Access to Fused Pyrroles from Cyclic 1,3-Dienyl Boronic Esters and Arylnitroso Compounds

Article abstract of DOI:10.1021/acs.joc.9b03214

Complimentary to classical hydroboration and boron-Wittig reactions, a new, efficient access to cyclic 1,3-dienyl boronic esters has been developed via diene or triene metathesis. Subsequently, fused pyrroles were synthesized with a broad substrate scope

Full text of DOI:10.1021/acs.joc.9b03214

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Article
Access to Fused Pyrroles from Cyclic 1,3-Dienyl
Boronic Esters and Arylnitroso Compounds
Benjamin François, Ludovic Eberlin, Fabienne Berrée, Andrew Whiting, and Bertrand Carboni
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03214 • Publication Date (Web): 20 Mar 2020
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of this family, other compounds for which the adjacent ring
Access to Fused Pyrroles from Cyclic 1,3-Dienyl
Boronic Esters and Arylnitroso Compounds
is not aromatic also exhibit remarkable biological activities.
This includes, in particular, 1 which acts as an inhibitor of
the HSP90 protein for regulation of the dopaminergic
pathway in Parkinson's disease,5 2 which blocks CFTR
protein for the treatment of severe diarrhea,6 3 for the
prevention of cellular replication of hepatitis C virus
(HCV),7 and 4, an inhibitor of histone deacetylases that play
an important role in the regulation of gene expression.8 Also,
ketorolac 5 is a nonsteroidal anti-inflammatory drug with
analgesic activity 9 and molindone 6 (Moban) has been used
in the United States as an antipsychotic for the treatment of
schizophrenia.10
Benjamin Francois,† Ludovic Eberlin,† Fabienne Berrée,†
Andrew Whiting,*,‡ Bertrand Carboni*,†
†Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques
de Rennes) - UMR 6226, F-35000 Rennes, France.
‡ Department of Chemistry, Durham University, Science
Laboratories, South Road, Durham DH1 3LE, U.K.
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E-mail: bertrand.carboni@univ-rennes1.fr;
andy.whiting@durham.ac.uk
O
O
N
RECEIVED DATE (will be automatically inserted after
manuscript is accepted).
O
N
N
Br
O
N
O
F
enynes
O
O
NH2
O
Bpin
1
ArNO
OH
2
,ß-unsaturated
aldehydes
N
Ar
O
N
NH2
trienes
H
N
O
O
N
19 examples
38-89 %
N
O
O
O2N
ABSTRACT. Complimentary to classical hydroboration
and boron-Wittig reactions, a new, efficient access to cyclic
1,3-dienyl boronic esters has been developed via diene or
triene metathesis. Subsequently, fused pyrroles were
synthesized with a broad substrate scope from the reaction
of cyclic 1,3-dienyl boronic esters with arylnitroso
4
3
O
O
N
N
HN
O
HO2C
6
5
compounds using
a one-pot hetero-Diels−Alder/ring
contraction sequence.
The synthesis of differently substituted pyrroles has been
the subject of a great deal of work and there are numerous
reviews describing various strategies.11,4c In addition to the
named, classical, methods and their variants, including
INTRODUCTION
14
Hantzsch,12 Knorr,13 Paal-Knorr reactions, or the more
Nitrogenous heterocycles are one of the most commonly
investigated and essential families of organic compounds,
mainly due to their presence in many important molecules
used in various fields ranging from life to materials sciences.
Pyrroles and their derivatives in particular occupy a
prominent place in this family, for example, as basic
structural units in many natural products,1 such as the
porphyrins of heme, the constituents of hemoglobins and
oxygen-carrying myoglobins, and chlorophyll, a pigment
essential to life. They are also found in vitamin B12 and in
many alkaloids isolated from marine organisms such as
15
recently reported van Leussen
and Barton-Zard
syntheses,16 a number of other original strategies based on
17
multicomponent
and (or) transition metal catalyzed
processes 18 have also been developed, as has the use of 3,6-
dihydro-1,2-oxazines as precursors.19 Indeed, some of these
approaches have been applied to fused pyrroles.20 We
recently proposed a new mild synthesis of N-aryl pyrroles
from dienyl pinacol boronic esters and nitrosoarenes 21 and,
in this paper, we expand the scope of this methodology to
22
the preparation of fused pyrroles 8 (Scheme 1) and also
2
lamellarins or spongiacidin B.3 In addition to natural
include new metathesis reactions to access cyclic precursors
7, which complements the classical routes usually employed
for the synthesis of these valuable building blocks.23
products, many pyrrole derivatives of synthetic origin have
remarkable biological activities, including anticancer, anti-
inflammatory, antibiotic, anti-HIV, anti-tuberculosis,
antimalarials, fungicides, etc. Some of them are used for
medicinal purposes, such as atorvastatin and tolmetin, or for
plant treatments, such as chlorfenapyr.4
Among all the molecules of interest having a pyrrole core,
a number of them have also a cyclic structure juxtaposed
with this moiety. While benzofused derivatives, as indoles,
isoindoles and carbazoles, are the most prominent examples
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Scheme 1. Synthesis of cyclic dienyl boronic esters
conversion to fused pyrroles 8.
7
and their
vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (vinyl-Bpin)
has been used occasionally as a metathesis partner with
dienes,28 to our knowledge, it has been never involved in a
one-pot, two-step sequence, making such an approach both
attractive and useful to access a wider range of boronate-
substituted dienes (Scheme 3).
oration
Hydrob
Bpin
Metathesis
Bora-Wittig
or
O
7
Scheme 3. Synthesis of cyclic dienes via a RCEM-CM sequence.
9
Bpin
10
11
12
13
14
15
16
17
18
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ArNO
R
RCEM
CM
Alkene
O
8
R = CO2Me, COMe, CHO, CH2SiMe3, Ph,
alkyl, CH2OAc, CH(OH)Me
Ref 27
pinB
B
N
=
O
Ar
R = Bpin
This work
RESULTS AND DISCUSSION
Hence, our investigations started with enyne 9h as a model
substrate. Conducting the RCEM reaction in DCM at RT for
18h in the presence of the 1st-generation Grubbs catalyst
afforded a mixture of dienes 10 and 7h (55/45 with no
residual starting material) (Eq 1). In the absence of vinyl-
Bpin, the ring closure was complete under the same
experimental conditions (Eq 2). Conversely, a 15%
conversion was observed with enyne 11 where the boronic
ester function was already present on the alkene moiety (Eq
3).29 In parallel, cross metathesis of the isolated diene 10
with vinyl-Bpin was carried out, to deliver only moderate
amounts of 7h (Eq 4). These results suggest that the
cyclization step takes place first in the tandem RCEM/CM
sequence. Finally, the best results were obtained by
conducting this process at reflux in DCM with three
equivalents of vinyl-Bpin over 4h to give boronate-
substituted diene 7h in 48% isolated yield (Eq 5).30
1,3-Dienyl boronic esters 7a-d were first prepared in 70-
86% yields by hydroboration of the corresponding 1,3-
enynes with pinacolborane in the presence of the Schwartz′
reagent (Scheme 2).24 In parallel, an (E)-stereoselective
boron-Wittig reaction between bis[(pinacolato)boryl]
methane and ,-unsaturated aldehydes with lithium
tetramethylpiperidide as base furnished 7e-g in good
yields.25
Scheme 2. Synthesis of cyclic dienyl boronic esters 7a-g by
hydroboration and boron-Wittig reactions.
A. Hydroboration
HBpin (0.8 eq.)
Bpin
Schwartz cat.(0.2 eq.)
0 °C, then rt, 64h
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Tos
N
Tos
N
Tos
N
+
(1)
Grubbs 1 (10%)
DCM, rt,18h
9h
7h
10
100% conversion
(55/45)
7a
7b
7c
7d
(86%)
(72%)
(84%)
(70%)
Grubbs 1 (10%)
B. Boron-Wittig reaction
Tos N
Tos
N
(2)
(3)
(4)
DCM, rt, 18h
LiTMP (1.2 eq.)
pinB-CH2-Bpin (1.2 eq.)
10
78% isolated
100% conversion
9h
Bpin
O
Bpin
THF, -78°C, 5h
Bpin
Grubbs 1 (10%)
Tos
N
Tos
N
DCM, rt, 18h
Bpin
Bpin
Bpin
Tos
15% conversion
7h
11
N
O
Bpin
Bpin
Tos
N
Tos
Tos
N
Grubbs 1 (10%)
DCM, rt,18h
7e
7f
7g
(62%)
(59%)
(56%)
7h
10
43% conversion
To increase the range of cyclic dienyl boronic esters, we
then turned our attention to another approach, i.e. the ring
closing enyne metathesis (RCEM), a powerful tool for the
synthesis of 1,3-diene.26 Such a reaction could be followed
by a cross-metathesis reaction (CM) that then allowed the
post-functionalization of the initial dienyl structure. The
reactants used in this second step were generally mono-
substituted alkenes, whether activated or not.27 Although 2-
Bpin
Bpin
N
Tos
N
Grubbs 1 (10%)
DCM, reflux, 4h
100% conversion
(5)
7h
48% isolated
9h
The scope of this approach was then evaluated under
these optimized conditions with various other enynes
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(Scheme 4). As previously observed for 7h, besides variable
pyrrole 8ba from 7b and nitrosobenzene 13a. Replacement
2
amounts of pinBCH=CHBpin resulting from the self-
coupling of pinacol vinylboronate, dienes 7h-7k were
obtained as (E)-isomers (3JH-H = 18.2 to 18.5 Hz) in moderate
isolated yields mainly due to the low stability of these
compounds during the purification step, in particular in the
case of the dihydrofuran derivative 7i.
of pinacol by diethanolamine (which causes quaternization
of boron, making the diene more electron-rich, and thus
increases the reactivity towards ArNO) had a beneficial
effect as exemplified in Scheme 7.21
3
4
5
6
7
8
Scheme 7. Synthesis of pyrrole 8ba from 7b or its diethanolamine
derivative 7’b.21
9
Scheme 4. Synthesis of cyclic dienyl boronic esters 7h-7k via
a
10
11
12
13
14
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17
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13a
PhNO
O
O
RCEM/CM sequence.
B
MeOH, rt, 16h
21%
N
7b
Bpin
Grubbs 1 (10%)
DCM, reflux, 4h
Bpin
H
+
8ba
13a
PhNO
(3 equiv.)
N
B
MeOH, rt, 2h
48%
9
7
O
7'b
O
Bpin
O
Bpin
Tos
N
However, although tetracoordinated diethanolamine
esters, such as 7’b, appear a priori to be more suitable in
these cycloaddition reactions through higher reactivity
towards nitroso species, their synthesis is sometimes
challenging, often involving only modest yields due to the
products not always being crystalline or readily isolated in a
pure form.33 Pinacol boronate esters remain the most readily
accessible, stable derivatives and are by far the most used in
organic synthesis. Therefore, we decided to study the
influence of an additional, external base/nucleophile, that
could be added in situ to achieve quaternization of the boron
atom as in the case of 7’b and, thus, significantly potentially
increase the yield in the nitroso additions reactions. Indeed,
this strategy was viable and improved reactivity was
observed with different basic/nucleophilic additives
compared to those involving the pinacol ester alone, as
exemplified in Table 1.
7h
(48%)
7i (
47%)
Bpin
Bpin
EtO2C
EtO2C
EtO2C
CbzHN
7j (
7k (
63%)
56%)
Having at our disposal the triene 12,31 we also envisaged
whether this compound could constitute a valuable precursor
of a different cyclic dienyl boronic ester 7l, provided that the
metathesis reaction was regioselective. This was indeed
found to be the case and, after heating in DCM for 24h at
45°C in the presence of the Grubbs 2nd generation catalyst,
the expected boronate 7l was obtained in 70% yield, without
any traces of the 7-membered ring (Scheme 5). Its structure
was confirmed by single crystal X-ray diffraction analysis.32
Table 1. Optimization of the Diels-Alder cycloaddition/cycle contraction
cascade for 7b and PhNO.
Scheme 5. Synthesis of diene 7l from 12 via a RCM reaction.
Bpin
PhNO (2 equiv.), Additive
O
Grubbs II
(5 mol%)
O
Bpin
MeOD, 1M, 3.5h, r.t.
N
Bpin
Ph
O
N
O
Ph
O
N
O
Ph
DCM, 45°C, 24h
7b
8ba
12
7l
70%
entry
1
equiv.
-
yield (%)a
additive
-
Having developed access to a series of different cyclic boryl
dienes 7a-l, we then undertook to evaluate their reactivity in
the presence of aryl nitroso compounds in order to obtain the
corresponding fused pyrroles. Mechanistic aspects of this
reaction have been already investigated and we rationalized
the observed formation of pyrroles by a [4+2]-Diels−Alder
cycloaddition, followed by a ring contraction of the resulting
oxazine (Scheme 6).21
21
20
2
PPh3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.8
0.5
0.8
0.8
3
TMP
27
30
4
DMAP
Diethanolamine
Bu4NOH
DBN
5
33
6
36
7
44
Scheme 6. Proposed mechanism for the formation of pyrroles from the
corresponding boronodienes and arylnitroso compounds.
8
DBU
49
9
DBU
51 (41)b
26
BX2
BX2
10
11
12
DBU
R
R
R
Ring
Nitroso
O
N
O
N
Ar
+
contraction
DBU c
44
N
Diels Alder
R'
Ar
Ar
R'
R'
DBU, mol. sieves d
49
To our knowledge, the only example of cyclic reactants
described to date was reported by us, giving a low yield of
a Yield determined by H NMR on the reaction crude with 1,3,5-
1
trimethoxybenzene as internal standard. b Yield in isolated product after
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c
purification by silica gel chromatography. Dropwise addition of a
diene solution to a mixture DBU and PhNO.d Under argon with
anhydrous DBU and molecular sieves previously activated under 1
mbar at 150 °C for 16 h..
at assisting the conversion of diene 7b to the pyrrole 8ba
(entries 7 and 8). Focussing more on the use of DBU, it was
found that its amount could be advantageously reduced to
0.8 equivalents (see entry 9 and 10). Further optimization by
slow addition of the diene to the nitrosobenzene/DBU
mixture or the presence of molecular sieves gave no positive
significant improvement (see entries 11-12). Hence, using
the best conditions developed herein, the yields, although
still moderate, were significantly improved up to 41% (entry
9), therefore providing a useful entry to the desired pyrrole
systems considering that two successive reactions were
involved in this process.
Examining Table 1, it can be seen that the addition of
triphenylphosphine was only poorly effective (20%, entry 2)
compared with no additive (entry 1). However, the use of an
amine, in general terms, enhanced product yields, perhaps
surprisingly so considering that even the use of a highly
9
10
11
12
13
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17
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hindered
secondary
amine,
i.e.
2,2,6,6,6-
tetramethylpiperidine (TMP, entry 3), increased the yield of
pyrrole 8ba to 27%. The use of the more nucleophilic
DMAP did not show any marked enhancement over the
more hindered TMP (entry 4). Diethanolamine and tetra-n-
butylammonium hydroxide both gave slightly better results
(entries 5 and 6). However, it was the bicyclic and stronger
amidine bases, DBN and DBU, that were the most efficient
We then examined the wider application of this reaction
to establish the scope of the Diels Alder cycloaddition/cycle
contraction cascade to access fused pyrroles from a variety
of cyclic dienes 7.
Scheme 8. Synthesis of fused pyrroles 8 from cyclic dienyl boronic esters 7.
Bpin
+
ArNO
N
MeOH, rt, 3.5h
Ar
13y
8xy
7x
O
N
N
a
N
N
N
N
a
a
a
a
a
8ea
8fa
(45%)
(55%)
8aa
8ba
8ca
8da
(46%)
(46%)
(41%)
(66%)
Cbz
Tos
N
O
EtO2C
EtO2C
N
EtO2C
Tos N
O
N
b
N
N
N
N
CbzHN
N
a
b,c
b,c
b,c
b,c
8ga
8ha
8ia
8ja
8ka
(38%)
(66%)
(52%)
(58%)
(42%)
8la
(89%)
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
N
O
N
O
N
O
N
O
N
O
N
O
N
N
N
N
N
N
Me
CO2Et
b
NO2
b
OMe
Cl
b
Br
b
b
b
8lb
8lc
8ld
8le
8lf
lg
(77%)
(73%)
(67%)
(82%)
(66%)
8
(75%)
a With addition of 0.8 equiv. of DBU.b Without DBU.c Overall yield starting from enynes 9h-k (three steps sequence).
As can be seen in Scheme 8, the borodiene additions
cycloaddition reaction,21 DBU may act to slow the
disproportion reaction relative to the cycloaddition-
rearrangement to the pyrrole, hence improving overall
conversion. Nevertheless, Scheme 8 also shows that the
DBU approach is not absolutely necessary if the diene is
reactive enough. Hence, the reactions of substituted
nitrosobenzenes to diene 7l successfully produced a range of
6,5-fused cycloadducts in 66-89% yields. The diene 7l
seems to be the most reactive system examined in this
reaction to date, whether reacting with either electron rich or
electron deficient nitrosobenzenes (see adducts 8la-8lg,
Scheme 8). All the NMR data were in agreement with the
proceeded in moderate to good yields using nitrosobenzene,
i.e. yields varying from 41-89%. There does not appear to be
any particular trend with respect to yields and ring size or
electronics. Running the reactions of dienes 7b, 7c and 7g
with nitrosobenzene and without the addition of DBU
caused a considerable drop in the yields of cycloadduct in
both cases, i.e. from 41% to 21% (for 7b), 66% to 31% (for
7c) and 66% to 42% (for 7g). This reinforces the positive
role that DBU plays in this reaction, but it is not clear
precisely what that is. In view of the production of azo and
azo-oxide side products in competition with the main
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proposed structures and, in the case of 8ga, it was confirmed
measured using either electrospray ionization (ESI) or
2
3
by single crystal X-ray diffraction analysis.32
atmospheric solids analysis probe (ASAP). X-ray
crystallographic data were collected on an APEXII crystal
diffractometer. Specific rotation (in deg cm3 g-1) was
measured on a Perkin Elmer-341 polarimeter. Melting
points were measured on a melting point apparatus. Stuart
SMP10.
4
5
6
7
8
9
The successful application of the aryl nitroso-cycloaddition
to the cyclic boronate-substituted diene, rearrangement and
pyrrole formation was also extended to outer-ring diene
systems of type 15 (Scheme 9), thus giving access to 3,4-
connected compounds 16, another family of annulated
pyrroles. To exemplify this type of approach, the precursors
15a and 15b were synthesized by a palladium-catalyzed
cycloisomerization of the corresponding enynes 11 and 14
according our previously reported procedure.34 Due to a low
stability observed during purification by chromatography on
silica gel, these dienes were not isolated and we carried out
the following step in the same pot without removing the
palladium catalyst. Products 16a-b were thus obtained in
moderate yields, mainly due to a partial deborylation of 15
during the cycloisomerisation process as previously
observed for similar processes (Scheme 9).34
1-Ethynylcyclopent-1-ene,35 1-ethynylcyclohex-1-ene,36 1-
ethynylcyclohept-1-ene,37 1-ethynylcyclooct-1-ene,37 5,6-
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
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41
42
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44
45
46
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dihydro-2H-pyran-3-carbaldehyde,38
1-tosyl-1,2,3,6-
tetrahydropyridine-4-carbaldehyde,39 9h,40 10,41 11,34 9j,42
9k 43 were prepared as previously described. Perillaldehyde
and 3-(allyloxy)-1-propyne 9i are commercially available.
General procedure for the synthesis of boronates 7a-7d
by catalytic hydroboration. To
a mixture of 1-
ethynylcycloalk-1-ene (1.86 mmol) and Schwartz catalyst
(104 mg, 0.37 mmol) at 0 °C under argon atmosphere, was
added dropwise H-Bpin (216 μL, 1.49 mmol). The reaction
mixture was stirred at room temperature for 64 h, then
diluted with Et2O (10 mL). H2O (5 mL) was cautiously
added. The aqueous layer was extracted with Et2O (3×15
mL). The combined organic layers were washed with brine
(5 mL), dried over anhydrous MgSO4 and evaporated. The
crude product was purified by filtration on silica gel pad,
eluted with a 95/5 pentane/Et2O mixture or by distillation.
Scheme 9. Synthesis of fused pyrroles 16a-b from enynes 11 and 14.
Bpin
Bpin
Pd2(dba)3.CHCl3,
P(o-tol)3, AcOH
PhNO
Tos
N
(
Tos
N
Tos
N
N Ph
toluene, rt, 2h
4h
)
n
(
)
n
11
14
n = 1
n = 2
16a
16b
48% (two steps)
35% (two steps)
15a,b
(E)-2-(2-(Cyclopent-1-en-1-yl)vinyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (7a). 158 mg (72%). Colorless oil, bp
= 70-80°C/0.1 mbar. 1H NMR (300 MHz, CDCl3)  7.25 (d,
J = 18.0 Hz, 1H), 5.94-5.86 (m, 1H), 5.41 (d, J = 18.0 Hz,
1H), 2.44 (t, J = 7.6 Hz, 4H), 1.91 (quint, J = 7.6 Hz, 2H),
1.28 (s, 12H). The spectroscopic data match with those
reported in the literature.44
(E)-2-(2-(Cyclohex-1-en-1-yl)vinyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (7b). 197 mg (84%). Colorless oil, bp
= 90-110°C/0.1 mbar. H NMR (400 MHz, CDCl3)  7.02
(d, J = 18.2 Hz, 1H), 6.01-5.92 (m, 1H), 5.42 (d, J = 18.2
Hz, 1H), 2.19-2.10 (m, 4H), 1.70-1.54 (m, 4H), 1.27 (s,
12H). The spectroscopic data match with those reported in
the literature.44
(E)-2-(2-(Cyclohept-1-en-1-yl)vinyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (7c). 325 mg (70%). Colorless oil. H
NMR (300 MHz, CDCl3) δ 6.99 (d, J = 18.2 Hz, 1H), 6.09
(t, J = 6.8 Hz, 1H), 5.45 (d, J = 18.2 Hz, 1H), 2.37-2.29 (m,
2H), 2.29-2.19 (m, 2H), 1.80-1.70 (m, 2H), 1.54-1.42 (m,
4H), 1.26 (s, 12H). 13C{1H} NMR (75 MHz, CDCl3) δ 153.9,
144.4, 139.1, 83.1, 32.3, 29.0, 26.7, 26.4, 26.2, 24.9. The
carbon α to boron was not observed. 11B{1H} NMR (96
MHz, CDCl3) δ 29.8. HRMS (ESI+) (M+Na)+ calculated for
C15H25O211BNa 271.1840, found 271.1843.
(E)-2-(2-(Cyclooct-1-en-1-yl)vinyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (7d). 421 mg (86%). Colorless oil, bp
= 100-120°C/0.1 mbar. 1H NMR (300 MHz, CDCl3) δ 6.98
(d, J = 18.2 Hz, 1H), 5.92 (t, J = 8.3 Hz, 1H), 5.48 (d, J =
18.2 Hz, 1H), 2.44-2.35 (m, 2H), 2.27-2.15 (m, 2H), 1.58-
1.36 (m, 8H), 1.28 (s, 12H). 13C{1H} NMR (75 MHz,
CONCLUSION
In summary, we have realized the synthesis of a series of
fused pyrroles from the corresponding 1,3-dienyl boronate
esters, which adds to the chemist's armory of classical
synthetic methods for accessing pyrrole-containing products
and especially the more unusual fused bicyclic systems. For
this particular application, a new route involving a ring
closing enyne metathesis / cross-metathesis sequence was
also developed to access novel boryl dienes that,
subsequently, give access to a supplementary range of
products with diversified structures.
1
EXPERIMENTAL SECTION
1
Solvents were freshly distilled from sodium/benzophenone
(THF, toluene) or phosphorus pentoxide (DCM). Methanol
and other commercially available chemicals were used
without further purification. Column chromatography
purifications were performed over silica gel (Merck
Geduran 60, 0.063–0.200 mm). Flash chromatography
purifications were performed on a Grace RevelerisTM with
PuriflashTM 15µm flash cartridges (Interchim). NMR spectra
were recorded at 300 or 400 MHz for 1H, 75 or 101 MHz for
13C and 96 or 128 MHz for 11B. 1H and 13C NMR chemical
shifts were referenced to Me4Si as internal reference, and 11B
NMR chemical shifts to external BF3·OEt2. All 13C and 11B
NMR were proton-decoupled. High-resolution mass spectra
(HMRS) were obtained on a Q-TOF instrument and
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CDCl3) δ 153.0, 140.9, 137.3, 83.2, 30.3, 28.6, 27.6, 27.0,
flask, under an argon atmosphere, was dissolved enyne (1.0
26.2, 25.0, 23.9. The carbon α to boron was not observed.
11B{1H} NMR (96 MHz, CDCl3) δ 29.6. HRMS (ESI+)
(M+Na)+ calculated for C16H27O211BNa 285.1996, found
285.1997.
mmol) in anhydrous DCM (35 mL). To this solution was
added vinylboronic acid pinacol ester (509 μL, 3.0 mmol).
The resulting mixture was degassed by slow bubbling of
argon for 10 minutes before the introduction of Grubbs 1
catalyst (81 mg, 0.1 mmol). The reaction mixture was stirred
at reflux for 4 hours. DCM was evaporated and the product
was purified by flash chromatography (cyclohexane/EtOAc:
100/0 to 95/5). The reaction was also carried out on a 2.5
mmol scale for 7h.
3
4
5
6
7
8
9
General procedure for the synthesis of boronates 7e-7g
via a Boron-Wittig reaction. An oven-dried Schlenk
charged with bis(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-
yl)methane (429 mg, 1.6 mmol) and dry THF (2.1 mL) was
sealed under argon with a septum cap. The reaction vial was
cooled to 0°C, and a solution of LiTMP (235 mg, 1.6 mmol)
in dry THF (1.6 mL) was added dropwise. The reaction was
allowed to stir for 5 min. at 0°C and then cooled to -78°C.
After addition of a solution of the aldehyde (1.3 mmol) in
dry THF (2.8 mL), the reaction mixture was stirred at -78°C
for additional 5 h. Upon completion, the solvent was
removed under reduced pressure. The product was isolated
by silica gel chromatography (cyclohexane/EtOAc: 100/0 to
90/10).
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(E)-3-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-
yl)vinyl)-1-tosyl-2,5-dihydro-1H-pyrrole (7h). 180 mg
(48%). 650 mg (69%) on a 2.5 mmol scale. Colorless oil,
1
Rf= 0.59 (cyclohexane/EtOAc: 95/5). H NMR (300 MHz,
CDCl3) δ 7.71 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H),
6.98 (d, J = 18.4 Hz, 1H), 5.72 (brs, 1H), 5.34 (d, J = 18.4
Hz, 1H), 4.21 (s, 4H), 2.42 (s, 3H), 1.26 (s, 12H). The
spectroscopic data match with those reported in the
literature.34
(E)-2-(2-(2,5-Dihydrofuran-3-yl)vinyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (7i). 103 mg (47%). Colorless oil, Rf=
0.69 (cyclohexane/EtOAc: 8/2). 1H NMR (300 MHz,
CDCl3) δ 7.16 (d, J = 18.5 Hz, 1H), 5.97 (brs, 1H), 5.31 (d,
J = 18.3 Hz, 1H), 4.79-4.67 (m, 4H), 1.27 (s, 12H). 13C{1H}
NMR (75 MHz, CDCl3) δ 141.4, 139.7, 128.3, 83.6, 76.3,
74.2, 24.9. The carbon α to boron was not observed. 11B{1H}
NMR (128 MHz, CDCl3) δ 29.3. HRMS (ESI+) (M+H)+
calculated for C12H2011BO3 223.1505, found 223.1495.
(S,E)-4,4,5,5-Tetramethyl-2-(2-(4-(prop-1-en-2-
yl)cyclohex-1-en-1-yl)vinyl)-1,3,2-dioxaborolane (7e). 76
mg (59%). Colorless oil, Rf= 0.52 (cyclohexane/EtOAc:
1
95/5). H NMR (300 MHz, CDCl3) δ 7.03 (d, J = 18.2 Hz,
1H), 6.00-5.92 (m, 1H), 5.42 (d, J = 18.2 Hz, 1H), 4.76-4.64
(m, 2H), 2.37-2.22 (m, 2H), 2.21-2.01 (m, 3H), 1.94-1.82
(m, 1H), 1.72 (d, J = 1.0 Hz, 3H), 1.55-1.38 (m, 1H), 1.26
(s, 12H). 13C{1H} NMR (75 MHz, CDCl3) δ 152.7, 149.5,
136.9, 133.5, 112.7 (br), 108.9, 83.1, 41.2, 31.7, 27.4, 24.9,
24.3, 20.9. 11B{1H} NMR (96 MHz, CDCl3) δ 31.0. HRMS
(ESI+) (M+Na)+ calculated for C17H27O211BNa 297.1996,
found 297.1996.
Ethyl
(E)-1-((benzyloxycarbonyl)amino)-3-(2-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)cyclopent-3-ene-
1-carboxylate (7j). 247 mg (56%). Colorless oil, Rf= 0.37
1
(cyclohexane/EtOAc: 8/2). H NMR (300 MHz, CDCl3) δ
7.37-7.31 (m, 5H), 7.16 (d, J = 18.2 Hz, 1H), 5.80 (s, 1H),
5.40 (brs, 1H), 5.39 (d, J = 18.2 Hz, 1H), 5.09 (s, 2H), 4.27-
4.11 (m, 2H), 3.26-3.07 (m, 2H), 2.87-2.70 (m, 2H), 1.27 (s,
12H), 1.21 (t, J = 7.2 Hz, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 173.8, 155.4, 144.8, 141.1, 136.4, 130.7, 128.6,
128.2, 128.2, 118.2 (br), 83.4, 66.8, 64.4, 61.9, 45.0, 43.1,
24.9, 14.2. 11B{1H} NMR (128 MHz, CDCl3) δ 31.0. HRMS
(ESI+) (M+Na)+ calculated for C24H32NO611BNa 464.2215,
found 464.2218.
Diethyl (E)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)vinyl)cyclopent-3-ene-1,1-dicarboxylate (7k). Colorless
oil, 229 mg (63%). Rf= 0.42 (cyclohexane/EtOAc: 8/2).1H
NMR (400 MHz, CDCl3) δ 7.13 (d, J = 18.3 Hz, 1H), 5.73-
5.77 (m, 1H), 5.45 (d, J = 18.4 Hz, 1H), 4.20 (q, J = 7.1 Hz,
4H), 3.10-3.15 (m, 4H), 1.27 (s, 12H), 1.25 (t, J = 7.2 Hz,
6H). 13C{1H} NMR (101 MHz, CDCl3) δ 172.0, 144.8,
141.3, 130.7, 118.2 (br), 83.4, 61.7, 58.9, 41.2, 39.1, 24.9,
14.1. 11B{1H} NMR (128 MHz, CDCl3) δ 31.2. HRMS
(ESI+) (M+Na)+ calculated for C19H29NO611BNa 387.1955,
found 387.1952.
(E)-2-(2-(3,6-Dihydro-2H-pyran-4-yl)vinyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (7f). 174 mg (56%).
Colorless oil, Rf= 0.24 (Cyclohexane/EtOAc: 9/1). 1H NMR
(400 MHz, CDCl3) δ 6.91 (d, J = 18.7 Hz, 1H), 6.03 (s, 1H),
5.26 (d, J = 18.7 Hz, 1H), 4.35-4.27 (m, 2H), 3.74 (t, J = 5.5
Hz, 2H), 2.30-2.23 (m, 2H), 1.26 (s, 12H). 13C{1H} NMR
(101 MHz, CDCl3) δ 148.8, 136.2, 129.9, 83.4, 65.3, 64.2,
26.1, 24.9. The carbon α to boron was not observed. 11B{1H}
NMR (128 MHz, CDCl3) δ 30.4. HRMS (ESI+) (M+Na)+
calculated for C13H21O311BNa 259.1476, found, 259.1479.
(E)-5-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-
yl)vinyl)-1-tosyl-1,2,3,6-tetrahydropyridine (7g). 318 mg
(62%). White solid, mp = 130-132 °C. Rf= 0.18
1
(cyclohexane/EtOAc: 9/1). H NMR (300 MHz, CDCl3) δ
7.67 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 6.90 (d, J
= 18.6 Hz, 1H), 5.97-5.92 (m, 1H), 5.36 (d, J = 18.6 Hz, 1H),
3.74-3.66 (m, 2H), 3.17 (t, J = 5.7 Hz, 2H), 2.42 (s, 3H),
2.38-2.29 (m, 2H), 1.26 (s, 12H). 13C{1H} NMR (75 MHz,
CDCl3) δ 148.7, 143.7, 133.43, 133.41, 130.3, 129.8, 127.8,
83.5, 44.4, 42.7, 26.1, 24.9, 21.6. The carbon α to boron was
not observed. 11B{1H} NMR (96 MHz, CDCl3) δ 30.1.
HRMS (ESI+) (M+Na)+ calculated for C20H28NO411BNaS
412.1724, found 412.1724.
Synthesis of benzyl (E)-4-(2-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)vinyl)-3,6-dihydro-2H-1,2-oxazine-2-
carboxylate (7l). In a flame dried Schlenk flask under an
argon flow, boronated triene 12 (170 mg, 0.43 mmol) 31 was
dissolved in anhydrous degassed dry DCM (13 mL) and
Grubbs catalyst 2nd generation (18 mg, 0.021 mmol) was
General procedure for the synthesis of boronates 7h-7k
via a RCEM-CM sequence. In a dry 2-neck round-bottom
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added. The reaction mixture was stirred at 45 °C for 24 h.
3H), 6.80 (d, J = 2.9 Hz, 1H), 6.13 (d, J = 2.9 Hz, 1H), 4.78
2
After evaporation of the solvent, the residue was purified by
silica gel chromatography (cyclohexane/EtOAc: 100/0 to
80/20) to afford 7l as a white solid (98 mg, 70%), mp = 124-5
(s, 2H), 2.78-2.53 (m, 4H), 2.42-2.32 (m, 1H), 2.04-1.94 (m,
1H), 1.78 (s, 3H), 1.76-1.66 (m, 1H). 13C{1H} NMR (101
MHz, CDCl3) δ 149.8, 140.3, 129.3, 127.9, 126.3, 124.7,
120.4, 118.8, 109.3, 108.0, 42.9, 29.0, 28.9, 23.5, 21.0.
HRMS (ASAP+) (M+H)+ calculated for C17H20N 238.1596,
found 238.1591.
1-Phenyl-1,4,5,7-tetrahydropyrano[3,4-b]pyrrole (8fa). 33
mg (55%). White solid, mp = 55-57°C, Rf= 0.19
(pentane/Et2O : 95/5). 1H NMR (300 MHz, CDCl3) δ 7.48-
7.40 (m, 2H), 7.31 (dt, J = 7.0, 3.0 Hz, 3H), 6.82 (d, J = 2.9
Hz, 1H), 6.07 (d, J = 2.9 Hz, 1H), 4.76 (t, J = 1.6 Hz, 2H),
3.93 (t, J = 5.5 Hz, 2H), 2.72 (t, J = 5.5 Hz, 2H). 13C{1H}
NMR (75 MHz, CDCl3) δ 139.7, 129.4, 126.5, 124.9, 124.2,
120.5, 117.8, 105.1, 65.6, 65.1, 24.7. HRMS (ESI+)
(M+Na)+ calculated for C13H13NONa 222.0889, found
222.0889.
3
4
5
6
7
8
9
1
°C. Rf= 0.05 (cyclohexane/EtOAc: 8/1). H NMR (400
MHz, CDCl3) δ 7.42-7.29 (m, 5H), 6.97 (d, J = 18.5 Hz, 1H),
5.98 (brs, 1H), 5.48 (d, J = 18.5 Hz, 1H), 5.21 (s, 2H), 4.53
(d, J = 2.7 Hz, 2H), 4.31 (d, J = 2.1 Hz, 2H), 1.27 (s, 12H).
13C{1H} NMR (101 MHz, CDCl3) δ 155.5, 147.0, 136.0,
133.0, 128.7, 128.4, 128.3, 127.2, 115.8 (br), 83.6, 68.7,
67.9, 44.8, 24.9.11B{1H} NMR (96 MHz, CDCl3) δ 30.0.
HRMS (ESI+) (M+H)+ calculated for C20H27NO510B
371.2019, found 371.2015.
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19
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25
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60
General procedure for the synthesis of fused pyrroles 8aa
to 8ga. In a flame dried round-bottom flask under an argon
atmosphere, was dissolved boronated diene 7 (0.30 mmol)
in MeOH (0.3 mL) and DBU (38 mg, 37μL, 0.25 mmol).
The resulting mixture was stirred at room temperature for 5
minutes and PhNO (64 mg, 0.60 mmol was added. The
reaction was stirred for 3.5 hours at room temperature.
MeOH was evaporated and the residue was purified by silica
gel chromatography (cyclohexane/EtOAc: 100/0 to 95/5).
1-Phenyl-5-tosyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-
c]pyridine (8ga). 70 mg (66%). Yellow solid, mp = 138-
1
139°C, Rf= 0.27 (cyclohexane/EtOAc: 9/1). H NMR (400
MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 2H), 7.41 (t, J = 7.7 Hz,
2H), 7.34-7.28 (m, 3H), 7.19 (d, J = 7.8 Hz, 2H), 6.77 (d, J
= 2.9 Hz, 1H), 6.05 (d, J = 2.9 Hz, 1H), 4.23 (s, 2H), 3.39 (t,
J = 5.7 Hz, 2H), 2.70 (t, J = 5.7 Hz, 2H), 2.41 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 143.5, 139.5, 134.4,
129.7, 129.5, 127.8, 126.8, 125.0, 124.3, 121.2, 115.1,
106.0, 44.6, 44.0, 23.9, 21.6. HRMS (ESI+) (M+Na)+
calculated for C20H20N2O2NaS 375.1138, found 375.1140.
1-Phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole (8aa).45
25 mg (46%). Yellow oil, Rf= 0.68 (pentane/Et2O: 94/6). 1H
NMR (300 MHz, CDCl3) δ 7.45-7.34 (m, 4H), 7.25-7.18 (m,
1H), 6.94 (d, J = 2.8 Hz, 1H), 6.13 (d, J = 2.9 Hz, 1H), 2.89
(t, J = 7.0 Hz, 2H), 2.70 (t, J = 7.0 Hz, 2H), 2.47 (p, J = 7.1
Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 140.9, 137.2,
129.5, 129.2, 125.2, 122.4, 121.0, 105.4, 29.4, 26.9, 25.5.
1-Phenyl-4,5,6,7-tetrahydro-1H-indole (8ba). 24 mg (41%).
General procedure for the synthesis of fused pyrroles 8ha
to 8ka.
In a flame dried round-bottom flask under an argon
atmosphere, was dissolved in MeOH (0.3 mL) the crude
boronated diene 7 (0.30 mmol) resulting from the RCEM-
CM sequence after evaporation of the methylene chloride.
To this mixture was added PhNO at room temperature (64
mg, 0.60 mmol). The reaction was stirred for 3.5 hours.
MeOH was evaporated and the residue was purified by silica
gel chromatography (cyclohexane/EtOAc: 100/0 to 95/5).
The reaction was also carried out on a 1.7 mmol scale for
8ha.
1
Colorless oil, Rf = 0.43 (cyclohexane/EtOAc: 95/5). H
NMR (300 MHz, CDCl3) δ 7.45-7.38 (m, 2H), 7.33-7.27 (m,
3H), 6.77 (d, J = 2.6 Hz, 1H), 6.10 (d, J = 2.6 Hz, 1H), 2.60
(m, 4H), 1.85-1.73 (m, 4H). 13C{1H} NMR (75 MHz,
CDCl3) δ ppm 140.4, 129.2, 128.2, 126.2, 124.6, 120.0,
119.1, 108.2, 23.8, 23.6, 23.5, 23.3. The spectroscopic data
match with those reported in the literature.21
1-Phenyl-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole
45
(8ca). 41 mg (66%). Yellow oil, Rf= 0.59 (cyclohexane
/EtOAc: 95/5). 1H NMR (300 MHz, CDCl3) δ 7.47-7.39 (m,
2H), 7.36-7.30 (m, 1H), 7.29-7.23 (m, 2H), 6.60 (d, J = 2.7
Hz, 1H), 6.06 (d, J = 2.7 Hz, 1H), 2.71-2.59 (m, 4H), 1.89-
1.79 (m, 2H), 1.79-1.69 (m, 2H), 1.68-1.58 (m, 2H). 13C{1H}
NMR (75 MHz, CDCl3) δ 140.7, 131.9, 129.0, 126.7, 126.3,
123.9, 119.0, 109.7, 32.4, 29.0, 28.7, 27.9, 27.1.
1-Phenyl-5-tosyl-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrole
(8ha). 53 mg (52%). 270 mg (47%) on a 1.7 mmol scale.
1
Yellow oil, Rf= 0.20 (cyclohexane/EtOAc: 9/1). H NMR
(300 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 2H), 7.46-7.38 (m,
2H), 7.34-7.19 (m, 5H), 6.93 (d, J = 2.9 Hz, 1H), 6.07 (d, J
= 2.9 Hz, 1H),4.67-4.59 (m, 2H), 4.51-4.44 (m, 2H), 2.40 (s,
3H). 13C{1H} NMR (75 MHz, CDCl3) δ 143.6, 139.6, 134.8,
130.0, 130.0, 129.1, 127.6, 126.2, 123.5, 122.7, 120.6,
104.1, 49.6, 49.0, 21.6. HRMS (ESI+) (M+Na)+ calculated
for C19H18N2O2NaS 361.0981, found 361.0979.
1-Phenyl-4,6-dihydro-1H-furo[3,4-b]pyrrole (8ia). 32 mg
(58%). Colorless oil, Rf= 0.75 (cyclohexane/EtOAc: 8/2). 1H
NMR (300 MHz, CDCl3) δ 7.46-7.37 (m, 2H), 7.26-7.18 (m,
3H), 7.05 (d, J = 2.8 Hz, 1H), 6.15 (d, J = 2.8 Hz, 1H), 5.10-
5.03 (m, 2H), 5.00-4.93 (m, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 139.8, 133.5, 129.8, 126.6, 125.5, 123.2, 119.7,
1-Phenyl-4,5,6,7,8,9-hexahydro-1H-cycloocta[b]pyrrole
(8da). 31 mg (46%). Yellow oil, Rf= 0.63
(cyclohexane/EtOAc: 95/5). 1H NMR (300 MHz, CDCl3) δ
7.47-7.39 (m, 2H), 7.37-7.27 (m, 3H), 6.68 (d, J = 2.8 Hz,
1H), 6.06 (d, J = 2.8 Hz, 1H), 2.70-2.58 (m, 4H), 1.72-1.61
(m, 2H), 1.59-1.39 (m, 6H). 13C{1H} NMR (75 MHz,
CDCl3) δ 140.9, 130.1, 129.1, 126.9, 126.4, 121.7, 120.1,
108.8, 31.3, 30.2, 26.1, 26.0, 25.8, 23.3. HRMS (ESI+)
(M+H)+ calculated for C16H20N 226.1590, found 226.1590.
(R)-1-Phenyl-6-(prop-1-en-2-yl)-4,5,6,7-tetrahydro-1H-
indole (8ea). 32 mg (45%). Yellow oil, Rf= 0.27
1
(cyclohexane). [α]20 = -48.2 (c= 0.01, CH2Cl2). H NMR
D
(400 MHz, CDCl3) δ 7.44 (t, J = 7.7 Hz, 2H), 7.33-7.28 (m,
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103.2, 69.4, 67.6. HRMS (ASAP+) (M+H)+ calculated for
C12H12NO 186.0919, found 186.0912.
13C{1H} NMR (101 MHz, CDCl3) δ 158.6, 155.6, 136.1,
132.2, 128.7, 128.4, 128.3, 124.8, 123.6, 121.3, 114.9,
114.0, 105.7, 67.9, 67.8, 55.7, 45.1. HRMS (ESI+) (M+H)+
calculated for C21H21N2O4365.1501, found 365.1500.
Ethyl
5-(((benzyloxy)carbonyl)amino)-1-phenyl-1,4,5,6-
tetrahydrocyclopenta[b]pyrrole-5-carboxylate (8ja). 51 mg
1
(42%). Yellow oil, Rf= 0.19 (cyclohexane/EtOAc: 9/1). H
Benzyl
1-(2-methylphenyl)-4,7-dihydropyrrolo[3,2-
NMR (300 MHz, CDCl3) δ 7.44-7.28 (m, 9H), 7.23 (t, J =
7.2 Hz, 1H), 6.94 (d, J = 2.9 Hz, 1H), 6.08 (d, J = 2.9 Hz,
1H), 5.53 (brs, 1H), 5.15-5.01 (m, 2H), 4.29-4.11 (m, 2H),
3.82 (d, J = 15.7 Hz, 1H), 3.33-3.16 (m, 2H), 2.88 (d, J =
15.3 Hz, 1H), 1.23 (t, J = 6.8 Hz, 3H). 13C{1H} NMR (75
MHz, CDCl3) δ 173.2, 155.5, 140.3, 136.4, 133.3, 129.6,
128.6, 128.3, 128.2, 125.6, 123.7, 123.2, 121.0, 105.2, 70.6,
67.0, 61.9, 39.4, 38.7, 14.2. HRMS (ESI+) (M+Na)+
calculated for C24H24N2O4Na 427.1628, found 427.1634.
d][1,2]oxazine-5(1H)-carboxylate (8ld). 46 mg (67%).
Yellow oil. Rf = 0.25 (cyclohexane/EtOAc: 6/1).1H NMR
(400 MHz, CDCl3) δ 7.41-7.29 (m, 7H), 7.24 (m, 1H), 7.14
(m, 1H), 6.63 (d, J = 2.8 Hz, 1H), 6.16 (d, J = 2.8 Hz, 1H),
5.24 (s, 2H), 4.76 (s, 2H), 4.70 (s, 2H), 2.08 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 155.7, 137.9, 136.2, 135.3,
131.3, 128.7, 128.6, 128.3, 128.2, 127.4, 126.8, 124.3,
122.0, 113.0, 105.2, 67.8, 67.5, 45.0, 17.4. HRMS (ESI+)
(M+H)+ calculated for C21H21N2O3 349.1552, found
349.1548.
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Diethyl
1-phenyl-4,6-dihydrocyclopenta[b]pyrrole-
5,5(1H)-dicarboxylate (8ka). 37 mg (38%). Colorless oil,
Benzyl
dihydropyrrolo[3,2-d][1,2]oxazine-5(1H)-carboxylate
(8le). 66 mg, (82%). Orange oil. Rf 0.25
1-(4-(ethoxycarbonyl)phenyl)-4,7-
1
Rf= 0.61 (cyclohexane/EtOAc: 8/2). H NMR (400 MHz,
CDCl3) δ 7.48-7.38 (m, 2H), 7.40-7.33 (m, 2H), 7.27-7.22
(m, 1H), 6.94 (d, J = 2.9 Hz, 1H), 6.08 (d, J = 2.9 Hz, 1H),
4.24 (qd, J = 7.1, 1.3 Hz, 4H), 3.59 (s, 2H), 3.39 (s, 2H), 1.29
(t, J = 7.2 Hz, 6H). 13C{1H} NMR (75 MHz, CDCl3) δ 171.8,
140.4, 132.5, 129.6, 125.5, 125.4, 123.4, 121.1, 105.2, 65.2,
61.9, 35.1, 34.3, 14.2. HRMS (ESI+) (M+Na)+ calculated for
C19H21NO4Na 350.1368, found 350.1360.
=
(cyclohexane/EtOAc: 6/1).1H NMR (400 MHz, CDCl3) δ
8.13-8.10 (m, 2H), 7.43-7.32 (m, 5H), 7.23-7.19 (m, 2H),
6.91 (d, J= 3.0 Hz, 1H), 6.22 (d, J= 3.0 Hz, 1H), 5.26 (s, 2H),
5.02 (s, 2H), 4.74 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J
= 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 165.8,
155.7, 142.7, 136.1, 131.4, 128.7, 128.6, 128.4, 128.3,
123.5, 122.1, 120.8, 115.9, 107.3, 68.0, 67.9, 61.4, 45.1,
14.5. HRMS (ESI+) (M+H)+ calculated for C23H23N2O5
407.1607, found 407.1603.
General procedure for the synthesis of fused pyrroles 8la
to 8lg. In a flame dried round-bottom flask under an argon
atmosphere, was dissolved boronated diene 7l (0.20 mmol)
and ArNO (0.40 mmol) in DCM/MeOH (6/1) (2 mL). The
resulting mixture was stirred at room temperature for 24h.
The solvent was evaporated and the residue was purified by
silica gel chromatography (cyclohexane/EtOAc: 100/0 to
95/5).
Benzyl
d][1,2]oxazine-5(1H)-carboxylate (8lf). 58 mg (66%).
Yellow solid, mp 92-95 °C. Rf 0.35
1-(4-bromophenyl)-4,7-dihydropyrrolo[3,2-
=
=
1
(cyclohexane/EtOAc: 6/1,). H NMR (400 MHz, CDCl3) δ
7.59-7.52 (m, 2H), 7.44-7.31 (m, 5H), 7.08-7.02 (m, 2H),
6.82 (d, J= 2.9 Hz, 1H), 6.19 (d, J = 2.9 Hz, 1H), 5.25 (s,
2H), 4.97 (s, 2H), 4.74 (s, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 155.6, 138.2, 136.1, 132.9, 128.7, 128.4, 128.3,
124.6, 123.4, 120.9, 120.4, 115.2, 106.8, 68.0, 67.7, 45.1.
HRMS (ESI+) (M+H)+ calculated for C20H1879BrN2O3
413.0501, found 413.0507.
Benzyl 1-phenyl-4,7-dihydropyrrolo[3,2-d][1,2]oxazine-
5(1H)-carboxylate (8la). 59 mg (89%). Orange oil, Rf = 0.30
1
(cyclohexane/EtOAc: 6/1). H NMR (400 MHz, CDCl3) δ
7.47-7.29 (m, 8H), 7.22-7.17 (m, 2H), 6.87 (d, J = 2.9 Hz,
1H), 6.19 (d, J = 2.9 Hz, 1H), 5.26 (s, 2H), 5.00 (s, 2H), 4.76
(s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.6, 139.1,
136.1, 129.8, 128.7, 128.4, 128.3, 126.9, 123.4, 123.1,
121.0, 114.7, 106.3, 68.0, 67.9, 45.1. HRMS (ESI+) (M+H)+
calculated for C20H19N2O3 335.1396, found 335.1391.
Benzyl
d][1,2]oxazine-5(1H)-carboxylate (8lg). 56 mg (75%).
Yellow solid, mp 143-144 °C, Rf= 0.30
1-(4-nitrophenyl)-4,7-dihydropyrrolo[3,2-
=
1
(cyclohexane/EtOAc: 6/1). H NMR (400 MHz, CDCl3) δ
8.35 (d, J = 9.0 Hz, 2H), 7.46-7.28 (m, 7H), 6.97 (d, J = 3.0
Hz, 1H), 6.29 (d, J = 3.0 Hz, 1H), 5.29 (s, 2H), 5.06 (s, 2H),
4.76 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.5,
145.5, 144.1, 135.8, 128.6, 128.4, 128.3, 125.6, 123.5,
122.2, 120.8, 116.9, 108.3, 68.0, 67.7, 45.0. HRMS (ESI+)
(M+H)+ calculated for C20H18N3O5 380.1246, found
380.1261.
Benzyl
1-(4-chlorophenyl)-4,7-dihydropyrrolo[3,2-
d][1,2]oxazine-5(1H)-carboxylate (8lb). 57 mg (77%).
Yellow oil, Rf= 0.35 (cyclohexane/EtOAc: 6/1).1H NMR
(400 MHz, CDCl3) δ 7.44-7.31 (m, 7H), 7.14-7.09 (m, 2H),
6.82 (d, J = 2.9 Hz, 1H), 6.19 (d, J = 2.9 Hz, 1H), 5.26 (s,
2H), 4.96 (s, 2H), 4.74 (s, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 155.6, 137.7, 136.1, 132.6, 130.0, 128.7, 128.4,
128.3, 124.3, 123.4, 121.0, 115.1, 106.7, 68.0, 67.7, 45.1.
HRMS (ESI+) (M+H)+ calculated for C20H18ClN2O3
369.1006, found 369.1013.
Synthesis
of
(E)-N-(But-3-yn-1-yl)-4-methyl-N-(3-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)allyl)benzenesulfonamide 14. To a Schlenk flame dried
under an argon atmosphere were sequentially added N-(but-
3-yn-1-yl)-4-methylbenzenesulfonamide (214 mg, 0.96
mmol), (E)-2-(3-chloroprop-1-en-1-yl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (289 mg, 1.43 mmol), potassium
carbonate (264 mg, 1.91 mmol), Bu4NI (177 mg, 0.48 mmol)
and anhydrous DMF (8 mL). The Schlenk was closed with a
Benzyl
1-(4-methoxyphenyl)-4,7-dihydropyrrolo[3,2-
d][1,2]oxazine-5(1H)-carboxylate (8lc). 53 mg (73%).
Orange oil, Rf = 0.15 (cyclohexane/EtOAc: 6/1) (1H NMR
(400 MHz, CDCl3) δ 7.43-7.31 (m, 5H), 7.15-7.09 (m, 2H),
6.97-6.91 (m, 2H), 6.78 (d, J = 2.9 Hz, 1H), 6.15 (d, J = 2.9
Hz, 1H), 5.25 (s, 2H), 4.94 (s, 2H), 4.75 (s, 2H), 3.84 (s, 3H).
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glass stopper and the reaction mixture was heated to 50°C in
1H, 13C and 11B spectra of compounds 7, 8, 14 and 16a-b; X-
2
3
4
5
6
7
8
9
an oil bath for 65 hours. After cooling to room temperature,
water (30 mL) and EtOAc (35 mL) were added. Layers were
separated and the organic phase was washed with water
(2×30 mL), dried over anhydrous MgSO4 and concentrated.
The residue was purified by silica gel chromatography
(cyclohexane/ EtOAc: 100/0 to 80/20) to afford 14 as a
colorless oil (228 mg, 61%). Rf= 0.30 (cyclohexane/EtOAc:
80/20).1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz,
2H), 7.28 (d, J = 8.3 Hz, 2H), 6.39 (dt, J = 18.0, 5.7 Hz, 1H),
5.53 (dt, J = 18.0, 1.6 Hz, 1H), 3.91 (dd, J = 5.7, 1.6 Hz, 2H),
3.31-3.27 (m, 2H), 2.46-2.39 (m, 5H), 1.95 (t, J = 2.7 Hz,
1H), 1.24 (s, 12H). 13C{1H} NMR (101 MHz, CDCl3) δ
147.0, 143.5, 137.0, 129.8, 127.3, 122.6, 83.5, 81.1, 70.3,
52.5, 46.6, 24.9, 21.6, 19.3. 11B{1H} NMR (128 MHz,
CDCl3) δ 29.4. HRMS (ESI+) (M+H)+ calculated for
C20H2910BNO4S 389.1924, found 389.1947.
ray diffraction data of 7l. This material is available free of
charge on the ACS Publications website at DOI:
AUTHOR INFORMATION
Corresponding Authors
* andy.whiting@durham.ac.uk
* bertrand.carboni@univ-rennes1.fr
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ORCID
Benjamin François: 0000-0002-8030-0809
Fabienne Berrée: 0000-0003-1811-0585
Andy Whiting: 0000-0001-8937-8445
Bertrand Carboni: 0000-0003-0529-715X
Notes
General procedure for the palladium-catalyzed
isomerisation/ring contraction sequence of boronated
enynes 11 and 14.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
A flame dried Schlenk was charged with Pd2dba3.CHCl3 (5.2
mg, 0.05 mmol), tri-o-tolylphosphine (3.0 mg, 0.01 mmol),
acetic acid (0.6 L, 0.001 mmol) and toluene (1 mL). After
stirring 15 min at room temperature, enyne 14 (0.2 mmol)
was added and the mixture was kept 2 hours at room
temperature under an argon atmosphere. To this crude
mixture was then added PhNO (64 mg, 0.6 mmol). After
stirring for 4h at room temperature, the volatiles were
removed and the residue was purified by silica gel
chromatography (cyclohexane/EtOAc: 100/0 to 85/15).
We acknowledge the Ministère de l’Education Nationale,
de la Recherche et de la Technologie, the Centre National de
la Recherche Scientifique (CNRS) and the Région Bretagne
for financial supports. We also thank Andrei S. Batsanov
(Chemistry Department, Durham University) and Marie
Cordier (Centre de Diffractométrie X, ISCR, Rennes) for X-ray
crystallographic structure determinations.
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(16a). 32 mg (48%). Colorless oil. Rf= 0.44
(cyclohexane/EtOAc: 8/2). H NMR (300 MHz, CDCl3) δ
1
7.78 (d, J = 8.2 Hz, 2H), 7.43-7.35 (m, 2H), 7.33-7.26 (m,
5H), 6.74 (s, 2H), 4.47 (s, 4H), 2.41 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 143.5, 140.85, 134.45, 129.9, 129.8,
127.7, 126.1, 124.9, 120.8, 110.7, 48.2, 21.7. HRMS (ESI+)
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(cyclohexane/EtOAc: 9/1). H NMR (400 MHz, CDCl3) δ
1
7.77-7.68 (m, 2H), 7.42-7.37 (m, 2H), 7.34-7.28 (m, 4H),
7.24 (tt, J = 7.1, 1.2 Hz, 1H), 6.78 (s, 2H), 4.25 (s, 2H), 3.39
(t, J = 5.9 Hz, 2H), 2.82 (t, J = 5.9 Hz, 2H), 2.44 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 143.5, 140.7, 134.2,
129.7, 129.7, 127.8, 125.7, 120.3, 118.3, 117.3, 115.1,
113.6, 44.8, 43.7, 22.5, 21.7. HRMS (ESI+) (M+Na)+
calculated for C20H20N2O2SNa 375.1143, found 375.1141.
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Benzopyrimido-pyrrolo-oxazine-dione CFTR inhibitor (R)-BPO-27 for
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ASSOCIATED CONTENT
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