Stereospecific Stille Cross-Couplings Using Mn(II)Cl2

Article abstract of DOI:10.1021/acs.joc.7b02780

Cross-coupling reactions are a staple in organic synthesis, especially for C-C bond formation with sp- and sp²-carbon electrophiles. In recent years, the range of accessible C-C bonds has been extended to stereogenic centers which expedites access to greater molecular complexity. However, these reactions predominantly depend upon late transition metal (LTM) catalysts whose cost, toxicity, and/or environmental impact have come under increasing scrutiny and governmental regulation. Here, we report Mn(II)Cl₂ complexes alone, or with assistance from copper, catalyze the stereospecific cross-coupling of α-alkoxyalkylstannanes with organic electrophiles with complete retention of configuration.

Full text of DOI:10.1021/acs.joc.7b02780

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Stereospecific Stille Cross-Couplings Using Mn(II)Cl2
Rambabu Dakarapu and John R. Falck*
Division of Chemistry, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United
States
S
* Supporting Information
ABSTRACT: Cross-coupling reactions are a staple in organic synthesis,
especially for C−C bond formation with sp- and sp2-carbon electrophiles.
In recent years, the range of accessible C−C bonds has been extended to
stereogenic centers which expedites access to greater molecular
complexity. However, these reactions predominantly depend upon late
transition metal (LTM) catalysts whose cost, toxicity, and/or environ-
mental impact have come under increasing scrutiny and governmental
regulation. Here, we report Mn(II)Cl2 complexes alone, or with assistance from copper, catalyze the stereospecific cross-coupling
of α-alkoxyalkylstannanes with organic electrophiles with complete retention of configuration.
complexes. Acceptable yields, however, required PyBOX
ligands. Among typical solvents, the combination of toluene/
EtOAc (4:1) afforded the best yields. CH2Cl2, THF, DMF,
NMP, and EtOH gave low or no cross-coupled adduct.
Stoichiometric amounts of NaCl also proved helpful, although
more than 3 equiv did not improve the yields. Other chloride
salts gave poor results. The inclusion of TEMPO (1.2 equiv)
had only a minor impact, suggesting that the reaction does not
involve a radical intermediate.
The scope of the MnCl2/(S)-BnCH2PyBOX catalytic system
for C−C bond formation was established using 119 and a panel
of representative electrophiles (Figure 1, panel A). Aryl iodides
bearing either electron-withdrawing (2a−h) or electron-rich
substituents (2i,j) were suitable coupling partners for stannane
1, although the reactions were slow even at temperatures up to
82 °C. In sharp contrast to the extensive or complete
Newman−Kwart rearrangement of the thiocarbamate that
accompanied copper(I)−thiophene-2-carboxylate (CuTC)-
mediated cross-couplings,19,21 we observed no rearrangement
using MnCl2/(S)-BnCH2PyBOX with any of the examples in
Figure 1. Repetition of the CuTc reactions as previously
described but in the presence of (S)-BnCH2PyBOX did not
prevent the Newman−Kwart rearrangement.
Aryl bromides were generally unreactive, although cinnamyl
bromide led to homoallylic alcohol 2k in good yield.
Heterocyclic iodides, which often decompose, protodehalogen-
ate, or dimerize during LTM-mediated cross-couplings,17 were
well behaved with MnCl2 (2l−p). Most notably, bond
formation between (S)-131 and a variety of electrophiles
proceeded with >98% retention of configuration (Figure 1,
panel B, (R)-2q−t).33 This suggested that manganese was
participating in the type of oxidative addition−reductive
elimination process normally associated with LTMs.34,35 The
presence of an adjacent asymmetric center as in acetonide 3
INTRODUCTION
■
Late transition metal (LTM)-catalyzed cross-couplings are well
established and popular synthetic procedures, especially for
additions to sp- and sp2-carbon electrophiles.1,2 Continuous
refinement of these processes has significantly improved
reaction conditions and expanded the range of accessible C−
C bonds. Couplings to stereogenic centers, in particular, have
attracted wide attention for their ability to increase molecular
complexity3−12 and drug-like functionality.13 Nevertheless,
limitations still persist for many cross-coupling reactions,14
e.g., (i) sensitivity to oxygen and water, (ii) dimerization and/
or decomposition of reactive electrophiles,15−18 (iii) rearrange-
ments,19−21 and (iv) β-elimination.19−21 In addition, the cost,
toxicity, and/or environmental impact of many of the LTM
catalysts have come under increasing scrutiny and governmen-
tal regulation.22 These restrictions as well as our long-standing
interest19−21 in Stille cross-couplings at α-functionalized
carbons prompted us to evaluate manganese because it is
among the most abundant and economic of all transition
metals, just behind iron and titanium, and comparatively
nontoxic.23,24
RESULTS AND DISCUSSION
■
The use of Mn(II) salts in C−C bond formation dates back to
1976,25−27 but it was 1997 before it was applied to Stille cross-
couplings.28,29 Adducts were obtained in generally good yields
at 100 °C in DMF or NMP, although the organostannane must
be added slowly to minimize dimerization. Homocoupling of
organostannanes,30 also at 100 °C in DMF or NMP, using
MnBr2 and iodine has been reported. Conspicuously absent are
practical Mn(II)-catalyzed cross-couplings at stereogenic
centers. Hence, the cross-coupling of protected α-alkoxy(tri-n-
butyl)stannanes31,32 with organic electrophiles was selected as a
readily available model system to probe the stereospecificity of
Mn(II)-mediated C−C bond formation at an sp3-center.33
Preliminary optimization studies demonstrated that MnCl2 out-
performed other common manganese salts as well as salen-type
Received: November 2, 2017
Published: January 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b02780
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Figure 1. Cross-coupling of α-alkoxy(tri-n-butyl)stannanes with organic electrophiles using MnCl2. Reaction conditions: E-X (1.2 equiv), MnCl2 and
(S,S)-BnCH2PyBOX (0.5 equiv), NaCl (3 equiv) at 0.5 M in PhCH3/EtOAc (4:1), except 2k that used PhCH3/CH2Cl2 (1:1). a>98% ee by chiral
b
1
phase HPLC. >98% de by H NMR.
and its C(1)-epimer 5 (Figure 1, panel C) did not affect the
stereofidelity of the cross-coupling and in some instances
actually improved yields, e.g., rising to 80% for 4f (cf., 2t).
Cross-coupled adducts were obtained from allylic, aryl,
heteroaryl, and olefinic electrophiles containing such common
functionality as nitro, cyano, acetyl, methoxy, trifluoromethyl,
bromide, and iodide (Figure 1, panel C, 4a−g, 6). The
stereochemistry of olefinic partners was also preserved, i.e., Z-
B
DOI: 10.1021/acs.joc.7b02780
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Figure 2. Stereospecific Mn(II)/Cu(II)-cocatalyzed cross-couplings with electrophiles. Reaction conditions: E-I (1.2 equiv), MnCl2·2LiCl2 and
a
1
Jackiephos (0.25 equiv), Cu(OTf)2 (0.2 equiv), NaCl and KF (3 equiv), K3PO4 (2 equiv), Ar atmosphere. >98% dr by H/13C NMR.
Figure 3. Proposed mechanism for Mn/Cu-cocatalyzed cross-coupling.
and E-olefinic iodides gave rise to Z- (4h−k) and E-adducts
(4l−n), respectively. Comparable couplings of 1 and 3 with the
same iodo electrophiles mediated by any of more than four
dozen LTM catalysts (Supporting Information (SI): Table S4)
and conditions commonly utilized in Stille reactions (SI: Table
S5) led to complex product mixtures and little, if any, cross-
coupled adducts.
Having established the heretofore unappreciated ability of
MnCl2 to catalyze the kind of stereospecific cross-couplings
that typically rely upon LTMs, we turned our attention to the
issue of synthetic practicality, i.e., the long reaction times and
moderately high temperatures used for the examples in Figure
1, and conducted screening studies. Despite numerous reports
of copper(I)34,36/palladium-cocatalyzed Stille couplings, the
combination of copper(I) salts and MnCl2 was disappointing.
On the other hand, Cu(OTf)2/MnCl2, especially in the
presence of the JackiePhos ligand,37,38 proved superior to the
original reaction conditions. While rare, the use of copper(II)/
palladium for Stille couplings has been reported.39 Also, K3PO4
helped suppress side reactions and thereby provided a cleaner
product. It likely functions as a mild base to neutralize any
adventitious acid. These new reaction conditions proved
significantly faster (6−24 h) and milder because many cross-
couplings now progressed at rt (Figure 2). The stereospecificity
remained >98% for all applicable examples (i.e., 4f,o−s) and no
thiocarbamate Newman−Kwart rearrangement was observed.
A tentative mechanistic hypothesis for the Mn/Cu-
cocatalyzed cross-couplings is shown in Figure 3. Specifically,
the organostannane undergoes initial transmetalation with
copper to generate intermediate B via cyclic transition state
A. Exchange of the copper in B with Mn(II) gives rise to
intermediate C. Subsequent oxidative addition with the
electrophile leads to organomanganate D that undergoes
reductive elimination to yield the final product. Consistent
with the essential role of manganese in the cross-couplings,
reaction of 3 or 3 plus 3-bromo-2-iodoquinoline with
Cu(OTf)2 (25 mol %) as described in Figure 1, but in the
absence of MnCl2, resulted in mainly the β-elimination product
(E)-O-(3-hydroxyprop-1-en-1-yl)pyrrolidine-1-carbothioate.19
This suggests that the exchange between B and C must be
closely coupled to avoid β-elimination. Conversely, 3 was
recovered mostly intact (85%) after stirring with MnCl2 (100
C
DOI: 10.1021/acs.joc.7b02780
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BnCH2PYBOX (0.047 mmol, 50 mol %), and anhydrous toluene/
EtOAc (3 mL, 4:1) and then degassed via four alternating high
vacuum−argon cycles. The electrophile (0.11 mmol, 120 mol %) in
anhydrous toluene (1 mL) was added via syringe. The reaction
mixture was stirred at room temperature for 2 h, during which time the
color changed from pale pink to yellow-brown, and was then heated at
68−82 °C as indicated for specific examples until TLC analysis
showed that all the stannane was consumed (24−120 h). The resultant
reddish-brown reaction mixture was cooled to rt, diluted with Et2O
(10 mL), and filtered through a small bed of neutral alumina. The filter
bed was washed with fresh Et2O (5 mL), and the combined filtrates
were concentrated under reduced pressure. Purification of the residue
via flash column chromatography gave the cross-coupled adducts in
the indicated yields.
Preparation of neutralized MnCl2: Manganese(II) chloride
tetrahydrate (99.99% trace metals basis, Aldrich, CAS no. 13446-34-
9) (1 g, 5.05 mmol) was stirred at rt with dry triethylamine (0.2 mL)
in anhydrous toluene (5 mL). After 5 min, all volatiles were removed
on a rotary evaporator, and the residue was further dried under high
vacuum for 16 h. The neutralized MnCl2 was used immediately for
cross-couplings.
O-(1-(4-Cyano-3-(trifluoromethyl)phenyl)-3-phenylpropyl) Pyrro-
lidine-1-carbothioate (2a). Stirring O-(3-phenyl-1-tri-n-butylstannyl)-
propyl) pyrrolidine-1-carbothioate (1)19 (50 mg, 0.093 mmol) and 4-
iodo-2-(trifluoromethyl)benzonitrile (33 mg, 0.11 mmol) at 82 °C for
3.75 d as described in Standard Stille Cross-Coupling Using MnCl2
(vide supra) afforded 2a (24 mg, 62%) as an oil following
chromatographic purification of the crude product using 10%
EtOAc/hexanes. TLC: Rf ≈ 0.4 (10% EtOAc/hexanes); 1H NMR
(400 MHz, CDCl3) δ 7.79 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.61 (d, J
= 8.2 Hz, 1H), 7.30−7.09 (m, 5H), 6.52 (dd, J = 8.4, 4.9 Hz, 1H),
3.69−3.65 (m, 2H), 3.55−3.52 (m, 2H), 2.71−2.68 (m, 2H), 2.34−
2.31 (m, 1H), 2.15−2.14 (m, 1H), 2.00−1.89 (m, 4H); 13C NMR
(101 MHz, CDCl3) δ 183.5, 147.1, 140.4, 134.8, 133.2, 132.85, 130.4,
128.5, 128.25, 126.25, 124.75 (q, JC,F = 5.0 Hz), 120.9, 115.3, 109.1,
79.7, 52.3, 48.0, 38.1, 31.8, 25.65, 24.4. HRMS Calcd for
C22H21F3N2NaOS [M + Na]+ 441.1219, found 441.1220.
O-(1-(4-Bromophenyl)-3-phenylpropyl) Pyrrolidine-1-carbo-
thioate (2b). Stirring 1 (50 mg, 0.093 mmol) and 1-bromo-4-
iodobenzene (31 mg, 0.11 mmol) at 82 °C for 3.75 d as described in
Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded 2b
(21 mg, 58%) as an oil following chromatographic purification of the
crude product using 10% EtOAc/hexanes. TLC: Rf ≈ 0.5 (10%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.49−7.41 (m, 2H),
7.31−7.09 (m, 7H), 6.42 (dd, J = 7.6, 5.7 Hz, 1H), 3.75−3.60 (m,
2H), 3.52−3.48 (m, 2H), 2.73−2.53 (m, 2H), 2.15−2.11 (m, 1H),
2.09−2.01 (m, 1H), 1.95−1.81 (m, 4H); 13C NMR (101 MHz,
CDCl3) δ 184.1, 141.2, 139.7, 131.55, 128.5, 128.4, 128.3, 125.9,
121.7, 80.7, 52.05, 47.8, 38.1, 31.7, 25.6, 24.5. HRMS Calcd for
C20H22BrNNaOS [M + Na]+ 426.0498, found 426.0505.
O-(1-(4-Nitrophenyl)-3-phenylpropyl) Pyrrolidine-1-carbothioate
(2c). Stirring 1 (50 mg, 0.093 mmol) and 1-iodo-4-nitrobenzene (27
mg, 0.11 mmol) at 82 °C for 3.75 d as described in Standard Stille
Cross-Coupling Using MnCl2 (vide supra) afforded 2c (17 mg, 52%)
as an oil following chromatographic purification of the crude product
using 10% EtOAc/hexanes. TLC: Rf ≈ 0.5 (10% EtOAc/hexanes); 1H
NMR (400 MHz, CDCl3) δ 8.23−8.15 (m, 2H), 7.53−7.43 (m, 2H),
7.30−7.10 (m, 5H), 6.52 (dd, J = 8.0, 5.3 Hz, 1H), 3.70−3.65 (m,
2H), 3.58−3.53 (m, 2H), 2.69−2.66 (m, 2H), 2.35−2.33 (m, 1H),
2.19−2.16 (m, 1H), 1.99−1.84 (m, 4H); 13C NMR (101 MHz,
CDCl3) δ 183.8, 148.2, 140.8, 128.5, 128.25, 127.4, 126.1, 123.8, 80.1,
52.2, 47.9, 38.2, 31.7, 25.65, 24.5. HRMS Calcd for C20H22N2NaO3S
[M + Na]+ 393.1249, found 393.1240.
O-(1-(4-Fluorophenyl)-3-phenylpropyl) Pyrrolidine-1-carbo-
thioate (2d). Stirring 1 (50 mg, 0.093 mmol) and 1-fluoro-4-
iodobenzene (25 mg, 0.11 mmol) at 82 °C for 3.75 d as described in
Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded 2d
(16 mg, 52%) as an oil following chromatographic purification of the
crude product using 10% EtOAc/hexanes. TLC: Rf ≈ 0.5 (10%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.38−7.31 (m, 2H),
mol %) in dioxane for 24 h at rt with Jackiephos (25 mol %),
NaCl (3 equiv), KF (3 equiv), and K3PO4 (2 equiv) but no
copper salts; none of the β-elimination product was observed.
Coupling of 3 with 3-bromo-2-iodoquinoline [dioxane
Jackiephos (25 mol %), NaCl (3 equiv), KF (3 equiv),
K3PO4 (2 equiv)] catalyzed by MnCl2 (100 mol %) alone
required 72 h at 82 °C to give 4f (67%). This contrasts sharply
with synergistic Mn(II)/Cu(II) cocatalysis that proceeds at rt
in just 12 h to yield 4f (62%) (Figure 2).40
Inclusion of KF, while not essential, did accelerate the
reaction rate, presumably by forming an insoluble adduct with
the tri-n-butylstannane byproduct, but might also involve
exchange with the metal ligands as proposed for Pd-catalyzed
cross-couplings.41
CONCLUSION
■
MnCl2, or MnCl2 assisted by Cu(OTf)2, provides a viable
alternative to LTM catalysts for the stereospecific cross-
coupling of α-alkoxyalkylstannanes with highly reactive electro-
philes that are prone to dimerization and/or decomposition
under traditional conditions. While much additional work is
needed to validate the mechanism of this new variant of the
Stille reaction, these results provide some insights into the rich
and complex chemistry lurking among the less well-studied
transition metals.42
EXPERIMENTAL SECTION
■
General Procedures and Materials. Nuclear magnetic resonance
spectra were recorded on a Bruker AV II 400 MHz spectrometer (1H
NMR at 400 MHz, 13C NMR at 101 MHz) or a Varian 500 MHz
spectrometer (1H NMR at 500 MHz, 13C NMR at 126 MHz). The 1H
NMR chemical shifts were measured relative to CDCl3 (δ = 7.26 ppm)
or CD3OD (δ = 3.31 ppm) as internal reference, unless otherwise
stated. The 13C NMR chemical shifts were measured relative to CDCl3
(δ = 77.00 ppm) or CD3OD (δ = 49.00 ppm) as internal reference. 1H
NMR data are reported as chemical shift (ppm), multiplicity (s =
singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, app q
= apparent quartet, qn = quintet, app qn = apparent quintet, m =
multiplet), and coupling constant (Hz). High resolution mass spectra
(HRMS) were obtained from the Shimadzu Center for Advanced
Analytical Chemistry, Univ. of Texas at Arlington, using a LCMS-8050
triple quadrupole liquid chromatograph mass spectrometer and at the
Medical College of Wisconsin, Dept. of Pharmacology and Toxicology,
using an Agilent 6460 triple quadrupole-LC mass spectrometer.
Melting points were measured with a Stanford Research Systems
OptiMelt and are uncorrected. Optical rotations were measured at
room temperature on a Rudolph Research Analytical Autopol IV
polarimeter. Analytical thin layer chromatography (TLC) used glass
plates precoated with EMD Chemicals TLC silica gel 60 F254 (0.040−
0.063 mm) with visualization by UV light and/or KMnO4 or
phosphomolybdic acid (PMA) solution followed by heating.
Chromatographic purifications utilized preparative TLC or flash
chromatography on prepacked, commercial SiO2 columns on a
CombiFlash Rf200 chromatograph (Teledyne Isco). Yields refer to
isolated, purified material with spectral data consistent with assigned
structures or, if known, concordant with literature values. All reactions
were conducted under an argon atmosphere in oven-dried glassware
with magnetic stirring, unless otherwise noted. Reaction solvents were
dried immediately before use via passage through drying columns
under positive nitrogen pressure. Reagents were purchased at the
highest commercial quality and used without further purification,
unless otherwise noted.
Standard Stille Cross-Couplings Using MnCl2 (Figure 1). A
Schlenk tube was charged with α-alkoxy-tri-n-butylstannane19,31 (0.093
mmol), neutralized MnCl2 (0.047 mmol, 50 mol %) (see preparation
of neutralized MnCl2 below), NaCl (0.27 mmol, 300 mol %), (S)-
D
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7.26−7.22 (m, 2H), 7.18−7.13 (m, 3H), 7.09−6.96 (m, 2H), 6.45 (dd,
J = 7.8, 5.9 Hz, 1H), 3.76−3.60 (m, 2H), 3.52−3.48 (m, 2H), 2.67−
2.58 (m, 2H), 2.35−2.31 (m, 1H), 2.20−2.05 (m, 1H), 1.97−1.81 (m,
4H); 13C NMR (101 MHz, CDCl3) δ 184.2, 162.2 (d, JC,F = 246.1
Hz), 141.3, 136.4 (d, JC,F = 3.1 Hz), 128.5 (d, JC,F = 8.4 Hz), 128.3,
128.3, 125.9, 115.3 (d, JC,F = 21.5 Hz), 80.8, 52.0, 47.8, 38.3, 31.8, 25.6,
24.5. HRMS Calcd for C20H22FNNaOS [M + Na]+ 366.1298, found
366.1294.
O-(1-(4-Cyano-2-fluorophenyl)-3-phenylpropyl) Pyrrolidine-1-
carbothioate (2e). Stirring 1 (50 mg, 0.093 mmol) and 3-fluoro-4-
iodobenzonitrile (27 mg, 0.11 mmol) at 82 °C for 4.6 d as described in
Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded 2e
(18 mg, 54%) as an oil following chromatographic purification of the
crude product using 10% EtOAc/hexanes. TLC: Rf ≈ 0.45 (10%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.46−7.10 (m, 8H),
6.64 (dd, J = 8.2, 5.1 Hz, 1H), 3.75−3.45 (m, 4H), 2.71−2.65 (m,
2H), 2.34−2.29 (m, 1H), 2.21−2.19 (m, 1H), 2.04−1.82 (m, 4H); 13C
NMR (101 MHz, CDCl3) δ 183.6, 159.2 (d, JC,F = 246.1 Hz), 140.7,
134.4 (d, JC,F = 13.0 Hz), 129.1 (d, JC,F = 4.6 Hz), 128.4, 128.2, 126.1,
8.1 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.60−7.44 (m, 4H), 7.36−7.23
(m, 3H), 7.20 (d, J = 7.3 Hz, 2H), 3.81−3.58 (m, 4H), 2.77−2.74 (m,
2H), 2.52−2.41 (m, 2H), 2.01−1.90 (m, 4H); 13C NMR (126 MHz,
CDCl3) δ 184.4, 141.5, 136.6, 133.9, 130.5, 128.9, 128.4, 128.35,
126.2, 125.9, 125.6, 125.3, 124.3, 123.6, 79.4, 52.1, 48.0, 38.0, 32.25,
25.7, 24.5. HRMS Calcd for C24H25NNaOS [M + Na]+ 398.1549,
found 398.1550.
O-(3-Phenyl-1-(p-tolyl)propyl) Pyrrolidine-1-carbothioate (2j).
Stirring 1 (50 mg, 0.093 mmol) and 1-iodo-4-methylbenzene (24
mg, 0.11 mmol) at 82 °C for 4.6 d following Standard Stille Cross-
Coupling Using MnCl2 (vide supra) afforded 2j (15 mg, 50%) as an oil
following chromatographic purification of the crude product using
10% EtOAc/hexanes. TLC: Rf ≈ 0.65 (10% EtOAc/hexanes); 1H
NMR (500 MHz, CDCl3) δ 7.31−7.22 (m, 4H), 7.18−7.16 (m, 5H),
6.47 (t, J = 6.8 Hz, 1H), 3.77−3.62 (m, 2H), 3.54−3.52 (m, 2H),
2.70−2.61 (m, 2H), 2.43−2.32 (m, 4H), 2.19−2.17 (m, 1H), 2.02−
1.84 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 184.3, 141.6, 137.6,
137.5, 129.1, 128.3, 126.8, 125.8, 81.5, 52.0, 47.8, 38.25, 31.9, 25.6,
24.5, 21.2. HRMS Calcd for C21H25NNaOS [M + Na]+ 362.1549,
found 362.1541.
119.4 (d, JC,F = 25.3 Hz), 117.45 (d, JC,F = 2.3 Hz), 112.7 (d, JC,F
=
10.0 Hz), 75.8, 52.2, 47.9, 36.95, 31.8, 25.65, 24.5. HRMS Calcd for
(E)-O-(1,6-Diphenylhex-5-en-3-yl) Pyrrolidine-1-carbothioate
(2k). Stirring 1 (50 mg, 0.093 mmol) and (E)-cinnamyl bromide
(22 mg, 0.11 mmol) at 68 °C for 2.5 d following the Standard Stille
Cross-Coupling Using MnCl2 (vide supra) afforded 2k (22 mg, 65%)
as an oil following chromatographic purification of the crude product
using 10% EtOAc/hexanes. The spectral data of 2k were concordant
with literature values.32
C21H21FN2NaOS [M + Na]+ 391.1251, found 391.1247.
O-(1-(2-Bromo-4-fluorophenyl)-3-phenylpropyl) Pyrrolidine-1-
carbothioate (2f). Stirring 1 (50 mg, 0.093 mmol) and 2-bromo-4-
fluoro-1-iodobenzene (33 mg, 0.11 mmol) at 82 °C for 4.6 d as
described in Standard Stille Cross-Coupling Using MnCl2 (vide supra)
afforded 2f (22 mg, 58%) as an oil following chromatographic
purification of the crude product using 10% EtOAc/hexanes. TLC: Rf
O-(1-(5-Acetylthiophen-2-yl)-3-phenylpropyl) Pyrrolidine-1-car-
bothioate (2l). Stirring 1 (50 mg, 0.093 mmol) and 1-(5-
iodothiophen-2-yl)ethan-1-one (28 mg, 0.11 mmol) at 82 °C for 2.5
d as described in Standard Stille Cross-Coupling Using MnCl2 (vide
supra) afforded 2l (19 mg, 55%) as an oil following chromatographic
purification of the crude product using 10% EtOAc/hexanes. TLC: Rf
1
≈ 0.4 (10% EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.35−
7.23 (m, 4H), 7.20−7.18 (m, 3H), 7.04−7.02 (m, 1H), 6.68 (dd, J =
7.8, 4.9 Hz, 1H), 3.78−3.50 (m, 4H), 2.80−2.72 (m, 2H), 2.23−2.21
(m, 2H), 2.01−1.93 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 183.9,
161.5 (d, JC,F = 250.3 Hz), 141.3, 136.5 (d, JC,F = 3.8 Hz), 128.4,
128.35, 125.95, 122.1 (d, JC,F = 9.6 Hz), 120.1 (d, JC,F = 24.0 Hz),
114.8 (d, JC,F = 21.1 Hz), 80.2, 52.2, 47.9, 37.4, 32.0, 25.7, 24.5. HRMS
Calcd for C20H21BrFNNaOS [M + Na]+ 444.0403, found 444.0391.
O-(1-(2-Chloro-4-(trifluoromethyl)phenyl)-3-phenylpropyl) Pyrro-
lidine-1-carbothioate (2g). Stirring 1 (50 mg, 0.093 mmol) and 2-
chloro-1-iodo-4-(trifluoromethyl)benzene (34 mg, 0.11 mmol) at 82
°C for 4.6 d as described in Standard Stille Cross-Coupling Using
MnCl2 (vide supra) afforded 2g (22 mg, 56%) as an oil following
chromatographic purification of the crude product using 10% EtOAc/
1
≈ 0.35 (10% EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.58
(d, J = 3.9 Hz, 1H), 7.28−7.26 (m, 2H), 7.25−7.15 (m, 3H), 7.09 (d, J
= 3.9 Hz, 1H), 6.80 (dd, J = 7.3, 5.9 Hz, 1H), 3.80−3.66 (m, 2H),
3.61−3.45 (m, 2H), 2.72−2.69 (m, 2H), 2.55 (s, 3H), 2.43−2.41 (m,
1H), 2.31−2.26 (m, 1H), 2.00−1.91 (m, 4H); 13C NMR (126 MHz,
CDCl3) δ 190.8, 183.5, 153.2, 143.6, 140.8, 132.4, 128.5, 128.35,
126.4, 126.1, 76.9, 52.25, 48.1, 38.4, 31.6, 26.6, 25.6, 24.5. HRMS
Calcd for C20H23NNaO2S2 [M + Na]+ 396.1062, found 396.1059.
O-(1-(5-Nitropyridin-2-yl)-3-phenylpropyl) Pyrrolidine-1-carbo-
thioate (2m). Stirring 1 (50 mg, 0.093 mmol) and 2-iodo-5-
nitropyridine (28 mg, 0.11 mmol) at 82 °C for 3.0 d as described in
the Standard Stille Cross-Coupling using MnCl2 (vide supra) afforded
2m (23 mg, 68%) as an oil following chromatographic purification of
the crude product using 10% EtOAc/hexanes. TLC: Rf ≈ 0.3 (10%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 9.41 (d, J = 2.5 Hz,
1H), 8.43 (dd, J = 8.6, 2.6 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.31−
7.15 (m, 5H), 6.56 (dd, J = 7.5, 5.1 Hz, 1H), 3.78−3.64 (m, 3H),
3.62−3.47 (m, 1H), 2.77 (t, J = 7.8 Hz, 2H), 2.48−2.33 (m, 2H),
2.09−1.84 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 183.9, 166.5,
144.8, 143.05, 140.9, 131.5, 128.4, 128.35, 128.3, 126.1, 121.3, 81.1,
52.3, 48.1, 36.4, 31.8, 25.7, 24.5. HRMS Calcd for C19H21N3NaO3S [M
+ Na]+ 394.1196, found 394.1185.
1
hexanes. TLC: Rf ≈ 0.4 (10% EtOAc/hexanes); H NMR (500 MHz,
CDCl3) δ 7.56 (d, J = 2.4 Hz, 1H), 7.53−7.43 (m, 2H), 7.30−7.27 (m,
2H), 7.20−7.18 (m, 3H), 6.84 (dd, J = 8.1, 4.6 Hz, 1H), 3.73−3.70
(m, 2H), 3.60−3.50 (m, 2H), 2.82−2.71 (m, 2H), 2.29−2.11 (m, 2H),
2.03−1.85 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 183.8, 141.0,
140.1, 130.3, 128.4, 128.34, 128.29, 126.0, 125.35 (q, JC,F = 3.4 Hz),
124.2 (app q), 78.05, 52.3, 47.9, 37.0, 31.95, 25.7, 24.4. HRMS Calcd
for C21H21ClF3NNaOS [M + Na]+ 450.0877, found 450.0862.
O-(1-(4-Methyl-2-nitrophenyl)-3-phenylpropyl) Pyrrolidine-1-car-
bothioate (2h). Stirring 1 (50 mg, 0.093 mmol) and 1-iodo-4-methyl-
2-nitrobenzene (29 mg, 0.11 mmol) at 82 °C for 4.6 d as described in
Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded 2h
(19 mg, 54%) as an oil following chromatographic purification of the
crude product using 10% EtOAc/hexanes. TLC: Rf ≈ 0.45 (10%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.42−
7.34 (m, 2H), 7.28−7.23 (m, 2H), 7.21−7.16 (m, 3H), 6.82 (dd, J =
8.3, 4.4 Hz, 1H), 3.71−3.48 (m, 4H), 2.90−2.81 (m, 2H), 2.40 (s,
3H), 2.34−2.31 (m, 2H), 1.99−1.88 (m, 4H); 13C NMR (101 MHz,
CDCl3) δ 184.0, 148.1, 141.4, 138.5, 134.55, 134.2, 128.35, 128.33,
127.5, 125.9, 124.7, 77.6, 52.1, 47.7, 38.2, 32.7, 25.7, 24.4, 20.8. HRMS
Calcd for C21H24N2NaO3S [M + Na]+ 407.1400, found 407.1394.
O-(1-(Naphthalen-1-yl)-3-phenylpropyl) Pyrrolidine-1-carbo-
thioate (2i). Stirring 1 (50 mg, 0.093 mmol) and 1-iodonaphthalene
(28 mg, 0.11 mmol) at 82 °C for 4.6 d as described in Standard Stille
Cross-Coupling Using MnCl2 (vide supra) afforded 2i (19 mg, 55%)
as an oil following chromatographic purification of the crude product
using 10% EtOAc/hexanes. TLC: Rf ≈ 0.55 (10% EtOAc/hexanes);
1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.3 Hz, 1H), 7.86 (d, J =
O-(3-Phenyl-1-(pyridin-2-yl)propyl) Pyrrolidine-1-carbothioate
(2n). Stirring 1 (50 mg, 0.093 mmol) and 2-iodopyridine (22 mg,
0.11 mmol) at 82 °C for 3.75 d as described in Standard Stille Cross-
Coupling Using MnCl2 (vide supra) afforded 2n (16 mg, 54%) as an
oil following chromatographic purification of the crude product using
10% EtOAc/hexanes. TLC: Rf ≈ 0.25 (10% EtOAc/hexanes); 1H
NMR (500 MHz, CDCl3) δ 8.61 (dd, J = 4.9, 1.8, Hz, 1H), 7.67−7.66
(m, 1H), 7.35−7.33 (m, 1H), 7.27−7.25 (m, 2H), 7.23−7.13 (m, 4H),
6.55 (dd, J = 7.7, 5.2 Hz, 1H), 3.79−3.62 (m, 3H), 3.57−3.52 (m,
1H), 2.80−2.66 (m, 2H), 2.41−2.37 (m, 2H), 2.04−1.87 (m, 4H); 13C
NMR (126 MHz, CDCl3) δ 184.4, 159.6, 149.4, 141.6, 136.5, 128.4,
128.3, 125.8, 122.5, 121.5, 81.9, 52.2, 47.95, 36.7, 31.9, 25.7, 24.5.
HRMS Calcd for C19H22N2NaOS [M + Na]+ 349.1345, found
349.1339.
E
DOI: 10.1021/acs.joc.7b02780
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
O-(1-(4-Bromoquinolin-6-yl)-3-phenylpropyl) Pyrrolidine-1-car-
bothioate (2o). Stirring 1 (50 mg, 0.093 mmol) and 4-bromo-6-
iodoquinoline (37 mg, 0.11 mmol) at 82 °C for 3.75 d as described in
Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded 2o
(24 mg, 58%) as an oil following chromatographic purification of the
crude product using 10% EtOAc/hexanes. TLC: Rf ≈ 0.4 (10%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 4.7 Hz,
1H), 8.20−8.04 (m, 2H), 7.80−7.65 (m, 2H), 7.30−7.12 (m, 5H),
6.71 (dd, J = 7.5, 5.6 Hz, 1H), 3.72−3.58 (m, 4H), 2.75−2.68 (m,
2H), 2.52−2.38 (m, 1H), 2.35−2.21 (m, 1H), 2.06−1.81 (m, 4H); 13C
NMR (101 MHz, CDCl3) δ 184.1, 149.8, 148.55, 141.1, 140.6, 134.2,
130.3, 129.0, 128.4, 128.3, 127.6, 126.0, 125.3, 124.6, 80.9, 52.1, 47.9,
38.25, 31.8, 25.7, 24.5. HRMS Calcd for C23H23BrN2NaOS [M + Na]+
477.0607, found 477.0605.
O-(1-(Isoquinolin-1-yl)-3-phenylpropyl) Pyrrolidine-1-carbo-
thioate (2p). Stirring 1 (50 mg, 0.093 mmol) and 1-iodoisoquinoline
(28 mg, 0.11 mmol) at 82 °C for 3.75 d as described in Standard Stille
Cross-Coupling Using MnCl2 (vide supra) afforded 2p (23 mg, 66%)
as an oil following chromatographic purification of the crude product
using 10% EtOAc/hexanes. TLC: Rf ≈ 0.4 (10% EtOAc/hexanes); 1H
NMR (500 MHz, CDCl3) δ 8.55 (d, J = 5.6 Hz, 1H), 8.35 (d, J = 8.5
Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.72−7.64 (m, 1H), 7.64−7.57 (m,
2H), 7.33−7.15 (m, 6H), 3.72−3.66 (m, 4H), 2.86−2.83 (m, 1H),
2.80−2.71 (m, 1H), 2.61−2.52 (m, 1H), 2.49−2.43 (m, 1H), 2.03−
1.83 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 184.5, 158.1, 141.9,
141.4, 136.5, 129.9, 128.4, 128.34, 128.30, 127.4, 127.3, 126.4, 125.85,
124.9, 120.7, 78.5, 52.1, 48.1, 36.2, 32.2, 25.6, 24.5. HRMS Calcd for
C23H24N2NaOS [M + Na]+ 399.1502, found 399.1500.
36.8, 31.9, 25.7, 25.3, 24.5. HRMS Calcd for C24H27NNaO3S [M +
Na]+ 432.1604, found 432.1612. HPLC: 96.2% ee (see HPLC
chromatogram in SI).
(R)-O-(1-(3-Bromoquinolin-2-yl)-3-phenylpropyl) Pyrrolidine-1-
carbothioate [(R)-2t]. Stirring (S)-1 (50 mg, 0.093 mmol) and 3-
bromo-2-iodoquinoline (37 mg, 0.11 mmol) at 82 °C for 3.0 d as
described in Standard Stille Cross-Coupling Using MnCl2 (vide supra)
afforded (R)-2t (26 mg, 62%) as an oil following chromatographic
purification of the crude product using 10% EtOAc/hexanes. TLC: Rf
1
≈ 0.35 (10% EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 8.30
(s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.67 (t, J = 8.0 Hz, 2H), 7.51 (d, J =
7.0 Hz, 1H), 7.32−7.11 (m, 5H), 6.82 (dd, J = 8.2, 4.7 Hz, 1H), 3.99−
3.88 (m, 1H), 3.75−3.59 (m, 3H), 2.96−2.90 (m, 1H), 2.86−2.79 (m,
1H), 2.51−2.30 (m, 2H), 2.01−1.89 (m, 4H); 13C NMR (101 MHz,
CDCl3) δ 184.6, 157.0, 146.3, 141.45, 139.2, 129.6, 129.5, 128.45,
128.34, 128.31, 127.2, 126.5, 125.9, 116.8, 80.0, 52.1, 48.2, 35.4, 32.25,
25.7, 24.6. HRMS Calcd for C23H23BrN2NaOS [M + Na]+ 477.0612,
found 477.0608. HPLC: 96.4% ee (see HPLC chromatogram in SI).
O-((S,E)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-4-phenylbut-3-en-
1-yl) Pyrrolidine-1-carbothioate (4a). Stirring O-((S)-((R)-2,2-
dimethyl-1,3-dioxolan-4-yl)(tri-n-butylstannyl)methyl) pyrrolidine-1-
carbothioate (3)31 (50 mg, 0.093 mmol) and (E)-(3-bromoprop-1-
en-1-yl)benzene (22 mg, 0.11 mmol) at 82 °C for 3.0 d as described in
Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded 4a
(22 mg, 68%) as an oil following chromatographic purification of the
crude product using 20% EtOAc/hexanes. TLC: Rf ≈ 0.5 (20%
EtOAc/hexanes). Spectral data were concordant with literature
values.32 1H NMR (400 MHz, CDCl3) δ 7.37−7.14 (m, 5H), 6.44
(d, J = 15.8 Hz, 1H), 6.20 (dt, J = 15.7, 7.2 Hz, 1H), 5.71 (q, J = 5.6
Hz, 1H), 4.33 (q, J = 6.0 Hz, 1H), 4.05 (dd, J = 8.4, 6.7 Hz, 1H), 3.92
(dd, J = 8.4, 6.0 Hz, 1H), 3.77−3.64 (m, 2H), 3.58−3.42 (m, 2H),
2.68−2.64 (m, 2H), 1.95−1.80 (m, 4H), 1.43 (s, 3H), 1.34 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 184.3, 137.3, 133.0, 128.5, 127.2,
(R)-O-(1-(4-Acetylphenyl)-3-phenylpropyl) Pyrrolidine-1-carbo-
thioate [(R)-2q]. Stirring (S)-131 (50 mg, 0.093 mmol) and 1-(4-
iodophenyl)ethan-1-one (27 mg, 0.11 mmol) at 82 °C for 3.0 d as
described in Standard Stille Cross-Coupling Using MnCl2 (vide supra)
afforded (R)-2q (20 mg, 60%) as an oil following chromatographic
purification of the crude product using 10% EtOAc/hexanes. TLC: Rf
126.1, 125.0, 109.6, 79.3, 76.7, 66.3, 52.1, 47.8, 34.3, 26.45, 25.55, 25.1,
24.4.
1
≈ 0.3 (10% EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.99−
7.91 (m, 2H), 7.48−7.40 (m, 2H), 7.33−7.24 (m, 2H), 7.24−7.14 (m,
3H), 6.53 (dd, J = 7.3, 5.4 Hz, 1H), 3.78−3.51 (m, 4H), 2.77−2.65
(m, 2H), 2.60 (s, 3H), 2.37−2.31 (m, 1H), 2.22−2.20 (m, 1H), 2.05−
1.85 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 197.7, 184.0, 146.1,
141.2, 136.5, 128.6, 128.43, 128.41, 128.3, 126.8, 126.0, 80.8, 52.1,
47.9, 38.2, 31.8, 26.7, 25.7, 24.5. HRMS Calcd for C22H25NNaO2S [M
+ Na]+ 390.1498, found 390.1498. HPLC: 99.2% ee (see HPLC
chromatogram in SI).
(R)-O-(1-(Naphthalen-2-yl)-3-phenylpropyl) Pyrrolidine-1-carbo-
thioate [(R)-2r]. Stirring (S)-1 (50 mg, 0.093 mmol) and 2-
iodonaphthalene (28 mg, 0.11 mmol) at 82 °C for 3.0 d as described
in Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded
(R)-2r (23 mg, 68%] as an oil following chromatographic purification
of the crude product using 10% EtOAc/hexanes. TLC: Rf ≈ 0.3 (10%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.89−7.80 (m, 4H),
7.56−7.44 (m, 3H), 7.32−7.23 (m, 2H), 7.22−7.15 (m, 3H), 6.69 (dd,
J = 7.3, 6.0 Hz, 1H), 3.72−3.59 (m, 4H), 2.72−2.62 (m, 2H), 2.52−
2.45 (m, 1H), 2.34−2.26 (m, 1H), 1.97−1.86 (m, 4H); 13C NMR
(101 MHz, CDCl3) δ 184.3, 141.5, 137.9, 133.15, 133.05, 128.35,
128.32, 128.1, 127.7, 126.14, 126.11, 126.0, 125.9, 124.5, 81.7, 52.05,
47.9, 38.2, 31.9, 25.6, 24.5. HRMS Calcd for C24H25NNaOS [M +
Na]+ 398.1549, found 398.1556. HPLC: 97.6−98.9% ee (see HPLC
chromatogram in SI).
(R)-O-(1-(6-Methoxy-1-oxo-2,3-dihydro-1H-inden-5-yl)-3-phenyl-
propyl) Pyrrolidine-1-carbothioate [(R)-2s]. Stirring (S)-1 (50 mg,
0.093 mmol) and 5-iodo-6-methoxy-2,3-dihydro-1H-inden-1-one (32
mg, 0.11 mmol) at 82 °C for 3.75 d as described in Standard Stille
Cross-Coupling Using MnCl2 (vide supra) afforded (R)-2s (20 mg,
55%) as an oil following chromatographic purification of the crude
product using 10% EtOAc/hexanes. TLC: Rf ≈ 0.3 (10% EtOAc/
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.29−7.08 (m, 7H), 6.78 (t,
J = 5.9 Hz, 1H), 3.87 (s, 3H), 3.78−3.49 (m, 4H), 3.04 (app d, J = 6.6
Hz, 2H), 2.81−2.63 (m, 4H), 2.28−2.16 (m, 2H), 2.06−1.83 (m, 4H);
13C NMR (101 MHz, CDCl3) δ 206.8, 184.1, 156.0, 147.7, 141.6,
O-((S)-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)(naphthalen-2-yl)-
methyl) Pyrrolidine-1-carbothioate (4b). Stirring 3 (50 mg, 0.093
mmol) and 2-iodonaphthalene (28 mg, 0.11 mmol) at 82 °C in
anhydrous toluene/EtOAc (3 mL, 4:1) for 3.0 d as described in
Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded 4b
(23 mg, 68%) as an oil following chromatographic purification of the
crude product using 20% EtOAc/hexanes. TLC: Rf ≈ 0.5 (20%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.90−7.78 (m, 4H),
7.57−7.43 (m, 3H), 6.72 (d, J = 5.4 Hz, 1H), 4.62 (d, J = 5.9 Hz, 1H),
4.09 (app d, J = 6.3 Hz, 2H), 3.82−3.64 (m, 4H), 2.08−1.89 (m, 4H),
1.38 (s, 3H), 1.34 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 184.0,
134.7, 133.2, 133.1, 128.2, 128.1, 127.7, 126.9, 126.2, 126.16, 125.14,
110.0, 81.0, 78.0, 66.1, 52.3, 48.1, 26.5, 25.7, 25.25, 24.5. HRMS Calcd
for C21H25NNaO3S [M + Na]+ 394.1447, found 394.1447.
O-((R)-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)(naphthalen-2-yl)-
methyl) Pyrrolidine-1-carbothioate (6). Stirring 5 (50 mg, 0.093
mmol) and 2-iodonaphthalene (28 mg, 0.11 mmol) at 82 °C in
anhydrous toluene/EtOAc (3 mL, 4:1) for 2.5 d as described in
Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded 6
(25 mg, 72%) as an oil following chromatographic purification of the
crude product using 20% EtOAc/hexanes. TLC: Rf ≈ 0.45 (20%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.89−7.79 (m, 4H),
7.57−7.44 (m, 3H), 6.68 (d, J = 6.3 Hz, 1H), 4.65 (d, J = 6.3 Hz, 1H),
3.89−3.76 (m, 3H), 3.75−3.62 (m, 3H), 2.09−1.83 (m, 4H), 1.50 (s,
3H), 1.38 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 184.2, 134.55,
133.3, 133.0, 128.3, 128.2, 127.7, 127.35, 126.3, 126.2, 125.2, 110.3,
81.8, 77.9, 65.9, 52.2, 48.1, 26.7, 25.7, 25.5, 24.5. HRMS Calcd for
C21H25NNaO3S [M + Na]+ 394.1447, found 394.1447.
O-((S)-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)(3-methoxyphenyl)-
methyl) Pyrrolidine-1-carbothioate (4c). Stirring 3 (50 mg, 0.093
mmol) and 1-iodo-3-methoxybenzene (26 mg, 0.11 mmol) at 82 °C in
anhydrous toluene/EtOAc (3 mL, 4:1) for 3.75 d as described in
Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded 4c
(18 mg, 56%) as an oil following chromatographic purification of the
crude product using 20% EtOAc/hexanes. TLC: Rf ≈ 0.4 (20%
138.1, 137.1, 128.5, 128.3, 125.8, 123.8, 104.0, 77.1, 55.9, 52.1, 47.8,
F
DOI: 10.1021/acs.joc.7b02780
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The Journal of Organic Chemistry
Article
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.31−7.24 (m, 1H),
7.00−6.89 (m, 2H), 6.89−6.81 (m, 1H), 6.55 (d, J = 5.3 Hz, 1H),
4.54−4.44 (m, 1H), 4.03 (dd, J = 6.2, 1.2 Hz, 2H), 3.81 (s, 3H), 3.79−
3.60 (m, 4H), 2.05−1.87 (m, 4H), 1.38 (s, 3H), 1.33 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 184.0, 159.5, 138.8, 129.4, 119.6, 113.4,
113.1, 109.9, 80.5, 78.0, 65.8, 55.2, 52.2, 48.0, 26.4, 25.6, 25.2, 24.5.
HRMS Calcd for C18H25NNaO4S [M + Na]+ 374.1397, found
374.1390.
O-((S)-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)(3,4,5-
trimethoxyphenyl)methyl) Pyrrolidine-1-carbothioate (4d). Stirring
3 (50 mg, 0.093 mmol) and 5-iodo-1,2,3-trimethoxybenzene (33 mg,
0.11 mmol) at 82 °C in anhydrous toluene/EtOAc (3 mL, 4:1) for
3.75 d as described in Standard Stille Cross-Coupling Using MnCl2
(vide supra) afforded 4d (16 mg, 42%) as an oil following
chromatographic purification of the crude product using 20%
EtOAc/hexanes. TLC: Rf ≈ 0.2 (20% EtOAc/hexanes); 1H NMR
(500 MHz, CDCl3) δ 6.61 (app s, 2H), 6.50 (d, J = 5.7 Hz, 1H), 4.49
(q, J = 6.0 Hz, 1H), 4.11−3.98 (m, 2H), 3.87 (s, 6H), 3.84 (s, 3H),
3.75−3.71 (m, 3H), 3.64−3.54 (m, 1H), 2.07−1.87 (m, 4H), 1.40 (s,
3H), 1.35 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 184.0, 153.1,
137.85, 132.6, 110.0, 104.7, 80.9, 77.9, 77.2, 66.1, 60.75, 56.1, 52.3,
48.0, 26.5, 25.65, 25.2, 24.5. HRMS Calcd for C20H29NNaO6S [M +
Na]+ 434.1608, found 434.1607.
O-((S)-(4-Acetylphenyl)((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-
methyl) Pyrrolidine-1-carbothioate (4e). Stirring 3 (50 mg, 0.093
mmol) and 1-(4-iodophenyl)ethan-1-one (27 mg, 0.11 mmol) at 82
°C in anhydrous toluene/EtOAc (3 mL, 4:1) for 3.0 d as described in
Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded 4e
(21 mg, 62%) as an oil following chromatographic purification of the
crude product using 20% EtOAc/hexanes. TLC: Rf ≈ 0.35 (20%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.98−7.91 (m, 2H),
7.46 (dd, J = 8.1, 0.7 Hz, 2H), 6.51 (d, J = 5.9 Hz, 1H), 4.50−4.44 (m,
1H), 4.09−4.00 (m, 2H), 3.72−3.66 (m, 4H), 2.58 (s, 3H), 2.04−1.89
(m, 4H), 1.36 (s, 3H), 1.31 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
197.6, 183.7, 178.9, 142.7, 136.75, 128.4, 127.7, 110.15, 80.45, 77.7,
66.2, 52.3, 48.1, 26.6, 26.4, 25.7, 25.1, 24.5. HRMS Calcd for
C19H25NNaO4S [M + Na]+ 386.1397, found 386.1402.
O-((S)-(3-Bromoquinolin-2-yl)((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)methyl) Pyrrolidine-1-carbothioate (4f). Stirring 3 (50 mg, 0.093
mmol) and 3-bromo-2-iodoquinoline (37 mg, 0.11 mmol) at 82 °C in
anhydrous toluene/EtOAc (3 mL, 4:1) for 2.5 d as described in
Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded 4f
(33 mg, 80%) as an oil following chromatographic purification of the
crude product using 20% EtOAc/hexanes. TLC: Rf ≈ 0.25 (20%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 8.33 (s, 1H), 8.04−
7.94 (m, 1H), 7.78−7.62 (m, 2H), 7.54−7.52 (m, 1H), 6.94 (d, J = 5.5
Hz, 1H), 4.71−4.70 (m, 1H), 4.46 (dd, J = 8.6, 5.4 Hz, 1H), 4.07 (dd,
J = 8.6, 6.8 Hz, 1H), 3.93−3.91 (m, 1H), 3.76−3.53 (m, 3H), 2.08−
1.92 (m, 4H), 1.53 (s, 3H), 1.34 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 183.9, 154.8, 146.4, 139.1, 129.6, 129.5, 128.6, 127.45,
126.6, 118.1, 109.8, 78.8, 76.7, 65.8, 52.15, 48.3, 26.35, 25.7, 25.05,
24.6. HRMS Calcd for C20H23BrN2NaO3S [M + Na]+ 473.0505, found
473.0513.
toluene/EtOAc (3 mL, 4:1) for 2.0 d as described in Standard Stille
Cross-Coupling Using MnCl2 (vide supra) afforded 4h (22 mg, 68%)
as an oil following chromatographic purification of the crude product
using 20% EtOAc/hexanes. TLC: Rf ≈ 0.45 (20% EtOAc/hexanes);
1H NMR (400 MHz, CDCl3) δ 7.49−7.40 (m, 2H), 7.37−7.29 (m,
2H), 7.26−7.24 (m, 1H), 6.70 (d, J = 11.7 Hz, 1H), 6.52 (ddd, J = 9.0,
4.3, 1.2 Hz, 1H), 5.64 (dd, J = 11.7, 9.0 Hz, 1H), 4.40−4.35 (m, 1H),
4.02 (dd, J = 8.4, 6.8 Hz, 1H), 3.82 (dd, J = 8.2, 6.2 Hz, 1H), 3.69−
3.66 (m, 2H), 3.55−3.53 (m, 1H), 3.43−3.42 (m, 1H), 1.98−1.83 (m,
4H), 1.35 (s, 3H), 1.31 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
183.8, 136.2, 134.2, 128.7, 128.3, 127.5, 125.9, 109.7, 76.8, 76.4, 65.9,
52.1, 47.85, 26.0, 25.6, 25.0, 24.5. HRMS Calcd for C19H25NNaO3S
[M + Na]+ 370.1447, found 370.1448. HPLC: 96.8%ee (see HPLC
chromatogram in SI).
O-((S,Z)-3-(3-Bromophenyl)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)allyl) Pyrrolidine-1-carbothioate (4i). Stirring 3 (50 mg, 0.093
mmol) and (Z)-1-bromo-3-(2-iodovinyl)benzene (34 mg, 0.11 mmol)
at 68 °C in anhydrous toluene/EtOAc (3 mL, 4:1) for 2.0 d as
described in Standard Stille Cross-Coupling Using MnCl2 (vide supra)
afforded 4i (19 mg, 48%) as an oil following chromatographic
purification of the crude product using 20% EtOAc/hexanes. TLC: Rf
1
≈ 0.55 (20% EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.61
(s, 1H), 7.47−7.35 (m, 2H), 7.28−7.16 (m, 1H), 6.67 (d, J = 11.9 Hz,
1H), 6.41 (ddd, J = 9.0, 5.2, 1.2 Hz, 1H), 5.70 (dd, J = 11.9, 8.8 Hz,
1H), 4.37−4.35 (m, 1H), 4.06 (dd, J = 8.5, 6.8 Hz, 1H), 3.84 (dd, J =
8.5, 6.4 Hz, 1H), 3.77−3.65 (m, 2H), 3.54−3.51 (m, 1H), 3.44−3.41
(m, 1H), 2.04−1.84 (m, 4H), 1.39 (s, 3H), 1.35 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 183.6, 138.35, 132.8, 131.55, 130.4, 129.8, 127.5,
127.2, 122.3, 109.9, 76.7, 76.3, 66.2, 52.2, 47.9, 26.1, 25.6, 25.1, 24.5.
HRMS Calcd for C19H24BrNNaO3S [M + Na]+ 448.0552, found
448.0546.
O-((S,Z)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-(4-nitrophenyl)-
allyl) Pyrrolidine-1-carbothioate (4j). Stirring 3 (50 mg, 0.093 mmol)
and (Z)-1-(2-iodovinyl)-4-nitrobenzene (30 mg, 0.11 mmol) at 68 °C
in anhydrous toluene/EtOAc (3 mL, 4:1) for 2.0 d as described in
Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded 4j
(19 mg, 52%) as an oil following chromatographic purification of the
crude product using 20% EtOAc/hexanes. TLC: Rf ≈ 0.3 (20%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 8.4 Hz,
2H), 7.69 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 11.9 Hz, 1H), 6.36 (dd, J =
9.2, 5.8 Hz, 1H), 5.81 (dd, J = 11.9, 9.2 Hz, 1H), 4.36−4.34 (m, 1H),
4.08 (dd, J = 8.5, 6.7 Hz, 1H), 3.85 (dd, J = 8.5, 6.1 Hz, 1H), 3.71−
3.69 (m, 2H), 3.59−3.42 (m, 2H), 1.95−1.92 (m, 4H), 1.36 (s, 3H),
1.35 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 183.4, 168.2, 142.8,
132.1, 129.8, 129.5, 123.5, 110.0, 109.99, 76.6, 76.3, 66.3, 52.3, 47.9,
26.0, 25.6, 25.0, 24.45. HRMS Calcd for C19H24N2NaO5S [M + Na]+
415.1298, found 415.1304.
O-((S,Z)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-5-phenylpent-2-
en-1-yl) Pyrrolidine-1-carbothioate (4k). Stirring 3 (50 mg, 0.093
mmol) and (Z)-(4-iodobut-3-en-1-yl)benzene (29 mg, 0.11 mmol) at
68 °C in anhydrous toluene/EtOAc (3 mL, 4:1) for 3.0 d as described
in Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded
4k (19 mg, 54%) as an oil following chromatographic purification of
the crude product using 20% EtOAc/hexanes. TLC: Rf ≈ 0.65 (20%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.33−7.15 (m, 5H),
6.28 (dd, J = 9.3, 4.7 Hz, 1H), 5.79−5.58 (m, 1H), 5.43−5.34 (m,
1H), 4.18−4.11 (m, 1H), 4.00 (dd, J = 8.3, 6.8 Hz, 1H), 3.81−3.70
(m, 3H), 3.62−3.47 (m, 2H), 2.81−2.79 (m, 1H), 2.75−2.64 (m, 2H),
2.60−2.47 (m, 1H), 1.95−1.92 (m, 4H), 1.40 (s, 3H), 1.34 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 184.0, 141.5, 135.7, 128.6, 128.3,
O-((S)-(5-Cyanopyridin-2-yl)((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-
methyl) Pyrrolidine-1-carbothioate (4g). Stirring 3 (50 mg, 0.093
mmol) and 6-iodonicotinonitrile (25 mg, 0.11 mmol) at 82 °C in
anhydrous toluene/EtOAc (3 mL, 4:1) for 2.5 d as described in
Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded 4g
(19 mg, 58%) as an oil following chromatographic purification of the
crude product using 20% EtOAc/hexanes. TLC: Rf ≈ 0.3 (20%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 8.78 (dd, J = 5.1, 0.9
Hz, 1H), 7.68−7.64 (m, 1H), 7.45 (dd, J = 5.0, 1.5 Hz, 1H), 6.55 (d, J
= 5.0 Hz, 1H), 4.77−4.73 (m, 1H), 4.11 (dd, J = 6.2, 1.5 Hz, 2H),
3.74−3.68 (m, 4H), 2.08−1.92 (m, 4H), 1.33 (s, 3H), 1.29 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 183.55, 150.1, 127.1, 125.4, 124.2,
120.5, 110.0, 80.5, 78.7, 65.8, 52.5, 48.3, 26.3, 25.7, 25.0, 24.5. HRMS
Calcd for C17H21N3NaO3S [M + Na]+ 370.1196, found 370.1186.
O-((S,Z)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-phenylallyl) Pyr-
rolidine-1-carbothioate (4h). Stirring 3 (50 mg, 0.093 mmol) and
(Z)-(2-iodovinyl)benzene (25 mg, 0.11 mmol) at 68 °C in anhydrous
125.8, 124.5, 109.6, 77.0, 76.0, 65.8, 52.1, 47.9, 35.5, 30.5, 26.3, 25.6,
25.1, 24.5. HRMS Calcd for C21H29NNaO3S [M + Na]+ 398.1760,
found 398.1761.
O-((S,E)-3-(2-Bromophenyl)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)allyl) Pyrrolidine-1-carbothioate (4l). Stirring 3 (50 mg, 0.093
mmol) and (E)-1-bromo-2-(2-iodovinyl)benzene (29 mg, 0.11 mmol)
at 68 °C in anhydrous toluene/EtOAc (3 mL, 4:1) for 1.5 d as
described in Standard Stille Cross-Coupling Using MnCl2 (vide supra)
afforded 4l (24 mg, 62%) as an oil following chromatographic
purification of the crude product using 20% EtOAc/hexanes. TLC: Rf
G
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The Journal of Organic Chemistry
Article
≈ 0.35 (20% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.57−
7.50 (m, 2H), 7.29−7.21 (m, 1H), 7.14−7.07 (m, 1H), 7.02 (d, J =
15.2 Hz, 1H), 6.30−6.21 (m, 2H), 4.49−4.43 (m, 1H), 4.13 (dd, J =
8.5, 6.8 Hz, 1H), 3.98 (dd, J = 8.5, 5.9 Hz, 1H), 3.78−3.67 (m, 4H),
2.04−1.93 (m, 4H), 1.45 (s, 3H), 1.38 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 183.6, 138.35, 132.8, 131.55, 130.4, 129.8, 127.5, 127.2,
122.3, 109.9, 76.7, 76.3, 66.2, 52.2, 47.9, 26.1, 25.6, 25.1, 24.5. HRMS
Calcd for C19H24BrNNaO3S [M + Na]+ 448.0552, found 448.0566.
O-((S,E)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-(4-iodophenyl)-
allyl) Pyrrolidine-1-carbothioate (4m). Stirring 3 (50 mg, 0.093
mmol) and (E)-1-iodo-4-(2-iodovinyl)benzene (40 mg, 0.11 mmol) at
68 °C in anhydrous toluene/EtOAc (3 mL, 4:1) for 2.0 d as described
for Standard Stille Cross-Coupling Using MnCl2 (vide supra) afforded
4m (25 mg, 58%) as an oil following chromatographic purification of
the crude product using 20% EtOAc/hexanes. TLC: Rf ≈ 0.35 (20%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.67−7.59 (m, 2H),
7.17−7.10 (m, 2H), 6.63 (d, J = 15.1 Hz, 1H), 6.30−6.19 (m, 2H),
4.44−4.41 (m, 1H), 4.11 (dd, J = 8.5, 6.8 Hz, 1H), 3.92 (dd, J = 8.6,
6.1 Hz, 1H), 3.77−3.74 (m, 2H), 3.71−3.55 (m, 2H), 2.04−1.90 (m,
4H), 1.43 (s, 3H), 1.37 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
184.7, 137.6, 135.7, 133.1, 131.8, 128.4, 124.7, 110.0, 79.8, 77.05, 66.1,
52.3, 48.0, 26.3, 25.6, 25.2, 24.5. HRMS Calcd for C19H24INNaO3S [M
+ Na]+ 496.0414, found 496.0416.
O-((S,E)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-(4-
(trifluoromethyl)phenyl)allyl)pyrrolidine-1-carbothioate (4n). Stir-
ring 3 (50 mg, 0.093 mmol) and (E)-1-(2-iodovinyl)-4-
(trifluoromethyl)benzene (33 mg, 0.11 mmol) at 68 °C in anhydrous
toluene/EtOAc (3 mL, 4:1) for 2.0 d as described in Standard Stille
Cross-Coupling Using MnCl2 (vide supra) afforded 4n (24 mg, 64%)
as an oil following chromatographic purification of the crude product
using 20% EtOAc/hexanes. TLC: Rf ≈ 0.5 (20% EtOAc/hexanes); 1H
NMR (500 MHz, CDCl3) δ 7.57 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.2
Hz, 2H), 6.74 (d, J = 16.0 Hz, 1H), 6.36 (dd, J = 16.0, 6.5 Hz, 1H),
6.26 (ddd, J = 6.4, 4.8, 1.2 Hz, 1H), 4.48−4.40 (m, 1H), 4.13 (dd, J =
8.5, 6.8 Hz, 1H), 3.94 (dd, J = 8.6, 6.0 Hz, 1H), 3.77−3.74 (m, 2H),
3.67−3.62 (m, 2H), 2.05−1.91 (m, 4H), 1.44 (s, 3H), 1.38 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 183.9, 139.7, 132.6, 126.9, 126.8,
Stille Cross-Coupling Procedure (vide supra) and chromatographic
purification of the crude product using 20% EtOAc/hexanes afforded
2p (25 mg, 71%) as an oil whose physical and spectral properties
matched an authentic sample. TLC: Rf ≈ 0.2 (10% EtOAc/hexanes).
(R)-O-(1-(3-Bromoquinolin-2-yl)-3-phenylpropyl) Pyrrolidine-1-
carbothioate [(R)-2t]. Stirring (S)-131 (50 mg, 0.093 mmol) and 3-
bromo-2-iodoquinoline (37 mg, 0.11 mmol) at rt in anhydrous
acetonitrile (3 mL) for 24 h as described in General Mn/Cu Stille
Cross-Coupling Procedure (vide supra) and chromatographic
purification of the crude product using 20% EtOAc/hexanes afforded
(R)-2t (28 mg, 68%) as an oil whose physical and spectral properties
matched an authentic sample. TLC: Rf ≈ 0.35 (10% EtOAc/hexanes).
HPLC: 98.0% ee (see HPLC chromatogram in SI).
O-(1-(6-Methoxy-1-oxo-2,3-dihydro-1H-inden-5-yl)-3-phenyl-
propyl) Pyrrolidine-1-carbothioate [( )-2s]. Stirring 1 (50 mg, 0.093
mmol) and 5-iodo-6-methoxy-2,3-dihydro-1H-inden-1-one (32 mg,
0.11 mmol) at 65 °C for 24 h as described in General Mn/Cu Stille
Cross-Coupling Procedure (vide supra) and chromatographic
purification of the crude product using 20% EtOAc/hexanes afforded
( )-2s (26 mg, 69%) as an oil whose spectral and physical properties,
except chirality, matched an authentic sample. TLC: Rf ≈ 0.3 (10%
EtOAc/hexanes).
O-((3-Bromophenyl)(3-bromoquinolin-2-yl)methyl) Pyrrolidine-1-
carbothioate (7). n-BuLi (1.6 M in hexanes, 4.72 mL, 7.56 mmol, 1.2
equiv) was added over 5 min to a stirring 0 °C solution of N,N-
diisopropylamine (1.05 mL, 7.56 mmol, 1.2 equiv) in THF (15 mL).
After 30 min, tri-n-butyltin hydride (1.85 mL, 2.0 g, 6.87 mmol, 1.1
equiv) was added dropwise over 10 min to the light yellow solution of
LDA. Following an additional 30 min, the reaction mixture was cooled
to −78 °C and a solution of 3-bromobenzaldehyde (1.1 g, 6.1 mmol,
1.00 equiv) in THF (2 mL) was slowly added. After 3 h, the reaction
mixture was quenched with saturated aq NH4Cl (20 mL). The layers
were separated, and the aqueous layer was extracted with EtOAc (2 ×
10 mL). The extracts and organic layer were combined and washed
sequentially with aq 1 N HC1 (2 × 5 mL), H2O (2 × 10 mL), and
brine (20 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure to afford crude (3-
bromophenyl)(tri-n-butylstannyl)methanol (1.1 g crude) as a yellow-
ish oil. TLC: Rf ≈ 0.45 (20% EtOAc/hexanes). Without purification,
the crude adduct was dissolved in CH2C12 (15 mL) containing DMAP
(10 mg) and thiocarbonyldiimidazole (0.45 g, 2.54 mmol, 1.1 equiv).
After 2 h, the reaction mixture was filtered through a short bed of silica
gel and the product was eluted with 30% EtOAc/hexane (100 mL) to
give the labile O-((3-bromophenyl)(tri-n-butylstannyl)methyl) 1H-
imidazole-1-carbothioate that was concentrated in vacuo and used
immediately in the next reaction without further characterization.
The imidazole in the above thiocarbamate was exchanged by stirring
the residue in a 2 M THF solution of pyrrolidine (4 mL) for 3 h.43
The excess pyrrolidine was evaporated in vacuo, and the residue was
flash chromatographed using 5−10% EtOAc/hexane to give O-((3-
bromophenyl)(tri-n-butylstannyl)methyl) pyrrolidine-1-carbothioate
(42% overall) as a light yellowish oil. TLC: Rf ≈ 0.75 (10% EtOAc/
hexanes); 1H NMR (500 MHz, CDCl3) δ 7.31−7.14 (m, 3H), 6.67 (s,
1H), 3.79−3.66 (m, 4H), 2.07−1.97 (m, 4H), 1.44−1.37 (m, 6H),
1.29−1.23 (m, 6H), 0.95−0.85 (m, 15H); 13C NMR (126 MHz,
CDCl3) δ 184.9, 146.0, 130.0, 127.8, 126.4, 122.7, 122.0, 78.8, 52.2,
47.9, 28.91, 28.89, 27.4, 25.9, 24.6, 13.7, 10.6. HRMS Calcd for
C24H40NNaOSBrSn [M + Na]+ 612.0920, found 612.0917.
126.7, 125.5 (d, JC,F = 3.9 Hz), 110.1, 110.0, 79.65, 77.0, 66.1, 52.3,
48.0, 26.35, 25.6, 25.1, 24.5. HRMS Calcd for C20H24F3NNaO3S [M +
Na]+ 438.1327, found 438.1312.
General Procedure for Manganese/Copper Stille Cross-
Couplings (Figure 2). A mixture of MnCl2·2LiCl (0.023 mmol, 25
mol %, 0.5 M solution in THF; Aldrich Chem. Co.), electrophile (0.11
mmol, 120 mol %), Cu(OTf)2 (20 mol %), Jackiephos (0.023 mmol,
25 mol %), KF (0.27 mmol, 300 mol %), K3PO4 (0.18 mmol, 200 mol
%), and NaCl (0.27 mmol, 300 mol %) in anhydrous dioxane (3 mL),
unless otherwise stated, was degassed via four alternating high vacuum-
argon cycles. After 1 h, the mixture developed a bright yellow
coloration indicative of the Jackiephos complex with manganese and
then a solution of α-alkoxy-tri-n-butylstannane (0.093 mmol) in
anhydrous dioxane (1 mL) was added via syringe. The reaction
mixture was stirred either at room temperature or heated at 68 °C as
indicated until TLC analysis showed all stannane was consumed. The
resultant maroon-colored reaction mixture was diluted with Et2O (10
mL) and filtered through a small bed of neutral alumina, and the filter
bed was washed with fresh Et2O (5 mL). The combined filtrates were
concentrated under reduced pressure, and the residue was purified via
flash SiO2 column chromatography to afford the cross-coupled adducts
in the indicated yields.
O-(1-(5-Acetylthiophen-2-yl)-3-phenylpropyl) Pyrrolidine-1-car-
bothioate (2l). Stirring 1 (50 mg, 0.093 mmol) and 1-(5-
iodothiophen-2-yl)ethan-1-one (28 mg, 0.11 mmol) in dioxane (3
mL) at 65 °C for 6 h as described in General Mn/Cu Stille Cross-
Coupling Procedure (vide supra) afforded 2l (22 mg, 64%) as an oil
identical in all respects with an authentic sample following SiO2
chromatographic purification using 10% EtOAc/hexanes. TLC: Rf ≈
0.35 (10% EtOAc/hexanes).
Stirring the above O-((3-bromophenyl)(tri-n-butylstannyl)methyl)
pyrrolidine-1-carbothioate (50 mg, 0.084 mmol) and 3-bromo-2-
iodoquinoline (34 mg, 0.11 mmol) at rt in anhydrous acetonitrile (3
mL) for 18 h as described in General Mn/Cu Stille Cross-Coupling
Procedure (vide supra) and chromatographic purification of the crude
product using 15% EtOAc/hexanes afforded 7 (25 mg, 58%) as an oil.
TLC: Rf ≈ 0.3 (10% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ
8.37 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.92 (s, 1H), 7.81−7.71 (m,
3H), 7.61−7.54 (m, 2H), 7.46 (dd, J = 8.0, 2.0 Hz, 1H), 7.23 (t, J = 7.9
Hz, 1H), 4.19−4.06 (m, 1H), 3.79−3.69 (m, 3H), 2.08−2.03 (m, 2H),
2.00−1.94 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 184.0, 155.6,
146.4, 139.6, 139.5, 131.5, 129.9, 129.79, 129.77, 128.6, 127.6, 127.4,
O-(1-(Isoquinolin-1-yl)-3-phenylpropyl) Pyrrolidine-1-carbo-
thioate (2p). Stirring 1 (50 mg, 0.093 mmol) and 1-iodoisoquinoline
(28 mg, 0.11 mmol) at 65 °C for 8 h as described in General Mn/Cu
H
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The Journal of Organic Chemistry
Article
126.6, 122.4, 117.0, 80.1, 52.2, 48.55, 25.75, 24.7. HRMS Calcd for
C21H19Br2N2OS [M + H]+ 504.9579, found 504.9580.
O-((S)-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)(naphthalen-1-yl)-
methyl) Pyrrolidine-1-carbothioate (4s). Stirring 3 (5:50 mg, 0.093
mmol) and 1-iodonaphthalene (28 mg, 0.11 mmol) at rt in anhydrous
dioxane (3 mL) for 24 h as described in General Mn/Cu Stille Cross-
Coupling Procedure (vide supra) and chromatographic purification of
the crude product using 20% EtOAc/hexanes afforded 4s (18 mg,
52%) as an oil. TLC: Rf ≈ 0.25 (20% EtOAc/hexanes); 1H NMR (400
MHz, CDCl3) δ 8.28 (d, J = 8.4 Hz, 1H), 7.89−7.76 (m, 2H), 7.63−
7.39 (m, 5H), 4.71−4.61 (m, 1H), 4.16 (dd, J = 8.5, 5.7 Hz, 1H),
3.97−3.62 (m, 5H), 2.07−1.84 (m, 4H), 1.39 (s, 3H), 1.29 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 184.2, 133.7, 133.3, 130.7, 128.8,
O-((S)-(3-Bromoquinolin-2-yl)((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)methyl) Pyrrolidine-1-carbothioate (4f). Stirring 3 (50 mg, 0.093
mmol) and 3-bromo-2-iodoquinoline (37 mg, 0.11 mmol) at rt in
anhydrous dioxane (3 mL) for 12 h as described in General Mn/Cu
Stille Cross-Coupling Procedure (vide supra) and chromatographic
purification of the crude product using 20% EtOAc/hexanes afforded
4f (26 mg, 62%) as an oil whose physical and spectral properties
matched an authentic sample. TLC: Rf ≈ 0.25 (20% EtOAc/hexanes).
O-((R)-(5-Acetylthiophen-2-yl)((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)methyl) Pyrrolidine-1-carbothioate (4o). Stirring 3 (50 mg, 0.093
mmol) and 1-(5-iodothiophen-2-yl)ethan-1-one (28 mg, 0.11 mmol)
at rt in anhydrous dioxane (3 mL) for 18 h as described in General
Mn/Cu Stille Cross-Coupling Procedure (vide supra) and chromato-
graphic purification of the crude product using 20% EtOAc/hexanes
afforded 4o (19 mg, 55%) as an oil. TLC: Rf ≈ 0.25 (20% EtOAc/
128.79, 126.4, 125.8, 125.2, 124.4, 123.5, 109.9, 78.0, 77.7, 65.5, 52.3,
48.1, 26.4, 25.7, 25.05, 24.5. HRMS Calcd for C21H26NO3S [M + H]+
372.1633, found 372.1634.
(S)-Standard of 2r [O-(1-(naphthalen-2-yl)-3-phenylpropyl)
Pyrrolidine-1-carbothioate]. Ti(OiPr)4 (383.6 mg, 1.35 mmol) was
added dropwise into a rt solution of (S)-BINOL (57.2 mg 0.2 mmol)
in dry TBME (1 mL) under an argon atmosphere. In a separate round-
bottom flask, phenethylmagnesium chloride (2.4 mL, 2.4 mmol, 1.0
mmol/mL in THF) was added over 5 min to a 0 °C solution of bis(2-
dimethylaminoethyl)ether (384.6 mg, 2.4 mmol, 99%; BDAEE) in dry
MTBE (2 mL) under an argon atmosphere. After stirring for 30 min,
the Ti(OiPr)4/(S)-BINOL mixture was introduced via cannula to the
phenethylmagnesium/BDAEE mixture and then allowed to warm to
rt. After 1 h, the yellow reaction mixture was recooled to 0 °C and a
solution of 2-naphthaldehyde (0.156 mg, 1.0 mmol) in THF (2 mL)
was added dropwise. After stirring at rt for 4 h, the reaction mixture
was quenched with cold 5% aq HCl to pH 4 and extracted with ether
(3 × 15 mL). The combined ethereal extracts were washed with brine
(8 mL), dried over Na2SO4, and concentrated in vacuo. Purification of
the residue by flash SiO2 column chromatography using 15% EtOAc/
hexane afforded (S)-1-(naphthalen-2-yl)-3-phenylpropan-1-ol44 (207
mg, 79%). TLC: Rf ≈ 0.25 (10% EtOAc/hexanes). The absolute
configuration was assigned by analogy with literature precedent.44 1H
NMR (500 MHz, CDCl3) δ 7.96−7.87 (m, 4H), 7.62−7.51 (m, 3H),
7.40−7.26 (m, 5H), 4.87 (dd, J = 7.7, 5.6 Hz, 1H), 2.90−2.72 (m,
2H), 2.33−2.15 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 142.0,
141.9, 133.4, 133.1, 128.6, 128.5, 128.46, 128.1, 127.8, 126.3, 126.0,
125.98, 124.8, 124.2, 74.0, 40.4, 32.2. The % ee was measured
following the next step.
1
hexanes); H NMR (500 MHz, CDCl3) δ 7.60 (dd, J = 3.8, 1.2 Hz,
1H), 7.17−7.14 (m, 1H), 6.81 (d, J = 6.0 Hz, 1H), 4.53−4.49 (m,
1H), 4.13 (ddd, J = 8.7, 6.6, 1.2 Hz, 1H), 4.03 (ddd, J = 8.7, 5.3, 1.2
Hz, 1H), 3.73−3.65 (m, 4H), 2.55 (s, 3H), 2.05−1.92 (m, 4H), 1.44
(s, 3H), 1.37 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 190.7, 183.2,
149.2, 144.3, 132.2, 127.6, 110.4, 77.5, 76.9, 66.2, 52.45, 48.2, 29.7,
26.5, 25.6, 25.1, 24.5. HRMS Calcd for C17H24NO4S2 [M + H]+
370.1147, found 370.1151.
O-((S,E)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)non-2-en-1-yl) Pyr-
rolidine-1-carbothioate (4p). Stirring 3 (50 mg, 0.093 mmol) and
(E)-1-iodooct-1-ene (26 mg, 0.11 mmol) at rt in anhydrous dioxane (3
mL) for 12 h as described in General Mn/Cu Stille Cross-Coupling
Procedure (vide supra) and chromatographic purification of the crude
product using 20% EtOAc/hexanes afforded 4p (22 mg, 68%) as an
1
oil. TLC: Rf ≈ 0.25 (20% EtOAc/hexanes); H NMR (500 MHz,
CD3CN) δ 6.07−6.00 (m, 1H), 5.89−5.78 (m, 1H), 5.56−5.47 (m,
1H), 4.35−4.27 (m, 1H), 4.05 (dd, J = 8.3, 6.7 Hz, 1H), 3.88 (dd, J =
8.3, 5.8 Hz, 1H), 3.72−3.53 (m, 4H), 2.15−2.06 (m, 2H), 2.03−1.91
(m, 4H), 1.48−1.27 (m, 15H), 0.93 (t, J = 6.7 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 184.2, 136.8, 123.9, 109.7, 80.1, 77.2, 65.9, 52.1,
47.8, 32.4, 31.6, 28.8, 28.7, 26.3, 25.6, 25.2, 24.5, 22.6, 14.1. HRMS
Calcd for C19H34NO3S [M + H]+ 356.2259, found 356.2250.
O-((S)-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)(isoquinolin-1-yl)-
methyl) Pyrrolidine-1-carbothioate (4q). Stirring 3 (50 mg, 0.093
mmol) and 1-iodoisoquinoline (28 mg, 0.11 mmol) at 65 °C in
anhydrous dioxane (3 mL) for 18 h as described in General Mn/Cu
Stille Cross-Coupling Procedure (vide supra) and chromatographic
purification of the crude product using 35% EtOAc/hexanes afforded
4q (22 mg, 63%) as an oil. TLC: Rf ≈ 0.15 (20% EtOAc/hexanes); 1H
NMR (500 MHz, CDCl3) δ 8.70 (dd, J = 7.5, 1.9 Hz, 1H), 8.50 (d, J =
5.5 Hz, 1H), 7.83 (dd, J = 7.5, 1.9 Hz, 1H), 7.73−7.58 (m, 3H), 7.50
(d, J = 5.0 Hz, 1H), 4.87 (dt, J = 6.6, 5.2 Hz, 1H), 4.42 (dd, J = 8.7, 5.3
Hz, 1H), 4.24 (dd, J = 8.7, 6.8 Hz, 1H), 3.79−3.59 (m, 4H), 2.00−
1.90 (m, 4H), 1.39 (s, 3H), 1.32 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 184.5, 156.1, 141.7, 136.4, 130.1, 127.6, 127.3, 127.1, 125.7,
121.2, 109.3, 77.5, 77.3, 66.4, 52.3, 48.2, 26.3, 25.6, 24.7, 24.5. HRMS
Calcd for C20H25N2O3S [M + H]+ 373.1580, found 373.1588.
1,1′-Thiocarbonyldiimidazole (112 mg, 0.63 mmol) was added to a
stirring solution of the above (S)-1-(naphthalen-2-yl)-3-phenylpropan-
1-ol (150 mg, 0.57 mmol) in dry CH2Cl2 (5 mL) containing DMAP (7
mg, 0.057 mmol) under an argon atmosphere.43 After 10 h, the
reaction mixture was filtered through a small pad of silica gel and the
filter cake was washed with EtOAc (5 mL). The combined filtrate was
concentrated under reduced pressure, and the residue was dissolved in
a 2 M THF solution of pyrrolidine (4 mL). After 2−4 h, all volatiles
were removed in vacuo and the residue was chromatographed over
SiO2 using 10% EtOAc/hexane affording (S)-O-(1-(naphthalen-2-yl)-
3-phenylpropyl) pyrrolidine-1-carbothioate [(S)-2r] (163 mg, 76%) as
1
a sticky semisolid. TLC: Rf ≈ 0.35 (10% EtOAc/hexanes). H/13C
NMR data were in complete agreement with those of (R)-2r produced
via Mn cross-coupling. HPLC: 82.7% ee (see HPLC chromatogram in
1
SI). H NMR (500 MHz, CDCl3) δ 7.93−7.89 (m, 4H), 7.66−7.48
O-((S,E)-3-(4-Bromophenyl)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)allyl) Pyrrolidine-1-carbothioate (4r). Stirring 3 (50 mg, 0.093
mmol) and (E)-1-bromo-4-(2-iodovinyl)benzene (34 mg, 0.11 mmol)
at rt in anhydrous dioxane (3 mL) for 18 h as described in General
Mn/Cu Stille Cross-Coupling Procedure (vide supra) and chromato-
graphic purification of the crude product using 20% EtOAc/hexanes
afforded 4r (28 mg, 71%) as an oil. TLC: Rf ≈ 0.25 (20% EtOAc/
(m, 3H), 7.45−7.20 (m, 5H), 6.77 (t, J = 6.7 Hz, 1H), 3.89−3.58 (m,
4H), 2.83−2.79 (m, 2H), 2.77−2.74 (m, 1H), 2.39−2.36 (m, 1H),
2.10−1.86 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 184.4, 141.6,
138.0, 133.2, 133.1, 128.44, 128.40, 128.2, 127.75, 126.23, 126.17,
126.1, 126.0, 124.6, 81.8, 52.1, 48.0, 38.3, 32.0, 25.7, 24.6. HRMS
Calcd for C24H25NNaOS [M + Na]+ 398.1555, found 398.1549.
Standard of ( )-O-(1-(naphthalen-2-yl)-3-phenylpropyl)
Pyrrolidine-1-carbothioate [( )-2r]. Phenethylmagnesium chloride
(2.4 mL, 2.4 mmol, 1.0 M in THF) added dropwise over 10 min to a
stirring, 0 °C solution of 2-naphthaldehyde (0.156 mg, 1.0 mmol) in
TBME/THF (8 mL, 1:1). After stirring for an additional 3 h at rt, the
reaction mixture was quenched with cold aqueous 5% HCl to pH 4
and extracted with ether (3 × 15 mL). The combined extracts were
washed with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified via SiO2 chromatography using 15% EtOAc/
1
hexanes); H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.4 Hz, 2H),
7.25 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 14.3 Hz, 1H), 6.29−6.14 (m,
2H), 4.40 (td, J = 6.3, 2.9 Hz, 1H), 4.10 (dd, J = 8.5, 6.8 Hz, 1H), 3.90
(dd, J = 8.4, 6.1 Hz, 1H), 3.78−3.52 (m, 4H), 1.99−1.90 (m, 4H),
1.42 (s, 3H), 1.35 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 184.0,
135.2, 133.0, 131.6, 128.3, 128.2, 124.6, 121.8, 110.0, 79.8, 77.3, 66.1,
52.3, 48.0, 26.4, 25.6, 25.2, 24.5. HRMS Calcd for C19H24BrNNaO3S
[M + Na]+ 448.0552, found 448.0560.
I
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The Journal of Organic Chemistry
Article
hexane to afford 1-(naphthalen-2-yl)-3-phenylpropan-1-ol (152 mg,
71%). TLC: Rf ≈ 0.25 (10% EtOAc/hexanes). Spectral data were in
complete agreement with literature values.44
The above 2-naphthylmagnesium bromide (7.1 mL of 0.49 M
solution in THF, 3.46 mmol, 3.0 equiv) was added to a stirring, rt
solution of ZnCl2 (2.3 mL of 0.5 M solution in THF, 1.15 mmol, 1.0
equiv) under an argon atmosphere. After 30 min, the triorganozincate
solution was cannulated slowly over 15 min into a −78 °C solution of
(R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (6) (0.15 mg, 1.15
mmol, 1 equiv) under an argon atmosphere. After 1 h, the reaction
mixture was quenched with aq NH4Cl (8 mL) and extracted with ether
(3 × 15 mL). The combined ethereal extracts were washed with brine,
dried over Na2SO4, and concentrated in vacuo. Purification of the
residue by SiO2 column chromatography using 30% EtOAc/hexane
afforded (S)-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)(naphthalen-2-yl)-
methanol (107 mg, 36%). TLC: Rf ≈ 0.34 (25% EtOAc/hexanes);
1H NMR (500 MHz, CDCl3) δ 7.95−7.79 (m, 4H), 7.62−7.44 (m,
3H), 5.09 (d, J = 4.4 Hz, 1H), 4.43 (td, J = 6.7, 4.4 Hz, 1H), 4.06 (dd,
J = 8.4, 6.7 Hz, 1H), 3.82−3.75 (m, 1H), 2.74 (s, 1H, OH), 1.52 (s,
3H), 1.39 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 137.0, 133.3,
133.1, 128.3, 128.0, 127.7, 126.25, 126.0, 124.9, 123.9, 109.65, 79.3,
72.7, 64.5, 26.6, 25.2. HRMS Calcd for C16H18NaO3 [M + Na]+
281.1148, found 281.1140.
1,1′-Thiocarbonyldiimidazole (112 mg, 0.63 mmol) was added to a
stirring solution of 1-(naphthalen-2-yl)-3-phenylpropan-1-ol (150 mg,
0.57 mmol) in dry CH2Cl2 (5 mL) containing DMAP (7 mg, 0.057
mmol) under an argon atmosphere.43 After 10 h, the reaction mixture
was filtered through a small pad of silica gel and the filter cake was
washed with EtOAc (5 mL). The combined filtrate was concentrated
under reduced pressure, and the residue was dissolved in a 2 M THF
solution of pyrrolidine (4 mL). After 4 h, all volatiles were removed in
vacuo and the residue was chromatographed over SiO2 using 10%
EtOAc/hexane to give ( )-2r (163 mg, 76%) as a sticky semisolid.
TLC: Rf ≈ 0.75 (10% EtOAc/hexanes). Spectral data were in
complete agreement with those of 2r.
Standards of (R,R)- and (R,S)- of O-((2,2-Dimethyl-1,3-
dioxolan-4-yl)(naphthalen-2-yl)methyl) Pyrrolidine-1-carbo-
thioate (4b and 6). Following literature procedure,45 magnesium
turnings (0.96 g, 40 mmol, 2.0 equiv) were added to a two-neck
round-bottom flask equipped with a stir bar and condenser. The
reaction apparatus was flame-dried under vacuum and cooled under an
argon atmosphere. Anhydrous THF (18 mL) was added to the
reaction apparatus, followed by a single crystal of I2 (ca. 2 mg), and
then 2-bromonaphthlene (4.1 g, 20 mmol, 1.0 equiv) was added
portionwise over 1 h. The reaction was stirred at ambient temperature
for an additional 1 h. The Grignard concentration was assumed to be
0.49 M from the reported method.
Following literature procedure,43 1,1′-thiocarbonyldiimidazole (75
mg, 0.42 mmol) was added to a stirring solution of the above (S)-
((R)-2,2-dimethyl-1,3-dioxolan-4-yl)(naphthalen-2-yl)methanol (100
mg, 0.38 mmol) in dry CH2Cl2 (5 mL) containing DMAP (5 mg,
0.038 mmol) under an argon atmosphere. After 10 h, the reaction
mixture was filtered through a small pad of SiO2 and the filter cake was
washed with EtOAc (5 mL). The combined filtrate was concentrated
under reduced pressure, and the residue was dissolved in a THF
solution of pyrrolidine (4 mL, 2 M). After 4 h, all volatiles were
removed in vacuo and the residue was chromatographed over SiO2
using 20% EtOAc/hexane to yield O-((S)-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)(naphthalen-2-yl)methyl) pyrrolidine-1-carbothioate
(4b) (92 mg, 64%). TLC: Rf ≈ 0.5 (20% EtOAc/hexanes); 1H
NMR (500 MHz, CDCl3) δ 7.90−7.80 (m, 4H), 7.58−7.44 (m, 3H),
6.73 (d, J = 5.5 Hz, 1H), 4.62 (q, J = 6.1 Hz, 1H), 4.09 (d, J = 6.3 Hz,
2H), 3.84−3.63 (m, 4H), 2.07−1.85 (m, 4H), 1.39 (s, 3H), 1.35 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 184.0, 134.7, 133.2, 133.1,
128.2, 128.1, 127.7, 126.9, 126.2, 126.16, 125.1, 110.0, 81.0, 78.0, 66.1,
52.3, 48.1, 26.5, 25.7, 25.25, 24.5. HRMS Calcd for C21H25NNaO3S
[M + Na]+ 394.1447, found 394.1442.
The above 2-naphthylmagnesium bromide (3.5 mL of 0.49 M
solution in THF, 1.73 mmol, 1.5 equiv) was added to a stirring
solution of CuI (0.372 mg, 1.96 mmol, 1.7 equiv) in THF/Me2S (5:1)
at −78 °C under an argon atmosphere. After 20 min, a solution of (R)-
2,2-dimethyl-1,3-dioxolane-4-carbaldehyde31 (0.15 mg, 1.15 mmol, 1
equiv) in THF (2 mL) was added dropwise over 15 min and the
reaction mixture was then allowed to gradually warm to rt over 2 h.
The reaction mixture was quenched with saturated aq NH4Cl (8 mL)
and extracted with ether (3 × 15 mL). The combined ethereal extracts
were washed with brine (8 mL), dried over Na2SO4, and concentrated
in vacuo. Purification of the residue via SiO2 column chromatography
using 30% EtOAc/hexane afforded (R)-((R)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)(naphthalen-2-yl)methanol (172 mg, 58%) whose stereo-
chemistry was assigned by analogy with literature precedent.46,47 TLC:
(Z)-1-Bromo-3-(2-iodovinyl)benzene. Following literature pro-
cedure,48 NaHMDS (1 mL of a 1 M solution in THF, 1.0 mmol, 1.2
equiv) was added slowly to a suspension of (iodomethyl)-
triphenylphosphonium iodide (0.550 g, 1.0 mmol, 1.2 equiv) in
THF (2.3 mL) and then cooled to −60 °C. HMPA (0.3 mL) was
added, and the solution was cooled further to −78 °C. 3-
Bromobenzaldehyde (0.16 mg, 0.8 mmol, 1 equiv) was added, and
the mixture was stirred at −78 °C for 5 min and then allowed to warm
to rt over 35 min. Et2O (20 mL) was added, and the mixture was
filtered over Celite and concentrated in vacuo. Purification of the
residue by SiO2 chromatography yielded (Z)-1-bromo-3-(2-
iodovinyl)benzene as a pale yellow liquid (0.177 g, 68%). TLC: Rf =
1
Rf ≈ 0.35 (25% EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ
7.86−7.81 (m, 4H), 7.51−7.45 (m, 3H), 4.72 (dd, J = 7.6, 2.8 Hz,
1H), 4.33 (dt, J = 7.6, 6.1 Hz, 1H), 3.82−3.75 (m, 2H), 2.86 (s, 1H,
OH), 1.52 (s, 3H), 1.37 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
137.1, 133.3, 133.2, 128.5, 128.0, 127.7, 126.3, 126.2, 126.18, 124.5,
110.2, 80.2, 76.1, 66.1, 27.0, 25.4. HRMS Calcd for C16H18NaO3 [M +
Na]+ 281.1148, found 281.1143.
Following literature procedure,43 1,1′-thiocarbonyldiimidazole (112
mg, 0.63 mmol) was added to a stirring solution of the above (R)-
((R)-2,2-dimethyl-1,3-dioxolan-4-yl)(naphthalen-2-yl)methanol (146
mg, 0.56 mmol) in dry CH2Cl2 (5 mL) containing DMAP (7 mg,
0.057 mmol) under an argon atmosphere. After 10 h, the reaction
mixture was filtered through a small pad of SiO2 and the filter cake was
washed with EtOAc (5 mL). The combined filtrate was concentrated
under reduced pressure, and the residue was dissolved in a solution of
pyrrolidine (4 mL, 2 M THF). After 4 h, all volatiles were removed in
vacuo and the residue was chromatographed over SiO2 (20% EtOAc/
hexane) to give O-((R)-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-
(naphthalen-2-yl)methyl) pyrrolidine-1-carbothioate (6) (151 mg,
72%) as an oil whose spectral and physical characteristics were
congruent with an authentic sample. TLC: Rf ≈ 0.45 (20% EtOAc/
1
0.72 (hexanes, 100%). H NMR (500 MHz, CDCl3) δ 7.80 (s, 1H),
7.62−7.56 (m, 1H), 7.51 (dd, J = 8.2, 1.6 Hz, 1H), 7.29 (td, J = 7.8,
1.6 Hz, 2H), 6.69 (dd, J = 8.7, 1.6 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 138.8, 137.3, 131.3, 131.25, 129.8, 127.0, 122.3, 81.5. HRMS
Calcd for C8H6BrI [M]+ 307.8693, found 307.8698.
(E)-1-Iodo-4-(2-iodovinyl)benzene. Following literature proce-
dure,49 a solution of CH2I2 (644 μL, 8.0 mmol) in THF (1.9 mL) was
added dropwise to a −78 °C solution of LiHMDS (8 mL of a 1 M
solution in THF, 1.34 g, 8.0 mmol) in ether (8 mL) in a darkened
room. After 20 min, a solution of 1-(bromomethyl)-4-iodobenzene
(1.2 g, 4.0 mmol) in THF (3 mL) was added dropwise. The reaction
mixture was allowed to slowly warm to rt. After 16 h, DBU (1.19 mL,
8.0 mmol) was added dropwise, stirred for 1 h, and then diluted with
Et2O (50 mL). The reaction mixture was filtered through a bed of
Celite (approximately 3 cm) layered on top of a bed of SiO2
(approximately 3 cm). The filtrate was concentrated under reduced
pressure, and the residue was purified by SiO2 chromatography using
100% hexane to give (E)-1-iodo-4-(2-iodovinyl)benzene (1.0 g, 69%,
1
hexanes); H NMR (500 MHz, CDCl3) δ 7.89−7.79 (m, 4H), 7.57−
7.44 (m, 3H), 6.68 (dd, J = 6.5, 1.2 Hz, 1H), 4.67−4.63 (m, 1H),
3.89−3.79 (m, 3H), 3.74−3.65 (m, 3H), 2.09−1.83 (m, 4H), 1.50 (s,
3H), 1.38 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 184.3, 134.6,
133.3, 133.1, 128.3, 128.2, 127.7, 127.35, 126.3, 126.26, 125.3, 110.25,
81.8, 78.0, 65.9, 52.2, 48.1, 26.7, 25.7, 25.6, 24.5. HRMS Calcd for
C21H25NNaO3S [M + Na]+ 394.1447, found 394.1438.
J
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The Journal of Organic Chemistry
Article
1
99:1 E/Z) as an oil. TLC: Rf = 0.74 (100% hexane); H NMR (400
MHz, CDCl3) δ 7.65 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 15.0 Hz, 1H),
7.03 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 15.0 Hz, 1H); 13C NMR (101
MHz, CDCl3) δ 143.9, 137.8, 137.1, 127.6, 93.9, 77.7. HRMS C8H6I2
[M]+ 355.8567, found 355.8559.
(22) Le Grognec, E.; Chret
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b02780.
(28) Kang, S.-K.; Kim, J.-S.; Choi, S.-C. J. Org. Chem. 1997, 62, 4208.
(29) Kang, S.-K.; Kim, W.-Y.; Lee, Y.-T.; Ahn, S.-K.; Kim, J.-C.
Tetrahedron Lett. 1998, 39, 2131.
Exploratory/control experiments, scanned NMR spectra,
and HPLC chromatograms (PDF)
(30) Kang, S.-K.; Baik, T.-G.; Jiao, X. H.; Lee, Y. T. Tetrahedron Lett.
1999, 40, 2383.
(31) He, A.; Falck, J. R. Angew. Chem., Int. Ed. 2008, 47, 6586.
(32) Mohapatra, S.; Bandyopadhyay, A.; Barma, D. K.; Capdevila, J.
H.; Falck, J. R. Org. Lett. 2003, 5, 4759.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: j.falck@utsouthwestern.edu.
(33) Hoffmann, R. W.; Holzer, B. J. Am. Chem. Soc. 2002, 124, 4204.
(34) Espinet, P.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43,
4704.
̈
ORCID
John R. Falck: 0000-0002-9219-7845
Notes
The authors declare no competing financial interest.
(35) García-Melchor, M.; Braga, A. A. C.; Lledos
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ACKNOWLEDGMENTS
■
Financial support provided by the Dr. Ralph and Marian Falk
Medical Research Trust, Bank of America, N.A., Trustee, the
Cystic Fibrosis Foundation (HURLEY16G0), NIH (RO1
HL111392), and the Robert A. Welch Foundation (Grant I-
0011).
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DOI: 10.1021/acs.joc.7b02780
J. Org. Chem. XXXX, XXX, XXX−XXX