Cascade Cyclizations of α,β-Unsaturated Thioesters: Additional Examples

Article abstract of DOI:10.1021/acs.joc.0c02091

Several additional examples of cascade cyclizations of α,β-unsaturated thioesters proceeding are reported, which proceed via two distinct mechanistic pathways: enantioselective acyl transfer promoted by amidine-based catalysts (ABCs) and a racemic chain mechanism mediated by a thiolate nucleophile.

Full text of DOI:10.1021/acs.joc.0c02091

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Cascade Cyclizations of α,β-Unsaturated Thioesters: Additional
Examples
Nicholas A. Ahlemeyer, Matthew R. Straub, David M. Leace, Benjamin A. Matz, and Vladimir B. Birman*
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ABSTRACT: Several additional examples of cascade cyclizations of α,β-unsaturated
thioesters proceeding are reported, which proceed via two distinct mechanistic pathways:
enantioselective acyl transfer promoted by amidine-based catalysts (ABCs) and a racemic
chain mechanism mediated by a thiolate nucleophile.
he α,β-unsaturated thioesters can be envisioned to
undergo cascade transformations proceeding with the
T
net 1,3-migration of the thiolate moiety from the acyl carbonyl
to the β-position of the conjugate system.1 These processes are
attractive from the synthetic standpoint, because they proceed
without requiring additional stoichiometric reagents or
generating byproducts. Two mechanistic scenarios are outlined
in Figure 1: Pathway A, which requires covalent Lewis base
Figure 1. Alternative reaction pathways.
catalysis, and Pathway B, which relies on a chain reaction
initiated by free thiolate. Four examples of reactions of this
type illustrated in Figure 2 have been reported by Matsubara
(eq 1),2 our group (eqs 2−4, see Figure 3 for structures of
catalysts),3 and Xu (eq 3).4 While reactions shown in eqs 2 and
3 clearly proceed via Pathway A to provide the products in
optically pure form, the enantioselective formation of lactone 2
in eq 1 can be rationalized as occurring via either pathway.
Rearrangement of 9 to 10 has been demonstrated to proceed
in both modes. In this Note, we wish to disclose several
previously unpublished results encountered in our studies that
provide further examples of both pathways.
Racemic pathway to thiochromenes. At the onset of our studies
on thiochromene synthesis (Figure 2, eq 2), we prepared the
rearrangement precursors 4 via acylation of the corresponding
o-mercaptobenzaldehydes (e.g., 19) with cinnamoyl chlorides
(Figure 4a). The yields of 4 were typically low. Furthermore,
we often observed significant amounts of racemic thiochro-
Figure 2. Rearrangements of thioesters.
menes 5 formed as byproducts of this seemingly straightfor-
ward reaction. Notably, slow addition of the acyl chloride to
the thiolate nucleophile led to an increased proportion of the
thiochromene. We knew that triethylamine, by itself, did not
promote the rearrangement of thioesters. Therefore, we
speculated that the reaction may be proceeding via an
Received: October 2, 2020
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© XXXX American Chemical Society
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A

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Figure 5. Modified synthesis of thiochromene precursors.
4-Substituted thiochromene. To extend the scope of our
asymmetric synthesis of thiochromenes (Figure 2, eq 2) we
sought to gain access to their derivatives bearing substituents at
C4 (e.g., 25), especially those that could not be introduced
using alternative published methods.8 With this objective in
mind, we prepared methylketone 24 and subjected it to the
standard reaction conditions with the achiral catalyst DHPB 13
(Figure 6). In contrast to the analogous aldehydes (4) tested
Figure 3. Amidine-based catalysts (ABCs).5
Figure 6. Synthesis of 4-substituted thiochromene 25.
under the same conditions in our original study, the conversion
of 24 was negligible. This did not bode well for the
development of a practical enantioselective protocol using
analogous chiral catalysts (e.g., 8a−c), and thus, the ketone
substrate 24 had to be on hold. However, after the discovery
that electron-rich amidine-based catalysts (ABCs) 15−18 work
well in the rearrangement of 6 to 7 (Figure 2, eq 2), we
decided to revisit this problematic case. Pleasingly, catalyst 17
smoothly converted 24 into the expected thiochromene 25 in
high yield and excellent enantioselectivity.
3-Fluoro-thiochromene. Another challenging case was presented
by the transformation of α-fluorothiocinnamate 26. Initially,
we speculated that it might react faster than the unsubstituted
thiocinnamate substrate 4a, due to the activation of the
thioester carbonyl by the adjacent fluorine atom. In practice,
however, DHPB 13 catalyzed the reaction much more slowly
(Table 1, entry 1). Even more disappointingly, its chiral
analogue HBTM-2.1 8c produced only 25% yield of the
fluorinated thiochromene 27 after 8 days, with negligible
asymmetric induction (entry 2). Thus, when electron-rich
ABCs became available, we decided to apply them to this
recalcitrant substrate. H-PIP 14 catalyzed the transformation
of 26 at an acceptable rate but produced only moderate ee
(entry 3). Fortunately, the bicyclic isothiourea 16 performed
much better in this case, in terms of both the rate and the
enantioselectivity (entry 4). We speculated that the fluorine
atom might slow down the third step (30 → 27) and thus
allow the intermediate zwitterionic enolate 29 to revert to ion
pair 28, leading to the erosion of ee. The higher
enantioselectivity of 16 would then be consistent with its
superior performance in the third step, which may not be due
to its electronic properties but rather its geometry being better
able to accommodate the fluorine atom. With this in mind, we
subjected substrate 26 to BTM 7, which is geometrically
similar to 16, albeit far less electron-rich. Although, as expected
Figure 4. Initial observation (a) and control experiment (b).
alternative chain pathway initiated by the conjugate addition of
the thiolate anion to the thioester, followed by aldol cyclization
and lactonization regenerating the thiolate. Indeed, when pure
thioester 4a was exposed to triethylamine in the presence of
free o-mercaptobenzaldehyde 19, 45% yield of racemic
thiochromene 5a was isolated (Figure 4b). Fortunately, the
racemic thiochromenes could be easily separated from the
thioesters by chromatography and thus did not compromise
the enantiopurity of thiochromenes obtained in the subsequent
asymmetric reaction. Still, they did contribute to the lower
yields of thioesters, which prompted us to devise an alternative
protocol for the preparation of our substrates. We reasoned
that we should try to avoid the presence of free
mercaptobenzaldehyde during the thioester formation. Mu-
kaiyama’s method, which employs in situ reduction of
disulfides with triphenylphosphine,6 looked promising. How-
ever, a full equivalent of a free thiol generated as a byproduct
would undergo Michael addition to the initially formed
conjugated thioester. To address this problem, we decided to
modify Mukaiyama’s original protocol by adding DCC, which
would activate cinnamic acid in situ and thus acylate the thiol
as it formed. After some experimentation, we developed a
procedure that utilized the easily obtainable disulfides 237 and
delivered the desired thioesters 4 in moderate to good yields in
most cases (Figure 5).
B
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Table 1) and fused thiochromanes (6 in Figure 2) the terminal
electrophile (aldehyde, ketone, or enone) was tethered to the
thioester moiety through the sulfur atom so that the latter
would be incorporated into the resulting heterocycle. We
wished to examine an alternative scenario, where the migrating
thiolate group would end up as a substituent attached to the
skeleton of the rearranged product. Thus, we designed
substrates 32a and 32b, which would be expected to give
rise to indane-fused dihydropyranones 33a and 33b,
respectively (Table 2).
Table 1. Optimization of Reaction Conditions
Table 2. Synthesis of Fused Indanes 33a and 33b
entry
catalyst
time
% yield
% ee
1
2
3
4
5
6
13
3 days
8 days
46 h
18 h
8 days
14 h
28
25
50
75
54
56
N/A
4
54
88
94
(R)-14c
(R)-16
(R)-18
(R)-12
31
b
a
entry
catalyst
R
temp
time
% yield
% ee
b
N/A
1
2
3
4
5
6
7
8
13
13
Me
Ph
Me
Ph
Me
Ph
Me
Ph
23
23
60
60
60
60
0
48 h
21 h
50
51
35
32
29
41
45
30
NA
NA
a
Conditions: 0.1 mmol of 26, 0.01 mmol of catalyst, 0.50 mL of
b
CDCl3, rt. 1.0 mL of CDCl3 was used.
(R)-12
(R)-12
(R)-14c
(R)-14c
(R)-16
(R)-16
168 h
168 h
168 h
168 h
72 h
67 (R)
16 (S)
23 (S)
69 (R)
88 (R)
35 (R)
from its lower Lewis basicity, BTM 7 catalyzed the reaction
much more slowly than 16, it produced the thiochromene in
even higher enantiomeric excess (entry 5).
Another interesting finding was made when the trans-
formation of substrate 26 was catalyzed by the achiral
isothiourea 31 (entry 6). Monitoring the reaction by 1H
NMR (Figure 7), we were able to observe the transient
0
72 h
a
Conditions: 0.1 mmol of substrate, 0.01 mmol of catalyst, 0.50 mL of
CDCl3.
DHPB 13 promoted the rearrangement of 32a and b at
room temperature, delivering the expected tricyclic products
with complete diastereoselectivity and in moderate yields
(entries 1 and 2). By contrast, the chiral catalysts BTM 12 and
HBTM-2.1 14c required heating at 60 °C for 1 week (entries
3−6). The enantioselectivities observed with both catalysts
were low to moderate. As expected, H-PIP 16 proved to be a
much more active catalyst, which allowed us to carry out the
rearrangement of both substrates at 0 °C (entries 7 and 8).
Under these conditions, the methyl-substituted 33a was
produced with high enantioselectivity, while the ee of 33b
was only moderate. More surprisingly, X-ray analysis of the two
products (see Supporting Information) indicated that their
absolute configurations were opposite from what we expected
based on the facial selectivity of the sulfa-Michael addition in
previously studied cases.3a,b To make matters even more
complicated, the two substrates responded differently to the
three chiral catalysts used. While the results with 32a were
consistent with the opposite absolute configuration of (R)-14c
vs (R)-12 and (R)-16 (see Figure 3), thioester 32b reacted
with the “normal” sulfa-Michael-controlled enantioselectivity
with (R)-12 and (R)-14c (entries 4 and 6) but with “inverse”
asymmetric induction with (R)-16 (entry 8). For the sake of
clarity, all cases of reversed enantioselectivity are shown in red
in Table 2. To explain the inversion of enantioselectivity, we
hypothesized that the conjugate addition within the
intermediate ion pairs 34a and b occurs reversibly (Figure 8).
Although the sulfa-Michael addition step favors diaster-
eomers 35a,b, their subsequent intramolecular Michael
addition is hampered by the mismatch between the substrate
control (the phenylthio group hinders the approach of the
1
Figure 7. Detection of putative β-lactone 30 by H NMR.
formation and gradual disappearance of fluorinated β-lactone
30.9 This was in contrast to the transformation of
thiocinnamate substrate 4a, where the analogous β-lactone
intermediate was never observed but only postulated.
Synthesis of fused indanes. In all the precursors to
thiochromenes (4 in Figure 2, 24 in Figure 6, and 26 in
C
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possibility of an alternative mode of asymmetric catalysis in
reactions of this type.
EXPERIMENTAL SECTION
■
1. General. All reagents were obtained commercially and used as
received unless specified otherwise. Catalysts 12−18 and 31 were
prepared as previously described.12 Dichloromethane and deuterated
chloroform used as reaction media were freshly distilled from calcium
hydride. Triethylamine was freshly distilled from potassium
hydroxide. Solvents used for chromatography were ACS or HPLC
grade. Sorbent Technologies XHL silica gel plates (glass-backed, 250
μm) were used for TLC analyses. Flash column chromatography was
performed over Sorbent Technologies silica gel (40−63 μm). HPLC
analyses were performed on a Shimadzu LC system using Chiralcel
OD-H or Chiralpak AD-H analytical chiral stationary phase columns
(4.6 × 250 mm, Chiral Technologies, Inc.) with a UV detector at 254
or 204 nm, with a flow rate of 1.0 mL/min. 1H and 13C NMR spectra
were recorded on Mercury 300 MHz and DD2 500 MHz Agilent
spectrometers. The chemical shifts are reported as δ values (ppm)
relative to TMS using residual CHCl3 (7.26 ppm for 1H NMR, 77.16
ppm for 13C NMR) or (CH3)2CO (29.84 ppm for 13C NMR) peaks
as the reference. Melting points were measured on a Stuart SMP10
melting point apparatus. High-resolution mass spectral analyses were
performed at Washington University MS Center on a Bruker MaXis
QTOF mass spectrometer using electrospray ionization (ESI).
Infrared spectra were recorded on a Bruker Alpha Platinum-ATR.
Optical rotations were measured on a Rudolph Autopol III
polarimeter.
2. Synthesis of Previously Unreported Substrates. Thio-
cinnamate 24.
Figure 8. Proposed explanation for the inversion of enantioselectivity.
enone moiety to the β-face of the enolate) and the catalyst
control (the phenyl group of the catalyst blocks the α-face)
(cf., 36a and b). On the other hand, the same factors are
matched in the kinetically disfavored diastereomer 37a,b (cf.,
38a,b: the α-face remains open). The high level of
enantioenrichment of 33a in entry 7 suggests that asymmetric
induction in this case is completely controlled by the second
step (i.e., the Curtin−Hammett scenario). By contrast, the low
ee in entry 8 reflects the residual influence of the sulfa-Michael
step, which is consistent with the higher electrophilicity of the
phenylenone moiety in 36b relative to the methylenone in 36a.
Comparison of the ee values obtained with three chiral
catalysts and both substrates reveals another interesting trend:
H-PIP 16 leads to the highest proportion of the Curtin−
Hammett-favored enantiomer, HBTM-2.1. 14c favors the
opposite outcome, while BTM 12 falls somewhere in between.
It should be noted that structurally similar substrates have been
subjected to tandem double Michael additions of enolate
nucleophiles. However, in the reported cases, the absolute
stereochemistry of the products was set during the irreversible
intermolecular Michael addition step and was not affected by
the mismatch in the subsequent cyclization.10,11
Cinnamoyl chloride (366 mg, 2.2 mmol, 1.16 equiv), 4-
dimethylaminopyridine (23 mg, 0.189 mmol, 0.1 equiv), and
triethylamine (300 μL, 2.2 mmol, 1.16 equiv) were dissolved in 4
mL of freshly distilled CH2Cl2 under an inert atmosphere. A solution
of o-mercaptoacetophenone13 (288 mg, 1.89 mmol, 1.0 equiv) in 3
mL of DCM (final concentration of ∼0.3 M in thiol) was added
dropwise at 0 °C over 30 min. The solution was allowed to slowly
warm to rt and stirred overnight. The mixture was concentrated by
rotovap and subjected to column chromatography (5 → 20% EtOAc/
hexanes). 24 was isolated as a very fine white powder (346 mg, 73%).
1H NMR (500 MHz, CDCl3): δ 7.71−7.68 (m, 1H), 7.68 (d, J = 16
Hz, 1H), 7.64−7.61 (m, 1H), 7.58−7.53 (m, 2H), 7.53−7.48 (m,
2H), 7.43−7.38 (m, 3H), 6.79 (d, J = 16 Hz, 1H), 2.61 (s, 3H).
13C{1H} NMR (125 MHz, CDCl3): δ 200.9, 187.3, 143.2, 142.0,
136.7, 134.0, 131.3, 131.0, 129.5, 129.1, 128.6, 128.6, 125.9, 124.2,
29.4. IR (cm−1): 2922, 1693, 1673, 1573, 1249, 1033, 973, 761, 693.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H14O2SNa,
305.0612; found, 305.0595. mp: 117−121 °C.
α-Fluorothiocinnamate 26.
Conclusions. In conclusion, several examples provided above
illustrate both extensions of the synthetic scope and some
limitations of the Lewis-base-catalyzed rearrangement of α,β-
unsaturated thioesters. Electron-rich chiral ABCs 16−18 have
enabled substantial improvement of several transformations
that were prohibitively slow and/or poorly enantioselective
when promoted by “conventional” ABCs (5 → 7, 24 → 25, 26
→ 27, 32a → 33a). Conversion of thioesters 4 and 9 to
racemic products (Figure 4 and eq 4 in Figure 2, respectively)
suggests that Pathway B (Figure 1) may contribute to the
erosion of enantioselectivity when traces of a thiol are present
as a contaminant. On the other hand, it also suggests the
26 was synthesized following a published procedure. To a solution of
α-fluorocinnamic acid14 (1.284 g, 7.73 mmol, 1.0 equiv) dissolved in
39 mL of freshly distilled THF (0.2 M) was added DCCN (0.796 g,
3.87 mmol, 0.5 equiv). This mixture was cooled to 0 °C and stirred
for 20 min. Then, triphenylphosphine (1.22 g, 4.64 mmol, 0.6 equiv)
and 2,2′-dithiobisbenzaldehyde 237 (1.06 g, 3.87 mmol, 0.5 equiv)
were added in one portion and allowed to slowly warm to rt. After the
mixture was stirred at rt for 24 h, it was filtered and concentrated
under reduced pressure. The product was isolated as a tan powder
D
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(434 mg, 1.51 mmol, 20% yield) after chromatography (2 → 8%
EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ 10.27 (s, 1H), 8.10
(dd, J = 8 Hz, 2 Hz, 1H), 7.71−7.62 (m, 4H), 7.59−7.56 (m, 1H),
7.45−7.41 (m, 3H), 6.88 (d, J = 37 Hz, 1H). 13C{1H} NMR (125
MHz, CDCl3): δ 190.5, 183.8 (d, J = 39 Hz), 151.5 (d, J = 269 Hz),
137.6, 137.0, 134.5, 131.2 (d, J = 8 Hz), 130.9, 130.6 (d, J = 3 Hz),
130.6 (d, J = 4 Hz), 129.5, 129.3 (d, J = 5 Hz), 129.2, 115.2 (d, J = 4
Hz). IR (cm−1): 2924, 2871, 1692, 1675, 1637, 1156, 942, 746.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H11FO2SNa,
309.0361; found, 309.0347. mp: 95−99 °C.
MHz, CDCl3): δ 7.39−7.36 (m, 1H), 7.35−7.33 (m, 2H), 7.31−7.27
(m, 2H), 7.26−7.21 (m, 2H), 7.17−7.10 (m, 2H), 5.95 (d, J = 6 Hz,
1H), 4.80 (d, J = 6 Hz, 1H), 2.20 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3): δ 141.9, 133.9, 133.6, 131.8, 128.8, 128.0, 127.8, 127.7,
127.3, 125.6, 125.1, 123.8, 42.7, 21.1. IR (cm−1): 3057, 3026, 2919,
1451, 1431, 1033, 752, 695. HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C16H14SNa, 261.0714; found, 261.0685. HPLC: (0.25%
isopropanol/hexane, AD-H): minor enantiomer: 6.9 min; major
enantiomer: 7.8 min, 96% ee. [α]2D2 = −63.1° (c = 0.867, CH2Cl2).
Thiochromene 27.
Thioester 32a.
27 was prepared as described above using thioester 26 (29 mg, 0.10
mmol, 1 equiv) and (R)-BTM 12 (100 μL of 0.10 M in CDCl3, 0.010
mmol, 0.1 equiv). After 1 week (>90% conversion), the mixture was
rotary evaporated and subjected to column chromatography (1%
EtOAc/hexanes). The product was isolated as a colorless oil (13 mg,
A stirring solution of o-(3-oxobutenyl)cinnamic acid10 (490 mg, 2.25
mmol, 1.0 equiv) in 15 mL of freshly distilled CH2Cl2 stirred was
treated with a solution of DMAP (6 mg, 0.045 mmol, 0.02 equiv) and
DCC (557 mg, 2.7 mmol, 1.2 equiv) in 7 mL of CH2Cl2 added
dropwise at 0 °C. This was stirred for 20 min. Then, thiophenol (185
μL, 1.8 mmol, 0.8 equiv) dissolved in 6 mL of CH2Cl2 was added
dropwise over 30 min. The reaction was left to slowly warm to rt and
stirred overnight. The mixture was then filtered, concentrated under
reduced pressure, and subjected to column chromatography (10 →
20% EtOAc/hexanes). 32a was isolated as a light tan solid (487 mg,
88% yield). 1H NMR (500 MHz, CDCl3): δ 8.03 (d, J = 16 Hz, 1H),
7.86 (d, J = 16 Hz, 1H), 7.64−7.58 (m, 2H), 7.52−7.48 (m, 2H),
7.47−7.42 (m, 5H), 6.71 (d, J = 16 Hz, 1H), 6.62 (d, J = 16 Hz, 1H),
2.40 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 197.9, 187.8,
139.8, 138.0, 135.1, 134.6, 134.1, 131.0, 130.7, 130.4, 129.7, 129.4,
128.0, 127.9, 127.6, 127.4, 27.8. IR (cm−1): 1662, 1258, 1127, 956,
749. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H16O2SNa,
331.0769; found, 331.0760. mp: 88−89 °C.
1
54% yield). H NMR (500 MHz, CDCl3): δ 7.33−7.24 (m, 5H),
7.20−7.17 (m, 1H), 7.14−7.09 (m, 3H), 6.42 (d, J = 15 Hz, 1H),
4.77 (d, J = 13 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 157.7
(d, J = 271 Hz), 139.8 (d, J = 3 Hz), 130.6 (d, J = 8 Hz), 129.0, 128.4,
127.9 (d, J = 9 Hz), 127.88, 126.9, 126.8, 126.5, 126.1, 107.5 (d, J =
23 Hz), 43.1 (d, J = 29 Hz). IR (cm−1): 3061, 2923, 2852, 1678,
1471, 1105, 749. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C15H11FSNa, 265.0463; found, 265.0431. HPLC: (0.25% isopropa-
nol/hexane, OD-H): major enantiomer: 12.0 min; minor enantiomer:
14.9 min, 94% ee. [α]2D6 = −80.3° (c = 0.467, CH2Cl2).
Tricycle 33a.
Thioester 32b.
33a was prepared as described above using thioester 32a (31 mg, 0.10
mmol, 1 equiv) and (R)-H-PIP 16 (100 μL of 0.10 M in CDCl3,
0.010 mmol, 0.1 equiv). After 3 days at 0 °C (complete consumption
of the starting material by 1H NMR), the mixture was rotary
evaporated, and the crude product was preadsorbed onto silica gel.
The pure product (14 mg, 45% yield) was obtained as a clear,
colorless oil after column chromatography (1 → 2% EtOAc/hexanes).
1H NMR (500 MHz, CDCl3): δ 7.48−7.45 (m, 2H), 7.37−7.35 (m,
1H), 7.34−7.24 (m, 5H), 7.18−7.16 (m, 1H), 5.42 (d, J = 2 Hz, 1H),
5.32 (dd, J = 6 Hz, 1 Hz, 1H), 4.11−4.06 (m, 1H), 3.33 (dd, J = 9 Hz,
2 Hz, 1H), 1.91−1.89 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ
169.0, 148.7, 143.7, 139.9, 135.0, 131.1, 129.3, 129.0, 128.0, 127.4,
125.7, 123.8, 99.4, 53.6, 48.8, 39.5, 19.1. IR (cm−1): 3069, 2921,
1748, 1706, 1169, 1150, 1090. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C19H17O2S, 309.0949; found, 309.0945. HPLC: (2%
isopropanol/hexane, AD-H): minor enantiomer: 12.1 min; major
enantiomer: 19.0 min, 88% ee. [α]2D6 = +63.1° (c = 0.800, CHCl3).
Aminolysis Product 33a-BnNH2.
32b was prepared analogously to the methyl derivative 32a (see
above) using the following quantities: o-(3-oxo-3-phenylpropenyl)-
cinnamic acid10 (626 mg, 2.25 mmol, 1.0 equiv), DCC (557 mg, 2.7
mmol, 1.2 equiv), DMAP (6 mg, 0.045 mmol, 0.02 equiv), thiophenol
(185 μL, 1.8 mmol, 0.8 equiv), and 28 mL of CH2Cl2. 32b was
isolated as a yellow solid (517 mg, 78%) after chromatography (5 →
1
15% EtOAc/hexanes). H NMR (500 MHz, CDCl3): δ 8.13 (d, J =
16 Hz, 1H), 8.10 (d, J = 16 Hz, 1H), 8.05−8.02 (m, 2H), 7.72−7.68
(m, 1H), 7.65−7.62 (m, 1H), 7.61−7.57 (m, 1H), 7.53−7.48 (m,
4H), 7.48−7.43 (m, 5H), 7.41 (d, J = 16 Hz, 1H), 6.72 (d, J = 16 Hz,
1H). 13C{1H} NMR (125 MHz, CDCl3): δ 190.1, 187.7, 141.4,
138.6, 138.0, 135.6, 134.7, 134.4, 133.1, 130.6, 130.3, 129.6, 129.4,
128.8, 128.7, 128.4, 128.0, 127.7, 127.5, 126.5. IR (cm−1): 1669,
1656, 1593, 1292, 1216. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C24H18O2SNa, 393.0925; found, 393.0902. mp: 61−65 °C.
3. Previously Unreported Catalytic Reactions. Thiochromene
25. Representative Procedure.
In order to determine its absolute configuration, tricycle 33a (56 mg,
0.182 mmol, 1.0 equiv) was subjected to aminolysis with benzylamine
(30 μL, 0.27 mmol, 1.5 equiv) in 900 μL of CH2Cl2 (20 h at rt). The
reaction mixture was washed successively with 1 M aqueous HCl,
water, and brine. The organic phase was dried over Na2SO4 and
concentrated under reduced pressure to yield almost pure product,
which was recrystallized from a 1:1 CH2Cl2/hexanes mixture. The
product was isolated as a colorless, crystalline solid (66 mg, 0.16
An NMR tube was charged with thiocinnamate ester 24 (28 mg, 0.10
mmol, 1 equiv), catalyst 17 (100 μL of 0.10 M in CDCl3, 0.010 mmol,
0.1 equiv), and an additional 400 μL of CDCl3, shaken, and left at rt.
The reaction progress was monitored by 1H NMR. After 18 h (>95%
conversion), the mixture was rotary evaporated and subjected to
column chromatography (0.5% EtOAc/hexanes). The product was
1
mmol, 87% yield). H NMR (500 MHz, CDCl3): δ 7.45−7.21 (m,
13H), 7.11−7.07 (m, 1H), 5.90 (br s, 1H), 5.10 (d, J = 7 Hz, 1H),
1
isolated as a clear colorless oil (19 mg, 79% yield). H NMR (500
E
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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
4.35 (dd, J = 15 Hz, 6 Hz, 1H), 4.24 (dd, J = 15 Hz, 5 Hz, 1H), 4.01−
3.95 (m, 1H), 3.23 (dd, J = 8 Hz, 7 Hz, 1H), 3.01 (dd, J = 19 Hz, 10
Hz, 1H), 2.63 (dd, J = 19 Hz, 5 Hz, 1H), 2.01 (s, 3H). 13C{1H} NMR
(125 MHz, CDCl3): δ 207.9, 171.7, 144.3, 141.8, 138.1, 134.6, 132.0,
129.1, 128.8, 128.4, 128.1, 127.8, 127.7, 127.4, 125.2, 123.7, 56.5,
54.0, 45.7, 43.9, 41.3, 30.3. IR (cm−1): 3306, 3023, 2924, 1703, 1641,
1525, 1360, 1234, 1211, 748, 738, 693. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C26H26NO2S, 416.1684; found, 416.1691. mp: 99−101
°C.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02091
Notes
The authors declare no competing financial interest.
CIF files for compounds 33a-BnNH2 and 33b have been
uploaded to Cambridge Structural Database.
Tricycle 33b.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Science Foundation
(CHE 1566588) and Washington University in Saint Louis for
their financial support. We also thank Dr. Nigam Rath
(University of Missouri-Saint Louis) for providing crystallo-
graphic data. The purchase of the Venture-Duo diffractometer
was made possible by a National Science Foundation grant
(MRI, CHE 1827756).
33b was prepared as described above using thioester 32b (37 mg, 0.10
mmol, 1 equiv) and (R)-H-PIP 16 (100 μL of 0.10 M in CDCl3,
0.010 mmol, 0.1 equiv). After 3 days at 0 °C, the mixture was rotary
evaporated and purified by chromatography (1 → 2% EtOAc/
hexanes). The pure product (11 mg, 30% yield) was obtained as a
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02091.
HPLC data, NMR spectra, and X-ray crystallographic
data (PDF)
Accession Codes
CCDC 2044687−2044688 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
■
Vladimir B. Birman − Department of Chemistry, Washington
University, St. Louis, Missouri 63130, United States;
orcid.org/0000-0003-0299-358X; Email: birman@
wustl.edu
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Authors
Nicholas A. Ahlemeyer − Department of Chemistry,
Washington University, St. Louis, Missouri 63130, United
States
Matthew R. Straub − Department of Chemistry, Washington
University, St. Louis, Missouri 63130, United States
David M. Leace − Department of Chemistry, Washington
University, St. Louis, Missouri 63130, United States
Benjamin A. Matz − Department of Chemistry, Washington
University, St. Louis, Missouri 63130, United States
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