A regioselective double Stille coupling reaction of bicyclic stannolanes

Article abstract of DOI:10.1039/c6ob01018k

A regioselective double Stille coupling reaction was explored using bicyclic stannolanes that were easily prepared from the radical cascade reaction of β-amino-α-methylene esters. Various 1-bromo-2-iodoarenes underwent the double coupling reaction to affo

Full text of DOI:10.1039/c6ob01018k

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10.1039/C6OB01018K.
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DOI: 10.1039/C6OB01018K
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Regioselective Double Stille Coupling Reaction of Bicyclic
Stannolanes
Received 00th January 20xx,
Accepted 00th January 20xx
Akio Kamimura,* Toshiyuki Tanaka, Masahiro So, Tomoyuki Itaya, Kantaro Matsuda and Takuji
Kawamoto
DOI: 10.1039/x0xx00000x
A regioselective double Stille coupling reaction was explored using bicyclic stannolanes that were easily prepared from the
radical cascade reaction of β-amino-α-methylene esters. Various 1-bromo-2-iodoarenes underwent the double coupling
reaction to aford benzoisoindole derivatives in a regioselective manner, where the carbon attached to the iodine
selectively coupled with the vinylic carbon, and then the carbon attached to bromine coupled with the alkyl carbon. The
combination of intra- and intermolecular coupling reactions provided hexahydroindeno[1,2-b]pyrrole derivatives in good
yields. The yields were further improved in the presence of excess amounts of CsF. An attempt to identify the reaction
intermediate was performed wherein the decomposition of the stannolanes with aqueous HCl and HBr afforded trigonal
bipyramidal (TBP) pentacoordinated tin complexes, as confirmed by microanalyses and 119Sn NMR. Using DCl for the
decomposition selectively introduced a deuterium to the E-position of the exomethylene unit. The complexes smoothly
underwent the intramolecular Stille coupling reaction in the presence of both a palladium catalyst and DABCO, affording
hexahydroindeno[1,2-b]pyrroles in good yields. These results suggest that the double coupling reaction progresses
through a TBP tin complex, promoting the second intramolecular coupling reaction between the aryl halide and Csp3-tin
bond.
www.rsc.org/
stannolane through a highly cumulated cascade radical
reaction wherein a radical addition-cyclization-substitution
occurred in one pot.8 This process prompted us to sequentially
Introduction
Palladium-catalysed coupling is a key reaction in organic
synthesis.1 Organotin compounds are frequently used as a
coupling partner in the Migita-Kosugi-Stille coupling
reaction.2,3 Vinylic and aromatic groups on tin compounds are
frequently employed as a coupling partner, whereas alkyl
groups on tin compounds are usually inert and rarely used in
the reaction unless an activating unit is present on the tin
compound.4 When two or more carbon-tin bonds exist in one
organotin compound, these compounds may be used in a one-
pot multicoupling reaction, which is recognized as a useful
domino method in organic synthesis.5 For example, this is a
useful strategy for preparing polycyclic aromatic hydrocarbons
(PAHs), which are the compounds of interest in the
development of organoelectronic devices.6 However, this
double coupling strategy is limited to the coupling between
Csp2-Csp2 type species, and there are only rare reports on the
double coupling between Csp2-Csp3 species.7 Thus, the
quantitative difference between the reactivities of the sp2
carbon-tin bond and the ordinary sp3 carbon-tin bond in this
double coupling reaction remains unclear.
develop a new type of double coupling reaction.9 In this study,
we report the details of a regioselective double coupling
reaction of stannolanes. We also explored substrate scope for
aryl halides and pseudohalides. With our methodology,
multicyclic benzoisoindoles10 and hexahydroindeno[1,2-
b]pyrroles11 are readily prepared in a few steps from simple
compounds. These structures are known to feature in
biologically active compounds.12,13 The identity of the
intermediate in the double coupling reaction was explored
through acidic hydrolysis of the stannolanes to afford
pentacoordinated trigonal bipyramidal (TBP) tin complexes.
Results and discussion
Double Stille coupling reaction with various 1,2-substituted
benzenes.
We first examined various 1,2-disubstituted benzenes for the
double coupling reaction with stannolane 1a. The results are
summarized in Table 1.
Recently, we developed a one-step synthesis of a bicyclic
The use of dichlorobenzene did not give any double coupling
products 2a (entry 1).14 Ditriflate underwent a slow and
sluggish reaction to give 2a in only 18% yield. The yield of 2a
was improved to 21% when CuI was used as an additive (entry
3).15 Dibromobenzene gave the coupling product 2a in 76%
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yield (entry 4) and iodobromobenzene also afforded 2a in 44%
yield (entry 5). Diiodobenzene underwent a smooth double
coupling reaction to give 2a in 79% yield (entry 6). The addition
of CsF was necessary to obtain 2a in good yield. Thus,
iodoarenes and bromoarenes are the best candidates for the
double coupling reaction.
View OArtHicle Online
Bu Bu
Sn
DOI: 10.1039/C6OB01018K
Me
p-Tol
Ph
OH
Pd(t-Bu3P)2
10 mol%
+
N Ts
p-Tol
dioxane, 100 ºC
DABCO (3 equiv)
20 h
Ph
N
3; 0%
I
Ts
(2 equiv.)
1a
Me
Table 1. Double coupling reaction of 1a with various 1,2-disubstituted benzene
Bu Bu
Sn
Me
Bu Bu
Sn
HO
Ph
OH
Br
OH
Pd(t-Bu3P)2
10 mol%
X
Y
+
OH
Pd(t-Bu3P)2
10 mol%
dioxane
+
N Ts
dioxane, 100 ºC
DABCO
N
I
Ph
N
(1 equiv.)
CsF (3 equiv)
20 h
Ts
N
conditions
(1 equiv.)
Ts
2a
1a
Ts
1b
4a
32% (DABCO 3 equiv)
80% (DABCO 0.2 equiv)
Entry
X
Y
Additivesa
Time
(h)
Tem
p
(°C)
100
100
80
100
100
100
2a;
Yield
(%)b
0
18
21
76
44
79
Scheme 1 Inter- and intramolecular double coupling reaction
1
2
3
4
5
6
Cl
OTf
OTf
Br
Br
I
Cl
OTf
OTf
Br
I
DABCO (3)
20
24
24
20
24
24
Intermolecular and inter- and intramolecular regioselective
double coupling reaction
DABCO (3), LiCl (2.3)
DABCO (3), CuI (2)
DABCO (3)
DABCO (3), CsF (5)
DABCO (0.2), CsF (3)
We next examined various iodobromobenzenes for the
coupling reaction with stannolane 1. The results are
summarized in Table 2.
I
a. equivalents in parentheses. b. isolated yield.
Table 2. Regioselective double coupling reaction of 1 with iodobenzenes
To investigate the reactivity of the sp2 and sp3 carbon-tin
bonds, we attempted to introduce two different aromatic
groups to 1a using two equivalents of iodobenzene (Scheme 1).
However, we could not obtain 3 under these conditions. This is
in contrast to the result that the double coupling product 4a
was obtained in 32% yield when 1b was used as the coupling
partner. These results clearly indicate that the sp3 carbon-tin
bond is less reactive and produces no coupling product with
any intermolecular coupling partner. The yield of 4a was
improved to 80% when three equivalents of CsF were used in
the reaction. With this improvement, the amount of DABCO
might be reduced to 20mol%. Thus, the presence of the
fluoride anion is effective in promoting the intramolecular
coupling reaction with the sp2-tin bond as well as the sp3-tin
bond.16
R1
R2
Bu Bu
Sn
Pd(t-Bu3P)2
(10mol%)
DABCO (3 equiv)
CsF (5 equiv)
R2
R1
Br
I
OH
+
OH
Ar
Ar
N
(1 equiv.)
dioxane, reflux,
24 h
N
1
Ts
2
Ts
Entry
1
Ar
R1
R2
2; Yield
Regiois
(%)a
omeric
ratiob
94/6
95/5
95/5
>99/1
>99/1
94/6
83/17
96/4
90/10
95/5
84/16
98/2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1a
1a
1a
1a
1a
1a
1a
1a
1c
1d
1c
1c
1c
1d
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Cl
H
H
Cl
H
2b; 68
2c; 38
2d; 53
2e; 44
2f; 51
2g; 63
2h; 38
2i; 58
2j; 54
2k; 50
2l; 55
2m; 19
2n; 28
2o; 35
2p; 26
Me
MeO
H
NO2
H
H
OMe
H
NO2
H
CF3
H
NO2
CF3
H
CF3
H
Me
H
H
Cl
2-MeC6H4
3-MeOC6H4
2-MeC6H4
2-MeC6H4
2-MeC6H4
3-MeOC6H4
87/13
94/6
80/20
H
H
F
Cl
a. Isolated yield. b. Determined by integration of 1H NMR spectra
The double coupling reaction progressed smoothly and
products 2 were isolated in moderate to good yields. For
example, 1-bromo-4-chloro-2-iodobenzene underwent the
2 | J. Name., 2012, 00, 1-3
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Entry
1
X
H
H
H
H
OMe
OMe
OMe
OMe
OMe
Ar
4; Yield (%)a
double coupling reaction to give 2b in 68% yield (entry 1),
whereas the double coupling of 1a with 2-bromo-4-chloro-1-
iodobenzene afforded its regioisomer 2c in 38% yield (entry 2).
View Article Online
DOI: 10.1039/C6OB01018K
1
2
3
4
5
6
7
8
9
1b
1b
1b
1b
1e
1e
1e
1e
1e
4-MeOC6H4
3-MeOC6H4
2-Me-4,5-(MeO)2C6H2
4-O2NC6H4
4b; 68
4c; 83
4d; 74
4e; 0
4f; 56
4g; 75
4h; 74
4i; 74
4j; 74
1
The regioselectivity was estimated by H NMR integration to
be 94/6 in the formation of 2b and 95/5 in the formation of 2c.
Other double couplings with various substituted
iodobromobenzenes provided the regioselective formation of
benzoisoindole 2. The selectivity ranged from 83/17 to 99/1
and nearly complete regioselective double coupling was
achieved. The major and minor isomers formed in the reaction
shown in entry 7, 2h and 2g, were inseparable by usual
chromatographic methods. The regioselectivity was
determined by the first coupling between haloarenes and sp2-
carbon-tin bond site. We expected that the aryl-iodine bond
reacted faster than the aryl-bromine bond. When the
substituent of the dihaloarene is located at the m-position to
the aryl-iodine bond site, high regioselectivity (>95/5) was
achieved (entries 1, 3, 4, 6, 8, and 10). conversely, a
substituent at the p-position to the aryl-iodine bond affected
the selectivity very much. For example, the presence of an
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-Me-4,5-(MeO)2C6H2
Ph
a. Isolated yield.
The inter- and intramolecular double coupling reaction
progressed smoothly in the presence of iodobenzene and 10
mol% of Pd(PtBu3)2, affording hexahydroindeno[1,2-b]pyrroles
4
in good yields. For example, 4-methoxyiodobenzene
underwent the coupling reaction at the vinylic carbon-tin bond
site, giving double coupling product 4b in 68% yield (entry 1).
Various substituted iodobenzenes smoothly reacted to give
compound 4, except for 4-nitroiodobenzene, which gave a
complex mixture (entry 4). Note that all aryl groups derived
from iodobenzene were selectively introduced to the E-
position of the alkylidene group. Thus, the intermolecular
coupling progressed selectively with the retention of the
vinylic tin unit configuration. Dimethoxy-substituted
stannolane 1e also acted as a good double coupling donor to
afford compound 4 in good yield (entries 5 - 9).
electron-withdrawing group such as
a
nitro or
a
trifluoromethyl group at the para position to the carbon-iodine
bond caused the regioselectivity to slight decrease to 90/10 or
83/17 (entries 7, 9 and 11), whereas an electron-donating
substituent at this position maintained high regioselectivity
(entry 5). Thus, the regioselectivity is partially affected by the
electronic effect of the substituents on the dihaloarenes.
The number of synthetic methods to prepare the multi-
substituted benzoisoindole 2 was limited because it is usually
difficult to control the position of substituents during the
synthesis of such heterocyclic compounds. However, in the
present synthesis, the starting materials 1 were prepared in
optically pure form from simple Michael/Mannich reactions
followed by a radical cascade reaction. Thus, this methodology
provides a new convenient preparation of benzoisoindoles in a
few steps in a highly regioselective manner.
I
Bu Bu
Sn
OH
(1 equiv.)
OH
Pd(t-Bu3P)2 10 mol%
DABCO 20 mol %
CsF 3 equiv
N
N
4k; 59 %
Ts
1f
dioxane, reflux 24 h
Ts
Br
OH
The inter- and intramolecular double coupling reaction of 1b
and 1e was examined using various iodobenzenes. The results
are summarized in Table 3.
N
Table 3. Inter- and intramolecular double coupling reaction of 1b and 1e
4l
Ts
Not observed
Bu Bu
Sn
Ar
OH
S
cheme 2 Double coupling reaction of 1f
OH
Br
Pd(t-Bu3P)2
10 mol%
dioxane, 100 ºC
DABCO (0.2 equiv)
CsF (3 equiv)
24 h
+
Ar-I
(1 equiv.)
X
We explored this strategy for the synthesis of tetrasubstituted
alkenes from 1f; however, we only obtained compound 4k in
59% yield, and not the desired compound 4l that was expected.
This is probably because of the steric hindrance caused by the
methyl group at the vinylic position, which prevents the Stille
coupling reaction with iodotoluene (Scheme 2).
N
N
X
Ts
Ts
X
1b; X = H
1e; X = OMe
4
X
Attempt to identify the reaction intermediate
We performed several experiments to identify the reaction
intermediate. As we previously reported,9 compound 1b gave
exomethylene hexahydroindeno[1,2-b]pyrrole 5 when treated
in the absence of aryl halide (Scheme 3). Thus, the vinylic tin
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unit was replaced by hydrogen during the reaction. To identify
the origin of the hydrogen, we performed the reaction with
dry dioxane containing small amounts of D2O (20:1). As
expected, compound 5-D instead of 5 was isolated in 76% yield.
Note that the deuterium atom was selectively installed at the
E-position of the exomethylene unit with 93/7 selectivity. The
D position in the alkene unit of 5D was determined by NOE
experiments wherein 6% and 7% NOE enhancements were
observed when the TsN-CH2 protons at δ = 5.01 and CH2OH
protons at δ = 5.96 were irradiated, respectively. We
concluded that the water in dioxane is the origin of the
hydrogen atom introduced in the substitution reaction to the
vinyl tin unit. Note that the yield of 5-D was greatly improved
to 95% without any change in the E/Z selectivity or D content
when the reaction was performed in the presence of DCl.
Bu
View Article Online
DOI: 10.1039/C6OB01018K
Cl
Bu Bu
Sn
Sn Bu
O
Pd(t-Bu3P)2
Ot-Bu 10mol%
CO2tBu
conc HCl
CsF (5 equiv.)
dioxane
reflux 25 h
N
N
Ts
Ts
Br
Br
6a; 72%
OH
1g
CO2t-Bu
DIBAl-H
CH2Cl2
N
N
Ts
Ts
7; 87%
5; 99%
Scheme 4 Intramolecular coupling reaction through TBP complex of 1g
The acidic treatment of 1b also yielded the corresponding TBP
complex 6b in 91% yield (Scheme 5). This is supported by the
fact that the signal for the OH proton in 6b was observed in
Bu Bu
D
OH
Sn
OH
Br
Pd(t-Bu3P)2 (10mol%)
DABCO (3equiv)
1
the H NMR at δ 2.84 (dd, J = 7.9, 3.8 Hz). Microanalysis data
indicated that a chlorine atom is contained in 6b. Compound
6b afforded intramolecular coupling product 5 in 62% yield by
treatment with the catalytic amounts of Pd(tBu3P)3 in the
presence of DABCO. We believe that the coordination of an
oxygen atom to the tin atom to promoted the coupling
reaction of the alkyl tin unit; however, some basic additive,
such as CsF, is necessary to achieve an efficient reaction.9
N
dioxane-D2O (20:1),
reflux, 20hr
N
Ts
Ts
1b
5-D
76 % (E/Z = 97/3)
w/DCl; 95 % (E/Z = 95/5)
7%
δ 5.01
H
H
OH
H
δ 4.96
H
H
6%
H
H
Bu
Cl
Bu Bu
Sn
N
OH
Sn Bu
Pd(t-Bu3P)2
10mol%
DABCO
3equiv
dioxane
reflux
Ts
OH
Br
O H
HCl
Et2O
Scheme 3 Introduction of deuterium and elucidation of stereochemistry of 5
N
N
N
We then attempted to identify the reaction intermediate of
the double coupling reaction. Exposure of stannolane 1g to
concentrated HCl resulted in the formation of
Ts
5; 62%
Ts
Ts
Br
6b; 91%
1b
a
pentacoordinated trigonal bipyramidal (TBP) tin complex 6a in
72% yield (Scheme 4).8a,17 We exposed the TBP complex 6a to
the standard reaction coupling conditions in the presence of
five equivalents of CsF, affording intermolecular coupling
product 7 in 87% yield. To confirm the structure of 7, reduction
was performed in the presence of DIBAL-H to give compound 5
in almost quantitative yield. Note that the intramolecular
coupling progressed only when CsF was employed in the
reaction.
Scheme 5 Intramolecular coupling reaction through TBP complex of 1b
To obtain further information on the TBP complex, we
performed simple acidic decomposition of 1a and analysed the
products using NMR and microanalytical studies (Scheme 6).
Treatment of 1a with HCl and HBr gave the corresponding
products 6c and 6d, respectively, in good yields. There are
several observations that should be noted for these
compounds. Again, the an OH proton signal was observed in
1
the H NMR spectra for these compounds. Microanalyses of
these compounds indicated that compounds 6c and 6d
included a halogen atom. Furthermore, the 119Sn NMR signals
of 6c and 6d in CDCl3 appeared at 33.3 and 28.8 ppm,
respectively, which are highly up-field shifted compared with
those of trialkychlorotin compounds, such as Bu3SnCl (152.8
ppm in CDCl3),18 but close to the chemical shift of TBP tin
complex 6e, which shows a 119Sn NMR peak at 25.4 ppm.8a
These results clearly suggested that the hydroxyl groups in
compounds 6c and 6d coordinate to the tin atom to form a
pentacoordinated tin complex, such as 6e. Unfortunately we
have not obtained any crystalline form of compounds 6b to 6d
4 | J. Name., 2012, 00, 1-3
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to date, and no further evidence for the complex is available.
Note that the bromine atom in compound 6d was replaced by
a chlorine or a fluorine atom by treatment with aqueous NaCl
or CsF solution. For example, compound 6f was obtained in
85% yield by the simple stirring of a biphasic mixture of 6d in
ether and aqueous CsF. We examined the intermolecular Stille
coupling reaction of compound 6f with an excess of
bromobenzene (10 equiv.). However, a complex mixture was
obtained, and no expected products were observed.
Conclusions
View Article Online
We have successfully developed a regioDseOlIe: c10ti.v10e39d/oCu6bOlBe01S0t1il8leK
coupling reaction with stannolanes. 1,2-Bromoiodoarene
served as a good partner for the double coupling reaction.
When a bromoarene was installed in a suitable position on the
stannolanes, an inter- and intramolecular double coupling
reaction smoothly occurred. Since the stannolanes are readily
obtained in good yields from simple aza-1,6-enynes, this
methodology provides a facile preparation of heterocyclic
compounds
hexahydroindeno[1,2-b]pyrroles.
such
as
benzoisoindoles
and
Bu
Bu
119Sn NMR
Cl
Cl
Bu
Sn
Sn Bu
δ = 25.4 ppm
O
O H
HCl aq
Ot-Bu
Et2O, r.t
Bu Bu
Sn
Experimental
N
N
1
General: All H and 13C NMR spectra were recorded on JEOL
OH
Ts
Ts
1
lamda-500 or JNM-ECA 500 Delta2 (500 MHz for H and 126
6e (ref. 8a)
6c; 95%
MHz for 13C) spectrometer. Palladium complexes were
purchased from Aldrich. Stannolanes 1 were prepared by the
previous reported method.8a All the reactions in this paper
were performed under nitrogen atmosphere unless otherwise
mentioned. High resolution mass spectra (HRMS) were
measured by JEOL JMS T-100LP LC-ESI mass spectrometer.
Preparation of ((3S,3aR)-3a-hydroxymethyl-3-phenyl-2-tosyl-
2,3,3a,4-tetrahydro-1H-benzo[f]isoindole (2a, Table 1, entry
4): Under nitrogen atmosphere, Pd(t-Bu3P)2 (0.015 g, 0.030
mmol), DABCO (0.096 g, 0.86 mmol) and 1,2-dibromobenzene
(0.067 g, 0.28 mmol) were added to a solution of 1a (0.168 g,
0.286 mmol) in 1,4-dioxane (2.0 mL) and the reaction mixture
was heated to refluxing temperature for 20 h. The solution
was filtered, and concentrated in vacuo. The residue was
subjected to flash column chromatography (silica gel/hexane-
EtOAc 5:1 then 3:1) to give 2a in 76% yield as viscose oil (0.094
g, 0.22 mmol).
N
Bu
Bu
Sn Bu
O H
Br
F
Ts
Sn Bu
O H
1a
CsF aq
2 h
HBr aq
Et2O, r.t
N
N
Ts
Ts
6d; 90%
6f; 85%
Scheme 6 Conversion to TBP complexes of 1a.
Considering these results, we suggest that the reaction
mechanism is as follows (Scheme 7); The aryliodide reacts with
the vinylic carbon-tin bond to afford arylalkene intermediate A,
a TBP complex in which the hydroxy group coordinates to a tin
atom.16 The aryl group is selectively introduced at the E-
position of the exomethylene unit. This intermediate is
sufficiently reactive toward intramolecular reaction by
activation in the presence of CsF or DABCO to give the double
coupling adduct 2 from bromoiodoarenes or 4 from o-
bromoaryl-substituted precursor 1. Conversely, in the
intermolecular reaction, intermediate A is less reactive and
does not give any intermolecular adduct.
[α]D +33.6 (c 1.83, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.52 (d,
J = 8.3 Hz, 2 H), 7.18 (d, J = 4.2 Hz, 3 H), 7.14 (d, J = 8.1 Hz, 2 H),
7.07 (t, J = 7.4 Hz, 1 H), 7.11 – 6.98 (m, 2 H), 7.01 (t, J = 7.5 Hz,
1 H), 6.95 (d, J = 6.4 Hz, 1 H), 6.94 (d, J = 6.1 Hz, 1 H), 6.43 (s, 1
H), 5.29 (s, 1 H), 4.42 (dd, J = 15.1, 2.3 Hz, 1 H), 4.33 (dd, J =
15.1, 1.3 Hz, 1 H), 3.4 – 3.6 (br, 1H), 3.26 (d, J = 10.7 Hz, 1 H),
3.10 (d, J = 10.7 Hz, 1 H), 2.58 (d, J = 16.1 Hz, 1 H), 2.35 (s, 3 H),
2.08 (d, J = 16.0 Hz, 1 H); 13C NMR (126 MHz, CDCl3) δ 143.4,
139.9, 139.3, 135.7, 133.2, 132.3, 129.5 (2C), 128.8, 128.5 (2C),
127.5, 127.4, 127.3 (2C), 126.8 (2C), 126.22, 126.21, 122.3,
69.1, 62.0, 53.0, 51.1, 31.8, 21.6; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C26H25NNaO3S 454.1453, found 454.1447.
Preparation of (3S,3aR)-7-chloro-3a-hydroxymethyl-3-phenyl-
2-tosyl-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole (2b): Under
nitrogen atmosphere, Pd(t-Bu3P)2 (0.0114 g, 0.0223 mmol),
DABCO (0.0750 g, 0.669 mmol), CsF (0.1018 g, 1.5 mmol), and
1-bromo-4-chloro-2-iodobenzene (0.0708 g, 0.223 mmol) were
added to a solution of 1a (0.1306 g, 0.222 mmol) in 1,4-
dioxane (2.2 mL) and the reaction mixture was heated to
refluxing temperature for 20 h. The solution was filtered, and
concentrated in vacuo. The residue was subjected to flash
column chromatography (silica gel/hexane-EtOAc 5:1 then 3:1)
R'
Ar = 2-Br-Ar
Bu
Cl
Ar
OH
Bu Bu
Bu
Sn
Sn
OH
OH
Ar-I
R
N
Ts
2
Pd(0)
R
R
N
Ts
N
Ts
Ar
OH
TBP complex
A
N
Ts
R = 2-Br-C6H4
4
Scheme 7 Plausible reaction mechanism.
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to give 2b in 68% yield as pale yellow viscose oil (0.0708 g, 130.0, 129.4 (2C), 128.6, 128.4 (2C), 128.1, 128.0-127.4 (br, 2C),
View Article Online
DOI: 10.1039/C6OB01018K
0.152 mmol).
127.4, 127.3 (2C), 127.1, 122.4, 69.1, 62.1, 53.1, 50.9, 31.4,
[α]D +47.2 (c 1.79, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.51 (d, 21.6, 21.0; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
J = 8.3 Hz, 2H), 7.22 – 7.17 (m, 3H), 7.15 (d, J = 7.9 Hz, 2H), 7.09 C27H27NNaO3S 468.1609, found 468.1600.
– 7.00 (m, 2H), 6.98 (dd, J = 8.0, 2.2 Hz, 1H), 6.94 (d, J = 2.1 Hz, Preparation of (3S,3aR)-3a-hydroxymethyl-7-methoxy-3-
1H), 6.86 (d, J = 8.2 Hz, 1H), 6.37 (d, J = 2.0 Hz, 1H), 5.25 (s, 1H), phenyl-2-tosyl-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole (2e):
4.42 (dd, J = 15.3, 2.4 Hz, 1H), 4.33 (dd, J = 15.3, 1.7 Hz, 1H), Under nitrogen atmosphere, Pd(t-Bu3P)2 (0.0169 g, 0.0330
3.23 (dd, J = 10.6, 4.7 Hz, 1H), 3.08 (ddd, J = 10.6, 5.9, 1.5 Hz, mmol), DABCO (0.0074 g, 0.066 mmol), CsF (0.1544 g, 1.016
1H), 2.53 (d, J = 16.1 Hz, 1H), 2.36 (s, 3H), 1.99 (dd, J = 15.9, 1.5 mmol), and 1-bromo-2-iodo-4-methoxybenzene (0.0983 g,
Hz, 1H), 1.70 – 1.64 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 143.4, 0.314 mmol) were added to a solution of 1a (0.1849 g, 0.314
141.1, 139.6, 135.6, 133.9, 132.2, 131.5, 129.9, 129.5 (2C), mmol) in 1,4-dioxane (5 mL) and the reaction mixture was
128.5 (2C), 128.1-127.4 (br, 2C), 127.6, 127.3 (2C), 127.2, 126.0, heated to refluxing temperature for 24 h. The solution was
121.3, 69.0, 61.9, 53.1, 50.9, 31.2, 21.6; HRMS (ESI-TOF) m/z filtered, and concentrated in vacuo. The residue was subjected
[M + Na]+ calcd for C26H24ClNNaO3S 488.1063, found 488.1055. to flash column chromatography (silica gel/hexane-EtOAc 5:1
Preparation of (3S,3aR)-6-chloro-3a-hydroxymethyl-3-phenyl- then 3:1) to give 2e in 44% yield as viscose oil (0.0638 g, 0.138
2-tosyl-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole (2c): Under mmol).
nitrogen atmosphere, Pd(t-Bu3P)2 (0.0114 g, 0.0223 mmol), [α]D -55.5 (c 1.62, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J
DABCO (0.0760 g, 0.678 mmol), CsF (0.1015 g, 0.668 mmol), = 8.2 Hz, 2H), 7.24 – 7.17 (m, 3H), 7.15 (d, J = 8.5 Hz, 2H), 7.12
and 2-bromo-4-chloro-1-iodobenzene (0.0716 g, 0.226 mmol) – 7.01 (m, 2H), 6.85 (dd, J = 8.3, 1.0 Hz, 1H), 6.57 (dd, J = 8.2,
were added to a solution of 1a (0.1319 g, 0.224 mmol) in 1,4- 2.7 Hz, 1H), 6.53 (d, J = 2.7 Hz, 1H), 6.39 (t, J = 2.1 Hz, 1H), 5.24
dioxane (2.2 mL) and the reaction mixture was heated to (s, 1H), 4.40 (dd, J = 15.2, 2.4 Hz, 1H), 4.33 (dd, J = 15.1, 1.7 Hz,
refluxing temperature for 20 h. The solution was filtered, and 1H), 3.72 (s, 3H), 3.26 (dd, J = 10.6, 4.4 Hz, 1H), 3.05 (dd, J =
concentrated in vacuo. The residue was subjected to flash 11.0, 6.8 Hz, 1H), 2.46 (d, J = 15.9 Hz, 1H), 2.36 (s, 3H), 1.99 (dt,
column chromatography (silica gel/hexane-EtOAc 5:1 then 3:1) J = 15.7, 1.4 Hz, 1H), 1.54 (dd, J = 6.0, 4.7 Hz, 1H); 13C NMR
to give 2c in 38% yield as pale yellow viscose oil (0.0708 g, (126 MHz, CDCl3) δ 158.5, 143.3, 140.1, 139.9, 135.7, 133.3,
0.085 mmol).
129.5 (2C), 129.4, 128.4 (2C), 127.7, 127.5, 127.3 (2C), 125.0
[α]D +6.6 (c 1.12, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J (2C), 122.3, 112.3, 112.2, 69.1, 62.1, 55.4, 53.3, 50.9, 30.9,
= 8.2 Hz, 2H), 7.24 – 7.18 (m, 3H), 7.16 (d, J = 7.7 Hz, 2H), 7.11 21.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C27H27NNaO4S
– 6.98 (m, 2H), 7.05 (dd, J = 8.1, 2.1 Hz, 2H), 6.94 (s, 1H), 6.88 484.1559, found 484.1562.
(d, J = 8.1 Hz, 1H), 6.41 (s, 1H), 5.25 (s, 1H), 4.41 (dd, J = 15.3, Preparation of (3S,3aR)-3a-hydroxymethyl-6-methoxy-3-
2.4 Hz, 1H), 4.34 (dd, J = 15.0, 1.2 Hz, 1H), 3.23 (dd, J = 10.6, phenyl-2-tosyl-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole (2f):
4.4 Hz, 1H), 3.07 (dd, J = 11.0, 5.3 Hz, 1H), 2.53 (d, J = 16.2 Hz, Under nitrogen atmosphere, Pd(t-Bu3P)2 (0.0104 g, 0.02 mmol),
1H), 2.37 (s, 3H), 2.04 (d, J = 16.9 Hz, 1H); 13C NMR (126 MHz, DABCO (0.0050 g, 0.04 mmol), CsF (0.1519 g, 1.0 mmol), and 2-
CDCl3) δ 143.4, 139.8, 139.6, 135.6, 135.1, 132.7, 130.8, 129.5 bromo-1-iodo-4-methoxybenzene (30 µL, 0.20 mmol) were
(2C), 128.9, 128.5 (2C), 128.0-127.4 (br, 2C), 127.6, 127.3 (2C), added to a solution of 1a (0.1195 g, 0.20 mmol) in 1,4-dioxane
127.2, 126.8, 121.4, 69.0, 61.9, 52.8, 50.9, 31.7, 21.6; HRMS (4.5 mL) and the reaction mixture was heated to refluxing
(ESI-TOF) m/z [M + H]+ calcd for C26H25ClNO3S 466.1244, found temperature for 24 h. The solution was filtered, and
466.1253.
concentrated in vacuo. The residue was subjected to flash
Preparation
of
(3S,3aR)-3a-hydroxymethyl-7-methyl-3- column chromatography (silica gel/hexane-EtOAc 10:1 then
phenyl-2-tosyl-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole (2d): 3:1) to give 2f in 63% yield as viscose oil (0.059 g, 0.13 mmol).
Under nitrogen atmosphere, Pd(t-Bu3P)2 (0.0182 g, 0.0356 [α]D -31.8 (c 0.02, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J
mmol), DABCO (0.0056 g, 0.052 mmol), CsF (0.1289 g, 0.849 = 8.2 Hz, 2H), 7.19 (d, J = 5.5 Hz, 3H), 7.15 (d, J = 8.0 Hz, 2H),
mmol), and 4-bromo-3-iodotoluene (0.0775 g, 0.261 mmol) 7.11 – 6.95 (m, 2H), 6.88 (d, J = 8.3 Hz, 1H), 6.60 (dd, J = 8.3,
were added to a solution of 1a (0.1540 g, 0.261 mmol) in 1,4- 2.6 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.38 (t, J = 2.2 Hz, 1H), 5.26
dioxane (4 mL) and the reaction mixture was heated to (s, 1H), 4.39 (dd, J = 15.0, 2.4 Hz, 1H), 4.32 (dd, J = 15.0, 1.6 Hz,
refluxing temperature for 24 h. The solution was filtered, and 1H), 3.69 (s, 3H), 3.26 (d, J = 10.6 Hz, 1H), 3.07 (d, J = 10.7 Hz,
concentrated in vacuo. The residue was subjected to flash 1H), 2.53 (d, J = 16.1 Hz, 1H), 2.36 (s, 3H), 2.09 – 2.02 (m, 1H),
column chromatography (silica gel/hexane-EtOAc 5:1 then 3:1) 1.87 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 159.0, 143.3, 140.0,
to give 2d in 53% yield as viscose oil (0.0619 g, 0.140 mmol).
136.3, 135.7, 135.0, 129.4 (2C), 128.5 (2C), 128.0-127.6 (br, 2C),
1
[α]D +12.0 (c 0.53, CHCl3); H NMR (500 MHz, CDCl3) δ 7.54 – 127.4, 127.3 (2C), 127.2, 125.4, 121.8, 115.0, 111.5, 69.1, 62.0,
7.45 (m, 2H), 7.23 – 7.17 (m, 3H), 7.17 – 7.13 (m, 2H), 7.10 – 55.3, 52.8, 50.9, 32.3, 21.6; HRMS (ESI-TOF) m/z [M + H]+ calcd
6.97 (m, 2H), 6.84 – 6.81 (m, 2H), 6.77 (d, J = 1.5 Hz, 1H), 6.39 for C27H28NO4S 462.1739, found 462.1728.
(t, J = 2.0 Hz, 1H), 5.24 (s, 1H), 4.40 (dd, J = 15.1, 2.4 Hz, 1H), Preparation of (3S,3aR)-3a-hydroxymethyl-7-nitro-3-phenyl-
4.32 (dd, J = 15.2, 1.6 Hz, 1H), 3.26 (dd, J = 10.7, 4.6 Hz, 1H), 2-tosyl-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole (2g): Under
3.07 (dd, J = 9.4, 5.2 Hz, 1H), 2.48 (d, J = 16.0 Hz, 1H), 2.36 (s, nitrogen atmosphere, Pd(t-Bu3P)2 (0.0115 g, 0.023 mmol),
3H), 2.23 (s, 3H), 2.09 – 1.95 (m, 1H), 1.54 (s, 1H); 13C NMR DABCO (0.0753 g, 0.671 mmol), CsF (0.1022 g, 0.673 mmol),
(126 MHz, CDCl3) δ 143.3, 139.9, 139.2, 136.3, 135.7, 132.1, and 1-bromo-2-iodo-4-nitrobenzene (0.0736 g, 0.224 mmol)
6 | J. Name., 2012, 00, 1-3
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were added to a solution of 1a (0.1315 g, 0.223 mmol) in 1,4- 5.29 (s, 1H), 4.46 (d, J = 15.4 Hz, 1H), 4.35 (d, J = V1ie5w.3ArtHiczle,O1nHlin)e,
dioxane (2.2 mL) and the reaction mixture was heated to 3.23 (d, J = 10.6 Hz, 1H), 3.15 (d, J = 10.D7OHI:z1,01.1H03)9,/2C.66O7B(0d10, 1J8=K
refluxing temperature for 20 h. The solution was filtered, and 16.3 Hz, 1H), 2.36 (s, 3H), 2.18 – 2.14 (br, 1H), 2.08 (d, J = 16.3
concentrated in vacuo. The residue was subjected to flash Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 143.5, 141.5, 139.5, 137.3,
column chromatography (silica gel/hexane-EtOAc 3:1 then 1:1) 135.6, 132.9, 129.5 (2C), 129.2 (d, J = 32.3 Hz), 129.0, 128.6
to give 2g in 51% yield as viscose oil (0.0545 g, 0.114 mmol).
(2C), 127.7, 128.0-127.5 (br, 2C) 127.3 (2C), 124.1 (q, J = 272.0
[α]D +56.4 (c 1.57, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.86 (dt, Hz), 124.1 (q, J = 3.8 Hz), 122.7 (q, J = 3.8 Hz), 121.4, 68.9, 62.0,
J = 8.4, 2.3 Hz, 1H), 7.80 (dd, J = 2.4, 1.3 Hz, 1H), 7.50 (d, J = 7.2 52.9, 50.9, 31.7, 21.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
Hz, 2H), 7.25 – 7.18 (m, 3H), 7.15 (d, J = 8.5 Hz, 2H), 7.09 (d, J = C27H24F3NNaO3S 522.132, found 522.1339.
8.0 Hz, 1H), 7.07 – 6.97 (m, 2H), 6.51 (t, J = 1.9 Hz, 1H), 5.30 (s, Preparation of (3S,3aR)-3a-hydroxymethyl-3-phenyl-2-tosyl-
1H), 4.47 (ddd, J = 15.9, 2.5, 1.0 Hz, 1H), 4.43 – 4.30 (m, 1H), 6-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole
3.21 (d, J = 10.6 Hz, 1H), 3.17 (d, J = 10.6 Hz, 1H), 2.75 (d, J = (2j): Under nitrogen atmosphere, Pd(t-Bu3P)2 (0.0112 g, 0.022
16.6 Hz, 1H), 2.36 (s, 3H), 2.09 (d, J = 17.7 Hz, 1H), 1.90 – 1.76 mmol), DABCO (0.0741 g, 0.661 mmol), CsF (0.0999 g, 0.658
(m, 1H); 13C NMR (126 MHz, CDCl3) δ 147.1, 143.6, 142.7, 141.1, mmol),
and
2-bromo-1-iodo-4-(trifluoromethyl)benzene
139.2, 135.5, 133.6, 129.5 (2C), 129.4, 128.7 (2C), 127.8, 127.7- (0.0769 g, 0.219 mmol) were added to a solution of 1a (0.1289
127.3 (br, 2C), 127.2 (2C), 122.3, 120.9, 120.6, 68.9, 62.1, 53.0, g, 0.219 mmol) in 1,4-dioxane (2.2 mL) and the reaction
50.8, 32.0, 21.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for mixture was heated to refluxing temperature for 20 h. The
C26H24N2NaO5S 499.1304, found 499.1308.
solution was filtered, and concentrated in vacuo. The residue
Preparation of (3S,3aR)-3a-hydroxymethyl-6-nitro-3-phenyl- was subjected to flash column chromatography (silica
2-tosyl-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole (2h): Under gel/hexane-EtOAc 3:1 then 1:1) to give 2j in 54% yield as pale
nitrogen atmosphere, Pd(t-Bu3P)2 (0.0105 g, 0.021 mmol), yellow viscose oil (0.0596 g, 0.119 mmol).
DABCO (0.0682 g, 0.607 mmol), CsF (0.0921 g, 0.606 mmol), [α]D +30.8 (c 1.93, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.53 (d,
and 2-bromo-1-iodo-4-nitrobenzene (0.0668 g, 0.204 mmol) J = 8.3 Hz, 2H), 7.32 (ddd, J = 7.8, 1.9, 0.9 Hz, 1H), 7.24 – 7.17
were added to a solution of 1a (0.1198 g, 0.204 mmol) in 1,4- (m, 5H), 7.16 (dd, J = 7.8, 0.9 Hz, 2H), 7.04 (d, J = 7.8 Hz, 2H),
dioxane (2.0 mL) and the reaction mixture was heated to 6.48 (d, J = 1.9 Hz, 1H), 5.30 (s, 1H), 4.45 (d, J = 14.1 Hz, 1H),
refluxing temperature for 20 h. The solution was filtered, and 4.37 (dd, J = 15.7, 1.9 Hz, 1H), 3.23 (dd, J = 10.7, 4.7 Hz, 1H),
concentrated in vacuo. The residue was subjected to flash 3.11 (dd, J = 10.7, 5.5 Hz, 1H), 2.66 (d, J = 16.3 Hz, 1H), 2.36 (s,
column chromatography (silica gel/hexane-EtOAc 3:1 then 1:1) 3H), 2.26 - 2.11 (m, 1H), 2.07 (d, J = 16.2 Hz, 1H); 13C NMR (126
to give 2h in 38% yield as pale yellow viscose oil (0.0367 g, MHz, CDCl3) δ 143.5, 142.5, 139.5, 135.5 (2C), 133.9, 129.5 (2C),
0.077 mmol).
129.2 (q, J = 32.2 Hz), 128.6 (2C), 127.8-128.5 (br, 2C), 127.7,
[α]D –16.6 (c 1.16, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.94 (dd, 127.3 (2C), 126.2, 125.5 (q, J = 3.6 Hz), 124.1 (q, J = 272.1 Hz),
J = 8.4, 2.3 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 8.0 Hz, 123.9 (q, J = 4.2 Hz), 121.4, 68.9, 61.9, 53.0, 51.0, 31.7, 21.6;
2H), 7.24 – 7.19 (m, 3H), 7.16 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.5 HRMS (ESI-TOF) m/z [M + H]+ calcd for C27H25F3NO3S 500.1507,
Hz, 1H), 7.05 – 6.93 (m, 2H), 6.60 – 6.47 (m, 1H), 5.31 (s, 1H), found 500.1513.
4.47 (dd, J = 15.9, 2.5 Hz, 1H), 4.39 (dd, J = 16.0, 1.6 Hz, 1H), Preparation of (3S,3aR)-3a-hydroxymethyl-7-methyl-3-(o-
3.21 (d, J = 10.8 Hz, 1H), 3.13 (d, J = 10.8 Hz, 1H), 2.72 (d, J = tolyl)-2-tosyl-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole (2k):
16.2 Hz, 1H), 2.36 (s, 3H), 2.09 (d, J = 16.3 Hz, 1H), 1.77 – 1.68 Under nitrogen atmosphere, Pd(t-Bu3P)2 (0.0106 g, 0.021
(m, 1H); 13C NMR (126 MHz, CDCl3) δ 146.6, 145.2, 143.6, 139.2, mmol), DABCO (0.1038 g, 0.925 mmol), CsF (0.2922 g, 1.92
138.5, 135.5, 134.8, 129.5 (2C), 128.7 (2C), 127.8 (2C), 127.3 mmol), and 4-bromo-3-iodotoluene (0.030 mL, 0.208 mmol)
(2C), 127.4-127.1, 126.4, 123.8, 122.6, 121.1, 76.9, 68.9, 62.0, were added to a solution of 1c (0.1254 g, 0.208 mmol) in 1,4-
52.9, 51.1, 31.7, 21.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for dioxane (10 mL) and the reaction mixture was heated to
C26H24N2NaO5S 499.1304, found 499.1294.
Preparation of (3S,3aR)-3a-hydroxymethyl-3-phenyl-2-tosyl- concentrated in vacuo. The residue was subjected to flash
7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole column chromatography (silica gel/hexane-EtOAc 5:1 then 3:1)
refluxing temperature for 20 h. The solution was filtered, and
(2i): Under nitrogen atmosphere, Pd(t-Bu3P)2 (0.0107 g, 0.021 to give 2k in 50% yield as viscose oil (0.0478 g, 0.104 mmol).
mmol), DABCO (0.0713 g, 0.636 mmol), CsF (0.0972 g, 0.640 [α]D +63.2 (c 1.47, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.45 (d,
mmol),
and
1-bromo-2-iodo-4-(trifluoromethyl)benzene J = 7.8 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 7.6 Hz, 1H),
(0.0750 g, 0.214 mmol) were added to a solution of 1a (0.1253 6.97 (t, J = 7.4 Hz, 1H), 6.83 (t, J = 7.5 Hz, 1H), 6.75 (s, 2H), 6.70
g, 0.213 mmol) in 1,4-dioxane (2.1 mL) and the reaction (d, J = 6.1 Hz, 3H), 6.32 (s, 1H), 5.55 (s, 1H), 4.35 (d, J = 15.0 Hz,
mixture was heated to refluxing temperature for 20 h. The 1H), 4.26 (d, J = 15.0 Hz, 1H), 3.20 (d, J = 10.5 Hz, 1H), 3.02 (d, J
solution was filtered, and concentrated in vacuo. The residue = 10.5 Hz, 1H), 2.50 (d, J = 15.9 Hz, 1H), 2.39 (s, 3H), 2.35 –
was subjected to flash column chromatography (silica 2.30 (m, 1H), 2.29 (s, 3H), 2.15 (s, 3H), 2.01 (d, J = 15.9 Hz, 1H);
gel/hexane-EtOAc 3:1 then 1:1) to give 2i in 58% yield as pale 13C NMR (126 MHz, CDCl3) δ 143.3, 139.2, 138.4, 136.3, 135.9,
yellow viscose oil (0.0622 g, 0.125 mmol).
135.7, 132.1, 130.4, 130.0, 129.4 (2C), 128.6, 128.1, 127.7,
[α]D +38.2 (c 1.45, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.51 (d, 127.3 (2C), 127.1, 127.0, 126.2, 122.5, 64.8, 62.2, 53.6, 51.0,
J = 8.0 Hz, 2H), 7.26 (d, J = 7.6 Hz, 1H), 7.23 – 7.18 (br, 5H), 30.2, 21.6, 21.0, 19.7; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
7.15 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 7.8 Hz, 2H), 6.47 (s, 1H), C28H29NNaO3S 482.1766, found 482.1765.
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J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
Page 8 of 13
ARTICLE
Journal Name
Preparation
of
(3S,3aR)-3a-hydroxymethyl-3-(3- column chromatography (silica gel/hexane-EtOAcV5ie:w1AtrhticelenO3n:li1ne)
DOI: 10.1039/C6OB01018K
methoxyphenyl)-6-nitro-2-tosyl-2,3,3a,4-tetrahydro-1H-
to give 2n in 28% yield as viscose oil (0.0205 g, 0.04 mmol).
benzo[f]isoindole (2l): Under nitrogen atmosphere, Pd(t- [α]D +62.1 (c 0.89, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J
Bu3P)2 (0.0105 g, 0.020 mmol), CsF (0.0978 g, 0.64 mmol), and = 8.1 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 7.6 Hz, 1H),
2-bromo-1-iodo-4-nitrobenzene (0.0706 g, 0.22 mmol) were 7.06 (t, J = 7.5 Hz, 1H), 6.98 (dd, J = 8.0, 2.0 Hz, 1H), 6.93 (d, J =
added to a solution of 1d (0.1268 g, 0.20 mmol) in 1,4-dioxane 1.6 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.74
(5 mL) and the reaction mixture was heated to refluxing (d, J = 7.7 Hz, 1H), 6.38 (s, 1H), 5.62 (s, 1H), 4.44 (dd, J = 15.4,
temperature for 24 h. The solution was filtered, and 2.1 Hz, 1H), 4.34 (d, J = 15.5 Hz, 1H), 3.25 (d, J = 10.5 Hz, 1H),
concentrated in vacuo. The residue was subjected to flash 3.13 (d, J = 10.3 Hz, 1H), 2.61 (d, J = 16.0 Hz, 1H), 2.46 (s, 3H),
column chromatography (silica gel/hexane-EtOAc 5:1 then 1:1) 2.36 (s, 3H), 2.04 (d, J = 16.0 Hz, 1H), 1.78 (s, 1H); 13C NMR
to give 2l in 55% yield as viscose oil (0.0568 g, 0.112 mmol).
(126 MHz, CDCl3) δ 143.4, 141.2, 138.1, 135.8, 135.8, 133.8,
[α]D –47.1 (c 0.28, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.93 (d, 132.2, 131.4, 130.5, 129.9, 129.4 (2C), 127.5, 127.3, 127.2 (2C),
J = 8.2 Hz, 1H), 7.83 (s, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 127.2, 126.3, 126.0, 121.5, 64.7, 62.0, 53.5, 51.0, 30.0, 21.6,
8.0 Hz, 2H), 7.14 – 7.09 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.95- 19.7; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C27H26ClNNaO3S
6.40 (br, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.50 (s, 1H), 5.27 (s, 1H), 502.1220, found 502.1209.
4.46 (d, J = 16.3 Hz, 1H), 4.36 (d, J = 15.8 Hz, 1H), 3.84 – 3.50 Preparation of (3S,3aR)-3a-hydroxymethyl-6-fluoro-3-(o-
(m, 4H), 3.20 (d, J = 10.7 Hz, 1H), 3.13 (d, J = 10.7 Hz, 1H), 2.75 tolyl)-2-tosyl-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole (2o):
(d, J = 16.3 Hz, 1H), 2.36 (s, 3H), 2.15 – 2.06 (m, 1H); 13C NMR Under nitrogen atmosphere, Pd(t-Bu3P)2 (0.0106 g, 0.0208
(126 MHz, CDCl3) δ 159.7, 146.6, 145.2, 143.6, 140.7, 138.5, mmol), DABCO (0.0803 g, 0.716 mmol), CsF (0.1740 g, 1.15
135.4, 134.8, 133.2, 129.7, 129.5 (3C), 127.3 (2C), 126.4, 123.8, mmol), and 2-bromo-4-fluoro-1-iodobenzene (0.030 mL, 0.208
122.5, 121.0, 112.8, 68.8, 61.9, 55.2, 53.0, 51.1, 31.5, 21.6; mmol) were added to a solution of 1c (0.1256 g, 0.208 mmol)
HRMS (ESI-TOF) m/z [M + H]+ calcd for C27H27N2O6S 507.1590, in 1,4-dioxane (12 mL) and the reaction mixture was heated to
found 507.1596.
refluxing temperature for 20 h. The solution was filtered, and
Preparation
of
(3S,3aR)-3a-hydroxymethyl-6- concentrated in vacuo. The residue was subjected to flash
(trifluoromethyl)-3-(o-tolyl)-2-tosyl-2,3,3a,4-tetrahydro-1H-
column chromatography (silica gel/hexane-EtOAc 5:1 then 2:1)
benzo[f]isoindole (2m): Under nitrogen atmosphere, Pd(t- to give 2o in 35% yield as pale yellow oil (0.0323 g, 0.073
Bu3P)2 (0.0109 g, 0.0213 mmol), DABCO (0.1112 g, 0.99 mmol), mmol).
CsF (0.1893 g, 1.246 mmol), and 2-bromo-1-iodo-4- [α]D +79.3 (c 1.13, CHCl3); 1H NMR (500 MHz, CDCl3) δ 77.51 (d,
(trifluoromethyl)benzene (0.040 mL, 0.213 mmol) were added J = 8.2 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.6 Hz, 2H),
to a solution of 1c (0.1286 g, 0.213 mmol) in 1,4-dioxane (8.5 7.06 (dd, J = 7.7, 6.9 Hz, 1H), 6.95 – 6.86 (m, 2H), 6.78 – 6.71
mL) and the reaction mixture was heated to refluxing (m, 2H), 6.66 (d, J = 8.9 Hz, 1H), 6.41 (s, 1H), 5.61 (s, 1H), 4.42
temperature for 20 h. The solution was filtered, and (d, J = 15.0 Hz, 1H), 4.33 (d, J = 15.0 Hz, 1H), 3.26 (d, J = 10.5 Hz,
concentrated in vacuo. The residue was subjected to flash 1H), 3.12 (d, J = 10.5 Hz, 1H), 2.61 (d, J = 16.1 Hz, 1H), 2.45 (s,
column chromatography (silica gel/hexane-EtOAc 5:1 then 3:1) 3H), 2.36 (s, 3H), 2.10 (d, J = 16.1 Hz, 1H); 13C NMR (126 MHz,
to give 2m in 19% yield as viscose oil (0.0205 g, 0.04 mmol).
CDCl3) δ 157.7, 143.3, 139.7, 138.6, 138.2, 135.8, 135.7, 130.5,
[α]D +60.7 (c 0.68, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J 129.4 (2C), 127.6, 127.4, 127.3 (2C), 126.2, 124.2, 121.5, 116.1,
= 8.3 Hz, 2H), 7.26 (d, J = 8.8 Hz, 1H), 7.22 – 7.01 (m, 6H), 6.91 116.0, 113.3 (d, J = 21.7 Hz), 64.7, 62.0, 53.1, 50.9, 30.8, 21.6,
(t, J = 7.5 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.47 (s, 1H), 5.64 (s, 19.7; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C27H26FNNaO3S
1H), 4.47 (dd, J = 15.4, 2.3 Hz, 1H), 4.36 (dd, J = 15.4, 1.3 Hz, 486.1515, found 486.1506.
1H), 3.25 (d, J = 10.5 Hz, 1H), 3.16 (d, J = 10.4 Hz, 1H), 2.72 (d, J Preparation of (3S,3aR)-3a-hydroxymethyl-6-chloro-3-(m-
= 16.3 Hz, 1H), 2.46 (s, 3H), 2.36 (s, 3H), 2.13 (d, J = 16.2 Hz, methoxyphenyl)-2-tosyl-2,3,3a,4-tetrahydro-1H-
1H), 1.82 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 143.4, 141.5, benzo[f]isoindole (2p): Under nitrogen atmosphere, Pd(t-
138.0, 137.2, 135.8, 132.8, 130.6, 129.4 (2C), 129.4, 129.1, Bu3P)2 (0.0151 g, 0.030 mmol), CsF (0.1285 g, 0.85 mmol), and
129.0, 127.5, 127.3, 127.2 (2C), 126.3, 124.6 (q, J = 273.3 Hz), 2-bromo-4-chloro-1-iodobenzene (0.040 mL, 0.30 mmol) were
124.1, 122.7, 121.5, 64.7, 62.1, 53.3, 51.0, 30.6, 21.6, 19.7; added to a solution of 1d (0.1835 g, 0.30 mmol) in 1,4-dioxane
HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H27F3NO3S 514.1658, (12 mL) and the reaction mixture was heated to refluxing
found 514.1663.
temperature for 24 h. The solution was filtered, and
Preparation of (3S,3aR)-3a-hydroxymethyl-7-chloro-3-(o- concentrated in vacuo. The residue was subjected to flash
tolyl)-2-tosyl-2,3,3a,4-tetrahydro-1H-benzo[f]isoindole (2n): column chromatography (silica gel/hexane-EtOAc 5:1 then 1:1)
Under nitrogen atmosphere, Pd(t-Bu3P)2 (0.0105 g, 0.0205 to give 2p in 26% yield as pale yellow oil (0.0386 g, 0.078
mmol), DABCO (0.0827 g, 0.737 mmol), CsF (0.2419 g, 1.592 mmol).
mmol), and 1-bromo-2-iodo-4-chlorobenzene (0.030 mL, 0.205 [α]D –5.81 (c 1.39, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J
mmol) were added to a solution of 1c (0.1239 g, 0.205 mmol) = 8.2 Hz, 2H), 7.34 – 7.24 (m, 1H), 7.21 – 7.11 (m, 1H), 7.16 (d, J
in 1,4-dioxane (8.5 mL) and the reaction mixture was heated to = 8.0 Hz, 2H), 7.04 (d, J = 7.8 Hz, 1H), 6.94 (s, 1H), 6.87 (d, J =
refluxing temperature for 20 h. The solution was filtered, and 8.0 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 6.67 – 6.57 (m, 1H), 6.39 (s,
concentrated in vacuo. The residue was subjected to flash 1H), 5.22 (d, J = 12.1 Hz, 1H), 4.41 (d, J = 15.8 Hz, 1H), 4.31 (d, J
= 15.0 Hz, 1H), 3.80 – 3.58 (br, 3H), 3.23 (d, J = 10.5 Hz, 1H),
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
3.10 (d, J = 10.9 Hz, 1H), 2.55 (d, J = 16.2 Hz, 1H), 2.37 (s, 3H), Preparation
ARTICLE
of
(3aR,8bS,E)-3a-hydroxymethyl-3-(3-
View Article Online
2.07 (d, J = 16.2 Hz, 1H), 1.73 – 1.66 (br, 1H); 13C NMR (126 methoxybenzylidene)-1-tosyl-1,2,3,3a,4,D8ObI-: 10.1039/C6OB01018K
MHz, CDCl3) δ 143.4, 139.8, 135.7, 135.1, 132.8, 132.7, 130.8, hexahydroindeno[1,2-b]pyrrole
(4c):
Under
nitrogen
129.6, 129.4 (2C), 128.9, 127.3, 127.2 (2C), 126.8, 121.4, 120.4, atmosphere, Pd(t-Bu3P)2 (0.0144 g, 0.028 mmol), DABCO
112.7, 101.5, 101.3, 68.9, 62.0, 55.1, 52.8, 51.0, 31.6, 21.6; (0.0072 g, 0.064 mmol), CsF (0.1313 g, 0.86 mmol), and 3-
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C27H26ClNNaO4S iodoanisole (0.0655 g, 0.28 mmol) were added to a solution of
518.1169, found 518.1181.
Preparation of
1b (0.1839 g, 0.28 mmol) in 1,4-dioxane (4.2 mL) and the
(3aR,8bS,E)-3a-hydroxymethyl-3-(4- reaction mixture was heated to refluxing temperature for 24 h.
methylbenzylidene)-1-tosyl-1,2,3,3a,4,8b-
hexahydroindeno[1,2-b]pyrrole (4a):
The solution was filtered, and concentrated in vacuo. The
nitrogen residue was subjected to flash column chromatography (silica
Under
atmosphere, Pd(t-Bu3P)2 (0.014 g, 0.027 mmol), DABCO gel/hexane-EtOAc 5:1 then 2:1) to give 4c in 83% yield as white
(0.0065 g, 0.0579 mmol), CsF (0.1141 g, 0.75 mmol), and 4- solid (0.1053 g, 0.23 mmol).
iodotoluene (0.0420 g, 0.19 mmol) were added to a solution of Mp 138.5-139.5 °C; [α]D –37.7 (c 0.56, CHCl3); H NMR (500
1
1b (0.121 g, 0.18 mmol) in 1,4-dioxane (3 mL) and the reaction MHz, CDCl3) δ 7.87 (d, J = 7.8 Hz, 2H), 7.65 (d, J = 7.4 Hz, 1H),
mixture was heated to refluxing temperature for 24 h. The 7.36 (d, J = 7.8 Hz, 2H), 7.28 – 7.19 (m, 3H), 7.01 (d, J = 7.2 Hz,
solution was filtered, and concentrated in vacuo. The residue 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.67 (s, 1H),
was subjected to flash column chromatography (silica 6.46 (s, 1H), 5.46 (s, 1H), 4.29 (d, J = 15.1 Hz, 1H), 4.08 (d, J =
gel/hexane-EtOAc 5:1 then 3:1) to give 4a in 80% yield as 15.2 Hz, 1H), 3.78 (s, 3H), 3.47 (d, J = 11.3 Hz, 1H), 3.15 (d, J =
viscose oil (0.0643 g, 0.14 mmol).
16.3 Hz, 1H), 3.07 (d, J = 11.4 Hz, 1H), 2.87 (d, J = 16.3 Hz, 1H),
[α]D –19.6 (c 0.66, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.87 (d, 2.46 (s, 3H), 1.47 – 1.43 (m, 1H); 13C NMR (126 MHz, CDCl3) δ
J = 8.4 Hz, 2H), 7.66 (d, J = 7.3 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 159.5, 143.9, 141.5, 141.3, 140.8, 137.4, 135.7, 129.8 (2C),
7.25 (dd, J = 18.0, 6.5 Hz, 1H), 7.21 (t, J = 6.6 Hz, 1H), 7.11 (d, J 129.5, 128.6, 127.9 (2C), 127.4, 126.5, 124.7, 124.4, 121.1,
= 7.9 Hz, 2H), 7.02 (d, J = 7.9 Hz, 3H), 6.45 (s, 1H), 5.46 (s, 1H), 114.5, 112.8, 72.9, 64.5, 59.5, 55.9, 55.3, 38.3, 21.7; HRMS
4.30 (dd, J = 15.1, 1.9 Hz, 1H), 4.09 (dd, J = 15.2, 2.2 Hz, 1H), (ESI-TOF) m/z [M + H]+ calcd for C27H28NO4S 462.1739, found
3.48 (d, J = 11.4 Hz, 1H), 3.18 (d, J = 16.5 Hz, 1H), 3.08 (d, J = 462. 1729.
11.2 Hz, 1H), 2.87 (d, J = 16.4 Hz, 1H), 2.46 (s, 3H), 2.34 (s, 3H), Preparation
1.34 – 1.24 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 143.9, 141.7, methylbenzylidene)-3a-hydroxymethyl-1-tosyl-1,2,3,3a,4,8b-
140.9, 140.6, 137.5, 135.9, 133.1, 129.9 (2C), 129.2 (2C), 128.7 hexahydroindeno[1,2-b]pyrrole (4d): Under nitrogen
of
(3aR,8bS,E)-3-(4,5-dimethoxy-2-
(2C), 128.6, 128.0 (2C), 127.5, 126.6, 124.9, 124.5, 73.0, 64.4, atmosphere, Pd(t-Bu3P)2 (0.0192 g, 0.038 mmol), DABCO
59.4, 56.0, 38.3, 21.7, 21.2. HRMS (ESI-TOF) m/z [M + H]+ calcd (0.0077 g, 0.069 mmol), CsF (0.1225 g, 0.81 mmol), and 2-iodo-
for C27H28NO3S 446.1790, found 446.1798.
Preparation of (3aR,8bS,E)-3a-hydroxymethyl-3-(4- solution of 1b (0.1609 g, 0.24 mmol) in 1,4-dioxane (4.0 mL)
methoxybenzylidene)-1-tosyl-1,2,3,3a,4,8b-
hexahydroindeno[1,2-b]pyrrole (4b):
4,5-dimethoxytoluene (0.0695 g, 0.25 mmol) were added to a
and the reaction mixture was heated to refluxing temperature
Under
nitrogen for 24 h. The solution was filtered, and concentrated in vacuo.
atmosphere, Pd(t-Bu3P)2 (0.0131 g, 0.026 mmol), DABCO The residue was subjected to flash column chromatography
(0.0059 g, 0.053 mmol), CsF (0.1093 g, 0.72 mmol), and 4- (silica gel/hexane-EtOAc 5:1 then 1:1) to give 4d in 74% yield
iodoanisole (0.0561 g, 0.24 mmol) were added to a solution of as viscose oil (0.0898 g, 0.18 mmol).
1b (0.1492 g, 0.22 mmol) in 1,4-dioxane (4 mL) and the [α]D –13.8 (c 2.99, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.88 (d,
reaction mixture was heated to refluxing temperature for 24 h. J = 7.6 Hz, 2H), 7.65 (d, J = 6.3 Hz, 1H), 7.36 (d, J = 7.6 Hz, 2H),
The solution was filtered, and concentrated in vacuo. The 7.25 (td, J = 7.2, 1.5 Hz, 1H), 7.21 (t, J = 7.3 Hz, 1H), 7.02 (dd, J
residue was subjected to flash column chromatography (silica = 7.5, 1.2 Hz, 1H), 6.65 (s, 1H), 6.57 (s, 1H), 6.38 (t, J = 1.7 Hz,
gel/hexane-EtOAc 5:1 then 2:1) to give 4b in 68% yield as 1H), 5.40 (s, 1H), 4.30 (dd, J = 15.0, 1.9 Hz, 1H), 4.11 (dd, J =
viscose oil (0.0698 g, 0.15 mmol).
15.0, 2.0 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.33 (dd, J = 11.2,
1
[α]D –64.1 (c 0.46, CHCl3); H NMR (500 MHz, CDCl3) δ 7.90 – 4.3 Hz, 1H), 3.11 (d, J = 9.6 Hz, 1H), 3.03 (d, J = 16.4 Hz, 1H),
7.81 (m, 2H), 7.65 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 2.71 (d, J = 16.4 Hz, 1H), 2.45 (s, 3H), 1.92 (s, 3H), 1.61 – 1.55
7.23 (d, J = 7.5 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 9.3 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 148.4, 146.5, 143.8, 141.3,
Hz, 2H), 7.01 (d, J = 6.8 Hz, 1H), 6.83 (d, J = 8.6 Hz, 2H), 6.42 (s, 141.0, 140.6, 135.9, 129.8 (2C), 128.7, 128.6, 128.0 (2C), 127.5,
1H), 5.44 (s, 1H), 4.28 (dd, J = 15.0, 2.0 Hz, 1H), 4.08 (dd, J = 127.2, 126.6, 124.3, 124.1, 113.0, 112.6, 72.7, 64.8, 59.4, 56.2,
15.1, 2.0 Hz, 1H), 3.80 (s, 3H), 3.48 (d, J = 11.3 Hz, 1H), 3.18 (d, 55.9, 55.6, 38.6, 21.7, 19.5; HRMS (ESI-TOF) m/z [M + H]+ calcd
J = 16.4 Hz, 1H), 3.08 (d, J = 11.3 Hz, 1H), 2.87 (d, J = 16.4 Hz, for C29H32NO5S 506.2001, found 506.1997.
1H), 2.45 (s, 3H), 1.71 – 1.56 (m, 1H); 13C NMR (126 MHz, Preparation of (3aR,8bS,E)-6,7-dimethoxy-3a-hydroxymethyl-
CDCl3) δ 159.0, 143.9, 141.5, 140.8, 139.7, 135.7, 130.0 (2C), 3-(4-methylbenzylidene)-1-tosyl-1,2,3,3a,4,8b-
129.8 (2C), 128.6, 128.2, 127.9 (2C), 127.4, 126.6, 124.6, 124.5, hexahydroindeno[1,2-b]pyrrole
(4f):
Under
nitrogen
113.8 (2C), 73.0, 64.4, 59.3, 56.1, 55.4, 38.1, 21.7; HRMS (ESI- atmosphere, Pd(t-Bu3P)2 (0.0107 g, 0.021 mmol), DABCO
TOF) m/z [M + H]+ calcd for C27H28NO4S 462.1739, found (0.0043 g, 0.038 mmol), CsF (0.0905 g, 0.60 mmol), and 4-
462.1736.
iodotoluene (0.0441 g, 0.20 mmol) were added to a solution of
1e (0.1353 g, 0.19 mmol) in 1,4-dioxane (3.0 mL) and the
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Organic & Biomolecular Chemistry
Page 10 of 13
ARTICLE
Journal Name
reaction mixture was heated to refluxing temperature for 22.5 15.3 Hz, 1H), 4.11 (d, J = 14.4 Hz, 1H), 3.85 (s, 3H)V,i3ew.7A9rtic(lse,O3nHlin)e,
DOI: 10.1039/C6OB01018K
h. The solution was filtered, and concentrated in vacuo. The 3.77 (s, 3H), 3.46 (d, J = 11.2 Hz, 1H), 3.12 (d, J = 16.0 Hz, 1H),
residue was subjected to flash column chromatography (silica 3.04 (d, J = 11.1 Hz, 1H), 2.81 (d, J = 16.1 Hz, 1H), 2.44 (s, 3H),
gel/hexane-EtOAc 3:1 then 2:1) to give 4f in 56% yield as 1.51 – 1.43 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 159.4, 150.0,
viscose oil (0.0527 g, 0.10 mmol).
149.0, 143.9, 141.7, 137.4, 135.9, 133.3, 132.3, 129.8 (2C),
[α]D –71.4 (c 1.76, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.86 (d, 129.4, 127.9 (2C), 124.4, 121.1, 114.5, 112.7, 108.4, 106.8,
J = 7.9 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 7.11 (s, 1 H), 7.10 (d, J = 73.5, 64.7, 60.5, 59.8, 56.0, 56.0, 55.3, 38.7, 21.7; HRMS (ESI-
7.9 Hz, 2H), 7.02 (d, J = 7.9 Hz, 2H), 6.51 (s, 1H), 6.44 (s, 1H), TOF) m/z [M + Na]+ calcd for C29H31NNaO6S 544.1770, found
5.41 (s, 1H), 4.31 (d, J = 15.2 Hz, 1H), 4.18 – 4.07 (m, 1H), 3.87 544.1774.
(s, 3H), 3.80 (s, 3H), 3.47 (d, J = 11.2 Hz, 1H), 3.15 (d, J = 16.1 Preparation
of
(3aR,8bS,E)-3-(4,5-dimethoxy-2-
Hz, 1H), 3.04 (d, J = 11.2 Hz, 1H), 2.82 (d, J = 16.0 Hz, 1H), 2.45 methylbenzylidene)-6,7-dimethoxy-3a-hydroxymethyl-1-
(s, 3H), 2.33 (s, 3H), 1.74 – 1.61 (m, 1H); 13C NMR (126 MHz, tosyl-1,2,3,3a,4,8b-hexahydroindeno[1,2-b]pyrrole
(4i):
CDCl3) δ 150.0, 149.0, 143.8, 140.8, 137.4, 135.9, 133.2, 133.0, Under nitrogen atmosphere, Pd(t-Bu3P)2 (0.0136 g, 0.027
132.2, 129.8 (2C), 129.1 (2C), 128.7 (2C), 127.9 (2C), 124.5, mmol), DABCO (0.0057 g, 0.051 mmol), CsF (0.1060 g, 0.698
108.4, 106.7, 73.6, 64.6, 60.5, 59.7, 56.1, 56.0, 38.6, 21.7, 21.2; mmol), and 2-iodo-4,5-dimethoxytoluene (0.0696 g, 0.25
HRMS (ESI-TOF) m/z [M + H]+ calcd for C29H32NO5S 506.2001, mmol) were added to a solution of 1e (0.1677 g, 0.23 mmol) in
found 506.2002.
1,4-dioxane (3.5 mL) and the reaction mixture was heated to
Preparation of (3aR,8bS,E)-6,7-dimethoxy-3a-hydroxymethyl- refluxing temperature for 24 h. The solution was filtered, and
3-(4-methoxybenzylidene)-1-tosyl-1,2,3,3a,4,8b-
hexahydroindeno[1,2-b]pyrrole (4g): Under
concentrated in vacuo. The residue was subjected to flash
nitrogen column chromatography (silica gel/hexane-EtOAc 3:1 then 1:1)
atmosphere, Pd(t-Bu3P)2 (0.0107 g, 0.021 mmol), DABCO to give 4i in 74% yield as pale yellow viscose oil (0.0958 g,
(0.0047 g, 0.042 mmol), CsF (0.1004 g, 0.66 mmol), and 4- 0.170 mmol).
iodoanisole (0.0500 g, 0.21 mmol) were added to a solution of [α]D –55.2 (c 3.19, CHCl3); 1H NMR (500 MHz, CHCl3) δ 7.86 (d,
1e (0.1385 g, 0.19 mmol) in 1,4-dioxane (3.0 mL) and the J = 7.7 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 7.10 (s, 1H), 6.64 (s, 1H),
reaction mixture was heated to refluxing temperature for 22.5 6.57 (s, 1H), 6.51 (s, 1H), 6.34 (s, 1H), 5.35 (s, 1H), 4.29 (d, J =
h. The solution was filtered, and concentrated in vacuo. The 15.1 Hz, 1H), 4.13 (d, J = 14.4 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H),
residue was subjected to flash column chromatography (silica 3.80 (s, 3H), 3.79 (s, 3H), 3.29 (d, J = 11.1 Hz, 1H), 3.06 (d, J =
gel/hexane-EtOAc 3:1 then 1:1) to give 4g in 75% yield as pale 11.8 Hz, 1H), 3.01 (d, J = 17.2 Hz, 1H), 2.68 (d, J = 16.0 Hz, 1H),
yellow viscose oil (0.0748 g, 0.14 mmol).
2.42 (s, 3H), 1.93 (s, 3H), 1.82 – 1.69 (m, 1H); 13C NMR (126
[α]D –52.1 (c 2.00, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.86 (d, MHz, CHCl3) δ 150.0, 149.1, 148.4, 146.5, 143.7, 141.0, 136.0,
J = 7.9 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.11 (s, 1H), 7.07 (d, J = 133.1, 132.5, 129.8 (2C), 128.7, 127.9 (2C), 127.3, 123.5, 113.1,
8.4 Hz, 2H), 6.83 (d, J = 8.2 Hz, 2H), 6.51 (s, 1H), 6.41 (s, 1H), 112.6, 108.5, 106.7, 73.3, 64.8, 60.5, 59.7, 56.2, 56.1, 56.0,
5.40 (s, 1H), 4.30 (d, J = 15.1 Hz, 1H), 4.11 (d, J = 14.9 Hz, 1H), 55.9, 55.6, 39.2, 21.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
3.86 (s, 3H), 3.79 (s, 3H), 3.79 (s, 3H), 3.49 (d, J = 11.2 Hz, 1H), C31H35NNaO7S 588.2032, found 588.2022.
3.16 (d, J = 16.0 Hz, 1H), 3.05 (d, J = 11.2 Hz, 1H), 2.83 (d, J = Preparation of (3aR,8bS,E)-3-benzylidene-6,7-dimethoxy-3a-
16.0 Hz, 1H), 2.44 (s, 3H), 1.37 – 1.33 (m, 1H); 13C NMR (126 hydroxymethyl-1-tosyl-1,2,3,3a,4,8b-hexahydroindeno[1,2-
MHz, CDCl3) δ 158.9, 149.9, 149.0, 143.8, 140.0, 135.9, 133.2, b]pyrrole (4j): Under nitrogen atmosphere, Pd(t-Bu3P)2
132.3, 130.1 (2C), 129.8 (2C), 128.3, 127.9 (2C), 124.2, 113.8 (0.0128 g, 0.025 mmol), DABCO (0.0076 g, 0.068 mmol), CsF
(2C), 108.3, 106.7, 73.6, 68.2, 64.6, 59.6, 56.0, 56.0, 55.3, 38.3, (0.1171 g, 0.77 mmol), and iodobenzene (0.0469 g, 0.23 mmol)
21.7; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H31NNaO6S were added to a solution of 1e (0.1693 g, 0.23 mmol) in 1,4-
544.1770, found 544.1761.
dioxane (4,0 mL) and the reaction mixture was heated to
Preparation of (3aR,8bS,E)-6,7-dimethoxy-3a-hydroxymethyl- refluxing temperature for 24 h. The solution was filtered, and
3-(3-methoxybenzylidene)-1-tosyl-1,2,3,3a,4,8b-
hexahydroindeno[1,2-b]pyrrole (4h): Under
concentrated in vacuo. The residue was subjected to flash
nitrogen column chromatography (silica gel/hexane-EtOAc 5:1 then 1:1)
atmosphere, Pd(t-Bu3P)2 (0.0120 g, 0.023 mmol), DABCO to give 4j in 74% yield as pale yellow viscose oil (0.0846 g, 0.17
(0.0077 g, 0.069 mmol), CsF (0.1120 g, 0.74 mmol), and 3- mmol).
iodoanisole (0.0562 g, 0.24 mmol) were added to a solution of [α]D –85.7 (c 2.82, CHCl3); 1H NMR (500 MHz, CHCl3) δ 7.86 (d, J
1e (0.1737 g, 0.24 mmol) in 1,4-dioxane (4.0 mL) and the = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 7.4 Hz, 2H),
reaction mixture was heated to refluxing temperature for 24 h. 7.25 (d, J = 7.3 Hz, 1H), 7.12 (d, J = 7.6 Hz, 2H), 7.09 (s, 1H),
The solution was filtered, and concentrated in vacuo. The 6.49 (s, 1H), 6.47 (s, 1H), 5.41 (s, 1H), 4.29 (d, J = 14.6 Hz, 3H),
residue was subjected to flash column chromatography (silica 4.12 (d, J = 15.2 Hz, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.46 (d, J =
gel/hexane-EtOAc 3:1 then 1:1) to give 4h in 74% yield as pale 11.2 Hz, 1H), 3.11 (d, J = 16.1 Hz, 1H), 3.01 (d, J = 11.4 Hz, 1H),
yellow viscose oil (0.0924 g, 0.18 mmol).
2.80 (d, J = 16.1 Hz, 1H), 2.44 (s, 3H), 1.35 (s, 1H); 13C NMR
[α]D –51.4 (c 3.08, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.85 (d, (126 MHz, CHCl3) δ 150.0, 149.0, 143.9, 141.5, 136.0, 135.9,
J = 8.0 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 7.21 (t, J = 7.9 Hz, 1H), 133.2, 132.2, 129.8 (2C), 128.7 (2C), 128.4 (2C), 127.9 (2C),
7.09 (s, 1H), 6.79 (d, J = 9.2 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 127.5, 124.6, 108.3, 106.7, 77.4, 73.5, 64.7, 59.8, 56.1, 56.0,
6.67 (s, 1H), 6.51 (s, 1H), 6.44 (s, 1H), 5.41 (s, 1H), 4.30 (d, J =
10 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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38.6, 21.7; HRMS (ESI-TOF) m/z [M + Na]+ calcd for Preparation of TBP complex 6a: A solution of 1g (0.6488 g,
View Article Online
DOI: 10.1039/C6OB01018K
C28H29NNaO5S 514.1664, found 514.1659.
((3aR,8bS,Z)-3-ethylidene-1-tosyl-3a-hydroxymethyl-1-tosyl-
0.88 mmol) in ether (88 mL) was added to 12M HCl (4.4 mL)
and the reaction mixture was stirred at room temperature for
1,2,3,3a,4,8b-hexahydroindeno[1,2-b]pyrrole (4k): Under 1.5 h. The organic phase was separated and washed with brine
nitrogen atmosphere, Pd(t-Bu3P)2 (0.0112 g, 0.018 mmol), (2 × 20 mL). After dried over Na2SO4, the organic phase was
DABCO (0.0036 g, 0.035 mmol), CsF (0.0892 g, 0.528 mmol), filtered and concentrated in vacuo. Obtained crude product
and 4-iodotoluene (0.0407 g, 0.176 mmol) were added to a was purified through flash chromatography (silica gel/hexane-
solution of 1f (0.1198 g, 0.176 mmol) in 1,4-dioxane (2.0 mL) EtOAc 5:1 then 2:1) to give 6a in 72% yield (0.4903 g, 0.63
and the reaction mixture was heated to refluxing temperature mmol) as colourless viscose oil.
for 24 h. The solution was filtered, and concentrated in vacuo. [α]D +10.6 (c 3.13, CHCl3); 1H NMR (500 MHz, CHCl3) δ 7.47 (d,
The residue was subjected to flash column chromatography J = 8.0 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.06 – 6.99 (m, 3H), 6.87
(silica gel/hexane-EtOAc 5:1 then 1:1) to give 4k in 59% yield as (t, J = 7.1 Hz, 1H), 6.56 (d, J = 6.8 Hz, 1H), 5.88 (s, 1H), 5.35 (s,
colourless viscose oil (0.0386 g, 0.104 mmol).
1H), 5.13 (s, 1H), 4.53 (d, J = 12.9 Hz, 1H), 4.11 (d, J = 12.9 Hz,
[α]D –23.2 (c 0.92, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.84 (d, 1H), 2.31 (s, 3H), 1.57 (s, 9H), 1.41 – 1.14 (m, 13H), 0.93 – 0.80
J = 8.2 Hz, 2H), 7.67 (d, J = 6.5 Hz, 1H), 7.35 (d, J = 7.7 Hz, 2H), (m, 6H), 0.50 (d, J = 13.8 Hz, J119Sn–1H = 54.1 Hz, 1H); 13C NMR
7.27 – 7.20 (m, 2H), 7.10 (d, J = 6.8 Hz, 1H), 5.45 (qt, J = 6.8, 2.6 (126 MHz, CHCl3) δ 178.8, 147.1, 143.1, 137.7, 137.1, 132.7,
Hz, 1H), 5.24 (s, 1H), 4.07 (ddq, J = 15.1, 3.2, 1.7 Hz, 1H), 4.01 129.4, 129.1 (2C), 127.5, 126.9 (2C), 124.4, 112.6, 87.4, 69.2,
(ddd, J = 15.1, 2.5, 1.4 Hz, 1H), 3.07 (d, J = 16.0 Hz, 1H), 3.03 (d, 60.3, 52.9, 28.1, 28.0, 27.9 (3C), 27.8, 26.8, 26.7, 22.1, 21.7,
J = 11.0 Hz, 1H), 2.96 (d, J = 16.0 Hz, 1H), 2.93 (d, J = 11.4 Hz, 21.5, 19.3, 13.8, 13.7; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
1H), 2.45 (s, 3H), 1.54 (dt, J = 6.9, 1.6 Hz, 3H), 1.35 – 1.20 (m, C32H45BrClNNaO4SSn 798.0840, found 798.0853.
1H); 13C NMR (126 MHz, CDCl3) δ 143.9, 141.4, 140.9, 140.5, Preparation of TBP complex 6b: A solution of 1b (0.2208 g,
135.9, 129.9, 128.5, 127.5, 127.4, 126.4, 124.7, 118.8, 70.7, 0.33 mmol) in ether (25 mL) was added to 12M HCl (2.0 mL)
65.7, 59.7, 50.4, 39.2, 21.7, 14.8; HRMS (ESI-TOF) m/z [M + and the reaction mixture was stirred at room temperature for
Na]+ calcd for C21H23NNaO3S 392.1296, found 392.1294.
Preparation of
deuterio)methylene-1-tosyl-1,2,3,3a,4,8b-hexahydroindeno-
17 h. The organic phase was separated and washed with brine
(3aR,8bS)-3a-hydroxymethyl-3-(E- (3 × 10 mL). After dried over Na2SO4, the organic phase was
filtered and concentrated in vacuo. Obtained crude product
[1,2-b]pyrrole (5-D): Under nitrogen atmosphere, Pd(t-Bu3P)2 was purified through flash chromatography (silica gel/hexane-
(0.0185 g, 0.036 mmol) and DABCO (0.1261 g, 1.12 mmol) and EtOAc 5:1 then 1:1) to give 6b in 91% yield (0.2108 g, 0.30
were added to a solution of 1b (0.2421 g, 0.36 mmol) in dry mmol) as colourless viscose oil.
1
1,4-dioxane (15 mL) with D2O (0.75 mL) and the reaction [α]D +21.7 (c 0.16, CHCl3); H NMR (500 MHz, CHCl3) δ 7.53 –
mixture was heated to refluxing temperature for 24 h. The 7.45 (m, 3H), 7.15 (d, J = 7.9 Hz, 2H), 7.11 – 7.00 (m, 2H), 6.86 –
solution was filtered, and concentrated in vacuo. The residue 6.79 (m, 1H), 5.37 (s, 1H), 5.12 (s, 1H), 5.03 (s, 1H), 4.28 (dt, J =
was subjected to flash column chromatography (silica 13.6, 2.4 Hz, 1H), 4.16 (d, J = 13.7 Hz, 1H), 3.42 (dt, J = 10.5, 3.0
gel/hexane-EtOAc 5:1 then 1:1) to give 5-D in 76% yield as Hz, 1H), 3.31 (dd, J = 10.9, 7.6 Hz, 1H), 2.84 (dd, J = 7.9, 3.8 Hz,
colourless viscose oil (0.0984 g, 0.27 mmol).
1H), 2.37 (s, 3H), 1.72 – 1.46 (m, 4H), 1.46 – 1.03 (m, 9H), 0.91
[α]D +16.4 (c 3.28, CHCl3); 1H NMR (500 MHz, CHCl3) δ 7.81 (d, (t, J = 7.3 Hz, 3H), 0.85 (t, J = 7.3 Hz, 3H), 0.54 (dd, J = 13.9, 2.5
J = 8.0 Hz, 2H), 7.65 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 7.6 Hz, 2H), Hz, J119Sn–1H = 56.7 Hz, 1H); 13C NMR (126 MHz, CHCl3) δ 147.2,
7.29 – 7.14 (m, 2H), 7.10 (d, J = 8.8 Hz, 1H), 5.27 (s, 1H), 5.01 (t, 144.0, 138.8, 138.0, 132.9, 129.7 (2C), 129.4, 128.7, 127.8,
J = 2.0 Hz, 1H), 4.13 (dd, J = 15.1, 2.3 Hz, 1H), 3.95 (dd, J = 15.1, 127.5 (2C), 124.3, 112.7, 77.2, 68.0, 67.2, 55.7, 51.7, 28.2, 28.2,
1.9 Hz, 1H), 3.11 (d, J = 15.7 Hz, 1H), 3.08 (d, J = 10.8 Hz, 1H), 26.9, 26.8, 22.2, 21.6, 19.2, 19.1, 13.8, 13.6; HRMS (ESI-TOF)
2.99 (d, J = 16.5 Hz, 1H), 2.96 (d, J = 12.1 Hz, 1H), 2.43 (s, 3H), m/z [M – HCl + Na]+ calcd for C28H38BrNNaO3SSn 690.0675,
1.75 – 1.68 (m, 1H); 13C NMR (126 MHz, CHCl3) δ 149.2, 144.0, found 690.0655.
141.3, 140.8, 135.5, 129.9 (2C), 128.6, 127.6 (2C), 127.5, 126.4, Preparation of TBP complex 6c: A solution of 1a (0.2697 g,
124.7, 108.3 (t, J = 23.7 Hz), 70.8, 65.2, 59.8, 52.9, 39.0, 21.7; 0.46 mmol) in ether (25 mL) was added to 12M HCl (2.5 mL)
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C20H20DNNaO3S and the reaction mixture was stirred at room temperature for
379.1203, found 379.1196.
3 h. The organic phase was separated and washed with brine
Preparation of (5-D) by the presence of DCl: Under nitrogen (2 × 10 mL). After dried over Na2SO4, the organic phase was
atmosphere, Pd(t-Bu3P)2 (0.01664 g, 0.033 mmol) and DABCO filtered and concentrated in vacuo. Obtained crude product
(0.1280 g, 1.14 mmol) and were added to a solution of 1b was purified through flash chromatography (silica gel/hexane-
(0.2173 g, 0.33 mmol) in dry 1,4-dioxane (15 mL) with D2O EtOAc 5:1 then 1:1) to give 6c in 95% yield (0.2471 g, 0.44
(0.75 mL) and conc. DCl aq (4 drops) and the reaction mixture mmol) as colourless viscose oil.
1
was heated to refluxing temperature for 24 h. The solution [α]D –77.1 (c 3.18, CHCl3); H NMR (500 MHz, CHCl3) δ 7.16 –
was filtered, and concentrated in vacuo. The residue was 7.09 (m, 4H), 6.99 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 7.3 Hz, 2H),
subjected to flash column chromatography (silica gel/hexane- 5.26 (s, 1H), 5.15 (s, 1H), 4.80 (s, 1H), 4.55 (d, J = 3.3 Hz, 1H),
EtOAc 5:1 then 1:1) to give 5-D in 95% yield as pale colourless 4.36 (d, J = 13.8 Hz, 1H), 3.97 (d, J = 13.8 Hz, 1H), 3.68 (dd, J =
viscose oil (0.1104 g, 0.31 mmol).
9.9, 4.5 Hz, 1H), 3.37 (dd, J = 9.9, 2.8 Hz, 1H), 2.31 (s, 3H), 1.67
– 1.46 (m, 4H), 1.39 – 1.17 (m, 8H), 1.08 (d, J = 13.7 Hz, J119Sn–
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
1H = 48.5 Hz, 1H), 0.92 (t, J = 8.0 Hz, 3H), 0.81 (t, J = 7.4 Hz, 3H), Preparation of (3aR,8bS)-tert-butyl 3-methylene-1-tosyl-
View Article Online
0.73 (d, J = 13.6 Hz, J119Sn–1H = 70.2 Hz, 1H); 13C NMR (126 1,2,3,3a,4,8b-hexahydroindeno[1,2-b]pyrrole-3a-carboxylate
DOI: 10.1039/C6OB01018K
MHz, CHCl3) δ 148.0, 143.3, 137.3, 135.1, 129.2 (2C), 128.5 (2C), (7): Under nitrogen atmosphere, Pd(t-Bu3P)2 (0.0172 g, 0.034
128.2, 128.1 (2C), 126.9 (2C), 110.7, 69.6, 68.0, 55.4, 51.0, 28.1, mmol) and CsF (0.2548 g, 1.70 mmol) were added to a solution
28.1, 26.9, 26.8, 21.5, 20.7, 20.4, 19.4, 13.7, 13.6; 119Sn NMR of 6a (0.2451 g, 0.32 mmol) in 1,4-dioxane (3.2 mL) and the
(186 MHz, CDCl3) δ 33.3; HRMS (ESI-TOF) m/z [M + H]+ calcd reaction mixture was heated to refluxing temperature for 25 h.
for C28H41ClNO3SSn 626.15176, found 626.15087; Anal. Calcd. The solution was filtered, and concentrated in vacuo. The
for C28H40ClNO3SSn: C, 53.82; H, 6.45; N, 2.24. Found: C, 53.76; residue was subjected to flash column chromatography (silica
H, 6.56; N, 2.22.
gel/hexane-EtOAc 15:1 then 8:1) to give 7 in 87% yield as pale
Preparation of TBP complex 6d: A solution of 1a (0.2239 g, yellow viscose oil (0.1172 g, 0.280 mmol).
0.38 mmol) in ether (21 mL) was added to 12M HCl (2.1 mL) [α]D +21.3 (c 0.45, CHCl3); 1H NMR (500 MHz, CHCl3) δ 7.83 (d,
and the reaction mixture was stirred at room temperature for J = 7.5 Hz, 2H), 7.75 – 7.67 (m, 1H), 7.31 (d, J = 9.1 Hz, 2H), 7.28
1.5 h. The organic phase was separated and washed with – 7.23 (m, 2H), 7.12 (d, J = 6.1 Hz, 1H), 5.80 (s, 1H), 5.29 (s, 1H),
aqueous NaBr solution (2 × 20 mL). After dried over Na2SO4, 5.09 (s, 1H), 4.17 (dt, J = 14.2, 2.5 Hz, 1H), 3.90 (dt, J = 14.2, 1.8
the organic phase was filtered and concentrated in vacuo to Hz, 1H), 3.49 (d, J = 16.9 Hz, 1H), 3.22 (d, J = 16.4 Hz, 1H), 2.41
give 6d in 90% yield (0.2295 g, 0.34 mmol) as colourless (s, 3H), 1.30 (s, 9H); 13C NMR (126 MHz, CHCl3) δ 160.8, 147.4,
viscose oil.
143.5, 140.9, 139.7, 136.1, 129.7 (2C), 128.7, 127.9 (2C), 127.8,
[α]D –83.6 (c 0.87, CHCl3); 1H NMR (500 MHz, CHCl3) δ 7.21 (t, 126.5, 124.4, 109.8, 81.9, 72.7, 63.5, 53.0, 41.2, 27.7 (3C), 21.6;
J = 7.3 Hz, 1H), 7.15 – 7.11 (m, 4H), 6.99 (d, J = 7.9 Hz, 2H), 6.91 HRMS (ESI-TOF) m/z [M + Na]+ calcd for C24H27NNaO4S
(d, J = 7.1 Hz, 2H), 5.27 (s, 1H), 5.16 (s, 1H), 4.81 (s, 1H), 4.68 (s, 448.1559, found 448.1560.
1H), 4.37 (d, J = 13.8 Hz, 1H), 3.97 (d, J = 13.9 Hz, 1H), 3.73 (t, J Conversion of compound 7 to 5: DIBAL (1.5 M in CH2Cl2, 2 mL,
= 8.6, 3.8 Hz, 1H), 3.37 (d, J = 9.8 Hz, 1H), 2.31 (s, 3H), 1.67 – 3 mmol) was added to a solution of 7 (1.8 mg, 0.0042 mmol) in
1.47 (m, 4H), 1.40 – 1.22 (m, 8H), 1.19 (d, J = 14.4 Hz, J119Sn–1H CH2Cl2 (5 mL) at –50 °C and the reaction mixture was stirred
= 73.6 Hz, 1H), 0.92 (t, J = 7.3 Hz, 3H), 0.81 (t, J = 7.7 Hz, 3H), for 11 h. The reaction mixture was allowed to heat to room
0.78 (d, J = 14.4 Hz, J119Sn–1H = 50.2 Hz, 1H); 13C NMR (126 temperature and aqueous Rochell’s salt solution (15 mL) was
MHz, CHCl3) δ 147.9, 143.4, 137.3, 135.0, 129.2 (2C), 128.5 (2C), added. The resulting biphasic mixture was extracted with
128.2 (2C), 128.1, 126.9 (2C), 110.7, 69.5, 68.1, 55.8, 51.0, 28.5 EtOAc (2 × 20 mL). The organic phase was combined and dried
(d, J13C –119Sn = 28.0 Hz), 28.4 (d, J13C –119Sn = 28.0 Hz), 26.8 (d, over Na2SO4. After filtration, the solution was concentrated in
J13C –119Sn = 82.9 Hz, J13C –117Sn = 80.5 Hz), 26.7 (d, J13C –119Sn vacuo to give crude product that was purified by recycled GPC
= 84.6 Hz, J13C –117Sn = 78.8 Hz), 21.5, 21.0 (d, J13C –119Sn = top give 5 in 99% yield (1.5 mg, 0.0042 mmol) as a white solid.
1
435.6 Hz, J13C –117Sn = 416.4 Hz), 20.9 (d, J13C –119Sn = 428.2 Hz, mp 165.0 – 166.0 °C; [α]D +15.8 (c 1.02, CHCl3); H NMR (500
J13C –117Sn = 410.8 Hz), 20.3 (d, J13C –119Sn = 400.0 Hz, J13C – MHz, CHCl3) δ 7.83 (d, J = 8.2 Hz, 2H), 7.68 – 7.62 (m, 1H), 7.34
117Sn = 381.4 Hz), 13.7, 13.6; 119Sn NMR (186 MHz, CDCl3) δ (d, J = 8.0 Hz, 2H), 7.28 – 7.20 (m, 2H), 7.11 (d, J = 6.6 Hz, 1H),
28.8; HRMS (ESI-TOF) m/z [M
+
Na]+ calcd for 5.27 (s, 1H), 5.08 (t, J = 2.2 Hz, 1H), 5.04 (s, 1H), 4.15 (ddd, J =
C28H40BrNNaO3SSn 692.08319, found 692.08200; Anal. Calcd. 15.1, 3.2, 1.5 Hz, 1H), 4.00 – 3.93 (m, 1H), 3.14 – 3.06 (m, 2H),
for C28H40BrNO3SSn: C, 50.25; H, 6.02; N, 2.09. Found: C, 50.45; 3.00 (t, J = 10.4 Hz, 2H), 2.44 (s, 3H), 1.71 – 1.61 (m, 1H) ; 13C
H, 6.13; N, 1.96.
NMR (126 MHz, CHCl3) δ 149.4, 144.0, 141.3, 140.7, 135.6,
Preparation of TBP complex 6f: A solution of 6d (0.125 g, 0.18 129.9 (2C), 128.6, 127.7 (2C), 127.5, 126.4, 124.7, 108.4, 70.8,
mmol) in ether (20 mL) was added to aqueous CsF solution (5g 65.3, 59.9, 52.9, 39.1, 21.7; HRMS (ESI-TOF) m/z [M + Na]+
in 20 mL) and the biphasic mixture was stirred at room calcd for C20H21NNaO3S 378.1140, found 378.1129.
temperature for 2 h. The organic phase was separated and Coupling reaction of 6b to give 5 (Scheme 5): Under nitrogen
dried over Na2SO4. After filtration, the organic phase was atmosphere, Pd(t-Bu3P)2 (0.01615 g, 0.0316 mmol) and DABCO
concentrated in vacuo to give 6f in 85% yield (0.0926 g, 0.152 (0.1130 g, 0.948 mmol) and were added to a solution of 6b
mmol) as colourless oil.
(0.2108 g, 0.299 mmol) in dry 1,4-dioxane (13 mL) and the
[α]D –82.5 (c 0.08, CHCl3); 1H NMR (500 MHz, CHCl3) δ 7.19 (t, reaction mixture was heated to refluxing temperature for 25 h.
J = 7.4 Hz, 1H), 7.16 – 7.08 (m, 4H), 6.97 (d, J = 7.9 Hz, 2H), 6.91 The solution was filtered, and concentrated in vacuo. The
(d, J = 7.7 Hz, 2H), 5.22 (s, 1H), 5.12 (s, 1H), 4.70 (s, 1H), 4.32 (d, residue was subjected to flash column chromatography (silica
J = 13.9 Hz, 1H), 3.95 (d, J = 14.0 Hz, 1H), 3.52 (d, J = 10.3 Hz, gel/hexane-EtOAc 5:1 then 1:1) to give 5 in 62% yield as
1H), 3.23 (d, J = 10.4 Hz, 1H), 2.30 (s, 3H), 1.91 (s, 1H), 1.67 – colourless viscose oil (0.0656 g, 0.185 mmol).
0.97 (m, 13H), 0.91 (t, J = 7.1 Hz, 3H), 0.85 (t, J = 7.7 Hz, 3H),
0.57 (d, J = 13.7 Hz, J119Sn–1H = 73.2 Hz, 1H); 13C NMR (126
MHz, CHCl3) δ 148.7, 143.1, 138.0, 135.8, 129.3 (2C), 128.5 (2C),
Acknowledgements
128.4 (2C), 128.2, 127.1 (2C), 110.4, 69.9, 67.9, 55.3, 51.3, 27.9
(2C), 27.1 (2C), 21.6, 19.0, 18.8, 16.6, 13.9 (2C); 119Sn NMR
(186 MHz, CDCl3) δ 15.56 (d, J = 2081.5 Hz); 19F NMR (376 MHz,
CDCl3) δ –183.8 (d, J = 2052.9 Hz); HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C28H40FNNaO3SSn 632.1633, found 632.1626.
We are grateful to Dr. Yousuke Oota and Dr. Kyouhei Shingai,
UBE Scientific Analysis Laboratory Inc., for the NMR analyses of
several compounds.
12 | J. Name., 2012, 00, 1-3
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Page 13 of 13
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
1979, 91, 140720p. (d) A. Achini, W. Oppolzer and E.
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