Photocatalytic initiation of thiol-ene reactions: Synthesis of thiomorpholin-3-ones

Article abstract of DOI:10.1016/j.tet.2014.03.041

A mild, redox neutral photocatalytic method for alkene hydrothiolation is reported. Utilizing visible-light activation, catalytic radical initiation is achieved with the transition metal complex Ru(bpy)₃Cl₂, enabling rapid access to a diverse set of thiol-ene coupled products in excellent yield. On the basis of a strong observed background reaction in some cases, we have developed a solvent-free, Lewis acid-promoted tandem amidation-hydrothiolation sequence, providing thiomorpholin-3-ones in a one-pot operation from commercially available materials.

Full text of DOI:10.1016/j.tet.2014.03.041

Tetrahedron xxx (2014) 1e6
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Photocatalytic initiation of thioleene reactions: synthesis of
thiomorpholin-3-ones
,
Mitchell H. Keylor a, James E. Park b, Carl-Johan Wallentin b, Corey R.J. Stephenson a
*
a Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA
b Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild, redox neutral photocatalytic method for alkene hydrothiolation is reported. Utilizing visible-light
activation, catalytic radical initiation is achieved with the transition metal complex Ru(bpy)3Cl2, enabling
rapid access to a diverse set of thioleene coupled products in excellent yield. On the basis of a strong
observed background reaction in some cases, we have developed a solvent-free, Lewis acid-promoted
tandem amidationehydrothiolation sequence, providing thiomorpholin-3-ones in a one-pot operation
from commercially available materials.
Received 22 January 2014
Received in revised form 7 March 2014
Accepted 12 March 2014
Available online xxx
Keywords:
Thioleene
Ó 2014 Elsevier Ltd. All rights reserved.
Photoredox catalysis
Hydrothiolation
Thiomorpholinone
Click reaction
1. Introduction
to access thiomorphilin-3-one heterocycles via a solvent-free Lewis
acid-promoted tandem amidationehydrothiolation sequence.
Described by Schlaad as the thioleene click (TEC) reaction,1 the
hydrothiolation of olefins is century-old synthetic trans-
It is worth noting that during our work in this area, Yoon and co-
workers reported novel applications of photoredox catalysis in
radical thioleene additions using the ruthenium complex
Ru(bpz)3(PF6)2.12 While the method here is similar in concept, the
systems are mechanistically distinguished by the way in which
thiyl radical generation is achieved.13 Contrary to our method in
which redox manipulations are not performed directly on either
the thiol or olefin coupling partners, Yoon proposes that the pho-
a
formation2 that has become a powerful tool in polymer and ma-
terials chemistry,3 with applications ranging from surface
patterning4 and lithography5 to dendrimer synthesis,6 and bio-
molecule functionalization.7,8 Traditionally, the TEC reaction is
performed under base-catalysis with electron-deficient alkenes or
with radical initiation when using unactivated olefins. While the
radical process is largely driven by propagation,9 initiation is typ-
ically achieved with UV irradiation or by thermolysis of a chemical
additive, limiting the application of the TEC reaction to relatively
simple systems.
2þ*
toexcited complex, Ru(bpz)3
, initiates coupling by either
direct12a or aminium-mediated12b single electron oxidation of the
mercaptan, with subsequent deprotonation to produce the requi-
site thiyl radical.
Photoredox catalysis has been developed as an attractive alter-
native to traditional methods of generating synthetically useful
radical intermediates in complex settings.10 Visible-light driven
catalysts enable reductive, oxidative, and redox neutral trans-
formations to be performed chemoselectively via single electron
transfers that are tunable by ligand modification and choice of
additive.10,11 Herein, we report a photocatalytic radical initiation
system for thioleene reactions employing Ru(bpy)3Cl2. This work
has also led to the development of an operationally simple method
We envisioned a system for thioleene coupling in which pho-
toredox catalytic initiation and reaction propagation operate con-
currently in distinct but synergistic cycles (Scheme 1). Irradiation of
Ru(bpy)3Cl2 with visible light promotes metal-to-ligand charge
transfer (MLCT), thus generating a photoexcited state in which the
metal center can perform a single electron oxidation of a sacrificial
electron donor. This provides a [Ru]þ species capable of single
electron reduction of an acceptor such as bromotrichloromethane.
We reasoned that the trichloromethyl radical thus produced could
initiate thioether bond formation by hydrogen atom abstraction
from the mercaptan. Subsequent capture of the electrophilic thiyl
radical by an alkene would take place exclusively with anti-
* Corresponding author. Tel.: þ1 734 763 8283; fax: þ1 734 647 4865; e-mail
Markovnikov regioselectivity, generating
a
carbon-centered
address: crjsteph@umich.edu (C.R.J. Stephenson).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.041
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2
M.H. Keylor et al. / Tetrahedron xxx (2014) 1e6
Scheme 1. Proposed system for implementation of mild photocatalytic radical initiation of the TEC reaction.
radical that, upon H-atom abstraction from another thiol molecule,
propagates the radical chain process. Reaction propagation for TEC
is known to be extremely efficient, with up to 100,000 thioether
linkages formed per thiyl radical generated.3a Such levels of re-
action amplification would allow for low catalyst loading and
substoichiometric quantities of both bromochloroform and the
sacrificial electron donor. Additionally, these conditions may be
better suited to systems that are sensitive to oxidation (Eox(2þ*/þ)
Ru(bpz)3(PF6)2¼þ1.35 V) or Brønsted acid formation.
With the optimized conditions in hand, we began to evaluate
the scope of thiols and olefins that are suitable for this trans-
formation. Alkyl, acyl, and benzyl thiols were tolerated, each giving
clean conversion within 3 h to the coupled product (Table 1, 3aed).
However, the reaction was unsuccessful with aryl thiols, giving
almost no conversion for electron rich, electron neutral, and elec-
tron poor thiophenols (3eeg). Additionally, low conversions were
observed for tertiary mercaptans 3i. Substituted alkenes were in-
corporated successfully, giving products with the expected anti-
Markovnikov regioselectivity 3j. A more complex substrate was
subjected to the optimized conditions and furnished the desired
coupled product 3m in high yield. Finally, the conditions proved to
be suitable for thioleyne coupling as well, giving the 1,2-
dithioether 3n in 85% yield. Notably, the photoredox conditions
developed by Yoon and co-workers under the reductive quenching
manifold convert alkynes to the corresponding vinyl sulfides.12a
2. Results and discussion
To realize this idea, we began investigating the TEC reaction
between phenylethyl mercaptan and ethyl undecylenate (Table 1).
Conditions were optimized along the following parameters: stoi-
chiometry, solvent, concentration, electron donor, electron accep-
tor/initiator, and reaction time. The highest levels of conversion
were observed when employing at least a threefold excess of thiol
relative to alkene. Presumably, excess thiol facilitates H-atom ab-
straction and radical chain propagation. The reaction performed
best in highly polar solvents, both protic and aprotic, and was not
sensitive to the presence of water. Sodium ascorbate performed
best as a reductive quencher (electron donor) for the photocatalyst,
with ammonium oxalate salts and tertiary amines being slightly
inferior. Under the optimized conditions, reaction initiation was
accomplished using Ru(bpy)3Cl2 (1 mol %) and bromotrichloro-
methane (5 mol %) in the presence of sodium ascorbate (3 mol %)
Table 2
Representative substrate scopea
as
a reductive quencher of the catalyst photoexcited state
(Table 1, entry 2).
Table 1
Reaction optimizationa
Entry
R-SH (equiv)
Concn (M)
Time (h)
Conversionb (%)
1
2
3
4
5
6
5
3
1.5
1.5
1.5
1.5
1
1
1
1
1
1
0.4
0.4
0.4
0.4
0.2
0.8
1.5
1.5
0.5
3
0.5
0.5
91
91c,d
69
75
48
68
a
All reactions performed with 10 mol % BrCCl3 and 6 mol % Na-ascorbate unless
otherwise noted.
b
Conversions determined by NMR analysis of crude reaction mixtures.
Identical result obtained using 5 mol % BrCCl3 and 3 mol % Na-ascorbate.
The lipophilicity of the addition product in Table 1 precluded its clean isolation.
c
d
Analogous trends observed for optimization model system using: RSH¼phenyle-
thylmercaptan, alkene¼5-hexen-1-ol (see Table 2, entry 3b).
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M.H. Keylor et al. / Tetrahedron xxx (2014) 1e6
3
2.1. Control studies
isolation of Markovnikov isomer 7a in 34% yield suggests that
amide bond formation takes place first, followed by a 6-exo-trig
cyclization to form the thiomorpholin-3-one.
The impact of each reaction parameter was analyzed through
a series of control experiments employing phenylethyl mercaptan
and ethyl undecylenate. Crude reaction mixtures were analyzed by
1H NMR. We were pleased to find that in the absence of a radical
initiator, photocatalyst, or a light source, only low conversion was
detected (<10%), supporting our proposed use of visible-light active
Ru(bpy)3Cl2 as a radical initiator. Later in the course of these
studies, however, a substantial background reaction was discovered
while attempting to develop this reaction in a flow-reactor. Initially,
we attributed this reactivity to the use of a more intense light
source (5.9 W vs 2 W blue LED) given the low BDE of bromotri-
chloromethane (49 kcal/mol).14 However, this finding prompted us
to revisit control experiments in our batch reactions, as these re-
actions are prone to substrate-dependent anomalies. A non-zero
background reaction was detected, with both the reaction rate
and the yield highly dependent on the thiol and alkene coupling
partners employed. In fact, methyl thioglycolate and 1-hexenol
were found to react nearly quantitatively even in the absence of
light. This thiol has seen recent use as a hydrogen atom transfer
(HAT) agent for photocatalytic CeH activation.15 The large back-
ground reaction was overlooked in the original control studies due
to an apparent induction period for the reaction (Fig. 1).
Scheme 2. Discovery of a solvent-free amidation/thioleene cyclization sequence to
access thiomorpholinones.
Thiomorpholin-3-one and its derivatives are important struc-
tural motifs with a heavy presence in the patent literature as a re-
sult of their interesting pharmacological profiles. These
heterocycles demonstrate a multitude of biological activities, in-
cluding antihypertensive17 and antimycobacterial18 activities, en-
hancement of neurotransmitter turnover,19 5-HT1b20 and EP421
receptor antagonism, and autophagy inhibition.22 As a result, the
development of efficient methods for their preparation is a worth-
while pursuit. Current approaches to the synthesis of thio-
morpholinones include Ugi reactions,23 microwave-assisted Smiles
rearrangements,24 copper-catalyzed cascade reactions,25 and ring-
opening/ring-closing rearrangements of 1,2-cyclic sulfamidates.26
Herein, we report an alternative synthetic route to thio-
morpholin-3-ones by a one-pot solvent-free tandem amidation/
hydrothiolation.
Initial screening using 4 and 5a as the model substrates revealed
that the highest yields were obtained when running the reaction
neat. In fact, only trace amounts of the desired product could be
isolated when employing various high boiling solvents. While the
rate of reaction was affected by the presence or absence of DMAP, it
was quite insensitive to the quantity employed. We isolated 48% of
the desired thiomorpholin-3-one 7a when performing the reaction
in refluxing diallylamine (1.5 equiv) in the presence of DMAP
(5 mol %).
Since DMAP provided only modest yields of the desired lac-
tam, we began to explore Lewis acid additives in an effort to
improve reaction yield and efficiency. Indeed, in nearly all cases
the presence of a Lewis acid offered improved yields (Table 3). The
best results were obtained using highly oxophilic Lewis acids such
as gadolinium (III) chloride (entry 2) and scandium (III) triflate
(entry 6).
Finally, we optimized reaction time using GCeMS. Using prod-
uct ion count as a metric for reaction progress, we determined that
product formation in the Sc(OTf)3-promoted reaction reached
completion at approximately 24 h.
With the optimized reaction conditions in hand, we probed
whether the reaction would tolerate differentially substituted
allylamines (Scheme 3). It was discovered that secondary amines
bearing just one reactive olefin (5bec) gave lower yields of the
corresponding thiomorpholin-3-ones. This lends support to the
proposed mechanism in which amide bond formation takes place
prior to thioleene coupling, as restricted rotation about the amide
bond would not allow ready access to the requisite conformer for
hydrothiolation of the alkene. Importantly, this method allows for
the synthesis of thiomorpholinones bearing N-benzyl groups,
which can be deprotected in high yields by Birch-type reductive
dealkylation.27
Fig. 1. Comparison of rates of photocatalytic and uncatalyzed reactions.
To account for this reactivity, we propose that molecular oxygen
in the reaction mixtures (present in trace quantities despite thor-
ough sparging with argon), can initiate the radical chain process via
a thioleolefin co-oxidation ‘TOCO’-type process from a thioleolefin
charge-transfer complex.16 Nonetheless, the observed kinetics for
our optimized photocatalytic system clearly demonstrate that cat-
alytic initiation is operative, enabling rapid access to a diverse set of
thioleene coupled products under mild conditions.
2.2. Solvent-free synthesis of thiomorpholin-3-ones
In an attempt to construct a substrate to demonstrate an
intramolecular thioleene cyclization, diallylamine (5a) was com-
bined with methyl thioglycolate (4) in the presence of 4-
dimethylaminopyridine (DMAP, Scheme 2). However, upon
workup and purification, we discovered that the thioleene reaction
had transpired in the absence of any source of initiation. The
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4
M.H. Keylor et al. / Tetrahedron xxx (2014) 1e6
Table 3
LiAlH4. Additionally, 7a was benzylated at the a-position to provide
Optimization studies for Lewis acid-promoted thiomorpholin-3-one formationa
9 as a 3:2 mixture of diastereomers. Finally, deallylation of the
amide was attempted using the conditions reported by Tokunaga
and co-workers.28 However, this reaction was unsuccessful with
our substrate, likely due to catalyst poisoning by the sulfide.
3. Conclusions
Entry
Lewis acid
Yieldb (%)
In conclusion, we have demonstrated the utility of photoredox
catalysis as a mild and selective method for radical initiation in the
thioleene click (TEC) reaction. This method is characterized by low
catalyst loadings and substoichiometric quantities of redox addi-
tives, enabling net redox neutral hydrothiolation reactions between
a wide scope of olefins and thiols. During the method development,
we fortuitously discovered a very efficient solvent-free tandem
amidation/hydrothiolation methodology that we then utilized to
prepare N-substituted-6-methylthiomorpholin-3-ones. This oper-
ationally simple protocol provides efficient access to a pharmaco-
logically relevant structural motif and allows for the rapid synthesis
of structurally diversified thiomorpholinone derivatives.
1
2
3
4
5
6
7
8
9
Bismuth(III) chloride
Gadolinium(III) chloride hexahydrate
Hafnium(IV) triflate
Lanthanum(III) chloride
Lithium perchlorate
Scandium(III) triflate
Titanium(IV) isopropoxide
Yttrium(III) chloride
Zirconium(IV) chloride
54
67
54
54
62
70
48
51
54
a
All reactions performed using 1.5 equiv of diallylamine and 1 equiv of methyl
thioglycolate.
b
Isolated yields unless otherwise noted.
4. Experimental section
4.1. General
Commercially available starting materials were used as received
without further purification unless otherwise noted. Bromotri-
chloromethane was purified immediately prior to use by passage
through a short plug of neutral alumina. Glassware was dried in
a 170 ꢀC oven or flame-dried before use. All reaction mixtures were
degassed by sparging for 15 min with argon. Reactions were
monitored by TLC and visualized by either dual short-wave/long-
wave UV lamp or staining with an ethanolic solution of potas-
sium permanganate or with subliming iodine. Column flash chro-
Scheme 3. Scope of allyl amine reaction partners.
While differentially substituted amines were tolerated, methyl
thioglycolate (4) proved to be the only thiol amenable to this
transformation; no product formation was observed when
employing the corresponding carboxylic acid. It is known that
mercaptopropionates exhibit similarly high thioleene reactivity to
thioglycolates as compared to alkyl thiols. However, neither 2- nor
3-mercaptopropionate esters were tolerated in the reaction. We
were particularly surprised to see that ethyl 2-mercaptopropionate
did not react as it was expected to exhibit similar reactivity as
methyl thioglycolate, and would provide direct access to thio-
morpholin-3-one substrates that are methylated at the 2-position.
However, it has been shown that alkyl groups can readily be in-
troduced at this position of thiomorpholin-3-ones by enolization
and alkylation (vide infra).22
matography was performed using 43e60
silica gel. 1H and 13C NMR spectra were recorded at ambient tem-
perature at 93.94 kG and 117.3 kG (1H 400 MHz and 500 MHz, 13
mm (230e400 mesh)
C
100 MHz and 125 MHz) using an internal deuterium lock on
a Varian Unity Plus 400 or a Varian 500 spectrometer. Hydrogen
chemical shifts are expressed in parts per million (ppm) relative to
the residual protio solvent resonance in CDCl3 using
d 7.26 as
standard for residual CHCl3. Multiplicity is reported as follows:
(br¼broad, s¼singlet, d¼doublet, t¼triplet, q¼quartet, spt¼septet,
dd¼doublet of doublets, dt¼doublet of triplets, m¼multiplet), and
the corresponding coupling constants are indicated as J values in
units of hertz (Hz). For 13C spectra, the center line of the solvent
Lastly, a handful of synthetic operations were performed on the
N-allyl-6-methylthiomorpholin-3-one product (Scheme 4). We
found that 7a could serve as a convenient access point to func-
tionalized thiomorpholines by simple reduction of the amide using
signal was used as internal reference: CDCl3
d 77.23. Infrared
spectra were recorded on a Nicolet Nexus 670 FT-IR spectropho-
tometer using an ATR mount. Absorption bands are expressed in
wavenumbers (cmꢁ1). High-resolution mass spectra (HRMS) were
obtained on a Waters quadrupolar time-of-flight (Q-TOF) API-US
mass spectrometer using electrospray ionization (ESI), positive
ion mode. Chemical names were generated using ChemDraw Ultra
13.0 (CambridgeSoft).
4.2. General procedure for photoredox-initiated thioleene
click (TEC) reactions
A 5 mL round-bottom flask equipped with a magnetic stir bar
and rubber septum was charged with the starting olefin (1 mmol,
1.0 equiv) and thiol (3.0 mmol, 3 equiv) coupling partners, and
sodium ascorbate (0.03 mmol, 3 mol %). The reaction components
were dissolved in MeOH (0.4 M). The metal complex Ru(bpy)3Cl2
(0.01 mmol, 1 mol %) was finally added, and the resultant mixture
was degassed by sparging with argon for 15 min in the dark. Finally,
while stirring at room temperature under an argon atmosphere,
Scheme 4. Synthetic applications of thiomorpholin-3-one 7a. DPPP¼1,3-
bis(diphenylphosphino)propane.
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M.H. Keylor et al. / Tetrahedron xxx (2014) 1e6
5
BrCCl3 (0.05 mmol, 5 mol %) was added and the reaction vessel was
surrounded by blue LEDs (2 W). Powering on of this light source
signified reaction commencement. Reactions were typically run for
3 h, at, which point the LEDs were powered off and the MeOH re-
moved by rotary evaporation. The reaction mixture was then dis-
solved in a 7:3 hexanes/ethyl acetate mixture and filtered through
a plug of Celite. The crude filtrate was concentrated in vacuo and
purified by flash chromatography over SiO2.
J¼6.6 Hz, 2H), 2.93 (br dd, J¼13.9, 5.0 Hz, 2H), 2.51 (t, J¼7.3 Hz, 2H),
1.61 (br s, 1H), 1.59e1.52 (m, overlap, 4H), 1.43 (s, 9H), 1.40e1.33 (m,
overlap, 4H); 13C NMR (125 MHz, CDCl3)
d 171.8, 155.4, 80.3, 62.9,
53.5, 52.7, 34.7, 32.8, 32.7, 29.6, 28.6, 28.5, 25.5; HRMS (ESI) m/z
calculated for C15H29NO5Sþ ([Mþ1]þ) 336.1845, found 358.1665
([MþNa]þ).
4.2.8. Ethyl 11-((2-methoxy-2-oxoethyl)thio)undecanoate (3l). IR
(neat) 2927, 2854, 1734, 1436, 1373, 1276, 1178, 1133, 1012 cmꢁ1; 1H
4.2.1. Methyl 2-((6-hydroxyhexyl)thio)acetate (3a). IR (neat) 3374,
NMR (500 MHz, CDCl3)
d
4.10 (q, J¼7.0 Hz, 2H), 3.71 (s, 3H), 3.20 (s,
2929, 2857, 1730, 1462, 1436, 1411, 1276, 1131, 1029 cmꢁ1
;
1H NMR
2H), 2.60 (t, J¼7.3 Hz, 2H), 2.26 (t, J¼7.5 Hz, 2H), 1.62e1.53 (m,
overlap, 4H), 1.34 (m, 2H), 1.29e1.24 (m, overlap, 10H), 1.23 (t,
(500 MHz, CDCl3)
2.59 (t, J¼7.3 Hz, 2H), 1.60e1.50 (m, overlap, 4H), 1.41e1.31 (m,
overlap, 4H); 13C NMR (125 MHz, CDCl3)
171.0, 62.7, 52.3, 33.4,
d
3.69 (s, 3H), 3.59 (t, J¼6.7 Hz, 2H), 3.18 (s, 2H),
J¼1.23 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 174.0, 171.2, 60.3, 52.5,
d
34.5, 33.6, 32.9, 29.6, 29.5, 29.4, 29.3, 29.3, 29.1, 28.9, 25.1, 14.4;
HRMS (ESI) m/z calculated for C16H30O4Sþ ([Mþ1]þ) 319.1943,
found 341.1769 ([MþNa]þ).
32.6, 32.50, 28.8, 28.4, 25.3; HRMS (ESI) m/z calculated for
C9H18O3Sþ ([Mþ1]þ) 207.1055, found 189.0952 (eH2O).
4.2.2. 3-(Phenethylthio)hexan-1-ol (3b). IR (neat) 3351, 3062, 3027,
4.2.9. Methyl 2-((3-(((3S,8R,9S,10S,13S,14S)-10,13-dimethyl-17-
oxohexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)propyl)
thio)acetate(3m). IR (neat) 2926, 2852, 1737, 1437, 1407, 1373, 1276,
2930, 2857, 1604, 1497, 1453, 1053, 1030 cmꢁ1; 1H NMR (500 MHz,
CDCl3)
d
7.31e7.28 (m, 2H), 7.23e7.20 (m, 3H), 3.64 (t, J¼6.6 Hz, 2H),
2.89 (tt, J¼8.6, 7.0 Hz, 2H), 2.77 (tt, J¼8.6, 8.2 Hz, 2H), 2.54 (t,
J¼7.0 Hz, 2H), 1.64e1.54 (m, overlap, 4H), 1.45e1.34 (m, overlap,
1132, 1105, 1012, 916, 731 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 3.69 (s,
3H), 3.49 (t, J¼6.1 Hz, 2H), 3.19 (s, 2H), 3.16 (dddd, J¼10.9, 9.5, 4.6,
4.6 Hz, 1H), 2.67 (t, J¼7.3 Hz, 2H), 2.38 (ddd, J¼19.2, 8.9, 0.9 Hz, 1H),
2.01 (dt, J¼19.2, 8.9 Hz, 1H), 1.88 (dddd, J¼12.4, 8.2, 6.1, 0.9 Hz, 1H),
1.82 (m, overlap, 1H), 1.79 (t, J¼7.3 Hz, 2H), 1.77e1.72 (m, 2H), 1.68
(dt, J¼13.4, 3.5 Hz, 1H), 1.60 (m, 2H), 1.53e1.41 (m, overlap, 2H),
1.35e1.15 (m, overlap, 8H), 1.04 (dddd, J¼12.4, 11.6, 4.0, 3.1 Hz, 1H),
0.96e0.87 (m, overlap, 2H), 0.81 (s, 3H), 0.78 (s, 3H), 0.64 (ddd, 11.9,
4H), 1.36 (br s, 1H); 13C NMR (125 MHz, CDCl3)
d 140.7, 128.5 (2C),
126.3, 62.9, 36.4, 33.7, 32.6, 32.2, 29.5, 28.6, 25.4; HRMS (ESI) m/z
calculated for C14H22OSþ ([Mþ1]þ) 239.1470, found 239.1460.
4.2.3. S-(6-Hydroxyhexyl) ethanethioate (3c). IR (neat) 3360, 2932,
2858, 1690, 1462, 1431, 1354, 1134, 1054, 954 cmꢁ1 1H NMR
;
(500 MHz, CDCl3)
d
3.54 (t, J¼6.6 Hz, 2H), 2.80 (t, J¼7.3 Hz, 2H), 2.30
10.9, 4.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 221.3, 171.0, 78.6,
(s, 1H), 2.25 (s, 3H), 1.54e1.46 (m, overlap, 4H), 1.35e1.27 (m,
66.2, 54.6, 52.4, 51.6, 47.9, 45.0, 37.1, 36.1, 35.9, 35.2, 34.9, 33.6, 31.7,
31.0, 29.7, 29.7 (2C), 28.6, 28.3, 21.9, 20.6, 13.9, 12.4; HRMS (ESI) m/z
calculated for C25H40O4Sþ ([Mþ1]þ) 437.2726, found 437.2724.
overlap, 4H); 13C NMR (125 MHz, CDCl3)
d 196.3, 62.6, 32.6, 30.7,
29.5, 20.1, 28.6, 25.3. HRMS (ESI) m/z calculated for C8H16O2Sþ
([Mþ1]þ) 177.0949, found 159.0844 (eH2O).
4.2.10. Dimethyl 2,20-((5-hydroxypentane-1,2-diyl)bis-(sulfanediyl))
diacetate (3n). IR (neat) 3445, 2951, 2926, 2853, 1730, 1436, 1409,
1279, 1195, 1152, 1130, 1058, 1007 cmꢁ1; 1H NMR (500 MHz, CDCl3)
4.2.4. 6-(Benzylthio)hexan-1-ol (3d). IR (neat) 3343, 3061, 3028,
2930, 2857, 1602, 1494, 1453, 1238, 1071, 1053, 1028 cmꢁ1; 1H NMR
(500 MHz, CDCl3)
d
7.33e7.29 (m, overlap, 4H), 7.26e7.21 (m, 1H),
d
3.74 (s, 3H), 3.74 (s, 3H), 3.67 (t, J¼6.2 Hz, 2H), 3.35 (d, J¼14.8 Hz,
3.70 (s, 2H), 3.63 (t, J¼6.6 Hz, 2H), 2.42 (t, J¼7.3 Hz, 2H), 1.60e1.52
1H), 3.29 (d, J¼14.7 Hz,1H), 3.26 (d, J¼14.7 Hz, 1H), 3.25 (d, J¼14.8 Hz,
1H), 3.06e3.00 (m, overlap, 2H), 2.80 (dd, J¼14.8, 9.8 Hz, 1H), 1.95
(dddd, J¼9.8, 9.8, 5.8, 4.4 Hz, 1H), 1.79 (dddd, J¼13.6, 9.8, 6.2, 5.2 Hz,
1H), 1.69 (dddd, J¼13.6, 9.8, 6.2, 6.1 Hz, 1H), 1.58 (dddd, J¼13.4, 9.5,
(m, overlap, 4H), 1.41e1.32 (m, overlap, 4H), 1.34 (br s, 1H); 13C NMR
(125 MHz, CDCl3)
d 138.8, 129.0, 128.7, 127.1, 63.1, 36.5, 32.8, 31.5,
29.3, 28.8, 25.5; HRMS (ESI) m/z calculated for C13H20OSþ ([Mþ1]þ)
225.1313, found 207.1239 (eH2O).
8.2, 5.2 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 171.2, 171.1, 62.5, 52.7
(2C), 45.6, 38.4, 34.0, 32.6, 29.8, 29.7; HRMS (ESI) m/z calculated for
4.2.5. 6-(Isopropylthio)hexan-1-ol (3h). IR (neat) 3346, 2929, 2860,
C
11H20O5Sþ2 ([Mþ1]þ) 297.0831, found 279.0903 (eH2O).
1461, 1382, 1365, 1241, 1155, 1052 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
3.64 (t, J¼6.6 Hz, 2H), 2.91 (spt, J¼6.7 Hz, 1H), 2.53 (t, J¼7.3 Hz,
4.3. General procedure for Lewis acid-promoted synthesis of
thiomorpholin-3-ones
2H), 1.62e1.55 (m, overlap, 2H), 1.45e1.35 (m, overlap, 5H), 1.26 (d,
J¼6.7 Hz, 3H), 1.25 (d, J¼6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
63.1, 35.0, 32.8, 30.7, 30.0, 29.0, 25.6, 23.7; HRMS (ESI) m/z cal-
A 5 mL round-bottom flask equipped with a magnetic stir bar,
reflux condenser, and rubber septum was charged with ScOTf
(2 mol %) followed by the allyl amine (10 mmol, 1.5 equiv) and
methyl thioglycolate (6.67 mmol, 1 equiv). The glass joint was
sealed with Teflon tape and the reaction mixture heated to 140 ꢀC
for 24 h, stirring under a nitrogen atmosphere. The reaction mix-
ture was cooled to room temperature, diluted with dichloro-
methane, and transferred to a separatory funnel containing cold 1 N
aqueous HCl. The layers were separated and the aqueous phase was
extracted with additional dichloromethane. The organic layers
were then combined, washed with brine, and dried over Na2SO4.
The crude material was concentrated in vacuo and purified by flash
chromatography over SiO2.
culated for C9H20OSþ ([Mþ1]þ) 177.1313, found 159.1208 (eH2O).
4.2.6. Methyl 2-((4-hydroxy-2 methylbutyl)thio)acetate (3j). IR
(neat) 3410, 2955, 2926, 2867, 2845, 1733, 1458, 1436, 1378, 1278,
1133, 1051, 1008 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d 3.74 (dddd,
J¼10.7, 6.7, 6.4,1.5 Hz, 1H), 3.68 (dddd, J¼10.7, 6.7, 6.5, 1.5 Hz, 1H),
3.73 (s, 3H), 3.21 (s, 2H), 2.67 (dd, J¼12.7, 5.8 Hz, 1H), 2.51 (dd,
J¼12.7, 7.3 Hz, 1H), 1.89 (ddqdd, J¼7.8, 7.3, 7.0, 6.7, 5.8 Hz, 1H), 1.72
(dddd, J¼13.6, 7.0, 6.5, 1.2 Hz, 1H), 1.55 (br s, 1H), 1.49 (dddd, J¼13.6,
7.8, 6.4,1.5 Hz,1H),1.02 (d, J¼6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
171.3, 60.7, 52.6, 40.2, 38.9, 33.9, 29.7, 19.6; HRMS (ESI) m/z cal-
culated for C8H16O3Sþ ([Mþ1]þ) 193.089, found 175.0787 (eH2O).
4.2.7. Methyl
teinate (3k). IR (neat) 3372, 2976, 2931, 2857, 1746, 1701, 1503,1437,
1392, 1367, 1249, 1215, 1163, 1052, 1024 cmꢁ1 1H NMR (500 MHz,
CDCl3)
5.35 (br d, J¼6.7 Hz, 1H), 4.51 (m, 1H), 3.74 (s, 3H), 3.61 (t,
Please cite this article in press as: Keylor, M. H.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.041
N-(tert-butoxycarbonyl)-S-(6-hydroxyhexyl)-
L
-cys-
4.3.1. 4-Allyl-6-methylthiomorpholin-3-one (7a). IR (neat): 2965,
2922, 1656, 1634, 1485, 1441, 1416, 1378, 1351, 1269, 1188, 1116, 994,
;
931, 817 cmꢁ1 1H NMR (CDCl3, 500 MHz, w2:1 mixture of
;
d
rotamers): d 5.79e5.72 (m, 1H), 5.21e5.16 (m, 2H), 4.11 (m, 1H),

6
M.H. Keylor et al. / Tetrahedron xxx (2014) 1e6
3.92 (m,1H), 3.47 (dd, J¼13, 3.8 Hz,1H), 3.37 (dd, J¼16.0,1.5 Hz,1H),
3.31 (dd, J¼16.0, 1.5 Hz, 1H), 3.28e3.26 (m, 1H), 3.24e3.19 (m, 1H),
References and notes
1.30 (d, J¼6.6 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d 166.3, 132.5,
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2. Posner, T. Ber. Dtsch. Chem. Ges. 1905, 38, 646e657.
117.9, 55.4, 50.2, 35.21, 30.20, 19.24; HRMS (ESI) m/z calculated for
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C8H13NOSþ ([Mþ1]þ) 172.0791, found 172.0796.
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(CDCl3, 500 MHz):
(d, J¼15 Hz, 1H), 3.47e3.38 (overlap, 3H), 3.27 (dd, J¼13.5, 9.5 Hz,
1H), 3.20e3.13 (m, 1H), 1.22 (d, J¼7.0 Hz, 3H).
(7b).29 1H
NMR
d
7.35e7.27 (m, 5H), 4.77 (d, J¼15 Hz, 1H), 4.50
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500 MHz):
d
7.34e7.03 (m, 10H), 4.74 (d, J¼14.5 Hz, 1H), 4.46 (d,
J¼14.5 Hz, 1H), 3.47e3.25 (overlap, 5H), 2.79 (dddd, J¼15.5, 7.5, 7.5,
7.5 Hz, 2H).
4.3.4. 4-Allyl-2-methylthiomorpholine (8). IR (neat): 3076, 2959,
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2923, 2868, 2796, 1642, 1454, 1414, 1334, 1272, 1116, 1078, 991,
919 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
5.82 (dddd, J¼16.7, 10.1, 6.5,
6.5 Hz, 1H), 5.19e5.12 (m, 2H), 3.05 (ddd, J¼11.7, 3.4, 3.4 Hz, 1H),
3.01e2.93 (m, overlap, 4H), 2.88 (ddd, J¼13.6, 11.2, 2.8 Hz, 1H), 2.51
(ddd, J¼13.4, 3.2, 3.2 Hz, 1H), 2.21 (ddd, 11.6, 11.6, 2.3 Hz, 1H), 1.97
(dd, J¼11.4, 9.9 Hz, 1H), 1.15 (d, J¼6.8 Hz, 3H); 13C NMR (CDCl3,
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3082, 3025, 2906, 2865, 1654, 1494, 1476, 1413, 1377, 1351, 1306,
1274, 1211, 1182, 1115, 1075, 1030, 991, 926, 698 cmꢁ1 1H NMR
;
(500 MHz, CDCl3, w3:2 mixture of diastereomers)
d 7.32e7.21 (m,
5H), 5.83e5.75 (m, 1H), 5.22e5.16 (m, 2H), 4.31 (dddd, J¼15.1, 5.8,
1.5, 1.5 Hz, 1H), 4.15 (dddd, J¼15.1, 5.8, 1.5, 1.5 Hz, 1H), 3.99 (dddd,
J¼15.1, 6.4, 1.5, 1.5 Hz, 1H), 3.85 (dddd, 15.1, 6.4, 1.5, 1.5 Hz, 1H), 3.79
(ddd, J¼8.9, 8.9, 4.7 Hz, 1H), 3.61 (dd, J¼14.3, 4.5 Hz, 1H), 3.53e3.49
(m, 1H), 3.47 (dd, J¼14.3, 4.5 Hz, 1H), 3.38 (dd, J¼13.5, 4.2 Hz, 1H),
3.31e3.22 (m, overlap, 3H), 3.21e3.14 (m, 1H), 2.89 (dd, J¼14.2,
8.6 Hz, 1H), 2.83 (dd, J¼14.4, 9.5 Hz, 1H), 1.22 (d, J¼6.6 Hz, 3H); 13
C
NMR (CDCl3, 125 MHz):
d 169.6, 169.0, 138.8, 133.2, 133.1, 129.6,
129.5, 128.52, 128.50, 126.9, 126.8, 118.14, 118.09, 54.71, 54.66, 51.3,
50.4, 44.8, 42.9, 37.4, 37.3, 35.88, 35.86, 20.5, 19.8; HRMS (ESI) m/z
calculated for C15H19NOSþ ([Mþ1]þ) 262.1260, found 262.1250.
Acknowledgements
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Financial support for this research from the NSF
(_501100000930) (CHE-1056568), the Alfred P. Sloan Foundation
(_100000879), Amgen, Boehringer Ingelheim, Eli Lilly, Novartis
(_100004336), Boston University and University of Michigan is
gratefully acknowledged. Postdoctoral support from the Swedish
Research Council (to C.J.W.) is gratefully acknowledged.
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Supplementary data
Copies of 1H and 13C NMR spectra for all products. Supple-
mentary data associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2014.03.041.
29. Magerramov, A. M.; Allakhverdiev, A. M.; Akhmedova, Z. I.; Caple, R.; Zhdankin,
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Please cite this article in press as: Keylor, M. H.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.041