided thioimidate 7a.
Subjecting 7a to the reaction conditions with 20 mol % of
catalyst provided 41% yield of thiazoline 6a in 87% ee (Table 5,
Table 5. Synthesis of 6a from Thioimidate 7a
Table 7. Investigations into the Addition Method for
DCDPH
a
b
entry
X
yield of 6a (%)
% ee
1
2
3
4
20
10
5
41
45
37
38
87
87
87
83
2
a
b
entry
DCDPH addition method
no change
four aliquots at 30 min intervals
yield (%)
43
% ee
a
b
Reactions were performed on 0.10 g scale at 0.05 M. Isolated yield.
1
2
83
85
52
entry 1). Lowering the catalyst loading to 10 and 5 mol % gave
no change in selectivity (entries 2 and 3). At 2 mol % of
catalyst, a slight decrease in selectivity to 83% ee was observed
(entry 4).
a
b
Reactions were performed on 0.05 g scale at 0.05 M. Isolated yield.
To ensure that the counterion was no longer having an effect
on the reaction selectivity, a few other thioimidates, including
chiral sulfonate salts were synthesized. Methanesulfonic acid
thioimidate 8a provided similar results to p-TsOH salt 7a,
providing 86% ee (Table 6, entries 1 and 2). Neither
Due to the product decomposition, any inhibition of the
catalyst by the product would slow the reaction rate and allow
for a negative effect on the yield. To probe the interaction of
catalyst and product, an NMR of 1 equiv of catalyst to
thiazoline 3a was compared to an NMR of pure 3a (Figure 5).
The chemical shifts for the two ring protons (blue) were shifted
upfield, indicating that they are shielded by the catalyst. Also,
the splitting of each proton into double doublets is an
indication of a diastereomeric pair formed between the
enantiopure catalyst and the racemic thiazoline. We are
continuing to evaluate the role of product inhibition of the
reaction and exploring a variety of approaches to overcome the
modest yields in the asymmetric processes.
Table 6. Screening of Sulfonate Thioimidate Salts for the
Synthesis of 6a
a
b
entry
X
compound
yield of 6a (%)
% ee
1
2
3
4
p-TsOH
MsOH
7a
8a
37
32
36
87
86
89
86
CONCLUSIONS
■
We have developed an efficient method for synthesizing S-allyl
thioimidate salts through the coupling of thioamides with allyl
bromide derivatives. The reaction has a broad scope tolerating a
variety of substituted olefins as well as alkyl- and
arylthioamides. We have demonstrated the use of these salts
in the rapid and efficient anti-diastereoselective synthesis of
quaternary-substituted thiazolines. The reaction works well for
various alkyl- and aryl-substituted thioimidates but does not
proceed with electron-poor olefins. The initial developments
for an efficient enantioselective synthesis of quaternary-
substituted thiazolines through the organo-catalyzed halocycli-
zation of sulfonate thioimidate salts has also been demon-
strated. Efforts to improve the yield of this reaction are ongoing
(+)-CSA
(−)-CSA
9a
10a
22
b
a
Reactions were done on 0.05 g scale at 0.05 M. Isolated yield.
enantiomer of camphorsulfonic acid ((+)-CSA and (−)-CSA)
salts 9a and 10a showed a matched preference for
enantioselectivity, providing thiazoline 6a in 89 and 86% ee,
respectively (entries 3 and 4). The absolute stereochemistry of
the hydrobromide salt of 6a was obtained though X-ray analysis
(Figure 4).
With the reaction enantioselectivity addressed, we moved on
to investigating possible causes for the modest reaction yields.
E
DOI: 10.1021/acs.joc.7b02299
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
Figure 5. Catalyst complexation with thiazoline 3a.
(neat) νmax 3172, 2916, 1595, 1449, 1267, 936, 861 cm−1; HRMS (ESI,
m/z) calcd for C11H14NS [M − Br]+ 192.0841, found 192.0842.
Allyl Benzimidothioate Hydrobromide (2b): Prepared from
thiobenzamide (1.0 g, 6.9 mmol) and allyl bromide (1.7 g, 14
mmol) according to general procedure A to yield 1.5 g (86%) of 2b as
a white solid; mp 140−142 °C; 1H NMR (400 MHz, CDCl3) δ 12.41
(s, 1H), 11.63 (s, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.65 (t, J = 7.5 Hz,
1H), 7.49 (t, J = 7.6 Hz, 2H), 5.91 (ddt, J = 17, 10, and 6.8 Hz, 1H),
5.61 (dd, J = 17 and 0.9 Hz, 1H), 5.34 (dq, J = 10 and 0.9 Hz, 2H),
4.41 (dt, J = 6.8 and 1.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
187.1, 135.8, 130.0, 129.4, 129.1, 127.9, 122.4, 36.9; IR (neat) νmax
3035, 2907, 1594, 1249, 1120, 947, 865, 698 cm−1; HRMS (ESI, m/z)
calcd for C10H12NS [M − Br]+ 178.0685, found 178.0683.
in our lab along with the use of these functionalized thiazolines
in natural product analogue synthesis.
EXPERIMENTAL SECTION
■
General Considerations. All reactions were performed under a
nitrogen atmosphere. All reagents were purchased through Acros
Organics or Sigma-Aldrich and used as received. However, further
purification of some thioamides was required prior to thioimidate
formation. Reactions were monitored by LC-MS analysis (Shimadzu
LC-MS 2020 with Kinetex 2.6 mm C18 50 × 2.10 mm). Enantiomeric
excess was monitored by chiral HPLC analysis (Shimadzu HPLC with
Lux 5 μm Amylose-2 LC Column 250 × 4.6 mm). Solvent system for
chiral HPLC was as follows: isocratic flow at 40% of a 20 mM solution
of NH4HCO3 in H2O, 60% MeCN, and 0.1% diethylamine. Flash
chromatography on silica gel was used to purify the thiazoline crude
reaction mixtures and performed on a Biotage Isolera utilizing Biotage
cartridges and linear gradients. Melting points were determined by
using a Thomas-Hoover capillary melting point apparatus. IR spectra
(E)-But-2-en-1-yl Benzimidothioate Hydrobromide (2c): Prepared
from thiobenzamide (1.0 g, 6.9 mmol) and crotyl bromide (2.2 g, 14
mmol) according to general procedure A to yield 1.6 g (87%) of 2c as
a white solid; mp 150−152 °C; 1H NMR (400 MHz, CDCl3) δ 12.64
(s, 1H), 11.91 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.63 (t, J = 7.5 Hz,
1H), 7.46 (t, J = 7.5 Hz, 2H), 6.03 (dqt, J = 15, 8.5, and 1.3 Hz, 1H),
5.51 (dtq, J = 15, 7.2, and 1.7 Hz, 1H), 4.35 (dd, J = 7.2 and 1.1 Hz,
2H), 1.67 (dd, J = 6.6 and 1.7 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 187.3, 135.7, 134.6, 130.0, 129.3, 129.0, 120.3, 36.9, 18.0; IR (neat)
νmax 3035, 2899, 1598, 1245, 1120, 974, 865, 698 cm−1; HRMS (ESI,
m/z) calcd for C11H14NS [M − Br]+ 192.0842, found 192.0834.
3-Methylbut-2-en-1-yl Benzimidothioate Hydrobromide (2d):
Prepared from thiobenzamide (1.0 g, 6.9 mmol) and 1-bromo-3-
methyl-2-butene (2.1 g, 14 mmol) according to general procedure A to
1
were recorded on Jasco FT/IR-4100 spectrometer. H (300 or 400
MHz) and 13C NMR (100 MHz) spectra were obtained on a Varian
Mercury-VX 300 or a Varian Mercury-VX 400 instrument. Chemical
shifts were reported in parts per million with the residual solvent peak
used as an internal standard (CDCl3: 1H δ = 7.26 and 13C δ = 77.16).
13C NMR spectra were run at 100 MHz using a proton-decoupling
pulse sequence with a d1 of 0 s unless otherwise noted. High-resolution
mass spectra were obtained on a Thermo Fisher Scientific, Exactive
Plus mass spectrometer (ion trap) using heated electrospray ionization
(HESI).
1
yield 1.7 g (86%) of 2d as a white solid; mp 147−149 °C; H NMR
(400 MHz, CDCl3) δ 12.35 (s, 1H), 11.65 (s, 1H), 8.08 (d, J = 7.4 Hz,
2H), 7.66 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.9 Hz, 2H), 5.31 (tq, J = 8.5
and 1.1 Hz, 1H), 4.39 (d, J = 8.0 Hz, 2H), 1.76 (s, 3H), 1.75 (d, J = 1.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 188.3, 143.1, 135.7, 130.2,
129.4, 129.1, 113.0, 34.1, 25.8, 18.5; IR (neat) νmax 3059, 2915, 1602,
1241, 1124, 865, 846, 698 cm−1; HRMS (ESI, m/z) calcd for
C12H16NS [M − Br]+ 206.0998, found 206.0991.
General Procedure A: Synthesis of S-Allyl Thioimidate
Hydrobromide Salts. Reactions can be performed on multigram
scale (see Supporting Information for experimental details). To a
solution of thioamide derivative in THF (0.5 M) was added allyl
bromide derivative (2 equiv), and the solution was stirred at reflux
until thioamide was consumed. The resulting solid was filtered and
washed with hexanes and EtOAc. If no precipitation was observed, the
solution was concentrated in vacuo. EtOAc was added to the
subsequent oil, and the slurry was sonicated for 5 min. The resulting
white solid was filtered and washed with hexanes and EtOAc. The
solid was dissolved in CHCl3, filtered to remove impurities, and
washed with CHCl3 to obtain pure product.
2-(Trifluoromethyl)allyl Benzimidothioate Hydrobromide (2e):
Prepared from thiobenzamide (1.0 g, 6.9 mmol) and 2-bromometh-
yl-3,3,3-trifluoropropene (2.7 g, 14 mmol) according to general
procedure A to yield 1.3 g (58%) of 2e as a white solid; mp 141−142
°C; 1H NMR (400 MHz, CDCl3) δ 12.51 (s, 1H), 11.92 (s, 1H), 8.07
(d, J = 7.3 Hz, 2H), 7.70 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 2H),
6.28 (s, 1H), 6.04 (s, 1H), 4.70 (s, 2H); 13C NMR (100 MHz, CDCl3)
δ 186.9, 136.4, 130.3, 130.0, 129.7, 129.6, 129.4, 127.2, 127.1, 127.1,
127.0, 33.4; IR (neat) νmax 3062, 2907, 1605, 1168, 1113, 857, 842,
698 cm−1; HRMS (ESI, m/z) calcd for C11H11F3NS [M − Br]+
246.0559, found 246.0551.
2-Methylallyl Benzimidothioate Hydrobromide (2a): Prepared
from thiobenzamide (1.0 g, 6.9 mmol) and 3-bromo-2-methylpropene
(1.9 g, 14 mmol) according to general procedure A to yield 1.7 g
1
(92%) of 2a as a white solid; mp 143−144 °C; H NMR (400 MHz,
CDCl3) δ (ppm) 12.42 (s, 1H), 11.62 (s, 1H), 8.09 (d, J = 8.1 Hz,
2H), 7.67 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.7 Hz, 2H), 5.26 (s, 1H),
5.07 (s, 1H), 4.40 (s, 2H), 1.90 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 187.7, 135.9, 135.9, 130.1, 129.5, 129.1, 118.1, 41.5, 21.9; IR
2-(Methylcarboxylate)allyl Benzimidothioate Hydrobromide (2f):
Prepared from thiobenzamide (0.069 g, 0.48 mmol) and methyl-2-
(bromomethyl)acrylate (0.18 g, 0.96 mmol) according to general
F
DOI: 10.1021/acs.joc.7b02299
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
procedure A to yield 0.096 g (64%) of 2f as a white solid; mp 126−
127 °C; 1H NMR (400 MHz, CDCl3) δ 12.38 (s, 1H), 11.83 (s, 1H),
8.09 (d, J = 7.3 Hz, 2H), 7.70 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 8.2 Hz,
2H), 6.57 (s, 1H), 6.49 (s, 1H), 4.73 (s, 2H), 3.82 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 187.4, 165.7, 136.1, 132.5, 132.3, 130.1, 129.6,
129.3, 52.7, 35.2; IR (neat) νmax 2950, 1721, 1605, 1442, 1337, 1206,
1144, 761, 702 cm−1; HRMS (ESI, m/z) calcd for C12H14NO2S [M −
Br]+ 236.0740, found 236.0732.
2-Bromoallyl Benzimidothioate Hydrobromide (2g): Prepared
from thiobenzamide (1.0 g, 6.9 mmol) and 2,3-dibromopropene (3.5
g, 14 mmol) according to general procedure A to yield 1.7 g (75%) of
2g as a white solid; mp 142−143 °C; 1H NMR (400 MHz, CDCl3) δ
12.49 (s, 1H), 11.79 (s, 1H), 8.13 (d, J = 7.4 Hz, 2H), 7.72 (t, J = 7.5
Hz, 1H), 7.57 (d, J = 7.6 Hz, 2H), 6.51 (t, J = 2.3 Hz, 1H), 5.76 (d, J =
2.3 Hz, 1H), 4.89 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 186.7,
136.4, 130.0, 129.7, 129.6, 125.2, 122.6, 44.4; IR (neat) νmax 2915,
1598, 1276, 1195, 1124, 865, 698 cm−1; HRMS (ESI, m/z) calcd for
C10H11BrNS [M − Br]+ 255.9790, found 255.9783.
191.4, 135.5, 117.5, 40.2, 24.0, 21.5; IR (neat) νmax 2923, 2652, 2574,
1656, 1602, 1423, 1377, 1287, 857 cm−1; HRMS (ESI, m/z) calcd for
C6H12NS [M − Br]+ 130.0685, found 130.0683.
2-Methylallyl 4-Methoxybenzimidothioate Hydrobromide (2m):
Prepared from 4-methoxythiobenzamide (0.75 g, 4.4 mmol) and 3-
bromo-2-methylpropene (1.2 g, 8.7 mmol) according to general
procedure A to yield 1.1 g (86%) of 2m as a white solid; mp 170−173
°C; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 9.0 Hz, 2H), 7.19 (d, J
= 9.0 Hz, 2H), 5.25 (s, 1H), 5.15 (s, 1H), 4.87 (s, 2H), 4.15 (s, 2H),
3.94 (s, 3H), 1.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 189.4,
167.7, 138.2, 132.1, 123.9, 117.7, 116.3, 56.7, 40.6, 21.7; IR (neat) νmax
3182, 2965, 1671, 1604, 1501, 1278, 1185, 1013, 836 cm−1; HRMS
(ESI, m/z) calcd for C12H16NOS [M − Br]+ 222.0947, found
222.0946.
2-Methylallyl 4-Nitrobenzimidothioate Hydrobromide (2n): Pre-
pared from 4-nitrothiobenzamide (0.60 g, 3.2 mmol) and 3-bromo-2-
methylpropene (0.89 g, 6.4 mmol) according to general procedure A
1
to yield 0.59 g (58%) of 2n as a white solid; mp 152−155 °C; H
2-(4-Bromobenzyl)allyl Benzimidothioate Hydrobromide (2h):
Prepared from thiobenzamide (0.027 g, 0.19 mmol) and 3-bromo-2-
(4-bromobenzyl)propene (0.12 g, 0.19 mmol) according to general
procedure A to yield 0.048 g (60%) of 2h as a white solid; mp 105−
106 °C; 1H NMR (400 MHz, CDCl3) δ 12.45 (s, 1H), 11.62 (s, 1H),
8.03 (d, J = 8.5 Hz, 2H), 7.70 (t, J = 7.7 Hz, 1H), 7.53 (t, J = 7.3 Hz,
2H), 7.41 (d, J = 8.3 2H), 7.12 (d, J = 8.5 2H), 5.46 (s, 1H), 5.08 (s,
1H), 4.41 (s, 2H), 3.53 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
187.5, 139.3, 136.7, 136.0, 131.9, 131.1, 130.1, 129.6, 129.2, 120.8,
119.0, 41.6, 39.2; IR (neat) νmax 3387, 2915, 1598, 1487, 1276, 1070,
1011, 700 cm−1; HRMS (ESI, m/z) calcd for C17H17BrNS [M − Br]+
346.0260, found 346.0268.
NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.7 Hz, 2H), 8.24 (d, J = 8.7
Hz, 2H), 5.30 (s, 1H), 5.14 (s, 1H), 4.44 (s, 2H), 1.92 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 186.7, 151.6, 135.3, 135.1, 130.5, 124.4,
118.8, 42.2, 21.9; IR (neat) νmax 3055, 2815, 1619, 1526, 1347, 848,
726, 691 cm−1; HRMS (ESI, m/z) calcd for C11H13N2O2S [M − Br]+
237.0692, found 237.0690.
2-Methylallyl 4-Chlorobenzimidothioate Hydrobromide (2o):
Prepared from 4-chlorothiobenzamide (0.50 g, 2.8 mmol) and 3-
bromo-2-methylpropene (0.79 g, 5.7 mmol) according to general
procedure A to yield 0.75 g (86%) of 2o as a white solid; mp 165−166
°C; 1H NMR (400 MHz, CDCl3) δ 12.47 (s, 1H), 11.67 (s, 1H), 8.06
(d, J = 8.9 Hz, 2H), 7.50 (d, J = 8.9 Hz, 2H), 5.27 (s, 1H), 5.09 (s,
1H), 4.40 (s, 2H), 1.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
186.7, 142.8, 135.8, 130.5, 129.9, 128.4, 118.4, 41.7, 21.9; IR (neat)
νmax 3082, 2973, 1590, 1485, 1404, 1233, 1128, 1093, 876, 838 cm−1;
HRMS (ESI, m/z) calcd for C11H13ClNS [M − Br]+ 226.0452, found
226.0446.
2-Methylallyl 4-Bromobenzimidothioate Hydrobromide (2p):
Prepared from 4-bromothiobenzamide (0.50 g, 2.2 mmol) and 3-
bromo-2-methylpropene (0.62 g, 4.5 mmol) according to general
procedure A to yield 0.63 g (80%) of 2p as a white solid; mp 162−164
°C; 1H NMR (400 MHz, CDCl3) δ 12.46 (s, 1H), 11.68 (s, 1H), 7.97
(d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 5.26 (s, 1H), 5.09 (s,
1H), 4.39 (s, 2H), 1.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
186.9, 135.7, 132.9, 131.6, 130.5, 128.8, 118.4, 41.7, 21.9; IR (neat)
νmax 3031, 2973, 1602, 1586, 1481, 1396, 1117, 1070, 1009, 729 cm−1;
HRMS (ESI, m/z) calcd for C11H13BrNS [M − Br]+ 269.9947, found
269.9941.
2-Phenylallyl Benzimidothioate Hydrobromide (2i): Prepared
from thiobenzamide (0.58 g, 4.0 mmol) and 2,3-dibromopropene
(1.6 g, 8.1 mmol) according to general procedure A to yield 1.2 g
1
(91%) of 2i as a white solid; mp 154−155 °C; H NMR (400 MHz,
CDCl3) δ 12.50 (s, 1H), 11.86 (s, 1H), 8.05 (d, J = 7.7 Hz, 2H), 7.67
(t, J = 7.5 Hz, 1H), 7.52−7.49 (m, 4H), 7.38−7.33 (m, 3H), 5.72 (s,
1H), 5.68 (s, 1H), 4.97 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
187.8, 139.1, 137.6, 136.0, 130.1, 129.5, 129.3, 128.9, 128.8, 126.4,
120.0, 40.2; IR (neat) νmax 2915, 1598, 1446, 1241, 1128, 869, 780,
698 cm−1; HRMS (ESI, m/z) calcd for C16H16NS [M − Br]+
254.0998, found 254.0990.
2-(Naphthalen-2-yl)allyl Benzimidothioate Hydrobromide (2j):
Prepared from thiobenzamide (0.19 g, 1.3 mmol) and 3-bromo-2-
(naphthalen-2-yl)propene (0.34 g, 1.3 mmol) according to general
procedure A to yield 0.36 g (70%) of 2j as a white solid; mp 168−169
°C; 1H NMR (400 MHz, DMSO) δ 12.01 (s, 1H), 8.20 (s, 1H), 7.96−
7.94 (m, 3H), 7.85−7.79 (m, 4H), 7.76−7.53 (m, 4H), 5.96 (s, 1H),
5.77 (s, 1H), 4.88 (s, 2H); 13C NMR (100 MHz, DMSO) δ 186.9,
138.9, 135.3, 134.4, 132.9, 132.7, 131.0, 129.5, 128.4, 128.3, 128.3,
127.5, 126.7, 126.6, 125.2, 124.0, 119.1, 37.0; IR (neat) νmax 3047,
2861, 1613, 1591, 1445, 1276, 1231, 1126, 920, 870, 826 cm−1; HRMS
(ESI, m/z) calcd for C20H18NS [M − Br]+ 304.1155, found 304.1156.
3-Phenylallyl Benzimidothioate Hydrobromide (2k). Prepared
from thiobenzamide (0.50 g, 3.5 mmol) and cinnamyl bromide (1.4 g,
6.9 mmol) according to general procedure A to yield 1.1 g (98%) of 2k
2-Methylallyl 4-(2-Methylthiazol-4-yl)benzimidothioate Hydro-
bromide (2q): Prepared from 4-(2-methyl-4-thiazolyl)thiobenzamide
(0.50 g, 2.1 mmol) and 3-bromo-2-methylpropene (0.59 g, 4.3 mmol)
according to general procedure A to yield 0.69 g (88%) of 2q as a
1
white solid; mp 165−166 °C; H NMR (400 MHz, DMSO) δ 11.85
(s, 1H), 8.35 (s, 1H), 8.34 (d, J = 8.3 Hz, 2H), 8.01 (d, J = 8.4 Hz,
2H), 5.23 (s, 1H), 5.07 (s, 1H), 4.24 (s, 2H), 2.73 (s, 3H), 1.87 (s,
3H); 13C NMR (100 MHz, DMSO) δ 186.7, 166.9, 152.1, 140.8,
137.6, 130.0, 129.8, 126.9, 118.7, 117.0, 39.4, 21.8, 19.4; IR (neat) νmax
3066, 2915, 1412, 1268, 1172, 846, 714 cm−1; HRMS (ESI, m/z) calcd
for C15H17N2S2 [M − Br]+ 289.0828, found 289.0823.
1
as a white solid; mp 178−179 °C; H NMR (400 MHz, CDCl3) δ
12.37 (s, 1H), 11.84 (s, 1H), 8.12 (d, J = 7.9 Hz, 2H), 7.67 (t, J = 7.5
Hz, 1H), 7.52 (t, J = 8.0 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.30−7.24
(m, 3H), 6.94 (d, J = 16 Hz, 1H), 6.26 (dt, J = 16 and 7.4 Hz, 1H)
4.64 (d, J = 7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 187.3, 137.5,
135.9, 135.6, 130.0, 129.5, 129.2, 128.7, 128.5, 126.7, 118.5, 37.5; IR
(neat) νmax 3055, 3028, 2915, 1598, 1446, 1272, 1233, 1124, 698 cm−1;
HRMS (ESI, m/z) calcd for C16H16NS [M − Br]+ 254.0998, found
254.0992.
2-Methylallyl Benzo[b]thiophene-3-carbimidothioate Hydrobro-
mide (2r): Prepared from 1-benzothiophene-3-carbothioamide (0.51 g,
2.6 mmol) and 3-bromo-2-methylpropene (0.74 g, 5.3 mmol)
according to general procedure A to yield 0.60 g (69%) of 2r as a
white solid; mp 143−144 °C; 1H NMR (400 MHz, CDCl3) δ 12.34 (s,
1H), 11.59 (s, 1H), 8.92 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 7.89 (d, J =
8.2 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 5.32 (s,
1H), 5.13 (s, 1H), 4.46 (s, 2H), 1.96 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 180.9, 140.8, 139.5, 136.0, 134.6, 126.5, 126.2, 126.2, 123.6,
123.3, 118.4, 41.9, 22.0; IR (neat) νmax 3086, 2899, 1586, 1480, 1420,
1254, 1235, 1070, 815, 764 cm−1; HRMS (ESI, m/z) calcd for
C13H14NS2 [M − Br]+ 248.0562, found 248.0561.
2-Methylallyl Ethanimidothioate Hydrobromide (2l): Prepared
from thioacetamide (0.50 g, 6.5 mmol) and 3-bromo-2-methylpropene
(1.8 g, 13 mmol) according to general procedure A to yield 1.0 g
1
(75%) of 2l as a white solid; mp 114−116 °C; H NMR (400 MHz,
CDCl3) δ 12.28 (s, 1H), 11.23 (s, 1H), 5.11 (s, 1H), 4.94 (s, 1H), 4.05
(s, 2H), 2.64 (s, 3H), 1.75 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
G
DOI: 10.1021/acs.joc.7b02299
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
But-3-en-1-yl Benzimidothioate Hydrobromide (2s): Prepared
from thiobenzamide (0.75 g, 5.2 mmol) and 4-bromo-1-butene (1.4 g,
10 mmol) according to general procedure A to yield 0.69 g (49%) of
2s as a white solid; mp 143−145 °C; 1H NMR (400 MHz, CDCl3) δ
12.35 (s, 1H), 11.67 (s, 1H), 8.04 (d, J = 7.4 Hz, 2H), 7.64 (t, J = 7.5
Hz, 1H), 7.48 (t, J = 8.0 Hz, 2H), 5.83 (ddt, J = 17, 10, and 6.7 Hz,
1H), 5.17 (dd, J = 17 and 1.4 Hz, 1H), 5.11 (dd, J = 10 and 1.2 Hz,
1H), 3.78 (t, J = 6.8 Hz, 2H), 2.58 (dt, J = 6.7 and 6.7 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 187.9, 135.7, 133.9, 130.2, 129.3, 128.9,
118.5, 33.8, 31.3; IR (neat) νmax 3051, 2853, 1594, 1446, 1405,
1273,1231, 1123, 866, 703 cm−1; HRMS (ESI, m/z) calcd for
C11H14NS [M − Br]+ 192.0842, found 192.0839.
(d, J = 8.4 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 8.4 Hz, 2H),
4.47−4.37 (m, 2H), 3.70 (dd, J = 13 and 3.3 Hz, 1H), 3.54 (ddd, J =
13, 7.1, and 1.3 Hz, 1H), 1.60 (d, J = 6.6 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 133.7, 129.3, 128.9, 127.6, 57.3, 43.1, 32.7, 20.9; IR
(neat) νmax 3060, 2927, 1673, 1605, 1425, 1202, 1130, 765, 687 cm−1;
HRMS (ESI, m/z) calcd for C11H13BrNS [M + H]+ 269.9947, found
269.9942.
4-(2-Bromopropan-2-yl)-2-phenyl-4,5-dihydrothiazole (3d):12
Prepared from 2d (0.10 g, 0.35 mmol) and NBS (0.069 g, 0.38
mmol) according to general procedure B and purified (hexanes/
EtOAc: 98/2) to yield 0.068 g (68%) of a mixture of 3d and 3d-1.
Further purification was accomplished by reverse-phase chromatog-
raphy (gradient of 10% to 65% MeCN in H2O) to yield 0.012 g (12%)
of 3d as a clear oil and 0.045 g (45%) of 3d-1 as a white solid. For
Pent-4-en-1-yl Benzimidothioate Hydrobromide (2t): Prepared
from thiobenzamide (0.75 g, 5.2 mmol) and 5-bromo-1-pentene (1.6
g, 10 mmol) according to general procedure A to yield 0.73 g (49%) of
1
compound 3d: H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.3 Hz,
1
2t as a white solid; mp 131−132 °C; H NMR (400 MHz, CDCl3) δ
2H), 7.49 (t, J = 6.9 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 4.79 (t, J = 9.1
Hz, 1H), 3.63 (dd, J = 9.7 and 7.4 Hz, 1H), 3.58 (dd, J = 8.1 and 5.9
Hz, 1H), 1.98 (s, 3H), 1.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
132.0, 129.1, 128.7, 126.7, 68.9, 35.9, 33.1, 30.4, 25.8; IR (neat) νmax
3028, 2925, 1606, 1578, 1490, 1447, 1106, 992, 942, 766, 689 cm−1;
HRMS (ESI, m/z) calcd for C12H15BrNS [M + H]+ 284.0103, found
12.37 (s, 1H), 11.64 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.64 (t, J = 7.5
Hz, 1H), 7.49 (t, J = 8.0 Hz, 2H), 5.75 (ddt, J = 17, 10, and 6.7 Hz,
1H), 5.05 (dd, J = 17 and 1.5 Hz, 1H), 4.99 (dt, J = 10 and 1.2 Hz,
2H), 3.69 (t, J = 7.2 Hz, 2H), 2.27 (dt, J = 7.3 and 7.3 Hz, 2H), 1.91
(p, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 187.9, 136.3,
135.6, 130.2, 129.3, 128.9, 116.5, 33.6, 32.1, 26.6; IR (neat) νmax 3442,
3055, 2919, 1594, 1265, 845, 699 cm−1; HRMS (ESI, m/z) calcd for
C12H16NS [M − Br]+ 206.0998, found 206.0994.
1
284.0097. For compound 3d-1: mp 44−47 °C; H NMR (400 MHz,
CDCl3) δ 7.75 (d, J = 8.2 Hz, 2H), 7.44−7.35 (m, 3H), 4.35 (dd, J =
10 and 4.2 Hz, 1H), 3.61 (dd, J = 13 and 10 Hz, 1H), 3.50 (dd, J = 13
and 4.2 Hz, 1H), 1.53 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 154.5, 138.8, 130.6, 128.5, 126.6, 56.4, 54.2, 31.5, 30.2, 24.4;
IR (neat) νmax 3028, 2980, 1596, 1577, 1443, 1422, 1306, 1235, 1209,
947, 921, 766, 691 cm−1; HRMS (ESI, m/z) calcd for C12H15BrNS [M
+ H]+ 284.0103, found 284.0099.
General Procedure B: anti-Diastereoselective Synthesis of 2-
Thiazolines. S-Allyl thioimidate hydrobromide salt was dissolved in
CH2Cl2 (0.05 M). NBS (1.1 equiv) was added, and the solution turned
orange. The reaction was complete upon addition of NBS, quenched
with Na2S2O3, and extracted with CH2Cl2 (×3). The combined
organic layers were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The crude residue was purified by flash
chromatography on silica gel.
4-(4-Bromobenzyl)-4-(bromomethyl)-2-phenyl-4,5-dihydrothia-
zole (3h): Prepared from 2h (0.043 g, 0.099 mmol) and NBS (0.020 g,
0.11 mmol) according to general procedure B and purified (hexanes/
4-(Bromomethyl)-4-methyl-2-phenyl-4,5-dihydrothiazole (3a):12
Prepared from 2a (0.05 g, 0.18 mmol) and NBS (0.036 g, 0.20 mmol)
according to general procedure B and purified (hexanes/EtOAc: 98/2)
1
EtOAc: 96/4) to yield 0.032 g (75%) of 3h as a clear oil; H NMR
(400 MHz, CDCl3) δ 7.80 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.3 Hz,
1H), 7.44−7.41 (m, 4H), 7.23 (d, J = 8.3 Hz, 2H), 3.59 (d, J = 11 Hz,
1H), 3.54 (s, 2H), 3.26 (d, J = 11 Hz, 1H), 3.20 (d, J = 14 Hz, 1H),
3.12 (d, J = 14 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 135.4, 133.8,
132.6, 131.8, 131.3, 128.7, 128.5, 121.0, 84.7, 42.7, 40.2, 38.4; IR
(neat) νmax 3062, 2923, 1594, 1488, 1445, 1258, 1072, 1012, 942, 766,
689 cm−1; HRMS (ESI, m/z) calcd for C17H16Br2NS [M + H]+
423.9365, found 423.9374.
4-(Bromomethyl)-2,4-diphenyl-4,5-dihydrothiazole (3i): Prepared
from 2i (0.10 g, 0.30 mmol) and NBS (0.059 g, 0.33 mmol) according
to general procedure B and purified (hexanes/EtOAc: 96/4) to yield
0.065 g (66%) of 3i as a clear oil; 1H NMR (400 MHz, CDCl3) δ 7.96
(d, J = 7.1 Hz, 2H), 7.57 (d, J = 7.2 Hz, 1H), 7.51−7.45 (m, 3H), 7.39
(t, J = 7.4 Hz, 2H), 7.32 (t, J = 7.3 Hz, 2H), 4.03 (d, J = 11 Hz, 1H),
3.95 (d, J = 10 Hz, 1H), 3.83 (d, J = 10 Hz, 1H), 3.71 (d, J = 11 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 143.4, 133.1, 131.7, 128.7,
128.7, 128.6, 128.1, 126.3, 86.6, 41.9, 41.9; IR (neat) νmax 3060, 2956,
1606, 1575, 1492, 1447, 1031, 942, 767, 690 cm−1; HRMS (ESI, m/z)
calcd for C16H15BrNS [M + H]+ 332.0103, found 332.0099.
1
to yield 0.045 g (90%) of 3a as a clear oil; H NMR (400 MHz,
CDCl3) δ 7.82 (d, J = 6.8 Hz, 2H), 7.50−7.37 (m, 3H), 3.66 (d, J = 10
Hz, 1H), 3.62 (d, J = 11 Hz, 1H), 3.60 (d, J = 10 Hz, 1H), 3.18 (d, J =
11 Hz, 1H), 1.59 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.6,
133.2, 131.6, 128.6, 128.5, 81.9, 41.7, 40.5, 24.9.
4-(Bromomethyl)-2-phenyl-4,5-dihydrothiazole (3b): Prepared
from 2b (0.10 g, 0.39 mmol) and NBS (0.077 g, 0.43 mmol)
according to general procedure B and purified (hexanes/EtOAc: 95/5)
1
to yield 0.059 g (60%) of 3b as a clear oil; H NMR (400 MHz,
CDCl3) δ 7.83 (d, J = 7.0 Hz, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7.42 (t, J =
7.7 Hz, 2H), 5.00 (tdd, J = 8.4, 7.1, and 3.9 Hz, 1H), 3.76 (dd, J = 10
and 3.9 Hz, 1H), 3.58 (dd, J = 11 and 8.5 Hz, 1H), 3.57 (dd, J = 10
and 8.3 Hz, 1H), 3.44 (dd, J = 11 and 7.1 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 132.9, 131.8, 128.7, 128.6, 77.9, 36.8, 34.3; IR (neat)
νmax 3060, 2958, 1604, 1576, 1490, 1446, 1244, 1014, 942, 767, 690,
607 cm−1; HRMS (ESI, m/z) calcd for C10H11BrNS [M + H]+
255.9790, found 255.9788.
4-(1-Bromoethyl)-2-phenyl-4,5-dihydrothiazole (3c): Prepared
from 2c (0.10 g, 0.37 mmol) and NBS (0.073 g, 0.40 mmol)
according to general procedure B and purified (hexanes/EtOAc: 97/3)
to yield 0.068 g (69%) of a mixture of 3c and 3c-1. Further purification
was accomplished by reverse-phase chromatography (gradient of 10%
to 90% MeCN in H2O) to yield 0.033 g (33%) of 3c as a clear oil and
0.034 g (34%) of 3c-1 as a clear oil. In this reaction, the starting
material contains a small amount of the cis-alkene, which leads to a
small amount of the corresponding minor diastereomer and these
4-(Bromomethyl)-4-(naphthalen-2-yl)-2-phenyl-4,5-dihydrothia-
zole (3j): Prepared from 2j (0.10 g, 0.26 mmol) and NBS (0.051 g,
0.29 mmol) according to general procedure B and purified (hexanes/
1
EtOAc: 96/4) to yield 0.057 g (57%) of 3j as a clear oil; H NMR
(400 MHz, CDCl3) δ 8.03−7.99 (m, 3H), 7.89−7.83 (m, 3H), 7.67
(dd, J = 8.6 and 1.8 Hz, 1H), 7.55−7.45 (m, 5H), 4.10 (d, J = 11 Hz,
1H), 4.03 (d, J = 10 Hz, 1H), 3.94 (d, J = 10 Hz, 1H), 3.83 (d, J = 11
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 140.6, 133.2, 133.1, 133.0,
131.8, 128.8, 128.7, 128.5, 128.5, 127.7, 126.5, 126.4, 125.4, 124.3,
86.8, 41.9, 41.7; IR (neat) νmax 3057, 1601, 1490, 1446, 1257, 1243,
1036, 942, 768, 750, 690 cm−1; HRMS (ESI, m/z) calcd for
C20H17BrNS [M + H]+ 382.0260, found 382.0258.
4-(Bromo(phenyl)methyl)-2-phenyl-4,5-dihydrothiazole (3k): Pre-
pared from 2k (0.10 g, 0.30 mmol) and NBS (0.059 g, 0.33 mmol)
according to general procedure B; the reaction was filtered and washed
with hexanes and EtOAc to yield 0.077 g (77%) of 3k as a white solid;
mp 203−205 °C; 1H NMR (400 MHz, DMSO) δ 7.84 (d, J = 7.0 Hz,
2H), 7.69 (t, J = 6.8 Hz, 1H), 7.59 (t, J = 7.5 Hz, 2H), 7.47−7.40 (m,
1
compounds are not readily separable. For compound 3c: H NMR
(400 MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 2H), 7.50 (t, J = 7.6 Hz,
1H), 7.43 (t, J = 7.6 Hz, 2H), 4.83 (td, J = 8.6 and 6.5 Hz, 1H), 4.51
(p, J = 6.8 Hz, 1H), 3.60 (dd, J = 11 and 8.9 Hz, 1H), 3.50 (dd, J = 11
and 8.3 Hz, 1H), 1.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 132.1,
131.9, 128.8, 128.7, 82.6, 52.7, 36.1, 24.0; IR (neat) νmax 3028, 2926,
1670, 1604, 1577, 1491, 1445, 1190, 1000, 768, 690 cm−1; HRMS
(ESI, m/z) calcd for C11H13BrNS [M + H]+ 269.9947, found
1
269.9942. For compound 3c-1: H NMR (400 MHz, CDCl3) δ 7.80
H
DOI: 10.1021/acs.joc.7b02299
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
5H), 5.50 (d, J = 5.6 Hz, 1H), 5.08−5.03 (m, 1H), 3.75 (dd, J = 14
and 6.9 Hz, 1H), 3.56 (dd, J = 14 and 3.1 Hz, 1H); 13C NMR (100
MHz, DMSO) δ 138.7, 133.3, 129.2, 128.9, 128.6, 127.5, 127.0, 126.2,
64.1, 44.3, 32.0; IR (neat) νmax 1591, 1568, 1409, 1225, 1017, 795, 761,
743, 701 cm−1; HRMS (ESI, m/z) calcd for C16H15BrNS [M + H]+
332.0103, found 332.0110.
4-(Bromomethyl)-2,4-dimethyl-4,5-dihydrothiazole (3l): Prepared
from 2l (0.10 g, 0.48 mmol) and NBS (0.094 g, 0.52 mmol) according
to general procedure B and purified (hexanes/EtOAc: 88/12) to yield
0.068 g (69%) of 3l as a clear oil; 1H NMR (400 MHz, CDCl3) δ 3.55
(d, J = 10 Hz, 1H), 3.51 (d, J = 12 Hz, 1H), 3.48 (d, J = 10 Hz, 1H),
3.06 (d, J = 11 Hz, 1H), 2.19 (s, 3H), 1.46 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 166.9, 81.5, 42.8, 40.6, 24.9, 20.5; IR (neat) νmax 3229,
2929, 1623, 1434, 1371, 1150, 785, 671 cm−1; HRMS (ESI, m/z) calcd
for C6H11BrNS [M + H]+ 207.9790, found 207.9790.
4-(Bromomethyl)-2-(4-methoxyphenyl)-4-methyl-4,5-dihydro-
thiazole (3m): Prepared from 2m (0.10 g, 0.33 mmol) and NBS
(0.065 g, 0.36 mmol) according to general procedure B and purified
(hexanes/EtOAc: 92/8) to yield 0.057 g (97%) of 3m as a clear oil; 1H
NMR (400 MHz, CDCl3) δ 7.76 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.0
Hz, 2H), 3.84 (s, 3H), 3.63 (d, J = 10 Hz, 1H), 3.59 (d, J = 11 Hz,
1H), 3.58 (d, J = 10 Hz, 1H), 3.15 (d, J = 11 Hz, 1H), 1.58 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 162.3, 130.2, 125.9, 113.9, 81.7, 55.6,
2-(Benzo[b]thiophen-3-yl)-4-(bromomethyl)-4-methyl-4,5-dihy-
drothiazole (3r): Prepared from 2r (0.10 g, 0.30 mmol) and NBS
(0.060 g, 0.34 mmol) according to general procedure B and purified
(hexanes/EtOAc: 96/4) to yield 0.087 g (88%) of 3r as a clear oil; 1H
NMR (400 MHz, CDCl3) δ 8.72 (ddd, J = 8.1, 1.3, and 0.64 Hz, 1H),
7.94 (s, 1H), 7.85 (ddt, J = 7.8, 1.2, and 0.62 Hz, 1H), 7.47 (td, J = 8.0
and 1.2 Hz, 1H), 7.41 (td, J = 7.8 and 1.4 Hz, 1H), 3.72 (d, J = 10 Hz,
1H), 3.68 (d, J = 10 Hz, 1H), 3.59 (d, J = 11 Hz, 1H), 3.16 (d, J = 11
Hz, 1H), 1.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 140.3, 136.5,
133.1, 125.5, 125.4, 122.5, 41.0, 40.5, 25.0; IR (neat) νmax 3064, 2928,
1594, 1497, 1459, 1424, 1117, 880, 759 cm−1; HRMS (ESI, m/z) calcd
for C13H13BrNS2 [M + H]+ 325.9667, found 325.9665.
4-(Bromomethyl)-2-phenyl-5,6-dihydro-4H-1,3-thiazine (3s): Pre-
pared from 2s (0.10 g, 0.37 mmol) and NBS (0.073 g, 0.40 mmol)
according to general procedure B and purified (hexanes/EtOAc: 96/4)
1
to yield 0.042 g (42%) of 3s as a clear oil; H NMR (400 MHz,
CDCl3) δ 7.81 (dd, J = 8.2 and 1.4 Hz, 2H), 7.45−7.36 (m, 3H),
3.84−3.79 (m, 2H), 3.57 (dd, J = 11 and 8.6 Hz, 1H), 3.25 (td, J = 12
and 4.3 Hz, 1H), 3.12 (dt, J = 12 and 4.5 Hz, 1H), 2.32 (ddd, J = 14,
7.6, and 4.5 Hz, 1H), 1.68 (dddd, J = 14, 12, 9.3, and 4.3 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 159.9, 139.1, 130.7, 128.4, 126.6, 57.8,
38.0, 25.6, 23.0; IR (neat) νmax 3449, 3059, 2956, 2848, 1603, 1576,
1444, 1309, 1287, 1229, 936 cm−1; HRMS (ESI, m/z) calcd for
C11H13BrNS [M + H]+ 269.9947, found 269.9951.
41.7, 40.4, 24.9; IR (neat) νmax 2969, 2838, 1606, 1509, 1308, 1254,
1172, 1033, 962, 836 cm−1; HRMS (ESI, m/z) calcd for
C12H15BrNOS [M + H]+ 300.0052, found 300.0059.
4-(Iodomethyl)-4-methyl-2-phenyl-4,5-dihydrothiazole (4a): Thi-
oimidate 2a (0.050 g, 0.18 mmol) was dissolved in CH2Cl2 (3.6 mL).
NIS (0.046 g, 0.20 mmol)) was added, and the solution turned orange.
The reaction was complete upon addition of NIS, quenched with
Na2S2O3, and extracted with CH2Cl2 (×3). The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated in
vacuo. The crude residue was purified by flash chromatography over
silica gel (hexanes/EtOAc: 97/3) to yield 0.053 g (91%) of 4a as a
4-(Bromomethyl)-4-methyl-2-(4-nitrophenyl)-4,5-dihydrothiazole
(3n): Prepared from 2n (0.10 g, 0.32 mmol) and NBS (0.062 g, 0.35
mmol) according to general procedure B and purified (hexanes/
EtOAc: 92/8) to yield 0.080 g (81%) of 3n as a white solid; mp 65−66
°C; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 9.0 Hz, 2H), 7.96 (d, J
= 9.0 Hz, 2H), 3.68 (d, J = 11 Hz, 3H), 3.68 (d, J = 10 Hz, 1H), 3.60
(d, J = 10 Hz, 1H), 3.25 (d, J = 11 Hz, 1H), 1.58 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 165.4, 149.5, 138.6, 129.4, 123.7, 82.4, 42.2,
40.3, 24.8; IR (neat) νmax 3066, 2929, 1585, 1521, 1346, 966, 855, 688
cm−1; HRMS (ESI, m/z) calcd for C11H12BrN2O2S [M + H]+
314.9797, found 314.9795.
1
clear oil: H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 6.7 Hz, 2H),
7.50−7.37 (m, 3H), 3.55 (d, J = 10 Hz, 1H), 3.54 (d, J = 11 Hz, 1H),
3.48 (d, J = 10 Hz, 1H), 3.20 (d, J = 11 Hz, 1H), 1.61 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 167.0, 133.2, 131.5, 128.6, 128.5, 81.1,
43.1, 26.0, 16.9; IR (neat) νmax 3060, 2926, 1593, 1576, 1446, 689
cm−1; HRMS (ESI, m/z) calcd for C11H13INS [M + H]+ 317.9808,
found 317.9805.
4-(Bromomethyl)-2-(4-chlorophenyl)-4-methyl-4,5-dihydrothia-
zole (3o): Prepared from 2o (0.10 g, 0.33 mmol) and NBS (0.065 g,
0.36 mmol) according to general procedure B and purified (hexanes/
(4-Methyl-2-phenyl-4,5-dihydrothiazol-4-yl)methyl Acetate (5a):
Thiazoline 4a (0.027 g, 0.085 mmol) was dissolved in DMF (0.23
mL). Cesium acetate (0.082 g, 0.43 mmol) was added, and the
solution was stirred at room temperature for 24 h. The reaction was
brought to room temperature, quenched with H2O, and extracted with
EtOAc (×3). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated in vacuo. The crude residue was
purified by flash chromatography over silica gel (hexanes/EtOAc: 90/
1
EtOAc: 95/5) to yield 0.081 g (81%) of 3o as a clear oil; H NMR
(400 MHz, CDCl3) δ 7.75 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.8 Hz,
2H), 3.64 (d, J = 10 Hz, 1H), 3.63 (d, J = 11 Hz, 1H), 3.59 (d, J = 10
Hz, 1H), 3.19 (d, J = 11 Hz, 1H), 1.58 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 137.7, 131.6, 129.8, 128.9, 82.0, 41.9, 40.4, 24.8; IR (neat)
νmax 3055, 2973, 1598, 1488, 1399, 1271, 1090, 961, 833, 608 cm−1;
HRMS (ESI, m/z) calcd for C11H12BrClNS [M + H]+ 303.9557,
found 303.9557.
1
10) to yield 0.019 g (91%) of 5a as a clear oil: H NMR (400 MHz,
CDCl3) δ 7.81 (d, J = 7.0 Hz, 2H), 7.46 (t, J = 6.4 Hz, 1H), 7.39 (t, J =
7.0 Hz, 1H), 4.27 (d, J = 11 Hz, 1H), 4.23 (d, J = 11 Hz, 1H), 3.44 (d,
J = 11 Hz, 1H), 3.14 (d, J = 11 Hz, 1H), 2.08 (s, 3H), 1.46 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 171.1, 167.2, 133.2, 131.5, 128.6,
128.5, 81.2, 68.9, 40.6, 23.3, 21.1; IR (neat) νmax 3062, 2973, 1742,
1604, 1447, 1370, 1236, 1043, 948, 768, 690 cm−1; HRMS (ESI, m/z)
calcd for C13H16NO2S [M + H]+ 250.0896, found 250.0895.
General Procedure C: Synthesis of S-Allyl Thioimidate
Sulfonate Salts. Thioimidate 1a was dissolved in THF (0.5 M).
Sulfonic acid derivative (1 equiv) was added, and the solution was
stirred at room temperature for 30 min. The solvent was removed, and
the crude residue was triturated in EtOAc. The resulting white
precipitate was filtered, washed with EtOAc, dissolved in CHCl3, and
filtered to remove insoluble impurities.
2-Methylallyl Benzimidothioate p-Toluenesulfonate (7a): Pre-
pared from 1a (3.0 g, 16 mmol) and p-TsOH (3.0 g, 16 mmol)
according to general procedure C to yield 5.1 g (89%) of 7a as a white
solid; mp 135−136 °C; 1H NMR (400 MHz, CDCl3) δ 12.39 (s, 1H),
11.57 (s, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.70 (d, J = 6.6 Hz, 2H), 7.60
(t, J = 7.4 Hz, 1H), 7.44−7.39 (m, 2H), 7.09 (d, J = 7.7 Hz, 2H), 5.13
(s, 1H), 5.02 (s, 1H), 4.13 (s, 2H), 2.31 (s, 3H), 1.81 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 188.4, 142.1, 140.0, 136.2, 135.2, 131.0,
4-(Bromomethyl)-2-(4-bromophenyl)-4-methyl-4,5-dihydrothia-
zole (3p): Prepared from 2p (0.10 g, 0.28 mmol) and NBS (0.056 g,
0.31 mmol) according to general procedure B and purified (hexanes/
1
EtOAc: 90/10) to yield 0.076 g (77%) of 3p as a clear oil; H NMR
(400 MHz, CDCl3) δ 7.68 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.4 Hz,
2H), 3.64 (d, J = 10 Hz, 1H), 3.62 (d, J = 11 Hz, 1H), 3.59 (d, J = 10
Hz, 1H), 3.19 (d, J = 11 Hz, 1H), 1.57 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 132.0, 131.8, 130.0, 126.2, 82.0, 41.9, 40.3, 24.8; IR (neat)
νmax 3052, 2974, 1595, 1486, 1396, 1269, 1068, 1011, 961, 831, 608
cm−1; HRMS (ESI, m/z) calcd for C11H12Br2NS [M + H]+ 347.9052,
found 347.9053.
4-(4-(4-(Bromomethyl)-4-methyl-4,5-dihydrothiazol-2-yl)phenyl)-
2-methylthiazole (3q): Prepared from 2q (0.10 g, 0.27 mmol) and
NBS (0.054 g, 0.30 mmol) according to general procedure B and
purified (hexanes/EtOAc: 89/11) to yield 0.089 g (90%) of 3q as a
white solid; mp 104−107 °C; 1H NMR (400 MHz, CDCl3) δ 7.90 (d,
J = 8.3 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H), 7.38 (s, 1H), 3.66−3.59 (m,
3H), 3.17 (d, J = 11 Hz, 1H), 2.76 (s, 3H), 1.59 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 167.2, 166.2, 154.1, 137.4, 132.4, 129.0, 126.3,
113.9, 81.9, 41.7, 40.4, 24.8, 19.5; IR (neat) νmax 3112, 2972, 2927,
1593, 1410, 1273, 1171, 961, 851, 757 cm−1; HRMS (ESI, m/z) calcd
for C15H16BrN2S2 [M + H]+ 366.9933, found 366.9932.
I
DOI: 10.1021/acs.joc.7b02299
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
129.4, 128.8, 128.8, 126.1, 117.9, 40.1, 21.7, 21.4; IR (neat) νmax 3460,
3125, 2939, 1638, 1236, 1181, 1169, 680 cm−1; HRMS (ESI, m/z)
calcd for C18H21NO3S2Na [M + Na]+ 386.0855, found 386.0846.
2-Methylallyl Benzimidothioate Methanesulfonate (8a): Prepared
from 1a (0.14 g, 0.73 mmol) and MsOH (0.071 g, 0.73 mmol)
according to general procedure C to yield 0.25 g (quant.) of 8a as a
clear oil; 1H NMR (400 MHz, CDCl3) δ 12.12 (s, 1H), 11.31 (s, 1H),
7.93 (d, J = 7.2 Hz, 2H), 7.66 (t, J = 7.1 Hz, 1H), 7.52 (t, J = 7.6 Hz,
2H), 5.21 (s, 1H), 5.07 (s, 1H), 4.14 (s, 2H), 2.74 (s, 3H), 1.89 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 188.6, 136.1, 135.5, 130.9,
129.5, 128.6, 118.0, 39.9, 39.4, 21.8; IR (neat) νmax 3437, 2975, 1650,
1449, 1280, 1204, 1046, 917 cm−1; HRMS (ESI, m/z) calcd for
C12H17NO3S2Na [M + Na]+ 310.0542, found 310.0539.
yield 0.21 g (85%) of 11a as a white solid: mp 188−189 °C; 1H NMR
(400 MHz, CDCl3) δ 8.29 (d, J = 7.5 Hz, 2H), 7.71 (t, J = 7.5 Hz,
1H), 7.54 (t, J = 7.8 Hz, 2H), 4.46 (d, J = 12 Hz, 1H), 4.02 (d, J = 12
Hz, 1H), 3.95 (d, J = 12 Hz, 1H), 3.60 (d, J = 12 Hz, 1H), 1.91 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 186.3, 137.1, 130.7, 129.8,
124.8, 76.1, 49.2, 39.7, 24.3; IR (neat) νmax 3050, 2984, 1589, 1572,
1449, 1387, 1376, 996, 954, 771, 711 cm−1; HRMS (ESI, m/z) calcd
for C11H13ClNS [M − Br]+ 226.0451, found 226.0450.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b02299.
2-Methylallyl Benzimidothioate (S)-Camphorsulfonate (9a):
Prepared from 1a (0.30 g, 1.1 mmol) and (+)-CSA (0.26 g, 1.1
mmol) according to general procedure C to yield 0.27 g (59%) of 9a
Gram-scale synthesis of thioimidate salt 2a, thermal
ellipsoid plot diagram of the X-ray crystal structure of
1
as a white solid; mp 138−139 °C; H NMR (400 MHz, CDCl3) δ
1
compound 11a, H and 13C NMR spectra for all new
11.98 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.64 (t, J = 8.4 Hz, 1H), 7.51
(t, J = 7.9 Hz, 2H), 5.20 (s, 1H), 5.05 (s, 1H), 4.23 (s, 2H), 3.24 (d, J
= 15 Hz, 1H), 2.68 (d, J = 15 Hz, 1H), 2.55 (ddd, J = 15, 12, and 4.0
Hz, 1H), 2.24 (dt, J = 18 and 3.7 Hz, 1H), 1.95 (t, J = 4.5 Hz, 1H),
1.89 (s, 3H), 1.80 (d, J = 18 Hz, 2H), 1.58 (ddd, J = 13, 9.3, and 4.7
Hz, 1H), 1.27 (ddd, J = 13, 9.4, and 4.0 Hz, 1H), 0.97 (s, 3H), 0.74 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 216.8, 188.0, 136.5, 135.1,
131.2, 129.4, 128.8, 117.9, 58.4, 47.9, 47.3, 42.9, 42.6, 40.1, 27.1, 24.4,
21.8, 20.0, 19.8; IR (neat) νmax 3448, 2959, 1740, 1642, 1189, 1042,
704, 617 cm−1; HRMS (ESI, m/z) calcd for C21H29NO4S2Na [M +
Na]+ 446.1430, found 446.1419.
compounds (PDF)
X-ray data (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: jgpierce@ncsu.edu.
■
ORCID
Joshua G. Pierce: 0000-0001-9194-3765
2-Methylallyl Benzimidothioate (R)-Camphorsulfonate (10a):
Prepared from 1a (0.3 g, 1.1 mmol) and (−)-CSA (0.26 g, 1.1
mmol) according to general procedure C to yield 0.38 g (81%) of 10a
Present Address
†Vertex Pharmaceuticals Inc., 50 Northern Ave, Boston, MA
02210, USA.
1
as a white solid; mp 139−140 °C; H NMR (400 MHz, CDCl3) δ
Notes
12.29 (s, 1H), 11.60 (s, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.67 (t, J = 8.1
Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 5.23 (s, 1H), 5.08 (s, 1H), 4.24 (s,
2H), 3.28 (d, J = 15 Hz, 1H), 2.74 (d, J = 15 Hz, 1H), 2.57 (ddd, J =
15, 12, and 4.1 Hz, 1H), 2.27 (dt, J = 18 and 4.0 Hz, 1H), 1.92 (t, J =
4.6 Hz, 1H), 1.92 (s, 3H), 1.83 (d, J = 18 Hz, 2H), 1.62 (ddd, J = 13,
9.9, and 4.8 Hz, 1H), 1.31 (ddd, J = 13, 9.4, and 4.0 Hz, 1H), 1.00 (s,
3H), 0.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 216.9, 188.1,
136.5, 135.2, 131.3, 129.5, 128.8, 118.1, 58.5, 48.0, 47.4, 42.7, 42.7,
40.2, 27.1, 24.6, 21.9, 20.0, 19.9; IR (neat) νmax 3491, 3168, 2919,
1737, 1610, 1189, 1042, 621 cm−1; HRMS (ESI, m/z) calcd for
C21H29NO4S2Na [M + Na]+ 446.1430, found 446.1422.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-1454845)
for funding this work and NC State University for general
support to our research program. We also thank Dr. Roger
Sommer (NC State) for X-ray analysis of 11a. Mass spectra
were obtained at the Mass Spectrometry Laboratory at NC
State University.
(R)-4-(Chloromethyl)-4-methyl-2-phenyl-4,5-dihydrothiazole
(6a): Thioimidate 2a (0.10 g, 0.28 mmol), (DHQD)2PHAL (0.011 g,
0.014 mmol), and Et3N (0.028 g, 0.28 mmol) were dissolved in TFE
(5.5 mL) in a screw cap vial. The vial was capped and placed in a
chiller set to −30 °C for 10 min. DCDPH (0.022 g, 0.069 mmol) was
added as one aliquot. An aliquot of DCDPH was added every 30 min
until a total of 0.28 mmol was reached (4 aliquots total). The reaction
stirred at −30 °C for 4 h. The reaction was quenched with Na2S2O3
and extracted with CH2Cl2 (×3). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated in vacuo. The
crude residue was purified by flash chromatography over silica gel
(hexanes/EtOAc: 98/2) to yield 0.040 g (52%) of 6a as a clear oil:
REFERENCES
■
(1) (a) Blunt, J. W.; Copp, B. R.; Keyzers, R. A.; Munro, M. H. G.;
Prinsep, M. R. Nat. Prod. Rep. 2014, 31, 160−258. (b) Kashman, Y.;
Rudi, A.; Pappo, D. Pure Appl. Chem. 2007, 79, 491−505. (c) Ishikawa,
H.; Colby, D. A.; Seto, S.; Va, P.; Tam, A.; Kakei, H.; Rayl, T. J.;
Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2009, 131, 4904−4916.
(2) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57,
10257−10274.
(3) (a) Wipf, P.; Reeves, J. T.; Day, B. W. Curr. Pharm. Des. 2004, 10,
1417−1437. (b) Hong, J.; Luesch, H. Nat. Prod. Rep. 2012, 29, 449−
456.
1
85% ee (S enantiomer Rt = 7.6 min; R enantiomer Rt = 9.0 min); H
(4) (a) Toogood, P. L.; Hollenbeck, J. J.; Lam, H. M.; Li, L. Bioorg.
Med. Chem. Lett. 1996, 6, 1543−1546. (b) Cortina, N. S.; Revermann,
NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 7.1
Hz, 1H), 7.40 (t, J = 8.0 Hz, 2H), 3.75 (d, J = 11 Hz, 1H), 3.70 (d, J =
11 Hz, 1H), 3.61 (d, J = 11 Hz, 1H), 3.16 (d, J = 11 Hz, 1H), 1.56 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 167.8, 133.1, 131.6, 128.6,
128.5, 82.5, 50.6, 40.8, 24.1; IR (neat) νmax 3061, 2975, 1599, 1449,
1267, 964, 940, 687 cm−1; HRMS (ESI, m/z) calcd for C11H13ClNS
[M + H]+ 226.0451, found 226.0451.
(R)-4-(Chloromethyl)-4-methyl-2-phenyl-4,5-dihydrothiazole Hy-
drobromide (11a): To a round-bottom flask were added thiazoline 6a
(0.18 g, 0.80 mmol) and THF (1.6 mL). Hydrobromic acid (0.13 g,
0.80 mmol) was added, and the reaction stirred for 30 min. The
solvent was removed, and the crude residue was triturated in EtOAc.
The resulting white precipitate was filtered, washed with EtOAc,
dissolved in CHCl3, and filtered to remove insoluble impurities to
O.; Krug, D.; Muller, R. ChemBioChem 2011, 12, 1411−1416.
̈
(5) Parsons, R. L., Jr.; Heathcock, C. H. J. Org. Chem. 1994, 59,
4733−4734.
(6) Soria-Mercado, I. E.; Pereira, A.; Cao, Z.; Murray, T. F.; Gerwick,
W. H. Org. Lett. 2009, 11, 4704−4707.
(7) (a) Amini, M.; Bayrami, A.; Marashi, M. N.; Arab, A.; Ellern, A.;
Woo, L. K. Inorg. Chim. Acta 2016, 443, 22−27. (b) Betz, A.; Yu, L.;
Reiher, M.; Gaumont, A.-C.; Jaffres
Chem. 2008, 693, 2499−2508.
̀
, P.-A.; Gulea, M. J. Organomet.
(8) (a) Reddy, G. R.; Thompson, W. C.; Miller, S. C. J. Am. Chem.
Soc. 2010, 132, 13586−13587. (b) Sun, Y.-Q.; Liu, J.; Wang, P.;
Zhang, J.; Guo, W. Angew. Chem., Int. Ed. 2012, 51, 8428−8430.
J
DOI: 10.1021/acs.joc.7b02299
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(9) (a) Gaumont, A.-C.; Gulea, M.; Levillain, J. Chem. Rev. 2009, 109,
1371−1401. (b) Alom, N.-E.; Wu, F.; Li, W. Org. Lett. 2017, 19, 930−
933. (c) Alsharif, Z. A.; Alam, M. A. RSC Adv. 2017, 7, 32647−32651.
(10) Souto, J. A.; Vaz, E.; Lepore, I.; Poppler, A.-C.; Franci, G.;
̈
́
́
Alvarez, R.; Altucci, L.; de Lera, A. R. J. Med. Chem. 2010, 53, 4654−
4667.
(11) (a) Shymanska, N. V.; An, I. H.; Pierce, J. G. Angew. Chem., Int.
Ed. 2014, 53, 5401−5404. (b) Moazami, Y.; Pierce, J. G. Synthesis
2015, 47, 3363−3370. (c) Lemercier, B. C.; Pierce, J. G. Org. Lett.
2015, 17, 4542−4545. (d) Parker, P. D.; Pierce, J. G. Synthesis 2016,
48, 1902−1909.
(12) Lemercier, B. C.; Pierce, J. G. Org. Lett. 2014, 16, 2074−2076.
(13) Fittig, R. Ber. Dtsch. Chem. Ges. 1883, 16, 373.
(14) Brown, R. S.; Nagorski, R. W.; Bennet, A. J.; McClung, R. E. D.;
Aarts, G. H. M.; Klobukowski, M.; McDonald, R.; Santarsiero, B. D. J.
Am. Chem. Soc. 1994, 116, 2448−2456.
(15) (a) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem.,
Int. Ed. 2012, 51, 10938−10953. (b) Cheng, Y. A.; Yu, W. Z.; Yeung,
Y.-Y. Org. Biomol. Chem. 2014, 12, 2333−2343. (c) Yu, Y.-M.; Huang,
Y.-N.; Deng, J. Org. Lett. 2017, 19, 1224−1227.
(16) Takano, S.; Murakata, C.; Imamura, Y.; Tamura, N.; Ogasawara,
K. Heterocycles 1981, 16, 1291−1294.
(17) Kitagawa, O.; Hanano, T.; Tanabe, K.; Shiro, M.; Taguchi, T. J.
J. Chem. Soc., Chem. Commun. 1992, 14, 1005−1007.
(18) Wang, M.; Gao, L. X.; Mai, W. P.; Xia, A. X.; Wang, F.; Zhang,
S. B. J. Org. Chem. 2004, 69, 2874−2876.
(19) (a) Yasuda, N.; Karikomi, M.; Toda, T. Chem. Lett. 1995, 24,
1141−1142. (b) Toda, T.; Karikoma, M.; Yasuda, N. Rev. Heteroatom
Chem. 1997, 16, 119−135.
(20) Nakajima, N.; Ubukata, M. Science of Synthesis; Thieme, 2005;
Vol. 22, pp 361−366.
(21) Compound 2a was freebased with sodium bicarbonate to give
1
quantitative yield of 1a. Decomposition of 1a was observed by H
NMR after 1 day at room temperature, whereas 2a is stable indefinitely
at room temperature.
(22) Reactions were monitored using LC-MS by observing low-
resolution MS and UV absorbance.
(23) Galeazzi, R.; Martelli, G.; Mobbili, G.; Orena, M.; Rinaldi, S.
Org. Lett. 2004, 6, 2571−2574.
(24) (a) Jaganathan, A.; Borhan, B. Org. Lett. 2014, 16, 3616−3619.
(b) Kawato, Y.; Kubota, A.; Ono, H.; Egami, H.; Hamashima, Y. Org.
Lett. 2015, 17, 1244−1247. (c) Wang, Y.-M.; Wu, J.; Hoong, C.;
Rauniyar, V.; Toste, F. D. J. Am. Chem. Soc. 2012, 134, 12928−12931.
(25) Jaganathan, A.; Garzan, A.; Whitehead, D. C.; Staples, R. J.;
Borhan, B. Angew. Chem., Int. Ed. 2011, 50, 2593−2596.
K
DOI: 10.1021/acs.joc.7b02299
J. Org. Chem. XXXX, XXX, XXX−XXX