Synthesis of 1,2-Dihydroisoquinolines by a Modified Pomeranz-Fritsch Cyclization

Article abstract of DOI:10.1021/acs.joc.9b02987

Isoquinolines (IQs) and their derivatives are present in many natural products and biologically active small molecules. Herein, we report a modified procedure for the classical Pomeranz-Fritsch protocol, which expands the scope of 1,2-dihydroisoquinoline (DHIQ) products. 1,2-DHIQs are an attractive branch point for the synthesis of IQs, but because of their innate reactivity, they have remained difficult to prepare. We demonstrate that the Fujioka/Kita conditions, combining trimethylsiyltriflate (TMSOTf) and an amine base, activate dimethylacetals required for Pomeranz-Fritsch cyclization under sufficiently mild conditions to prepare a broad range of 1,2-DHIQ products. We also demonstrate the synthetic value of these DHIQs by further functionalization to either reduced tetrahydroisoquinoline (THIQ) or fully aromatized IQ natural products.

Full text of DOI:10.1021/acs.joc.9b02987

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Article
Synthesis of 1,2-Dihydroisoquinolines by
a Modified Pomeranz-Fritsch Cyclization
Xiang Ji, Zheng Huang, and Jean-Philip Lumb
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02987 • Publication Date (Web): 19 Dec 2019
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Page 1 of 14
The Journal of Organic Chemistry
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Synthesis of 1,2-Dihydroisoquinolines by a Modified Pomeranz-Fritsch
Cyclization
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Xiang Ji,† Zheng Huang, and Jean-Philip Lumb*
Department of Chemistry, McGill University, 801 Sherbrooke Street West, QC H3A 0B8, Canada
Supporting Information Placeholder
MeO
OMe
TMS-OTf
Amine Base
Tf
Tf
N
N
N
Modified Pomeranz-
Fritsch
mild conditions
selective for 1,2-DHIQ
diversely substituted
isoquinoline alkaloids
ABSTRACT: Isoquinolines (IQs) and their derivatives are present in many natural products and biologically active small
molecules. Herein, we report a modified procedure for the classical Pomeranz-Fritsch protocol, which expands the scope of
1,2-dihydroisoquinoline (DHIQs) products. 1,2-DHIQs are an attractive branch point for the synthesis of IQs, but because of
their innate reactivity, they have remained difficult to prepare. We demonstrate that the Fujioka/Kita conditions, combining
trimethylsiyltriflate (TMSOTf) and an amine base, activate dimethylacetals required for Pomeranz-Fritsch cyclization under
sufficiently mild conditions to prepare a broad range of 1,2-DHIQ products. We also demonstrate the synthetic value of
these DHIQs by further functionalization to either reduced tetrahydroisoquinoline (THIQ) or fully aromatized IQ natural
products.
INTRODUCTION
Pomeranz-Fritsch, which typically requires strong aqueous
acid (6M) and reaction temperatures in excess of 100 C
o
Isoquinoline alkaloids contain heterocyclic motifs that
are commonly found in biologically active small molecules
(Scheme 1A).1 The scaffold appears most commonly in two
discrete redox tautomeric forms that constitute a formal
4e | 4H+ redox couple. These are the fully saturated
1,2,3,4-tetrahydroisoquinolines (THIQs) or the aromatized
isoquinonlines (IQs) (Scheme 1A).2 The intermediary
dihydroisoquinonlines (DHIQs) can exist as either 1,2- or
3,4-dihydro-isomers, and while they are less commonly
encountered as natural products, both isomers have been
the targets of previous synthetic studies.3 3,4-DHIQs are
immediate products from the classic Bischler-Napieralski
synthesis,4 and are well-known synthetic precursors to
enantiomerically pure 1-substituted THIQs by asymmetric
hydrogenation.5 By comparison, the synthesis and isolation
of 1,2-DHIQs is less well-developed,6 despite their
importance as intermediates in the synthesis of alkaloid
natural products, including the pavines (Scheme 1B,
right).7 Classical methods for their preparation include the
Pomeranz-Fritsch cyclization of benzylamine dimethyl
acetals (Scheme 1C).3,8 However, the enamine of the 1,2-
DHIQ product can be unstable under these conditions, and
it is common for either acid-mediated elimination8c or
disproportionation6 to lead to mixtures of IQ and THIQ
(Scheme 1B, left). This has limited the scope of the
under Jackson’s typical conditions.8c Modifications have
been reported, including Perchonock’s9 use of excess
aluminum trichloride (AlCl3, >4 equiv.) at room
temperature, and Miranda’s10 use of triflouoroacetic acid
as a solvent at 50 oC. However, in spite of these
adjustments,
Pomeranz-Fritsch
reactions
remain
capricious, and 1,2-DHIQs are more commonly prepared
by partial dearomatization of IQs,11,12 or transition-metal
mediated annulation reactions.13 Each comes with its own
set of limitations, including the need for a previously
constructed IQ core, the potential for over-reduction to the
THIQ, or a carbonyl at C1 that leads to isoquinolinones.14
Despite its limitations, the Pomeranz-Fritsch cyclization
provides an attractive disconnection for preparing 1,2-
DHIQs from readily available acyclic starting materials.3
Recognizing that the use of strong acids presents
challenges of chemoselectivity, we questioned whether
conditions developed by Fujioka and Kita,15 combining a
silyl triflate and a sterically encumbered pyridine base,
could be used in their place, to allow acetal activation
under milder, more chemoselective conditions (Scheme
1c). Herein, we report the success of this hypothesis, and
demonstrate the synthetic value of the resulting 1,2-DHIQs
for the preparation of either IQ or THIQ derivatives.2,6
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Page 2 of 14
A.
3
2e | 2H+
2e | 2H+
4
N
N
N
1
2
3
4
3,4-dihydroisoquinoline
tetrahydroisoquinoline
isoquinoline
IQ
( )
DHIQ
THIQ
(
3,4-
)
5
6
CH3
2
N
N
N
7
1
8
9
MeO
MeO
MeO
OH
OMe
1,2-dihydroisoquinoline
DHIQ
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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51
52
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54
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56
57
58
59
60
1,2-
OMe
papaverine
OMe
reticuline
B.
N
acid catalyzed
cyclization
disproportionation
N
H
THIQ
R
Me
N
N
Me
N
DHIQ
1,2-(
)
Int-I
pavine alkaloids
IQ
MeO
MeO
C.
PG
N
O
PG
PG
Me
N
N
6M HCl
dioxane
N


MeOH
PG
H
1
> 100 o
C
ref. 8c
Int-II
DHIQ
1,2-
unstable to
reaction conditions
IQ
This Work
O
O
TMS-OTf
N
S
N
CF3
N
N
oxidation / reduction
or
or
elimination
diversely substituted
isoquinoline alkaloids
selective for
DHIQ
1,2-
Scheme 1. A) Redox States of Isoquinoline Compounds. B) Unique properties of 1,2-DHIQ. C) This Work: An Improved
Pomeranz-Fritsch Synthesis of 1,2-DHIQ and other isoquinoline compounds.
RESULTS AND DISCUSSION
aliphatic amines in Fujioka/Kita protocols.15-16 When using
diisopropylethylamine (DIPEA), we also observed a
dramatic increase in rate (4h to 15 min), allowing us to
reduce the reaction temperature from 80 oC to room
temperature (Entry 7). Next, we explored the effects of the
substituent on nitrogen, and observed an improved yield
of 92% for the N-nosyl derivative (Entry 8).17 More Lewis-
basic carbonate groups, including Boc or Cbz, were
incompatible with the reaction conditions, and led instead
to competitive formation of cyclic carbamate 3 (Entries 9
and 10). While both tosyl- and nosyl-groups performed
well, the resulting products were difficult to purify by
standard chromatography, leading to diminished isolated
yields. This complication was addressed by using the
corresponding triflate and lowering the quantity of DIPEA
to 6 equivalents (Entry 11), which allowed us to maintain
NMR yields in excess of 95% with more straightforward
purification (1.0 mmol scale, 80% isolated yield, 259.4
mg).
As a point of departure, we selected substrate 1a for our
optimization studies, anticipating
a
regioselective
cyclization at C4′ (isoquinoline numbering) based upon
steric effects (Table 1). The desired 1,2-DHIQ product 2a
would possess a 5,6-dimethoxy substitution pattern that is
widely found in isoquinoline alkaloid natural products.3
Under Fujioka and Kita’s15 previously reported conditions,
consisting of TMSOTf (3 equiv.) and 2,6-lutidine (10
o
equiv.) in 1,2-DCE at 80 C, we obtained an encouraging
yield of 50%, along with the formation of a complex
mixture (Entry 1). The nature of the amine base has a
profound impact on the course of the reaction, and using
less sterically demanding pyridines resulted in the
formation of non-cyclized pyridinium salts 4 (Entries 2
and 3), which have been observed previously.15 While the
use of 2,4,6-collidine provided some improvement (Entry
4), it was not until we evaluated sterically encumbered
tertiary amines that we observed yields of 70% or higher
(Entries 5 and 6). This stands in contrast to the literature,
where pyridine bases have typically outperformed
Since the Pomeranz-Fritsch cyclization follows well-
established trends for electrophilic aromatic substitution
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The Journal of Organic Chemistry
(EArS), less electron-rich aromatic rings were more
Table 1. Reaction Optimization and Substituent Effects.a
converted to the product at elevated temperatures.19 As
1
2
3
4
5
6
7
the aromatic nucleophile became less electron rich, we
observed decreasing yields of the 1,2-DHIQ product, such
that 3-methylphenyl substrate 1c afforded only a 34%
yield of 2c under our more forcing conditions, and phenyl
substrate 1d did not undergo cyclization at all. In both
cases, elimination to the vinyl ether 6 was competitive, and
accounted for the majority of the reaction’s mass balance.
MeO
MeO
OMe
O
O
N
N
N
4'
TMSOTf
4'
(3.0 equiv)
8
8
Base
MeO
MeO
MeO
OMe
OMe
OMe
Our modified conditions demonstrated good functional
group compatibility (Table 2). This included aromatic rings
with electron donating groups (2e-2g, 2k), as well as a
diaryl amine (2h). In addition to classical 1,2-DHIQ
substructures, heterocyclic analogues could also be
prepared from the corresponding thiophene (1i) or indole
(1j) starting materials, demonstrating compatibility with
these more acid sensitive functionalities. Finally, 7,8-
substituted-1,2-DHIQ 2k, representative of the cularine
alkaloids,20 could be synthesized in 88% yield with
8
9
1
2
3
Yield (%)b,c
T (oC)
Entry
Base (equiv)
OTf
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
3
N
OMe
1d
2d
3d
4d
5d
6d
7f
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ns
2,6-Lutidine (10.0)
Py (10.0)
2-MePy (10.0)
2,4,6-Collidine (10.0)
NEt3
DIPEA (10.0)
DIPEA (10.0)
DIPEA (10.0)
DIPEA (10.0)
DIPEA (10.0)
DIPEA (6.0)
80
80
80
80
80
80
rt
rt
rt
rt
rt
50
n.d.e
6e
62
70
74
65
92
Ts
N
MeO
8f
OMe
= H | Entry 2
= Me | Entry 3
9f
Boc
Cbz
Tf (1a)
n.d.
59
86
36
10f
11
4
97/80 j (2a)
complete regioselectivity. This has been
a difficult
MeO
OMe
OMe
Tf
substitution pattern to prepare by more conventional
Pictet-Spengler or Bischler-Napieralski syntheses, since
they preferentially cyclize to the undesired 6,7-isomers
(not shown).21
Tf
N
Tf
MeO
Tf
N
N
N
otherwise
standard
While the preparation of 1- or 3-substituted-1,2-DHIQs
was also possible, these substrates were prone to
competitive reduction to the corresponding THIQ under
our standard reaction conditions. For example, using 3
equiv. of TMSOTf and 6 equiv. of DIPEA, 1-methyl-DHIQ 2l
was obtained in only 60% yield, along with 20% of THIQ
2l’. The formation of 2l’ was consistent with hydride
transfer from DIPEA to para-quinone methide 7, which is
not observed when using substrates lacking a C1-
substituent. We speculate that the C1-substituent may
increase the rate of cyclization, and thus the concentration
of para-quinone methide 7, allowing hydride transfer to
compete with the elimination. Therefore, to avoid this
complication, we replaced DIPEA with the non-reducing
amine base 2,6-lutidine, and were pleased to see the yield
of 2l improve to 78% on 1.0 mmol scale, and 85% on 10
mmol scale. This allowed us to prepare >3 g of 2l in a
single pass. A range of synthetically useful functional
handles are tolerated at C1, including a terminal alkene
(2n), a 1o alcohol (2o) and a primary alkyl iodide (2p).
Additionally, 3-methyl-DHIQ 2q could also be prepared in
73% yield, although more forcing conditions, including a
prolonged reaction time (18 h) and elevated reaction
conditions
1b
2b
5b
6b
Entry 12
Entry 13d
7
59
10
36h
24h
Temp. = rt
80 o
C
63g/52g,j
OMe
Tf
MeO
OMe
Tf
MeO
Tf
Tf
N
N
N
N
standard
conditions
80 o
C
= Me (6c)
2c
5c
)
= Me (
)
= Me (
5d
)
1
6d
= H (
)
2d
= H (
)
= H (
Entry 14d
Entry 15d
= Me (
)
34i,j
--- (
)
--- (
--- (
)
48h,j
(
1c
2c
(
5c
6c
)
1d
= H (
2d
5d
6d
)
)
)
)
99h
(
[a] Unless otherwise noted, reactions were performed using 0.2
mmol of 1, CH2Cl2 as solvent and a 4h reaction time; [b] Yield
determined by H-NMR using hexamethylbenzene as internal
standard; [c] Complete consumption of 1 was detected in all
entries; [d] reaction performed in 1,2-dichloroethane; [e]
uncyclized pyridinium salts 4 were formed as the major
products; [f] 15 min reaction time; [g] An inseparable 20:1
regio-isomeric mixture was obtained; [h] A 5:1 ratio of Z/E
olefin isomers was observed; [i] An inseparable 5:1 regio-
isomeric mixture was obtained. [j] Isolated yield.
1
o
temperature (80 C), were required. We attribute these
reluctant to undergo cyclization under our standard
conditions. For example, naphthyl substrate 1b afforded
only 7% yield of 2b, along with a mixture of the
intermediate 5b and the elimination byproduct 6b (Entry
12). Notably, 6b is formed as a 5:1 mixture of olefin
isomers in favor of the (Z)-configured vinyl ether.18
Nevertheless, synthetically useful reactivity for this more
recalcitrant substrate could be recovered by heating the
reaction to 80 oC in 1,2-DCE, to provide the desired
product in an improved yield of 63% (Entry 13). We
observed similar amounts of premature elimination in
both cases, suggesting that vinyl ethers 6b are not reaction
intermediates, but rather products of an irreversible shunt
changes to the increased steric demands of elimination,
which involves deprotonation of a 3o C-H bond.
Since 1,2-DHIQs are attractive synthetic intermediates,
our modified Pomeranz-Fritsch conditions provide entry
into IQ and THIQ derivatives (Scheme 2). For example,
reduction of the double bond by hydrogenation over Pd/C
followed by reductive removal of the triflate with lithium
aluminum hydride (LiAlH4) provided THIQ (±)-salsolidine
(8) in a 63% yield over two steps.22 Alternatively,
isohypsic elimination mediated by KOtBu in DMSO
afforded the aromatized IQ natural product nigellimine (9)
in a 50% yield.23 Finally, oxidation using standard Upjohn
conditions for dihydroxylation provided the 3,4-THIQ diol
10 in 70% yield and > 20:1 d.r.24 Taken together, these
that decreases selectivity. Benzylic ether 5b is
constructive intermediate that could be productively
a
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transformations demonstrate the synthetic value of 1,2-
Page 4 of 14
1
DHIQs for
2
3
4
Table 2. Substrate Scope with Aromatic and Aliphatic Substitutions.a
5
MeO
OMe
6
7
TMSOTf (3 equiv.)
DIPEA or 2,6-lutidine
(4-6 equiv.)
Tf
Tf
N
N
8
9
CH2Cl2
rt, 4 h
1
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aromatic & heteroaromatic:
Tf
N
Tf
N
Tf
Tf
N
N
MeO
MeO
HN
O
O
OMe
OMe
CN
O
2e
|
90
Tf
2f
|
92
2g
|
89
2h | 78b
Tf
Tf
N
N
N
X = H
Pictet-Spangler
N
H
or
Bn
N
8
S
X
R
OMe
7
OMe
X = OH
Bischler-Napriolski
OMe
OMe
2i | 62c
2j | 56d
2k
|
88
N
C1 / C3 aliphatic:
Tf
H
Tf
Tf
Me
N
N
iPr
N
H
Me
Me
Me
iPr
MeO
MeO
MeO
standard
conditions
OMe
OMe
O
OTf
Me
2l | 60e | 78f | 85f,g
2l' | 20e
7
> 3g scale
Me
Tf
N
Tf
Tf
N
R
Tf
N
N
Ph
MeO
MeO
MeO
MeO
f,h
OMe
OMe
OMe
OMe
2o
| R = OH | 95
f
f
f
d,i
2m
2n
2p
2q
| 73
| 64
| 84
| R = I | 74
[a] Unless otherwise noted, reactions were performed using 1.0 mmol of 1 in the presence of TMSOTf (3 equiv.), DIPEA (6
equiv.) in CH2Cl2 (0.2 M) for 4 h at rt; [b] TMSOTf (4 equiv.) and DIPEA (8 equiv.) was used; [c] Reaction performed at 80 oC
in 1,2-DCE; [d] 2,6-Lutidine (6 equiv.) was used instead of DIPEA; [e] 2l’ was also obtained in 20% yield; [f] 2,6-Lutidine (4
equiv.) was used instead of DIPEA; [g] Reaction performed on 10 mmol scale; [h] TMSOTf (4 equiv.) and 2,6-Lutidine (6
equiv.) was used; [i] Reaction performed at 80 oC in 1,2-DCE for 18 h.
Tf
N
NH
a) H2, Pd/C
b) LiAlH4, Et2O
the synthesis of isoquinolines with complementary
oxidation states and substitution patterns.
Me
Me
63% yield
MeO
MeO
(two steps)
2l'
reductive
In conclusion, we have developed a new isoquinoline
synthesis by modifying the classical Pomeranz-Fritsch
protocol.25 We have shown that the strong acids and
elevated temperatures used previously can be replaced by
a combination of TMSOTf with a sterically encumbered
amine, following the precedent of Fujioka and Kita.15 This
modification tolerates acid-sensitive functional groups and
heterocycles, and should facilitate the synthesis of diverse
1,2-DHIQ family members. Given their synthetic utility for
the preparation of downstream isoquinoline products, we
anticipate a number of opportunities for their future
implementation.
OMe
OMe
(±)-salsolidine (
8
)
N
isohypsic
Tf
N
c) KOtBu, DMSO
Me
Me
MeO
OH
50% yield
MeO
OMe
OMe
9
nigellimine,
2l
-DHIQ
1,2
HO
Tf
N
oxidative
Me
d) OsO4, NMO
10
(±)-
76% yield
Me2CO/tBuOH/H2O
rt, 8 h
MeO
EXPERIMENTAL SECTION
OMe
Scheme 2. Synthetic Derivatization. Conditions and reagents:
a) 10 wt% Pd/C, H2 (10 psi), MeOH; b) LiAlH4 (3 equiv.), Et2O,
t
ACS Paragon Plus Environment
reflux, 63% over 2 steps; c) KO Bu (3 equiv.), DMSO, rt, 50%; d)
OsO4 (2 mol%), NMO (1.5 equiv.), Me2CO/tBuOH/H2O, rt, 76%,
> 20:1 dr.

Page 5 of 14
The Journal of Organic Chemistry
General Information. Chemicals and solvents were
6,7-dimethoxy-2-((trifluoromethyl)sulfonyl)-1,2-
1
2
3
4
5
6
7
8
purchased from Sigma Aldrich, Alfa Aesar, Strem
Chemicals, TCI or Oakwood, and used as received without
further purification. Solvents were dried and purified using
a PureSolv MD 7 (from Innovative Technology) or MB SPS
800 (from MBraun). We have not observed differences in
the reaction outcome using either of these solvent
purifiers. Proton nuclear magnetic resonance (1H NMR)
spectra were acquired using Bruker Ascend 500 MHz or
400 MHz spectrometers. Chemical shifts (δ) are reported
in parts per million (ppm) and are calibrated to the
residual solvent peak. Coupling constants (J) are reported
in Hz. Multiplicities are reported using the following
abbreviations: s = singlet; d = doublet; t = triplet; q =
quartet; m = multiplet (range of multiplet is given); br =
broad. Carbon nuclear magnetic resonance (13C NMR)
spectra were acquired using Bruker Ascend 125 MHz or
100 MHz spectrometers. Fluorine nuclear magnetic
resonance (19F NMR) spectra were acquired using a Bruker
Ascend 470 MHz spectrometer. Chemical shifts (δ) are
reported in parts per million (ppm) and are calibrated to
the residual solvent peak. High resolution mass spectra
(HRMS) were recorded using a Bruker maXis Impact TOF
mass spectrometer by electrospray ionization time of flight
reflectron experiments. Fourier-transform infrared (FT-IR)
spectra were recorded on a Thermo Scientific Nicolet 6700
FT-IR spectrometer. Analytical thin-layer chromatography
was performed on pre-coated 250 mm layer thickness
silica gel 60 F254 plates (EMD Chemicals Inc.). Visualization
was performed by ultraviolet light and/or by staining with
potassium permanganate or cerium molybdate.
Purifications by column chromatography were performed
using standard column chromatography using silica gel
(40-63 μm, 230-400 mesh).
dihydroisoquinoline (2a). White solid, 259.4 mg, yield =
80%. Rf = (hexanes/ethyl acetate 2:1): 0.60; IR (neat) v =
2940, 2840, 1634, 1608, 1519, 1465, 1455, 1417, 1223,
1
1186, 1142 cm-1; H NMR (500 MHz, CDCl3) δ 6.64 (s, 1H),
6.62 (s, 1H), 6.50 (d, J = 7.6 Hz, 1H), 6.10 (d, J = 7.6 Hz, 1H),
4.79 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 149.3, 149.1, 122.5, 122.4, 120.0 (q, JF =
324.3 Hz), 119.9, 115.0, 109.0, 109.0, 56.3, 56.2, 48.4; 19F
NMR (470 MHz, CDCl3) δ -75.4 (s, 3F); HRMS (ESI-TOF):
Calcd. for C12H12F3NO4SNa [M+Na]+ = 346.0331 m/z, found
= 346.0328 m/z. We attributed the decreased isolated yield
of 2a (80%) compared to the NMR yield (97%) to the
instability of the 1,2-dihydroisoquinoline to silica gel.
9
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3-((trifluoromethyl)sulfonyl)-3,4-
dihydrobenzo[f]isoquinoline (2b). White solid, 163.5 mg,
yield = 52%, 20:1 mixture of inseparable regio-isomers. Rf
= (hexanes/ethyl acetate 20:1): 0.46; IR (neat) v = 3103,
1632, 1566, 1412, 1397, 1286, 1270, 1193, 1145 cm-1; H
1
NMR (500 MHz, CDCl3) major regio-isomer: δ 8.05 (d, J =
8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H),
7.62 – 7.56 (m, 1H), 7.56 – 7.51 (m, 1H), 7.21 (d, J = 8.3 Hz,
1H), 6.91 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 5.01 (s,
2H); 13C{1H} NMR (126 MHz, CDCl3) major regio-isomer: δ
133.6, 129.0, 128.8, 128.4, 127.2, 126.4, 125.3, 124.8,
124.7, 123.5, 122.5, 120.0 (q, JF = 324.1 Hz), 111.0, 49.2; 19
NMR (470 MHz, CDCl3) major regio-isomer: δ -75.3 (s, 3F);
HRMS (ESI-TOF): Calcd. for C14H10F3NO2SNa [M+Na]+
336.0277 m/z, found = 336.0268 m/z. We attributed the
decreased isolated yield of 2b (52%) compared to the NMR
yield (63%) to the instability of the 1,2-dihydroisoquinoline
to silica gel.
F
=
7-methyl-2-((trifluoromethyl)sulfonyl)-1,2-
dihydroisoquinoline (2c). Brown oil, 93.1 mg, yield = 34%,
5:1 mixture of inseparable regio-isomers. Rf
General procedure for the synthesis of 2a-2q, 3 and
6c. A flame-dried, 10 mL test tube equipped with a Teflon-
coated stir bar and a rubber septum was charged with the
triflamide (1.0 mmol, 1.0 equiv). It was purged with N2 for
5 min prior to the addition of dry and degassed CH2Cl2 or
1,2-DCE (5 mL, 2M). DIPEA or 2,6-lutidine (4.0 – 6.0 equiv)
was added via syringe followed by dropwise addition of
TMSOTf (3.0 equiv). The reaction was then stirred for 4 h
at the indicated temperature and then quenched with 1M
HCl (10 mL). The mixture was extracted with CH2Cl2 (3 
20 mL). The combined organic fractions were then dried
over MgSO4, filtered and concentrated in vacuo. The
residue was then purified on silica gel using hexanes/ethyl
acetate as eluent to afford the dihydroisoquinoline
product.
=
(hexanes/ethyl acetate 1:10): 0.68; IR (neat) v = 2925,
1
1621, 1392, 1224, 1186, 1150, 1108 cm-1; H NMR (500
MHz, CDCl3) major regio-isomer: δ 7.10 (d, J = 7.6 Hz, 1H),
7.02 (d, J = 7.7 Hz, 1H), 6.92 (s, 1H), 6.55 (d, J = 7.6 Hz, 1H),
6.16 (d, J = 7.6 Hz, 1H), 4.82 (s, 2H), 2.35 (s, 3H); minor
regio-isomer: δ 7.16 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 7.6 Hz,
1H), 6.95 (d, J = 7.4 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 6.36 (d,
J = 7.8 Hz, 1H), 4.82 (s, 2H), 2.35 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) mixture of two regio-isomers: δ 138.8, 133.3,
130.4, 129.3, 128.3, 128.0, 127.6, 127.4, 126.9, 126.3,
125.5, 124.0, 123.4, 123.2, 120.0 (q, JF = 324.2 Hz), 115.0,
112.2, 49.0, 48.7, 21.4, 18.8; 19F NMR (470 MHz, CDCl3)
major regio-isomer: δ -75.38 (s, 3F); minor regio-isomer: δ -
75.41 (s, 3F); HRMS (APCI-TOF): Calcd. for C11H10F3NO2S
[M]+ = 277.0379 m/z, found = 277.0381 m/z.
3-(3,4-dimethoxybenzyl)-5-methoxyoxazolidin-2-one (3).
Rf = (hexanes/ethyl acetate 2:1): 0.11; IR (neat) v = 2938,
(Z/E)-1,1,1-trifluoro-N-(2-methoxyvinyl)-N-(3-
1
2838, 1743, 1515, 1418, 1258, 1235, 1138, 1123 cm-1; H
methylbenzyl)methanesulfonamide (6c).
Colorless oil,
NMR (500 MHz, CDCl3) δ 6.85 – 6.75 (m, 3H), 5.32 (dd, J =
6.4, 2.3 Hz, 1H), 4.38 (d, J = 14.9 Hz, 1H), 4.34 (d, J = 14.8
Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.50 (dd, J = 10.1, 6.4 Hz,
1H), 3.49 (s, 3H), 3.18 (dd, J = 10.1, 2.3 Hz, 1H); 13C{1H}
NMR (126 MHz, CDCl3) δ 156.7, 149.5, 148.9, 128.0, 120.6,
111.21, 111.15, 98.1, 56.3, 56.04, 56.02, 50.2, 47.7; HRMS
(ESI-TOF): Calcd. for C13H17NO5Na [M+Na]+ = 290.0999
m/z, found = 290.0992 m/z.
149.9 mg, yield = 48%, 4:1 mixture of inseparable
diastereomers. Rf = (hexanes/ethyl acetate 1:10): 0.43; IR
(neat) v = 3021, 2942, 2859, 1670, 1386, 1183, 1140 cm-1;
1H NMR (500 MHz, CDCl3) major diastereomer: δ 7.28 –
7.22 (m, 1H), 7.18 – 7.08 (m, 3H), 5.86 (d, J = 4.4 Hz, 1H),
5.04 (d, J = 4.4 Hz, 1H), 4.74 (s, 2H), 3.70 (s, 3H), 2.36 (s,
3H); minor diastereomer: δ 7.28 – 7.21 (m, 1H), 7.17 – 7.08
(m, 3H), 6.48 (d, J = 11.3 Hz, 1H), 5.33 (d, J = 11.3 Hz, 1H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
4.55 (s, 2H), 3.52 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (126
6-((trifluoromethyl)sulfonyl)-6,7-dihydrothieno[2,3-
Page 6 of 14
1
2
3
4
5
6
7
8
MHz, CDCl3) mixture of diastereomers: δ 154.7, 146.9,
138.7, 138.4, 135.4, 134.4, 129.5, 129.3, 129.2, 129.0,
128.7, 128.5, 126.0, 125.6, 120.5 (q, JF = 324.9 Hz), 120.4
(q, JF = 324.3 Hz), 102.9, 101.7, 61.0, 57.4, 56.4, 53.5, 21.52,
21.50; 19F NMR (470 MHz, CDCl3) major diastereomer: δ -
75.2 (s, 3F); minor diastereomer: δ -73.8 (s, 3F); HRMS
(ESI-TOF): Calcd. for C12H14F3NO3SNa [M+Na]+ = 332.0539
m/z, found = 332.0542 m/z.
c]pyridine (2i). Pale-orange oil, 166.4 mg, yield = 62%. Rf =
(hexanes/ethyl acetate 20:1): 0.39; IR (neat) v = 3109,
2859, 1624, 1395, 1333, 1276, 1225, 1186, 1152, 1110 cm-
1
1; H NMR (500 MHz, CDCl3) δ 7.21 (d, J = 5.1 Hz, 1H), 6.89
(d, J = 5.1 Hz, 1H), 6.49 (d, J = 7.6 Hz, 1H), 6.19 (d, J = 7.6
Hz, 1H), 5.04 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ
131.8, 125.6, 124.6, 124.5, 121.8, 119.9 (q, JF = 324.2 Hz),
110.6, 46.0; 19F NMR (470 MHz, CDCl3) δ -75.3 (s, 3F);
HRMS (ESI-TOF): Calcd. for C8H7F3NO2S2 [M+H]+
269.9865 m/z, found = 269.9857 m/z.
=
9
7-methoxy-2-((trifluoromethyl)sulfonyl)-1,2-
dihydroisoquinoline (2e). White solid, 263.9 mg, yield =
90%. Rf = (hexanes/ethyl acetate 10:1): 0.32; IR (neat) v =
3102, 3016, 2942, 2916, 2845, 1608, 1566, 1500, 1388,
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5-benzyl-2-((trifluoromethyl)sulfonyl)-2,5-dihydro-1H-
pyrido[4,3-b]indole (2j). Dark-red solid, 217.9 mg, yield =
56%. Rf = (hexanes/ethyl acetate 10:1): 0.49; IR (neat) v =
3120, 3057, 3031, 2923, 1740, 1453, 1330, 1199, 1149 cm-
1; 1H NMR (500 MHz, CDCl3) δ 7.49 (dd, J = 6.8, 1.6 Hz, 1H),
7.38 – 7.29 (m, 4H), 7.26 – 7.19 (m, 2H), 7.10 (d, J = 6.8 Hz,
2H), 6.59 (d, J = 8.0 Hz, 1H), 6.06 (d, J = 8.0 Hz, 1H), 5.35 (s,
2H), 5.33 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 137.8,
137.2, 130.2, 129.0, 127.9, 126.3, 124.4, 124.3, 122.7,
120.8, 120.0 (q, JF = 324.5 Hz), 118.1, 110.1, 103.1, 102.1,
46.9, 46.0; 19F NMR (470 MHz, CDCl3) δ -74.9 (s, 3F); HRMS
(ESI-TOF): Calcd. for C19H15F3N2O2SNa [M+Na]+ = 415.0699
m/z, found = 415.0685 m/z.
1
1305, 1279, 1253, 1185, 1127 cm-1; H NMR (500 MHz,
CDCl3) δ 7.05 (d, J = 8.4 Hz, 1H), 6.81 (dd, J = 8.4, 2.6 Hz,
1H), 6.66 (d, J = 2.4 Hz, 1H), 6.48 (d, J = 7.6 Hz, 1H), 6.15 (d,
J = 7.6 Hz, 1H), 4.81 (s, 2H), 3.81 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 160.0, 129.1, 126.9, 122.5, 121.8, 120.0 (q, JF
= 324.2 Hz), 115.0, 113.6, 111.7, 55.5, 48.7; 19F NMR (470
MHz, CDCl3) δ -75.3 (s, 3F); HRMS (ESI-TOF): Calcd. for
C11H10F3NO3SNa [M+Na]+ = 316.0217 m/z, found =
316.0226 m/z.
6-((trifluoromethyl)sulfonyl)-5,6-dihydro-
[1,3]dioxolo[4,5-g]isoquinoline (2f). White solid, 281.7 mg,
yield = 92%. Rf = (hexanes/ethyl acetate 10:1): 0.53; IR
(neat) v = 2971, 1641, 1506, 1485, 1390, 1375, 1286,
1257, 1187, 1144 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.61 (s,
1H), 6.60 (s, 1H), 6.50 (d, J = 7.6 Hz, 1H), 6.08 (d, J = 7.6 Hz,
1H), 5.97 (s, 2H), 4.74 (s, 2H); 13C{1H} NMR (126 MHz,
CDCl3) δ 147.9, 147.8, 123.9, 122.6, 121.2, 120.0 (q, JF =
324.3 Hz), 115.4, 106.5, 106.2, 101.6, 48.6; 19F NMR (470
MHz, CDCl3) δ -75.4 (s, 3F); HRMS (ESI-TOF): Calcd. for
C11H9F3NO4S [M+H]+ = 308.0199 m/z, found = 308.0191
m/z.
7,8-dimethoxy-2-((trifluoromethyl)sulfonyl)-1,2-
dihydroisoquinoline (2k). Pale-orange oil, 284.4 mg, yield =
88%. Rf = (hexanes/ethyl acetate 4:1): 0.45; IR (neat) v =
3104, 2944, 2840, 1636, 1605, 1495, 1273, 1186,1146 cm-
1
1; H NMR (500 MHz, CDCl3) δ 6.83 (d, J = 8.7 Hz, 1H), 6.81
(d, J = 8.8 Hz, 1H), 6.47 (d, J = 7.6 Hz, 1H), 6.10 (d, J = 7.6
Hz, 1H), 4.91 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 153.1, 144.8, 123.0, 122.0, 122.0,
121.3, 120.0 (q, JF = 324.3 Hz), 114.8, 111.8, 60.9, 55.9,
43.6; 19F NMR (470 MHz, CDCl3) δ -75.4 (s, 3F); HRMS (ESI-
TOF): Calcd. for C12H12F3NO4SNa [M+Na]+ = 346.0331 m/z,
found = 346.0332 m/z.
6,7,8-trimethoxy-2-((trifluoromethyl)sulfonyl)-1,2-
dihydroisoquinoline (2g). White solid, 314.6 mg, yield =
89%. Rf = (hexanes/ethyl acetate 4:1): 0.42; IR (neat) v =
2995, 2939, 2847, 1569, 1497, 1416, 1389, 1332, 1224,
6,7-dimethoxy-1-methyl-2-((trifluoromethyl)sulfonyl)-1,2-
dihydroisoquinoline (2l). White solid, 264.5 mg, yield =
78% on 1.0 mmol scale, 2.87 g, yield = 85% on 10.0 mmol
scale. Rf = (hexanes/ethyl acetate 5:1): 0.26; IR (neat) v =
3006, 2982, 2960, 2936, 1636, 1515, 1384, 1268, 1137 cm-
1
1150 cm-1; H NMR (500 MHz, CDCl3) δ 6.49 (d, J = 7.7 Hz,
1H), 6.43 (d, J = 7.4 Hz, 1H), 6.43 (s, 1H), 4.74 (s, 2H), 3.89
(s, 3H), 3.86 (s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ
153.9, 149.3, 142.0, 123.4, 121.9, 120.0 (q, JF = 324.2 Hz),
116.7, 110.0, 105.1, 61.6, 61.1, 56.3, 48.4; 19F NMR (470
MHz, CDCl3) δ -75.4 (s, 3F); HRMS (ESI-TOF): Calcd. for
C13H14F3NO5SNa [M+Na]+ = 376.0437 m/z, found =
376.0426 m/z.
1
1; H NMR (500 MHz, CDCl3) δ 6.65 (s, 1H), 6.59 (s, 1H),
6.40 (d, J = 7.4 Hz, 1H), 6.14 (d, J = 7.5 Hz, 1H), 5.17 (q, J =
6.5 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 1.41 (d, J = 6.7 Hz,
3H); 13C{1H} NMR (126 MHz, CDCl3) δ 149.4, 148.8, 126.1,
120.9, 119.9 (q, JF = 324.3 Hz), 119.6, 114.9, 109.1, 108.5,
56.2, 56.1, 55.7, 22.8; 19F NMR (470 MHz, CDCl3) δ -76.0 (s,
3F); HRMS (ESI-TOF): Calcd. for C13H15F3NO4S [M+H]+ =
338.0668 m/z, found = 338.0666 m/z.
4-((2-((trifluoromethyl)sulfonyl)-1,2-dihydroisoquinolin-
7-yl)amino)benzonitrile (2h). Pale-yellow solid, 295.6 mg,
yield = 78%. Rf = (hexanes/ethyl acetate 3:1): 0.45; IR
(neat) v = 3400, 3331, 2216, 1596, 1515, 1441, 1390,
6,7-dimethoxy-1-phenyl-2-((trifluoromethyl)sulfonyl)-1,2-
dihydroisoquinoline (2m). Off-white solid, 256.7 mg, yield =
64%. Rf = (hexanes/ethyl acetate 5:1): 0.36; IR (neat) v =
3007, 2939, 2839, 1634, 1576, 1495, 1452, 1349, 1144,
1090 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.31 – 7.26 (m, 3H),
7.19 (dd, J = 6.7, 2.7 Hz, 2H), 6.77 (s, 1H), 6.66 (s, 1H), 6.40
(d, J = 7.4 Hz, 1H), 6.25 (d, J = 7.4 Hz, 1H), 6.18 (s, 1H), 3.93
(s, 3H), 3.86 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
149.6, 149.2, 139.0, 128.7, 128.6, 127.5, 122.9, 122.2,
120.4, 120.1 (q, JF = 324.9 Hz), 116.9, 109.9, 109.0, 61.1,
56.2, 56.1; 19F NMR (470 MHz, CDCl3) δ -75.2 (s, 3F); HRMS
1
1274, 1188, 1128 cm-1; H NMR (500 MHz, CDCl3) δ 7.51
(d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.1 Hz, 1H), 7.07 (dd, J = 8.2,
2.0 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 2.0 Hz, 1H),
6.54 (d, J = 7.6 Hz, 1H), 6.27 (br s, 1H), 6.17 (d, J = 7.6 Hz,
1H), 4.81 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 147.0,
140.7, 134.0, 129.1, 126.9, 125.1, 123.1, 120.1, 119.9 (q, JF
= 332.5 Hz), 119.7, 117.3, 115.9, 114.6, 102.9, 48.6; 19F
NMR (470 MHz, CDCl3) δ -75.2 (s, 3F); HRMS (ESI-TOF):
Calcd. for C17H12F3N3O2SNa [M+Na]+ = 402.0495 m/z,
found = 402.0476 m/z.
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The Journal of Organic Chemistry
(ESI-TOF): Calcd. for C18H17F3NO4S [M+H]+ = 400.0845
m/z, found = 400.0821 m/z.
min, and dissolved in dry and degassed MeOH (5 mL, 0.1
1
2
3
4
5
6
7
8
M). The resulting mixture was then purged with H2 for 5
min, and then pressurize to 10 psi, and stirred at rt for 4 h.
The mixture was then filtered through celite. The filtrate
was then concentrated in vacuo to afford the crude
hydrogenation product, which was used for the next step
directly. To the crude product was added LiAlH4 (56.9 mg,
1.5 mmol, 3 equiv) and purged with N2 for 5 min, prior to
the addition of dry and degassed Et2O (5 mL, 0.1 M). The
resulting mixture was then refluxed for 12 h, and cooled to
1-allyl-6,7-dimethoxy-2-((trifluoromethyl)sulfonyl)-1,2-
dihydroisoquinoline (2n). White solid, 304.4 mg, yield =
84%. Rf = (hexanes/ethyl acetate 5:1): 0.30; IR (neat) v =
3076, 3019, 2979, 2903, 1573, 1466, 1414, 1350, 1270,
1149 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.66 (s, 1H), 6.57 (s,
1H), 6.40 (d, J = 7.4 Hz, 1H), 6.18 (d, J = 7.4 Hz, 1H), 5.78 –
5.65 (m, 1H), 5.09 (d, J = 10.0 Hz, 1H), 5.04 – 4.98 (m, 2H),
3.860 (s, 3H), 3.855 (s, 3H), 2.55 – 2.29 (m, 2H); 13C{1H}
NMR (126 MHz, CDCl3) δ 149.1, 148.9, 132.8, 124.2, 121.3,
119.9 (q, JF = 324.6 Hz), 119.9, 119.2, 116.1, 109.3, 109.0,
59.3, 56.1, 56.0, 40.2; 19F NMR (470 MHz, CDCl3) δ -75.8 (s,
3F); HRMS (ESI-TOF): Calcd. for C15H17F3NO4S [M+H]+ =
364.0825 m/z, found = 364.0825 m/z.
9
o
0 C in an ice bath. Water (0.3 mL), 15% NaOH solution
10
11
12
13
14
15
16
17
18
19
20
21
22
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48
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60
(0.1 mL) was then added dropwise. The mixture was then
warmed to rt and stirred for 30 min, and filtered through
celite. The filtrate was poured on 10 mL 15% NaOH and
extracted with EtOAc (3  20 mL). The combined organic
fractions were then dried over Na2SO4, filtered and
concentrated in vacuo. The crude product was then
purified on silica gel (25% EtOAc in hexanes to 20% MeOH
in EtOAc) to afford (±)-8 (65.2 mg, 0.31 mmol, 63%) as a
brown oil. 1H NMR (500 MHz, CDCl3) δ 6.60 (s, 1H), 6.55 (s,
1H), 4.05 (q, J = 6.6 Hz, 1H), 3.83 (s, 3H), 3.83 (s, 3H), 3.24
(dt, J = 12.5, 5.1 Hz, 1H), 2.99 (ddd, J = 13.0, 8.4, 4.6 Hz, 1H),
2.84 (br s, 1H), 2.79 (ddd, J = 15.1, 9.0, 6.1 Hz, 1H), 2.65 (dt,
J = 16.1, 4.8 Hz, 1H), 1.44 (d, J = 6.7 Hz, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 147.5, 147.4, 132.1, 126.7, 111.8,
109.1, 56.1, 55.9, 51.2, 41.7, 29.3, 22.8. The
characterization data matches the data that has been
reported previously.26
3-(6,7-dimethoxy-2-((trifluoromethyl)sulfonyl)-1,2-
dihydroisoquinolin-1-yl)propan-1-ol (2o). Colorless oil,
362.3 mg, yield = 95%. Rf = (hexanes/ethyl acetate 1:1):
0.25; IR (neat) v = 2942, 2873, 1633, 1515, 1391, 1221,
1
1187, 1145 cm-1; H NMR (500 MHz, CDCl3) δ 6.66 (s, 1H),
6.60 (s, 1H), 6.40 (d, J = 7.4 Hz, 1H), 6.20 (d, J = 7.4 Hz, 1H),
5.05 – 4.98 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.69 – 3.57
(m, 2H), 1.92 – 1.78 (m, 1H), 1.75 – 1.57 (m, 3H), 1.55 (br s,
1H); 13C{1H} NMR (126 MHz, CDCl3) δ 149.3, 148.8, 125.0,
121.2, 120.0 (q, JF = 325.0 Hz), 119.8, 116.6, 109.12,
109.10, 62.4, 59.6, 56.2, 56.1, 32.1, 28.6; 19F NMR (470
MHz, CDCl3) δ -75.5 (s, 3F); HRMS (ESI-TOF): Calcd. for
C15H18F3NO5SNa [M+Na]+ = 404.0750 m/z, found =
404.0750 m/z.
6,7-dimethoxy-1-methylisoquinoline (9). A flame-dried, 5
mL microwave vial equipped with a Teflon-coated stir bar
and a rubber septum was charged with 2l (168.7 mg, 0.5
mmol), KOtBu (168.3 mg) and purged with N2 for 5 min,
and dissolved in dry and degassed DMSO (0.5 mL, 1 M).
The resulting mixture was stirred at rt for 4 h. The solution
was then poured on 10 mL 15% NaOH and extracted with
EtOAc (3  20 mL). The combined organic fractions were
then dried over Na2SO4, filtered and concentrated in vacuo.
The crude product was then purified on silica gel using
EtOAc/MeOH (5:1) as eluent to afford 9 (50.9 mg, 0.25
1-(3-iodopropyl)-6,7-dimethoxy-2-
((trifluoromethyl)sulfonyl)-1,2-dihydroisoquinoline
(2p).
Pale-yellow oil, 365.9 mg, yield = 74%. Rf = (hexanes/ethyl
acetate 5:1): 0.34; IR (neat) v = 3003, 2939, 2839, 1633,
1
1575, 1464, 1416, 1220, 1141 cm-1; H NMR (500 MHz,
CDCl3) δ 6.68 (s, 1H), 6.59 (s, 1H), 6.42 (d, J = 7.4 Hz, 1H),
6.23 (d, J = 7.4 Hz, 1H), 4.99 (t, J = 6.3 Hz, 1H), 3.90 (s, 3H),
3.89 (s, 3H), 3.24 – 3.12 (m, 2H), 1.96 – 1.84 (m, 3H), 1.75 –
1.65 (m, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 149.5,
149.0, 124.6, 121.2, 120.0 (q, JF = 324.9 Hz), 119.8, 116.8,
109.2, 108.9, 58.7, 56.3, 56.2, 36.2, 29.1, 5.7; 19F NMR (470
MHz, CDCl3) δ -75.4 (s, 3F); HRMS (ESI-TOF): Calcd. for
C15H18F3NIO4S [M+H]+ = 491.9948 m/z, found = 491.9950
m/z.
1
mmol, 50%) as a brown oil. H NMR (500 MHz, CDCl3) δ
8.26 (d, J = 5.7 Hz, 1H), 7.39 (d, J = 5.7 Hz, 1H), 7.24 (s, 1H),
7.04 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 2.88 (s, 3H); 13C{1H}
NMR (126 MHz, CDCl3) δ 155.7, 153.0, 150.1, 140.1, 133.0,
123.3, 118.6, 105.4, 103.9, 56.2, 56.1, 22.0. The
characterization data matches the data that has been
reported previously.23
6,7-dimethoxy-3-methyl-2-((trifluoromethyl)sulfonyl)-1,2-
dihydroisoquinoline (2q). Off-white solid, 245.7 mg, yield =
73%. Rf = (hexanes/ethyl acetate 5:1): 0.21; IR (neat) v =
(±)-(1S,3S,4S)-6,7-dimethoxy-1-methyl-2-
1
2939, 2838, 1648, 1509, 1380, 1277, 1121 cm-1; H NMR
((trifluoromethyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-
3,4-diol (10). The literature procedure was followed:24
A
(500 MHz, CDCl3) δ 6.66 (s, 1H), 6.63 (s, 1H), 6.24 (s, 1H),
4.68 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 2.25 (d, J = 1.1 Hz,
3H); 13C{1H} NMR (126 MHz, CDCl3) δ 148.99, 148.96,
133.0, 123.9, 121.7, 119.8 (q, JF = 324.0 Hz), 119.7, 108.28,
108.26, 56.2, 56.1, 50.9, 20.9; 19F NMR (470 MHz, CDCl3) δ -
75.9 (s, 3F); HRMS (ESI-TOF): Calcd. for C13H15F3NO4S
[M+H]+ = 338.0668 m/z, found = 338.0669 m/z.
flame-dried, 25 mL round bottom flask equipped with a
Teflon-coated stir bar and a rubber septum was charged
with 2l (168.7 mg, 0.5 mmol), NMO (87.9 mg, 0.75 mmol)
and dissolved in Me2CO/ H2O (2 mL/0.5 mL). A solution of
t
OsO4 (2.54 mg, 0.01 mmol) in BuOH (1 mL) was added.
The mixture was stirred at rt for 8 h. It was then quenched
by the addition of Na2S2O3 (satd., 20 mL) and extracted
with EtOAc (3  20 mL). The combined organic fractions
were then dried over Na2SO4, filtered and concentrated in
vacuo. The crude product was then purified on silica gel
(30% EtOAc in hexanes) to afford (±)-10 (140.6 mg, 0.38
mmol, 76%, > 20:1 d.r.) as a white solid. The relative
(±)-6,7-dimethoxy-1-methyl-1,2,3,4-
tetrahydroisoquinoline (8). A flame-dried, 50 mL round
bottom flask equipped with a Teflon-coated stir bar and a
rubber septum was charged with 2l (168.7 mg, 0.5 mmol),
10 wt% Pd/C (33.0 mg, 20 wt%) and purged with N2 for 5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 14
stereochemistry was assigned based on literature
crude, 5.0 mmol, 1.28 g, 1.0 equiv) and dissolved in CH2Cl2
precedent.24 Rf = (ethyl acetate/hexane 1:2): 0.13; IR (neat)
v = 3512, 3442, 3328, 1615, 1518, 1469, 1445, 1383, 1370,
1351, 1330, 1296, 1258, 1225, 1198, 1183, 1160, 1102 cm-
(20 mL, 0.25 M). Then NEt3 (15 mmol, 2.08 mL, 3.0 equiv),
DMAP (0.5 mmol, 61.1 mg, 10 mol%) and TsCl (7.5 mmol,
1.43 g, 1.5 equiv) were added. The resulting mixture was
stirred at room temperature for 12h and quenched by the
addition of HCl (50 mL, 1M). The phases were then
separated, and the aqueous phase was extracted with
CH2Cl2 (3  50 mL). The combined organic fractions were
then dried over MgSO4, filtered and concentrated in vacuo.
The residue was then purified on silica gel using
hexanes/ethyl acetate (2:1) as eluent to afford 1a-Ts (1.96
g, 4.79 mmol, 96%) as a brown solid. Rf = (ethyl
1
2
3
4
5
6
7
8
1
1; H NMR (500 MHz, CDCl3) δ 7.15 (s, 1H), 6.57 (s, 1H),
5.74 (br s, 1H), 4.99 (br s, 1H), 4.79 (br s, 1H), 3.90 (s, 3H),
3.88 (s, 3H), 3.49 (br s, 1H), 2.64 (br s, 1H), 1.81 (d, J = 6.7
Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 149.2, 149.1,
127.2, 124.3, 119.7 (q, JF = 322.1 Hz), 109.5, 108.4, 78.5,
67.6, 56.2, 56.2, 54.0, 27.6; 19F NMR (470 MHz, CDCl3) δ -
77.0 (s, 3F); HRMS (ESI-TOF): Calcd. for C13H15F3NO6S [M-
H]- = 370.0578 m/z, found = 370.0577 m/z.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
acetate/hexane 1:2): 0.26; H NMR (500 MHz, CDCl3) δ
General procedure for the synthesis of 1a-1q. Step 1:
Reductive amination. A flame-dried, 250 mL round bottom
flask equipped with a Teflon-coated stir bar and a rubber
septum was charged with the aldehyde (20.0 mmol, 1.0
equiv) and dissolved in MeOH (40 mL, 0.5 M). Then AcOH
(10 mmol, 0.5 equiv) and the amine (20.0 mmol, 1.0 equiv)
were added via a syringe. The resulting mixture was
7.72 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.75 – 6.70
(m, 2H), 6.66 (d, J = 1.3 Hz, 1H), 4.39 (s, 2H), 4.34 (t, J = 5.3
Hz, 1H), 3.82 (s, 3H), 3.72 (s, 3H), 3.23 (s, 6H), 3.19 (d, J =
5.3 Hz, 2H), 2.40 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
149.1, 148.7, 143.3, 137.8, 129.7, 128.6, 127.2, 121.2,
111.4, 110.8, 104.0, 55.9, 55.8, 54.7, 52.4, 48.4, 21.5. The
characterization data matches the data that has been
reported previously.27
o
stirred at room temperature for 2h, and cooled to 0 C in
an ice bath, prior to the portion-wise addition of NaBH4
(30.0 mmol, 1.5 equiv). The resulting solution was then
warmed to room temperature and stirred for 12h. The
solution was then concentrated in vacuo and diluted with
sat. NaHCO3 (50 mL) and extracted with EtOAc (3  100
mL). The combined organic fractions were then dried over
MgSO4, filtered and concentrated in vacuo. The crude
product was directly used for the next step. Step 2: N-
triflation. A 250 mL round bottom flask containing the
crude amine product was equipped with a Teflon-coated
stir bar and a rubber septum. It was dissolved in CH2Cl2
(0.2 – 0.5 M), followed by the addition of DIPEA (1.5
equiv). The solution was cooled to -78 oC in a dry
ice/acetone bath. Tf2O (1.0 – 1.2 equiv) was added to the
solution dropwise. The reaction was then stirred for 30
min at -78 oC, warmed to rt and stir for another 30 min and
then quenched with H2O and 1M HCl (10 mL / mmol). The
phases were then separated, and the aqueous phase was
extracted with CH2Cl2 (3  10 mL / mmol). The combined
organic fractions were then dried over MgSO4, filtered and
concentrated in vacuo. The residue was then purified on
silica gel using hexanes/ethyl acetate as eluent to afford
the triflamide product.
N-(3,4-dimethoxybenzyl)-N-(2,2-dimethoxyethyl)-2-
nitrobenzenesulfonamide (1a-Ns). A flame-dried, 100 mL
round bottom flask equipped with a Teflon-coated stir bar
and
a rubber septum was charged with N-(3,4-
dimethoxybenzyl)-2,2-dimethoxyethan-1-amine (used as
crude, 10.0 mmol, 2.55 g, 1.0 equiv) and dissolved in
CH2Cl2 (20 mL, 0.5 M). Then NEt3 (30 mmol, 4.16 mL, 3.0
equiv) and nosyl chloride (12 mmol, 2.66 g, 1.2 equiv)
were added. The resulting mixture was stirred at room
temperature for 12h and quenched by the addition of HCl
(50 mL, 1M). The phases were then separated, and the
aqueous phase was extracted with CH2Cl2 (3  50 mL). The
combined organic fractions were then dried over MgSO4,
filtered and concentrated in vacuo. The residue was then
purified on silica gel using hexanes/ethyl acetate (2:1) as
eluent to afford 1a-Ns (3.88 g, 8.80 mmol, 88%) as a pale-
yellow oil. Rf = (ethyl acetate/hexane 1:2): 0.18; IR (neat) v
= 2938, 2836, 1541, 1515, 1464, 1441, 1421, 1369, 1343,
1
1257, 1238, 1191, 1159, 1140, 1121 cm-1; H NMR (500
MHz, CDCl3) δ 8.02 – 7.96 (m, 1H), 7.70 – 7.59 (m, 3H), 6.79
– 6.72 (m, 3H), 4.59 (s, 2H), 4.36 (t, J = 5.2 Hz, 1H), 3.85 (s,
3H), 3.75 (s, 3H), 3.36 (d, J = 5.2 Hz, 2H), 3.28 (s, 6H);
13C{1H} NMR (126 MHz, CDCl3) δ 149.3, 148.9, 148.0, 134.5,
133.4, 131.7, 131.2, 128.0, 124.2, 121.2, 111.3, 111.0,
104.0, 56.0, 55.9, 55.0, 52.4, 48.2; HRMS (ESI-TOF): Calcd.
for C19H24N2O8SNa [M+Na]+ = 463.1146 m/z, found =
463.1136 m/z.
N-(3,4-dimethoxybenzyl)-N-(2,2-dimethoxyethyl)-1,1,1-
trifluoromethanesulfonamide (1a). Off-white solid, 2.48 g,
yield = 64%. Rf = (EtOAc : Hexanes 1:3): 0.23; IR (neat) v =
2940, 2838, 1608, 1517, 1421, 1259, 1184, 1137, 1119 cm-
1; 1H NMR (500 MHz, CDCl3) δ 6.90 (s, 1H), 6.91 – 6.87 (m,
1H), 6.84 (d, J = 8.7 Hz, 1H), 4.58 (br s, 2H), 4.46 (t, J = 5.5
Hz, 1H), 3.88 (s, 3H), 3.88 (s, 3H), 3.38 (s, 6H), 3.30 (br s,
2H). 13C{1H} NMR (126 MHz, CDCl3) δ 149.5, 149.4, 126.6,
122.1, 120.2 (q, JF = 325.1 Hz), 111.9, 111.1, 104.0, 56.1,
56.0, 55.2, 53.2, 47.9; 19F NMR (470 MHz, CDCl3) δ -75.5 (s,
3F); HRMS (ESI-TOF): Calcd. for C14H20F3NO6SNa [M+Na]+ =
410.0856 m/z, found = 410.0845 m/z.
tert-butyl
(3,4-dimethoxybenzyl)(2,2-
dimethoxyethyl)carbamate (1a-Boc). A flame-dried, 100
mL round bottom flask equipped with a Teflon-coated stir
bar and a rubber septum was charged with N-(3,4-
dimethoxybenzyl)-2,2-dimethoxyethan-1-amine (used as
crude, 5.0 mmol, 1.28 g, 1.0 equiv) and dissolved in THF
(10 mL, 0.5 M). Then Boc2O (6.0 mmol, 1.31 g, 1.2 equiv)
was added. The resulting mixture was stirred at room
temperature for 12h and concentrated in vacuo. The
residue was then purified on silica gel using hexanes/ethyl
acetate (2:1) as eluent to afford 1a-Boc (1.29 g, 3.63 mmol,
73%) as a colorless oil. Rf = (ethyl acetate/hexane 1:2):
0.31; IR (neat) v = 2935, 2834, 1687, 1514, 1460, 1407,
N-(3,4-dimethoxybenzyl)-N-(2,2-dimethoxyethyl)-4-
methylbenzenesulfonamide (1a-Ts). A flame-dried, 100 mL
round bottom flask equipped with a Teflon-coated stir bar
and
a rubber septum was charged with N-(3,4-
dimethoxybenzyl)-2,2-dimethoxyethan-1-amine (used as
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The Journal of Organic Chemistry
1318, 1260, 1234, 1158, 1120 cm-1; H NMR (500 MHz,
CDCl3) mixture of rotamers δ 6.87 – 6.67 (m, 3H), 4.56 –
4.36 (m, 3H), 3.84 (s, 6H), 3.37 (s, 3H), 3.35 (s, 3H), 3.26
(br s, 1H), 3.17 (br s, 1H), 1.49 and 1.45 (s, 9H); 13C{1H}
NMR (126 MHz, CDCl3) mixture of rotamers δ 155.9, 149.1,
148.2, 131.2, 131.0, 120.4, 119.7, 111.3, 111.0, 110.6,
104.4, 103.7, 80.0, 56.0, 55.9, 54.8, 51.5, 50.6, 48.2, 48.0,
28.5; HRMS (ESI-TOF): Calcd. for C18H29NO6Na [M+Na]+ =
378.1887 m/z, found = 378.1882 m/z.
N-benzyl-N-(2,2-dimethoxyethyl)-1,1,1-
1
1
2
3
4
5
6
7
8
trifluoromethanesulfonamide (1d). Colorless oil, 1.37 g,
yield = 84%. Rf = (EtOAc : Hexanes 1:3): 0.59; IR (neat) v =
1
2942, 2839, 1456, 1384, 1224, 1184, 1143, 1120 cm-1; H
NMR (500 MHz, CDCl3) δ 7.42 – 7.30 (m, 5H), 4.65 (br s,
2H), 4.45 (t, J = 5.5 Hz, 1H), 3.36 (s, 6H), 3.31 (br s, 2H);
13C{1H} NMR (126 MHz, CDCl3) δ 134.4, 129.0, 128.6, 120.1
(q, JF = 323.0 Hz), 103.9, 55.2, 53.4, 48.3; 19F NMR (470
MHz, CDCl3) δ -75.4 (s, 3F); HRMS (ESI-TOF): Calcd. for
C12H16F3NO4SNa [M+Na]+ = 350.0644 m/z, found =
350.0630 m/z.
9
benzyl
(3,4-dimethoxybenzyl)(2,2-
dimethoxyethyl)carbamate (1a-Cbz). A flame-dried, 100
mL round bottom flask equipped with a Teflon-coated stir
bar and a rubber septum was charged with N-(3,4-
dimethoxybenzyl)-2,2-dimethoxyethan-1-amine (used as
crude, 5.0 mmol, 1.28 g, 1.0 equiv), K2CO3 (1.38 g, 10 mmol,
2.0 equiv) and dissolved in MeCN (10 mL, 0.5 M). Then
CbzCl (7.5 mmol, 1.07 mL, 1.5 equiv) was added. The
resulting mixture was stirred at room temperature for 4h
and diluted with H2O (10 mL) and brine (10 mL). The
mixture was extracted with EtOAc (3  50 mL). The
combined organic fractions were then dried over MgSO4,
filtered and concentrated in vacuo. The residue was then
purified on silica gel using hexanes/ethyl acetate (2:1) as
eluent to afford 1a-Cbz (1.09 g, 2.80 mmol, 56%) as a
colorless oil. Rf = (ethyl acetate/hexane 1:2): 0.27; IR
(neat) v = 2938, 2834, 1695, 1514, 1462, 1412, 1364,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(2,2-dimethoxyethyl)-1,1,1-trifluoro-N-(3-
methoxybenzyl)methanesulfonamide (1e). Pale-yellow oil,
2.53 g, yield = 71%. Rf = (EtOAc : Hexanes 1:3): 0.48; IR
(neat) v = 2942, 2839, 1602, 1491, 1458, 1384, 1223, 1120
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.29 (t, J = 7.8 Hz, 1H),
6.92 (d, J = 7.6 Hz, 1H), 6.90 – 6.85 (m, 2H), 4.62 (s, 2H),
4.46 (t, J = 5.5 Hz, 1H), 3.81 (s, 3H), 3.37 (s, 6H), 3.32 (s,
2H); 13C{1H} NMR (126 MHz, CDCl3) δ 160.2, 135.9, 130.0,
121.2, 120.1 (q, JF = 323.0 Hz), 114.4, 114.1, 103.8, 55.4,
55.1, 53.3, 48.3; 19F NMR (470 MHz, CDCl3) δ -75.4 (s, 3F);
HRMS (ESI-TOF): Calcd. for C13H18F3NO5SNa [M+Na]+
380.0750 m/z, found = 380.0736 m/z.
=
N-(benzo[d][1,3]dioxol-5-ylmethyl)-N-(2,2-
dimethoxyethyl)-1,1,1-trifluoromethanesulfonamide
(1f).
White solid, 2.96 g, yield = 80%. Rf = (EtOAc : Hexanes 1:3):
0.38; IR (neat) v = 2945, 2844, 1503, 1491, 1334, 1245,
1
1319, 1298, 1260, 1231, 1116 cm-1; H NMR (500 MHz,
CDCl3) mixture of rotamers δ 7.46 – 7.26 (m, 5H), 6.85 –
6.63 (m, 3H), 5.20 (d, J = 4.9 Hz, 2H), 4.60 – 4.34 (m, 3H),
3.86 (s, 3H), 3.81 and 3.68 (s, 3H), 3.40 (s, 3H), 3.34 (d, J =
5.0 Hz, 1H), 3.30 (s, 3H), 3.26 (d, J = 4.9 Hz, 1H); 13C{1H}
NMR (126 MHz, CDCl3) mixture of rotamers δ 149.2, 130.4,
128.6, 128.2, 128.1, 120.0, 111.4, 111.1, 110.8, 104.2,
103.6, 67.5, 56.0, 55.8, 54.8, 51.3, 48.6, 47.8; HRMS (ESI-
TOF): Calcd. for C21H27NO6Na [M+Na]+ = 412.1731 m/z,
found = 412.1725 m/z.
1
1146, 1116 cm-1; H NMR (500 MHz, CDCl3) δ 6.86 (d, J =
1.4 Hz, 1H), 6.81 (dd, J = 8.0, 1.6 Hz, 1H), 6.78 (d, J = 7.9 Hz,
1H), 5.97 (s, 2H), 4.54 (s, 2H), 4.46 (t, J = 5.5 Hz, 1H), 3.39
(s, 6H), 3.30 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ
148.3, 148.0, 127.9, 123.2, 120.1 (q, JF = 323.0 Hz), 109.4,
108.5, 104.0, 101.4, 55.3, 53.1, 47.8; 19F NMR (470 MHz,
CDCl3) δ -75.6 (s, 3F); HRMS (ESI-TOF): Calcd. for
C13H16F3NO6SNa [M+Na]+ = 394.0543 m/z, found =
394.0542 m/z.
N-(2,2-dimethoxyethyl)-1,1,1-trifluoro-N-(naphthalen-2-
ylmethyl)methanesulfonamide (1b). Pale-yellow oil, 3.12 g,
yield = 83%. Rf = (EtOAc : Hexanes 1:5): 0.46; IR (neat) v =
N-(2,2-dimethoxyethyl)-1,1,1-trifluoro-N-(3,4,5-
trimethoxybenzyl)methanesulfonamide (1g). Pale-yellow
oil, 3.08 g, yield = 74%. Rf = (EtOAc : Hexanes 1:3): 0.17; IR
(neat) v = 2942, 2839, 1593, 1383, 1239, 1183cm-1; 1H
NMR (500 MHz, CDCl3) δ 6.57 (s, 2H), 4.57 (s, 2H), 4.46 (t, J
= 5.4 Hz, 1H), 3.85 (s, 6H), 3.84 (s, 3H),3.39 (s, 6H), 3.33 (s,
2H); 13C{1H} NMR (126 MHz, CDCl3) δ 153.6, 138.2, 129.8,
120.1 (q, JF = 323.1 Hz), 106.1, 104.0, 61.0, 56.3, 55.3, 53.6,
48.2; 19F NMR (470 MHz, CDCl3) δ -75.4 (s, 3F); HRMS (ESI-
TOF): Calcd. for C15H22F3NO7SNa [M+Na]+ = 440.0961 m/z,
found = 440.0954 m/z.
1
2940, 2838, 1510, 1445, 1384, 1223, 1184, 1120 cm-1; H
NMR (500 MHz, CDCl3) δ 7.90 – 7.82 (m, 3H), 7.79 (s, 1H),
7.55 – 7.45 (m, 3H), 4.82 (br s, 2H), 4.49 (t, J = 5.4 Hz, 1H),
3.36 (s, 8H); 13C{1H} NMR (126 MHz, CDCl3) δ 133.3, 131.7,
129.0, 128.5, 128.1, 127.9, 126.7, 126.1, 120.2 (q, JF = 323.1
Hz), 103.9, 55.2, 53.6, 48.3; 19F NMR (470 MHz, CDCl3) δ -
75.3 (s, 3F); HRMS (ESI-TOF): Calcd. for C16H18F3NO4SNa
[M+Na]+ = 400.0801 m/z, found = 400.0790 m/z.
N-(2,2-dimethoxyethyl)-1,1,1-trifluoro-N-(3-
N-(3-bromobenzyl)-N-(2,2-dimethoxyethyl)-1,1,1-trifluo-
romethanesulfonamide. Dark-red oil, 9.26 g, yield = 76%. Rf
= (EtOAc : Hexanes 1:2): 0.76; IR (neat) v = 2941, 2838,
methylbenzyl)methanesulfonamide (1c). Colorless oil, 1.31
g, yield = 77%. Rf = (EtOAc : Hexanes 1:3): 0.59; IR (neat) v
= 2941, 2839, 1610, 1491, 1384, 1259, 1183, 1120 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.26 (d, J = 7.7 Hz, 1H), 7.17 –
7.13 (m, 3H), 4.61 (s, 2H), 4.45 (t, J = 5.5 Hz, 1H), 3.37 (s,
6H), 3.31 (s, 2H), 2.36 (s, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ 138.8, 134.2, 129.6, 129.4, 128.9, 126.1, 120.2 (q,
JF = 323.1 Hz), 103.8, 55.2, 53.3, 48.3, 21.5; 19F NMR (470
MHz, CDCl3) δ -75.4 (s, 3F); HRMS (ESI-TOF): Calcd. for
C13H18F3NO4SNa [M+Na]+ = 364.0801 m/z, found =
364.0790 m/z.
1
1597, 1431, 1224, 1185, 1143, 1120 cm-1; H NMR (500
MHz, CDCl3) δ 7.53 – 7.44 (m, 2H), 7.29 (d, J = 7.7 Hz, 1H),
7.25 (t, J = 7.6 Hz, 1H), 4.61 (s, 2H), 4.44 (t, J = 5.4 Hz, 1H),
3.37 (s, 6H), 3.32 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ
136.9, 131.9, 131.7, 130.5, 127.4, 123.0, 120.1 (q, JF = 323.1
Hz), 103.9, 55.3, 52.8, 48.7; 19F NMR (470 MHz, CDCl3) δ -
75.4 (s, 3F); HRMS (ESI-TOF): Calcd. for C12H15BrF3NO4SNa
[M+Na]+ = 427.9749 m/z, found = 427.9732 m/z.
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N-(3-((4-cyanophenyl)amino)benzyl)-N-(2,2- N-(2,3-dimethoxybenzyl)-N-(2,2-dimethoxyethyl)-1,1,1-
Page 10 of 14
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dimethoxyethyl)-1,1,1-trifluoromethanesulfonamide (1h).
The literature procedure was followed:28 A flame-dried, 25
mL Schlenk flask equipped with a Teflon-coated stir bar
and a glass stopper was charged with XPhos-Pd-G1 (22.16
mg, 0.03 mmol), 4-aminobenzenitrile (425.3 mg, 3.6 mmol)
and K2CO3 (580.5 mg, 4.2 mmol). The mixture was then
evacuated and filled with N2 (this process was repeated
three times). Under a positive pressure of nitrogen, the
stopper was opened, at which point a solution of N-(3-
bromobenzyl)-N-(2,2-dimethoxyethyl)-1,1,1-
trifluoromethanesulfonamide (1k). Pale-orange oil, 3.40 g,
yield = 87%. Rf = (EtOAc : Hexanes 1:3): 0.38; IR (neat) v =
2941, 2838, 1589, 1483, 1384, 1183, 1144, 1122 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.07 (t, J = 8.0 Hz, 1H), 6.96 (dd, J
= 7.8, 1.2 Hz, 1H), 6.89 (dd, J = 8.1, 1.3 Hz, 1H), 4.70 (s, 2H),
4.46 (t, J = 5.5 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.40 (s,
2H), 3.33 (s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 152.8,
147.5, 128.4, 124.4, 121.3, 120.1 (q, JF = 323.8 Hz), 112.6,
103.2, 60.8, 56.0, 54.9, 49.4, 48.1; 19F NMR (470 MHz,
CDCl3) δ -75.2 (s, 3F); HRMS (ESI-TOF): Calcd. for
C14H20F3NO6SNa [M+Na]+ = 410.0856 m/z, found =
410.0857 m/z.
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t
trifluoromethanesulfonamide (1.22 g, 3.0 mmol) in BuOH
(6 mL) was added via a syringe. The stopper was then
capped under N2, and the resulting mixture was stirred at
N-(2,2-dimethoxyethyl)-1-(3,4-dimethoxyphenyl)-
o
110 C in a pre-heated oil bath for 4 h. The mixture was
methanimine. A flame-dried, 250 mL round bottom flask
equipped with a Teflon-coated stir bar and a rubber
septum was charged with 3,4-dimethoxybenzaldehyde
(8.31 g, 50.0 mmol) and MgSO4 (18.05 g, 150.0 mmol). Dry
CH2Cl2 (100 mL) was added via syringe followed by 2-
aminoacetaldehyde dimethylacetal (5.45 mL, 50.0 mmol).
The resulting mixture was stirred at room temperature
overnight and filtered through celite. The filtrate was then
concentrated in vacuo and dried under high vacuum to
provide the imine product (12.38 g, 98%) as a white solid.
1H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.42 (d, J = 1.8 Hz,
1H), 7.16 (dd, J = 8.2, 1.9 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H),
4.67 (t, J = 5.3 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.75 (dt, J
= 5.3, 2.6 Hz, 2H), 3.42 (s, 6H); 13C{1H} NMR (126 MHz,
CDCl3) δ 163.2, 151.6, 149.4, 129.5, 123.4, 110.5, 109.0,
104.1, 63.6, 56.1, 56.1, 54.3. The characterization data
matches the data that has been reported previously.27
then cooled to RT and poured on water (50 mL) and
extracted with EtOAc (3  50 mL). The combined organic
fractions were then dried over MgSO4, filtered and
concentrated in vacuo. The crude product was then
purified on silica gel using hexanes/ethyl acetate (5:1) as
eluent to afford 1h (888.3 mg, 2.0 mmol, 67%) as a white
solid. Rf = (EtOAc : Hexanes 1:5): 0.20; IR (neat) v = 3339,
2937, 2840, 2218, 1613, 1588, 1480, 1452, 1410, 1366,
1
1226, 1187 cm-1; H NMR (500 MHz, CDCl3) δ 7.48 (d, J =
8.7 Hz, 2H), 7.34 (dd, J = 8.5, 7.8 Hz, 1H), 7.34 (dd, J = 8.5,
7.8 Hz, 1H), 7.17 – 7.12 (m, 2H), 7.05 (d, J = 7.6 Hz, 1H),
7.01 (d, J = 8.8 Hz, 2H), 6.32 (s, 1H), 4.62 (br s, 2H), 4.46 (t,
J = 5.4 Hz, 1H), 3.38 (s, 6H), 3.34 (br s, 2H); 13C{1H} NMR
(126 MHz, CDCl3) δ 147.5, 140.9, 136.1, 133.9, 130.2,
123.8, 120.7, 120.4, 120.0 (q, JF = 323.0 Hz), 119.9, 115.4,
103.9, 102.0, 55.3, 53.1, 48.5; 19F NMR (470 MHz, CDCl3) δ -
75.4 (s, 3F); HRMS (ESI-TOF): Calcd. for C19H20F3N3O4SNa
[M+Na]+ = 466.1019 m/z, found = 466.0997 m/z.
N-(1-(3,4-dimethoxyphenyl)ethyl)-2,2-dimethoxyethan-1-
amine. A flame-dried, 100 mL round bottom flask equipped
with a Teflon-coated stir bar and a rubber septum was
N-(2,2-dimethoxyethyl)-1,1,1-trifluoro-N-(thiophen-2-
ylmethyl)methanesulfonamide (1i). Pale-orange oil, 2.70 g,
yield = 81%. Rf = (EtOAc : Hexanes 1:5): 0.46; IR (neat) v =
charged
with
(E)-N-(2,2-dimethoxyethyl)-1-(3,4-
dimethoxyphenyl)-methanimine (1.27 g, 5.0 mmol),
purged with N2 for 5 min, and dissolved in dry and
degassed THF (25 mL, 0.2 M). The resulting mixture was
1
2941, 2839, 1385, 1278, 1224, 1185, 1117 cm-1; H NMR
(500 MHz, CDCl3) δ 7.33 (dd, J = 5.1, 1.2 Hz, 1H), 7.08 (d, J =
3.4 Hz, 1H), 6.99 (dd, J = 5.1, 3.5 Hz, 1H), 4.84 (s, 2H), 4.50
(t, J = 5.4 Hz, 1H), 3.42 (s, 6H), 3.37 (d, J = 5.2 Hz, 2H);
13C{1H} NMR (126 MHz, CDCl3) δ 136.6, 129.4, 127.2, 127.1,
120.0 (q, JF = 322.7 Hz), 104.2, 55.4, 47.85, 47.81; 19F NMR
(470 MHz, CDCl3) δ -75.8 (s, 3F); HRMS (ESI-TOF): Calcd.
for C10H14F3NO4S2Na [M+Na]+ = 356.0209 m/z, found =
356.0206 m/z.
o
stirred and cooled to -78 C in a dry ice bath, prior to the
dropwise addition of MeLi (2.42 mL, 7.5 mmol, 3.1 M). The
resulting solution was stirred for 30 min and the dry ice
bath was removed and the solution was stirred for another
5 mins and then quenched with H2O (10 mL) and sat.
NH4Cl (10 mL). The solution was then extracted with
EtOAc (3  50 mL). The combined organic fractions were
then dried over Na2SO4, filtered and concentrated in vacuo.
The crude product was then purified on silica gel using
hexanes/ethyl acetate (1:1) as eluent to afford the amine
product (899.7 mg, 59%) as a pale-yellow oil. 1H NMR (500
MHz, CDCl3) δ 6.89 (d, J = 1.4 Hz, 1H), 6.83 (dd, J = 8.2, 1.6
Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 4.43 (t, J = 5.5 Hz, 1H), 3.89
(s, 3H), 3.86 (s, 3H), 3.71 (q, J = 6.6 Hz, 1H), 3.36 (s, 3H),
3.31 (s, 3H), 2.63 (dd, J = 12.1, 5.6 Hz, 1H), 2.56 (dd, J =
12.1, 5.3 Hz, 1H), 1.63 (br s, 1H), 1.35 (d, J = 6.6 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 149.2, 148.1, 138.1, 118.9,
111.1, 109.6, 104.0, 58.2, 56.0, 56.0, 54.2, 53.8, 49.2, 24.6.
The characterization data matches the data that has been
reported previously.29
N-((1-benzyl-1H-indol-3-yl)methyl)-N-(2,2-
dimethoxyethyl)-1,1,1-trifluoromethanesulfonamide
(1j).
Dark-red oil, 8.67 g, yield = 70%. Rf = (EtOAc : Hexanes
1:10): 0.17; IR (neat) v = 2940, 2838, 1736, 1550, 1468,
1
1270, 1129 cm-1; H NMR (500 MHz, CDCl3) δ 7.89 (d, J =
7.2 Hz, 1H), 7.41 – 7.28 (m, 4H), 7.28 – 7.20 (m, 3H), 7.15
(d, J = 6.7 Hz, 2H), 5.34 (s, 2H), 4.92 (br s, 2H), 4.53 (t, J =
5.5 Hz, 1H), 3.43 (br s, 1H), 3.40 (s, 6H); 13C{1H} NMR (126
MHz, CDCl3) δ 137.1, 136.8, 129.8, 128.9, 127.9, 127.7,
126.9, 122.5, 120.4, 120.2 (q, JF = 323.4 Hz), 119.4, 110.1,
108.0, 104.1, 55.1, 50.2, 47.7, 45.0; 19F NMR (470 MHz,
CDCl3) δ -75.4 (s, 3F); HRMS (ESI-TOF): Calcd. for
C21H23F3N2O4SNa [M+Na]+ = 479.1223 m/z, found =
479.1206 m/z.
N-(2,2-dimethoxyethyl)-N-(1-(3,4-
dimethoxyphenyl)ethyl)-1,1,1-trifluoromethanesulfonamide
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The Journal of Organic Chemistry
(1l). The general procedure for the N-triflation was septum was charged with (E)-N-(2,2-dimethoxyethyl)-1-
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followed. White solid, 3.38 g, yield = 64%. Rf = (EtOAc :
Hexanes 1:3): 0.27; IR (neat) v = 2992, 2960, 2941, 2841,
(3,4-dimethoxyphenyl)-methanimine (1.27 g, 5.0 mmol),
Zn powder (653.8 mg, 10 mmol) and purged with N2 for 5
min, and dissolved in dry and degassed THF (10 mL, 0.5
M). The resulting mixture was stirred and cooled to 0 oC in
an ice bath, prior to the dropwise addition of allyl bromide
(649.1 µL, 7.5 mmol). The resulting mixture was stirred
overnight at rt. The solution was then extracted with
EtOAc (3  50 mL). The combined organic fractions were
then dried over Na2SO4, filtered and concentrated in vacuo.
The crude product was then purified on silica gel using
hexanes/ethyl acetate (1:1) as eluent to afford the amine
1
1605, 1446, 1345, 1241, 1147 cm-1; H NMR (500 MHz,
CDCl3) δ 6.95 (br s, 1H), 6.94 (dd, J = 8.4, 1.4 Hz, 1H), 6.84
(d, J = 8.3 Hz, 1H), 5.17 (d, J = 6.3 Hz, 1H), 4.22 (br s, 1H),
3.87 (s, 3H), 3.87 (s, 3H), 3.31 (s, 3H), 3.21 (s, 3H), 3.25 –
3.16 (m, 1H), 3.15 – 3.01 (m, 1H), 1.67 (d, J = 6.3 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 149.3, 149.2, 130.3,
120.20 (q, JF = 319.5 Hz), 120.19, 111.6, 110.8, 103.4, 58.9,
56.0, 55.9, 55.4, 54.7, 47.1, 17.4; 19F NMR (470 MHz, CDCl3)
mixture of rotamers: δ -74.4 & -76.0 (s, 3F); HRMS (ESI-
TOF): Calcd. for C15H22F3NO6SNa [M+Na]+ = 424.1012 m/z,
found = 424.1007 m/z.
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product (1.40 g, 95%) as a pale-yellow oil. H NMR (500
MHz, CDCl3) δ 6.89 (d, J = 1.4 Hz, 1H), 6.83 (dd, J = 8.3, 1.6
Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 5.78 – 5.66 (m, 1H), 5.09
(dd, J = 17.1, 1.7 Hz, 1H), 5.07 – 5.03 (m, 1H), 4.41 (t, J = 5.5
Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.58 (t, J = 6.9 Hz, 1H),
3.34 (s, 3H), 3.30 (s, 3H), 2.58 (dd, J = 11.5, 5.0 Hz, 1H),
2.55 (dd, J = 11.4, 4.4 Hz, 1H), 2.43 – 2.36 (m, 2H), 1.63 (br
s, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 149.2, 148.2,
136.4, 135.5, 119.6, 117.6, 111.1, 109.9, 103.9, 62.6, 56.04,
56.02, 54.0, 53.7, 49.0, 43.2. The characterization data
matches the data that has been reported previously.30
N-((3,4-dimethoxyphenyl)(phenyl)methyl)-2,2-dimeth-
oxyethan-1-amine. A flame-dried, 100 mL round bottom
flask equipped with a Teflon-coated stir bar and a rubber
septum was charged with (E)-N-(2,2-dimethoxyethyl)-1-
(3,4-dimethoxyphenyl)-methanimine (1.27 g, 5.0 mmol),
purged with N2 for 5 min, and dissolved in dry and
degassed THF (25 mL, 0.2 M). The resulting mixture was
o
stirred and cooled to -78 C in a dry ice bath, prior to the
dropwise addition of PhLi (5 mL, 9.5 mmol, 1.9 M). The
resulting solution was stirred for 2 h with the temperature
ramping from -78 oC to -40 oC and then quenched with H2O
(10 mL) and sat. NH4Cl (10 mL). The solution was then
extracted with EtOAc (3  50 mL). The combined organic
fractions were then dried over Na2SO4, filtered and
concentrated in vacuo. The crude product was then
purified on silica gel using hexanes/ethyl acetate (1:1) as
eluent to afford the amine product (1.19 g, 72%) as a pale-
yellow oil. Rf = (EtOAc : Hexanes 1:1): 0.40; IR (neat) v =
2996, 2935, 2905, 2831, 1592, 1451, 1345, 1129, 1025 cm-
N-(2,2-dimethoxyethyl)-N-(1-(3,4-dimethoxyphenyl)but-3-
en-1-yl)-1,1,1-trifluoromethanesulfonamide
(1n).
The
general procedure for the N-triflation was followed. Pale-
yellow, 6.55 g, yield = 56%. Rf = (EtOAc : Hexanes 1:3):
0.23; IR (neat) v = 2939, 2838, 1606, 1518, 1260, 1222,
1
1183, 1110 cm-1; H NMR (500 MHz, CDCl3) δ 6.96 (d, J =
8.1 Hz, 1H), 6.96 (br s, 1H), 6.85 (d, J = 8.3 Hz, 1H), 5.66
(ddt, J = 17.1, 10.2, 6.8 Hz, 1H), 5.13 (dd, J = 17.1, 1.3 Hz,
1H), 5.05 (d, J = 10.2 Hz, 1H), 4.99 (dd, J = 9.8, 5.6 Hz, 1H),
4.32 (br s, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.39 (br s, 3H),
3.27 (s, 3H), 3.23 (d, J = 15.8 Hz, 1H), 3.13 (dd, J = 12.5, 5.4
Hz, 1H), 3.04 (ddd, J = 15.3, 9.4, 6.2 Hz, 1H), 2.77 (br s, 1H);
13C{1H} NMR (126 MHz, CDCl3) δ 149.4, 149.2, 134.00,
121.5, 118.3, 112.7, 110.9, 104.2, 63.8, 56.0, 55.9, 55.7,
54.9, 47.6; 19F NMR (470 MHz, CDCl3) mixture of rotamers:
δ -74.1 & -75.7 (s, 3F); HRMS (ESI-TOF): Calcd. for
C17H24F3NO6SNa [M+Na]+ = 450.1169 m/z, found =
450.1154 m/z.
1
1; H NMR (500 MHz, CDCl3) δ 7.40 (d, J = 7.5 Hz, 2H), 7.29
(t, J = 7.5 Hz, 2H), 7.20 (t, J = 7.3 Hz, 1H), 6.99 – 6.91 (m,
2H), 6.80 (d, J = 8.1 Hz, 1H), 4.78 (s, 1H), 4.53 (t, J = 5.4 Hz,
1H), 3.84 (d, J = 10.4 Hz, 6H), 3.35 (s, 6H), 2.72 (d, J = 5.5
Hz, 2H), 1.78 (br s, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ
149.0, 148.0, 144.1, 136.6, 128.5, 127.2, 127.0, 119.4,
111.1, 110.3, 103.8, 67.0, 55.9, 55.9, 53.8, 53.7, 49.4; HRMS
(ESI-TOF): Calcd. for C19H26NO4 [M+H]+ = 332.1856 m/z,
found = 332.1857 m/z.
N-(2,2-dimethoxyethyl)-N-(1-(3,4-dimethoxyphenyl)-4-
N-(2,2-dimethoxyethyl)-N-((3,4-
dimethoxyphenyl)(phenyl)methyl)-1,1,1-
hydroxybutyl)-1,1,1-trifluoromethanesulfonamide (1o). A
flame-dried, 100 mL round bottom flask equipped with a
Teflon-coated stir bar and a rubber septum was charged
with 1n (2.14 g, 5.0 mmol) and purged with N2 for 5 min,
and dissolved in dry and degassed THF (10 mL, 0.5 M).
Borane (2.5 mL, 2.5 mmol, 1 M in THF) was added
dropwise via the syringe. The resulting solution was
stirred at RT for 4 h, prior to the addition of H2O2 (2 mL,
20.0 mmol) and NaOH (10 mL, 1M aq.) and stirred for
another 1 h. The solution was then extracted with EtOAc (3
 50 mL). The combined organic fractions were then dried
over MgSO4, filtered and concentrated in vacuo. The crude
product was then purified on silica gel using hexanes/ethyl
acetate (1:1) as eluent to afford 1o (1.21 g, 77%) as a
colorless oil. Rf = (EtOAc : Hexanes 1:1): 0.14; IR (neat) v =
3511, 2941, 2839, 1737, 1518, 1379, 1221, 1184, 1108 cm-
trifluoromethanesulfonamide (1m). The general procedure
for the N-triflation was followed. Pale-yellow oil, 700.1 mg,
yield = 30%. Rf = (EtOAc : Hexanes 1:5): 0.17; IR (neat) v =
2938, 2837, 1594, 1515, 1418, 1222, 1182, 1140 cm-1; H
1
NMR (500 MHz, CDCl3) δ 7.40 – 7.31 (m, 3H), 7.29 (d, J =
7.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H),
6.81 (s, 1H), 6.34 (s, 1H), 3.93 (br s, 1H), 3.88 (s, 3H), 3.80
(s, 3H), 3.44 (d, J = 5.0 Hz, 2H), 3.16 (s, 3H), 3.13 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 149.2, 149.0, 138.1, 128.5,
128.2, 122.3, 120.1 (q, J = 324.5 Hz), 112.9, 110.9, 102.4,
67.5, 56.0, 55.9, 54.2, 54.0, 48.3; 19F NMR (470 MHz, CDCl3)
δ -74.0 (s, 3F); HRMS (ESI-TOF): Calcd. for C20H24F3NO6SNa
[M+Na]+ = 486.1169 m/z, found = 486.1157 m/z.
N-(2,2-dimethoxyethyl)-1-(3,4-dimethoxyphenyl)but-3-en-
1-amine. A flame-dried, 100 mL round bottom flask
equipped with a Teflon-coated stir bar and a rubber
1
1; H NMR (500 MHz, CDCl3) δ 6.96 (d, J = 8.1 Hz, 1H), 6.96
(br s, 1 H), 6.85 (d, J = 8.3 Hz, 1H), 4.95 (dd, J = 9.4, 6.1 Hz,
1H), 4.32 (br s, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.67 (t, J = 5.4
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Hz, 2H), 3.37 (br s, 3H), 3.28 (s, 3H), 3.22 (d, J = 15.2 Hz, Supporting Information
Page 12 of 14
1
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5
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7
1H), 3.13 (dd, J = 15.1, 6.2 Hz, 1H), 2.38 – 2.28 (m, 1H), 2.09
(br s, 1H), 1.61 – 1.51 (m, 2H), 1.46 (br s, 1H); 13C{1H} NMR
(126 MHz, CDCl3) δ 149.5, 149.3, 121.4, 112.6, 111.0,
104.1, 63.9, 62.3, 56.02, 55.96, 55.7, 54.8, 47.4, 29.8; 19F
NMR (470 MHz, CDCl3) mixture of rotamers: δ -74.0 & -75.7
(s, 3F); HRMS (ESI-TOF): Calcd. for C17H26F3NO7SNa
[M+Na]+ = 468.1274 m/z, found = 468.1257 m/z.
The Supporting Information is available free of charge on the
ACS Publications website.
Optimization tables and copies of 1H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
8
9
N-(2,2-dimethoxyethyl)-N-(1-(3,4-dimethoxyphenyl)-4-
Corresponding Author
iodobutyl)-1,1,1-trifluoromethanesulfonamide
(1p).
A
* jean-philip.lumb@mcgill.ca
flame-dried, 100 mL round bottom flask equipped with a
Teflon-coated stir bar and a rubber septum was charged
with 1o (1.34 g, 3.0 mmol) in dry CH2Cl2 (15 mL, 0.2 M). I2
(913.7 mg, 3.6 mmol), imidazole (306.4 mg, 4.5 mmol) and
triphenylphosphine (944.2 mg, 3.6 mmol) was added. The
resulting mixture was stirred at rt for 12 h. Hexanes (15
mL) was added to the mixture to allow the precipitation of
the triphenylphosphine oxide byproduct. The mixture was
then filtered, and the filtrate was concentrated in vacuo.
The crude product was then purified on silica gel using
hexanes/ethyl acetate (3:1) as eluent to afford 1p (1.60 g,
96%) as a white solid. Rf = (EtOAc : Hexanes 1:3): 0.38; IR
(neat) v = 2938, 2837, 1606, 1517, 1421, 1383, 1221, 1127
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60
Present Addresses
†Department of Chemistry, New York University, Silver Center
for Arts and Science, 100 Washington Square East, New York,
NY 10003, United States
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support was provided by the Natural Sciences and
Engineering Council (NSERC) of Canada (Discovery Grant to J.-
P. L.); the Fonds de Recherche Quebecois Nature et
Technologies (FRQNT) (Team Grant to J.-P. L.); McGill
University Faculty of Science (Milton Leong Fellowship in
Science to Z. H.) the FRQNT Center for Green Chemistry and
Catalysis (Fellowship to X. J.).
1
cm-1; H NMR (500 MHz, CDCl3) δ 6.95 (d, J = 8.6 Hz, 1H),
6.94 (s, 1H), 6.87 (d, J = 8.6 Hz, 1H), 4.93 (dd, J = 9.9, 5.6 Hz,
1H), 4.36 (br s, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.44 (br s,
3H), 3.31 (s, 3H), 3.29 – 3.02 (m, 4H), 2.48 (br d, J = 9.5 Hz,
1H), 2.06 (br s, 1H), 1.88 – 1.63 (m, 2H); 13C{1H} NMR (126
MHz, CDCl3) δ 149.6, 149.3, 121.6, 112.5, 111.1, 104.6,
63.5, 56.0, 55.0, 47.4, 30.4; 19F NMR (470 MHz, CDCl3)
mixture of rotamers: δ -74.0 & -75.8 (s, 3F); HRMS (ESI-
TOF): Calcd. for C17H25F3NIO6SNa [M+Na]+ = 578.0292 m/z,
found = 578.0304 m/z.
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2842, 1737, 1593, 1421, 1259, 1222, 1155, 1126 cm-1; H
NMR (500 MHz, CDCl3) δ 6.98 (s, 1H), 6.87 (d, J = 8.2 Hz,
1H), 6.81 (d, J = 8.2 Hz, 1H), 4.96 – 4.06 (m, 3H), 3.89 (s,
3H), 3.87 (s, 3H), 3.22 (br s, 6H), 1.21 (br s, 3H); 13C{1H}
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