Supporting Information for Yu,
‡
Sercel,
‡
Rezgui, Farhi, Virgil, and Stoltz
S
1
Supporting Information for
Total Synthesis of Aleutianamine
Hao Yu,
‡
Zachary P. Sercel,
‡
Samir P. Rezgui,
Jonathan Farhi
,
Scott C. Virgil,
and Brian M.
Stoltz*
Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering,
Division
of Chemistry and Chemical Engineering, California Institute of Technology,
MC 101
-
20,
Pasadena, California 91125, United States
stoltz@caltech.edu
Table of Contents:
Materials and Methods........................................................................................2
List of abbreviations...........................................................................................3
Experimental Procedures.....................................................................................4
Comparison of Natural and Synthetic
Aleutianamine...................................................
31
References.....................................................................................................
3
4
Spectral
Data..................................................................................................3
6
X
-
ray Crystal Structure Data...............................................................................7
8
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2
Materials and Methods
Unless otherwise stated, reactions were performed in flame
-
dried glassware under an argon
or nitrogen atmosphere using dry,
deoxygenated solvents. Solvents were dried by passage through
an activated alumina column under argon.
1
NBS was recrystallized from boiling water prior to use,
amines and TMSCl were distilled under nitrogen prior to use, and K
2
CO
3
was flame
-
dried under
vacuum and stored in a nitrogen
-
filled glovebox prior to use. All other reagents were purchased
from commercial sources and used as received unless otherwise indicated. Reaction progress was
monitored by thin
-
layer chromatography (TL
C) or Agilent 1290 UHPLC
-
M
S. TLC was
performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by
UV fluorescence quenching or KMnO
4
staining. Silicycle Silia
Flash
® P60 Academic Silica gel
(particle size 40
–
63 nm) was used for flash chromatography.
Preparative HPLC was performed on
an Agilent 1100 Series HPLC system using a 9.4 x 250 mm Agilent Eclipse XDB
-
C18 column, or
on an Agilent 1200 Series HPLC system using a 9.4 x 250 mm Agilent Zorbax Rx
-
SIL column.
1
H NMR spectra were recorded on
Varian Inova 500 MHz, Varian 600 MHz, and Bruker 400 MHz
spectrometers and are reported relative to residual CHCl
3
(δ 7.26 ppm), C
6
D
6
(δ 7.16 ppm),
DMSO
-
d
6
(δ 2.50 ppm), CD
2
Cl
2
(δ 5.32 ppm), or CD
3
OD (δ 3.31 ppm).
13
C NMR spectra were
recorded on a Bruker 400 MHz spectrometer (100 MHz) and are reported relative to CHCl
3
(δ
77.16 ppm), C
6
D
6
(δ 128.06 ppm), DMSO
-
d
6
(δ 39.52 ppm), CD
2
Cl
2
(δ 53.84 ppm), or CD
3
OD (δ
49.00 ppm). Data for
1
H NMR are reported as follows: chemical shift (δ ppm) (multiplicity,
coupl
ing constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet,
t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d = broad
doublet. Data for
13
C NMR are reported in terms of chemical shifts (δ ppm). Some reported spectra
include minor solvent impurities of water, ethyl acetate, diethyl ether, methylene chloride, acetone,
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3
grease, and/or silicon grease, which do not impact product assignments. IR spectra were obtained
by use of a Perkin Elmer Spectrum BXII spectrometer using thin films deposited on NaCl plates
and reported in frequency of absorption (cm
–
1
). High resolution mass spectra (HRMS) were
obtained from an
Agilent 6230 LC/TOF with an Agilent Jet Stream ion source
in electrospray
ionization (ESI+ or ESI
–
) mode, or from the Caltech Mass Spectrometry Laboratory using a JEOL
JMS
-
T2000GC AccuTOF
™
GC
-
Alpha in field desorpti
on (FD+) mode.
List of Abbreviations
CAN
–
Diammonium cerium(IV) nitrate
, CDI
–
Carbonyldiimidazole
, DDQ
–
2,3
-
Dichloro
-
5,6
-
dicyano
-
1,4
-
benzoquinone
, DIAD
–
Diisopropyl azodicarboxylate
, DIBAL
–
Diisobutylaluminium
hydride
, DMA
–
N,N
-
Dimethylacetamide
, DMAP
–
N,N
-
Dimethylpyridin
-
4
-
amine
, DPPA
–
Diphenoxyphosphoryl azide
, HPLC
–
high
-
pressure liquid chromatography
, LCMS
–
liquid
chromatography/mass spectrometry
, NBS
–
N
-
Bromosuccinimide
, NMP
–
N
-
Methyl
-
2
-
pyrrolidone
,
NMR
–
nuclear magnetic resonance
, TBSOTf
–
Trimethylsilyl trifluoromethanesulfonate
, TFA
–
Trifluoroacetic acid
, TFAA
–
Trifluoroacetic anhydride
, T
HF
–
Tetrahydrofuran
,
TLC
–
thin layer
chromatography
, TsCl
–
4
-
Toluenesulfonyl chloride
.
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Experimental Procedures
2
-
(5
-
chloro
-
2
-
methoxyphenyl)hydrazin
-
1
-
ium chloride
13
Prepared according to the procedure of
Thibeault
and coworkers from 4
-
chloro
-
2
-
methoxyaniline.
2
All characterization data matched those reported in the literature.
2
-
(4
-
chloro
-
7
-
methoxy
-
1
H
-
indol
-
3
-
yl)ethan
-
1
-
ol
14
To a 250 mL round bottom flask were added (5
-
chloro
-
2
-
methoxyphenyl)hydrazine
hydrochloride (
13
, 8.60 g, 41.1 mmol, 1.0 equiv)
.
DMA (65 mL), H
2
O (65 mL), and 25% (v/v) aq.
H
2
SO
4
(11.0 mL, 51.4 mmol, 1.25 equiv). 2,3
-
dihydrofuran (3.42 mL, 45.2 mmol, 1.1 equiv) was
added slowly with stirring, resulting in a slow color change to yellow, whereafter the flask was
equipped with an air
-
cooled reflux condenser and heated to 60 °C in an
oil bath for 6 h. The
reaction mixture was then allowed to cool to 23 °C and transferred to a separatory funnel
containing 1:1 satura
ted aq. NaHCO
3
/brine (250 mL). The mixture was then extracted with EtOAc
(4
x
100 mL), and the combined organic extracts were washed with water, dried over Na
2
SO
4
, and
concentrated under reduced pressure. The crude product was purified by silica gel flash
chromatography (60% EtOAc/hexanes) to afford the title compound as a thick, red
-
brown
oil
that
slowly crystallized upon storage at
–
20 °C
(2.66 g, 11.79 mmol, 29% yield)
.
1
H NMR (400 MHz, CDCl
3
)
:
δ 8.54 (
br
s, 1H), 7.00 (d,
J
= 2.2 Hz, 1H), 6.96 (d,
J
= 8.2 Hz, 1H),
6.50 (d,
J
= 8.2 Hz, 1H), 3.94 (t,
J
= 6.4 Hz, 2H), 3.91 (s, 3H), 3.23 (td,
J
= 6.4, 0.8 Hz, 2H)
OMe
Cl
H
N
H
3
N
Cl
13
H
N
OMe
14
HO
Cl
OMe
Cl
H
N
H
3
N
Cl
13
H
2
SO
4
,
2,3-dihydrofuran
DMA/H
2
O
60 °C
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5
13
C NMR (100 MHz, CDCl
3
)
:
δ 145.2, 128.4, 124.8, 123.8, 120.2, 118.2, 113.1, 102.4, 63.7, 55.7,
29.5
.
IR (Neat Film, NaCl)
:
3416, 2935, 2580, 1786, 1703, 1626, 1571, 1494, 1452, 1339, 1230, 1115,
1052, 937, 789, 736, 694, 628 cm
–
1
.
HRMS (FD
+
)
:
m/z
calc’d for
C
11
H
13
ClNO
2
[M+H]
+
:
225.0557
, found
225.0552.
3
-
(2
-
azidoethyl)
-
4
-
chloro
-
7
-
methoxy
-
1
H
-
indole
SI1
To a 250 mL round bottom flask was added tryptophol
14
(3.36 g, 14.89 mmol, 1.0 equiv).
Traces of water were azeotropically removed by addition of three portions of benzene followed by
rotary evaporation. PPh
3
(4.69 g, 17.87 mmol, 1.2 equiv) was added, and the headspace of the flask
was evacuated and backfilled with nitrogen. THF (60 mL) was added, and the reaction mixture
was cooled to 0 °C. Then, DIAD (3.52 mL, 17.87 mmol, 1.2 equiv) was added dropwise over 4
min. The reaction mixture was stirred at 0 °C
for an additional 15 min, after which DPPA (3.85
mL, 17.87 mmol, 1.2 equiv) was added rapidly and the reaction mixture was allowed to warm to
23 °C. The reaction mixture became cloudy over several minutes. TLC analysis after 16 h indicated
a high degree of
conversion to product. Stirring for another 24 h led to no change in the reaction
profile by TLC analysis.
The
reaction mixture was concentrated under reduced pressure and
purified by automated
silica gel flash c
hromatography (Teledyne ISCO, 0→40% EtOAc/h
exanes)
to afford a
zide
SI1
as an orange
-
brown solid (2.50 g, 9.97 mmol, 67% yield).
1
H NMR (
6
00 MHz, CDCl
3
)
:
δ 8.34 (s, 1H), 7.05 (d,
J
= 2.4 Hz, 1H), 6.98 (d,
J
= 8.2 Hz, 1H),
6.53 (d,
J
= 8.2 Hz, 1H), 3.93 (s, 3H), 3.59 (t,
J
= 7.2 Hz, 2H), 3.27 (td,
J
= 7.1, 0.8 Hz, 2H).
H
N
OMe
14
HO
Cl
H
N
OMe
SI1
N
3
Cl
DIAD, PPh
3
, DPPA
THF, 0
→
23 °C
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6
13
C NMR (100 MHz, CDCl
3
)
:
δ 145.2, 128.2, 124.5, 123.5, 120.3, 117.9, 113.2, 102.5, 55.6, 52.8,
25.9.
IR (Neat Film, NaCl):
3890, 3864,
3668, 3316, 3132, 3084, 3008, 2938, 2876, 2588, 2492, 2352
,
2204, 2106, 1768, 1652, 1630, 1574, 1494, 1464, 1450, 1434, 1380, 1332,
1294, 1272, 1236, 1194,
1172, 1154, 1130, 1070, 1034, 958, 930, 864,
830, 808, 782, 760, 740, 708, 684, 670, 662, 632,
cm
–
1
.
HRMS (ESI+)
:
m/z
calc’d
for
C
11
H
1
2
ClN
2
O
[M+H]
+
:
22
3
.0
638
, found
22
3
.0
630
.
Tosyl
indo
le
SI2
To a 250 mL round bottom flask under air were added azide
SI1
(5.11 g, 20.4 mmol, 1.0
equiv), CH
2
Cl
2
(41 mL), and
Bu
4
NHSO
4
(69 mg, 0.204 mmol, 1 mol %), followed by 50% w/v
aq. NaOH (14 mL).
After stirring for 5 min, TsCl (7.78 g, 40.8 mmol, 2.0 equiv) was added in a
single portion. The reaction mixture was subjected to vigorous magnetic stirring for 10 min, then
diluted with H
2
O (100 mL) and CH
2
Cl
2
(
30 mL
)
.
The layers were separated, and the aqueous phase
was extracted with CH
2
Cl
2
(
3x50 mL
)
. The combined organic phases were washed with brine,
dried over Na
2
SO
4
, and concentrated under reduced pressure.
The crude product was
pu
rified by
automated
silica gel flash c
hromatography (Teledyne ISCO, 0→45% EtOAc/hexanes) to afford
an intermediate tosyl indole as a white solid (6.77 g, 16.7 mmol, 82% yield)
.
1
H NMR (400 MHz, CDCl
3
)
:
δ 7.74 (s, 1H), 7.71 (d,
J
= 8.4 Hz, 2H), 7.29
–
7.26 (m, 2H), 7.08
(d,
J
= 8.5 Hz, 1H), 6.58 (d,
J
= 8.5 Hz, 1H), 3.64 (s, 3H), 3.63
–
3.59 (m, 2H), 3.26 (td,
J
= 7.1,
1.0 Hz, 2H), 2.40 (s, 3H).
H
N
OMe
SI1
N
3
Cl
Ts
N
OMe
SI2
N
3
Cl
TsCl, NaOH,
Bu
4
NHSO
4
CH
2
Cl
2
/H
2
O, 23 °C
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7
13
C NMR (100 MHz, CDCl
3
)
:
δ 146.9, 144.9, 137.6, 129.9, 129.6, 128.6, 127.6, 126.7, 125.0,
118.5, 116.7, 108.0, 56.1, 52.2, 26.7, 22.1.
IR (Neat Film, NaCl):
3992, 3892, 3854, 3752, 3630, 3620, 3608, 3586, 3402, 3116, 2926, 2514,
2368, 2098, 1598, 1572, 1540, 1518, 1488, 1464, 1362, 1294, 1252, 1234, 1192, 1172, 1146,
1120, 1092, 1058, 994, 910, 858, 846, 808, 798,
772, 736, 702, 676, 662, 632, 624, cm⁻¹
HRMS (ESI+):
m/z calc’d for C
1
8
H
1
7
ClN
4
O
3
SNa
[M+
Na
]
+
:
427
.06
08,
found
427.0603.
Tryptamine
11
To a 500 mL round bottom flask under air were added this tosyl azide
SI2
(11.73 g, 28.97
mmol, 1.0 equiv), PPh
3
(9.88 g, 37.66 mmol, 1.3 equiv), and THF (190 mL). The reaction mixture
was stirred at 23 °C for 15 h, whereafter deionized water (9.5 mL) was added. After an additional
30 h, the reaction mixture was concentrated under reduced pressure and
purified by
silica gel flash
c
hromatography (10% MeOH/CH
2
Cl
2
+ 1% Et
3
N) to afford the title compound as a white solid
(10.41 g, 27.48 mmol, 95% yield)
1
H NMR (400 MHz, CDCl
3
)
:
δ 7.72
–
7.65 (m, 3H), 7.29
–
7.23 (m, 2H), 7.05 (d,
J
= 8.5 Hz,
1H), 6.56 (d,
J
= 8.5 Hz, 1H), 3.62 (s, 3H), 3.14
–
3.00
(m, 4H), 2.39 (s, 3H)
.
13
C NMR (100 MHz, CDCl
3
)
:
δ 146.5, 144.4, 137.4, 129.7, 129.5, 127.4, 127.2, 126.5, 124.6,
118.5, 118.1, 107.5, 55.8, 42.9, 30.7, 21.7
.
IR (Neat Film, NaCl):
2938, 2686, 2595, 2515, 2363, 1574, 1487, 1366, 1290, 1237, 1171, 1092,
1052, 997, 937, 809, 662 cm
–
1
.
HRMS (ESI
+
)
:
m/z
calc’d for
C
18
H
20
ClN
2
O
3
S
[M+
H
]
+
:
379.0878
, found
379.0877
.
Ts
N
OMe
SI2
N
3
Cl
Ts
N
OMe
11
H
2
N
Cl
PPh
3
, H
2
O
THF, 23 °C
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Tricycle
15
A 20 mL glass vial containing tryptamine
11
(1.0 g, 2.64 mmol, 1.0 equiv
) was brought
into a nitrogen
-
filled glovebox. To this vial were added BrettPhos Pd G4 (121 mg, 0.132 mmol, 5
mol %), BrettPhos (71 mg, 0.132 mmol, 5 mol %), and K
3
PO
4
(784 mg, 3.70 mmol, 1.4 equiv),
followed by
t
-
BuOH (6.6 mL). The vial was sealed with a PTFE
-
lined cap
and electrical tape
,
removed from the glovebox, and stirred at 100 °C in a metal heating block. After 3 days, the
reaction mixture was partitioned between CH
2
Cl
2
and water and the layers were separated. The
aqueous phase was extracted with CH
2
Cl
2
(
3x
)
, and the combined organic phases were
concentrated under reduced pressure. The crude product was
purified by
silica gel flash
chromatography (40% EtOAc/hexanes) to afford the title compound as a beige foam (816 mg, 2.38
mmol, 90% yield)
.
1
H NMR (400 MHz, CDCl
3
)
:
δ 7.79 (d,
J
= 8.4 Hz, 2H), 7.32 (s, 1H), 7.23 (d,
J
= 7.9 Hz, 2H),
6.56 (d,
J
= 8.1 Hz, 1H), 6.27 (d,
J
= 8.1 Hz, 1H), 3.70 (s, 3H), 3.37 (t,
J
= 5.9 Hz, 2H), 2.91 (t,
J
= 5.2 Hz, 2H), 2.36 (s, 3H)
.
13
C NMR (100 MHz, CDCl
3
)
:
δ 144.1, 140.5, 137.1, 135.8, 129.4, 127.7, 124.0, 122.6, 120.2,
115.2, 110.7, 105.0, 57.5, 43.0, 22.8, 21.7
.
IR (Neat Film, NaCl)
:
3384, 2956, 2834, 1595, 1512, 1421, 1356, 1260, 1170, 1103, 1035, 977,
937, 795, 664 cm
–
1
.
HRMS (ESI+):
m/z calc’d for C
18
H
19
N
2
O
3
S [M+H]
+
: 343.1111, found 343.1127.
BrettPhos Pd G4 (5 mol %),
BrettPhos (5 mol %), K
3
PO
4
OMe
TsN
NH
15
Ts
N
OMe
11
H
2
N
Cl
t
-BuOH, 100 °C
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9
Aminothiophene
16
Prepared according to the procedure of Andersen,
Møller
, and coworkers from 1,4
-
cyclohexandione monoethylene ketal
(
SI3
)
.
3
To a 500 mL round bottom flask were added 1,4
-
cyclohexanedione monoethylene ketal (20 g, 128 mmol, 1.0 equiv), S
8
(4.1 g, 128 mmol, 1.0
equiv
), ethyl cyanoacetate (14 mL, 128 mmol, 1.0 equiv), morpholine (11 mL, 128
mmol, 1.0
equiv), and EtOH (250 mL). The mixture was refluxed for 12 h
,
at which point TLC analysis
showed full conversion. The reaction mixture was
cooled to
23 °C
and concentrated under reduced
pressure until the amount of solution became approximately half. Then
,
the product was collected
by
vacuum
filtration to afford aminothiophene
16
as a light yellow solid (30.3 g, 107 mmol, 83%
yield).
All characterization data matched those
reported in the
literature.
Amino acid hydrochloride
SI
4
To a 350 mL glass pressure vessel under air were added aminothiophene
16
(22.2 g, 78.35
mmol, 1.0 equiv), KOH (17.6 g, 313.4 mmol, 4.0 equiv
), EtOH (165 mL), and water (33 mL). The
flask was sealed, and the reaction mixture was stirred at 75 °C in an oil bath for 12 h. The reaction
mixture was subsequently transferred to an Erlenmeyer flask and cooled to 0 °C in an ice bath.
The solution was a
cidified with 1 N aq. HCl (375 mL), resulting in the formation of a thick
precipitate. The product was collected by vacuum filtration and washed with water. The resulting
clay
-
like material was transferred to a round bottom flask with MeOH. The solvent was
removed
under reduced pressure and the product was dried under high vacuum to afford the title compound
O
O
ethyl cyanoacetate, S
8
, morpholine
SI3
S
NH
2
CO
2
Et
O
O
16
O
EtOH, 78 °C
S
NH
2
CO
2
Et
O
O
16
S
NH
3
+
Cl
-
CO
2
H
O
O
SI4
KOH
EtOH, reflux
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10
as a cream
-
colored powder (17.95 g, 61.53 mmol, 79% yield assuming complete conversion to
hydrochloride)
.
Note
: Conducting this transformation in a vessel with increased headspace
generally leads to lower yields, likely due to atmospheric oxidation.
1
H NMR (400 MHz, DMSO)
:
δ 11.81 (
br
s, 1H), 7.20 (
br
s, 2H), 3.90 (s, 4H), 2.72 (t,
J
= 6.4 Hz,
2H), 2.59 (s, 2H), 1.75 (t,
J
= 6.5 Hz, 2H)
.
13
C NMR (100 MHz, DMSO)
:
δ
166.7, 163.4, 130.9, 112.4, 107.6, 102.6, 63.9, 34.3, 31.0, 25.1.
IR (Neat Film, NaCl)
:
3409, 2890, 1635, 1580, 1474, 1451, 1353, 1294, 1267, 1105, 1054, 1036,
926, 642
cm
–
1
.
HRMS (ESI
–
):
m/z
calc’d fo
r
C
11
H
12
NO
4
S
[M
–
H]
–
:
254.0493
, found
254.0494
.
Trifluoroa
cetamidothiophene
SI
5
To a 500 mL round bottom flask was added hydrochloride
salt
SI
4
(14.29 g, 48.98 mmol,
1.0 equiv). Then, the headspace of the flask was
evacuated and backfilled with nitrogen, and
CH
2
Cl
2
(150 mL) and TFA (11.2 mL, 146.9 mmol, 3.0 equiv) were added. After 15 min, additional
CH
2
Cl
2
(50 mL) was added to reduce the viscosity of the mixture. The reaction mixture was stirred
for 2.5 h at 23 °C, whereafter it was cooled to 0 °C in an ice bath and pyridine (19.7 mL, 244.9
mmol, 5.0 equiv) was added rapidly. TFAA (10.2 mL, 73.47 mmol, 1.5
equiv) was then added,
and the ice bath was removed. After stirring for an additional 16 h at 23 °C, silica gel
was added,
and the reaction mixture was concentrated under reduced pressure and purified by silica gel flash
chromatography (33% EtOAc/hexanes) to afford the title compound as an orange solid (9.67 g,
31.47 mmol, 64% yield)
.
S
NH
3
+
Cl
-
CO
2
H
O
O
SI4
S
NHTFA
O
O
SI5
TFA,
then
TFAA, py
CH
2
Cl
2
, 23 °C
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11
1
H NMR (400 MHz, CDCl
3
)
:
δ 8.72 (s, 1H), 6.59 (s, 1H), 4.06
–
3.98 (m, 4H), 2.91 (d,
J
= 1.5
Hz, 2H), 2.74 (tt,
J
= 6.5, 1.6 Hz, 2H), 1.94 (t,
J
= 6.5 Hz, 2H)
.
13
C NMR (100 MHz, CDCl
3
)
:
δ
153.6 (q,
J
= 38.3 Hz)
, 133.4, 131.8, 127.9,
11
7.0
(q,
J
= 287.1
Hz),
116.1, 108.5, 64.8, 34.9, 31.7, 24.0
.
IR (Neat Film, NaCl)
:
3248, 3097, 2894, 1713, 1589, 1434, 1362, 1250, 1169, 1060, 946, 905,
842, 739 cm
–
1
.
HRMS (ESI
+
):
m/z
calc’d for
C
12
H
13
F
3
NO
3
S
[M+H]
+
:
308.0563
, found
308.0561
.
Thiophene
-
k
etone
12
To a 100 mL round bottom flask containing thiophene
-
ketal
SI
5
(1.64 g, 5.34 mmol, 1.5
equiv) under nitrogen and equipped with a reflux condenser were added THF (27 mL) and 4 N aq.
HCl (5.3 mL, 21.2 mmol, 4.0 equiv w.r.t. ketal). The reaction mixture was heated to reflux and
stirred for 1.5 h, then allowed to cool an
d quenched with saturated aq. NaHCO
3
(100 mL). The
resulting mixture was extracted with CH
2
Cl
2
(3x40 mL). The combined organic extracts were
washed with brine, and the brine phase was back
-
extrac
ted once with CH
2
Cl
2
. The combined
organic phases were dried over Na
2
SO
4
and MgSO
4
and concentrated under reduced pressure to
afford crude
thiophene
-
ketone
12
as an orange solid that was used directly
without further
purification
.
SI5
S
NHTFA
O
O
12
S
NHTFA
4N HCl
THF, 66 °C
O
OMe
TsN
NH
15
+
InCl
3
, Et
3
SiH
OMe
TsN
N
S
NHTFA
SI6
MeOH, 23 °C
12
S
NHTFA
O
Supporting Information for Yu,
‡
Sercel,
‡
Rezgui, Farhi, Virgil, and Stoltz
S
12
Arene
SI
6
To a 50 mL round bottom flask were added tricyclic aniline
15
(1.22 g, 3.56 mmol, 1.0
equiv)
,
t
he crude
thiophene
-
ketone resulting from hydrolysis of
t
rifluoroacetamidothiophene
SI
5
(th. 5.34 mmol),
and
InCl
3
(1.57 g, 7.12 mmol, 2.0 equiv). The headspace of the flask was
evacuated and replaced with nitrogen. MeOH (12 mL) and Et
3
SiH (5.7 mL, 35.6 mmol, 10 equiv)
were added and the reaction mixture was stirred at 23 °C for 24 h, whereafter it was transferred to
a separatory funnel containing saturated aq. NaHCO
3
(200 mL). The resulting suspension was
extracted with
CH
2
Cl
2
(3x70 mL). The combined organic extracts (still containing a significant
quantity of water and indium salts) were dried over Na
2
SO
4
, concentrat
ed under reduced pressure,
and purified by automated silica gel flash chromatography (Teledyne ISCO, 0→60%
EtOAc/hexanes) to afford the title compound as a golden
-
colored foam of sufficient purity for use
in the next step (1.80 g, 3.05 mmol, 86% yield). A
sample for analysis was obtained by preparative
TLC on silica gel (33% EtOAc/hexanes)
.
1
H NMR (400 MHz, CDCl
3
)
:
δ 8.40 (
br
s, 1H), 7.82
–
7.75 (m, 2H), 7.34 (t,
J
= 1.5 Hz, 1H), 7.26
–
7.21 (m, 2H), 6.60 (s, 1H), 6.58 (d,
J
= 8.3 Hz, 1H), 6.30 (d,
J
= 8.8 Hz, 1H), 4.15
–
4.01 (m,
1H), 3.68 (s, 3H), 3.33 (dt,
J
= 11.0, 5.4 Hz, 1H), 3.21 (dt,
J
= 11.5, 6.2 Hz, 1H), 2.99
–
2.92 (m,
3H), 2.91
–
2.66 (m, 3H), 2.37 (s, 3H), 2.07
–
1.98 (m, 2H)
.
13
C NMR (100 MHz, CDCl
3
)
:
δ
153.6 (q,
J
= 38.1 Hz)
, 144.2, 140.0, 137.1, 136.3, 133.2, 132.4,
129.5, 129.4, 127.7, 124.2, 123.2, 119.7, 116.5, 115.4,
114.
4
(q,
J
= 287.3 Hz),
110.3, 102.7, 57.3,
53.5, 42.2, 27.0, 26.0, 25.9, 23.5, 21.7
.
IR (Neat Film, NaCl)
:
3281, 3126, 3058, 2935, 2841, 1714, 1588, 1510, 1442, 1356, 1251, 1169,
1108, 1056, 996, 903, 739, 663 cm
–
1
.
HRMS (ESI
+
):
m/z
calc’d fo
r
C
28
H
2
7
F
3
N
3
O
4
S
2
[M+H]
+
:
590.1390
, found
590.1404
.
Supporting Information for Yu,
‡
Sercel,
‡
Rezgui, Farhi, Virgil, and Stoltz
S
13
Bromoarene
10
To a 250 mL round bottom flask was added
arene
SI
6
(1.78 g, 3.02 mmol, 1.0 equiv)
and
the headspace of the flask was evacuated and backfilled with nitrogen. The starting material was
taken up in THF (50 mL), and the flask was cooled to
–
78 °C and protected from light. A solution
of NBS (484 mg, 2.72 mmol, 0.9 equiv) in THF (50 mL) was a
dded as a slow stream with rapid
stirring. Following addition, the reaction mixture was allowed to stir at
–
78 °C for 5 additional
min
utes
, whereafter the cooling bath was removed and the reaction mixture allowed to warm to 23
°C. The reaction mixture was
concentrated under reduced pressure and purified by automated silica
gel flash chromatography (Teledyne ISCO, 0→50% EtOAc/hexanes) to afford the title compound
as a brown foam (1.16 g, 1.74 mmol, 57% yield from
arene
SI
6
or 64% from NBS)
.
1
H
NMR (
4
00 MHz, C
6
D
6
)
:
δ 7.83 (
d,
J
= 8.3 Hz, 2H
), 7.54 (s, 1H), 6.75 (s, 1H), 6.64 (
d,
J
= 8.2
Hz, 2H
), 6.01 (s, 1H), 4.17 (dddd,
J
= 13.7, 11.3, 5.3, 2.6 Hz, 1H), 3.19 (s, 3H), 2.99
–
2.75 (m,
3H), 2.58 (tdd,
J
= 11.7, 3.9, 2.0 Hz, 1H), 2.36
–
2.09 (m, 4H), 1.80
–
1.71 (m,
1
H), 1.76 (s, 3H),
1.45 (tdd,
J
= 12.2, 10.7, 6.7 Hz, 1H)
.
13
C NMR (100 MHz, C
6
D
6
)
:
δ
153.2 (q,
J
= 38.7 Hz)
, 144.1, 143.0, 137.8, 134.6, 133.6, 131.9,
129.6, 129.5,
123.1, 122.4, 116.6, 115.2, 114.2, 106.2, 59.5, 56.3, 43.0, 29.5, 28.5, 26.0, 22.6, 21.1
.
(
Note:
t
he
–
CF
3
carbon
is
omitted due to low intensity resulting from C
-
F splitting
. Two of the
tosyl signals are obscured by
the
solvent
peak
.
)
IR (Neat Film, NaCl)
:
3295, 2931, 1714, 1588, 1490, 1438, 1347, 1251, 1172, 1111, 908, 804,
737, 665 cm
–
1
.
HRMS (ESI
+
):
m/z
calc’d for
C
28
H
26
BrF
3
N
3
O
4
S
2
[M+H]
+
:
668.0495
, found
668.0502
.
OMe
TsN
N
S
NHTFA
SI6
OMe
TsN
N
S
NHTFA
10
Br
THF, –78
→
23 °C
NBS
Supporting Information for Yu,
‡
Sercel,
‡
Rezgui, Farhi, Virgil, and Stoltz
S
14
Thioimidate
17
To a 40 mL glass vial was added bromoarene
10
(331 mg, 0.495 mmol, 1.0 equiv). Traces
of water were azeotropically removed by addition of three portions of benzene followed by rotary
evaporation, the vial was transferred to a nitrogen
-
filled glovebox, and K
2
CO
3
(96 mg, 0.695
mmol, 1.4 equiv) was added. In a separate vial, a stock solution of Pd(dba)
2
(46.2 mg) and XPhos
(64.2 mg) in 1,4
-
dioxane (13.3 mL) was prepared and stirred at 28 °C for 10 min. Then, 12.4 mL
of this solution were transferred to the vi
al containing bromoarene
10
(for 43 mg Pd(dba)
2
(0.0748
mmol, 15 mol %) and 59.1 mg XPhos (0.124 mmol, 25 mol %)). The vial was sealed with a
PTFE/silicone septum cap
and electrical tape
, removed from the glovebox, and stirred at 100 °C
for 6 h. The reaction mixture was then allowed to cool and passed through a PTFE syringe filter,
which was subsequently rinsed with EtOAc. The solution was concentrated under reduced pressure
and purified
by silica gel flash chromatography (100% EtOAc → 100% acetone) to affo
rd the title
compound as an off
-
white solid (145 mg, 0.295 mmol, 60% yield)
.
1
H NMR (400 MHz, CD
2
Cl
2
)
:
δ 7.81
–
7.72 (m, 2H), 7.32
–
7.24 (m, 3H), 6.81 (s, 1H), 5.78 (d,
J
= 1.7 Hz, 1H), 3.64 (s, 3H), 3.59 (p,
J
= 2.7 Hz, 1H), 3.35 (ddd,
J
= 11.1, 9.7, 5.7 Hz, 1H), 3.25
(ddd,
J
= 11.1, 4.8, 3.5 Hz, 1H), 3.04
–
2.94 (m, 2H), 2.65 (dt,
J
= 12.5, 2.9 Hz, 1H), 2.54
–
2.47
(m, 1H), 2.40 (qd,
J
= 5.3, 3.1 Hz, 1H), 2.37 (s, 3H), 2.33 (dd,
J
= 12.5, 2.9 Hz, 1H), 2.06
–
1.97
(m,
1
H), 1.61 (tdd,
J
= 13.7, 5.3, 2.9 Hz, 1H)
.
N
NTs
OMe
S
NH
Pd(dba)
2
(15 mol %),
XPhos (25 mol %)
K
2
CO
3
OMe
TsN
N
S
NHTFA
Br
dioxane, 100 °C
10
17
Supporting Information for Yu,
‡
Sercel,
‡
Rezgui, Farhi, Virgil, and Stoltz
S
15
13
C NMR (100 MHz, CD
2
Cl
2
)
:
δ 178.5, 168.3, 144.9, 139.3, 137.2, 133.5, 129.7, 128.0, 123.5,
122.3, 121.7, 120.6,
115.2, 114.5, 109.1, 63.5, 57.4, 47.6, 41.9, 31.9, 24.8, 23.2, 21.7
(
the
bridgehead methine
13
C resonance is obscured by the solvent peak
)
.
IR (Neat Film, NaCl)
:
2925, 2851, 1595, 1503, 1462, 1349, 1284, 1226, 1174, 1106, 1011, 898,
808, 738, 704, 672 cm
–
1
.
HRMS (ESI
+
):
m/z
calc’d for
C
26
H
26
N
3
O
3
S
2
[M+H]
+
:
492.1410
, found
492.141
0.
N
-
tosylthioimidate
18
To a 1
-
dram glass vial containing TsCl (16 mg, 0.0814 mmol, 2.0 equiv) under nitrogen
was added thioimidate
17
(20 mg, 0.0407 mmol, 1.0 equiv) as a stock solution in CH
2
Cl
2
(1 mL),
followed by pyridine (10 μL, 0.122 mmol, 3.0 equiv). The reaction mixture was stirred at 23 °C
for 3 days, after which it was concentrated under reduced pressure and purified by silica gel flash
chromatography (50% EtOAc/hexanes) to afford the tit
le compound as an orange film (23.7 mg,
0.0367 mmol, 90% yield)
.
1
H NMR (400 MHz, CDCl
3
)
:
δ 7.93 (d,
J
= 8.1 Hz, 2H), 7.83
–
7.74 (m, 2H), 7.36
–
7.28 (m,
3H), 7.28
–
7.22 (m, 2H), 6.49 (s, 1H), 5.97 (d,
J
= 1.6 Hz, 1H), 3.65
–
3.61 (m, 1H), 3.59 (s, 3H),
3.37 (dt,
J
= 10.9, 7.6 Hz, 1H), 3.27 (dt,
J
= 11.1, 4.2 Hz, 1H), 3.06
–
2.97 (m, 2H), 2.83 (dt,
J
=
12.6, 2.8 Hz, 1H), 2.68
–
2.58 (m, 1H), 2.49
–
2.44 (m, 1H), 2.43 (s, 3H), 2.38 (s, 3H), 2.21
–
2.04
(m, 2H), 1.59
–
1.51 (m, 1H)
.
N
NTs
OMe
S
NH
N
NTs
OMe
S
NTs
TsCl, DMAP, Py
CH
2
Cl
2
, 23 °C
17
18