Co(I)-Catalyzed [3 + 2] Annulation of o -Haloaryl Imines with Alkenes for the Synthesis of Indanamines

Article abstract of DOI:10.1021/acs.joc.8b00551

The use of a CoBr₂/1,10-phenanthroline catalytic system together with Zn as the reductant was developed to prepare diversely substituted indanamines by a Co(I)-catalyzed [3 + 2] annulation of o-haloaryl imines with electron-deficient alkenes in good yields. The use of Mn as the reductant allowed the elaboration of a three-component version of this reaction. These conditions were also found to be suitable for the activation of various halides and were extended to the preparation of the indenamine and strigolactam scaffolds.

Full text of DOI:10.1021/acs.joc.8b00551

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Co(I)-catalyzed [3+2] annulation of o-haloaryl imines
with alkenes for the synthesis of indanamines
Jérôme Paul, Lisa Luong Van My, Myriam Behar-Pirès, Coralie
Guillaume, Eric Leonel, Marc Presset, and Erwan Le Gall
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00551 • Publication Date (Web): 21 Mar 2018
Downloaded from http://pubs.acs.org on March 22, 2018
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Co(I)ꢀcatalyzed [3+2] annulation of oꢀhaloaryl imines with alkenes for the synthesis of
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indanamines
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Jérôme Paul, Lisa Luong Van My, Myriam BeharꢀPirès, Coralie Guillaume, Eric Léonel,
Marc Presset,* Erwan Le Gall*
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Électrochimie et Synthèse Organique, Université Paris Est, ICMPE (UMR 7182), CNRS,
UPEC, 2ꢀ8 rue Henri Dunant, Fꢀ94320 Thiais, France
presset@icmpe.cnrs.fr; legall@icmpe.cnrs.fr
Abstract
The use of a CoBr2 / 1,10ꢀphenanthroline catalytic system together with Zn as the reductant
has been developed to prepare diversely substituted indanamines by a Co(I)ꢀcatalyzed [3+2]
annulation of oꢀhaloaryl imines with electronꢀdeficient alkenes in good yields. The use of Mn
as the reductant allowed the elaboration of a threeꢀcomponent version of this reaction. These
conditions were also found to be suitable for the activation of various halides and were
extended to the preparation of the indenamine and strigolactam scaffolds.
Introduction
The use of first row transition metals in catalysis is of increasing importance thanks to their
broad availability, reduced cost and low toxicity.1 Among them, cobalt is particularly
interesting because it can catalyze a large number of reactions, with a great substrate scope
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due to a high tolerance to various functional groups. Cobalt complexes are particularly
suitable for annulation reactions, and especially [2+2+2] cycloadditions,2,3 owing to its high
affinity to πꢀsystems.4,5 The crucial field of crossꢀcoupling reactions has also greatly benefited
from cobalt catalysis, in traditional reactions between an organometallic species and an
electrophile6,7 and, more recently, in reductive couplings between two electrophiles.8,9 The
merge of cobaltꢀcatalyzed annulation and coupling reactions has been achieved by Cheng in
2003 with the development of the [3+2] annulation reaction between oꢀiodoaryl aldehydes or
ketones with carbonꢀcarbon π bonds of alkenes or alkynes in a new synthesis of indenes and
indanols.10,11 The closely related nitrogenated counterpart indanamines are relevant targets in
organic synthesis. For instance, this scaffold is a key feature of the broadꢀspectrum herbicide
Indaziflam,12 HIVꢀ1 entry inhibitors like (+)ꢀDMJꢀIIꢀ12113 and strigolactam phytohormones
(Figure 1).14
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Figure 1. Selected bioactive indanamines.
The first Coꢀcatalyzed preparation of indanamines has been reported by Cheng in 2012.15
However, these conditions remained limited to the use of oꢀiminoarylboronic acids and
Michael acceptors (Scheme 1a). The use of related oꢀhalogenated starting materials was only
described in multicomponent annulation reactions with alkynes leading to indenamines. In
this case, the imine function was formed in situ by condensation of a primary aliphatic or
aromatic amine on a carbonyl compound16 However, the process was only exemplified
starting from iodinated substrates. In the past few years, our group has developed some
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efficient Co(I)ꢀcatalyzed transformations based on a halide activation by a Co(II) / reductant
catalytic system. These methodologies have been successfully applied to organometallic
Mannich reactions involving aryl halides,17,18 ultimately leading to multicomponent
procedures initiated by a Michael addition.19 More precisely, we recently reported a new
synthesis of β2,3ꢀaminoesters by multicomponent assembly of aryl halides, Michael acceptors
and sulfonated imines.20,21 Herein, we describe the development of an intramolecular version
of this reaction leading to indanamines through a [3+2] annulation of oꢀhaloaryl imines with
Michael acceptors (Scheme 1b), as well as the elaboration of the corresponding threeꢀ
component version of the reaction.
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Scheme 1. Coꢀcatalyzed syntheses of indanamines.
Results and Discussion
We started our investigations of the twoꢀcomponent [3+2] annulation reaction (2CR) from our
previously optimized conditions developed for the related multicomponent reaction (MCR)
involving aryl halides, imines and Michael acceptors.21 As a test reaction, we thus submitted a
mixture of brominated imine 1a (1.0 equiv) and methyl acrylate 2a (2.0 equiv) to the presence
of CoBr2 (10 mol%) and activated zinc dust (4.0 equiv) in acetonitrile at 80 °C.22 The
expected indanamine 3a was gratifyingly isolated in a promising 52% yield (entry 1, Table 1).
Having noticed the beneficial influence of ligated cobalt species in similar transformations,16
we next evaluated the effect of the addition of a ligand (L) to the catalytic system. While the
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use of diphenylphosphinoethane (dppe) as disclosed in Cheng's work showed a slight
improvement (66%, entry 2), the use of 1,10ꢀphenanthroline (1,10ꢀphen) afforded a good 82%
yield (entry 3). It should be noted that the nature of the catalytic system has no influence on
the diastereoselectivity of the reaction as 3a was obtained in a constant 3.6:1
diastereoisomeric ratio, the major product being the trans stereoisomer, determined by
NOESY analysis.23 We also evaluated the influence of the nature of the halogen atom on the
reaction outcome. Under the same reaction conditions, iodinated derivative worked equally
well (78%, entry 4) and, interestingly, the chlorinated analog of the starting imine allowed the
isolation of the product in a reasonable 68% yield (entry 5).
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Table 1. Study of the 2CR.a
Entry X
L
Yield
52%
66%
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Br ꢀ
Br dppe
Br 1,10ꢀPhen 82%
1,10ꢀPhen 78%
Cl 1,10ꢀPhen 68%
I
a
Yields of isolated products. Reaction conditions: 1 (1.0 mmol), 2a (2.0 equiv), CoBr2
(10 mol%), L (10 mol%), Zn (4.0 equiv) activated with BrCH2CH2Br (10 mol%) and TFA
(10 mol%), CH3CN (C=0.5 M), 80 °C, 16 h.
With these optimized conditions in hands, we next turned our attention to the scope of the
2CR using various oꢀbrominated and oꢀchlorinated aromatic imines (Table 2). From a general
point of view, bromide derivatives demonstrated higher activities as anticipated. Various
Michael acceptors were first evaluated using bromide derivatives as a compromise of
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efficiency and availability. While ethyl and butyl acrylates worked efficiently (3b: 63% and
3c: 68%, respectively) with similar diastereoselectivities in favor of the trans product, the
reaction performed with N,Nꢀdimethylacrylamide allowed only the isolation of a cis
diastereoisomer of 3d, albeit in a modest 23% yield. Other electronꢀdeficient alkenes such as
acrylonitrile (64%, 3e)24 and phenylvinylsulfone (62%, 3f) were also efficient partners but
showed poorer stereocontrol. However, the use of substituted Michael acceptors was not
tolerated in the reaction. The presence of an electronꢀwithdrawing group on the imine
function was also required but gave the opportunity to access to the free amine group using a
removable substituent. Thus, the use of starting materials bearing a mesyl group or a 2ꢀ
thiophenesulfonyl group was examined. Mesylated products 3g and 3h were obtained in a
moderate 53% using a chlorinated substrate and in an improved 75% for the brominated one.
In the case of imines bearing a 2ꢀthiophenesulfonyl group (product 3i), a similar observation
could be done. Nevertheless, this group appeared more suitable and allowed the use of
chlorinated starting materials with ethyl acrylate (3j) and acrylonitrile (3k) in useful yields.
Substitution of the aromatic ring of 1 was also examined using either chlorinated or
brominated starting materials. Therefore, the introduction of a trifluoromethyl group on a
chlorinated substrate allowed the synthesis of 3l in 33%. Once again, bromide derivatives
were more efficient and the introduction of a fluorine atom provided similarly good results
(3m, 77%),25 whereas the use of a naphthaleneꢀderived substrate allowed the formation of the
corresponding tricyclic product 3n in 51% yield.
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Table 2. Scope of the twoꢀcomponent synthesis of indanamines.a
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a
Yields of isolated products. Reaction conditions: 1 (1.0 mmol), 2 (2.0 equiv), CoBr2
(10 mol%), 1,10ꢀphen (10 mol%), Zn (4.0 equiv) activated with BrCH2CH2Br (10 mol%) and
TMSCl or TFA (10 mol%), CH3CN (C=0.5 M), 80 °C, 16 h.
Based on previous studies, the reaction is believed to occur through a classical Coꢀcatalyzed
carbometallation followed by an intramolecular addition of the resulting enolate on the imine
moiety (Scheme 2). More precisely, a Co(I) complex A, generated in situ by reduction of
CoBr2 with activated Zn dust,26 underwent an oxidative addition into the C(sp2)–Br bond to
generate the organocobalt species B. This latter could perform a carbocobaltation on the
Michael acceptor 2,27 leading to intermediate C. Upon reaction with zinc, Co(III) is reduced
to Co(I) concomitantly with the formation of zinc enolate D, which evolved by an
intramolecular addition on the C=N bond to produce the zinc salt of 3 and release the Co(I)
catalyst.
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Scheme 2. Plausible reaction mechanism (ligands are omitted for clarity).
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The stereoꢀdeterminating step should thus be the intramolecular addition of the enolate
function onto the imine moiety of D. Regarding the particular result obtained in the case of
N,Nꢀdimethylacrylamide, the geometry of the intermediate enolate appeared to be crucial and
suggested the intervention of a tethered transition state as in the ZimmermanꢀTraxler model.
However, in the present case, the use of a bimetallic Co / Zn catalytic system should favor an
equilibrium between (E)ꢀ and (Z)ꢀenolates and the formation of boatꢀlike conformation,28
through a cobalt – zinc interaction, as previously proposed by Lam.29 Therefore, in this
hypothesis, the formation of a (E)ꢀenolate would lead to TS1 and thus to the major trans
product whereas a (Z)ꢀenolate would lead to TS2, precursor of the minor cis product
(Scheme 3). The transition state TS1 should be the predominant form as the substituent of the
enolate is in pseudoꢀequatorial position. As amides are known to produce exclusively (Z)ꢀ
enolates, the present model explained the exclusive formation of the cisꢀproduct albeit in poor
yield due to the formation of the unfavorable intermediate TS2.
Scheme 3. Diastereoselectivity of the reaction (ligands are omitted for clarity).
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As the development of original MCRs is of constant interest,30 we wondered if a threeꢀ
component version of this reaction would be feasible. Indeed, the starting imines can be
prepared by simple condensation of an aromatic aldehyde with a primary sulfonamide. Such a
modification should be possible thanks to the higher electrophilicity of the sulfonated imines
in comparison with the corresponding aldehydes31 and to the low rates of the azaꢀMichael
additions of sulfonamides onto electronꢀdeficient alkenes. We thus started a short
optimization of the threeꢀcomponent protocol (Table 3).
Using our previous conditions with a 1:1 mixture of aldehyde 4a and sulfonamide 5a, we
were pleased to detect the expected product 3a in an encouraging 19% yield (entry 1).
Increasing the amount of sulfonamide 5a had a negative effect on the reaction (entry 2)
presumably due to its Lewis base character. Based on our previous study on the
organometallic Mannich reaction involving sulfonamide derivatives,32 we switched the
reductant from Zn to Mn. This modification resulted in an improvement of the reaction (30%,
entry 3), even in the absence of the stabilizing ligand (29%, entry 4). The nature of the acidic
additive was ultimately evaluated (entry 5) and the use of TFA instead of TMSCl afforded the
best 31% isolated yield.
Table 3. Optimization of the threeꢀcomponent synthesis of indanamines.a
Entry [Co]
n M Additive Yieldb
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CoBr2 + 1,10ꢀphen 1 Zn TMSCl
CoBr2 + 1,10ꢀphen 2 Zn TMSCl
CoBr2 + 1,10ꢀphen 1 Mn TMSCl
19%
15%
30%
29%
31%c
CoBr2
1 Mn TMSCl
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CoBr2 + 1,10ꢀphen 1 Mn TFA
a Reaction conditions: 4a (1.0 mmol), 5a (n equiv), 2b (2.0 equiv), CoBr2 (10 mol%), L
(10 mol%), M (4.0 equiv) activated with BrCH2CH2Br (10 mol%) and additive (10 mol%),
CH3CN (C=0.5 M), 80 °C, 16 h. b GC yields determined using an internal standard
(mesitylene). c Isolated yield.
The scope of this new threeꢀcomponent protocol was also briefly examined, and the results
are reported in Table 4. In all cases, yields are lower than those observed for 2CRs, due in
particular to more complex purifications, but remained useful for the rapid elaboration of a
small library of compounds. Remarkably, diastereoselectivities are the same than those
observed in 2CRs. All previously used acrylates underwent this reaction, albeit in more
moderate yields (3a-c, 30–40%). Interestingly, the less expensive oꢀchlorobenzaldehyde was
also a suitable substrate and, in this case, 3b could be isolated in 23% yield. The 3CR also
tolerated various reaction partners. The use of acrylonitrile as the Michael acceptor,
mesylamide as the nitrogenated partner and 3ꢀfluoro oꢀbromobenzaldehyde as the aldehyde
yielded 3e, 3g and 3i in 29%, 19% and 20%, respectively.
Table 4. Scope of the threeꢀcomponent synthesis of indanamines.a
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a Yields of isolated products. Reaction conditions: 4 (1.0 mmol), 5 (1.0 equiv), 2 (2.0 equiv),
CoBr2 (10 mol%), 1,10ꢀphen (10 mol%), Mn (4.0 equiv) activated with BrCH2CH2Br
(10 mol%) and TFA (10 mol%), CH3CN (C=0.5 M), 80 °C, 16 h.
As illustrated above, the present annulation reaction led to the substitution of the nitrogen
atom by an electronꢀwithdrawing group. This requirement could be advantageously used to
recover the free amine derivative 6. Indeed, by using an excess of magnesium in methanol
following Carretero's protocol,33 the cleavage of the 2ꢀthiophenesulfonyl group of 3i had been
achieved under mild conditions in an unoptimized 52% yield (Scheme 4).34
Scheme 4. Removal of the 2ꢀthiophenesulfonyl group.
To further demonstrate the usefulness of these conditions for Coꢀcatalyzed annulation
reactions, the procedure was extended to the preparation of other scaffolds. First, the reaction
performed using bromoimine 1a and 3ꢀhexyne 7 afforded the expected indenamine 8 in a fair
64% isolated yield (Scheme 5a). Importantly, the threeꢀcomponent version of this reaction
using oꢀbromobenzaldehyde 4a and pꢀtoluenesulfonamide 5a instead of preformed imine 1a
worked well, affording 8 in 53% with Mn as the reductant. The present method is
complementary to those of Cheng as it allowed the use of an imine substituted by an electronꢀ
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withdrawing group. On the other hand, the present conditions were also suitable for the
synthesis of strigolactam precursors. Indeed, by switching the acrylate for dimethyl itaconate
9,35 a domino reaction involving a final intramolecular lactamization took place and led to the
expected tricyclic product 10 in 31% yield with an exclusive cis ring junction (Scheme 5b).
Scheme 5. Syntheses of an indenamine (a) and a strigolactam precursor (b).
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In conclusion, we have developed a general and efficient Coꢀbased catalytic system for the
[3+2] annulation of oꢀhaloaryl imines with alkenes or alkynes. These conditions were built on
the use of cheap and broadly available cobalt complexes and allowed the straightforward
preparation of indanamines through twoꢀ or threeꢀcomponent reactions. These conditions
could additionally be applied to the synthesis of indenamines and strigolactams precursors.
Experimental Section
General considerations: All commercially available reagents were used as received. In
particular, cobalt bromide and zinc dust (<10 ꢁm) were purchased from SigmaꢀAldrich and
manganese powder from Acros. Imines 1 were prepared by condensation of the required
aldehyde and amine catalyzed by Dowex 50WX4 hydrogen form in refluxing toluene using a
DeanꢀStark apparatus. Acetonitrile was distilled over calcium hydride prior to use. Unless
other precision, reactions were performed under an argon atmosphere in 10 mL microwave
tubes sealed with a Teflonꢀcoated stopper under magnetic stirring. Diastereomeric ratios were
1
determined by H NMR analysis of the crude mixture. Analytical thinꢀlayer chromatography
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(TLC) was performed on TLC silica gel plates (0.25 mm) precoated with a fluorescent
indicator. Flash chromatography (FC) was performed on 40–63 ꢁm silica gel with mixtures of
ethyl acetate (EtOAc) and petroleum ether (PE). Visualization was effected with ultraviolet
light and ethanolic KMnO4. Melting points (mp) are uncorrected and were measured on a
Büchi Bꢀ545 apparatus. Infrared spectra were recorded on a FTꢀIR spectrometer in ATR
mode. Only IR band frequencies of major functional groups are reported in cmꢀ1. NMR
spectra were recorded on a Bruker Avance II 400 MHz spectrometer. 1H NMR chemical shifts
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13
were referenced to the residual solvent signal; C NMR chemical shifts were referenced to
the deuterated solvent signal. Multiplicity was defined by DEPT 135 analysis. 19F NMR
chemical shifts were referenced to external CFCl3 (0.0 ppm). Data are presented as follows:
chemical shift δ (ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br =
broad), coupling constant J (Hz), integration. HighꢀResolution Mass Spectra were obtained at
the ICOA of the Université of Orléans by electrospray ionization using a QꢀTOF analyzer.
General procedure A (2CR): In air, an ovenꢀdried 10 mL reaction tube equipped with a stir
bar was charged with Zn (262 mg, 4.0 mmol, 4.0 equiv), closed with a septum and flushed
with Ar. CH3CN (2 mL, C=0.5 M) and BrCH2CH2Br (9 ꢁL, 0.1 mmol, 10 mol%) were added
and the mixture was heated to reflux using a heat gun and then cooled down to room
temperature. TMSCl (13 ꢁL, 0.1 mmol, 10 mol%) or TFA (8 ꢁL, 0.1 mmol, 10 mol%) was
added and the mixture was heated to reflux with a heat gun and then cooled down to room
temperature. CoBr2 (22 mg, 0.1 mmol, 10 mol%) and 1,10ꢀphenanthroline (18 mg, 0.1 mmol,
10 mol%) were added and the mixture was stirred at room temperature for 2 min. Acrylate 2
(2.0 mmol, 2.0 equiv) and halogenated imine 1 (1.0 mmol, 1.0 equiv) were successively
added and the tube was sealed. The reaction was stirred at 80 °C (external temperature) for 16
h. Then, the reaction mixture was poured into sat aq NH4Cl (50 mL) and the solution was
extracted with EtOAc (2x25 mL). The combined organic layers were washed with brine (50
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General procedure B (3CR): In air, an ovenꢀdried 10 mL reaction tube equipped with a stir
bar was charged with Mn (220 mg, 4.0 mmol, 4.0 equiv), closed with a septum and flushed
with Ar. CH3CN (2 mL, C=0.5 M) and BrCH2CH2Br (9 ꢁL, 0.1 mmol, 10 mol%) were added
and the mixture was heated to reflux using a heat gun and then cooled down to room
temperature. TFA (8 ꢁL, 0.1 mmol, 10 mol%) was added and the mixture was heated to reflux
with a heat gun and then cooled down to room temperature. CoBr2 (22 mg, 0.1 mmol, 10
mol%) and 1,10ꢀphenanthroline (18 mg, 0.1 mmol, 10 mol%) were added and the mixture
was stirred at room temperature for 2 min. Acrylate 2 (2.0 mmol, 2.0 equiv), sulphonamide 5
(1.0 mmol, 1.0 equiv) and halogenated aldehyde 4 (1.0 mmol, 1.0 equiv) were successively
added and the tube was sealed. The reaction was stirred at 80 °C (external temperature) for 16
h. Then, the reaction mixture was poured into sat aq NH4Cl (50 mL) and the solution was
extracted with EtOAc (2x25 mL). The combined organic layers were washed with brine (50
mL), dried (Na2SO4) and evaporated. The crude material by FC to afford the desired product
3.
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Compound 3a: Following the general procedure A, the reaction performed with bromoimine
1a (338 mg, 1.0 mmol) and methyl acrylate 2a (180 ꢁL, 2.0 mmol) with TFA (8 ꢁL, 0.1
mmol, 10 mol%) afforded, after purification by flash chromatography [50 mL SiO2,
EtOAc/PE:2/8 then 4/6], 3a (293 mg, d.r.=3.6:1, 82%) as a white solid. Following the general
procedure B, the reaction performed with 2ꢀbromobenzaldehyde 4a (117 ꢁL, 1.0 mmol), pꢀ
toluenesulfonamide 5a (171 mg, 1.0 mmol) and methyl acrylate 2a (180 ꢁL, 2.0 mmol)
afforded, after purification by flash chromatography [50 mL SiO2, EtOAc/PE:2/8 then 4/6],
3a (141 mg, d.r.=3.6:1, 40%) as a white solid. mp: 126–130 °C. Rf (PE/EtOAc:8/2,
UV+KMnO4): 0.21. IR (neat) ν: 1702, 1327, 1154. HRMS (ESI/Q-TOF) m/z: [M+H]+
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Calcd for C18H20NO4S 346.1107; Found 346.1106. H NMR (CDCl3, 400 MHz): (2
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diastereoisomers) δ 7.82–7.77 (m, 4H), 7.31–7.29 (m, 4H), 7.21–7.07 (m, 7H), 6.97 (d, J=7.4
Hz, 1H), 5.62 (d, J=10.0 Hz, 1H), 5.27 (d, J=8.7 Hz, 1H), 5.15–5.11 (m, 1H), 5.11–5.06 (m,
1H), 3.56 (s, 3H), 3.52 (s, 3H), 3.35 (td, J=7.3, 4.2 Hz, 1H), 3.23–3.00 (m, 5H), 2.44 (s, 3H),
2.43 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz): (2 diastereoisomers) δ 173.9 (C), 173.3 (C),
143.5 (C), 143.5 (C), 140.7 (C), 140.6 (C), 140.2 (C), 139.9 (C), 138.5 (C), 137.9 (C), 129.8
(2 CH), 129.7 (2 CH), 128.8 (CH), 128.7 (CH), 127.5 (2 CH), 127.4 (3 CH), 127.2 (CH),
124.7 (CH), 124.6 (CH), 124.3 (CH), 124.2 (CH), 61.8 (CH), 59.4 (CH), 52.7 (CH), 52.0
(CH3), 51.9 (CH3), 48.0 (CH), 34.6 (CH2), 34.2 (CH2), 21.6 (2 CH3).
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Compound 3b: Following the general procedure A, the reaction performed with bromoimine
1a (338 mg, 1.0 mmol) and ethyl acrylate 2b (220 ꢁL, 2.0 mmol) with TMSCl (13 ꢁL, 0.1
mmol, 10 mol%) afforded, after purification by flash chromatography [50 mL SiO2,
EtOAc/PE:2/8 then 3/7], 3b (227 mg, d.r.=3.3:1, 63%) as a white solid. Following the general
procedure B, the reaction performed with 2ꢀbromobenzaldehyde 4a (117 ꢁL, 1.0 mmol), pꢀ
toluenesulfonamide 5a (171 mg, 1.0 mmol) and ethyl acrylate 2b (220 ꢁL, 2.0 mmol)
afforded, after purification by flash chromatography [50 mL SiO2, EtOAc/PE:2/8 then 3/7],
3a (113 mg, d.r.=3.3:1, 31%) as a white solid. Following the general procedure B, the reaction
performed with 2ꢀchlorobenzaldehyde 4b (113 ꢁL, 1.0 mmol), pꢀtoluenesulfonamide 5a (171
mg, 1.0 mmol) and ethyl acrylate 2b (220 ꢁL, 2.0 mmol) afforded, after purification by flash
chromatography [50 mL SiO2, EtOAc/PE:2/8 then 3/7], 3a (74 mg, d.r.=3.3:1, 20%) as a
white solid. mp: 109–111 °C. Rf (PE/EtOAc:8/2, UV+KMnO4): 0.16 & 0.22. IR (neat) ν:
1704, 1334, 1184. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C19H22NO4S 360.1264;
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Found 360.1265. H NMR (CDCl3, 400 MHz): (2 diastereomers) δ 7.82 (d, J=8.3, 2H), 7.79
(d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 4H), 7.22ꢀ7.10 (m, 4H), 7.06 (d, J=7.5 Hz, 2H), 6.96 (d,
J=7.5 Hz, 2H), 5.71 (d, J=10.0 Hz, 1H), 5.23 (d, J=8.7 Hz, 1H), 5.19 (dd, J=8.7, 7.1 Hz, 1H),
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5.08 (dd, J=10.0, 7.5 Hz, 1H), 4.09ꢀ4.01 (m, 4H), 3.36ꢀ3.31 (m, 1H), 3.28ꢀ3.21 (m, 1H), 3.18ꢀ
3.16 (m, 1H), 3.14ꢀ3.09 (m, 2H), 3.07ꢀ3.03 (m, 1H), 2.47 (s, 3H), 2.46 (s, 3H), 1.24 (t, J=7.1
Hz, 3H), 1.21 (t, J=7.1 Hz, 3H). 13C{1H} NMR (CDCl3, 100 MHz): (2 diastereomers) δ
173.5 (C), 173.0 (C), 143.6 (C), 143.5 (C), 140.9 (C), 140.6 (C), 140.3 (C), 139.7 (C), 138.5
(C), 137.8 (C), 129.8 (2 CH), 129.8 (2 CH), 128.8 (CH), 128.6 (CH), 127.5 (CH), 127.4 (3
CH), 127.2 (2 CH), 124.7 (CH), 124.6 (CH), 124.3 (CH), 124.1 (CH), 61.8 (CH), 61.1 (2
CH2), 59.4 (CH), 52.9 (CH), 47.9 (CH), 34.7 (CH2), 34.5 (CH2), 21.6 (2 CH3), 14.2 (CH3),
14.1 (CH3).
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Compound 3c: Following the general procedure A, the reaction performed with bromoimine
1a (338 mg, 1.0 mmol) and nꢀbutyl acrylate 2c (287 ꢁL, 2.0 mmol) with TMSCl (13 ꢁL, 0.1
mmol, 10 mol%) afforded, after purification by flash chromatography [50 mL SiO2,
EtOAc/PE:1/9 then 2/8], 3c (263 mg, d.r.=2.7:1, 68%) as a white solid. Following the general
procedure B, the reaction performed with 2ꢀbromobenzaldehyde 4a (117 ꢁL, 1.0 mmol), pꢀ
toluenesulfonamide 5a (171 mg, 1.0 mmol) and nꢀbutyl acrylate 2c (287 ꢁL, 2.0 mmol)
afforded, after purification by flash chromatography [50 mL SiO2, EtOAc/PE:1/9 then 2/8], 3c
(116 mg, d.r.=2.7:1, 30%) as a white solid. mp: 62–67 °C. Rf (PE/EtOAc:8/2,
UV+KMnO4): 0.15 & 0.21. IR (neat) ν: 1703, 1358, 1111. HRMS (ESI/Q-TOF) m/z:
[M+H]+ Calcd for C21H26NO4S 388.1577; Found 388.1575. 1H NMR (CDCl3, 400 MHz): (2
diastereomers) δ 7.82 (d, J=8.3 Hz, 2H), 7.79 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 4H), 7.23–
7.12 (m, 6H), 7.07ꢀ7.01 (m, 2H), 5.74 (d, J=10.1 Hz, 1H), 5.19–5.15 (m, 1H), 5.11–5.05 (m,
2H), 3.99ꢀ3.94 (m, 2H), 3.88–3.82 (m, 2H), 3.31–3.21 (m, 2H), 3.14–3.01 (m, 4H), 2.44 (s,
6H), 1.60–1.49 (m, 4H), 1.38–1.29 (m, 4H), 0.93 (t, J=7.4 Hz, 3H), 0.91 (t, J=7.4 Hz, 3H).
13C{1H} NMR (CDCl3, 100 MHz): (2 diastereomers) δ 173.5 (C), 173.2 (C), 143.5 (C),
143.5 (C), 141.0 (C), 140.6 (C), 140.4 (C), 139.6 (C), 138.5 (C), 137.8 (C), 129.8 (2 CH),
129.8 (2 CH), 128.9 (CH), 128.6 (CH), 127.6 (CH), 127.4 (3 CH), 127.2 (2 CH), 124.7 (2
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CH), 124.3 (CH), 124.1 (CH), 65.0 (CH2), 65.0 (CH2), 61.8 (CH), 59.4 (CH), 52.9 (CH), 48.0
(CH), 34.8 (CH2), 34.6 (CH2), 30.6 (CH2), 30.5 (CH2), 21.6 (2 CH3), 19.2 (CH2), 19.1 (CH2),
13.8 (CH3), 13.8 (CH3).
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Compound 3d: Following the general procedure A, the reaction performed with bromoimine
1a (338 mg, 1.0 mmol) and N,Nꢀdimethylacrylamide 2d (206 ꢁL, 2.0 mmol) with TMSCl (13
ꢁL, 0.1 mmol, 10 mol%) afforded, after purification by flash chromatography [50 mL SiO2,
EtOAc/PE:5/5 then 8/2], 3d (82 mg, d.r.>25:1, 23%) as a white solid. mp: 166–170 °C. Rf
(PE/EtOAc:5/5, UV+KMnO4): 0.21. IR (neat) ν: 1628, 1301, 1150. HRMS (ESI/Q-TOF)
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m/z: [M+Na]+ Calcd for C19H22N2NaO3S 381.1243; Found 381.1242. H NMR (CDCl3, 400
MHz): (1 diastereomer) δ 7.78 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 7.17–7.09 (m, 4H),
6.49 (d, J=9.8 Hz, 1H), 5.04 (dd, J=9.8, 7.4 Hz, 1H), 3.45 (td, J=7.4, 6.0 Hz, 1H), 3.06 (d,
J=6.0 Hz, 2H), 2.76 (s, 3H), 2.75 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz): (1
diastereomer) δ 172.4 (C), 143.2 (C), 141.8 (C), 140.0 (C), 138.8 (C), 129.6 (2 CH), 128.2
(CH), 127.2 (CH), 127.2 (2 CH), 124.5 (CH), 123.9 (CH), 59.4 (CH), 43.9 (CH), 37.2 (CH3),
35.4 (CH3), 35.1 (CH2), 21.5 (CH3).
Compound 3e: Following the general procedure A, the reaction performed with bromoimine
1a (338 mg, 1.0 mmol) and acrylonitrile 2e (133 ꢁL, 2.0 mmol) with TMSCl (13 ꢁL, 0.1
mmol, 10 mol%) afforded, after purification by flash chromatography [50 mL SiO2,
EtOAc/PE: 2/8], 3e (200 mg, d.r.=2.1:1, 64%) as a white solid. Following the general
procedure B, the reaction performed with 2ꢀbromobenzaldehyde 4a (117 ꢁL, 1.0 mmol), pꢀ
toluenesulfonamide 5a (171 mg, 1.0 mmol) and acrylonitrile 2e (133 ꢁL, 2.0 mmol) afforded,
after purification by flash chromatography [50 mL SiO2, EtOAc/PE: 2/8], 3e (92 mg,
d.r.=2.1:1, 29%) as a white solid. mp: 191–194 °C. Rf (PE/EtOAc:8/2, UV+KMnO4): 0.13
& 0.19. IR (neat) ν: 2242, 1326, 1092. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for
C17H16N2NaO2S 335.0824; Found 335.0824. 1H NMR (CDCl3, 400 MHz): (2 diastereomers)
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δ 7.88–7.85 (m, 4H), 7.38–7.36 (m, 4H), 7.30–7.19 (m, 6H), 7.10–7.06 (m, 2H), 5.65 (d,
J=10.0 Hz, 1H), 5.62 (d, J=8.4 Hz, 1H), 5.11 (dd, J=10.0, 7.0 Hz, 1H), 5.03 (dd, J=8.4, 7.2
Hz, 1H), 3.46 (td, J=7.2, 2.9 Hz, 1H), 3.42–3.35 (m, 1H), 3.24 (dd, J=16.1, 2.9 Hz, 1H), 3.19–
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3.09 (m, 3H), 2.48 (s, 6H). C{1H} NMR (CDCl3, 100 MHz): (2 diastereomers) δ 144.2 (2
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C), 139.0 (C), 138.8 (C), 138.4 (2 C), 137.5 (C), 137.1 (C), 130.1 (2 CH), 130.1 (2 CH), 129.5
(CH), 129.4 (CH), 128.1 (2 CH), 127.4 (2 CH), 127.3 (2 CH), 125.2 (CH), 124.9 (CH), 124.5
(CH), 124.3 (CH), 120.4 (C), 119.5 (C), 62.4 (CH), 59.2 (CH), 37.4 (CH), 36.5 (CH), 35.0
(CH2), 34.7 (CH2), 21.7 (2 CH3).
Compound 3f: Following the general procedure A, the reaction performed with bromoimine
1a (338 mg, 1.0 mmol) and phenyl vinyl sulfone 2f (336 mg, 2.0 mmol) with TMSCl (13 ꢁL,
0.1 mmol, 10 mol%) afforded, after purification by flash chromatography [50 mL SiO2,
EtOAc/PE: 3/7 then 5/5], 3f (265 mg, d.r.=1.5:1, 62%) as a yellow solid. mp: 100–103 °C. Rf
(PE/EtOAc:5/5, UV+KMnO4): 0.51 & 0.6. IR (neat) ν: 1304, 1289, 1145, 1119. HRMS
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(CDCl3, 400 MHz): (2 diastereomers) δ 7.79–7.71 (m, 7H), 7.64–7.57 (m, 3H), 7.50–7.45
(m, 3H), 7.29–7.19 (m, 6H), 7.16–7.10 (m, 2H), 7.05–7.00 (m, 3H), 6.89 (d, J=7.6 Hz, 2H),
6.27 (d, J=9.1 Hz, 1H), 5.76 (d, J=7.4 Hz, 1H), 5.23 (dd, J=7.4, 3.5 Hz, 1H), 5.18–5.16 (m,
1H), 4.06–3.97 (m, 2H), 3.48 (dd, J=17.0, 4.6 Hz, 1H), 3.28–3.26 (m, 2H), 3.07 (dd, J=17.0,
7.8 Hz, 1H), 2.43 (s, 3H), 2.41 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz): (2 diastereomers)
δ 143.5 (C), 143.1 (C), 139.7 (C), 139.7 (C), 139.3 (C), 139.1 (C), 138.5 (C), 138.0 (C), 137.6
(C), 137.3 (C), 133.9 (CH), 133.8 (CH), 129.7 (CH), 129.6 (2 CH), 129.5 (2 CH), 129.2 (2
CH), 129.1 (CH), 129.1 (CH), 128.7 (2 CH), 128.4 (2 CH), 127.5 (CH), 127.5 (CH), 127.2 (2
CH), 127.1 (CH), 126.2 (2 CH), 124.9 (CH), 124.4 (CH), 124.4 (CH), 123.9 (CH), 69.0 (CH),
65.7 (CH), 59.0 (CH), 58.4 (CH), 31.8 (CH2), 30.8 (CH2), 21.5 (CH3), 21.5 (CH3).
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Compound 3g: Following the general procedure A, the reaction performed with chloroimine
1b (218 mg, 1.0 mmol) and methyl acrylate 2a (180 ꢁL, 2.0 mmol) with TFA (8 ꢁL, 0.1
mmol, 10 mol%) afforded, after purification by flash chromatography [50 mL SiO2,
EtOAc/PE: 2/8 then 4/6], 3g (144 mg, d.r.=2.5:1, 53%) as a white solid. mp: 106–107 °C. Rf
(PE/EtOAc:6/4, UV+KMnO4): 0.47. IR (neat) ν: 1727, 1305, 1141. HRMS (ESI/Q-TOF)
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m/z: [M+H]+ Calcd for C12H16NO4S 270.0794; Found 270.0793. H NMR (CDCl3, 400
MHz): (2 diastereoisomers) δ 7.45–7.42 (m, 2H), 7.28–7.25 (m, 4H), 7.20–7.18 (m, 2H),
5.33–5.25 (m, 2H), 5.21 (dd, J=9.5, 7.6 Hz, 1H), 5.02 (d, J=9.4 Hz, 1H), 3.78 (s, 3H), 3.72 (s,
3H), 3.60 (dd, J = 13.8, 7.8 Hz, 1H), 3.35–3.26 (m, 2H), 3.22–3.13 (m, 3H), 3.09 (s, 3H), 3.00
(s, 3H). 13C{1H} NMR (CDCl3, 100 MHz): (2 diastereoisomers) δ 174.0 (C), 173.2 (C),
140.8 (C), 140.7 (C), 140.4 (C), 139.8 (C), 129.0 (CH), 128.9 (CH), 127.7 (CH), 127.6 (CH),
125.0 (CH), 124.7 (CH), 124.6 (CH), 124.5 (CH), 61.6 (CH), 59.6 (CH), 52.7 (CH3), 52.4
(CH3), 52.2 (CH), 48.6 (CH), 42.2 (CH3), 41.8 (CH3), 34.1 (CH2), 33.8 (CH2).
Compound 3h: Following the general procedure A, the reaction performed with bromoimine
1c (262 mg, 1.0 mmol) and ethyl acrylate 2b (220 ꢁL, 2.0 mmol) with TFA (8 ꢁL, 0.1 mmol,
10 mol%) afforded, after purification by flash chromatography [50 mL SiO2, EtOAc/PE: 2/8
then 4/6], 3h (213 mg, d.r.=2.9:1, 75%) as a white solid. Following the general procedure B,
the reaction performed with 2ꢀbromobenzaldehyde 4a (117 ꢁL, 1.0 mmol),
methanesulfonamide 5b (95 mg, 1.0 mmol) and ethyl acrylate 2b (220 ꢁL, 2.0 mmol)
afforded, after purification by flash chromatography [50 mL SiO2, EtOAc/PE: 2/8 then 4/6],
3h (54 mg, d.r.=2.9:1, 19%) as a white solid. mp: 85–90 °C. Rf (PE/EtOAc:8/2,
UV+KMnO4): 0.17. IR (neat) ν: 1732, 1307, 1145. HRMS (ESI/Q-TOF) m/z: [M+H]+
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diastereoisomers) δ 7.39–7.36 (m, 2H), 7.22–7.19 (m, 4H), 7.13–7.11 (m, 2H), 5.46 (d, J=9.8
Hz, 1H), 5.31 (d, J=9.2 Hz, 1H), 5.19 (t, J=8.5 Hz, 1H), 5.15–5.11 (m, 1H), 4.18 (qd, J=7.1,
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2.0 Hz, 2H), 4.14–4.03 (m, 2H), 3.53–3.47 (m, 1H), 3.29–3.19 (m, 2H), 3.15–3.09 (m, 2H),
3.07–3.02 (m, 1H), 3.00 (s, 3H), 2.92 (s, 3H), 1.27 (t, J=7.1 Hz, 3H), 1.23 (t, J=7.1 Hz; 3H).
13C{1H} NMR (CDCl3, 100 MHz): (2 diastereoisomers) δ 173.5 (C), 172.7 (C), 141.0 (C),
140.8 (C), 140.4 (C), 139.7 (C), 128.8 (CH), 128.6 (CH), 127.4 (CH), 127.4 (CH), 124.8
(CH), 124.5 (CH), 124.4 (CH), 124.4 (CH), 61.4 (CH), 61.2 (CH2), 61.1 (CH2), 59.5 (CH),
52.6 (CH), 48.6 (CH), 42.0 (CH3), 41.6 (CH3), 34.0 (CH2), 33.7 (CH2), 14.2 (CH3), 14.1
(CH3).
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Compound 3i: Following the general procedure A, the reaction performed with bromoimine
1d (388 mg, 1.0 mmol) and methyl acrylate 2a (180 ꢁL, 2.0 mmol) with TFA (8 ꢁL, 0.1
mmol, 10 mol%) afforded, after purification by flash chromatography [50 mL SiO2,
EtOAc/PE: 2/8 then 4/6], 3i (315 mg, d.r.=3.9:1, 93%) as a white solid. Following the general
procedure A, the reaction performed with chloroimine 1e (286 mg, 1.0 mmol) and methyl
acrylate 2a (180 ꢁL, 2.0 mmol) with TFA (8 ꢁL, 0.1 mmol, 10 mol%) afforded, after
purification by flash chromatography [50 mL SiO2, EtOAc/PE: 2/8 then 4/6], 3i (236 mg,
d.r.=3.9:1, 70%) as a white solid. mp: 110–112 °C. Rf (PE/EtOAc:8/2, UV+KMnO4): 0.16.
IR (neat) ν: 1739, 1339, 1152. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for
C15H15NNaO4S2 360.0334; Found 360.0334. 1H NMR (CDCl3, 400 MHz): (2
diastereoisomers) δ 7.64 (dd, J=3.7, 1.2 Hz, 1H), 7.62–7.58 (m, 3H), 7.20–7.15 (m, 2H),
7.13–7.09 (m, 4H), 7.08–7.04 (m, 3H), 6.90 (d, J=7.5 Hz, 1H), 5.83 (d, J=9.8 Hz, 1H), 5.64
(d, J=8.5 Hz, 1H), 5.19 (dd, J=7.7, 7.7 Hz, 1H), 5.15–5.11 (m, 1H), 3.58 (s, 3H), 3.56 (s, 3H),
3.41 (td, J=8.0, 4.9 Hz, 1H), 3.24–3.20 (m, 1H), 3.18–3.07 (m, 3H), 3.02 (dd, J=14.4, 7.3 Hz,
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1H). C{1H} NMR (CDCl3, 100 MHz): (2 diastereoisomers) δ 173.9 (C), 173.2 (C), 142.2
(C), 141.6 (C), 140.2 (C), 140.2 (C), 140.1 (C), 140.0 (C), 132.6 (2 CH), 132.1 (CH), 132.0
(CH), 128.8 (CH), 128.7 (CH), 127.6 (CH), 127.4 (2 CH), 127.4 (CH), 124.7 (CH), 124.6
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(CH), 124.2 (CH), 124.0 (CH), 61.9 (CH), 59.6 (CH), 52.3 (CH), 52.1 (CH3), 52.1 (CH3),
47.8 (CH), 34.5 (CH2), 34.1 (CH2).
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Compound 3j: Following the general procedure A, the reaction performed with chloroimine
1e (286 mg, 1.0 mmol) and ethyl acrylate 2b (220 ꢁL, 2.0 mmol) with TFA (8 ꢁL, 0.1 mmol,
10 mol%) afforded, after purification by flash chromatography [50 mL SiO2, EtOAc/PE: 2/8
then 4/6], 3j (133 mg, d.r.=2.7:1, 38%) as a white paste. Rf (PE/EtOAc:6/4, UV+KMnO4):
0.46 & 0.61. IR (neat) ν: 1732, 1339, 1152. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for
C16H17NNaO4S2 374.0491; Found 374.0489. 1H NMR (CDCl3, 400 MHz): (2
diastereoisomers) δ 7.66 (d, J = 3.7, 1.3 Hz, 1H), 7.64–7.59 (m, 3H), 7.22–7.18 (m, 2H),
7.16–7.12 (m, 4H), 7.09–7.07 (m, 2H), 7.03 (d, J = 7.8 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H), 5.88
(d, J = 9.9 Hz, 1H), 5.52 (d, J = 8.5 Hz, 1H), 5.23 (dd, J = 7.7, 7.7 Hz, 1H), 5.14 (dd, J = 9.5,
7.9 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 4.01 (q, J = 7.2 Hz, 2H), 3.39 (td, J = 7.9, 4.6 Hz, 1H),
3.24 (dd, J = 14.9, 8.4 Hz, 1H), 3.18–3.09 (m, 3H), 3.04 (dd, J = 15.2, 7.8 Hz, 1H), 1.23 (t, J
= 7.1 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (CDCl3, 100 MHz): (2
diastereoisomers) δ 173.4 (C), 173.0 (C), 142.4 (C), 141.7 (C), 140.4 (C), 140.3 (C), 140.3
(C), 139.9 (C), 132.7 (CH), 132.1 (2 CH), 132.0 (CH), 128.8 (CH), 128.7 (CH), 127.6 (CH),
127.5 (CH), 127.5 (CH), 127.4 (CH), 124.7 (CH), 124.7 (CH), 124.2 (CH), 124.0 (CH), 61.9
(CH), 61.2 (CH2), 61.2 (CH2), 59.6 (CH), 52.7 (CH), 47.9 (CH), 34.7 (CH2), 34.3 (CH2), 14.2
(CH3), 14.1 (CH3).
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Compound 3k: Following the general procedure A, the reaction performed with chloroimine
1e (286 mg, 1.0 mmol) and acrylonitrile 2e (133 ꢁL, 2.0 mmol) with TFA (8 ꢁL, 0.1 mmol,
10 mol%) afforded, after purification by flash chromatography [50 mL SiO2, EtOAc/PE: 2/8
then 3/7], 3k (95 mg, d.r.=1.3:1, 30%) as a white solid. mp: 162–167 °C. Rf (PE/EtOAc:7/3,
UV+KMnO4): 0.44.& 0.41. IR (neat) ν: 2246, 1338, 1156. HRMS (ESI/Q-TOF) m/z:
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[M+H]+ Calcd for C14H13N2O2S2 305.0412; Found 305.0414. H NMR ((CD3)2CO, 400
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MHz): (2 diastereoisomers) δ 7.94–7.93 (m, 2H), 7.80–7.77 (m, 3H), 7.61 (d, J = 7.6 Hz,
1H), 7.29–7.17 (m, 8H), 6.96 (d, J = 7.5 Hz, 1H), 6.85 (d, J = 7.0 Hz, 1H), 5.26–5.20 (m, 2H),
3.86–3.82 (m, 1H), 3.46 (dd, J = 14.9, 8.2 Hz, 1H), 3.37–3.25 (m, J = 3H), 3.16 (dd, J = 14.9,
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8.0 Hz, 1H). C{1H} NMR ((CD3)2CO, 100 MHz): (2 diastereoisomers) δ 143.7 (C), 143.4
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(C), 140.5 (2 C), 140.1 (C), 139.9 (C), 133.4 (CH), 133.2 (CH), 133.1 (CH), 132.9 (CH),
129.7 (2 CH), 128.6 (CH), 128.5 (CH), 128.3 (CH), 128.2 (CH), 125.7 (CH), 125.5 (CH),
125.0 (CH), 124.9 (CH), 120.8 (C), 120.2 (C), 63.2 (CH), 60.2 (CH), 37.8 (CH), 37.1 (CH),
35.5 (CH2), 35.3 (CH2).
Compound 3l: Following the general procedure A, the reaction performed with chloroimine
1f (286 mg, 1.0 mmol) and methyl acrylate 2a (180 ꢁL, 2.0 mmol) with TFA (8 ꢁL, 0.1
mmol, 10 mol%) afforded, after purification by flash chromatography [50 mL SiO2,
EtOAc/PE: 3/7 then 4/6], 3l (111 mg, d.r.=2.5:1, 30%) as a white solid. mp: 108–110 °C. Rf
(PE/EtOAc:6/4, UV+KMnO4): 0.36. IR (neat) ν: 1736, 1320, 1114. HRMS (ESI/Q-TOF)
m/z: [M+Na]+ Calcd for C13H14F3NNaO4S 360.0487; Found 360.0488. 1H NMR (CDCl3, 400
MHz): (2 diastereoisomers) δ 7.68–7.65 (m, 2H), 7.53–7.51 (m, 2H), 7.33 (d, J = 8.1 Hz,
1H), 7.30 (d, J = 7.9 Hz, 1H), 5.52 (d, J = 10.0 Hz, 1H), 5.31–5.21 (m, 3H), 3.78 (s, 3H), 3.71
(s, 3H), 3.64 (dd, J = 12.7, 8.0 Hz, 1H), 3.35–3.29 (m, 2H), 3.26–3.20 (m, 2H), 3.16–3.12 (m,
1H), 3.09 (s, 3H), 3.02 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz): (2 diastereoisomers) δ
173.4 (C), 172.9 (C), 144.3 (C), 143.8 (C), 141.9 (C), 141.8 (C), 130.4 (q, J = 32.3 Hz, C),
130.3 (q, J = 32.5 Hz, C), 126.1 (q, J = 3.9 Hz, CH), 126.0 (q, J = 3.8 Hz, CH), 125.4 (CH),
125.2 (CH), 124.2 (q, J = 272.3 Hz, 2C), 121.7 (q, J = 3.7 Hz, CH), 121.5 (q, J = 3.8 Hz, CH),
61.2 (CH), 59.2 (CH), 52.7 (CH3), 52.6 (CH3), 52.4 (CH), 48.7 (CH), 42.3 (CH3), 41.8 (CH3),
34.0 (CH2), 33.9 (CH2). 19F NMR (CDCl3, 377 MHz): ꢀ62.0 (s, 3F), ꢀ62.0 (s, 3F).
Compound 3m: Following the general procedure A, the reaction performed with bromoimine
1g (356 mg, 1.0 mmol) and ethyl acrylate 2b (220 ꢁL, 2.0 mmol) with TMSCl (13 ꢁL, 0.1
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mmol, 10 molafforded, after purification by flash chromatography [50 mL SiO2, EtOAc/PE:
2/8 then 3/7], 3m (294 mg, d.r.=2.6:1, 77%) as a yellow solid. Following the general
procedure B, the reaction performed with 2ꢀbromo,5ꢀfluorobenzaldehyde 4c (203 mg, 1.0
mmol), pꢀtoluenesulfonamide 5a (171 mg, 1.0 mmol) and ethyl acrylate 2b (220 ꢁL, 2.0
mmol) afforded, after purification by flash chromatography [50 mL SiO2, EtOAc/PE: 2/8 then
3/7], 3m (78 mg, d.r.=2.6:1, 20%) as a yellow solid. mp: 106–109 °C. Rf (PE/EtOAc:8/2,
UV+KMnO4): 0.12 & 0.2. IR (neat) ν: 1707, 1330, 1193. HRMS (ESI/Q-TOF) m/z:
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[M+Na]+ Calcd for C19H20FNNaO4S 400.0989; Found 400.0990. H NMR (CDCl3, 400
MHz): (2 diastereomers) δ 7.79–7.75 (m, 4H), 7.33–7.29 (m, 4H), 7.08–7.03 (m, 2H), 6.88–
6.83 (m, 2H), 6.76 (dd, J=8.6, 1.6 Hz, 1H), 6.56 (dd, J=8.6, 1.6 Hz, 1H), 5.97 (d, J=10.0 Hz,
1H), 5.80 (d, J=9.0 Hz, 1H), 5.11 (dd, J=9.0, 7.7 Hz, 1H), 5.04 (dd, J=10.0, 7.7 Hz, 1H),
4.01–3.90 (m, 4H), 3.34–3.29 (m, 1H), 3.19–3.08 (m, 3H), 3.04–2.96 (m, 2H), 2.45 (s, 3H),
2.43 (s, 3H), 1.18 (t, J=7.1 Hz, 3H), 1.17 (t, J=7.1 Hz, 3H). 13C{1H} NMR (CDCl3, 100
MHz): (2 diastereomers) δ 173.1 (C), 172.8 (C), 162.4 (d, J=244.8 Hz, C), 162.3 (d, J=244.9
Hz, C), 143.7 (C), 143.6 (C), 143.0 (d, J=7.9 Hz, C), 142.9 (d, J=7.9 Hz, C), 138.2 (C), 137.8
(C), 135.4 (d, J=2.5 Hz, C), 135.1 (d, J=2.5 Hz, C), 129.9 (2 CH), 129.7 (2 CH), 127.2 (2
CH), 127.0 (2 CH), 125.7 (d, J=8.7 Hz, CH), 125.6 (d, J=8.7 Hz, CH), 115.8 (d, J=22.7 Hz,
CH), 115.5 (d, J=22.7 Hz, CH), 111.4 (d, J=23.1 Hz, CH), 111.1 (d, J=23.3 Hz, CH), 61.4 (d,
J=1.9 Hz, CH), 61.1 (CH2), 61.1 (CH2), 59.1 (d, J=1.9 Hz, CH), 52.9 (CH), 48.4 (CH), 33.8
(CH2), 33.5 (CH2), 21.4 (2 CH3), 14.0 (CH3), 13.9 (CH3). 19F NMR (CDCl3, 377 MHz): ꢀ
114.9 (s, 1F), ꢀ115.2 (s, 1F).
Compound 3n: Following the general procedure A, the reaction performed with bromoimine
1h (388 mg, 1.0 mmol) and methyl acrylate 2a (180 ꢁL, 2.0 mmol) with TFA (8 ꢁL, 0.1
mmol, 10 mol%) afforded, after purification by flash chromatography [50 mL SiO2,
EtOAc/PE: 2/8 then 3/7], 3n (203 mg, d.r.=3.2:1, 51%) as a white solid. mp: 173–176 °C. Rf
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(PE/EtOAc:8/2, UV+KMnO4): 0.20. IR (neat) ν: 1729, 1369, 1156. HRMS (ESI/Q-TOF)
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m/z: [M+Na]+ Calcd for C22H21NNaO4S 418.1083; Found 418.1081. H NMR (CDCl3, 400
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MHz): (2 diastereomers) δ 7.84–7.79 (m, 6H), 7.72–7.63 (m, 4H), 7.52–7.44 (m, 4H), 7.33–
7.30 (m, 4H), 7.18 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 5.55 (d, J=10.1 Hz, 1H), 5.35–
5.32 (m, 1H), 5.32–5.27 (m, 1H), 5.17 (d, J=8.9 Hz, 1H), 3.60 (s, 3H), 3.54 (s, 3H), 3.39–3.34
(m, 1H), 3.31–3.27 (m, 2H), 3.25–3.19 (m, 3H), 2.46 (s, 3H), 2.44 (s, 3H). 13C{1H} NMR
(CDCl3, 100 MHz): (2 diastereomers) δ 174.1 (C), 173.3 (C), 143.6 (C), 143.6 (C), 138.5 (C),
137.9 (C), 137.5 (C), 137.1 (C), 136.7 (C), 136.6 (C), 133.8 (C), 133.8 (C), 129.9 (2 CH),
129.8 (2 CH), 129.8 (2 C), 128.7 (CH), 128.6 (CH), 128.6 (CH), 128.5 (CH), 127.5 (2 CH),
127.2 (2 CH), 126.7 (CH), 126.7 (CH), 126.3 (CH), 126.3 (CH), 124.2 (CH), 124.2 (CH),
121.9 (CH), 121.9 (CH), 62.6 (CH), 60.4 (CH), 52.3 (CH), 52.2 (CH3), 52.1 (CH3), 47.6
(CH), 33.3 (CH2), 32.8 (CH2), 21.7 (2 CH3).
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Synthesis of the free indanamine 6: In air, a 25 mL RBF equipped with a stir bar was
charged with 3i (127 mg, 0.38 mmol), CH3OH (8 mL, C = 0.05 M) and magnesium turnings
(91 mg, 3.8 mmol, 10.0 equiv). The flask was closed with a septum and the reaction was
stirred at room temperature for 4 h. Then, the reaction mixture was poured into sat aq NH4Cl
(50 mL) and the solution was extracted with EtOAc (2x25 mL). The combined organic layers
were washed with brine (50 mL), dried (Na2SO4) and evaporated. The crude material by flash
chromatography [50 mL SiO2, EtOAc/PE: 5/5 then 10/0] to afford the desired product 6 (38
mg, single trans diastereomer, 52%) as a brown solid. mp: 50–54 °C. Rf (EtOAc,
UV+KMnO4): 0.17. IR (neat) ν: 3351, 1726. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for
C11H13NNaO2 214.0838; Found 214.0839. 1H NMR (CDCl3, 400 MHz): (major
diastereomer) δ 7.27 (d, J = 6.3 Hz, 1H), 7.18–7.13 (m, 3H), 4.51 (d, J = 8.5 Hz, 1H), 3.71 (s,
3H), 3.08 (t, J = 8.4 Hz, 2H), 2.88–2.81 (m, 1H), 1.86 (br s, 2H). 13C{1H} NMR (CDCl3, 100
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MHz): (major diastereomer) δ 174.7 (C), 144.8 (C), 140.2 (C), 127.8 (CH), 127.1 (CH),
124.5 (CH), 123.5 (CH), 60.8 (CH), 56.3 (CH), 52.1 (CH3), 33.7 (CH2).
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Synthesis of indenamine 8: Following the general procedure A, the reaction performed with
bromoimine 1a (338 mg, 1.0 mmol) and 3ꢀhexyne 7 (230 ꢁL, 2.0 mmol) with TMSCl (13 ꢁL,
0.1 mmol, 10 mol%) afforded, after purification by flash chromatography [50 mL SiO2,
EtOAc/PE: 1/9 then 2/8], 7 (217 mg, 63%) as a yellow solid. Following the general procedure
B, the reaction performed with 2ꢀbromobenzaldehyde 4a (117 mg, 1.0 mmol), pꢀ
toluenesulfonamide 5a (171 mg, 1.0 mmol) and 3ꢀhexyne 7 (230 ꢁL, 2.0 mmol) afforded,
after purification by flash chromatography [50 mL SiO2, EtOAc/PE: 1/9 then 2/8], 8 (183 mg,
53%) as a yellow solid. mp: 133–140 °C. Rf (PE/EtOAc:9/1, UV+KMnO4): 0.22. IR (neat)
ν: 1324, 1163. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C20H23NNaO2S 364.1341;
Found 364.1342. 1H NMR (CDCl3, 400 MHz): δ 7.88 (d, J=8.2 Hz, 2H), 7.36 (dd, J=8.5, 0.6
Hz, 2H), 7.20 (td, J=7.5, 0.6 Hz, 1H), 7.12 (d, J=7.2 Hz, 1H), 6.97 (td, J=7.4, 1.1 Hz, 1H),
6.82 (dd, J=7.3, 0.6 Hz, 1H), 4.82 (d, J=9.7 Hz, 1H), 4.51 (d, J=9.7 Hz, 1H), 2.48 (s, 3H),
2.43 (q, J=7.5 Hz, 2H), 2.36ꢀ2.29 (m, 1H), 2.24ꢀ2.16 (m, 1H), 1.11 (t, J=7.6 Hz, 3H), 0.93 (t,
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J=7.5 Hz, 3H). C{1H} NMR (CDCl3, 100 MHz): δ 144.2 (C), 143.6 (C), 143.5 (C), 143.4
(C), 139.8 (C), 138.8 (C), 129.9 (2 CH), 128.3 (C), 127.4 (2 CH), 125.1 (CH), 123.5 (CH),
118.7 (CH), 60.2 (CH), 21.7 (CH3), 18.6 (CH2), 18.5 (CH2), 14.5 (CH3), 13.5 (CH3).
Synthesis of a strigolactam 10: Following the general procedure A, the reaction performed
with bromoimine 1a (338 mg, 1.0 mmol) and dimethyl itaconate 9 (280 ꢁL, 2.0 mmol) with
TFA (8 ꢁL, 0.1 mmol, 10 mol%)afforded, after purification by flash chromatography [50 mL
SiO2, EtOAc/PE: 2/8 then 4/6], 10 (120 mg, 31%) as a white solid. mp: 170 °C (dec). Rf
(PE/EtOAc:8/2, UV+KMnO4): 0.19. IR (neat) ν: 1736, 1342, 1154. HRMS (ESI/Q-TOF)
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m/z: [M+Na]+ Calcd for C20H19NNaO5S 408.0876; Found 408.0875. H NMR (CDCl3, 400
MHz): (1 diastereoisomer) δ 7.87 (d, J=8.2 Hz, 2H), 7.84–7.78 (m, 1H), 7.28–7.25 (m, 4H),
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7.18–7.15 (m, 1H), 5.80 (s, 1H), 3.47 (d, J=16.4 Hz, 1H), 3.46 (s, 3H), 2.95 (d, J=16.4 Hz,
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1H), 2.80 (d, J=17.5 Hz, 1H), 2.47 (d, J=17.5 Hz, 1H), 2.36 (s, 3H). C{1H} NMR (CDCl3,
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100 MHz): (1 diastereoisomer) δ 173.5 (C), 171.1 (C), 145.3 (C), 139.4 (C), 138.4 (C), 135.5
(C), 129.7 (CH), 129.5 (2 CH), 128.6 (2 CH), 128.4 (CH), 127.0 (CH), 125.3 (CH), 71.5
(CH), 53.2 (C), 52.9 (CH3), 41.5 (CH2), 39.5 (CH2), 21.8 (CH3).
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Acknowledgments
The financial support of this work by the CNRS and the University ParisꢀEst (PhD grant to J.
P.) is gratefully acknowledged.
Supporting Information
Copies of NMR spectra for all products.
References
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Catalysis without Precious Metals; Bullock, R. M., Ed.; WileyꢀVCH: Weinheim, Germany,
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Gandon, V.; Aubert, C.; Malacria, M. Recent Progress in CobaltꢀMediated [2+2+2]
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Broere, D. L. J.; Ruijter, E. Recent Advances in TransitionꢀMetalꢀCatalyzed [2+2+2]ꢀ
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Pellissier, H.; Clavier, H. Enantioselective CobaltꢀCatalyzed Transformations. Chem. Rev.
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Gandeepan, P.; Cheng, C.–H. Cobalt Catalysis Involving π Components in Organic
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Gosmini, C.; Bégouin, J.ꢀM.; Moncomble, A. CobaltꢀCatalyzed CrossꢀCoupling Reactions.
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Chem. Commun. 2008, 3221−3233.
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The use of both EtBr2 and TMSCl or TFA as activators for zinc dust allowed a better
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23 For more details, see the Supporting Information.
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Contrary to Cheng's work (ref 11), no noticeable decyanation was observed in the present
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major trans diastereomer was isolated after purification by flash chromatography.
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