Synthesis of 1-Amino-1H-Indenes via a Sequential Suzuki-Miyaura Coupling/Petasis Condensation Sequence

Article abstract of DOI:10.1021/acs.joc.6b02549

An efficient and straightforward synthesis of 1-amino-1H-indenes is reported from 1,2-bis(boronates) via a sequential Suzuki-Miyaura coupling/Petasis cyclization reaction. Starting from the same monoboronic ester intermediates, an intermolecular version of this approach also afforded (Z)-α,β-unsaturated amino esters in moderate to good yields.

Full text of DOI:10.1021/acs.joc.6b02549

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Note
Synthesis of 1-Amino-1H-Indenes via a Sequential Suzuki–
Miyaura Coupling/Petasis Condensation Sequence
Vankudoth Jayaram, Tailor Sridhar, Gangavaram V. M. Sharma, Fabienne Berrée, and Bertrand Carboni
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02549 • Publication Date (Web): 05 Jan 2017
Downloaded from http://pubs.acs.org on January 6, 2017
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Synthesis of 1-Amino-1H-Indenes via a Sequential Suzuki–Miyaura
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Coupling/Petasis Condensation Sequence
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Vankudoth Jayaram,a Tailor Sridhar,a Gangavaram V. M. Sharma,a* Fabienne Berrée,b and
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Bertrand Carboni b*
a
Organic and Biomolecular Chemistry Division, CSIRꢀIndian Institute of Chemical
Technology, Tarnaka, Hyderabadꢀ500 607, India.
b
Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes 1, 263,
Avenue du Général Leclerc, Campus de Beaulieu, 35042 Rennes Cedex, France.
esmvee@iict.res.in (G.V.M.S.)
bertrand.carboni@univ-rennes1.fr (B.C.).
Abstract:
An efficient and straightforward synthesis of 1ꢀaminoꢀ1Hꢀindenes is reported from 1,2ꢀ
bis(boronates) via a sequential Suzuki–Miyaura coupling / Petasis cyclisation reactions.
Starting from the same monoboronic ester intermediates, an intermolecular version of this
approach also afforded (Z)ꢀ α,βꢀunsaturated amino esters in moderate to good yields.
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The significance of organoboron chemistry has been amply demonstrated in diverse
areas of organic synthesis.1 In particular, alkenyl boronic acids and derivatives were
recognized as versatile buildings blocks in a variety of chemical transformations being
engaged in a range of CꢀC and Cꢀheteroatom bond formation,2 Diels Alder cycloadditions,3
sigmatropic rearrangements,4 olefin metathesis,5 and conjugate additions.6 In the field of
multicomponent process, the threeꢀcomponent reactions of carbonyl compounds, amines, and
unsaturated organoboronic acids, referred as "Petasis reaction", give access to a variety of
structurally and functionally diverse amino compounds and heterocycles.7 In this context, we
recently demonstrated that this BoronoꢀMannich reaction occurred regioꢀ and stereoꢀ
selectively at the terminal C−B bond of (E)ꢀalkenyl 1,2ꢀbis(boronates) (Scheme 1, eq 1).8,9
Indenes and their corresponding hydrogenated derivatives, indanes, have found
multiple applications as synthetic targets or building blocks, whether for their biological
properties, as ligands of metal complexes or in material science.10 The hitherto reported
strategies mainly based on: transitionꢀmetal catalyzed [3+2]annulation,11 reaction of
metallacycloꢀpentadienes with thiourea,12 metathesis,13 αꢀamidoalkylation of enolizable
aldehydes,14 nitrene insertion,15 cascade reaction from propargyl alcohols,16 and
intramolecular cyclization of Nꢀsulfonyl aldimines,17 or oꢀethynylbenzaldehyde.18
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Herein, we report an attractive and complementary alternative to these approaches
based on a two steps sequence starting with SuzukiꢀMiyaura couplings of (E)ꢀalkenyl 1,2ꢀ
bis(boronic esters) and substituted 2ꢀbromobenzaldehydes. Further cyclization via a Petasis
reaction provides access to substituted 1ꢀaminoꢀ1Hꢀindenes (Scheme 1, eq 2). When the
coupling partner is devoid of an aldehyde group, the monoboronic ester intermediates can be
engaged in an intermolecular Borono Mannich condensation with glyoxylic acid and amines
to afford (E)ꢀ α,βꢀunsaturated amino esters (Scheme 1, eq 3).
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Scheme 1. Multistep sequences involving a Petasis reaction and a SuzukiꢀMiyaura coupling.
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Previous work (Ref 8)
R1
N
R1
N
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BPin
1) R1R2NH, HOCCO2H
2) Esterification
MeO2C
PinB
R
MeO2C
R2
R2
PinB
boronic ester
(1)
R'
transformations
R
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O
O
R
PinB =
B
R' = Ar, N3, OH
R2
Br
R1
R
R3
OHC
N
This work
R3
R4
when ArBr =
R1R2NH
(2)
(3)
R4
Ar
BPin
ArBr, PdCl2(dppf)
K3PO4, THF/H2O
PinB
PinB
R
R2
R
R1
Ar
N
R
1) R1R2NH, HOCCO2H
2) CH2N2
MeO2C
(E)ꢀAlkenyl 1,2ꢀbis(boronates) 1a-d, selected as model compounds, were first prepared
in good yields from the corresponding 1ꢀalkynes: 1ꢀhexyne, 3ꢀphenylꢀ1ꢀpropyne, 3ꢀ
cyclohexylꢀ1ꢀpropyne and propargyl trimethylsilane, and bis(pinacolato)diboron in the
presence of tetrakis(triphenylphosphine)platinum as catalyst, according to reported
procedures.19 These boronic esters were then engaged in Suzuki–Miyaura crossꢀcouplings
with aromatic halides in the presence of [1,1′ꢀbis(diphenylphosphino) ferrocene]dichloro
palladium(II) and potassium phosphate tribasic monohydrate in THF/H2O at reflux.20 As
previously reported, this reaction occurred regioselectively at the terminal CꢀB bond that
indicates that the coupling of a second aryl moiety is unfavorable. Yields are good to
moderate with the formation of a single (E)ꢀstereoisomer 2 (Scheme 2).
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Scheme 2. Suzuki–Miyaura crossꢀcouplings with 1,2ꢀbis(boronates) 1a-1d a,b
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We then decided to explore the cyclization of compounds 2fꢀ2n, which have an aldehyde
function in proper position for a Petasis condensation. While aryl aldehydes and pinacol
boronic esters are usually poor substrates for such reaction, we expected that, in our case,
entropic factors should greatly favor the formation of an indenyl substructure.21 To our
delight, the treatment of boronates 2fꢀ2n with amines afforded the corresponding 1ꢀaminoꢀ
1Hꢀindenes in yields ranging from 66% to 92% (Scheme 3). Best results were obtained in
HFIP (1,1,1,3,3,3ꢀhexafluoropropanꢀ2ꢀol) as solvent, probably due to the beneficial effect of
HFIP on charged intermediates and stabilization of polar transition states (see proposed
mechanism, Scheme 5). By comparison, with MeOH and trifluoroethanol as solvents, we
observed the formation of 1-amino-1H-indene 3a in 58% and 37% respectively under the same
experimental conditions. Secondary amines, cyclic or acyclic, are good partners for this
cyclization, as primary amine, with no significant influence of the presence of one or two
methoxy groups on the aryl moiety. Moreover, the reaction was proven to be scalable with
1,2ꢀbis(boronates) 1d as model substrate, delivering the desired product 3v in 45% isolated
yield over two steps (Scheme 4).
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The postulated mechanism is outlined in the Scheme 54. The formation of an iminium
ion was followed by the quaternarization of the boronate function to give the corresponding
ate complex. The migration of the alkenyl moiety afforded the 1ꢀaminoꢀ1Hꢀindene.
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Scheme 3. Petasis reactions from boronates 2fꢀn. Synthesis of 1ꢀaminoꢀ1Hꢀindenes 3aꢀ3v.a,b
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Scheme 4. Gram scale synthesis of a 1ꢀaminoꢀ1Hꢀindene
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Scheme 5. Postulated mechanism for the formation of 1ꢀaminoꢀ1Hꢀindenes 3
Due to the crucial role of amino acids and derivatives in biological processes, we also
engaged the trisubstituted alkenyl boronates 2aꢀe in intermolecular Petasis reactions to
synthesize (Z)ꢀ α,βꢀunsaturated amino esters 4. Various amines and glyoxylic acid reacted in
HFIP at room temperature. The crude material was directly subjected to esterification with an
ethereal solution of CH2N2. Cyclic secondary amines, as morpholine or Nꢀphenylpiperazine,
can be used, as the acyclic diallylamine, with yields ranging from 48 to 66% (Scheme 6).
These results, in addition to our precedent study,8 reveal that the simple inversion of the two
reactions allows the divergent synthesis of structurally diverse α,β−unsaturated amino esters
from a common precursor, as illustrated in Scheme 7.
Scheme 6. Intermolecular Petasis reactions from boronates 2aꢀe. Synthesis of α,βꢀ
unsaturated amino esters 4aꢀ4g a,b
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Scheme 7. Divergent synthesis of amino esters 4c and 4’c.
In conclusion, an efficient preparation of 1ꢀaminoꢀ1Hꢀindenes from easily accessible or
commercially available reactants was described. The key features of this method are a
regioselective Suzuki coupling at the terminal CꢀB bond of a (E)ꢀ1ꢀalkeneꢀ1,2ꢀdiboronic ester
and an Petasis condensation. We have also demonstrated the divergent approach to
α,β−unsaturated aminoesters via an intermolecular version of this sequence starting from a
common bisꢀboronate precursor.
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EXPERIMENTAL SECTION
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General Information and Materials. All commercially available chemicals were used
without further purification. Tetrahydrofuran (THF), diethylether and 1,1,1,3,3,3ꢀ
hexafluoropropanꢀ2ꢀol (HFIP) were used as received. Analytical thin layer chromatography
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was performed on Silica Gel 60 F254 plates. The compounds were characterized by H, 13C
NMR and 11B techniques. 1H and 13C spectra were recorded in CDCl3 (internal standard: 7.26
ppm, H; 77.00 ppm, 13C) and 11B NMR chemical shifts to external BF3·OEt2 (0.0 ppm).
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Highꢀresolution mass spectra (HMRS) were recorded on a microꢀTOFꢀQ II mass analyzer or
QꢀTOF 2 using positive ion electrospray. Compounds 1a,22 1b,23 1c,24 and 1d have been
prepared according to known protocol.19 The ethereal solution of CH2N2 was generated from
NꢀnitrosoꢀNꢀmethylurea according to the literature.26
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General procedure for the Suzuki–Miyaura cross-couplings with 1,2-bis(boronates) 1a-
1d. Synthesis of compounds 2a-2n. A solution of bispinacolate ester 1 (0.5 mmol) in THF
(5 mL) and water (0.1 mL) was degassed under argon atmosphere, before the addition of [1,
1’ꢀbis (diphenyl phosphino)ferrocene] dichloropalladium(II) (7.5 mg, 0.01 mmol), potassium
phosphate tribasic monohydrate (346 mg, 1.5 mmol) and arylbromide (0.5 mmol). The
reaction mixture was heated at reflux for 1h, cooled to room temperature, diluted with water
and extracted with Et2O (2 x 15 mL). The combined organic extracts were dried over MgSO4
and evaporated under vacuum. The residue was purified by column chromatography (230ꢀ
400 mesh Silica gel, EtOAc in cyclohexane) to give the corresponding Suzuki products.
(E)-4,4,5,5-tetramethyl-2-(1-phenylhex-1-en-2-yl)-1,3,2-dioxaborolane (2a): 86 mg (60%).
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Colourless oil, Rf = 0.10 (EtOAc/Hexane 10:90); HNMR (500 MHz, CDCl3): δ 7.33ꢀ7.31
(m, 2H), 7.25ꢀ7.22 (m, 2H), 7.20ꢀ7.16 (s, 1H), 6.87 (s, 1H), 2.31ꢀ2.28 (m, 2H,), 1.49ꢀ1.43 (m,
2H), 1.38ꢀ1.34 (m, 2H), 1.25 (s, 12H), 0.90 (t, 3H, J = 7.3 Hz); 13C NMR (100 MHz, CDCl3):
δ 139.6, 139.0, 128.0, 127.7, 126.7, 83.4, 37.7, 31.8, 24.7, 22.4, 14.0 (The carbon α to boron
was not found); 11B NMR (96 MHz, CDCl
): δ 31.1 (br); IR (neat); 3746, 3395, 3060, 3026,
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2957, 2925, 2854, 1713, 1622, 1599, 1454, 1373, 1303, 1252, 1213, 1143, 1078, 1032, 1007,
982, 964, 919, 854, 750, 697, 672, 620, 577; HRMS (ESI+): m/z (M++H) calculated for
C18H28BO2 287.2176, found 287.2161.
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(E)-4,4,5,5-tetramethyl-2-(1-p-tolylhex-1-en-2-yl)-1,3,2-dioxaborolane (2b). 87 mg (58%).
Colourless oil, Rf = 0.10 (EtOAc/Hexane 10:90). 1H NMR (300 MHz, CDCl3): δ 7.21 (d, 2H,
J = 7.9 Hz), 7.04 (d, 2H, J = 7.7 Hz), 6.83 (s, 1H), 2.34ꢀ2.25 (m, 5H), 1.51ꢀ1.41 (m, 2H),
1.34ꢀ1.26 (m, 2H), 1.27 (s, 12H), 0.89 (t, 3H, J = 6.6 Hz). 13C NMR (75 MHz, CDCl3): δ
139.6, 136.4, 136.1, 128.4, 128.0, 83.3, 38.1, 31.5, 24.7, 22.5, 21.1, 14.0 (The carbon α to
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boron was not found). 11B NMR (96 MHz, CDCl
): δ 31.1 (br) IR (neat): 3861, 3745, 3611,
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2956, 2923, 2853, 1728, 1624, 1567, 1549, 1511, 1462, 1392, 1374, 1338, 1302, 1253, 1215,
1144, 1071, 1037, 964, 945, 860, 828, 804, 772, 708, 670, 574. HRMS (ESI+): m/z (M++Na)
calculated for C19H29O2BNa 323.2158, found 323.2156.
(E)-2-(1-(4-methoxyphenyl)-hex-1-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2c). 98
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mg (62%). Colourless oil, Rf = 0.15 (EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ
7.27 (d, 2H, J = 8.4 Hz), 6.81 (s, 1H), 6.78 (d, 2H, J = 8.8 Hz), 3.79 (s, 3H), 2.28ꢀ2.24 (m,
2H), 1.50ꢀ1.42 (m, 2H), 1.35ꢀ1.30 (m, 2H), 1.27 (s, 12H), 0.89 (t, 3H, J = 6.8 Hz). 13C NMR
(125 MHz, CDCl3): δ 158.6, 138.9, 131.5, 129.1, 113.2, 83.2, 55.1, 38.1, 31.0, 25.0, 22.5,
13.8 (The carbon α to boron was not found). IR (neat); 3746, 3611, 2955, 2924, 2853, 1729,
1607, 1573, 1510, 1462, 1374, 1298, 1245, 1175, 1143, 1035, 965, 941, 859, 831, 771, 705,
671, 577. HRMS (ESI+): m/z (M++H) calculated for C19H30BO3 317.2282, found 317.2287.
(E)-2-(1-(4-methoxyphenyl)-3-phenylprop-1en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
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(2d). 101 mg (58%). Colourless oil, Rf = 0.10 (EtOAc/Hexane 10:90). HNMR (500 MHz,
CDCl3): δ 7.32 (d, 2H, J = 8.6 Hz), 7.25ꢀ7.15 (m, 5H), 6.90 (s, 1H), 6.80 (d, 2H, J = 8.6 Hz),
3.79 (s, 3H), 3.63 (s, 2H), 1.08 (s, 12H). 13C NMR (100 MHz, CDCl3): δ 158.8, 141.1, 140.6,
131.3, 129.4, 129.3, 128.1, 125.9, 113.2, 83.4, 55.3, 44.2, 25.0 (The carbon α to boron was
not found). IR (neat); 3429, 3028, 2978, 2930, 2838, 1714, 1605, 1511, 1456, 1392, 1304,
1249, 1173, 1143, 1111, 1077, 1032, 965, 832, 737, 700, 672. HRMS (ESI+): m/z (M++Na)
calculated for C22H28BO3Na 373.1945, found 373.1945.
(E)-2-(3-cyclohexyl-1-(4-methoxyphenyl)prop-1en-2-yl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2e). 107 mg (60%). Colorless oil, Rf = 0.10 (EtOAc/Hexane 10:90). 1H NMR
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(500 MHz, CDCl3): δ 7.31ꢀ7.27 (m, 2H), 6.81ꢀ6.77 (m, 3H), 3.79 (s, 1H), 2.16 (dt, 2H, J =
10.3, 5.2 Hz), 1.82ꢀ1.61 (m, 6H), 1.47ꢀ1.33 (m, 1H), 1.27 (s, 12H), 1.24ꢀ1.08 (m, 4H). 13C
NMR (101 MHz, CDCl3): δ 158.7, 140.6, 131.8, 129.4, 113.2, 83.3, 55.3, 46.2, 38.2, 33.3,
26.7, 26.4, 24.8 (The carbon α to boron was not found). IR (neat); 3445, 2976, 2921, 2850,
1707, 1607, 1511, 1444, 1393, 1373, 1346, 1302, 1243, 1174, 1135, 1080, 1038, 964, 886,
859, 829, 767, 713, 667. HRMS (ESI+): m/z (M++Na) calculated for C22H33BO3Na 379.2415,
found 379.2414.
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(E)-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-hex-1-enyl)benzaldehyde (2f). 118 mg
(75%), colourless oil, Rf = 0.20 (EtOAc/Hexane 10:90). 1H NMR (400 MHz, CDCl3): δ 10.28
(s, 1H), 7.85 (dd, 1H, J = 1.8, 7.7 Hz), 7.45 (dd, IH, J = 1.6, 7.5 Hz), 7.38ꢀ7.31 (m, 1H), 7.31ꢀ
7.27 (m, 2H), 2.36 (td, 2H, J = 1.5, 7.5 Hz), 1.54ꢀ1.46 (m, 2H), 1.41ꢀ1.34 (m, 2H), 1.09 (s,
12H), 0.94 (t, 3H, J = 7.3 Hz). 13C NMR (100 MHz, CDCl3): δ 192.4, 143.2, 141.2 (br),
135.9, 133.6, 133.0, 130.4, 127.7, 127.4, 83.0, 37.2, 31.7, 24.55, 24.4, 13.6. 11B NMR (96
MHz, CDCl
): δ 30.4 (br. HRMS (ESI+): m/z (M++Na) calculated for C19H27O3BNa
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337.1950, found 337.1951.
(E)-5-methoxy-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-hex-1-enyl)benzaldehyde
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(2g). 100 mg (58%). Colourless oil, Rf = 0.40 (EtOAc/Hexane 20:80). H NMR (500 MHz,
CDCl3): δ 10.25 (s, 1H), 7.36 (d, 1H, J = 2.8 Hz), 7.23ꢀ7.21 (m, 2H), 7.04 (dd, 1H, J = 2.8 ,
8.5 Hz), 3.85 (s, 3H), 2.37ꢀ2.33 (m, 2H), 1.52ꢀ1.46 (m, 2H), 1.41ꢀ1.34 (m, 2H), 1.11 (s, 12H),
0.93 (t, 3H, J = 7.3 Hz). 13C NMR (100 MHz, CDCl3): δ 191.4, 158.7, 136.2, 135.6, 134.5,
131.6, 120.7, 109.8, 83.4, 55.4, 37.2, 31.8, 24.5, 22.4, 13.9 (The carbon α to boron was not
found). IR (neat): 2956, 2924, 2853, 1741, 1691, 1602, 1564, 1493, 1463, 1392, 1308, 1262,
1220, 1161, 1144, 1037, 964, 862, 836, 772, 706. HRMS (ESI+): m/z (M++Na) calculated for
C20H29BO4Na 367.2051, found 367.2059.
(E)-4,5-dimethoxy-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hex-1-enyl)
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benzaldehyde (2h). 97 mg (52%). Colourless oil, Rf = 0.60 (EtOAc/Hexane 20:80). H NMR
(500 MHz, CDCl3): δ 10.11 (s, 1H), 7.38 (s, 1H), 7.17 (s, 1H), 6.78 (s, 1H), 3.95 (s, 3H), 3.93
(s, 3H), 2.36 (dd, 2H, J = 11.0, 4.1 Hz), 1.53ꢀ1.47 (m, 2H), 1.43ꢀ1.35 (m, 2H), 1.09 (s, 12H),
0.94 (t, 3H, J = 7.3 Hz). 13C NMR (100 MHz, CDCl3): δ 190.7, 152.9, 148.1, 141.3 (br),
138.7, 135.3, 127.3, 112.1, 108.1, 83.3, 55.7, 55.6, 37.0, 31.7, 24.5, 22.3, 13.8. IR (neat):
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2956, 2924, 2853, 1678, 1594, 1564, 1507, 1462, 1391, 1340, 1308, 1268, 1217, 1143, 1108,
1034, 1003, 964, 858, 772, 700, 671. HRMS (ESI+): m/z (M++H) calculated for C21H32BO5
375.2337, found 375.2323.
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(E)-1-(2-(4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl)-hex-1-enyl)-2-naphthaldehyde (2i). 93 mg
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(51%). Colourless oil, Rf = 0.15 (EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ
10.43 (s, 1H), 8.12 (d, 1H, J = 8.3 Hz), 7.96 (d, 1H, J = 8.5 Hz), 7.83 (d, 1H, J = 7.9 Hz),
7.80 (d, 1H, J = 8.6 Hz), 7.60ꢀ7.57 (m, 1H), 7.54ꢀ7.51 (m, 1H), 7.36 (s, 1H), 2.54 (dd, 2H, J
= 16.9, 7.8 Hz), 1.64ꢀ1.58 (m, 2H), 1.50ꢀ1.44 (m, 2H), 0.99 (t, 3H, J = 7.3 Hz), 0.87 (s, 6H),
0.80 (s, 6H). 13C NMR (125 MHz, CDCl3): 193.0, 144.2, 135.6, 133.5, 132.4, 131.5, 128.4,
128.1, 127.3, 126.8, 126.4, 121.9, 83.2, 36.9, 31.9, 24.2, 22.6, 14.0 (The carbon α to boron
was not found). IR (neat): 3059, 2957, 2924, 2853, 1681, 1617, 1595, 1461, 1427, 1397,
1374, 1314, 1256, 1225, 1142, 1029, 964, 857, 818, 747, 705, 668. . HRMS (ESI+): m/z
(M++Na) calculated for C23H29BO3Na 386.2138, found 386. 2146.
(E)-2-(3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-enyl)-4,5-
dimethoxybenzaldehyde (2j). 135 mg (65%). Colourless oil, Rf = 0.60 (EtOAc/Hexane
20:80). 1HNMR (500 MHz, CDCl3): δ 10.13 (s, 1H), 7.39 (s, 1H), 7.13 (s, 1H), 6.77 (s, 1H),
3.95 (s, 3H), 3.93 (s, 3H), 2.26 (d, 2H, J = 7.1 Hz), 1.88ꢀ1.62 (m, 6H), 1.55ꢀ1.38 (m, 1H),
1.31ꢀ1.13 (m, 4H), 1.08 (s, 12H). 13C NMR (75 MHz, CDCl3): δ 190.8, 153.0, 148.3, 138.8,
136.5, 127.4, 112.3, 108.2, 83.4, 56.0, 45.6, 37.9, 33.4, 26.5, 26.4, 24.5 (The carbon α to
boron was not found). IR (neat); 3860, 3812, 3669, 3610, 3593, 4370, 3396, 3342, 3287,
3245, 2977, 2921, 2847, 1785, 1752, 1678, 1595, 1566, 1522, 1510, 1449, 1388, 1337, 1309,
1270, 1216, 1137, 1109, 1034, 1004, 965, 852, 772. HRMS (ESI+): m/z (M++H) calculated
for C24H36BO5 415.2650, found 415. 2647.
(E)-5-(tert-butyldimethylsilyloxy)-2-(3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)prop-1-enyl)-4-methoxybenzaldehyde (2k). 159 mg (62%). Colourless oil, Rf = 0.20
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(EtOAc/Hexane 10:90). HNMR (500 MHz, CDCl3): δ 10.18 (s, 1H), 7.36(s, 1H), 7.13 (s,
1H), 6.73 (s, 1H), 3.87 (s, 3H), 2.25 (d, 2H, J = 7.1 Hz), 1.82ꢀ1.61 (m, 6H), 1.51ꢀ1.40 (m,
1H), 1.32ꢀ1.16 (m, 4H), 1.08 (s, 12H), 0.99 (s, 9H), 0.15 (s, 6H). 13C NMR (101 MHz,
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CDCl3): δ 190.9, 155.2, 139.2, 137.0, 118.9, 112.8, 83.3, 77.36, 70.0, 76.7, 55.5, 45.5, 38.0,
33.4, 26.4 (The carbon α to boron was not found). IR (neat); 3744, 3609, 3394, 3338, 3308,
3246, 2925, 2853, 1657, 1642, 1550, 1513, 1448, 1389, 1325, 1286, 1219, 1140, 1064, 1012,
898, 838. HRMS (ESI+): m/z (M++H) calculated for C29H48O5BSi 515.3358, found 515.3347.
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(E)-4,5-dimethoxy-2-(3-phenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-
enyl)benzaldehyde (2l). 130 mg (64%). Rf = 0.60 (EtOAc/Hexane 20:80). 1HNMR (400
MHz, CDCl3): δ 10.11 (s, 1H), 7.38 (s, 1H), 7.33ꢀ7.27 (m, 4H), 7.24ꢀ7.17 (m, 2H), 6.80(s,
1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.69 (d, 2H, J =1.2 Hz), 0.97 (s, 12H). 13C NMR (101MHz,
CDCl3): δ 190.6, 153.0, 148.4, 139.9, 138.3, 137.0, 129.2, 128.3, 127.4, 126.2, 112.3, 108.5,
83.5, 56.1, 43.3, 24.5 (The carbon α to boron was not found). IR (neat); 3448, 3066, 2978,
2929, 2832, 2718, 1686, 1594, 1557, 1508, 1451, 1397, 1343, 1263, 1218, 1112, 1031, 1000,
960, 886, 858, 777, 699. HRMS (ESI+): m/z (M++Na) calculated for C24H29BO5Na,
431.2000; found, 431.1981.
(E)-5-methoxy-2-(3-phenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-
enyl)benzaldehyde (2m). 109 mg (58%). Colourless oil, Rf = 0.30 (EtOAc/Hexane 10:90). 1H
NMR (400 MHz, CDCl3): δ 10.24 (s, 1H), 7.36 (d, 1H, J = 2.8 Hz), 7.32ꢀ7.22 (m, 6H), 7.21ꢀ
7.16 (m, 1H), 7.04 (dd, 1H, J = 8.5, 2.8 Hz), 3.86 (s, 3H), 3.69 (d, 2H, J = 1.2 Hz), 0.98 (s,
12H). 13C NMR (101MHz, CDCl3): δ 191.8, 159.0, 140.0, 137.2, 135.6, 134.6, 131.7, 129.2,
128.3, 126.1, 120.6, 110.4, 83.5, 55.5, 43.4, 24.4 (The carbon α to boron was not found). IR
(neat): 3420, 2980, 2934, 2100, 1666, 1521, 1452, 1374, 1220, 1166, 1113, 1078, 1020, 854,
769, 697. HRMS (ESI+): m/z (M++H) calculated for C23H28BO4, 379.2075; found, 379.2070,
(M++Na) calculated for C23H27BO4Na, 401.1894; found, 401.1890.
(E)-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trimethylsilyl)vinyl)benzaldehyde
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(2n). 117 mg (65%). Colourless oil, Rf = 0.10 (EtOAc/Hexane 10:90). HNMR (400 MHz,
CDCl3): δ 10.28 (s, 1H), 7.85 (dt, 1H, J = 12.3, 6.1 Hz), 7.79 (s, 1H), 7.53ꢀ7.46 (m, 1H),
7.44ꢀ7.35 (m, 2H), 1.12(s, 12H), 0.23(s, 9H). 13C NMR (75 MHz, CDCl3): δ 191.9, 146.7,
144.5, 133.1, 129.2, 128.7, 127.6, 83.4, 24.7, ꢀ1.0 (The carbon α to boron was not found). IR
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(neat); 3743, 3438, 3396, 3064, 2954, 2897, 2837, 1696, 1587, 1557, 1466, 1370, 1317, 1245,
1215, 1138, 1096, 1008, 984, 951, 838, 760, 719, 690, 630. HRMS (ESI+): m/z (M++Na)
calculated for C18H27BO3SiNa 353.1714, found 353.1721.
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General Procedure for Petasis cyclization from Boronates 2f-2n. Synthesis of
Compounds 3a-3v. Amine (0.5 mmol) was added to a stirred solution of boronate 2 (0.3
mmol) in 1,1,1,3,3,3ꢀhexafluoropropanꢀ2ꢀol (1 mL) under argon atmosphere at room
temperature. The reaction mixture was stirred during 8 h. The solvent was removed under
reduced pressure to give a residue that was purified by column chromatography (230ꢀ400
mesh Silica gel, EtOAc in cyclohexane) to afford amino indenes 3.
4-(2-Butyl-1H-inden-1-yl) morpholine (3a). 71 mg (92%). Colourless oil, Rf = 0.10
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(EtOAc/Hexane 10:90). H NMR (400 MHz, CDCl3): δ 7.45 (d, 1H, J = 7.3 Hz), 7.23ꢀ7.15
(m, 2H), 7.09ꢀ7.04 (m, 1H), 6.41 (s, 1H), 4.12 (s, 1H), 3.71ꢀ3.62 (m, 4H), 2.72ꢀ2.69 (m, 2H),
2.59ꢀ2.54 (m, 2H), 2.44ꢀ2.38 (m, 2H), 1.68ꢀ1.52 (m, 2H), 1.44ꢀ1.35 (m, 2H), 0.95 (t, 3H, J =
7.3 Hz). 13C NMR (125 MHz, CDCl3): δ 151.9, 144.3, 143.1, 127.5, 126.55, 124.5, 123.8,
120.2, 72.9, 67.75, 49.3, 30.6, 29.0, 22.6, 14.0. IR (neat):3062, 2955, 2924, 2852, 1718,
1616, 1508, 1458, 1376, 1318, 1290, 1271, 1244, 1168, 1115, 1011, 929, 888, 848, 752, 732,
690. HRMS (ESI+): m/z (M++H) calculated for C17H24NO, 258.1852; found, 258.1854.
N,N-Diallyl-2-butyl-1H-inden-1-amine (3b). 66 mg (75%). Colourless oil, Rf = 0.10
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(EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ 7.47 (d, 1H, J = 7.3 Hz), 7.23ꢀ7.13
(m, 2H), 7.06 (td, 1H, J = 7.2, 1.4 Hz), 6.39 (s, 1H), 5.88ꢀ5.78 (m, 2H), 5.22, (dd, 2H, J =
17.2, 1.1 Hz), 5.10 (d, 2H, J = 10.1 Hz, CH=H2), 4.38 (s, 1H), 3.14ꢀ3.01 (m, 4H), 2.46ꢀ2.33
(m, 2H), 1.66ꢀ1.46 (m, 2H), 1.44ꢀ1.33 (m, 2H), 0.94 (t, 3H, J = 7.3 Hz). 13C NMR (125 MHz,
CDCl3): δ 153.8, 144.6, 144.35, 137.3, 127.3, 125.9, 124.2, 123.6, 120.3, 116.8, 67.2, 53.3,
30.3, 29.0, 22.45, 14.1. IR (neat): 3072, 2957, 2924, 2854, 1721, 1644, 1620, 1462, 1399,
1377, 1287, 1261, 1118, 1074, 995, 919, 876, 803, 751, 733. HRMS (ESI+): m/z (M++Na)
calculated for C19H25NNa 290.1879, found 290.1883.
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4-(2-Butyl-6-methoxy-1H-inden-1-yl) morpholine (3c). 63 mg (73%). Colourless oil, Rf = 0.25
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(EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ 7.08 (s, 1H), 7.04 (d, 1H, J = 8.2
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Hz), 6.75 (dd, 1H, J = 2.2, 8.0 Hz), 6.34 (s, 1H), 4.09 (s, 1H), 3.81 (s, 3H), 3.70ꢀ3.63 (m,
4H), 2.71ꢀ2.70 (m, 2H), 2.60ꢀ2.55 (m, 2H), 2.40ꢀ2.34 (m, 2H), 1.63ꢀ1.51 (m, 2H), 1.43ꢀ1.35
(m, 2H), 0.94 (t, 3H, J = 7.3 Hz). 13C NMR (75 MHz, CDCl3): δ 157.0, 149.7, 144.9, 137.2,
126.2, 120.4, 112.1, 111.8, 72.8, 67.8, 55.9, 49.4, 30.6, 29.0, 22.5, 14.2. IR (neat): 2955,
2922, 2852, 1728, 1609, 1581, 1468, 1318, 1284, 1219, 1115, 1034, 1010, 854, 771 cmꢀ1.
HRMS (ESI+): m/z (M++H) calculated for C18H26NO2, 288.1958; found, 288.1949.
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N,N-Diallyl-2-butyl-6-methoxy-1H-inden-1-amine (3d). 72 mg (81%). Colourless oil, Rf =
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0.10 (EtOAc/Hexane 10:90). H NMR (400 MHz, CDCl3): δ 7.09 (dd, 1H, J = 3.9, 2.9 Hz),
7.05 (d, 1H, J = 8.1 Hz), 6.74 (dd, 1H, J = 8.1, 2.4 Hz), 6.33 (d, 1H, J = 0.9 Hz), 5.90ꢀ5.80
(m, 2H), 5.23 (dd, 2H, J = 17.2, 1.3 Hz), 5.13ꢀ5.08 (m, 2H), 4.30 (s, 1H), 3.81 (s, 3H), 3.15ꢀ
3.04 (m, 4H), 2.40ꢀ2.34 (m, 2H), 1.63ꢀ1.51 (m, 2H), 1.43ꢀ1.35 (m, 2H), 0.93 (t, 3H, J = 7.3
Hz). 13C NMR (125 MHz, CDCl3): δ 156.8, 151.5, 146.3, 137.3, 125.3, 120.1, 116.7, 112.0,
111.1, 67.4, 55.5, 53.4, 30.6, 28.8, 22.6, 14.0. IR (neat): 3745, 3076, 2955, 2923, 2853, 2832,
1641, 1607, 1581, 1471, 1429, 1355, 1282, 1258, 1153, 1136, 1092, 1035, 995, 918, 859,
804, 772, 726. HRMS (ESI+): m/z (M++H) calculated for C20H28NO, 298.2165; found,
298.2155.
N-Benzyl-2-butyl-6-methoxy-N-methyl-1H-inden-1-amine (3e). 75 mg (78%). Colourless oil,
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Rf = 0.25 (EtOAc/Hexane 10:90). H NMR (400 MHz, CDCl3): δ 7.39 (d, 2H, J = 7.2 Hz),
7.31 (dd, 2H, J = 10.2, 4.7 Hz, Arꢀ), 7.23 (dd, 1H, J = 8.3, 6.2 Hz), 7.16 (d, 1H, J = 2.1 Hz),
7.08ꢀ7.05 (m, 1H), 6.75 (dd, 1H, J = 8.1, 2.4 Hz), 6.35 (d, 1H, J = 0.8 Hz), 4.30 (s, 1H), 3.81
(s, 3H), 3.76ꢀ3.67 (m, 2H), 2.45.2.41 (m, 2H), 2.20 (s, 3H), 1.63ꢀ1.51 (m, 2H), 1.43ꢀ1.35 (m,
2H), 0.93 (t, 3H, J = 7.3 Hz). 13C NMR (125 MHz, CDCl3): δ 157.1, 151.0, 145.6, 140.1,
137.5, 128.7, 128.3, 126.9, 125.6, 120.2, 112.4, 111.4, 71.8, 58.2, 55.6, 37.8, 30.8, 28.7, 23.0,
13.5. IR (neat): 3060, 3027, 2953, 2927, 2855, 2833, 2794, 1705, 1605, 1581, 1471, 1438,
1359, 1310, 1282, 1255, 1230, 1133, 1103, 1034, 976, 923, 861, 806, 771, 739, 698, 603.
HRMS (ESI+): m/z (M++H) calculated for C22H28NO, 322.2165; found, 322.2152.
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1-(2-Butyl-6-methoxy-1H-indene-1-yl) pyrrolidine (3f). 66 mg (82%). Colourless oil, Rf =
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0.10 (EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ 7.10 (s, 1H), 7.04 (d, 1H, J =
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8.2 Hz), 6.73 (dd, 1H, J = 2.4 , 8.1 Hz), 6.30 (s, 1H), 4.42 (s, 1H), 3.80 (s, 3H), 2.83ꢀ2.81 (m,
2H), 2.60ꢀ2.56 (m, 2H), 2.40ꢀ2.33 (m, 2H), 1.75ꢀ1.70 (m, 4H), 1.64ꢀ1.51 (m, 2H), 1.43ꢀ1.36
(m, 2H), 0.94 (t, 3H, J = 7.3 Hz). 13C NMR (101 MHz, CDCl3): δ 156.9, 151.4, 145.7, 137.7,
124.6, 119.8, 112.5, 111.3, 68.2, 55.5, 48.2, 30.6, 29.1, 24.0, 22.6, 14.0. IR (neat): 3448,
3027, 2594, 2853, 1742, 1605, 1509, 1452, 1385, 1247, 1175, 1116, 1072, 1028, 873, 829,
771, 699. HRMS (ESI+): m/z (M++H) calculated for C18H26NO, 272.2014; found, 272.2003.
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1-(2-Butyl-6-methoxy-1H-indene-1-yl) piperidine (3g). 64 mg (75%). Colourless oil, Rf = 0.10
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(EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ 7.08 (s, 1H), 7.02 (d, 1H, J = 8.2
Hz), 6.72 (dd, 1H, J = 2.3, 8.7 Hz), 6.31 (s, 1H), 4.08 (s, 1H), 3.81 (s, 3H), 2.65ꢀ2.61 (m,
2H), 2.50ꢀ2.48 (m, 2H), 2.35 (t, 2H, J = 7.6 Hz), 1.64ꢀ1.50 (m, 6H), 1.43ꢀ1.36 (m, 4H), 0.94
(t, 3H, J = 7.3 Hz). 13C NMR (125 MHz, CDCl3): δ 156.8, 151.0, 145.7, 137.4, 125.0, 120.0,
112.3, 111.2, 73.6, 55.5, 50.1, 30.6, 29.0, 26.8, 24.7, 22.6, 14.0. IR (neat): 3051, 2929, 2854,
2802, 2744, 1711, 1607, 1582, 1471, 1432, 1379, 1357, 1308, 1281, 1207, 1166, 1134, 113,
1090, 1034, 1002, 858, 770, 602. HRMS (ESI+): m/z (M++H) calculated for C19H28NO,
286.2165; found, 286.21.
1-(2-Butyl-6-methoxy-1H-indene-1-yl)-4-phenyl piperazine (3h). 78 mg (72%). Colourless
oil, Rf = 0.10 (EtOAc/Hexane 10:90). 1H NMR (500 MHz, CDCl3): δ 7.25ꢀ7.22 (m, 2H, 7.10
(s, 1H), 7.05 (d, 1H, J = 8.0 Hz), 6.90 (d, 2H, J = 7.9 Hz), 6.83 (t, 1H, J = 7.3 Hz), 6.74 (dd,
1H, J = 2.2, 8.0 Hz), 6.36 (s, 1H), 4.20 (s, 1H), 3.80 (s, 3H), 3.20ꢀ3.10 ( m, 4H), 2.90ꢀ2.80
(m, 2H), 2.75ꢀ2.71 (m, 2H), 2.42ꢀ2.36 (m, 2H), 1.64ꢀ1.51 (m, 2H), 1.45ꢀ1.36 (m, 2H), 0.94 (t,
3H, J = 7.3 Hz). 13C NMR (125 MHz, CDCl3): δ 157.0, 151.5, 149.9, 144.9, 137.2, 128.9,
125.8, 120.1, 119.5, 116.0, 1112.2, 111.8, 72.6, 55.5, 50.0, 48.7, 30.6, 29.0, 22.6, 14.0. IR
(neat): 3745, 3639, 3017, 2925, 2852, 1730, 1694, 1694, 1600, 1499, 1470, 1380, 1282,
1216, 1140, 1033, 1013, 926, 858, 770, 667. HRMS (ESI+): m/z (M++H) calculated for
C24H31N2O, 363.2430; found, 363.2421.
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4-(2-Butyl-5,6-dimethoxy-1H-inden-1-yl) morpholine (3i). 67 mg (71%). Colourless oil, Rf =
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0.80 (EtOAc/Hexane 20:80). H NMR (500 MHz, CDCl3): δ 7.08 (s, 1H), 6.76 (s, 1H), 6.32
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(s, 1H), 4.07 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.75ꢀ3.64 (m, 4H), 2.74ꢀ2.70 (m, 2H), 2.60ꢀ
2.57 (m, 2H), 2.41ꢀ2.33 (m, 2H), 1.63ꢀ1.50 (m, 2H), 1.44ꢀ1.35 (m, 2H), 0.95 (t, 3H, J = 7.3
Hz). 13C NMR (100 MHz, CDCl3): δ 150.7, 148.7, 146.0, 137.1, 135.1, 125.9, 109.5, 104.2,
72.8, 67.7, 56.4, 55.9, 49.2, 30.7, 29.0, 22.5, 13.9. IR (neat): 3745, 3611, 3396, 2954, 2923,
2852, 1694, 1602, 1582, 1490, 1461, 1411, 1315, 1216, 1140, 1114, 1089, 1012, 992, 933,
861, 772. HRMS (ESI+): m/z (M++H) calculated for C19H28NO3, 318.2063; found, 318.2051.
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1-(2-Butyl-5,6-dimethoxy-1H-indene-1-yl)-4-phenyl piperazine (3j). 96 mg (82%). Colourless
oil, Rf = 0.70 (EtOAc/Hexane 20:80). 1H NMR (500 MHz, CDCl3): δ 7.26ꢀ7.22 (m, 2H), 7.09
(s, 1H), 6.92 (dd, 2H, J = 8.7, 0.8 Hz), 6.84 (t, 1H, J = 7.3 Hz), 6.79 (s, 1H), 6.34 (s, 1H),
4.17 (s, 1H), 3.88 (s, 6H), 3.20ꢀ3.11 (m, 4H), 2.88ꢀ2.83 (m, 2H), 2.77ꢀ2.72 (m, 2H), 2.41ꢀ
2.37 (m, 2H), 1.64ꢀ1.51 (m, 2H), 1.44ꢀ1.34 (m, 2H), 0.94 (t, 3H, J = 7.2 Hz). 13C NMR (125
MHz, CDCl3): δ 151.4, 151.0, 148.7, 145.9, 137.1, 135.2, 128.9, 125.8, 119.5, 116.0, 109.5,
104.2, 72.6, 56.3, 55.9, 49.9, 48.7, 30.7, 29.0, 22.5, 13.9. IR (neat): 3057, 2953, 2926, 2854,
2827, 1677, 1599, 1492, 1455, 1410, 1380, 1304, 1232, 1143, 1085, 1101, 992, 927, 863,
814, 760. HRMS (ESI+): m/z (M++H) calculated for C25H33N2O2, 393.2536; found,
393.2524.
N,N-Diallyl-2-butyl-5,6-dimethoxy-1H-inden-1-amine (3k). 78 mg (78%). Colourless oil, Rf =
1
0.60 (EtOAc/Hexane 20:80). H NMR (500 MHz, CDCl3): δ 7.07 (s, 1H), 6.75 (s, 1H), 6.30
(s, 1H), 5.88ꢀ5.80 (m, 2H), 5.22 (dd, 2H, J = 17.2, 1.2 Hz), 5.11 (d, 2H, J = 10.1 Hz), 4.31 (s,
1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.15ꢀ3.04 (m, 4H), 2.42ꢀ2.35 (m, 2H), 1.63ꢀ1.46 (m, 2H),
1.42ꢀ1.32 (m, 2H), 0.94 (t, 3H, J = 7.3 Hz). 13C NMR (125 MHz, CDCl3): δ 152.6, 148.6,
145.9, 137.2, 136.6, 125.4, 116.6, 109.3, 104.2, 67.6, 56.5, 55.9, 53.5, 30.7, 29.0, 22.6, 14.0.
IR (neat): 3360, 2926, 2833, 1742, 1659, 1487, 1453, 1415, 1336, 1218, 1112, 1017, 918,
772. HRMS (ESI+): m/z (M++H) calculated for C21H30NO2, 328.2271; found, 328.2259.
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N-Benzyl- 2-butyl-5, 6- dimethoxy-N-methyl-1H-inden-1-amine (3l). 86 mg (82%). Colourless
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oil, Rf = 0.50 (EtOAc/Hexane 20:80). H NMR (400 MHz, CDCl3): δ 7.40ꢀ7.37 (m, 2H),
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7.33ꢀ7.30 (m, 2H), 7.25ꢀ7.22 (m, 1H), 7.13 (s, 1H), 6.80 (s, 1H), 6.33 (s, 1H), 4.21 (s, 1H),
3.92 (s, 3H), 3.88 (s, 3H), 3.71ꢀ3.62 (m, 2H), 2.50ꢀ2.43 (m, 2H), 2.33 (s, 3H, NCH3), 1.65ꢀ
1.50 (m, 2H, CH2), 1.46ꢀ1.37 (m, 2H, CH2), 0.95 (t, 3H, J = 7.3 Hz, CH3). 13C NMR (125
MHz, CDCl3): δ 151.9, 148.7, 146.0, 139.9, 137.3, 135.8, 128.5, 128.1, 126.8, 125.5, 109.5,
104.2, 71.8, 57.9, 56.5, 55.9, 37.9, 30.8, 29.1, 22.7, 14.0. IR (neat): 2924, 2853, 1679, 1491,
1463, 1335, 1218, 1099, 1027, 772.HRMS (ESI+): m/z (M++H) calculated for C23H30NO2,
352.2271; found, 352.224760.
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2-Butyl-5,6-dimethoxy-N-(prop-2-ynyl)-1H-inden-1-amine (3m). 64 mg (75%). Colourless
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oil, Rf = 1.50 (EtOAc/Hexane 20:80). H NMR (500 MHz, CDCl3): δ 7.08 (s, 1H), 6.77 (s,
1H), 6.36 (s, 1H), 4.27 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.04 (d, 2H, J = 2.5 Hz), 2.42ꢀ2.31
(m, 2H), 2.18 (t, 1H, J = 2.4 Hz), 1.94 (s, 1H), 1.66ꢀ1.50 (m, 2H), 1.45ꢀ1.37 (m, 2H), 0.95 (t,
3H, J = 7.3 Hz). 13C NMR (75 MHz, CDCl3): δ 150.3, 148.7, 146.6, 136.5, 135.6, 126.0,
107.8, 104.1, 82.4, 71.1, 65.3, 56.1, 55.9, 32.4, 30,5, 28.0, 22.4, 13.8. IR (neat): 3745, 3610,
3286, 3062, 2954, 2927, 2857, 1673, 1645, 1605, 1496, 1312, 1265, 1215, 1125, 1030, 864,
771, 668. HRMS (ESI+): m/z (M++H) calculated for C18H24NO2, 286.1801; found, 286.1791.
N-Benzyl-2-butyl-5,6-dimethoxy-1H-inden-1-amine (3n). 73 mg (72%). Colourless oil, Rf =
0.70 (EtOAc/Hexane 20:80). 1H NMR (400 MHz, CDCl3): δ 7.28ꢀ7.17 (m, 5H), 7.06 (s, 1H),
6.80 (s, 1H), 6.40 (s, 1H), 4.30 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.40 (d, 1H, J = 12.8 Hz),
3.34 (d, 1H, J = 12.8 Hz) 2.47ꢀ2.33 (m, 2H), 1.85 (br, 1H), 1.67ꢀ1.51 (m, 2H), 1.46ꢀ1.37 (m,
2H), 0.95 (t, 3H, J = 7.3 Hz). 13C NMR (100 MHz, CDCl3): δ 151.4, 148.7, 146.7, 140.8,
136.8, 128.2, 128.1, 126.8, 125.7, 107.9, 104.2, 66.2, 56.3, 56.0, 47.4, 30.7, 28.2, 22.6, 13.9.
IR (neat): 2924, 2923, 2853, 1652, 1604, 1492, 1460, 1312, 1264, 1217, 1126, 1028, 993,
863, 771, 700. HRMS (ESI+): m/z (M++H) calculated for C22H28NO2, 338.2114; found,
338.2103.
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4-(2-Butyl-3H-cyclopenta[
α
]napthalen-3-yl) morpholine (3o). 61 mg (66%). Colourless oil,
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Rf = 0.10 (EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ 8.02 (d, 1H, J = 8.3 Hz),
7.84 (d, 1H, J = 7.9 Hz), 7.68 (d, 1H, J = 8.2 Hz), 7.61 (d, 1H, J = 8.2 Hz), 7.48ꢀ7.40 (m,
2H), 7.00 (s, 1H), 4.25 (s, 1H), 3.73ꢀ3.64 (m, 4H), 2.77 (br, 2H, C2), 2.65ꢀ2.61 (m, 2H), 1.73ꢀ
1.60 (m, 2H), 1.69ꢀ1.56 (m, 2H), 1.49ꢀ1.36 (m, 2H), 0.98 (t, 3H, J = 7.3 Hz). 13C NMR (101
MHz, CDCl3) δ 152.9, 140.6, 140.3, 133.3, 128.3, 127.1, 125.4, 125.1, 123.8, 123.7, 123.6,
122.9, 73.8, 67.8, 49.6, 31.0, 29.4, 22.7, 14.1. IR (neat): 3056, 2956, 2924, 2853, 1682, 1620,
1595, 1563, 1515, 1459, 1374, 1315, 1255, 1226, 1143, 1116, 1071, 1015, 963, 858, 820,
766, 670. HRMS (ESI+): m/z (M++H) calculated for C21H25NO, 308.2008; found, 308.2010.
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2-(Cyclohexylmethyl)-5,6-dimethoxy-N-(prop-2-ynyl)-1H-1-amine (3p). 78 mg (80%).
Colourless oil, Rf = 0.60 (EtOAc/Hexane 10:90). 1H NMR (400 MHz, CDCl3): δ 7.08 (s, 1H),
6.78 (s, 1H), 6.36 (s, 1H), 4.25 (s, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.02 (d, 2H, J = 2.5 Hz),
2.29 (ddd, 1H, J = 14.7, 5.5, 1.3 Hz), 2.25 – 2.17 (m, 2H), 1.91ꢀ1.70 (m, 5H), 1.61ꢀ1.47 (m,
1H), 1.34ꢀ1.15 (m, 4H), 1.10ꢀ0.96 (m, 1H), 0.94ꢀ0.80 (m, 1H). 13C NMR (75 MHz, CDCl3): δ
148.8, 146.8, 136.7, 135.8, 127.6, 108.0, 104.3, 82.6, 71.2, 65.5, 56.4, 56.1, 37.5, 36.4, 34.1,
32.9, 32.5, 26.5, 26.4, 26.2. IR (neat); 3855, 3744, 3611, 3525, 3416, 3395, 3285, 3116,
3051, 2995, 2920, 2847, 1695, 1608, 1579, 1490, 1448, 1410, 1315, 1286, 1215, 1125, 1085,
1028, 991, 868, 845, 760, 694, 670, 642. HRMS (ESI+): m/z (M++H) calculated for
C21H28NO2, 326.2114; found, 326.2108.
1-(2-(Cyclohexylmethyl)-5,6-dimethoxy-1H-inden-1-yl)-4-phenylpiperazine (3q). 106 mg
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(82%). Colourless oil, Rf = 0.30 (EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ
7.29ꢀ7.20 (m, 2H), 7.10 (d, 1H, J = 8.1 Hz), 6.92 (d, 2H, J = 8.1 Hz), 6.83 (dd, 1H, J = 13.3,
6.0 Hz), 6.78 (s, 1H), 6.33 (s, 1H), 4.14 (s, 1H), 3.88 (s, 6H), 3.22ꢀ3.09 (m, 4H), 2.86 (dd,
2H, J = 10.5, 5.2 Hz), 2.80ꢀ2.68 (m, 2H), 2.37 (dd, 1H, J = 14.7, 4.6 Hz), 2.27ꢀ2.14 (m, 1H),
1.80ꢀ1.62 (m, 5H), 1.29ꢀ1.18 (m, 4H), 1.07ꢀ0.96 (m, 1H), 0.93ꢀ 0.82 (m, 1H). 13C NMR (101
MHz, CDCl3): δ 151.6, 149.5, 148.8, 146.0, 137.1, 135.4, 129.0, 127.1, 119.6, 116.1, 109.6,
104.3, 72.6, 56.5, 56.0, 50.0, 48.9, 37.3, 34.2, 33.1, 26.6, 26.4, 26.3. IR (neat); 3315, 2925,
2848, 1637, 1493, 1450, 1232, 1143, 1014. HRMS (ESI+): m/z (M++H) calculated for
C28H37N2O2 433.2855, found 433.2856.
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4-(6-(Tert-butyldimethylsilyloxy)-2-(cyclohexylmethyl)-5-methoxy-1H-inden-1-yl) morpholine
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(3r). 104 mg (76%). Colourless oil, Rf = 0.20 (EtOAc/Hexane 10:90). H NMR (500 MHz,
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CDCl3) δ 7.00 (s, 1H), 6.71 (s, 1H), 6.29 (s, 1H), 4.02 (s, 1H), 3.79 (s, 3H), 3.72–3.56 (m,
4H), 2.64 (br s, 2H), 2.54 (dd, 2H, J = 7.3, 4.0 Hz), 2.32 (dt, 1H, J = 17.1, 8.6 Hz), 2.22ꢀ2.11
(m, 1H), 1.87ꢀ1.64 (m, 4H), 1.60ꢀ1.49 (m, 1H), 1.33ꢀ1.12 (m, 4H), 1.01 (s, 9H), 0.93ꢀ0.81
(m, 2H), 0.17 (s, 3H), 0.15 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 150.4, 149.3, 141.6, 138.0,
135.3, 127.3, 118.2, 104.7, 72.6, 67.8, 55.6, 49.3, 37.3, 37.2, 34.2, 33.0, 26.6, 26.4, 26.3,
25.8, 18.5, ꢀ4.4, ꢀ4.5. IR (neat); 3317, 2951, 2926, 2847, 1645, 1484, 1450, 1412, 1343, 1294,
1250, 1213, 1115, 1013, 906. HRMS (ESI+): m/z (M++H) calculated for C27H44NO3Si
458.3090, found 458.3094.
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amine (3s). 99 mg (78%). Colourless oil, Rf = 0.60 (EtOAc/Hexane 30:70). H NMR (400
MHz, CDCl3) δ 6.97 (s, 1H), 6.73 (s, 1H), 6.33 (s, 1H), 4.23 (s, 1H), 3.80 (s, 3H), 3.03ꢀ3.01
(m, 2H), 2.28 (dt, 1H, J = 16.1, 8.0 Hz), 2.24–2.13 (m, 2H), 1.82 (d, 1H, J = 12.8 Hz), 1.72
(dd, 4H, J = 12.8, 3.3 Hz), 1.60–1.47 (m, 1H), 1.35–1.10 (m, 4H), 1.00 (s, 9H), 0.88 (ddd,
2H, J = 11.6, 10.2, 3.2 Hz), 0.16 (s, 3H), 0.14 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 150.7,
149.0, 142.4, 137.7, 136.1, 127.6, 116.8, 104.8, 82.6, 71.1, 65.2, 55.7, 37.4, 36.4, 34.1, 33.0,
32.6, 26.5, 26.4, 26.2, 25.8, 18.5, ꢀ4.5, ꢀ4.6. IR (neat); 3744, 3671, 3609, 3395, 3341, 3310,
3282, 2993, 2925, 2853, 1785, 1752, 1645, 1577, 1549, 1487, 1451, 1415, 1344, 1296, 1252,
1215, 1126, 1086, 1014, 908, 839, 780, 631. HRMS (ESI+): m/z (M++H) calculated for
C26H40NO2Si 426.2828, found 426.2836.
4-(2-Benzyl-5,6-dimethoxy-1H-inden-1-yl) morpholine (3t). 76 mg (72%). Colourless oil, Rf =
1
0.50 (EtOAc/Hexane 30:70). H NMR (500 MHz, CDCl3): δ 7.35–7.24 (m, 4H), 7.21 (t, 1H,
J = 7.0 Hz, 7.04 (s, 1H), 6.74 (s, 1H), 6.25 (s, 1H), 4.02 (s, 1H), 3.87 (s, 3H), 3.85 (s, 1H,,
3.77ꢀ3.62 (m, 6H), 2.74ꢀ2.63 (m, 2H), 2.63 ꢀ2.51 (m, 2H). 13C NMR (101 MHz, CDCl3): δ
149.4, 148.8, 146.3, 140.2, 136.8, 135.3, 129.1, 128.3, 127.7, 126.0, 109.5, 104.7, 72.4, 67.8,
56.4, 56.0, 49.3, 36.0. IR (neat): 3451, 2952, 2850, 1627, 1490, 1457, 1410, 1314, 1288,
1244, 1214, 1140, 1113, 1088, 991, 861, 769, 702. HRMS (ESI+): m/z (M++H) calculated for
C22H26NO3 352.1907; found, 352.1894.
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4-(2-Benzyl-6-methoxy-1H-inden-1-yl) morpholine (3u). 73 mg (76%). Colourless oil, Rf =
0.30 (EtOAc/Hexane 10:90). 1H NMR (500 MHz, CDCl3): δ 7.34ꢀ7.23 (m, 5H), 7.21 (t, 1H, J
= 7.0 Hz), 7.08ꢀ7.00 (m, 1H), 6.73 (dd, 1H, J = 8.1, 1.9 Hz), 6.28 (s, 1H), 4.05 (s, 1H, NꢀC),
3.79 (s, 3H), 3.76ꢀ3.60 (m, 6H), 2.80ꢀ2.66 (m, 2H), 2.64ꢀ 2.48 (m, 2H). 13C NMR (101 MHz,
CDCl3): δ 157.3, 148.3, 144.9, 140.2, 136.9, 129.1, 128.3, 127.7, 126.0, 120.7, 112.2, 111.9,
72.3, 67.8, 55.5, 49.2, 36.0. IR (neat): 3445, 3058, 3025, 2929, 2822, 2741, 1606, 1576,
1468, 1428, 1349, 1316, 1282, 1233, 1147, 1106, 1022, 921, 852, 809, 755, 695. HRMS
(ESI+): m/z (M++H) calculated for C21H24NO2, 322.1801; found, 322.1793.
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N-(Prop-2-ynyl)-2-(trimethylsilyl)-1H-inden-1-amine (3v). 54 mg (75%). Colourless oil, Rf =
1
0.10 (EtOAc/Hexane 10:90). H NMR (300 MHz, CDCl3): δ 7.48 (d, 1H, J = 7.2 Hz), 7.30ꢀ
7.22 (m, 2H), 7.21ꢀ7.15 (m, 1H), 7.00 (d, 1H, J = 1.8 Hz), 4.66 (d, 1H, J = 1.6 Hz), 3.13ꢀ3.01
(m, 2H), 2.16 (t, 1H, J = 2.5 Hz), 1.76 (br s, 1H), 0.27 (s, 9H). 13C NMR (101 MHz, CDCl3):
δ 152.8, 148.3, 145.1, 142.6, 128.6, 126.5, 124.1, 122.1, 83.5, 72.0, 69.9, 34.1, 0.02. IR
(neat): 3299, 3067, 2926, 2099, 1710, 1650, 1605, 1541, 1461, 1327, 1282, 1248, 1208,
1118, 1083, 1023, 841, 758, 635. HRMS (ESI+): m/z (M++H) calculated for C15H20NSi
242.1365, found, 242.1378.
General procedure for the intermolecular Petasis reactions from boronates 2a-2e.
Synthesis of compounds 4a-4g. Glyoxylic acid monohydrate (51 mg, 0.5 mmol) and amine
(0.5 mmol) were added to a stirred solution of the boronate 2 (0.3 mmol) in 1,1,1,3,3,3ꢀ
hexafluoropropanꢀ2ꢀol) (1 mL) under argon atmosphere at room temperature. The reaction
mixture was stirred during 78h. The solvent was removed under reduced pressure to give a
residue which was directly used for further esterification reaction. To a solution of the crude
o
acid in diethyl ether (5 mL) at 0 C a solution of CH2N2 in ether (2 mL, 0.5M) (Due to its
explosiveness and toxicity, diazomethane was directly generated in diethyl ether and used
without further purification after simple decantation)22 was added until the persistence of
yellow color. After 2 h, the solvent was evaporated and residue was purified by column
chromatography (230ꢀ400 mesh Silica gel, EtOAc in cyclohexane) to afford unsaturated
amino esters 4.
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Methyl-(Z)-3-benzylidene-2-morpholinoheptanoate (4a). 57 mg (60%). Colourless oil, Rf =
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0.50 (EtOAc/Hexane 30:70). H NMR (500 MHz, CDCl3): δ 7.36ꢀ7.31 (m, 4H), 7.27ꢀ7.24
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(m, 1H), 6.69 (s, 1H), 4.07 (s, 1H), 3.75 (s, 3H), 3.73ꢀ3.64 (m, 4H), 2.31 (br, 4H) 2.27ꢀ2.24
(m, 2H), 1.55ꢀ1.46 (m, 2H), 1.43ꢀ1.37 (m, 2H), 0.94 (t, 3H, J = 7.1 Hz). 13C NMR (125 MHz,
CDCl3): δ 171.3, 137.0, 136.5, 131.7, 130.0, 128.1, 126.7, 69.1, 66.6, 52.0, 51.4, 30.5, 30.3,
22.5, 14.1. IR (neat): 3745, 3730, 3610, 3056, 3022, 2955, 2923, 2853, 2812, 2765, 1745,
1644, 1598, 1570, 1549, 1492, 1452, 1380, 1337, 1266, 1245, 1193, 1167, 1136, 1118, 1072,
1025, 989, 931, 905, 881, 860, 772, 744, 700, 667, 635, 585. HRMS (ESI+): m/z (M++H)
calculated for C19H28NO3 318.2063, found 318.2062.
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Methyl-(Z)-3-benzylidene-2-(diallylamino)heptanoate (4b). 65 mg (66%). Colourless oil, Rf =
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0.20 (EtOAc/Hexane 10:90). H NMR (500 MHz, CDCl3): δ 7.37ꢀ7.32 (m, 4H), 7.26ꢀ7.22
(m, 1H), 6.64 (s, 1H), 5.71ꢀ5.63 (m, 2H), 5.04ꢀ5.00 (m, 4H), 4.48 (s, 1H), 3.69 (s, 3H), 3.17ꢀ
3.05 (m, 4H), 2.32ꢀ2.28 (m, 2H), 1.53ꢀ1.47 (m, 2H), 1.43ꢀ1.37 (m, 2H), 0.94 (t, 3H, J = 7.3
Hz). 13C NMR (100 MHz, CDCl3): δ 172.1, 138.0, 137.1, 134.7, 130.7, 129.0, 127.6, 126.6,
117.7, 64.5, 53.0, 51.7, 31.0, 31.0, 22.6, 14.1. IR (neat): 3859, 3825, 3746, 3610, 3076, 3019,
2955, 2923, 2853, 1743, 1642, 1549, 1493, 1461, 1372, 1261, 1214, 1193, 1163, 1122, 1073,
1013, 995, 919, 854, 747, 700, 667, 572. HRMS (ESI+): m/z (M++H) calculated for
C21H29NO2Na 350.2091, found 350.2116.
Methyl-(Z)-3-(4-methylbenzylidene)-2-morpholinoheptanoate (4c). 48 mg (48%). Colourless
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oil, Rf = 0.40 (EtOAc/Hexane 30:70). H NMR (400 MHz, CDCl3): δ 7.21 (d, 2H, J = 7.9
Hz), 7.16 (d, 2H, J = 7.9 Hz), 6.65 (s, 1H), 4.08 (s, 1H), 3.75 (s, 3H), 3.73ꢀ3.64 (m, 4H), 2.36
(s, 3H), 2.32 (br, 4H), 2.17 (t, 2H, J = 7.2 Hz), 1.55ꢀ1.44 (m, 2H), 1.43ꢀ1.36 (m, 2H), 0.93 (t,
3H, J = 7.2 Hz). 13C NMR (125 MHz, CDCl3): δ 171.2, 136.4, 136.0, 134.1, 131.7, 128.8,
69.1, 66.6, 52.0, 51.4, 30.5, 30.3, 22.6, 21.1, 14.1. IR (neat): 3860, 3745, 3669, 3610, 2955,
2923, 2853, 2812, 1746, 1549, 1511, 1454, 1379, 1339, 1266, 1244, 1214, 1194, 1166, 1138,
1118, 1071, 1024, 990, 948, 905, 879, 810, 668, 640, 576. HRMS (ESI+): m/z (M++Na)
calculated for C20H29NO3Na 354.2045, found 354.2042.
Methyl-(Z)-3-(4-methoxybenzylidene)-2-morpholinoheptanoate (4d). 53 mg (51%).
Colourless oil, Rf = 0.40 (EtOAc/Hexane 30:70). 1H NMR (500 MHz, CDCl3): δ 7.29 (d, 2H,
J = 8.5 Hz), 6.90 (d, 2H, J = 8.6 Hz), 6.63 (s, 1H), 4.08 (s, 1H), 3.83 (s, 3H), 3.76 (s, 3H),
3.73ꢀ3.64 (m, 4H), 2.35ꢀ2.28 (m, 4H) 2.24ꢀ2.12 (m, 2H), 1.54ꢀ1.44 (m, 2H), 1.38ꢀ1.31 (m,
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2H), 0.90 (t, 3H, J = 6.8 Hz). 13C NMR (125 MHz, CDCl3): δ 172.0, 158.4, 135.5, 131.3,
130.2, 129.5, 113.5, 69.2, 66.6, 55.2, 52.0, 51.4, 31.7, 30.6, 22.6, 14.0. IR (neat): 3733, 3611,
2954, 2922, 2853, 2813, 1744, 1607, 1574, 1510, 1457, 1379, 1338, 1246, 1212, 1175, 1135,
1118, 1070, 1031, 990, 942, 866, 838, 766, 667, 595. HRMS (ESI+): m/z (M++H) calculated
for C20H30NO4 348.2169, found 348.2168, m/z (M++Na) calculated for C20H29NO4Na
370.1988, found 370.1987.
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Methyl-(Z)-3-(4-methoxybenzylidene)-2-(4-phenylpiperazin-1-yl)heptanoate (4e). 78 mg
(62%). Colourless oil, Rf = 0.30 (EtOAc/Hexane 10:90). 1H NMR (500 MHz, CDCl3): δ 7.30
(d, 1H, J = 8.5 Hz), 7.23 (dd, 1H, J = 8.6, 7.4 Hz), 7.24ꢀ7.21 (m, 2H), 6.90ꢀ6.81 (m, 5H),
6.64 (s, 1H), 4.14 (s, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.22ꢀ3.12 (m, 4H), 2.50 (br, 4H), 2.27 (t,
1H, J = 7.9 Hz), 1.53ꢀ1.47 (m, 2H), 1.42ꢀ1.37 (m, 2H), 0.94 (t, 3H, J = 7.1 Hz). 13C NMR
(125 MHz, CDCl3): δ 171.7, 158.4, 151.1, 136.0, 131.0, 130.2, 129.5, 129.0, 119.6, 116.0,
113.5, 69.0, 55.2, 52.0, 51.0, 50.0, 30.6, 30.4, 22.6, 14.1. IR (neat): 3020, 2928, 1743, 1602,
1509, 1452, 1384, 1214, 1023, 908, 746, 667, 625. HRMS (ESI+): m/z (M++H) calculated for
C26H34N2O3 423.26425, found 423.2645.
(Z)-Methyl 3-benzyl-4-(4-methoxyphenyl)-2-morpholinobut-3-enoate (4f). 71 mg (62%).
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Colourless oil, Rf = 0.40 (EtOAc/Hexane 30:70). H NMR (500 MHz, CDCl3): δ 7.30ꢀ7.21
(m, 7H), 6.87 (d, 2H, J = 8.6 Hz), 6.41 (s, 1H), 4.16 (s, 1H), 3.82 (s, 3H), 3.73ꢀ3.68 (m, 4H),
3.60 (s, 2H), 3.59 (s, 3H), 2.41ꢀ2.37 (m, 4H). 13C NMR (125 MHz, CDCl3): δ 171.7, 158.7,
139.3, 134.8, 134.7, 130.3, 129.6, 128.3, 126.2, 113.6, 68.9., 66.8, 55.3, 51.9, 51.5, 37.8. IR
(neat); 3448, 3027, 2594, 2853, 1742, 1605, 1509, 1452, 1385, 1247, 1175, 1116, 1072, 1028,
873, 829, 771, 699. HRMS (ESI+): m/z (M++Na) calculated for C23H27NO4Na 404.1832,
found, 404.1850.
(Z)-methyl3-(cyclohexylmethyl)-4-(4-methoxyphenyl)-2-morpholinobut-3-enoate (4g). 71 mg
(61%). Colourless oil, Rf = 0.50 (EtOAc/Hexane 30:70). 1H NMR (300 MHz, CDCl3): δ 7.30
(d, 2H, J = 8.6 Hz), 6.90 (d, 2H, J = 8.6 Hz), 6.63 (s, 1H), 4.09 (s, 1H), 3.83 (s, 3H), 3.75 (s,
3H), 3.68 (ddd, 4H, J = 16.0, 9.4, 4.7 Hz), 2.33 (s, 4H), 2.11 (dd, 2H, 15.6, 7.2 Hz), 1.88ꢀ1.66
(m, 4H), 1.58ꢀ1.39 (m, 1H), 1.38ꢀ1.05 (m, 4H), 0.94ꢀ0.82 (m, 2H). 13C NMR (126 MHz,
CDCl3): δ 171.5, 158.5, 133.1, 132.6, 130.3, 129.5, 113.6, 69.1, 66.7, 55.2, 51.8, 51.5, 38.8,
36.2, 33.5, 33.2, 26.6, 26.5. IR (neat); 3451, 2923, 2849, 1744, 1606, 1509, 1448, 1247, 1174,
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1117, 1070, 1030, 945, 874, 830, 771. HRMS (ESI+): m/z (M++H) calculated for C23H34NO4
388.2482, found 388.2490.
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Supporting Information. H and 13C spectra of compounds 2a-n, 3aꢀ3v and 4aꢀ4g. This
material is available free of charge via the Internet at http://pubs.acs.org.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research has been performed as part of the IndoꢀFrench ״Joint Laboratory for
Sustainable Chemistry at Interfaces", and ORIGIN (CSIR)ꢀCSCꢀ0108. We thank CSIR,
CNRS, and the University of Rennes 1 for support of this research. V.J. thanks UGCꢀNew
Delhi for research fellowship.
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