Modulation of Amide Bond Rotamers in 5-Acyl-6,7-dihydrothieno[3,2-c]pyridines

Article abstract of DOI:10.1021/acs.joc.5b00205

2-Substituted N-acyl-piperidine is a widespread and important structural motif, found in approximately 500 currently available structures, and present in nearly 30 pharmaceutically active compounds. Restricted rotation of the acyl substituent in such molecules can give rise to two distinct chemical environments. Here we demonstrate, using NMR studies and density functional theory modeling of the lowest energy structures of 5-acyl-6,7-dihydrothieno[3,2-c]pyridine derivatives, that the amide E:Z equilibrium is affected by non-covalent interactions between the amide oxygen and adjacent aromatic protons. Structural predictions were used to design molecules that promote either the E- or Z-amide conformation, enabling preparation of compounds with a tailored conformational ratio, as proven by NMR studies. Analysis of the available X-ray data of a variety of published N-acyl-piperidine-containing compounds further indicates that these molecules are also clustered in the two observed conformations. This finding emphasizes that directed conformational isomerism has significant implications for the design of both small molecules and larger amide-containing molecular architectures. (Figure Presented).

Full text of DOI:10.1021/acs.joc.5b00205

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Article
pubs.acs.org/joc
Modulation of Amide Bond Rotamers in 5‑Acyl-6,7-
dihydrothieno[3,2‑c]pyridines
Thomas Lanyon-Hogg,†,§ Markus Ritzefeld,†,§ Naoko Masumoto,† Anthony I. Magee,‡ Henry S. Rzepa,*,†
and Edward W. Tate*,†
†Department of Chemistry, Imperial College London, London SW7 2AZ, U.K.
‡National Heart and Lung Institute, Imperial College London, London SW7 2AZ, U.K.
S
* Supporting Information
ABSTRACT: 2-Substituted N-acyl-piperidine is a widespread and important structural
motif, found in approximately 500 currently available structures, and present in nearly
30 pharmaceutically active compounds. Restricted rotation of the acyl substituent in
such molecules can give rise to two distinct chemical environments. Here we
demonstrate, using NMR studies and density functional theory modeling of the lowest
energy structures of 5-acyl-6,7-dihydrothieno[3,2-c]pyridine derivatives, that the amide
E:Z equilibrium is affected by non-covalent interactions between the amide oxygen and
adjacent aromatic protons. Structural predictions were used to design molecules that promote either the E- or Z-amide
conformation, enabling preparation of compounds with a tailored conformational ratio, as proven by NMR studies. Analysis of
the available X-ray data of a variety of published N-acyl-piperidine-containing compounds further indicates that these molecules
are also clustered in the two observed conformations. This finding emphasizes that directed conformational isomerism has
significant implications for the design of both small molecules and larger amide-containing molecular architectures.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
The 2-substituted N-acyl-piperidine motif is present in a wide
range of molecular architectures,1 including those of bio-
logically active compounds.2 Restricted rotation about the
amide bond affects the chemical space sampled by the acyl
substituent and can therefore have an impact on molecular
properties; the pharmacological influence of restricted rotation
and atropisomerism is increasingly recognized in drug
discovery.3 This emerging challenge necessitates tools to
analyze and manipulate the conformation of target compounds.
5-Acyl-6,7-dihydrothieno[3,2-c]pyridines are a known class of
inhibitors of the protein Hedgehog acyltransferase, a key
regulator of embryonic neurogenesis and carcinogenesis.4 This
class of compounds contains a core 2-substituted N-acyl-
piperidine motif and exhibits an unequal distribution of
rotameric species. Low-temperature selective NOE assignment
of rotamers, in combination with density functional theory
(DFT) modeling, indicated the existence of a non-covalent
interaction (NCI) between the ortho position of a 2-phenyl N-
acyl-piperidine and the amide carbonyl, altering the amide
conformation. These tools were therefore used for de novo
design and analysis of 5-acyl-6,7-dihydrothieno[3,2-c]pyridines
with manipulated conformational preferences. Analysis of N-
acyl-piperidine-containing molecules identified an approxi-
mately equal distribution of rotamers in non-lactam compounds
that contain a rotatable amide, which would be amenable to
such conformational modulation. Moreover, strategies for
directing conformation are also of interest in larger peptide-
and peptoid-based architectures.
Compound 1 was synthesized from thiophene ethylamine by a
previously reported synthetic strategy5 with microwave
assistance to promote Bischler−Napieralski cyclization (Figure
1).6
1
The H NMR spectrum of 1 shows the presence of several
additional hydrogen environments (Figure 2A). The most
prominently shifted of these proton signals are a singlet and a
multiplet at 5.92 and 4.86 ppm, respectively, which are
separated from other hydrogen environments by >1 ppm.
Additional peaks can be observed at 6.69 and 2.28 ppm (Figure
2A). To investigate the significance of the amide bond in
generating these additional environments, we synthesized
acrylamide derivative 2, along with the corresponding
decarbonyl derivative 3, through reaction with allyl bromide.
As postulated, the acrylamide derivative exhibits the additional
hydrogen environments, whereas these are absent in the allyl
derivative (Figures S7 and S12), demonstrating the dependence
on the amide carbonyl and implicating restricted rotation about
the N−C bond.
1
To confirm that the additional peaks observed in the H
NMR spectrum corresponded to isomers of 1, we recorded the
NOESY spectra to identify exchangeable proton environments
(Figure S3). NOESY exchange peaks identify the prominently
shifted hydrogen environments at δ = 5.92 and 4.86 ppm as
corresponding to H6 and one H4 proton, respectively. In both
cases, the shifted protons are adjacent to the amide nitrogen.
Received: January 29, 2015
© XXXX American Chemical Society
A
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Figure 1. Synthesis strategy and structures of all 6,7-dihydrothieno[3,2-c]pyridines. General procedures: (A) PyBOP, DIPEA, DMF, rt, overnight;
(B) TEA, DCM, rt, overnight; (C) POCl3, P2O5, toluene, microwave (140 °C, 30 min); (D) POCl3, P2O5, toluene, 85 °C, 2 h; (E) NaBH4, rt, 1 h or
overnight; (F) TEA, DCM, rt, 2 h or overnight.
generates an NOE at piperidine H6 (Figure 2B), thus
confirming the minor and major conformations as E and Z,
respectively, in a 22:78 E:Z ratio.
It has been proposed that N-α aromatic amides may form
n−π*aryl interactions between the lone pair of the carbonyl and
the anti-bonding orbital of the adjacent aromatic ring.8 In such
cases, changes in the electronics of the ring system8,9 or the
nature of the lone pair donor have been used to modulate
n−π* interactions.10,11 In order to probe putative n−π*aryl
interactions in the described dihydrothieno[3,2-c]pyridine
system, the phenyl ring was replaced with a cyclohexane
moiety in compound 4 using the established synthetic route.
218 K NOESY of 4 (Figure S17) and selective NOE irradiation
of the methyl peaks (Figures S18 and S19) indicate a significant
increase in the proportion of the E-amide conformation, giving
an E:Z ratio of 57:43 (Table S6).
The cyclohexane ring of 4 causes a minimal increase in steric
encumbrance compared to 3, suggesting that the altered
conformational preference resulted from electronic factors.12
This promotion of the Z-conformer, however, could not be
definitively ascribed to the absence of the π* orbital and a loss
of a putative n−π*aryl interaction. We therefore proceeded to
increase the lone pair donor capability in the molecule by
1
Figure 2. (A) H NMR spectra of 1. (B) Selective NOE pulse of
exchanging the carbonyl oxygen with sulfur.11 The latter should
methyl environments at 2.19 (black) and 2.35 (red) ppm at 218 K
exhibit increased n−π*aryl donation and thereby result in a
demonstrates the major Z-conformer. All NMR spectra were recorded
higher population of the Z-amide.11 Thioamide 5 was
in CDCl3.
synthesized by thionation of 1 with Lawesson’s reagent, and
the conformations were assigned using low-temperature
NOESY and selective NOE experiments (Figures S24 and
S25). Analysis indicates an E:Z ratio similar to that of the
parent amide 1 (Figure S1), thus indicating that n−π*aryl
interactions are unlikely to modulate the amide conformation
in this system.
Molecular modeling was therefore applied to better under-
stand the factors governing the amide conformation. Although
n−CHσ*aryl “hydrogen-bonding” interactions have been
proposed to direct amide conformation in N-α aromatic
peptoids,12 natural bond orbital (NBO) analysis of compound
1 did not identify any substantial bonding interactions, and did
not prove to be discriminatory enough to detect the weaker
interactions affecting amide conformation. NBO analysis is
better suited for the investigation of through-bond effects rather
The two peaks presented by the acetyl methyl group also
exhibit exchangeable hydrogen environments, and the addi-
tional environment at 6.79 ppm corresponds to the H8 proton
of the thiophene ring. In order to assign E- and Z-amide
conformations to the major and minor proton environments,
we performed selective NOE experiments by pulsing at 2.19 or
2.35 ppm. At 298 K, significant crosstalk is observed between
environments due to amide rotation (data not shown). We
therefore performed low-temperature NMR experiments to
limit rotation on the NMR time scale.7 The corresponding
NOESY spectra at 218 K indicate the loss of exchange between
the proton peaks (Figure S4). Selective irradiation of the major
methyl environment at 2.19 ppm generates an NOE at
piperidine H4 (Figure 2B). Similarly, irradiation at 2.35 ppm
B
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Figure 3. Computed NCI surfaces of the lowest energy conformations of 1 (A), 4 (B), 6 (C), and 8 (D). NCI surfaces are color-coded from red and
yellow indicating destabilizing interactions to green and blue indicating increasing stabilization. See also Web-enhanced table table for interactive
versions of these diagrams and ref 15.
than through-space effects. In the described dihydrothieno[3,2-
c]pyridine system, the stereoselectivity is controlled by a
combination of stereoelectronically controlled bond orienta-
tions that are influenced by NCIs within the molecular
architecture. The balance of these interactions can be difficult
to compute from total free energies alone; however, the
recently introduced reduced electron density gradient is a more
useful means to reveal such NCIs.13,14 This index enables the
identification and characterization of the strength of NCIs as
chemically intuitive and visual isosurfaces that highlight
stabilizing hydrogen-bonding interactions in blue, weaker van
der Waals interactions in green, and destabilizing interactions
such as steric clashes in yellow to red.
We therefore applied DFT modeling and NCI analysis
(ωB97XD/TZVP/SCRF = chloroform)15 to compare small
energy differences between structures and the corresponding
populations of compounds 1 and 4 (Figure 3). This model
predicts that the amide lone pair in the Z-configuration is not in
the correct orientation to participate in an n−π*aryl interaction.
Compound 1 exhibits four potential conformations, corre-
sponding to two potential amide rotamers and the two
piperidine ring-flipped conformations (cf. Web-enhanced
table). Comparison of the relative energy of these conforma-
tions of 1 reveals that the Z-amide isomer is lower in free
energy than the E-amide (Table S1). The Boltzmann
population distribution of the four energy minima indicates
only significant population of the E- and Z-ground-state
conformers in a 16:84 E:Z ratio, in good agreement with
observed values (Tables S1 and S2). Prediction of the 1H NMR
chemical shifts for Z-1 provided resonances of the acetyl methyl
protons at an average value of 2.01 ppm and for the equatorial
H4 proton at 3.57 ppm, in good agreement with NOE results
(Table S3, Figure 2B). The predicted shifts for E-1 gave the
methyl protons at an averaged resonance of 2.36 ppm and H6
at 6.09 ppm, also in excellent agreement with experimental data
(Table S4, Figure 2B).
To understand the interactions influencing the energetic
stability of each rotamer of 1, NCI surfaces for each
conformation were inspected (Figure 3A).13,14,16 In the lowest
energy (Z)-amide conformation, the amide carbonyl group
forms a stabilizing NCI with the piperidine H6 proton and the
ortho aromatic proton. Additional favorable interactions are
found in both conformers between the thiophene ring and the
ortho proton of the phenyl ring, as well as between the phenyl
ring and the axial H4 proton of the piperidine ring. Compound
4 exhibits eight potential conformations, corresponding to
combinations of two potential amide rotamers, two piperidine
ring-flipped conformations, and two chair forms of the
cyclohexyl ring (cf. Web-enhanced table). The NCI surfaces
of the lowest energy conformations of 4 (Table S5) indicate
that the Z-conformation no longer benefits from favorable
interaction with the ortho position of the cyclohexyl ring
(Figure 3B). Correspondingly, the lowest energy E- and Z-
conformations are energetically equal, with the next highest
energy levels corresponding to rotation about the C6-
cyclohexyl bond. The calculated energy levels did not indicate
any prominent interactions favoring E- or Z-conformers (Table
S5), in good agreement with the observed 57:43 E:Z ratio.
1
Weighting the predicted H NMR chemical shifts for each E-
and Z-energy level against the predicted Boltzmann population
gives an average chemical shift prediction. The calculated
average resonance for the Z-4 acetyl methyl protons is 2.03
ppm (Table S7, Figure S14); low-temperature selective NOE
experiments irradiating at the piperidine H4 resonances give an
NOE at 2.14 ppm (Table S8, Figure S19).
With robust systems in place to predict and measure amide
conformations, molecules were designed to promote either the
E- or Z-conformer. Replacing the ortho CH of the phenyl
moiety of 1 with 2-pyridyl derivative 6 was envisaged to
promote the E-configuration by reversing the electrostatic
interactions. Compound 6 exhibits eight potential conforma-
tions, corresponding to combinations of two amide rotamers,
two piperidine ring-flipped conformations, and two rotated
C
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conformations about the C6-pyridine bond (cf. Web-enhanced
table). The NCI surface prediction for 6 indicates that the
nitrogen atom induces electrostatic repulsion with the carbonyl
oxygen in the Z-conformer (Figure 3C), resulting in no
predicted preference for the E- or Z-conformer within the
accuracy of the calculations. Compound 6 was synthesized from
2-picolinic acid using the established synthetic route, and the
conformation was assigned using the described approach
NOE pulsed at the methyl environment at 2.23 ppm, both at
room temperature, were used to confirm the exclusive presence
of the intended Z-conformation (Figures S39−S41). The
existence of the proposed hydrogen bond between the carbonyl
and hydroxyl groups was supported by good agreement
between the predicted and observed chemical shifts at 9.94
and 9.83 ppm, respectively. DFT prediction of the 1H chemical
shift has been applied to a crystallographically validated
hydrogen-bonded proton, similarly demonstrating good agree-
ment between predicted and observed values.20 In order to
confirm the presence of the putative hydrogen bond, the solid-
state IR spectrum of 8 was recorded (Figure S43). This
demonstrated a νmax(OH) at 3088 cm−1, indicative of a strong
intramolecular hydrogen bond to the hydroxyl group.21 The
lower hydroxyl vibrational frequency observed was also in
agreement with DFT calculation of the lowered harmonic
1
combining weighted H NMR prediction (Tables S11 and
S12), low-temperature NOESY, and selective NOE experi-
ments (Figures S29 and S30). As predicted, 6 exhibits an
increased propensity for the E-conformer compared to
compound 1, with an E:Z ratio of 48:52, in good agreement
with the predicted absence of Z-conformational preference.
1
Additionally, H NMR spectra of compounds 4 and 6 were
recorded from 297 to 378 K and from 308 to 408 K which gave
coalescence temperatures of 368 and 358 K, approximately
corresponding to ΔG⧧ values of 18.9 and 18.4 kcal/mol,
respectively (section 2.16 in the Supporting Information). Both
free activation energies are typical for hindered internal
rotations in N,N-dialkylamides.17
1
oscillation of the hydroxyl group of 8 (Figure S43). The H
NMR spectra of 8 recorded in DMSO-d6 resulted in an E:Z
ratio of 40:60 (Figure S42). As a polar aprotic solvent, DMSO
acts as a potent hydrogen-bond acceptor, thereby disrupting the
internal hydrogen bond of 8. Attempts to assess the effect of
polar protic solvents (D2O, MeOD) on the hydrogen-bonding
and conformational ratio of 8 were unsuccessful due to poor
solubility. Mixed-solvent D2O:DMSO-d6 1H NMR analysis of 8
maintained a 40:60 E:Z ratio up to 30% D2O, above which D2O
concentration 8 precipitated. Investigation of the conformation
properties of more water-soluble 5-acyl-6,7-dihydrothieno[3,2-
c]pyridine derivatives in polar protic solvents is therefore
continuing in our laboratory.
Increasing the strength of the interaction between the
carbonyl group and the aromatic ring should promote the Z-
conformation.18 A hydroxyl group was therefore inserted at the
phenyl ortho position, which was predicted to be in correct
alignment to hydrogen-bond with the carbonyl with a CO−HO
bond distance of 1.71 Å and a 6° deviation from linearity in the
CO−HO bond (Figure 3D).19 Indeed, NBO analysis of the
ground state of the ortho-hydroxy derivative indicated strong
bonding interactions between both carbonyl oxygen lone pairs
and the hydroxyl σ* (16.7 and 6.5 kcal/mol for σ-character and
π-character lone pairs, respectively) (cf. Web-enhanced table).
Compound 8 exhibits eight potential conformations, corre-
sponding to combinations of two amide rotamers, two
piperidine ring-flipped conformations, and two rotated
conformations about the C6−phenol bond (cf. Web-enhanced
table). DFT analysis of the energy levels of these conformations
predicted that the three lowest energy conformers exhibit the
Z-conformation. The lowest energy E-conformer was less
favored by 5.1 kcal/mol, equating to a relative population
distribution of ∼5000:1. The required molecule was synthe-
sized from 2-methoxybenzoic acid, initially affording 2-methoxy
derivative 7. Low-temperature NOESY and NOE spectra
indicate that 7 preferentially adopted the E-conformation,
with and E:Z of 80:20, providing a more effective means to
repel the amide carbonyl into the E-conformation. Demethy-
lation of 7 with tribromoborane furnished the required phenol
8 (Figure 1). 1H NMR spectra of 8 recorded in CDCl3 indicate
that, as predicted, only a single amide conformation is observed
(Table 1, Figure S37). NOESY spectroscopy and selective
CONCLUSION
■
The 2-substituted N-acyl-piperidine motif can be found in a
range of known molecular architectures and biologically active
compounds. Further analysis of the 474 2-substituted N-acyl-
piperidine-containing structures available in the Cambridge
Crystallographic Database identifies a subset of 186 amides in
which an acyclic amide bond is present. Evaluation of the
torsion angle about the C−N−C−O bond in these hits
indicates a clustering of the compounds in approximately equal
population for the E- and Z-conformers at 0° and 180°,
respectively (Figure S74).1 These 186 compounds should be
amenable to predictive and designed conformational modu-
lation using the approach presented here. Remarkably, the ortho
phenol 2-substituted N-acyl-piperidine motif of compound 8
represents a currently unreported molecular architecture. We
speculate that predictable modulation of the amide conforma-
tion in this class of molecules may additionally be used to
promote target binding of bioactive molecules by biasing
toward the correct binding conformation. Of the 29 bioactive
compounds in the DrugBank database containing the core
motif, including 13 approved and 3 investigational drugs, 20
have rotatable amide substituents.2 Strategies to lock molecules
in the correct binding conformation commonly involve
rigidifying the molecule through the insertion of a ring system;
however, this often results in decreased solubility, through
increased lattice energy and predominantly increased logP.22
The use of heteroatom insertion presented here may be seen as
an alternative to cyclization to promote the required amide
conformation without concomitant increase in clogP (Table
S15). Ongoing research in our laboratory is focused on
assessing the effect of conformational modulation on the
biological activity of the 5-acyl-6,7-dihydrothieno[3,2-c]-
pyridines.
Table 1. Comparison of Calculated and Observed Amide E:Z
Ratios of 6,7-Dihydrothieno[3,2-c]pyridine Derivatives at
298 K
compd
substituent (R1)
cald E:Z
obsd E:Z
solvent
1
4
6
7
phenyl
16:84
57:43
59:41
N/D
0:100
N/D
22:78
57:43
48:52
80:20
0:100
40:60
CDCl3
CDCl3
cyclohexyl
2-pyridyl
CDCl3
2-methoxyphenyl
CDCl3
CDCl3
8
2-phenol
DMSO-d6
D
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mmol, 10 equiv) were added to a suspension of P2O5 (160 mg, 1.14
mmol, 3 equiv) in dry toluene (2 mL). The mixture was heated by
microwave irradiation at 140 °C for 0.5 h. The temperature was
gradually increased. Subsequently, the reaction mixture was basified
(pH = 10) using an aqueous solution of NaOH (20% v/v). The
organic phase was separated and dried over MgSO4, the solvent was
removed in vacuum, and the residual was purified by column
chromatography.
General Procedure D: Bischler−Napieralski Reaction under
Reflux Conditions. A mixture of the acylated thiophene ethylamine
derivative (0.84 mmol, 1 equiv), POCl3 (0.23 mL, 388 mg, 2.53 mmol,
3 equiv), and P2O5 (359 mg, 2.53 mmol, 3 equiv) dissolved in xylene
(3 mL) was heated at 85 °C for 2 h. Subsequently, the reaction
mixture was basified (pH = 10) using an aqueous solution of NaOH
(20% v/v). The organic phase was diluted with toluene, separated, and
dried over MgSO4, and the solvent was removed in vacuum. The cyclic
imine was used without further purification.
General Procedure E: Reduction of the Imine. The cyclic
imine obtained from general procedure C (12b−15b) or 7-cyclohexyl-
6,7-dihydrothieno[3,2-c]pyridine (16b) (0.41 mmol, 1 equiv) was
dissolved in dry methanol (1.6 mL). NaBH4 (23 mg, 0.62 mmol, 1.5
equiv) was added to the solution in small portions, and the reaction
mixture was stirred at rt for 1 h or overnight. Afterward, the mixture
was concentrated in vacuum, and the residual was redissolved in H2O
(1 mL) and extracted using DCM. The organic phase was dried over
MgSO4 and the solvent removed in vacuum. The amine was used
without further purification.
General Procedure F: Coupling of the Side Chain Using Acid
Chlorides. The amine obtained from general procedure E (0.09
mmol, 1 equiv) and TEA (0.025 mL, 18 mg, 0.18 mmol, 2 equiv) were
dissolved in dry DCM (1 mL). Subsequently, the corresponding acid
chloride (0.11 mmol, 1.2 equiv) was added, and the reaction mixture
was stirred at rt for 2 h. Afterward the solvent was removed in vacuum,
and the residual was purified by column chromatography.
The computational studies presented here provide a
powerful tool for the design and analysis of molecules with
required conformations. NCI analysis is a superior method
compared to NBO analysis for determining low-energy,
through-space interactions that may have profound implications
on the conformational properties of molecules. The combina-
tion of chemical shift predictions for conformers with weighting
from the Boltzmann population distribution of the calculated
energy levels provides an accurate method for predicting NMR
signals of each conformer. Calculated NMR shifts predom-
inantly show <0.3 ppm deviation from observed values, with
the exception of the six-membered aromatic ring protons
(Tables S3, S4, S7, S8, S11, S12, and S14). NCI surface
visualization provides a simple visual model for the analysis of
detailed intramolecular interactions that impact on the
conformation, and we envisage that this approach will be
adopted as a facile tool to aid synthetic chemists in the design
and understanding of molecules.15
In summary, we have identified amide bond rotamers in 2-
substituted N-acyl-piperidines, assigned their conformations
through a combination of NOE experiments at low temperature
to limit amide rotation, and established a predictive structural
model that enabled design of molecules with programmed
changes in conformational preference. Taken together, the de
novo design and heteroatom insertions presented here provide a
powerful method for modulation of amide conformation
through either attractive hydrogen-bonding or repulsive
electronic interactions.
EXPERIMENTAL SECTION
■
Microwave reactions were performed using a Biotage Initiator. 1H
NMR and 13C NMR spectra were recorded at room temperature at
500 and 125 MHz, or 400 and 100 MHz, respectively. Chemical shifts
(δ) are reported in parts per million (ppm) relative to residual solvent
peaks as internal standard. Coupling constants (J) are reported in hertz
(Hz). The peaks corresponding to the conformers are labeled with E
or Z, respectively. Selective NOE and 2D-NOESY spectra were
recorded at 400 and 500 MHz at room temperature or 221 and 218 K,
respectively. High-temperature 1H NMR spectra were recorded at 500
MHz in 1,1,2,2-tetrachloroethane-d2 from 308 to 408 K in steps of 10
K. High-resolution mass spectrometry (HRMS) was performed using
electrospray ionization (ESI) and time-of-flight (TOF) mass analysis.
All details regarding the DFT modeling can be found at doi:10.6084/
m9.figshare.1181739.
N-[2-(2-Thienyl)ethyl]benzamide (9a). The amide 9a was
obtained from 2-(3-thienyl)ethylamine (0.50 mL, 543 mg, 4.3 mmol,
1 equiv) and benzoic acid (557 mg, 4.7 mmol, 1.1 equiv), using
general procedure A, as a cream-colored solid (692 mg, 5.6 mmol,
70%). Rf = 0.44 (SiO2; EtOAc:Hex, 4:6); 1H NMR (400 MHz,
3
4
CDCl3) δ = 7.77−7.67 (m, 2H), 7.57−7.44 (tt, J = 7.4 Hz, J = 1.4
Hz, 1H), 7.44−7.33 (m, 2H), 7.17 (dd, 3J = 5.1 Hz, 4J = 1.2 Hz, 1H),
6.96 (dd, 3J = 5.2, 3.4 Hz, 1H), 6.88−6.85 (m, 1H), 6.47 (s, 1H), 3.72
3
(q, 3J = 6.5 Hz, 2H), 3.15 (t, J = 6.5 Hz, 2H); 13C NMR (101 MHz,
CDCl3) δ = 167.6, 141.3, 134.6, 131.5, 128.6, 127.2, 126.9, 125.5,
124.1, 41.4, 30.0; HRMS (ESI, m/z) calcd for C13H14NOS 232.0796,
found 232.0796.
4-Phenyl-6,7-dihydrothieno[3,2-c]pyridine (9b). The cyclic
imine 9b was obtained from N-[2-(2-thienyl)ethyl]benzamide (9a)
(290 mg, 1.3 mmol, 1 equiv), using general procedure D, as an orange
oil (159 mg, 0.75 mmol, 57%). Rf = 0.43 (SiO2; EtOAc:TEA, 100:1);
1H NMR (400 MHz, CDCl3) δ = 7.69−7.65 (m, 2H), 7.46−7.40 (m,
General Procedure A: Thiophene Ethylamide Preparation
Using (Benzotriazol-1-yloxy)tripyrrolidinophosphonium Hexa-
fluorophosphate (PyBOP). 2-(3-Thienyl)ethylamine (0.5 mL, 543
mg, 4.3 mmol, 1 equiv) was added to a solution of the corresponding
carboxylic acid (4.73 mmol, 1.1 equiv), PyBOP (2.45 g, 4.73 mmol, 1.1
equiv), and N,N-diisopropylethylamine (DIPEA, 2.3 mL, 1.67 g, 12.9
mmol, 3 equiv) in DMF (2 mL). The reaction mixture was stirred at rt
overnight. Afterward, DCM (30 mL) was added, and the solution was
washed with an aqueous solution of LiCl (5% m/m) and brine to
remove excess DMF. The organic layer was dried over MgSO4, the
solvent was removed in vacuum, and the residual was purified by
column chromatography.
General Procedure B: Thiophene Ethylamide Preparation
Using Acid Chlorides. Thiophene ethylamine (0.5 mL, 543 mg, 4.3
mmol, 1 equiv) was added dropwise (exothermic reaction) to a
solution of the corresponding carboxylic acid chloride (5.16 mmol, 1.2
equiv) and triethylamine (TEA, 1.2 mL, 870 mg, 2 equiv) in dry DCM
(5 mL). The reaction mixture was stirred at rt overnight. Afterward,
the solvent was removed in vacuum, and the residual was purified by
column chromatography.
3
3
3H), 7.09 (d, J = 5.2 Hz, 1H), 7.01 (d, J = 5.2 Hz, 1H), 3.97−3.93
(m, 2H), 2.95−2.91 (m, 2H); 13C NMR (101 MHz, CDCl3) δ =
162.9, 144.5, 139.2, 130.9, 129.7, 128.4, 128.2, 126.2, 121.5, 48.4, 22.4;
HRMS (ESI, m/z) calcd for C13H11NS 214.0690, found 214.0695.
4-Phenyl-4,5,6,7-tetrahydrothiene[3,2-c]pyridine (9c). The
cyclic amine 9c was obtained from 4-phenyl-6,7-dihydrothiene[3,2-
c]pyridine (9b) (149 mg, 0.70 mmol, 1 equiv), using general
1
procedure, E as a yellow solid (106 mg, 0.49 mmol, 70%). H NMR
(400 MHz, CDCl3) δ = 7.36−7.27 (m, 5H), 7.01 (d, 3J = 5.2 Hz, 1H),
6.47 (d, 3J = 5.2 Hz, 1H), 5.04 (s, 1H), 3.34−3.29 (m, 1H), 3.14−3.08
(m, 1H), 3.04−2.96 (m, 1H), 2.89−2.82 (m, IH), 2.09 (br s, 1H); 13C
NMR (101 MHz, CDCl3) δ = 143.7, 136.8, 135.1, 128.6, 128.5, 127.7,
126.5, 121.9, 60.2, 42.7, 26.1; HRMS (ESI, m/z) calcd for C13H14NS
216.0847, found 216.0855.
[2-(2-Thienyl)ethylamino](m-tolyl)formaldehyde (10a). The
amide 10a was obtained from 2-(3-thienyl)ethylamine (0.79 mL, 0.85
mg, 6.7 mmol, 1 equiv) and m-toluic acid (1000 mg, 7.3 mmol, 1.1
equiv), using general procedure A, as a white solid (1480 mg, 7.2
General Procedure C: Bischler−Napieralski Reaction under
Microwave Conditions. The acylated thiophene ethylamine
derivative (0.38 mmol, 1 equiv) and POCl3 (0.35 mL, 578 mg, 3.8
1
mmol, 98%). Rf = 0.3 (SiO2; EtOAc:Hex, 4:6); H NMR (400 MHz,
E
DOI: 10.1021/acs.joc.5b00205
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
CDCl3) δ 7.59 (s, 1H), 7.51 (t, 3J = 3.5 Hz, 1H), 7.32−7.30 (m, 2H),
7.20 (dd, 3J = 5.1 Hz, 4J = 1.0 Hz, 1H), 6.98 (dd, 3J = 5.1 Hz, 3J = 3.5
Hz, 1H), 6.89 (d, 3J = 3.3 Hz, 1H), 3.74 (q, 3J = 6.5 Hz, 2H), 3.17 (t,
3J = 6.6 Hz, 2H), 2.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 167.7,
141.4, 138.4, 134.5, 132.2, 128.4, 127.7, 127.1, 125.5, 124.0, 123.8,
60.4, 41.3, 30.0, 21.4, 14.2; HRMS (ESI, m/z) calcd for C14H16NOS
246.0947, found 246.0960.
164.4, 149.9, 148.1, 141.3, 137.3, 127.0, 126.2, 125.3, 123.9, 122.2,
40.9, 30.1; HRMS (ESI, m/z) calcd for C12H13N2OS 233.0749, found
233.0752.
7-(2-Pyridyl)-6,7-dihydrothieno[3,2-c]pyridine (12b). The
cyclic imine 12b was obtained from 2-picolinic acid (2-thiophen-2-
ylethyl)amide (12a) (400 mg, 1.7 mmol, 1 equiv), using general
procedure C, as a brown oil (124 mg, 0.6 mmol, 34%). Rf = 0.38
1
(SiO2; EtOAc:TEA, 100:1); H NMR (400 MHz, CDCl3) δ = 8.68
4-(m-Tolyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (10c).
The cyclic imine, 4-(m-tolyl)-6,7-dihydrothieno[3,2-c]pyridine (10b),
was obtained from [2-(2-thienyl)ethylamino](m-tolyl)formaldehyde
(10a) (700 mg, 2.9 mmol, 1 equiv), using general procedure D, as an
orange oil (620 mg, 2.7 mmol, 93%). Rf = 0.8 (MeOH:EtOAc:NEt3,
10:90:1). The subsequent reduction was carried out without
3
4
3
4
(dt, J = 5.1 Hz, J = 1.5 Hz, 1H), 8.00 (dd, J = 7.7 Hz, J = 1.3 Hz,
1H), 7.81 (td, 3J = 7.7 Hz, 4J = 1.5 Hz, 1H), 7.54 (d, 3J = 5.3 Hz, 1H),
7.36 (m, 1H), 7.12 (d, 3J = 5.3 Hz, 1H), 4.03 (t, 3J = 8.5 Hz, 2H), 2.97
(t, J = 8.5 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ = 161.4, 156.9,
3
148.5, 144.6, 136.7, 130.0, 127.1, 124.1, 122.6, 121.2, 48.5, 22.2;
HRMS (ESI, m/z) calcd for C12H11N2S 215.0643, found 215.0655.
7-(2-Pyridyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (12c).
The amine 12c was obtained from 7-(2-pryidyl)-6,7-dihydrothieno-
[3,2-c]pyridine (12b) (105 mg, 0.5 mmol, 1 equiv), using general
procedure E, as a brown oil (61 mg, 0.3 mmol, 58%). Rf = 0.10 (SiO2;
1
purification. H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.46 (d,
3J = 7.5 Hz, 1H), 7.32 (t, 3J = 7.5 Hz, 1H), 7.27 (d, 3J = 7.2 Hz, 1H),
3
3
7.08 (d, J = 6.7 Hz, 1H), 7.03 (d, J = 5.2 Hz, 1H), 3.99−3.93 (m,
2H), 2.97−2.89 (m, 2H), 2.41 (s, 3H). The cyclic amine 10c was
obtained from 10b (620 mg, 2.7 mmol, 1 equiv), using general
procedure E, as a yellow solid (yield over two steps: 387 mg, 1.7
mmol, 63%). Rf = 0.3 (SiO2; MeOH:EtOAc:NEt3, 10:90:1); 1H NMR
1
3
EtOAc:TEA, 100:1); H NMR (400 MHz, CDCl3) δ = 8.60 (dt, J =
4.9 Hz, 4J = 1.5 Hz, 1H), 7.66 (td, 3J = 7.7 Hz, 4J = 1.5 Hz, 1H), 7.25
(dd, 3J = 7.7 Hz, 4J = 1.0 Hz 1H), 7.18−7.22 (m, 1H), 7.05 (d, 3J = 5.2
Hz, 1H), 6.58 (d, 3J = 5.2 Hz, 1H), 5.19 (t, 3J = 2.0 Hz, 1H), 3.32 (dt,
3
(400 MHz, CDCl3) δ 7.26 (t, J = 7.5 Hz, 1H), 7.18−7.09 (m, 2H),
7.04 (d, 3J = 5.2 Hz, 1H), 6.53 (d, 3J = 5.2 Hz, 1H), 5.03 (s, 1H), 3.36
(dt, 2J = 12.0 Hz, 3J = 4.8 Hz, 2H), 3.18−3.11 (m, 1H), 3.09−2.99 (m,
1H), 2.89 (dt, 2J = 15.9 Hz, 3J = 3.3 Hz, 2H), 2.39 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ = 143.7, 138.2, 137.0, 134.9, 129.0, 128.4, 128.4,
126.5, 125.4, 121.7, 77.5, 77.2, 76.9, 60.2, 42.7, 26.2, 21.5; HRMS (ESI,
m/z) calcd for C14H16NS 230.0998, found 230.1003.
3J = 12.4 Hz, J = 4.9 Hz, 1H), 3.22−3.09 (m, 1H), 3.06−2.95 (m,
3
1H), 2.93−2.86 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 162.2,
149.5, 136.6, 135.3, 135.3, 125.9, 122.5, 122.5, 122.1, 61.0, 42.2, 25.9;
HRMS (ESI, m/z) calcd for C12H13N2S 217.0803, found 217.0799.
2-Methoxybenzoic Acid (2-Thiophen-2-ylethyl)amide (13a).
The amide 13a was obtained from 2-(3-thienyl)ethylamine (0.5 mL,
543 mg, 4.3 mmol, 1 equiv) and 2-methoxybenzoic acid (719 mg, 4.73
mmol, 1.1 equiv), using general procedure A, as a colorless oil (769
Cyclohexanecarboxylic Acid (2-Thiophen-2-ylethyl)amide
(11a). The amide 11a was obtained from 2-(3-thienyl)ethylamine
(0.46 mL, 496 mg, 3.9 mmol, 1 equiv) and cyclohexanecarboxylic acid
chloride (0.64 mL, 689 mg, 4.7 mmol, 1.2 equiv), using general
procedure B, as a colorless oil (881 mg, 3.7 mmol, 85%). Rf = 0.36
1
mg, 3.1 mmol, 73%). Rf = 0.52 (SiO2; EtOAc:Hex, 4:6); H NMR
(400 MHz, CDCl3) δ = 8.22 (dd, J = 7.8 Hz, J = 1.9 Hz, 1H), 8.04
3
4
1
3
4
(SiO2; EtOAc:Hex, 3:7); H NMR (400 MHz, CDCl3) δ = 7.16 (dd,
(s, 1H, NH), 7.45−7.40 (m, 1 H), 7.19 (dd, J = 5.1 Hz, J = 1.2 Hz,
1H), 7.09−7.05 (m, 1H), 6.98−6.89 (m, 3H), 3.82 (s, 1H), 3.77 (q, 3J
= 6.8 Hz, 3J = 12.2 Hz, 2H), 3.15 (t, 3J = 6.8 Hz, 2H); 13C NMR (101
MHz, CDCl3) δ = 165.3, 157.6, 142.1, 132.8, 132.4, 127.1, 125.5,
124.0, 121.6, 121.4, 111.4, 110.1, 55.8, 41.2, 30.1; HRMS (ESI, m/z)
calcd for C14H16NO2S 262.0902, found 262.0916.
3J = 5.1 Hz, 4J = 1.2 Hz, 1H), 6.95 (dd, 3J = 5.1 Hz, 3J = 3.4 Hz, 1H),
6.82 (dd, 3J = 3.4 Hz, 4J = 1.2 Hz, 1H), 5.61 (s, 1H, NH), 3.51 (q, 3J =
3
3
6.4 Hz, 2H), 3.02 (t, J = 6.4 Hz, 2H), 2.03 (tt, J = 11.8 Hz, 3J = 3.4
3
3
Hz, 1H), 1.79 (m, 4H), 1.65 (m, 1H), 1.4 (qd, J = 11.8 Hz, J = 2.4
Hz, 4H), 1.23 (m, 6H); 13C NMR (101 MHz, CDCl3) δ = 177.1,
141.6, 127.1, 125.4, 123.9, 45.5, 40.6, 30.0, 29.7, 25.7; HRMS (ESI, m/
z) calcd for C13H20NOS 238.1266, found 238.1257.
7-(2-Methoxyphenyl)-6,7-dihydrothieno[3,2-c]pyridine
(13b). The cyclic imine 13b was obtained from 2-methoxybenzoic
acid (2-thiophen-2-ylethyl)amide (13a) (100 mg, 0.38 mmol, 1 equiv),
using general procedure C, as a colorless oil (40 mg, 0.16 mmol, 43%).
Rf = 0.48 (SiO2; EtOAc:TEA, 100:1); 1H NMR (400 MHz, CDCl3) δ
7-Cyclohexyl-6,7-dihydrothieno[3,2-c]pyridine (11b). The
cyclic imine 11b was obtained from cyclohexanecarboxylic acid (2-
thiophen-2-ylethyl)amide (11a) (200 mg, 0.84 mmol, 1 equiv), using
general procedure D, as a colorless oil (150 mg, 0.68 mmol, 81%). 1H
NMR (400 MHz, CDCl3) δ = 7.13 (d, 3J = 5.2 Hz, 1H), 7.08 (d, 3J =
5.2 Hz, 1H), 3.78 (t, 3J = 8.2 Hz, 2H), 2.80 (t, 3J = 8.2 Hz, 2H), 2.66
(m, 1H), 1.87 (m, 5), 1.73 (m, 1H), 1.37 (m, 4H); 13C NMR (101
MHz, CDCl3) δ = 124.1, 122.0, 47.7, 44.6, 30.9, 26.6, 26.4, 22.4;
HRMS (ESI, m/z) calcd for C13H18NS 220.1160, found 220.1164.
7-Cyclohexyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (11c).
The cyclic amine 11c was obtained from 7-cyclohexyl-6,7-
dihydrothieno[3,2-c]pyridine (11b) (90 mg, 0.41 mmol, 1 equiv),
using general procedure E, as an orange oil (56 mg, 0.25 mmol, 62%).
1H NMR (400 MHz, CDCl3) δ = 7.05 (d, 3J = 5.2 Hz, 1H), 6.81 (d, 3J
= 5.2 Hz, 1H), 3.82 (dt, 3J = 3.7 Hz, 3J = 1.9 Hz, 1H), 3.35−3.30 (m,
1H), 2.99−2.92 (m, 1H), 2.84−2.69 (m, 2H), 1.86−1.79 (m, 1H),
1.72−1.66 (m, 5H), 1.45−1.01 (m, 5H); 13C NMR (101 MHz,
CDCl3) δ = 137.4, 135.0, 127.2, 125.2, 121.6, 60.1, 43.2, 42.9, 30.7,
27.1, 27.0, 26.8, 26.7, 26.4; HRMS (ESI, m/z) calcd for C13H20NS
222.1316, found 222.1317.
3
4
= 7.40−7.34 (m, 2H), 7.01 (td, J = 7.5 Hz, J = 1.0 Hz, 1H), 6.97−
6.93 (m, 2H), 6.69 (d, 3J = 5.2 Hz, 1H), 4.00 (t, 3J = 8.2 Hz, 2H), 3.73
(s, 3H), 2.96 (t, J = 8.2 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ =
3
162.1, 157.2, 142.4, 132.2, 130.4, 130.0, 129.0, 127.1, 126.2, 121.2,
120.9, 111.2, 110.1, 55.6, 48.3, 43.0, 22.2; HRMS (ESI, m/z) calcd for
C14H14NOS 244.0796, found 244.0805.
7-(2-Methoxyphenyl)-4,5,6,7-tetrahydrothieno[3,2-c]-
pyridine (13c). The amine 13c was obtained from 7-(2-
methoxyphenyl)-6,7-dihydrothieno[3,2-c]pyridine (13b) (235 mg,
0.97 mmol, 1 equiv), using general procedure E, as a white solid
1
(160 mg, 0.65 mmol, 67%). Rf = 0.40 (SiO2; EtOAc:TEA, 100:1); H
3
NMR (400 MHz, CDCl3) δ = 7.29−7.24 (m, 1H), 7.05 (d, J = 5.2
3
Hz, 1H), 6.95−6.93 (m, 2H), 6.87 (td, J = 7.4 Hz, 4J = 1.1 Hz, 1H),
3
6.56 (d, J = 5.2 Hz, 1H), 5.51 (s, 1H), 3.90 (s, 3H), 3.20−3.14 (m,
1H), 3.10−3.04 (m, 1H), 2.93−2.90 (m, 2H); 13C NMR (101 MHz,
CDCl3) δ = 157.2, 136.3, 135.4, 131.6, 129.5, 128.5, 126.6, 121.7,
120.3, 110.5, 55.5, 53.0, 41.4, 26.3; HRMS (ESI, m/z) calcd for
C14H16NOS 246.0953, found 246.0952.
2-Picolinic Acid (2-Thiophen-2-ylethyl)amide (12a). The
amide 12a was obtained from 2-(3-thienyl)ethylamine (0.50 mL,
543 mg, 4.3 mmol, 1 equiv) and 2-picolinic acid (582 mg, 4.7 mmol,
1.1 equiv), using general procedure A, as a colorless oil (638 mg, 2.8
1-[4-Phenyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-
ethanone (1). The amide 1 was obtained from 7-phenyl-4,5,6,7-
tetrahydrothieno[3,2-c]pyridine (9c) (30 mg, 0.14 mmol, 1 equiv) and
acetyl chloride (0.012 mL, 13 mg, 0.17 mmol, 1.2 equiv), using general
procedure G, as a white solid (16 mg, 0.06 mmol, 44%). Rf = 0.50
(SiO2; EtOAc); 1H NMR (400 MHz, CDCl3) δ = 7.34−7.21 (m, 5H),
1
mmol, 64%). Rf = 0.64 (SiO2; EtOAc:TEA, 100:1); H NMR (400
3
4
MHz, CDCl3) δ = 8.52 (dt, J = 5.0 Hz, J = 1.4 Hz, 1H), 8.34−8.14
(s, 1H), 8.20 (dt, 3J = 7.8 Hz, 4J = 0.8 Hz, 1H), 7.83 (td, 3J = 7.8 Hz, 4J
= 1.4 Hz, 1H), 7.41 (m, 1H), 7.16 (dd, 3J = 5.2 Hz, 4J = 1.5 Hz, 1H),
3
3
7.12 (d, J = 5.1 Hz, 1H), 6.89 (s, 1H, ma), 6.75 (d, J = 5.1 Hz, 1H,
6.95 (dd, J = 5.2, 3.5 Hz, 1H), 6.91−6.84 (m, 1H), 3.76 (q, J = 6.8
mi), 6.69 (d, 3J = 5.1 Hz, 1H, ma), 5.92 (s, 1H, mi), 4.86−4.82 (m, 1H,
mi), 3.81 (dd, J = 14.0, 5.2 Hz, 1H, ma), 3.39−3.31 (m, 1H, ma),
3
3
Hz, 2H), 3.16 (t, 3J = 6.8 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ =
3
F
DOI: 10.1021/acs.joc.5b00205
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3.02−2.85 (m, 2H), 2.82−2.78 (m, 1H, mi), 2.28 (s, 3H, mi), 2.15 (s,
3H, ma); 13C NMR (101 MHz, CDCl3) δ = 168.9, 141.2, 134.3, 133.9,
128.8, 128.7, 128.3, 128.0, 127.7, 127.3, 126.7, 126.1, 123.3, 123.3,
58.8, 53.4, 40.2, 36.3, 25.7, 24.7, 22.2, 21.8; HRMS (ESI, m/z) calcd
for C15H16NOS 258.0953, found 258.0965.
1-[4-(3-Methylphenyl)-6,7-dihydrothieno[3,2-c]pyridin-
5(4H)-yl]prop-2-en-1-one (2). The amide 2 was obtained from 4-(3-
methylphenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (10c) (20 mg,
0.09 mmol, 1 equiv) and acryloyl chloride (0.0089 mL, 9.9 mg, 0.11
mmol, 1.2 equiv), using general procedure F, as a colorless oil (16 mg,
0.056 mmol, 63%). Rf = 0.38 (SiO2; EtOAc:Hex, 3:7); 1H NMR (500
dihydrothieno[3,2-c]pyridin-5(4H)-yl)ethanone (1) (20 mg, 0.077
mmol, 1 equiv) dissolved in 1.5 mL of dry THF. The reaction was
stirred at rt over 72 h. Removing the solvent in vacuum and purifying
the residual by column chromatography provided the thioamide 5 as a
colorless oil (19 mg, 0.069 mmol, 89%). Rf = 0.56 (SiO2; EtOAc:Hex,
3:7); 1H NMR (500 MHz, CDCl3) δ = 8.21 (s, 1H, E), 7.45−7.44 (m,
1H, E), 7.38−7.36 (m, 1H, Z), 7.35−7.34 (m, 1H, Z), 7.33−7.32 (m,
1H, Z), 7.31 (m, 1H, E), 7.30−7.29 (m, 2H, Z), 7.23−7.22 (m, 1H,
Z), 7.22−7.21 (m, 2H, Z), 7.20 (d, 3J = 5.5 Hz, 1H, Z/E), 6.81 (d, 3J =
5 Hz, 1H, Z), 6.78 (d, 3J = 5.5 Hz, 1H, E), 6.43 (s, 1H, Z), 5.78−5.75
(m, 1H, E), 4.22 (m, 1H, E), 3.56−3.50 (m, 1H, E), 3.33−3.23 (m,
2H, Z), 3.00−2.95 (m, 1H, E), 2.93 (s, 1H, E), 2.89−2.85 (m, 1H, Z),
2.75 (s, 3H, E); 13C NMR (125 MHz, CDCl3) δ = 199.5, 198.9, 140.0,
138.7, 136.2, 134.1, 133.5, 132.7, 129.1, 128.6, 128.5, 128.4, 127.5,
126.8, 125.9, 124.3, 124.1, 62.1, 60.7, 44.1, 43.5, 33.2, 32.4, 25.9, 24.1;
HRMS (ESI, m/z) calcd for C15H16NS2 274.0724, found 274.0714.
1-[4-(2-Pyridyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-
ethanone (6). The amide 6 was obtained from 7-(2-pyridyl)-4,5,6,7-
tetrahydrothieno[3,2-c]pyridine (12c) (19 mg, 0.09 mmol, 1 equiv)
and acetyl chloride (0.01 mL, 11 mg, 0.14 mmol, 1.5 equiv), using
general procedure G, as a colorless oil (12 mg, 0.05 mmol, 55%). Rf =
3
3
MHz, CDCl3) 7.19 (d, J = 7.5 Hz, 1H, E), 7.15 (d, J = 5.2 Hz, 2H,
3
3
E), 7.10−7.05 (dd, J = 15.8 Hz, J = 7.5 Hz, 3H, E), 6.94 (s, 1H, E),
6.85 (dd, 3J = 15.6 Hz, 3J = 11.4 Hz, 1H, Z), 6.77 (s, 1H, Z), 6.72 (d, 3J
= 4.7 Hz, 1H, E), 6.61 (dd, 3J = 16.7 Hz, 3J = 10.4 Hz, 1H, E), 6.42 (s,
1H, Z), 6.35 (d, 3J = 16.7 Hz, 1H, E), 6.09 (s, 1H, Z), 5.79 (s, 1H, Z),
5.73 (d, 3J = 10.4 Hz, 1H, E), 4.86 (s, 1H, Z), 4.01 (dd, 2J = 13.8 Hz, 3J
= 4.2 Hz, 1H, E), 3.40 (td, J = 13.8 Hz, J = 4.2 Hz, 1H, E), 3.08−
2.83 (m, 2H, E), 2.32 (s, 3H, Z/E); 13C NMR (125 MHz, CDCl3) δ =
165.5, 141.1, 138.2, 134.4, 133.9, 129.5, 128.8, 128.3, 128.3, 128.1,
128.0, 126.8, 126.2, 125.9, 124.7, 123.4, 57.9, 54.1, 39.8, 36.8, 26.2,
24.9, 21.6; HRMS (ESI, m/z) calcd for C17H18NOS 284.1109, found
284.1119.
3
3
1
0.32 (SiO2; EtOAc:TEA, 100:1); H NMR (400 MHz, CDCl3) δ =
8.61 (d, 3J = 5.7 Hz, 1H, mi), 8.53 (d, 3J = 4.7 Hz, 1H, ma), 7.64 (m,
1H), 7.45 (d, 3J = 7.8 Hz, 1H, ma), 7.21 (dd, 3J = 7.6, 4.8 Hz, 1H, mi),
7.18−7.12 (m, 2H), 7.10 (t, 3J = 6.4 Hz, 2H), 6.93 (d, 3J = 5.1 Hz, 1H,
mi), 6.75 (d, 3J = 5.1 Hz, 1H, ma), 6.70 (s, 1H, ma), 6.05 (s, 1H, mi),
1-[4-(3-Methylphenyl)-6,7-dihydrothieno[3,2-c]pyridin-
5(4H)-yl]prop-2-en-1-one (3). A mixture of 4-(3-methylphenyl)-
4,5,6,7-tetrahydrothieno[3,2-c]pyridine (10c) (20 mg, 0.087 mmol, 1
equiv), allyl bromide (0.012 mL, 17 mg, 0.14 mmol, 1.6 equiv), and
K2CO3 (19 mg, 0.14 mmol, 1.6 equiv) dissolved in 1 mL of acetone
was stirred at rt overnight. A precipitate formed that was removed by
filtration. Afterward, the solvent was removed in vacuum and the
residual purified by column chromatography to afford the tertiary
amine 3 as a colorless oil (12 mg, 0.045 mmol, 52%). Rf = 0.73 (SiO2;
3
5.00 (dd, J = 14.0, 3.7 Hz, 1H, mi), 4.03−3.97 (m, 1H, ma), 3.97−
3.87 (m, 1H, ma), 3.06 (dd, 3J = 11.6, 3.7 Hz, 1H, mi), 3.02−2.91 (m,
2H), 2.86 (dd, 3J = 16.7, 3.1 Hz, 1H, mi), 2.33 (s, 3H, mi), 2.20 (s, 3H,
ma); 13C NMR (101 MHz, CDCl3) δ = 170.7, 169.3, 160.0, 159.9,
149.8, 149.6, 136.8, 136.6, 135.6, 134.0, 133.4, 132.7, 126.4, 126.3,
123.3, 123.1, 122.9, 122.8, 122.5, 121.0, 60.6, 55.8, 42.0, 36.7, 25.7,
24.9, 22.5, 22.0; HRMS (ESI, m/z) calcd for C14H15N2OS 259.0905,
found 259.0909.
1
3
EtOAc:Hex, 3:7); H NMR (500 MHz, CDCl3) δ = 7.19 (t, J = 7.5
Hz, 1H), 7.11 (s, 1H), 7.08 (t, J = 7.5 Hz, 2H), 6.94 (d, 3J = 5.2 Hz,
1H), 6.33 (d, J = 5.2 Hz, 1H), 5.91−5.83 (m, 1H), 5.18−5.13 (m,
3
3
1-[4-(2-Methoxyphenyl)-6,7-dihydrothieno[3,2-c]pyridin-
5(4H)-yl]ethanone (7). The amide 7 was obtained from 7-(2-
methoxyphenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (13c) (80
mg, 0.37 mmol, 1 equiv) and acetyl chloride (0.039 mL, 43 mg,
0.55 mmol, 1.5 equiv), using general procedure F, as a white solid (79
2H), 4.45 (s, 1H), 3.28−3.24 (m, 2H), 3.09−3.03 (m, 1H), 2.90−2.84
(m, 2H), 2.68−2.63 (m, 1H), 2.33 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ = 141.3, 140.8, 135.6, 134.4, 134.0, 129.4, 128.1, 128.0,
126.8, 126.0, 122.0, 117.5, 66.2, 57.0, 47.8, 25.0, 21.4; HRMS (ESI, m/
z) calcd for C17H20NS 270.1316, found 270.1326.
1
mg, 0.27 mmol, 74%). Rf = 0.44 (SiO2; EtOAc:Hex, 6:4); H NMR
3
(500 MHz, CDCl3) δ = 7.29−7.23 (m, 1H, Z), 7.10 (d, J = 5.2 Hz,
1-(4-Cyclohexyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-
ethanone (4). The amide 4 was obtained from 7-cyclohexyl-4,5,6,7-
tetrahydrothieno[3,2-c]pyridine (11c) (30 mg, 0.14 mmol, 1 equiv)
and acetyl chloride (0.015 mL, 16 mg, 0.21 mmol, 1.5 equiv), using
general procedure F, as a colorless oil (20 mg, 0.076 mmol, 54%). Rf =
1H, Z), 7.07−7.06 (m, 2H, E), 6.93 (d, 3J = 8.0 Hz, 1H, Z), 6.91−6.88
3
(m, 2H, E), 6.86−6.81 (m, 2H, Z), 6.67 (s, 1H, E), 6.66 (d, J = 5.2
Hz, 1H, Z), 6.33 (s, 1H, Z), 4.80−4.73 (m, 1H, Z), 3.91 (s, 3H, Z),
3.87 (m, 1H, E), 3.84 (s, 3H, E), 3.55 (m, 1H, E), 3.04−2.97 (m, 2H,
Z), 2.91 (td, 2J = 16.6 Hz, 2J = 15.9 Hz, 3J = 4.4 Hz 1H, E), 2.84−2.77
(m, 1H, Z), 2.31 (s, 3H, Z), 2.16 (s, 3H, E); 13C NMR (125 MHz,
CDCl3) δ = 170.7, 168.8, 157.7, 156.8, 135.9, 135.5, 134.3, 133.3,
130.0, 129.6, 129.4, 129.1, 128.9, 126.6, 125.9, 123.2, 122.9, 120.4,
120.1, 111.1, 110.6, 55.7, 55.3, 53.7, 49.6, 41.1, 36.3, 25.9, 24.8, 22.2,
21.7; HRMS (ESI, m/z) calcd for C16H18NO2S 288.1058, found
288.1051.
1
0.28 (SiO2; EtOAc:Hex, 3:7); H NMR (500 MHz, CDCl3) δ = 7.08
(d, 3J = 5.2 Hz, 1H, E), 7.06 (d, 3J = 5.2 Hz, 1H, Z), 6.82 (d, 3J = 5.2
Hz, 1H, Z), 6.80 (d, 3J = 5.2 Hz, 1H, E), 5.38 (d, 3J = 8.6 Hz, 1H, Z),
2
3
3
4.88 (dd, J = 12.6 Hz, J = 5.8 Hz, 1H, E), 4.38 (d, J = 8.9 Hz, 1H,
E), 3.95 (dd, 2J = 14.1 Hz, 3J = 5.9 Hz, 1H, Z), 3.55 (m, 1H, Z), 3.03
(td, 2J = 12.2 Hz, 3J = 4.4 Hz, 1H, E), 2.98−2.89 (m, 1H, Z/E), 2.86−
2.81 (m, 1H, Z), 2.76−2.72 (m, 1H, E), 2.17 (s, 3H, Z), 2.12 (s, 3H,
E), 1.91−1.63 (m, 7H, Z/E), 1.27−0.99 (m, 5H, Z/E); 13C NMR (125
MHz, CDCl3) δ = 170.0, 169.4, 136.1, 135.1, 134.9, 132.7, 127.5,
126.8, 122.1, 122.0, 61.3, 55.4, 43.2, 42.8, 41.0, 35.7, 31.0, 30.7, 30.4,
1-[4-(2-Hydroxyphenyl)-6,7-dihydrothieno[3,2-c]pyridin-
5(4H)-yl]ethanone (8). BBr3 (0.93 mL of 1 M BBr3 in DCM, 0.93
mmol, 9 equiv) was added dropwise to a solution of 1-[4-(2-
methoxyphenyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]ethanone
(7) (30 mg, 0.10 mmol, 1 equiv) in 2 mL of dry DCM at −78 °C
(isopropanol−dry ice bath) under an argon atmosphere. The reaction
mixture was allowed to warm to room temperature while being stirred
overnight under argon. A 1:1 mixture of methanol and water (1 mL)
was added to quench the reaction. Afterward, the organic phase was
washed with brine and dried over MgSO4, and the organic solvent was
removed in vacuum. The residual was purified by column
chromatography to provide the product 8 as a white solid (15 mg,
0.055 mmol, 55%). Rf = 0.69 (SiO2; EtOAc:Hex, 6:4); 1H NMR (500
1
29.8, 26.4, 26.4, 26.4, 26.3, 26.3, 26.3, 25.8, 24.7, 21.9; H NMR (500
3
3
MHz, C2D2Cl4) δ = 7.11 (d, J = 5.1 Hz, 1H, Z/E), 6.84 (d, J = 5.1
Hz, 1H, Z), 6.82 (d, 3J = 5.2 Hz, 1H, E), 5.32 (d, 3J = 8.6 Hz, 1H, Z),
4.85−4.82 (m, 1H, E), 4.36 (d, 3J = 8.9 Hz, 1H, E), 3.92 (dd, 2J = 14.3
2
Hz, 3J = 5.8 Hz, 1H, Z), 3.52 (m, 1H, Z), 3.01 (td, J = 12.3 Hz, 3J =
3
3
4.6 Hz, 1H, E), 2.95−2.82 (m, 2H, Z/E), 2.76 (dd, J = 16.2 Hz, J =
4.2 Hz, 1H, E), 2.14 (s, 3H, Z), 2.11 (s, 3H, E), 1.89−1.60 (m, 7H, Z/
E), 1.26−1.00 (m, 5H, Z/E); 13C NMR (125 MHz, C2D2Cl4) δ =
169.6, 169.2, 135.7, 134.7, 134.7, 132.8, 127.2, 126.7, 122.1, 122.0,
60.9, 55.0, 42.8, 42.2, 40.7, 35.4, 30.7, 30.5, 30.2, 29.5, 26.2, 26.1, 26.0,
25.5, 24.5, 22.1, 21.7; HRMS (ESI, m/z) calcd for C15H22NOS
264.1422, found 264.1431.
3
MHz, CDCl3) δ = 9.83 (s, 1H), 7.22−7.19 (m, 1H), 7.15 (d, J = 5.2
3
3
Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.75−6.71 (m, 3H), 6.59 (d, J =
2
3
2
5.2 Hz, 1H), 3.86 (dd, J = 14.1 Hz, J = 4.8 Hz, 1H), 3.50 (td, J =
1-(4-Phenyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-
ethanethione (5). Lawesson’s reagent (26 mg, 0.064 mmol, 0.75
equiv) dissolved in 3 mL of dry THF was added to 1-(4-phenyl-6,7-
3
3
14.1 Hz, J = 13.2 Hz, J = 4.4 Hz, 1H), 3.09−2.97 (m, 2H), 2.20 (s,
3H); 13C NMR (125 MHz, CDCl3) δ = 171.7, 156.1, 133.7, 230.1,
G
DOI: 10.1021/acs.joc.5b00205
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
129.8, 126.6, 125.7, 124.0, 119.3, 117.9, 50.9, 40.7, 25.5, 21.6; HRMS
(ESI, m/z) calcd for C15H16NO2S 274.0902, found 274.0893.
(15) An interactive table corresponding to the data for these
calculations and the experimental details can be retrieved from a digital
repository: Rzepa, H. S.; Lanyon-Hogg, T.; Ritzefeld, M.; Masumoto,
N.; Magee, A. I.; Tate, E. W. Figshare 2014, doi:10.6084/m9.figshare.
1181739, shortdoi: vz9. NCI surfaces were created using the resource
doi:10.6084/m9.figshare.811862, shortdoi: n5b. Retrieved 08:15, Nov
08, 2014 (GMT). This data is also available in the Web-enhanced
table.
ASSOCIATED CONTENT
■
S
* Supporting Information
Supplemental Figures S1−74 and supplementary Tables S1−
15. This material is available free of charge via the Internet at
http://pubs.acs.org. Full information for the systems reported
in the Web-enhanced table is available via the links to the digital
repository. The function of this repository is explained in ref 15.
(16) Armstrong, A.; Boto, R. A.; Dingwall, P.; Contreras-Garcia, J.;
Harvey, M. J.; Mason, N. J.; Rzepa, H. S. Chem. Sci. 2014, 5, 2057−
2071.
(17) Hammaker, R. M.; Gugler, B. A. J. Mol. Spectrosc. 1965, 17,
356−364.
AUTHOR INFORMATION
■
(18) Stringer, J. R.; Crapster, J. A.; Guzei, I. A.; Blackwell, H. E. J.
Org. Chem. 2010, 75, 6068−6078.
Corresponding Authors
*E-mail: h.rzepa@imperial.ac.uk.
*E-mail: e.tate@imperial.ac.uk.
(19) Berndt, K. D.; Guntert, P.; Wuthrich, K. J. Mol. Biol. 1993, 234,
̈
̈
735−750.
(20) Rzepa, H. S. The Winnower 2015, DOI: 10.15200/
winn.142433.30598.
Author Contributions
§T.L.-H. and M.R. contributed equally.
(21) Rostkowska, H.; Nowak, M. J.; Lapinski, L.; Adamowicz, L. Phys.
Chem. Chem. Phys. 2001, 3, 3012−3017.
(22) Wassvik, C. M.; Holmen, A. G.; Draheim, R.; Artursson, P.;
Bergstrom, C. A. J. Med. Chem. 2008, 51, 3035−3039.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Olivia Boyd for synthesis of intermediate 1c,
Peter Haycock for performing NOE experiments, and Prof.
Alan Spivey for helpful discussions. T.L.-H. acknowledges
funding by a Cancer Research UK grant to E.W.T. and A.I.M.
(C6433/A16402). M.R. was generously funded by a Marie
Curie Intra European Fellowship from the European
Commission’s Research Executive Agency (FP7-PEOPLE-
2013-IEF). N.M. was funded from the Imperial College
London Institute of Chemical Biology EPSRC Centre for
Doctoral Training (grant EP/F500416/1).
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DOI: 10.1021/acs.joc.5b00205
J. Org. Chem. XXXX, XXX, XXX−XXX