Employing Small Polyfunctionalized Molecules for a Diastereoselective Synthesis of Highly Substituted Indolines

Article abstract of DOI:10.1002/ejoc.201800528

An efficient approach has been developed for the diastereoselective synthesis of 1,2,3-trisubstituted indolines. The reaction sequence includes the highly diastereoselective reductive amination of 2-oxo-1,3-propanediols, which are prepared by postfunctionalization of Morita–Baylis–Hillman (MBH) adducts, to give substituted 2-amino-1,3-propanediols with an anti relative configuration. A subsequent intramolecular palladium-catalyzed Buchwald coupling reaction provided the 1,2,3-trisubstituted indolines in 47–82 % yield. The preference for the anti diastereomer was investigated by Gibbs free energy diagrams and applying theoretical calculations at the M06–2X/6-31+G** level.

Full text of DOI:10.1002/ejoc.201800528

A Journal of
Accepted Article
Title: Employing small poly-functionalized molecules for a
diastereoselective synthesis of highly substituted indolines
Authors: Fernando Antonio Santos Coelho, Fabio de Souza
Fernandes, Rodrigo Antonio Cormanich, Lucas André Zeoly,
and André Luiz Barboza Formiga
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800528
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800528
Supported by

10.1002/ejoc.201800528
European Journal of Organic Chemistry
FULL PAPER
Employing small poly-functionalized molecules for a
diastereoselective synthesis of highly substituted indolines
Fábio de Souza Fernandes, [a] Rodrigo A. Cormanich, [a] Lucas A. Zeoly, [a] André Luiz B. Formiga [b]
and Fernando Coelho*[a]
Abstract: An efficient approach to the diastereoselective synthesis
of 1,2,3-trisubstituted indolines is described. The sequence is based
on a highly diastereoselective reductive amination of 2-oxo-1,3-
propanediols prepared by post-functionalization of Morita-Baylis-
Hillman (MBH) adducts giving substituted 2-amino-1,3-propanediols
with anti relative stereochemistry, that were submitted to an
intramolecular palladium catalyzed Buchwald coupling reaction to
provide 1,2,3-trisubstituted indolines in 47-82% yield. The preference
for the anti diastereomer was investigated by obtaining reaction
Gibbs free energy diagrams applying M06-2X/6-31+G** theoretical
calculations.
Introduction
The indoline scaffold is present in the structure of a large
amount of bioactive alkaloids. Some representative examples of
those are depicted below (Figure 1).
Strempeliopine (1) was isolated by Laguna et al. from the Cuban
plant Strempeliopsis strempelioides K. Schum. [1][2] Derivatives of
this alkaloid, isolated from East-African monotypic shrub
Schizozygia coffaeoides (Boj.) Bull are used for the treatment of
skin diseases and also exhibit antifungal and antimicrobial
activity.[3]
OH
N
O
O
H
N
H2N
OH
N
H
N
N
H
H
N
H
H
OH
MeO2C
O
N
OAc
Strempeliopine (1)
Vinblastine (2)
Benzastatin E (3)
H
Me CO2Me
HO
CO2CH3
N
HO
Oleracein A: R1= glu; R2 = R3= H (5a)
Oleracein B: R1= glu; R2 = H; R3 = OCH3
(5b)
Oleracein C: R1= R2= glu, R3 = H (5c)
Olarecein D: R1 = R2 = glu; R3 = OCH3 (5d)
O
N
H
R1O
N
CO2H
R3
CH3
O
Corymine (4)
OR2
O
O
OHC
N
H
N
N
OH
O
N
N
HN
N
N
O
H
CO2CH3
N
N
H
H
O
CH3
CH3
Communensin F (7)
Aspidophylline A (8)
Chaetominine (6)
Figure 1. Some representative examples of biologically active natural products having the indoline scaffold into theirs structures.
Vinblastine (2), a vinca alkaloid isolated from Catharanthus
roseus is a selective tubulin inhibitor currently used in cancer
chemotherapy,[4] while Benzastatin E (3) is a free radical
scavenger with potential use on the treatment of brain ischemia
present anticonvulsant activity.[6] The indoline amide glycosides
oleracein A-B (5a-d) present a good anti-oxidant activity,[7] quite
similar to that showed by Vitamin C.[8] These compounds
present a varied range of biological activities.[8] Finally, the
structurally complex alkaloids Chaetominine (6),[9] Communensin
(7)[10] and Aspidophylline A (8)[11] showed a high potential as
candidate for anticancer agents.
injury.[5] Corymine (4),
akuammiline alkaloids, is a glycine receptor antagonist and
a structurally complex member of
Due to the combination of intriguing structural complexity and
interesting biological activities, efforts to develop approaches to
the synthesis of indoline alkaloids have attracted considerable
attention in the world.[1-11]
[a]
[b]
Dr. Fabio de Souza Fernandes, Mr. Lucas A. Zeoly, Prof. Dr.
Rodrigo A. Cormanich and Prof. Dr. Fernando Coelho
Institute of Chemistry, Department of Organic Chemistry
Prof. Dr. André Luiz B. Formiga
As these compounds are isolated in very small quantities from
their natural sources, organic synthesis is an efficient tool to
circumvent this issue.
Institute of Chemistry, Department of Inorganic Chemistry
University of Campinas - Rua Josué de Castro, s/n – PO Box 6154
13083-970 – Campinas,SP – Brazil; E-mail:coelho@iqm.unicamp.br
Currently, the methodologies for the synthesis of indolines can
be divided in metal-catalyzed reactions, metal-free reactions,
Supporting information for this article is given via a link at the end of
the document
1
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10.1002/ejoc.201800528
European Journal of Organic Chemistry
FULL PAPER
and radical-mediated reactions.[12] Among the metal mediated
reactions, Pd-catalyzed cross-coupling reactions are widely
used, because of the continued development of reliable and
versatile catalysts that function under operationally simple and
user-friendly conditions.[13] The method introduced by Buchwald
and Hartwig became a classical in the synthesis of indolines via
intramolecular C–N coupling between an aryl halide and an
amine.[14],[15] This approach showed to be an efficient way for the
construction of a variety of indolines in mild conditions with great
functional group tolerance and broad substrate compatibility.
Since then, a variety of methods were developed for the
2004, Lira and Wolfe described a Pd-catalyzed sequential N-
arylation/cyclization/C-arylation reaction between 2-allylaniline
and two different aryl halides obtaining a diverse variety of
indolines. By in situ modification of the Pd catalyst through
ligand exchange, the protocol became one-pot (Scheme 1, part
B). [17]
So far, the methodologies described using C-N cross-coupling
via Pd were employed only for the synthesis of 1,2-disubstituted
indolines. Most recently, Presset and co-workers [18] developed a
methodology to obtain 1,2,3-trisubstituted indolines using a zinc-
mediated Mannich reaction, followed by an intramolecular Pd
catalyzed aromatic amination (Scheme 1, part C). However, the
step to formation of key intermediates showed poor yields, low
diastereoselectivity and in the case of 1,2,3-trisubstituted
indolines the dihalogenated compound used is not commercialy
available. Also, variation in the group at benzyl position can take
construction of indolines through
a combination of the
intramolecular aryl amination reaction with other reactions. In
2003, Doye et al. developed a protocol to obtain β-arylamines
from ortho-bromoiodobenzenes, terminal alkynes and primary
amines. Finally, the indolines were obtained by a Pd-catalyzed
intramolecular amination of aryl halides (Scheme 1, part A).[16] In
a
formation of dimerics and not desired products.
I
R1
A
3 steps
Pd2(dba)3
+
+ R2-NH2
R1
R1
Disubstituted
indolines
NHR2
N
Cl
Br
Br
R2
N
N
Pd2(dba)3
Pd2(dba)3
DPEphos
B
(tBu )P( -biphenyl)
Ar1
o
2
Disubstituted
indolines
N
ArBr
Ar1Br
R
NH2
Ar
Br
Br
C
PdCl2(PPh3)2
NaOtBu or Cs2CO3
O
R1
Zn
+
Trisubstituted
indolines
+ R2-NH2
R1
H
R1
NHR2
TFA
N
Br
R2
Scheme 1. Some methodologies for the synthesis of indolines using intramolecular C-N cross-coupling reactions.
Inspired by the synthetic and biological relevance of the indoline
scaffold and based in our accumulated experience in the
synthesis of N-heterocyclic compounds using Morita-Baylis-
Hillman (MBH) adducts,[19] we envisioned that functionalized
1,2,3-trisubstituted
indolines
could
be
obtained
diastereoselectively from these small functionalized molecules
(MBH adducts), according to the retrosynthetic sequence
depicted below ( Scheme 2).
Substituted indolines
R1
OH
R1
R2
CO2Me
R2
R
NHR3
R
R
N
X
X
R3
a-Amino-b-hydroxy-ester
or a-Amino-1,3-diol
Poly-functionalized
small molecules
(MBH adducts)
R = EWG or EDG
R1 = OTBS
R2 = CO2Me(Et) or CH2OTBS
R3 = COCH3
Scheme 2. Retrosynthetic analysis for the synthesis of substituted indolines from MBH adducts.
The target substituted indolines could be prepared from a metal
mediated cyclization reaction, the Buchwald-Hartwig reaction,
required aminoesters or aminodiols, as consequence of that we
expect to attain a good control on the diastereoselectivity of the
synthesis of indolines.[20]
[14],[15]
for example, using a -amino--hydroxyester or a 2-
amino-1,3-diol, easily prepared from Morita-Baylis-Hillman
adducts. Based on previous results, we can anticipate a good
control on the diastereoselectivity of the preparation of the
In this work we describe the diastereoselective synthesis of
substituted indolines from Morita-Baylis-Hillman adducts,
2
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10.1002/ejoc.201800528
European Journal of Organic Chemistry
FULL PAPER
theoretical NMR calculations to explain some observed J-
experiments. Probably the presence of a voluminous silane
protecting group, as TBS, might explain this experimental result
(Scheme 3).
coupling constants and
a theoretical calculation study to
rationalize the high level of diastereoselectivity observed. As far
as we know this is the first report on the synthesis of indolines
starting from small poly-functionalized molecules, as MBH
adducts.
Table 1. Morita-Baylis-Hillman reaction. Preparation of the starting materials
OH
O
O
CO2R
Ar
OR
Ar
H
DABCO, AcOH
ultrasound
Results and Discussion
MBH adducts
(9-15)
We began our studies by preparing a set of different MBH
adducts 9-15 using an optimization of an experimental protocol
previously described by us.[21] Thus, a set of commercial
aldehydes were treated with methyl or ethyl acrylate (3 equiv.) in
the presence of DABCO (2 equiv.) and acetic acid (2 equiv.).
The crude mixtures were placed in an ultrasound bath for some
hours to form the corresponding adducts in good to excellent
yields (Table 1).
Entry
Aldehyde
R
Time (h)
Product,
Yield (%)[a]
1
2
3
4
5
6
7
2-Br-Phenyl
2-Br-Phenyl
2-Br-piperonyl
Ethyl
6
9, 95
Methyl
Ethyl
5
10, 97
11, 97
12, 98
13, 93
14, 99
15, 98
144
96
4
2-Br-3,5-dimethoxy-Phenyl
2-Br-6-F-Phenyl
Ethyl
With MBH adducts 9-15 in hands, 9 was chosen as model to
optimize the synthetic route (Scheme 2). So, based on previous
results,[20] 9 was transformed into the key intermediate 20, which
in turn could be used for the synthesis of indolines. Thus, using
a straighforward sequence, the secondary hydroxyl group of
adduct 9 was silylated to give the silyl ether 16 in excellent
Ethyl
2-Br-4-F-Phenyl
Methyl
Methyl
8
2-Br-5-NO2-Phenyl
2
0
yield.[21] The ozonolysis of 16 at -78 C for 15 minutes, followed
[a] Refer to isolated and purified products.
by the reductive work-up with dimethyl sulfide afforded the -
ketoester 17, which was not isolated and treated in situ with
hydroxylamine hydrochloride in the presence of pyridine, at 60
0C, to give, after 2h, the corresponding oxyimino ester 18 in
good yield. This step led to a mixture of cis/trans isomers, which
Attempts to perform directly the intramolecular C-N cross-
coupling reaction of amino ester 19 using NaOtBu and Cs2CO3
failed. In both cases, the desired indoline was not detected, but
just a complex mixture of side-products. In the literature there
are several examples of this cross-coupling reaction using an
amide instead of an amine.[14]
was reduced in the presence of
a
mixture of
NaBH3CN/MoCl5/NaHSO4.H2O to form the corresponding amino
ester 20, in excellent diastereoselectivity, confirmed by NMR
OR
O
OR
O
OR
O
OTBS
CO2Et
a,b
c, d, e
OEt
f
OEt
OEt
NHR1
X
Br
N
Br
Br
Ac
9, R = H
21
19, R = TBS; R1 = H
20, R = TBS; R1 = Ac
only diastereoisomer
16, R = TBS, X = CH2
17, R = TBS, X = O
18, R = TBS, X = N OH
Reagents and conditions: a) TBSOTf, Et3N, CH2Cl2, 0 °C to r.t, 30 min, 95%. b) O3, 20 min, -78 °C, CH3OH then DMS, 30 min, r.t. c) NH2OH.HCl, Pyridine,
CH3OH, 60 °C, 2h, 73% for two steps. d) MoCl5, NaBH3CN, NaHSO4.H2O, EtOH, 60 °C, 2h, 55%. e) Ac2O, pyridine, CH2Cl2, 0 °C to r.t., 1h, 99%. f) Pd2(dba)3
10mol%, P(o-tolyl)3 20 mol%, Cs2CO3 (2 equiv.), toluene (0.55 mol-1), 100 °C, 5h, N2, 37%.
Scheme 3. Synthetic sequence for the preparation of indoline 21.
Thus, -aminoester 19 (see Scheme 3) was treated with acetic
anhydride in pyridine to furnish 20, in almost quantitative yield.
To complete the sequence the intramolecular aromatic
amination of β-arylamide 20 was performed, according to a
protocol established by Buchwald [14] giving the indoline 21, as a
The lower yield for this step can be attributed a possible cross-
coupling between the dba of catalyst with aryl bromo moiety of
20.[22]. Briefly, 1,2,3-trisubstituted indoline 21 was synthesized in
5 steps in an overall yield of 17%.
When this sequence was applied to MBH adduct 11 we isolated,
at the end, an indole, instead of the required indoline. Attempts
to circumvent this issue, by changing the temperature and the
solvent were completely unsuccessful. Then, we decided to
change the catalyst and we carried out some reactions using
mixture of rotamers at room temperature. In
experiment at 90 °C no NOE effect was observed between the
five-membered ring hydrogens, suggesting trans
stereochemistry for the product (see supporting information).
a NOESY
a
3
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10.1002/ejoc.201800528
European Journal of Organic Chemistry
FULL PAPER
copper.[23] Unfortunately, all attempts failed. We believe that the
presence of an acidic hydrogen atom in position  of the ester
carboxyl group could be responsible for the undesired
observed on double bond oxidation. Compound 24 was treated
by a flow of ozone/oxygen at –78 °C for 20 minutes to give, after
reductive work-up with dimethyl sulfide, the di-protected 2-oxo-
1,3-propanediols 25, which in turn, was used as substrate for a
reductive amination reaction. So, a methanolic solution of 25
was treated, at room temperature, with an excess of NH4OAc, as
nitrogen source, in the presence of NaHCO3 and sodium
cyanoborohydride (NaBH3CN) to afford the aminodiol 26 in an
overall yield of 45% (two step). The NMR analysis of the crude
mixture indicated again the presence of only one diastereomer
(Scheme 4).
elimination reaction. To avoid this problem, we made
a
modification in our synthetic sequence by including an ester
reduction step to the corresponding alcohol, thus disfavoring the
elimination and consequently the indole formation.
Then, the secondary hydroxyl group of the MBH adduct was
silylated to form 22 in 95% yield. Ester reduction, followed by
acetylation of the primary hydroxyl group gave the di-protected
allyl diol 24 in 46%, for two steps. The acetylation of the primary
hydroxyl group was necessary to prevent some byproducts
Reagents and conditions: a) TBSOTf, Et3N, CH2Cl2, 0 °C to r.t., 30 min., 95%. (b) DIBAL-H, CH2Cl2, -78 °C, 1h, 53%. (c) Ac2O, CH2Cl2, pyridine, 0 °C to r.t., 30
min., 80%. (d) O3, 20 min, -78 °C, CH3OH then DMS, 30 min, r.t. e) NH4OAc, NaHCO3, NaBH3CN, r.t., 16h, 45% (2 steps from 23). f) TBSOTf, Et3N, CH2Cl2, 0 °C
to r.t., 30 min, 35%. g) Pd2(dba)3 10 mol%, P(o-tolyl)3 20 mol%, Cs2CO3 (2 equiv.), toluene (0.55 mol-1), 100 °C, 5h, N2, 84%.
Scheme 4. Modified synthetic sequence for the preparation of indoline.
In this step we observed an internal migration of the acetyl group
from the oxygen atom to the newly incorporated nitrogen
atom.[24] To facilitate the final purification step and avoiding
chelation issues,[25] a dichloromethane solution of amino-diol 26
was treated with TBSTf, at 0 ºC, in the presence of triethylamine,
to give the corresponding silylated compound 27 in 35% for this
particular case. Attempts to improve this yield by changing the
solvent, silylating agent or base failed. Finally, 27 was submitted
to the conditions of the Buchwald-Hartwig reaction to provide tri-
substituted indoline 28 in 84% yield. By using this approach, 28
was synthesized, for the first time, as a sole diastereomer, in 7
steps in an overall yield of 5%. Although this approach is longer
than that initially developed, it proved to be reliable, being easily
extended to other MBH adducts, as depicted below (Scheme 5).
OTBS
OTBS
OH
OTBS
R1
R1
a
b
c
OAc
OH
R
R
R
R
Br
Br
Br
Br
10, R = H; R1= CO2CH3
12
13, R = 6-F;R1= CO2Et
29, R = H; R1= CO2CH3
34, R = H;
35
36, R = 6-F;
37, R = 4-F;
38
, R = 5-O2N
39, R = H;
40
R
,
= 3,5-CH3O; R1= CO2Et
30
R
R
, = 3,5-CH3O
,
= 3,5-CH3O; R1= CO2Et
R
,
= 3,5-CH3O
41, R = 6-F;
42
31, R = 6-F; R1= CO2Et
32, R = 4-F; R1= CO2CH3
14, R = 4-F;R1= CO2CH3
, R = 4-F;
43, R = 5-O2N
15
, R = 5-O2NR1= CO2CH3
33
, R = 5-O2N; R1= CO2CH3
d
OTBS
OTBS
OTBS
O
OTBS
OR1
f
a or c
e
OR1
OH
NHAc
OAc
NHAc
N
R
R
R
R
Br
Br
Br
Ac
59, R = H; R1 = Ac
60, R = 3,5-CH3O; R1 = TBS
61
49
, R = H;
50, R = 3,5-CH3O
, R = 6-F;
, R = 4-F;
44
, R = H;
54
, R = H; R1 = Ac
45, R = 3,5-CH3O
46
55, R = 3,5-CH3O; R1 = TBS
51
52
56
, R = 6-F;
, R = 6-F; R1 = Ac
57, R = 4-F; R1 = Ac
58
, R = 6-F; R1 = Ac
62, R = 4-F; R1 = Ac
63
47, R = 4-F;
48, R = 5-O2N
53, R = 5-O2N
, R = 5-O2N; R1 = Ac
, R = 5-O2N; R1 = Ac
Highly diastereoselective
Only anti isomer detected
Reagents and conditions: a) TBSOTf, Et3N, CH2Cl2, 0 °C to r.t., 30 min., 29 (98%), 30 (92%), 31 (97%), 32 (92%), 33 (82%). b) DIBAL-H, CH2Cl2, -78 °C, 1h, 34
(56%), 35 (67%) 36 (57%), 37 (51%), 38 (71%). c) Ac2O, CH2Cl2, pyridine, 0 °C to r.t, 30 min., 39 (92%), 40 (68%) 41 (92%), 42 (89%), 43 (93%). d) O3, 20 min, -
78 °C, CH3OH then DMS, 30 min, r.t. e) NH4OAc, NaHCO3, NaBH3CN, r.t., 16h, 49 (51% for 2 steps from 39), 50 (75% for 2 steps from 40), 51 (41% from 2 steps
from 41), 52 (45% from 2 steps from 42), 53 (32% from 2 steps from 43). a) Silylation, 55 (26%). (c) 54 (81%). 56 (49%), 57 (83%), 58 (88%). f) Pd2(dba)3
10mol%, P(o-tolyl)3 20 mol%, Cs2CO3 (2 equiv.), PhMe (0.55 Mol/L), 100 °C, 5h, N2, 59 (55%), 60 (67%), 61 (82%), 62 (47%), 63 (47%).
Scheme 5. Straightforward total synthesis of tri-substituted indolines from Morita-Baylis-Hillman adducts.
4
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10.1002/ejoc.201800528
European Journal of Organic Chemistry
FULL PAPER
By using a simple sequence we were able to synthesize a set of
silylated acyloins (44-48),[26] which were transformed to tri-
substituted indolines with a total control on the process
diastereoselectivity. Is important to mention that the indoline 60
was not obtained as a mixture of rotamers at room temperature.
It can be relationated to steric effect because of presence of
methoxy group adjacent of acyl group. These new heterocyclic
compounds were prepared in 7 steps in moderate overall yield.
The high level of diastereoselectivity observed in the 1,2-
asymmetric induction of the reductive amination step was
studied by applying theoretical calculations at the M06-2X/6-
31+G** level and using the IEFPCM (Integral Equation
Formalism variant of the Polarizable Continuum Model) method
form the syn product (see Figure S2 in the SI). Although the syn
product is considered to be more stable than the anti, hence,
being the first the thermodynamic product (Figure S2 in the SI),
the anti product is formed faster and should be the major
compound obtained when the reaction is conducted over kinetic
control.
A similar approach was then carried out for the reductive
amination step of 47 to form 52 (Figure 2). Only for the lowest
energy and less sterically hindered transition states, which have
a nucleophile approach through a H atom in  position to the
carbonyl carbon atom are shown in Figure 2. It was considered
the ortho Br atom in two different conformations (see the SI for
TS graphical pictures and Cartesian coordinates). The presence
of the Br atom in ortho position (Figure 2) increases the TS
energies for both faces in comparison with its analogue without
any substituents in the phenyl ring. However the energy
increase is higher for the TS that lead to formation of the syn
product in comparison to the anti, being the ΔΔG≠ of 5.32 kcal
mol-1 favoring the anti product (Figure 2). The analogue without
the Br atom in ortho position has a lower ΔΔG≠ of 4.78 kcal mol-1
(Figure S2 in the SI), i.e., the ortho Br atom increases the
diastereoselectivity of the reductive amination step favouring the
anti diastereomer. That is in agreement with the experimental
results, which indicate a anti:syn ratio of 87:13[24] for the
analogue without any substituents in the phenyl ring and of
>99:1 for 38.
with parameters for methanol.[27] In
a first approach we
investigated the reaction without any substituents in the phenyl
ring (see Figure S2, in supporting information), which was
compared with the conversion of 47 to 52 (Scheme 5 and Figure
2).
The syn (P1) or anti (P2) product formation ratios are dependent
on the preferred iminium ion carbon atom face of attack by the
NaBH3CN reactant. By considering the Felkin-Ahn model[28] and
the Bürgi–Dunitz angle of attack[29], we calculated three different
transition states (TS) for each iminium ion carbon face (Figure
S2 in the SI). As anticipated by the Felking-Ahn model, the
nucleophile approach through the less hindered group (H atom
in this case) is the lowest in energy on both iminium ion faces
(TS1a and TS2a in Figure S2 in the SI). However, the energy
barrier to form the anti product is 4.78 kcal mol-1 lower than to
OAc
NCH2B
H
H
OTBS
NH2
Br
TS1b
Br
F
12.41
TBSO NH2
OAc
G = 5.32 kcal mol-1
TS1a
NCH2B
H
F
H
OTBS
12.26
H
Br
OAc
NH2
TS2b
NCH2B
H
7.51
F
TS2a
TBSO NH2
H
6.93
F
OAc
Br
NCH2B
H
SM
0.00
P2
Br
OTBS
O
-3.26
O
Br
OTBS
O
P1
NH2
F
-4.86
O
OTBS
O
Br
NH2
+
F
NaBH3CN
O
NH2
F
Figure 2. Theoretical calculations for the reductive amination step obtained at the M06-2X/6-31+G** level in methanol (IEFPCM) for 47. The relative Gibbs free
energies (ΔG) and relative Gibbs free energies between the lowest energy transition states (ΔΔG≠) were obtained at standard temperature and pressure and
values in kcal mol-1 are shown for each species.
5
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10.1002/ejoc.201800528
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The data obtained from theoretical calculations clearly confirmed
our experimental observations referring the high degree of
diastereoselection achieved in this synthetic sequence.
frequency calculations obtained at B3LYP/6-31G(d) optimized
geometries (see the SI for the cartesian coordinates of all
conformers employed in the SSCC calculations) .
Although no correlation was observed in the NOESY experiment
previously done, we decided to perform theoretical NMR
calculations in order to confirm the relative stereochemistry of
the synthesized indolines. The spin-spin coupling constant
(SSCC) between the hydrogens of the 5-membered ring was
calculated for both diastereomers (pseudo-cis and pseudo-trans)
As shown in the Figure 3, the 3JHH SSCC is predicted to be large
for 21-cis and very small for 21-trans. Such result from the
theoretical calculations in line with the expected Karplus curve
3
that correlates JHH SSCC values and the dihedral angle
between the coupled H atoms.[33] Indeed, the calculated H-C-C-
H dihedral angle for 21-cis lowest energy conformer is 22.736°
and for 21-trans lowest energy conformer is 102.297°. Thus, our
3
of the cyclic indoline 21 (Figure 3). The JHH SSCC can be a
valuable tool in the stereochemical analysis of cyclic compounds. theoretical calculations indicate the experimentally obtained
3
For rigid 5-membered rings, the vicinal SSCC JHH-cis has in
diastereomer of 21, that shows an observed 3JHH SSCC of 0 Hz,
as 21-trans, which has a close to zero calculated JHH of 0.95
3
3
most cases a larger value than the JHH-trans, which is close to
zero depending on the dihedral angle between the two H atoms
being analyzed.[30] Indoline 21 was chosen due to its simplicity
and lack of flexibility. After a Monte Carlo conformational search
with the MMFF force field, the most stable conformers (within
5.25 kcal mol-1 potential energy threshold) of both diastereomers
(21-cis and 21-trans) were reoptimized at the B3LYP/6-31G(d)
level of theory using the IEF-PCM implicit solvent model with
parameters for DMSO.[27] The SSCCs were calculated by the
GIAO[31] method and using the B3LYP functional and EPR-III
basis set for hydrogens and the 6-31+G(d,p) basis set for
heavier atoms.[32] The calculated SSCCs were Boltzmann
averaged using the populations obtained from Gibbs free
energies calculated at the M06-2X/6-31+G(d,p) single points
corrected with the results from the previous B3LYP/6-31G(d)
Hz.
The results obtained by theoretical NMR calculations about the
relative stereochemistry of indolines were confirmed by X-ray
diffraction of crystal of 28 (Figure 4). The trans sterochemistry is
unequivocally assigned in the crystal structure of 28
(crystallographic data is shown on supporting information file).
The experimental H-C-C-H dihedral angle is –102.66 and the
H2C-C-C-O dihedral is +145.10. Bond distances are in the
typical range, e.g. the carbonyl C=O distance is 1.225(3) Å and
the Si-O distances are 1.65 Å in average. The numbering
scheme, tables with bond distances and angles, cell packing
diagrams as well as detailed information on the crystallographic
determination are available as Supporting Information.
21-trans lowest energy configuration
21-cis lowest energy configuration
OTBS
H
OTBS
O
H
O
H
N
OEt
N
H OEt
Ac
Ac
Indoline21-trans
3JHH(calc.) = 0.95 Hz
Dihedral angle= - 102.297°
Indoline21-cis
3JHH(calc.) = 10.79 Hz
Dihedral angle= 22.736°
3JHH(exp.) = 0 Hz
Figure 3. Calculated SSCCs values (in Hz) and dihedral angles (degrees) for 21-cis and 21-trans diastereoisomers
Figure 4. Crystal structure of indoline 28 with atomic displacement ellipsoids at the 50% probability level. Silicon is shown in light orange, oxygen in red, nitrogen
in blue and carbon in light gray and hydrogen in cyan.
6
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10.1002/ejoc.201800528
European Journal of Organic Chemistry
FULL PAPER
Conclusions
favorable forming the anti product when there is an Br atom in
the ortho position. The synthetic approach is very simple and
relies on methods that can be reproducible in any organic
synthesis laboratory over the world. In principle is possible to
synthesize a huge collection of poly-substituted indolines simply
changing the aldehyde used on the Morita-Baylis-Hillman, which
pointed out the great versatility of the approach described herein.
We believe that this new methodology can be employed in the
synthesis of natural compounds in the future. Efforts on this
direction are ongoing in our laboratory and the results will be
disclosed in due time. As far as we know, this is the first report
describing the synthesis of indolines from Morita-Baylis-Hillman
adducts.
In summary, in this work we reported on the synthesis of 1,2,3-
substituted indolines using poly-functionalized molecules, as the
MBH adducts, as substrates. The first route developed allowed
us to synthesize indoline 21 in 7 steps with 17% overall yield.
The second route developed allowed us to obtain the indolines
28, 59-63 in 7 steps with overall yields of 5,0%, 4,3%, 4,8%,
7,8%, 7,0%, and 7,0% respectively. The reductive amination
was the key step to control the diastereoselectivity giving 1,2,3-
trisubstituted indolines with trans-conformation, which was
confirmed by 2D NMR experiment. The diastereoselectivity of
this step was evaluated by DFT theoretical calculations, which
highlighted, in agreement with experiment, that the anti product
is formed faster than the syn, being the reaction even more
General procedure for silylation of compounds 16, 22, 27, 29-33, 55
To a stirred solution of starting material (16, 22, 27, 29-33, 55) in 0.05M
of anhydrous dichloromethane at 0°C, were added (under an inert gas
atmosphere), triethylamine (1.5 eq), TBSOTf (1.2 eq) and then, it was
allowed to warm-up to r.t. After 30 minutes, the analysis by TLC revealed
the complete consumption of the starting material. The solvent was
evaporated under vacuum and was made the extraction with Ethyl
acetate and solution of HCl 10% m/v. The organic layers was dried with
Na2SO4 and filtered. The organic solvent was removed under reduced
pressure and purified by silica gel column chromatography using
Hexane/Ethyl acetate as solvent to give the corresponding silytated
compounds
Experimental Section
General information.
The reagents used were commercial, unless otherwise noted, and were
acquired from Aldrich Chemical Company, Inc. All reagents were used as
received. All anhydrous solvents were previously treated, following
specific procedures for each type of solvent. Ethereal solvents were
initially distilled over CaH2 then redistilled from Na/benzophenone. Anhyd
CH2Cl2 was obtained by distillation over CaH2. Purification of the
products was performed by column chromatography (silica 70–230 mesh
or flash silica 230–400 mesh). All reactions were monitored using TLC in
pre-coated Merck chromatographic plates, and were revealed under UV
light (254 nm), 5% ammonium phosphomolybdate in EtOH, 2,4-
dinitrophenylhydrazine, sulfur vanillin or ninhydrin. The NMR spectra of
1H and 13C were recorded in an Inova Varian 500 (500 MHz for 1H and
125 MHz for 13C), Bruker 400 MHz for 1H and 100 MHz for 13C, and
Ethyl 2-((2-bromophenyl)(tert-butyldimethylsilyloxy)methyl)acrylate (16).
Purified by flash column chromatography (10% Ethyl Acetate/Hexanes)
1
to afford a colorless oil; 95% yield. H NMR (250 MHz, CDCl3) δ 7.51 –
7.44 (t, J = 8,1 Hz, 2H), 7.31 – 7.26 (m, 1H), 7.14 – 7.06 (m, 1H), 6.29 (s,
1H), 6.01 (s, 1H), 5.79 (s, 1H), 4.17 - 4.13 (m, 2H), 1.24 (t, J = 7.1 Hz,
2H), 0.87 (s, 5H), 0.12 (s, 2H), -0.08 (s, 2H). 13C NMR (100 MHz, CDCl3)
δ 166.35, 143.01, 141.43, 132.58, 129.50, 128.96, 127.32, 125.46,
122.96, 71.52, 51.71, 25.78, 25.71, 18.10, -2.94, -4.77, -4.96.
1
Bruker 250 MHz for H and 62.5 MHz for 13C with CDCl3, and DMSO-d6
as solvents, and their signals as reference. Chemical shifts (δ) were
reported in ppm and the coupling constants (J) in Hertz (Hz). Signal
multiplicity was assigned as singlet (s), doublet (d), double doublet (dd),
triplet (t), and multiplet (m). High-resolution mass spectrometry (HRMS)
was measured using electrospray ionization (ESI) (Thermo Q Exactive).
Crystal structure determination. Single crystals were obtained by slow
evaporation from a diluted dimethyl sulfoxide/CH2Cl2 solution of the
indoline. Data collection was performed in a Bruker APEX II CCD
diffractometer using Cu K ( = 1.54178 Å) radiation and the APEX2
software (Bruker, 2010) using a Oxford cryosystem to control the
temperature. Cell refinement and data reduction were performed in
SAINT (Bruker, 2010) and SHELXT [Sheldrick, G. M. (2015). Acta Cryst.
A71, 3–8.] and SHELXL [Sheldrick, G. M. (2015). Acta Cryst. C71, 3–8 .]
were used for solution and refinement of the structure. All the refinement
process was performed with OLEX2 [Dolomanov, O. V., Bourhis, L. J.,
Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst.
42, 339–341.] which was also used to prepare molecular graphics for
publication. One tert-butyldimethylsilyloxy group was refined in two
disordered positions. All non-hydrogen atoms were refined anisotropically,
including those in disorder. Hydrogen atoms were modelled in idealized
positions and refined according to the riding model. Further
crystallographic information is available as supporting information as well
as a CCDC file (1831222). These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12
Union Road, Cambridge CB2 1EZ, UK; fax, + 44 1223 336033; e-mail,
deposit@ccdc.cam.ac.uk).
Ethyl
2-((6-bromobenzo[d][1,3]dioxol-5-yl)(tert-
butyldimethylsilyloxy)methyl)acrylate (22). Purified by flash column
chromatography (10% Ethyl Acetate/Hexanes) to give a light yellow oil;
95% yield. H NMR (400 MHz, CDCl3) δ 6.94 (s, 1H), 6.89 (s, 1H), 6.28
(s, 1H), 5.96 (s, 1H), 5.93 (s, 1H), 5.85 (s, 1H), 4.19 – 4.13 (m, 2H), 1.24
(t, J = 7.2 Hz, 3H), 0.87 (s, 9H), 0.13 (s, 3H), -0.05 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 165.76, 147.67, 147.38, 143.46, 134.87, 124.77,
113.44, 112.15, 108.87, 101.70, 71.51, 60.64, 25.80, 18.08, 14.17, -4.67,
-4.92.
1
N-(5-(6-Bromobenzo[d][1,3]dioxol-5-yl)-2,2,3,3,9,9,10,10-octamethyl-4,8-
dioxa-3,9-disilaundecan-6-yl)acetamide (27). Purified by flash column
chromatography (35% Ethyl Acetate/Hexanes) to furnish a tinged yellow
oil; 35 % yield. 1H NMR (400 MHz, CDCl3) δ 7.03 (s, 1H), 6.87 (s, 1H),
5.98 (s, 1H), 5.96 (s, 1H), 5.83 (d, J = 5.9 Hz, 1H), 5.18 (d, J = 6.0 Hz,
1H), 4.09 – 4.03 (m, 2H), 4.02 – 4.00 (dd, J = 12.0, 2.4 Hz, 1H), 3.61 (dd,
J = 12.0, 2.4 Hz, 1H), 1.76 (s, 3H), 0.95 (s, 9H), 0.87 (s, 9H), 0.08 (s, 3H),
0.07 (s, 3H), 0.06 (s, 3H), -0.19 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
168.58, 147.80, 147.67, 135.03, 112.84, 111.21, 108.92, 101.73, 70.84,
61.20, 56.73, 25.87, 25.73, 23.07, 18.20, 17.94, -4.69, -5.25, -5.30, -5.60.
Methyl 2-((2-bromophenyl)(tert-butyldimethylsilyloxy)methyl)acrylate (29)
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800528
European Journal of Organic Chemistry
FULL PAPER
Purified by flash column chromatography (10% Ethyl Acetate/Hexanes)
to give an yellow tinged oil; 95% yield. 1H NMR (400 MHz, CDCl3) δ 7.53
– 7.47 (m, 2H), 7.33 – 7.31 (m, 1H), 7.15 – 7.11 (m, 1H), 6.30 (s, 1H),
Experimental procedure for preparation of oxime 18. To stirred
methanolic solution (30 mL) of α-hydroxy-oxo-ester 17 (3 mmol) was
added pyridine (3.6 mmol) and NH2OH·HCl (3.6 mmol). The resulting
6.02 (s, 1H), 5.77 (s, 1H), 3.73 (s, 3H), 0.88 (s, 9H), 0.13 (s, 3H), -0.07 (s, mixture was heated under refluxed for 1 h. After that, analysis by TLC
3H). 13C NMR (100 MHz, CDCl3) δ 166.35, 143.01, 141.43, 132.58,
129.50, 128.96, 127.32, 125.46, 122.96, 71.52, 51.71, 25.78, 18.10, -
4.77, -4.96.
showed the complete consumption of the starting material. The solvents
were removed under reduced pressure and the residue was extracted
with CH2Cl2 (40 mL) and the organic phase was washed with a 10%
aqueous hydrochloric acid solution (3 x 15 mL). The organic layer was
dried over Na2SO4, filtered and the solvent was removed under reduced
pressure. The crude was purified by silica gel column chromatography
using 30% Ethyl Acetate/Hexanes to provide α-hydroxy-oxoimino-ester
18, as a yellow tinged oil, in 73% of yield (mixture of diastereoisomers).
1H NMR (250 MHz, CDCl3) δ 9.56 (s, 1H), 7.64 (dd, J = 7.8, 1.6 Hz, 1H),
7.51 (dd, J = 8.0, 1.1 Hz, 1H), 7.34 (td, J = 7.6, 1.0 Hz, 2H), 7.16 (td, J =
7.7, 1.7 Hz, 2H), 5.97 (s, 1H), 4.30 (q, J = 4.6 Hz, 2H), 1.31 (t, J = 7.1 Hz,
3H), 0.89 (s, 9H), 0.11 (s, 5H), -0.05 (s, 3H). 13C NMR (62.5 MHz, CDCl3)
δ 166.58, 151.41, 140.96, 139.99, 139.52, 138.93, 132.72, 132.33,
132.14, 130.29, 129.63, 129.47, 129.29, 129.00, 128.42, 127.64, 127.22,
126.90, 126.79, 123.17, 121.12, 72.25, 71.47, 66.88, 61.70, 61.46, 61.13,
25.69, 25.60, 18.10, 14.05, -4.94, -5.03, -5.18.
Ethyl
2-((6-bromo-3,5-dimethoxyphenyl)(tert-
butyldimethylsilyloxy)methyl)acrylate (30). Purified by flash column
chromatography (15% Ethyl Acetate/Hexanes) to give a yellow tinged oil;
92% yield. 1H NMR (250 MHz, CDCl3) δ 6.87 (d, J = 2.0 Hz, 2H), 6.14 (s,
1H), 5.81 (s, 1H), 5.62 (s, 1H), 4.09 (q, J = 5.1 Hz, 2H), 3.76 (s, 3H), 3.74
(s, 3H), 1.17 (t, J = 7.1 Hz, 3H), 0.77 (s, 9H), 0.02 (s, 3H), -0.16 (s, 3H).
13C NMR (62.5 MHz, CDCl3) δ 165.95, 148.80, 148.34, 143.54, 133.43,
124.73, 114.86, 112.85, 111.63, 71.49, 60.65, 56.03, 55.88, 25.74, 18.07,
14.15, -4.79, -4.97.
Ethyl
2-((2-bromo-6-fluorophenyl)(tert-
butyldimethylsilyloxy)methyl)acrylate (31). Purified by flash column
chromatography (10% Ethyl Acetate/Hexanes) to give a yellow oil; 97%
yield. 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.0 Hz, 1H), 7.09 (td, J =
8.1, 5.6 Hz, 1H) 6.98 (dd, J = 7.8, 2.6 Hz, 1H), 6.49 (s, 1H), 6.26 (s, 1H),
6.09 (s, 1H), 4.13 (q, J = 5.3 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H), 0.90 (s,
9H), 0.13 (s, 3H), -0.08 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.65,
161.90, 140.47, 129.73 (d, J = 9.6 Hz), 129.23, 129.07 (d, J = 3.5 Hz),
126.32 (d, J = 2.3 Hz), 124.46 (d, J = 5.2 Hz), 115.52 (d, J = 22.9 Hz),
69.66, 60.52, 25.69, 18.07, 14.04, -4.99, -5.07.
Experimental procedure for preparation of α-hydroxy-aminoester 19.
To a stirred solution of oxyimino ester 18 (1 mmol) in EtOH (2 mL) at
0 °C, was carefully added a solid mixture of NaBH3CN (4 mmol), MoCl5
(1 mmol) and NaH2SO4·H2O (3 mmol). After 10 minutes (time to release
of gas) the resultant mixture was stirred under reflux for 40 minutes,
when the TCL showed the consumption of the starting material. Then, a
solution of NaHCO3 (10%) was added and the mixture was extracted with
CH2Cl2. The organic layer was dried over Na2SO4, filtered and the
solvent was removed under reduced pressure. The crude was purified by
Ethyl
2-((2-bromo-4-fluorophenyl)(tert-
silica gel column chromatography using
a
mixture of 3%
butyldimethylsilyloxy)methyl)acrylate (32). Purified by flash column
chromatography (10% Ethyl Acetate/Hexanes) to afford a yellow tinged
oil; 92% yield. 1H NMR (400 MHz, CDCl3) δ 7.44 (dd, J = 8.7, 6.2 Hz, 1H),
7.28 (dd, J = 8.4, 2.5 Hz, 1H), 7.04 (td, J = 8.4, 2.5 Hz, 1H), 6.31 (s, 1H),
5.97 (s, 1H), 5.83 (s, 1H), 3.72 (s, 3H), 0.88 (d, J = 1.5 Hz, 9H), 0.12 (s,
3H), -0.06 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 166.17, 161.52, 142.87,
137.53 (d, J = 3.5 Hz), 130.50 (d, J = 8.4 Hz), 125.38, 122.84 (d, J = 9.6
Hz), 119.57 (d, J = 24.3 Hz), 114.69 (d, J = 20.9 Hz), 70.98, 51.74, 27.24,
24.38, 18.06, -4.77, -4.97.
Methanol/Dichlorometane to give α-hydroxy-aminoester 19, as
a
colorless oil, in 55% of yield. 1H NMR (250 MHz, CDCl3) δ 7.51 (t, J =
7.4 Hz, 2H), 7.36 – 7.29 (m, 1H), 7.15 (d, J = 7.7, 1.8 Hz, 1H), 5.24 (d, J
= 6.2 Hz, 1H), 4.11 (q, J = 4.2 Hz, 1H), 3.66 (d, J = 6.2 Hz, 1H), 1.58 (s,
1H), 1.21 (t, J = 7.2 Hz, 2H), 0.87 (s, 9H), 0.07 (s, 3H), -0.19 (s, 3H). 13
C
NMR (62.5 MHz, CDCl3) δ 173.13, 140.74, 132.31, 129.19, 129.10,
127.27, 122.88, 75.97, 61.56, 60.68, 25.61, 17.95, 14.00, -4.85, -5.31.
General procedure for the preparation of allylic alcohols 23 and 34-
38. To a stirred solution of esters 22, 29-33 (0.05 M of anhydrous
dichloromethane) at -72 °C, was slowly added (under an inert gas
atmosphere) a solution of DIBAL-H in toluene (3 eq). After 1 h, the
analysis by TLC revealed the complete consumption of the starting
material. Then, a saturated solution of sodium acetate with same volume
used of dichloromethane was carefully added in the flask and stirred at r.t
for 1 h. The resulting mixture was filtered over a pad of celite and
extracted with ethyl acetate and saturated solution of NH4Cl. The organic
layer was dried over Na2SO4, filtered and the solvent was removed under
reduced pressure. The crude was purified by silica gel column
chromatography to give the corresponding allylic alcohols.
Ethyl
2-((2-bromo-5-nitrophenyl)(tert-
butyldimethylsilyloxy)methyl)acrylate (33). Purified by flash column
chromatography (15% Ethyl Acetate/Hexanes) to give a colorless oil;
82% yield. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 2.7 Hz, 1H), 7.99
(dd, J = 8.7, 2.7 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 6.41 (s, 1H), 6.02 (s,
1H), 5.94 (s, 1H), 3.73 (s, 3H), 0.89 (s, 9H), 0.14 (s, 3H), -0.02 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 165.78, 147.42, 144.12, 141.77, 133.72,
129.86, 126.70, 124.36, 123.41, 71.22, 51.91, 25.70, 18.06, -2.95, -4.80,
-4.88.
N-(5-(2-Bromo-3,5-dimethoxyphenyl)-2,2,3,3,9,9,10,10-octamethyl-4,8-
dioxa-3,9-disilaundecan-6-yl)acetamide (55). Purified by flash column
chromatography (30% Ethyl Acetate/Hexanes) to give a yellow tinged oil;
2-((6-Bromobenzo[d][1,3]dioxol-5-yl)(tert-butyldimethylsilyloxy)methyl)-
prop-2-en-1-ol (23). Eluent: 35% Ethyl Acetate/Hexanes to give a
colorless oil; 53% yield. 1H NMR (500 MHz, CDCl3) δ 7.02 (s, 1H), 6.95
(s, 1H), 6.00 (s, 1H), 5.97 (s, 1H), 5.60 (s, 1H), 5.20 (s, 1H), 5.18 (s, 1H),
4.09 – 4.06 (m, 2H), 2.07 (t, J= 5.8 Hz, 1H), 0.91 (s, 9H), 0.11 (s, 3H), -
0.04 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 149.01, 147.72, 147.66,
135.19, 112.40, 112.37, 112.03, 108.45, 101.75, 74.90, 63.34, 25.79,
18.12, -4.86, -5.10.
1
26% yield. H NMR (500 MHz, CDCl3) δ 7.03 (s, 1H), 6.85 (s, 1H), 5.80
(d, J = 5.9 Hz, 1H), 5.16 (d, J = 6.0 Hz, 1H), 4.12 – 4.00 (m, 1H), 3.99 (dd,
J = 12.0, 1.7 Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.61 (dd, J = 12.0, 1.7
Hz, 1H), 1.71 (s, 3H), 0.92 (s, 9H), 0.84 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H),
0.03 (s, 3H), -0.24 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 168.58, 148.92,
148.67, 133.57, 113.95, 112.52, 111.49, 70.80, 61.22, 56.67, 56.00,
55.84, 25.87, 25.68, 23.06, 18.19, 17.94, -4.75, -5.25, -5.31, -5.58.
2-((2-Bromophenyl)(tert-butyldimethylsilyloxy)methyl)prop-2-en-1-ol (34).
Eluent: 30% Ethyl Acetate/Hexanes to provide a yellow tinged oil; 56%
yield. 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 7.8, 1.6 Hz, 1H), 7.52
(dd, J = 7.8, 1.6 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H),
5.71 (s, 1H), 5.21 (s, 1H), 5.19 (s, 1H), 4.16 – 4.05 (m, 2H), 2.12 (s, 1H),
0.91 (s, 9H), 0.12 (s, 3H), -0.06 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
General procedure for ozonolysis reaction (17, 25, 44-48): To a
stirred solution of starting material (17, 25, 44-48, 2 mmol) in 15 mL of
methanol (at -72 °C), a flow of ozone was slowly passed through for 20
minutes. After this time, TLC analysis showed the complete consumption
of the starting material. Then, dimethyl sulfide (30 mmol) was added and
the mixture was stirred at r.t. for 1 h. The solvent was evaporated and the
crude product was used in the next step without purification.
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800528
European Journal of Organic Chemistry
FULL PAPER
148.55, 141.59, 132.52, 129.01, 128.98, 127.52, 122.17, 113.20, 75.31,
63.44, 25.77, 18.13, -4.90, -5.11.
(s, 3H), 0.90 (s, 9H), 0.07 (s, 3H), -0.17 (s, 3H). 13C NMR (126 MHz,
CDCl3) δ 171.46, 140.09, 132.58, 129.44, 128.90, 127.53, 122.02, 74.52,
61.41, 54.83, 25.85, 25.79, 25.75, 23.43, 18.02, -4.92, -5.24.
2-((2-Bromo-3,5-dimethoxyphenyl)(tert-butyldimethylsilyloxy)methyl)prop-
2-en-1-ol (35). Eluent: 35% Ethyl Acetate/Hexanes to give a colorless
viscous oil; 67% yield. 1H NMR (500 MHz, CDCl3) δ 7.02 (s, 1H), 6.91 (s,
1H), 5.54 (s, 1H), 5.14 (s, 1H), 5.09 (s, 1H), 4.07 – 4.04 (m, 1H), 3.82 (s,
3H), 3.81 (s, 3H), 2.31 (s, 1H), 0.87 (s, 9H), 0.07 (s, 3H), -0.11 (s, 3H).
13C NMR (125 MHz, CDCl3) δ 149.06, 148.84, 148.59, 133.73, 114.69,
112.20, 112.00, 111.08, 74.83, 63.32, 56.04, 55.87, 25.73, 18.07, -4.90, -
5.15.
N-(1-(2-Bromo-3,5-dimethoxyphenyl)-1-(tert-butyldimethylsilyloxy)-3-
hydroxypropan-2-yl)acetamide (50). Yellow tinged oil, 75% yield. 1H NMR
(500 MHz, CDCl3) δ 7.02 (s, 1H), 6.83 (s, 1H), 5.80 (d, J = 5.9 Hz, 1H),
5.13 (d, J = 5.0 Hz, 1H), 4.10 – 4.06 (m, 1H), 3.98 (dd, J = 11.9, 6.7 Hz,
1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.59 (dd, J = 11.9, 6.7 Hz, 1H), 3.58 (dd, J
= 11.9, 6.7 Hz, 1H), 1.69 (s, 3H), 0.82 (s, 9H), 0.02 (s, 3H), -0.02 (s, 3H).
13C NMR (126 MHz, CDCl3) δ 168.72, 148.93, 148.68, 133.50, 113.94,
112.47, 111.49, 70.76, 61.17, 56.70, 25.65, 22.93, 18.05, -5.35, -5.62.
2-((2-Bromo-6-fluorophenyl)(tert-butyldimethylsilyloxy)methyl)prop-2-en-
1-ol (36). Eluent: 35% Ethyl Acetate/Hexanes to provide a yellow tinged
oil; 57% yield. H NMR (500 MHz, CDCl3) δ 7.38 – 7.36 (m, 1H), 7.17 –
7.13 (m, 1H), 7.05 – 7.01 (m, 1H), 5.91 (s, 1H), 5.22 (s, 1H), 5.10 (s, 1H),
4.21 – 4.18 (m, 2H), 1.99 (t, J = 6.1 Hz, 1H), 0.90 (s, 9H), 0.13 (s, 3H), -
0.12 (s, 4H). 13C NMR (125 MHz, CDCl3) δ 162.76, 160.73, 148.02,
129.96 (d, J = 9.6 Hz), 129.75 (d, J = 13.8 Hz), 128.87 (d, J = 3.0 Hz),
123.76 (d, J = 5.5 Hz), 115.85 (d, J = 23.0 Hz), 112.00, 73.05, 64.27,
25.66, 18.04, -5.10, -5.27.
N-(1-(2-Bromo-6-fluorophenyl)-1-(tert-butyldimethylsilyloxy)-3-
hydroxypropan-2-yl)acetamide (51). Colorless oil, 41% yield. 1H NMR
(400 MHz, CDCl3) δ 7.39 – 7.38 (m, 1H), 7.18 – 7.12 (m, 1H), 7.08 – 7.03
(m, 1H), 6.18 (d, J = 5.3 Hz, 1H), 5.41 (d, J = 6.7 Hz, 1H), 4.39 – 4.35 (m,
1H), 4.06 (dd, J = 11.3, 2.2 Hz, 1H), 3.73 (dd, J = 11.3, 2.2 Hz, 1H), 1.90
(s, 3H), 0.88 (s, 9H), 0.09 (s, 3H), -0.16 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 169.93 (s), 163.67 (s), 161.64 (s), 131.84 (d, J = 10.4 Hz),
130.41 (d, J = 9.6 Hz), 129.22 (d, J = 21.0Hz), 128.49 (d, J = 2.6 Hz),
124.19 (d, J = 6.5 Hz), 116.41 (d, J = 23.0 Hz), 74.01, 62.21, 53.99,
25.72, 23.33, 18.07, -5.05, -5.25.
1
2-((2-bromo-4-fluorophenyl)(tert-butyldimethylsilyloxy)methyl)prop-2-en-
1-ol (37). Eluent: 35% Ethyl Acetate/Hexanes to afford a yellow oil; 51%
yield. 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 8.7, 6.2 Hz, 1H), 7.28 –
7.25 (m, 1H), 7.08 (td, J = 8.7, 2.6 Hz, 1H), 5.65 (s, 1H), 5.21 (s, 1H),
5.17 (s, 1H), 4.14 – 4.03 (m, 2H), 2.04 (s, 1H), 0.90 (s, 9H), 0.11 (s, 3H),
-0.06 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.77, 160.28, 148.54,
137.67 (d, J = 3.3 Hz), 130.04 (d, J = 8.5 Hz), 121.91 (d, J = 9.4 Hz),
119.46 (d, J = 24.3 Hz), 114.90 (d, J = 21.0 Hz), 113.15, 74.65, 63.32,
25.73, 18.10, -4.92, -5.12.
N-(1-(2-Bromo-4-fluorophenyl)-1-(tert-butyldimethylsilyloxy)-3-
hydroxypropan-2-yl)acetamide (52). Yellow tinged oil. 45% yield. 1H NMR
(400 MHz, CDCl3) δ 7.56 (dd, J = 8.7, 6.1 Hz, 1H), 7.28 (dd, J = 8.1, 2.6
Hz, 1H), 7.10 (td, J = 8.3, 2.6 Hz, 1H), 6.21 (d, J = 5.6 Hz, 1H), 5.31 (d, J
= 5.2 Hz, 1H), 4.18 – 4.13 (m, 1H), 3.90 (dd, J = 11.4, 2.8 Hz, 1H), 3.58
(dd, J = 11.4, 2.8 Hz, 1H), 2.83 (s, 1H), 1.97 (s, 3H), 0.91 (s, 9H), 0.09 (s,
3H), -0.15 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 169.62, 162.99, 160.49,
136.31 (d, J = 3.4 Hz), 129.87 (d, J = 8.5 Hz), 121.97 (d, J = 9.5 Hz),
119.69 (d, J = 24.2 Hz), 114.89 (d, J = 21.0 Hz), 74.43 (s), 61.53 (s),
54.11, 25.72, 23.32, 17.96, -4.97, -5.34.
2-((2-Bromo-5-nitrophenyl)(tert-butyldimethylsilyloxy)methyl)prop-2-en-1-
ol (38). Eluent: 25% Ethyl Acetate/Hexanes to afford a bright yellow oil;
71% yield. 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 2.6 Hz, 1H), 7.99
(dd, J = 8.7, 2.6 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 5.68 (s, 1H), 5.27 (s,
1H), 5.17 (s, 1H), 4.17 – 4.04 (m, 2H), 1.91 (t, J = 5.4 Hz, 1H), 0.90 (s,
9H), 0.12 (s, 3H), -0.05 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 147.76,
147.52, 144.21, 133.64, 128.93, 124.02, 123.39, 113.93, 74.38, 62.86,
25.69, 18.10, -4.96, -5.04.
N-(1-(2-bromo-5-nitrophenyl)-1-(tert-butyldimethylsilyloxy)-3-
hydroxypropan-2-yl)acetamide (53). Colorless oil, 32 % yield. 1H NMR
(400 MHz, CDCl3) δ 8.46 (d, J = 2.6 Hz, 1H), 8.00 (dd, J = 8.7, 2.6 Hz,
1H), 7.70 (d, J = 8.7 Hz, 1H), 5.85 (d, J = 5.4 Hz, 1H), 5.19 (d, J = 6.6 Hz,
1H), 4.58 – 4.52 (m, 1H), 4.37 (dd, J = 11.5, 5.6 Hz, 1H), 4.05 (dd, J =
11.5, 5.6 Hz, 1H), 1.87 (s, 3H), 0.92 (s, 9H), 0.06 (s, 3H), -0.20 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 169.05, 147.43, 142.95, 133.40, 128.85,
124.40, 123.88, 72.60, 62.82, 52.93, 25.62, 23.11, 17.95, -4.88, -5.35.
General procedure and analytical data for reductive amination (26,
49-53). To
a stirred methanolic (anhydrous methanol) solution of
compounds 25, 44-48 (0.06 mol/L, 2 mmol) (under an inert gas
atmosphere) was added NaHCO3 (4 mmol) and NH4OAc (60 mmol.). To
the resulting mixture was added NaBH3CN (3 mmol) in two portions in
intervals of 30 min. The reaction was maintained under stirring for 12 h.
After that, the solvent was removed under reduced pressure and the
crude residue was suspended in ethyl acetate (20 mL). The organic
phase was washed with distilled water (2 × 10 mL), brine (10 mL), dried
over Na2SO4, filtered and the solvent removed under reduced pressure.
The crude was purified by silica gel column chromatography using 2%
Methanol/Dichlorometane mixture to give the corresponding amidodiols.
General procedure for acetylation of compounds 20, 25, 39-43, 54,
56-58. To a stirred 0.05M solution of compounds 19, 24, 34-38, 49, 51-
53 in anhydrous dichloromethane at 0 °C, was added (under an inert gas
atmosphere), pyridine (1.2 eq), acetic anhydride (1.5 eq). Then, the
reaction medium was allowed to warm-up to r.t. After 1 h, the analysis by
TLC revealed the complete consumption of the starting material. The
solvent was evaporated under vacuum and the residue was dissolved in
a mixture of dichloromethane and solution of HCl 10% m/v. The organic
layers was dried over Na2SO4 and filtered. The organic solvent was
removed under reduced pressure and purified by silica gel column
chromatography to afford acetylated compounds.
N-(1-(6-Bromobenzo[d][1,3]dioxol-5-yl)-1-(tert-butyldimethylsilyloxy)-3-
hydroxypropan-2-yl)acetamide (26). Yellow tinged oil, 45% yield. 1H NMR
(400 MHz, CDCl3) δ 7.14 (s, 1H), 7.07 (s, 1H), 6.38 (d, J = 6.0 Hz, 1H),
6.13 (s, 1H), 6.11 (s, 1H), 5.34 (d, J = 5.7 Hz, 1H), 4.27 – 4.21 (m, 1H),
4.02 (dd, J = 11.4, 3.6 Hz, 1H), 3.74 (dd, J = 11.4, 3.6 Hz, 1H), 2.07 (s,
3H), 1.03 (s, 9H), 0.21 (s, 3H), -0.005 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 168.31, 143.33, 134.83, 130.50, 128.98, 128.40, 125.45,
101.45, 73.12, 71.67, 62.70, 25.85, 25.79, 23.37, 18.03, -4.20, -5.45.
Ethyl
2-acetamido-3-(2-bromophenyl)-3-(tert-
(20). Eluente: 20% Ethyl
butyldimethylsilyloxy)propanoate
Acetate/Hexanes to provide a colorless oil; 99% yield. 1H NMR (250 MHz,
CDCl3) δ 7.47 (d, J = 9.0 Hz, 2H), 7.26 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 7.5
Hz, 1H), 6.18 (d, J = 7.0 Hz, 1H), 5.28 (d, J = 5.9 Hz, 1H), 4.92 (dd, J =
7.0, 5.9 Hz, 1H), 4.05 – 3.93 (m, 2H), 1.91 (s, 3H), 1.06 (t, J = 7.1 Hz,
3H), 0.86 (s, 9H), 0.03 (s, 3H), -0.21 (s, 3H). 13C NMR (62.5 MHz, CDCl3)
δ 170.00, 168.90, 139.57, 132.26, 129.43, 129.10, 127.15, 122.03, 74.03,
61.08, 57.39, 25.58, 13.75, -4.93, -5.43.
N-(1-(2-Bromophenyl)-1-(tert-butyldimethylsilyloxy)-3-hydroxypropan-2-
1
yl)acetamide (49). Colorless oil, 51% yield. H NMR (500 MHz, CDCl3) δ
7.50 (dd, J = 9.0, 3.0 Hz, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz,
1H), 6.32 (d, J = 5.1 Hz, 1H), 5.19 (d, J = 3.2 Hz, 1H), 4.22 – 4.21 (m,
1H), 3.76 (dd, J = 11.0, 6.5 Hz, 1H), 3.60 (dd, J = 11.0, 6.5 Hz, 1H), 1.94
2-((6-Bromobenzo[d][1,3]dioxol-5-yl)(tert-
butyldimethylsilyloxy)methyl)allyl acetate (24). Eluent: 10% Ethyl
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800528
European Journal of Organic Chemistry
FULL PAPER
Acetate/Hexanes to give a yellow tinged oil; 80% yield. 1H NMR (500
MHz, CDCl3) δ 6.97 (s, 1H), 6.94 (s, 1H), 6.00 (s, 1H), 5.97 (s, 1H), 5.59
(s, 1H), 5.33 (s, 1H), 5.20 (s, 1H), 4.54 – 4.45 (m, Hz, 2H), 2.05 (s, 3H),
0.91 (s, 9H), 0.11 (s, 3H), -0.04 (s, 3H). 13C NMR (125 MHz, CDCl3) δ
170.58, 147.78, 147.67, 145.08, 134.99, 113.71, 112.62, 111.96, 108.53,
101.74, 73.61, 64.02, 25.77, 20.92, 18.14, -4.86, -5.09.
CDCl3) δ 7.30 – 7.28 (m, 1H), 7.15 – 7.10 (m, 1H), 7.03 (t, J = 9.0 Hz,
1H), 5.69 (d, J = 5.7 Hz, 1H), 5.22 (d, J = 6.3 Hz, 1H), 4.84 – 4.82 (m,
1H), 4.54 (dd, J = 11.0, 2.9 Hz, 1H), 4.19 (dd, J = 11.0, 2.9 Hz, 1H), 2.12
(s, 3H), 1.76 (s, 3H), 0.84 (s, 9H), 0.03 (s, 3H), -0.23 (s, 3H). 13C NMR
(125 MHz, CDCl3) δ 170.78, 169.05, 163.64, 155.87, 134.76 (d, J= 3.5
Hz), 130.37 (d, J = 9.3 Hz), 127.83 (d, J = 3.3 Hz), 124.05 (d, J = 26.0
Hz), 116.38 (d, J = 20.0 Hz), 72.13, 63.82, 51.76, 25.47, 22.98, 20.84,
17.84, -5.15, -5.54.
2-((2-Bromophenyl)(tert-butyldimethylsilyloxy)methyl)allyl acetate (39).
Eluent: 10% Ethyl Acetate/Hexanes to provide a bright yellow oil; 92%
yield. 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 7.8, 1.5 Hz, 1H), 7.50
(dd, J = 8.0, 0.9 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H),
5.66 (s, 1H), 5.30 (s, 1H), 5.21 (s, 1H), 4.59 – 4.47 (m, J = 31.3, 13.4 Hz,
2H), 2.00 (s, 3H), 0.89 (s, 9H), 0.09 (s, 3H), -0.08 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 166.37, 144.77, 141.48, 132.42, 129.18, 128.99, 127.52,
122.33, 114.33, 73.85, 63.91, 22.15, 20.86, 18.14, -4.93, -5.11.
2-Acetamido-3-(2-bromo-4-fluorophenyl)-3-(tert-
butyldimethylsilyloxy)propyl
acetate
(57).
Eluent:
30%
Ethyl
Acetate/Hexanes to give a colorless oil; 83% yield. 1H NMR (500 MHz,
CDCl3) δ 7.54 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.06 (t, J = 8.3
Hz, 1H), 5.78 (d, J = 5.4 Hz, 1H), 5.13 (d, J = 6.1 Hz, 1H), 4.47 – 4.46 (m,
1H), 4.37 (dd, J = 11.3, 5.2 Hz, 1H), 4.07 (dd, J = 11.3, 5.2 Hz, 1H), 2.05
(s, 3H), 1.84 (s, 3H), 0.88 (s, 9H), 0.04 (s, 3H), -0.22 (s, 3H). 13C NMR
(125 MHz, CDCl3) δ 170.88, 169.00, 162.71, 160.71, 136.39 (d, J = 3.2
Hz), 130.29 (d, J = 8.6 Hz), 122.11 (d, J = 9.4 Hz), 119.19 (d, J = 24.4
Hz), 115.08 (d, J = 21.0 Hz), 72.08, 63.09, 53.34, 25.64, 23.09, 20.78,
17.93, -4.86, -5.44.
2-((2-Bromo-3,5-dimethoxyphenyl)(tert-butyldimethylsilyloxy)methyl)allyl
acetate (40). Eluent: 10% Ethyl Acetate/Hexanes to give a viscous oil;
1
68% yield. H NMR (500 MHz, CDCl3) δ 7.02 (s, 1H), 6.95 (s, 1H), 5.57
(s, 1H), 5.27 (s, 1H), 5.20 (s, 1H), 4.57 – 4.49 (m, 2H), 3.88 (s, 3H), 3.86
(s, 3H), 2.05 (s, 3H), 0.91 (s, 9H), 0.11 (s, 3H), -0.07 (s, 3H). 13C NMR
(62.5 MHz, CDCl3) δ 166.17, 149.02, 148.55, 143.75, 133.65, 124.94,
115.07, 113.06, 111.84, 71.71, 60.86, 56.25, 56.09, 25.96, 25.83, 18.28,
-4.57, -4.75.
2-Acetamido-3-(2-bromo-5-nitrophenyl)-3-(tert-
butyldimethylsilyloxy)propyl
acetate
(58).
Eluent:
30%
Ethyl
Acetate/Hexanes to afford a yellow tinged oil; 88% yield. 1H NMR (400
MHz, CDCl3) δ 8.47 (d, J = 2.6 Hz, 1H), 8.01 (dd, J = 8.7, 2.6 Hz, 1H),
7.71 (d, J = 8.7 Hz, 1H), 5.87 (d, J = 5.4 Hz, 1H), 5.21 (d, J = 6.6 Hz, 1H),
4.59 – 4.54 (m, 1H), 4.39 (dd, J = 11.5, 5.6 Hz, 1H), 4.06 (dd, J = 11.5,
5.6 Hz, 1H), 2.07 (s, 3H), 1.89 (s, 3H), 0.93 (s, 9H), 0.07 (s, 3H), -0.18 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 170.88, 169.05, 147.43, 142.95,
133.40, 128.85, 124.40, 123.88, 72.60, 62.82, 52.93, 25.62, 23.11, 20.75,
17.95, -4.88, -5.35.
2-((2-Bromo-6-fluorophenyl)(tert-butyldimethylsilyloxy)methyl)allyl acetate
(41). Eluent: 10% Ethyl Acetate/Hexanes) to provide a yellow tinged oil;
92%) yield. 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 9.0 Hz, 1H), 7.16 –
7.11 (m, 1H), 7.03 – 6.99 (m, 1H), 5.85 (s, 1H), 5.40 (s, 1H), 5.29 (s, 1H),
4.60 – 4.51 (m, 2H), 2.03 (s, 3H), 0.89 (s, 9H), 0.12 (s, 3H), -0.12 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 165.65, 163.16, 160.63, 140.47, 129.73 (d,
J = 9.6 Hz), 129.23, 129.07 (d, J = 3.5 Hz), 126.32 (d, J = 2.3 Hz), 124.46
(d, J = 5.2 Hz), 115.52 (d, J = 22.9 Hz), 69.66, 60.52, 25.66, 14.04, -4.99,
-5.07.
General procedure for the preparation of indolines 59-63: A flame
dried 25 mL Schlenk flask equipped with a stir bar was charged with β-
arylethylamines 20, 27 and 54-58 (0.2 mmol, 1.0 equiv.) and toluene
(0.55 mol-1). The solution was degazed by N2 bubbling for 10 min.
Cs2CO3 (0.4 mmol, 2.0 equiv), Pd2(DBA)3 (0.02 mmol, 10 mol%) and
P(o-tolyl)3 (0.04 mmol, 20 mol%) were successively added under an N2
flow and the flask was sealed (glass stopper). The reaction was heated
at 80 °C for 5 h. Then, the reaction mixture was filtered through a pad of
Celite (10 mL), thoroughly rinsed with EtOAc (ca. 50 mL), and the filtrate
was evaporated. The crude material was purified by silica gel flash
chromatography to afford the desired product 21, 28 and 59-63.
2-((2-bromo-4-fluorophenyl)(tert-butyldimethylsilyloxy)methyl)allyl acetate
(42). Eluent: 10% Ethyl Acetate/Hexanes to furnish a yellow oil; 89%
yield. 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J = 8.0, 6.0 Hz, 1H), 7.25
(dd, J = 8.0, 3.0 Hz, 1H), 7.06 (td, J = 8.0, 3.0 Hz, 1H), 5.61 (s, 1H), 5.29
(s, 1H), 5.22 (s, 1H), 4.56 – 4.45 (m, 2H), 2.01 (s, 3H), 0.89 (s, 9H), 0.09
(s, 3H), -0.08 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 166.38, 162.79,
160.30, 144.66, 137.56 (d, J = 3.6 Hz), 130.22 (d, J = 8.5 Hz), 122.06 (d,
J = 9.5 Hz), 119.34 (d, J = 24.3 Hz), 114.93 (d, J = 20.9 Hz), 114.49,
73.31, 63.81, 25.71, 22.14, 18.11, -4.94, -5.11.
Ethyl
1-acetyl-3-[(tert-butyldimethylsilyl)oxy]-2,3-dihydro-1H-indoline-2-
carboxylate (21). Elueant: 30% Ethyl Acetate/Hexanes to give 21 (17 mg,
0.047 mmol, 37%) as an oil.1H NMR (600 MHz, DMSO-d6, 90 °C) δ 7.35
(d, J = 7.9 Hz, 2H, Ar), 7.12 (t, J = 7.9 Hz, 2H, Ar), 5.30 (s, 1H), 4.78 (s,
1H), 4.21 (q, J = 7.1 Hz, 2H, CH2), 2.21 (s, 3H, Ac), 1.24 (t, J = 7.1 Hz,
3H, CH3), 0.92 (s, 9H, TBS), 0.22 (s, 3H, TBS), 0.19 (s, 3H, TBS). 13C
NMR (150 MHz, DMSO-d6, 90 °C) δ 169.56, 168.87, 130.27, 126.08,
123.99, 79.57, 71.18, 62.01, 26.11, 23.89, 18.09, 14.23, -4.08. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd. for C19H19NO4SiH 364.1944, found
364.1959.
2-((2-Bromo-5-nitrophenyl)(tert-butyldimethylsilyloxy)methyl)allyl acetate
(43). Eluent: 10% Ethyl Acetate/Hexanes to give a tinged yellow oil; 93%
yield. 1H NMR (500 MHz, CDCl3) δ 8.43 (d, J = 2.3 Hz, 1H), 8.00 (dd, J =
8.6, 2.3 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 5.67 (s, 1H), 5.32 (s, 1H), 5.30
(s, 1H), 4.59 – 4.48 (m, 2H), 1.99 (s, 3H), 0.91 (s, 9H), 0.12 (s, 3H), -0.04
(s, 3H). 13C NMR (125 MHz, CDCl3) δ 170.32, 147.57, 144.05, 143.57,
133.59, 128.99, 124.22, 123.44, 116.17, 73.61, 63.66, 25.68, 20.78,
18.11, -4.96, -5.05.
2-Acetamido-3-(2-bromophenyl)-3-(tert-butyldimethylsilyloxy)propyl
acetate (54). Eluent: 30% Ethyl Acetate/Hexanes to provide a tinged
yellow oil; 81% yield. 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.7 Hz,
1H), 7.47 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.12 (t, J = 7.5 Hz,
1H), 5.84 (d, J = 5.7 Hz, 1H), 5.17 (d, J = 6.9 Hz, 1H), 4.51 – 4.47 (m,
1H), 4.36 (dd, J = 11.3, 5.5 Hz, 1H), 4.07 (dd, J = 11.3, 5.5 Hz, 1H), 2.03
(s, 3H), 1.83 (s, 3H), 0.88 (s, 9H), 0.02 (s, 3H), -0.23 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 170.96, 169.09, 147.25, 140.27, 132.16, 129.43,
129.15, 127.64, 122.33, 72.58, 63.10, 53.30, 25.68, 23.11, 20.81, 17.97,
-4.85, -5.42.
1-{7-[(tert-Butyldimethylsilyl)oxy]-6-{[(tert-butyldimethylsilyl)oxy]methyl}-
2H,5H,6H,7H-[1,3]dioxolo[4,5-f]indoline-5-yl}ethan-1-one (28). Eluent:
30% Ethyl Acetate/Hexanes) to give 28 (27 mg, 0.056 mmol, 84%) as a
yellow solid. m.p. 98-99°C. 1H NMR (500 MHz, DMSO-d6 90 °C) δ 7.76 (s,
1H, Ar), 7.45 (s, 1H, Ar), 5.99 (s, 1H, O-CH2-O), 5.97 (s, 1H, O-CH2-O),
4.90 (s, 1H, CH-OTBS), 4.20 (t, J = 6.1Hz, CH-NAc), 3.74 (dd, J = 6.1
and 11.6 Hz, CH2), 3.51 (dd, J = 6.1 and 11.6 Hz, CH2), 2.22 (s, 3H, CH3),
0.87 (s, 9H, TBS), 0.82 (s, 9H, TBS), 0.13 (s, 3H, TBS), 0.10 (s, 3H,
TBS), 0.02 (s, 3H, TBS), -0.00 (s, 3H, TBS). 13C NMR (125 MHz, DMSO-
d6, 90 °C) δ 168.16, 148.48, 143.94, 143.02, 129.34, 128.84, 101.86,
73.35, 71.40, 62.87, 26.13, 26.08, 23.46, 18.24, 18.06, -3.88, -3.94, -5.18,
-5.24. HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C24H41NO5Si2H 480.2602,
found 480.2582.
2-Acetamido-3-(2-bromo-6-fluorophenyl)-3-(tert-
butyldimethylsilyloxy)propyl
acetate
(56).
Eluent:
30%
Ethyl
Acetate/Hexanes to give a yellow oil; 49% yield. 1H NMR (500 MHz,
10
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10.1002/ejoc.201800528
European Journal of Organic Chemistry
FULL PAPER
{1-Acetyl-3-[(tert-butyldimethylsilyl)oxy]-2,3-dihydro-1H-indoline-2-
yl}methyl acetate (59). Eluent: 30% Ethyl Acetate/Hexanes to afford 59
(12 mg, 0.033 mmol, 55%) as an oil. 1H NMR (500 MHz, DMSO-d6,
110 °C) δ 7.39 (d, J = 7.4 Hz, 1H, Ar), 7.34 (t, J = 7.4 Hz, 2H, Ar), 7.12 (d,
J = 7.4 Hz, 1H, Ar), 5.01 (s, 1H, CH-OTBS), 4.42 (t, J = 5.4 Hz, 1H, CH-
NAc), 4.20 (dd, J = 11.5 and 5.4 Hz, 1H, CH2), 4.00 (dd, J = 11.5 and 5.4
Hz, 2H, CH2), 2.31 (s, 3H, CH3), 1.91 (s, 3H, CH3), 0.88 (s, 9H, TBS),
0.16 (s, 3H, TBS), 0.12 (s, 3H, TBS). 13C NMR (125 MHz, DMSO-d6,
110 °C) δ 170.29, 168.83, 142.85, 133.90, 129.46, 126.32, 123.85,
116.99, 72.03, 67.79, 63.44, 26.26, 23.57, 20.56, 18.11, -2.82. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd. for C19H30NO4SiH 364.1939 found
364.1951.
Acknowledgements
We thank our technician team and the members of the NMR, X-
ray and MS at Institute of Chemistry for their excellent service.
F.S.F and F.C. thank the São Paulo Science Foundation
(FAPESP) for
#2016/23005-06
a
research fellowship for (Processes
and 2013/07600-3) and to R.A.C.
(#2017/02364-0). F.C thanks CNPq-Brazil for research
a
fellowship (processes # 307840/2014-0 and 422890/2016-2).
CESUP, CENAPAD-SP and CENAPAD-UFC computational
resources are also gratefully acknowledged.
1-{3-[(tert-Butyldimethylsilyl)oxy]-2-{[(tert-butyldimethylsilyl)oxy]methyl}-
5,7-dimethoxy-2,3-dihydro-1H-indoline-1-yl}ethan-1-one (60). Eluent:
30% Ethyl Acetate/Hexanes to give 60 (37 mg, 0.075 mmol, 67%) as an
oil. 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H, Ar), 6.80 (s, 1H, Ar), 4.91 (s,
Keywords: Indolines • Palladium • Morita-Baylis-Hillman •
Buchwald • heterocycles
3
1H, CH-OTBS), 4.13 (dd, J (H,H)= 7.7 and 6.2 Hz, 1H, CH-NAc) , 3.90
[1]
a) A. Laguna, L. Novotny, L. Dolejs, M. Budesinsky, Panta Med. 1984,
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(s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.67 (dd, 2,3J (H,H) = 11.2 and 6.2
Hz,1H, CH2-OTBS), 3.41 (dd, 2,3J (H,H) = 11.2 and 7.7 Hz,1H, CH2-
OTBS), 2.28 (s, 3H, Ac), 0.87 (s, 3H, TBS), 0.86 (s, 3H, TBS), 0.13 (s,
3H, TBS), 0.09 (s, 3H, TBS), 0.03 (s, 3H, TBS), 0.01 (s, 3H, TBS). 13C
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for C25H46NO5Si2H 496.2909, found 496.2915.
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{1-Acetyl-3-[(tert-butyldimethylsilyl)oxy]-4-fluoro-2,3-dihydro-1H-indoline-
2-yl}methyl acetate (61). Eluent: 30% Ethyl Acetate/Hexanes to furnish
61 (26 mg, 0.068 mmol, 82%) as an oil. 1H NMR (500 MHz, DMSO-d6,
90 °C) δ 7.68 (d, J = 8.0 Hz, 1H, Ar), 7.39 (dd, J = 8.1 and 5.1 Hz, 1H,
Ar), 6.90 (t, J = 8.6 Hz, 1H, Ar), 5.20 (s, 1H, CH-OTBS), 4.46 (t, J = 6.0
Hz, 1H, CH-NAc), 4.23 (dd, J = 11.6 and 6.0 Hz, 1H, CH2), 4.06 (dd, J =
11.6 and 6.0 Hz, 1H, CH2), 2.32 (s, 3H, CH3), 1.92 (s, 3H, CH3), 0.88 (s,
9H, TBS), 0.16 (s, 3H, TBS), 0.12 (s, 3H, TBS). 13C NMR (125 MHz,
DMSO-d6, 90 °C) δ 170.24 (s), 168.79 (s), 159.49, 144.97 (d, J = 7.5 Hz),
132.39 (d, J = 8.3 Hz), 119.37 (d, J = 20.8 Hz), 113.37 (s), 110.79 (d, J =
20.1 Hz), 70.33 (s), 68.65 (s), 62.64 (s), 25.96 (s), 23.60 (s), 20.57 (s),
18.08 (s), -4.44 (s), -4.56 (s). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd. for
C19H28NO4SiNa 404.1619, found 404.1662.
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{1-Acetyl-3-[(tert-butyldimethylsilyl)oxy]-6-fluoro-2,3-dihydro-1H-indoline-
2-yl}methyl acetate (62). Eluent: 30% Ethyl Acetate/Hexanes to give 62
(14 mg, 0.037 mmol, 37%) as an oil. 1H NMR (600 MHz, DMSO-d6,
90 °C) δ 7.65 (d, J = 8.3 Hz, 1H, Ar), 7.40 (dd, J = 8.3, 5.8 Hz, 1H, Ar),
6.92 (ddd, J = 9.1, 8.3, 5.8 Hz, 1H, Ar), 5.01 (s, 1H, CH-OTBS), 4.46 (dd,
J = 6.9, 5.2 Hz, 1H, CH-NAc), 4.23 (dd, J = 11.7, 5.2 Hz, 1H, CH2), 4.04
(dd, J = 11.7, 6.9 Hz, 1H, CH2), 2.32 (s, 3H, CH3), 1.93 (s, 3H, CH3), 0.88
(s, 9H, TBS), 0.17 (s, 3H, TBS), 0.13 (s, 3H, TBS). 13C NMR (125 MHz,
DMSO-d6, 90 °C) δ 170.26, 169.06, 164.39, 162.46, 144.19 (d, J = 10.6
Hz), 128.87 (s), 127.49 (d, J = 10.3 Hz), 110.71 (d, J = 23.0 Hz), 104.80
(d, J = 26.7 Hz), 72.89, 68.95 , 62.83, 26.09, 23.45, 20.60, 18.07, -3.98, -
4.06. HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C19H28NO4SiNa 404.1619,
found 404.1662.
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{1-Acetyl-3-[(tert-butyldimethylsilyl)oxy]-5-nitro-2,3-dihydro-1H-indoline-2-
yl}methyl acetate (63). Eluent: 30% Ethyl Acetate/Hexanes to yield 63
(12 mg, 0.029 mmol, 27%) as an oil. 1H NMR (500 MHz, DMSO-d6,
90 °C) δ 8.26 (dd, J = 9.0, 2.3 Hz, 1H, Ar), 8.19 (d, J = 2.3 Hz, 1H, Ar),
8.08 (d, J = 9.0 Hz, 1H, Ar), 5.17 (s, 1H, CH-OTBS), 4.54 (dd, J = 6.7
and 5.0 Hz, 1H, CH-NAc), 4.26 (dd, J = 11.8 and 5.0 Hz, 1H, CH2), 4.10
(dd, J = 11.8 and 6.7 Hz, 1H, CH2), 2.38 (s, 3H, CH3), 1.91 (s, 3H, CH3),
0.88 (s, 9H, TBS), 0.20 (s, 3H, TBS), 0.17 (s, 3H, TBS). 13C NMR (125
MHz, DMSO-d6, 90°C) δ 170.25, 169.71, 147.93, 143.81, 134.31, 126.52,
121.84, 117.10, 72.56, 68.86, 62.77, 26.07, 23.69, 20.59, 18.05, 14.46, -
3.96, -4.05. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd. for C19H29N2O6SiNa
431.1609, found 431.1594
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European Journal of Organic Chemistry
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12
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FULL PAPER
FULL PAPER
Fábio de Souza Fernandes, Rodrigo A.
Cormanich, Lucas A. Zeoly, André Luiz
B. Formiga, Fernando Coelho *
Page No. – Page No.
Employing small poly-functionalized
molecules for the diastereoselective
synthesis of highly substituted
indolines
We described herein a straightforward approach for the synthesis of 2,3-substituted
indolines. The method is based on the use of small poly-functionalized molecules
as building blocks. The indolines were prepared in few steps in high trans
diastereoselectivity and overall yields of up to 35%. This is the first report on the
synthesis of 2,3-substituted indolines from Morita-Baylis-Hillman adducts.
13
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