Redox-neutral α-sulfenylation of secondary amines: Ring-fused N,S-acetals

Article abstract of DOI:10.1021/ol501509b

Secondary amines react with thiosalicylaldehydes in the presence of catalytic amounts of acetic acid to generate ring-fused N,S-acetals in redox-neutral fashion. A broad range of amines undergo α-sulfenylation, including challenging substrates such morpholine, thiomorpholine, and piperazines. Computational studies employing density functional theory indicate that acetic acid reduces the energy barriers of two separate steps, both of which involve proton transfer.

Full text of DOI:10.1021/ol501509b

Letter
pubs.acs.org/OrgLett
Redox-Neutral α‑Sulfenylation of Secondary Amines: Ring-Fused
N,S‑Acetals
Claire L. Jarvis,† Matthew T. Richers,† Martin Breugst,‡,§ K. N. Houk,*,‡ and Daniel Seidel*,†
†Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854,
United States
‡Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
§Department fur Chemie, Universitat zu Koln, Greinstraße 4, 50939 Koln, Germany
̈
̈
̈
̈
S
* Supporting Information
ABSTRACT: Secondary amines react with thiosalicylaldehydes in the
presence of catalytic amounts of acetic acid to generate ring-fused N,S-
acetals in redox-neutral fashion. A broad range of amines undergo α-
sulfenylation, including challenging substrates such morpholine,
thiomorpholine, and piperazines. Computational studies employing
density functional theory indicate that acetic acid reduces the energy barriers of two separate steps, both of which involve proton
transfer.
he N,S-acetal motif is common in nature and is present as a
Scheme 1. Selected Approaches to N,S-Acetals
T
key functional group in pharmacologically active com-
pounds (Figure 1).1 N,S-Acetals have been investigated as
Figure 1. Examples of bioactive N,S-acetals.
sedatives (e.g., 1 and 2),1a antibacterials (e.g., 3),1d and cell
growth inhibitors (e.g., 4).1c Penicillins such as amoxicillin (5)
are widely used as antibacterial medicines.1i Traditional synthetic
approaches to ring-fused N,S-acetals include the condensation of
preformed imines with thiosalicylic acid, often requiring the
addition of a coupling reagent (e.g., Scheme 1).1a,2,3 Here we
report a new approach to N,S-acetals starting from thiosalicyl-
aldehydes and secondary amines. The key feature of this process
is a redox-neutral amine α-C−H bond functionalization with
concurrent N-alkylation/α-sulfenylation.4,5
Previous work in our group has focused on the redox-neutral
α-C−H bond functionalization of amines,6−8 including the α-
amination of secondary amines with o-aminobenzaldehydes7 and
α-oxygenation with salicylaldehydes.8 Through extensive ex-
perimental and computational studies, we have established the
mechanisms of the α-amination and α-oxygenation reactions and
revealed an important role for azomethine ylides as reactive
intermediates.9,10 We recognized that an analogous α-
sulfenylation of secondary amines with thiosalicylaldehydes
would provide a practical entry to ring-fused N,S-acetals not
easily accessible by other means. Based on the greater
nucleophilicity of thiols compared to alcohols, we anticipated
that α-sulfenylation might occur with a wider range of substrates.
The title reaction was evaluated using thiosalicylaldehyde (6-
S) and 1,2,3,4-tetrahydroisoquinoline (THIQ) as the model
substrates. Starting from conditions that were similar to those
found ideal for the formation of the corresponding aminal and
N,O-acetal analogues, a brief optimization survey was conducted
(Table 1). Remarkably, the reaction of thiosalicylaldehyde (6-S)
and THIQ was found to proceed in the absence of any additive at
room temperature in ethanol solution to provide product 7a in
40% yield (entry 1). In toluene as the solvent, an increased yield
of 51% was observed (entry 2). While higher temperatures
served to improve the yield further (entries 3 and 4), the addition
Received: May 26, 2014
© XXXX American Chemical Society
A
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Letter
a
Table 1. Evaluation of Reaction Conditions for α-
Scheme 2. Substrate Scope for the α-Sulfenylation
Sulfenylation of 1,2,3,4-Tetrahydroisoquinoline with
a
Thiosalicylaldehyde (6-S)
entry
AcOH (equiv)
solvent
temp (°C)
time (h)
yield (%)
1
2
3
4
5
6
0
EtOH
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
rt
9
18
0.5
0.17
2
40
51
0
rt
0
60
66
b
0
120
60
0.1
0.1
0.1
1.0
1.0
rt
90
60
60
rt
0.5
1
93
c
7
46
8
9
36
1.5
trace
18
60
a
Reactions were conducted on a 1 mmol scale. Yields correspond to
b
isolated yields of chromatographically purified product. Microwave
irradiation in sealed vial. Without molecular sieves.
c
of acetic acid was found to have a more dramatic effect. With 10
mol % of acetic acid, 7a was obtained in 90% yield following a
reaction time of just 2 h at room temperature (entry 5). Raising
the reaction temperature to 60 °C in an otherwise identical
experiment led to full conversion in only 30 min while allowing
for the isolation of 7a in 93%, the highest yield observed (entry
6). As previously noted in the corresponding N,O-acetal
formation,8 removal of water from the reaction mixture was
crucial in order to achieve rapid conversion. A reaction
conducted under otherwise optimal conditions but in the
absence of molecular sieves led to the formation of 7a in only
46% yield after 1 h (entry 7). Interestingly, increasing the amount
of acetic acid to one equivalent had a detrimental effect on
conversion and product yield while leading to an increased
formation of unidentified byproducts (entries 8 and 9). This
observation is in contrast to what was seen for N,O-acetal
formation where an increase in the amount of acid proved highly
beneficial.8
a
b
Reactions were performed on a 1 mmol scale. With 3 equiv of
amine.
aldehyde with either electron-donating or -withdrawing groups
was well tolerated.
In order to explore the regioselectivity of the N,S-acetal
formation for substrates with electronically similar α-C−H
bonds, 6-S was allowed to react with 1-methyl pyrrolidine and 1-
methylpiperidine (Scheme 3). Interestingly, in both cases the
a
Scheme 3. Regioselectivity of the α-Sulfenylation
The α-sulfenylation with thiosalicylaldehyde was evaluated
with a broad range of secondary amines (Scheme 2). A number of
cyclic amines such as pyrrolidine, piperidine, and azepane
underwent the reaction with thiosalicylaldehyde at moderate
temperatures to give products in generally good yields. Relatively
electron-deficient amines such as morpholine and N-phenyl-
piperazine, substrates that are typically rather reluctant to
undergo α-C−H bond functionalization, furnished the corre-
sponding products at elevated temperatures (microwave
irradiation at 120−150 °C). Initial attempts to synthesize these
N,S-acetals at 60−90 °C required longer reaction times to reach
complete consumption of the starting materials. In addition, it
was found that for these substrates, oxidative dimerization of
thiosalicylaldehyde to the corresponding disulfide was a
competing process. This undesirable reaction pathway was
reduced at elevated temperatures and further minimized by using
a larger excess of the amine (3 equiv). Under these conditions,
dibenzylamine, a representative open-chain substrate, generated
the corresponding product 7i in good yield. Several other cyclic
amines with benzylic α-C−H bonds, including the sterically
demanding 1-phenyl-THIQ, underwent N,S-acetal formation
under mild conditions. Finally, ring-substitution of thiosalicyl-
a
Reactions were performed on a 1 mmol scale.
product distribution reflects a preference for functionalization of
a secondary over an electronically favorable tertiary C−H bond.
With the increased atomic radius size of sulfur relative to oxygen,
steric constraints appear to have a far greater effect, outweighing
electronic effects in these instances. This is in stark contrast to the
corresponding aminal formation with 1-methylpyrrolidine and 1-
methylpiperidine that exhibit a pronounced preference for
tertiary C−H bond functionalization.7 Interestingly, the major
products 7r and 7t were also obtained in higher diastereomeric
ratios than their aminal counterparts.
To rationalize the enhanced reactivities in the N,S-acetal series
compared to the corresponding N,O-acetals, we analyzed the
model reaction between thiosalicylaldehyde (6−S) and THIQ
by the same computational method described previously (M06-
2X-D3/def2-TZVPP/IEFPCM(toluene)//TPSS-D2/6-31+
B
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Letter
G(d,p)/IEFPCM(toluene); see the Supporting Information for
details of the computational method).8
For the uncatalyzed reactions without acetic acid, the
calculated free energy profiles for the oxo- and thio pathways
are summarized in Figure 2. The hemiaminals 8-O and 8-S as
Figure 2. Free energy profile [in kcal·mol−1, M06-2X-D3/def2-TZVPP/
IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM] for uncatalyzed trans-
formations of 6-O (black) and 6-S (red) and THIQ in toluene.
Figure 3. Calculated transition-state structures [M06-2X-D3/def2-
TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM], relative free
energies (in kcal·mol−1), and selected bond lengths (in Å) for the
uncatalyzed and acetic-acid-catalyzed transformation of 6-S and THIQ.
well as the transition states for the dehydration (TS1-O/S) are
very similar for both systems. In contrast, a substantial difference
was calculated for all other intermediates and transition states.
While the sulfur-compound of 9, TS2, and 10 is 4−5 kcal mol−1
more stable than the oxygen analogue, differences of more than
10 kcal mol−1 were calculated for TS3, 11, and 7a. This stability
difference can also be rationalized with the higher acidity of
thiophenol compared to phenol in both DMSO (ΔpKa ≈ 8) and
aqueous solution (ΔpKa ≈ 3).11 This difference in acidity might
also be responsible for the fact that no thiosalicylaldehyde-
mediated proton transfer (e.g., the thio-analogue of TS3-O-
Sali)8 could be located.
Next, we analyzed whether acetic acid has the same catalytic
effect for the synthesis of N,S-acetals as previously described for
the corresponding N,O-acetals.8 Figure 3 summarizes the
calculated transition states for the uncatalyzed and acetic-acid-
catalyzed N,S-acetal formation. Similar to the formation of N,O-
acetals, acetic acid stabilizes the transition states TS1-S (ΔΔG⧧ =
−1.5 kcal mol−1) and TS3−S (ΔΔG⧧ = −2.6 kcal mol−1). As
previously reported for the formation of N,O-acetals,8 transition
state TS2−S for the endergonic transformation of 9-S to 10-S is
actually destabilized by acetic acid (ΔΔG⧧ = +10.9 kcal mol−1).
Again, a small barrier (with respect to 10-S) and the entropic
penalty (−TΔS) render TS2-S-HOAc less favorable than TS2-S
and are responsible for the preference of the intramolecular
proton transfer over the intermolecular process for this step.
Because of the higher acidities of thiols, the rate-determining
step (TS3-S) is lowered to a much smaller extent than in the
N,O-acetal series (2.6 vs 13.1 kcal mol−1). These computational
findings are also reflected in the experimental data of Table 1, as
acetic acid is not necessarily required as a catalyst for the
formation of N,S-acetals but is ultimately needed in the N,O-
acetal series.
In summary, a relatively mild and effective approach to ring-
fused N,S-acetals has been developed. Further exploration of
related processes is under active investigation.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, details of
computational methods, Cartesian coordinates, and energies of
all reported structures. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: houk@chem.ucla.edu.
*E-mail: seidel@rutchem.rutgers.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the NIH−NIGMS (Grant
R01GM101389-01 to D.S.) is gratefully acknowledged. We
thank Alena Yu. Platonova (Rutgers University) for conducting
preliminary experimental studies. This work used resources from
the UCLA Institute for Digital Research and Education (IDRE)
and the Cologne High Efficiency Operating Platform for
Sciences (CHEOPS). We are grateful to the Alexander von
Humboldt foundation (Feodor Lynen fellowship to M.B.), the
Fonds der Chemischen Industrie (Liebig scholarship to M.B.),
C
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Letter
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and the National Science Foundation (Grant No. CHE-1059084
to K.N.H.) for support of this research.
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