Stereoselective synthesis of (E)-3,3-diaryl and (E)-3-aryl-3-aryloxy allylamines and allylalcohols from trans-cinnamyl chloride and alcohol

Article abstract of DOI:10.1039/c4ra08036j

In this work we describe the regio and stereoselective synthesis of (E)-3,3-diaryl and (E)-3-aryl-3-aryloxy allylamines and allylalcohols. The starting materials are the non-expensive commercially available cinnamyl alcohol and chloride. The bromination/dehydrobromination sequence furnished the (E)-3-bromo-3-phenylallyl amines and alcohol as single regioisomers and with high stereoselectivity (>98%). These vinyl bromides were used as substrates in cross-coupling reactions furnishing the arylated products with good to excellent yields and total E-configuration retention. With this protocol, we were able to produce regio and stereospecifically trisubstituted olefins and vinyl ethers by Suzuki cross-coupling and Ullmann vinylation.

Full text of DOI:10.1039/c4ra08036j

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Stereoselective synthesis of (E)-3,3-diaryl and (E)-3-
aryl-3-aryloxy allylamines and allylalcohols from
trans-cinnamyl chloride and alcohol†
Cite this: RSC Adv., 2014, 4, 45558
*
Jones Limberger, Thiago S. Claudino and Adriano L. Monteiro
In this work we describe the regio and stereoselective synthesis of (E)-3,3-diaryl and (E)-3-aryl-3-aryloxy
allylamines and allylalcohols. The starting materials are the non-expensive commercially available
cinnamyl alcohol and chloride. The bromination/dehydrobromination sequence furnished the (E)-3-
bromo-3-phenylallyl amines and alcohol as single regioisomers and with high stereoselectivity (>98%).
These vinyl bromides were used as substrates in cross-coupling reactions furnishing the arylated
products with good to excellent yields and total E-configuration retention. With this protocol, we were
able to produce regio and stereospecifically trisubstituted olefins and vinyl ethers by Suzuki cross-
coupling and Ullmann vinylation.
Received 2nd August 2014
Accepted 9th September 2014
DOI: 10.1039/c4ra08036j
www.rsc.org/advances
3-Arylated allyl amines such as abamine-SG, abamine and
naine are bioactive compounds.23 In our ongoing research,
Introduction
we need to obtain selective protocols for the synthesis of 3,3-
diarylated allyl amines and alcohols. In this context, we wish to
describe here a highly regio and stereoselective approach to the
synthesis of (E)-3,3-diaryl allyl amines and alcohols and (E)-3-
aryl-3-aryloxy allyl amines and alcohols. Our strategy is based on
the regio and stereoselective formation of vinyl bromides 5 from
commercially available and inexpensive starting materials
(trans-cinnamyl alcohol and trans-cinnamyl chloride). This
strategy allowed us to synthesise the target trisubstituted-
olens via Suzuki and C–O cross-coupling reactions, in both
cases as single regioisomers with E : Z ratios greater than 98 : 2.
Regio and stereocontrol in the production of multi-substituted
unsaturated compounds remains an important challenge in
organic synthesis.1–4 Particularly, the controlled insertion of aryl
and aryloxy fragments into olen scaffolds is an important task
for the synthesis of bioactive compounds, such as Z-tamox-
ifene,2,5–7 sertraline,8 indatraline,8 and tolterodine,9 among
others.10–12
1,1-Diaryl trisubstituted alkenes, specically, are usually
synthesised by mono or di Heck arylation of cinnamates,13–16
a,b-unsaturated adehydes17 and acrylonitriles.18,19 However,
these methodologies contain some drawbacks. For instance, the
presence of an unsaturated electron-withdrawing group conju-
gated to the olen is imperative to drive the regioselectivity for
the formation of the 1,1-diaryl product. In addition, and
depending on the conditions, stereoisomeric mixtures are
obtained. An example of lack of regio and stereoselectivity
caused by the absence of conjugation at double bond is the
Heck arylation of cinnamic alcohol, where mixtures of
regioisomers and double bound isomerisation are obtained.20
Allyl alcohols can be also obtained by hydrogenation21 or
transfer hydrogenation22 of the corresponding a,b-unsaturated
aldehyde. Considering allylamines, to ensure regioselectivity in
Heck arylation, is necessary the presence of an electron with-
drawing group bounded to the nitrogen.23,24
Results and discussion
Initially, trans-cinnamyl chloride was allowed to react with dii-
sopropylamine and N,N-methylbenzylamine leading to the (E)-
N,N-dialkyl-3-phenylprop-2-en-1-amines 3a and 3b in yields of
86% and 88%, respectively (Scheme 1). The products 3a and 3b
wereꢀthen protonated and submitted to bromination in CH2Cl2
at 0 C affording the antiperiplanar dibrominated products 4a
and 4b as crystalline solids in good yields (81 and 77%,
respectively). It must be mentioned that the protonation is
imperative since bromination of the free amine led to a complex
mixture of products. Cinnamic alcohol was also brominated
in the same conditions affording the intermediate 4c at a yield
of 86%.
In order to establish the best dehydrobromination condi-
tions, a range of solvent, base and reaction temperature
combinations were tested to achieve high regio and stereo-
selectivity (Table 1 of ESI†). As a result, by using KOH, THF and
35 ꢀC, the vinyl bromides 5a and 5b were formed as single
´
Laboratory of Molecular Catalysis. Instituto de Quımica
– UFRGS, Av. Bento
Gonçalves, 9500, Porto Alegre 91501-970 – CP 15003, RS, Brazil. E-mail: adriano.
monteiro@ufrgs.br
† Electronic supplementary information (ESI) available: Dehydrobromination
optimisation, NMR spectra and NOE-stereochemistry characterisation. See DOI:
10.1039/c4ra08036j
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Scheme 1 Regio and stereoselective synthesis of vinyl bromides 5a, 5b and 5c.
regioisomers in 88% and 84% yields, respectively, with stereo-
selectivity greater than 98%. It must be mentioned that the
work-up was very simple since no column chromatography was
necessary. A simple ltration and solvent evaporation furnished
the desired products with high purity (>99% as judged by GC
and 1H-NMR). Concerning the vinyl bromide 5c obtained from
the cinnamic alcohol, the regioselectivity was slightly lower
since a mixture 90 : 10 of regioisomers was obtained at the end
of the reaction. In this case, chromatographic separation of
regioisomers was necessary, and aer that, vinylic compound 5c
was obtained at a yield of 78% and with a E : Z ratio of 98 : 2.
The stereochemistry E of all vinyl bromides was ascribed
through NOE experiments. Correlations between aromatic and
allylic CH2 hydrogens were observed for the olens 5a–c
Fig. 1 Transition states that provide the major regioisomer (Path A)
(see ESI†).
In previous works, we have used the dehydrobromination of
and minor regioisomer (Path B).
(1,2-dibromoethyl)benzene in order to obtain the a-bromostyr-
ene with regioselectivities up to 95%.25,26 Here we have used the
same simple KOH-promoted dehydrobromination protocol and
were delighted to see that for the dibromides 4a and 4b, only the
a-bromo regioisomers were observed and that for 4c, a 90 : 10
regioisomeric ratio was obtained. It is important to mention
that the dehydrobromination reaction does not require high
temperatures, microwave irradiation, ionic liquid as media or
metal additives.27,28 We believe that the reaction is facilitated
due to an anchimeric assistance of amine or alcohol group in
the transition state that removes the benzylic proton and
provides the 3-phenyl-3-bromo regioisomer (Path A in Fig. 1).
On the other hand, in the transition state that provides the
opposite regioisomer (3-phenyl-2-bromo product), this assis-
tance is not possible (Path B); therefore, the Path A and
consequently 3-phenyl-3-bromo allylamines and allyl alcohol 5
are favored. The high stereoselectivity obtained for the dehy-
drobromination product (E/Z ¼ $98%) is related to the strong
preference for the anti-elimination process.6,29
Table 1 Condition optimisation for Suzuki cross-coupling of vinyl
bromide 5aa
Entry Catalyst
Conv. (%) Yieldb (%) Reduction (%)
1
2
3
4
5
6c
Pd(OAc)2
70
62
53
70
75
42
47
48
67
73
98 (93)
28
10
3
3
2
Pd(OAc)2/P(o-Tol)3
Pd(OAc)2/BINAP
PdCl2(PPh3)2
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
100
2
a
Reaction conditions: 5a (0.5 mmol), arylboronic acid (0.6 mmol), KOH
(1.0 mmol), THF (4 mL), [Pd] (0.5 mol%), phosphine (1 mol%), 25 ꢀC, 1
h. Internal standard: tetradecane. By-products detected: vinyl bromide
reduction and arylboronic acid homocoupling. For isolated yield a 2.0
With vinyl bromides 5 in hands, we evaluated the Suzuki
cross-coupling, starting with the conditions already established
for (E)-bromostilbene.6,30 The optimisation was carried out at
b
mmol scale were used. GC yields. c 2.5 h.
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room temperature for one hour using substrate 5a and 2- triphenylphosphine is a cheap phosphine and only 0.5 mol% of
methoxy-5-methylphenylboronic acid as coupling partners Pd(OAc)2 is necessary for the complete conversion at room
(Table 1). Initially, a phosphine-free system was tested (entry 1), temperature.
giving a high conversion but with a considerable amount of
Aer determination of the best Suzuki coupling conditions,
vinyl bromide reduction as a by-product. In a sequence, systems the scope of the reaction was tested. In this way, the reaction
based on Pd(OAc)2/P(o-Tol)3 and Pd(OAc)2/BINAP were applied, was performed with 5a, 5b and 5c and a plethora of arylboronic
leading to yields of 47% and 48%, respectively. The systems that acids (Table 2). Good to excellent results were observed,
achieved the best results were those based on PPh3: 67% yield considering that yields ranging from 71 to 94% were attained
with PdCl2(PPh3)2 and 73% yield with Pd(OAc)2/PPh3; these with the products being obtained with complete (E)-stereo-
were the same conditions described by us as being the best for chemistry retention. The best yields were observed with the
the coupling between (E)-bromostilbene and arylboronic electron-rich 4-methoxyphenylboronic acid (entries 1 and 9).
acids.6,30 Finally, in order to obtain complete conversion, the Moreover, the reaction proceeds very well with both deactivated
reaction time was increased to 2.5 h, giving the product with (entry 3) and steric demanding arylboronic acids (entry 5);
98% GC yield, 93% isolated yield and with complete retention of however, in these cases a larger excess of arylboronic acid is
the double bond conguration. Again, the stereochemistry of needed to afford the complete conversion of vinyl bromide.
the product was determined by NOE, where a correlation
Beside Suzuki cross-coupling, the Ullmann reaction of
between the olenic hydrogen and the aryl ortho-methyl phenols was also applied to the vinyl bromides 5b and 5c in
hydrogen was observed (see ESI†). It must to be mentioned that order to obtain novel (E)-trisubstituted vinyl-ethers regio and
these conditions are very practical and convenient since stereospecically. We applied the same conditions as described
Table 2 Stereoselective synthesis of 3,3-diaryl allylamines and allyl alcohols via Suzuki cross-coupling of 5a–ca
Entry Product
Yieldb (%) Entry Product
Yieldb (%) Entry Product
Yieldb (%)
1
7a 94
5c
11a 84
9c
7c 77
2
8a 81
6c
12a 71
10
8c 86
3c
9a 83
7c
6b 74
11
9c 82
4
10a 92
8
6c 93
a
Reaction conditions: 5 (2.0 mmol), arylboronic acid (2.4 mmol), KOH (4.0 mmol), THF (16 mL), Pd(OAc)2 (0.5 mol%), PPh3 (1 mol%), 25 ꢀC, 2.5 h.
b
Isolated yields. c 3 mmol of arylboronic acid was necessary to achieve complete vinyl bromide conversion.
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Table
3 Stereospecific synthesis of trisubstituted vinyl-ethers by
coupling products with good to excellent yields and total E-
conguration retention. This strategy represents an innovative
method for the stereo-controlled synthesis of (E)-3,3-diaryl
allylamines and allylalcohols since no double bond conjugation
is needed in the substrate to attain high regioselectivity.
Moreover, by using this approach, it is also possible to access
novel vinyl ethers with complete regio and stereocontrol.
Ullmann coupling of 5b and 5c with substituted phenolsa
Experimental
General information
Entry R1
Product
Yield (%)
Allylic substitution, bromination and dehydrobromination
reactions were performed in air atmosphere, using solvents and
reagents as received. The catalytic Suzuki cross-couplings and
copper-catalyzed Ullmann vinylation were performed under
argon atmosphere. For these reactions THF and dioxane were
distilled over Na/benzophenone and the MeOH was degassed
before the use. NMR spectra were recorded on a Varian XL300
spectrometer and in a Bruker Avance 400 MHZ. IR spectra were
recorded on a Shimadzu FTIR-8300 spectrometer. Mass spectra
were obtained on a GC/MS Shimadzu QP-5050 (EI, 70 eV). Gas
chromatography analyses were performed on a Shimadzu
equipment equipped with a 30 meter DB-5 column and FID
detector. ESI-(+) HRMS analyses were performed on a Q-Tof
(Micromass) mass spectrometer.
1
2
4-OMe
8b 86
2-Me
9b 86
3
4
4-COMe
4-COMe
10b 43
10c 51
Synthesis of the amines 3a and 3b
A mixture of 10 g (66.0 mmol) of cinnamyl chloride, 262 mmol
of diisopropylamine (or N,N-benzylmethylamine) 36.2 g (262
mmol) of K2CO3, 120 mL of toluene and 120 mL of tert-butanol
were stirred for 24 h at 90 ꢀC. The cinnamyl chloride
consumption was monitored by GC. Aer, the reaction was
ltered and the solvent was removed. The product was dissolved
in Et2O and extracted with HCl 1.0 M. The aqueous phase was
neutralized with NaOH 1.0 M, extracted with Et2O, washed with
brine and dried over MgSO4. The solvent was removed to give
the corresponding (E)-N,N-dialkyl-3-phenylprop-2-en-1-amine
as yellow oils.
(E)-N,N-Diisopropyl-3-phenylprop-2-en-1-amine (3a). Yellow
oil, yield: 88%. IR (neat): n 3025, 2962, 2930, 1600, 1448, 1380,
1170, 963, 689 cmꢁ1. MS (IE 70 eV): m/z (relat. int.): 217 (18, M+),
202 (56), 174 (5), 144 (6), 126 (11), 117 (100), 115 (81), 91 (60), 77
(19). 1H-NMR (300 MHz, CDCl3) d ppm 0.95 (d, J ¼ 6.6 Hz, 12H),
3.00 (hept, J ¼ 6.6 Hz, 2H), 3.18 (dd, J ¼ 4.6 Hz, 1.5 Hz, 2H), 6.15
(m, 1H), 6.48 (d, J ¼ 15.8 Hz, 1H), 7.06–7.32 (m, 5H). 13C-NMR
(75 MHz, CDCl3) d ppm 21.4; 48.3; 48.9; 126.8; 127.6; 129.1;
130.6; 132.4; 138.2. HRMS: m/z calcd for C15H24N (M + H+):
218.1909; found: 218.1899.
5
4-OMe
11c 74
a
Reaction conditions: 5 (2.0 mmol), phenol (3.0 mmol), K3PO4 (4.0
mmol), CuI (10 mol%), phenanthroline (10 mol%), dioxane (8 mL).
for Ullmann reaction of (E)-bromostilbene with phenols and
azole31 and the results obtained are described in Table 3.
Initially, the reaction was performed with the electron rich 4-
methoxyphenol and the substrate 5b; thus, the product 8b was
obtained with 86% yield (entry 1). Aer this, we tested the C–O
coupling with a high steric demanding o-cresol and the result
was not affected, since the same yield was observed (entry 2).
Lower yields are usually obtained for the Ullmann coupling of
aryl or vinyl halides with phenols containing electron-with-
drawing groups.32,33 Indeed, when the reaction was performed
with the less nucleophilic 40-hydroxyacetophenone, an impor-
tant decrease in yield was observed for both substrates 5b and
5c. It is important to mention that similarly to Suzuki coupling,
the products were obtained with total E-conguration retention.
(E)-N-Benzyl-N-methyl-3-phenylprop-2-en-1-amine
(3b).
Yellow oil, yield: 86%. IR (atr): n 3059, 3026, 2784, 1599, 1494,
1451, 1364, 1022, 967, 736 cmꢁ1. MS (IE 70 eV): m/z (relat. int.):
237 (14), 236 (10), 167 (4), 146 (100), 134 (7), 117 (41), 91 (77). 1H-
Conclusions
In summary, we described herein the regio and stereoselective NMR (300 MHz, CDCl3) d ppm 2.0 (s, 3H), 3.25 (d, J ¼ 6.5 Hz, 2H)
synthesis of vinyl bromides derived from cinnamic alcohol and 3.67 (s, 2H), 6.37 (m, 1H), 6.60 (d, J ¼ 15.9 Hz, 1H), 7.20–7.56 (m,
cinnamic amines. These bromides were used as the substrate 10H). 13C-NMR (75 MHz, CDCl3) d ppm 42.2; 59.8; 61.8; 126.2;
for Suzuki cross-coupling and Ullmann vinylation, furnishing 126.9; 127.3; 127.5; 128.2; 128.5; 129.0; 132.5; 137.0; 138.9.
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HRMS: m/z calcd for C17H20N (M + H+): 238.1596; found: 13C-NMR (75 MHz, CDCl3) d ppm 52.2; 59.3; 65.8; 127.8; 128.7;
238.1588.
128.9; 139.8.
Dehydrobromination reactions of 4a–4c
Bromination of 3a and 3b
A mixture of dibrominated product 4 (5.0 mmol), KOH (10.0
mmol) and THF (25 mL) was stirred at 35 ꢀC for 48 h. The
mixture was then ltered and the THF was evaporated. For the
substrates 4a and 4b the mixture was dissolved in hexane, in
order to precipitate inorganic salts and ltered again. Finally,
the hexane was evaporated to give the corresponding (E)-3-
bromo-N,N-dialkyl-3-phenylprop-2-en-1-amines 5a and 5b as
pale yellow oils. It is important to mention that single
regioisomers and almost single diastereoisomer (E : Z $ 98%)
were obtained. For 4c, aer the end of the reaction, the mixture
was ltered, the THF was evaporated and the crude product 5c
was analysed by NMR. It was observed a regioisomeric mixture
of 9 : 1. The regioisomers were then separated by column
chromatography in silica, with a hexane/ethyl acetate eluent.
The (E)-conguration of the products 5a–c were determined by
1D- and 2D-NOESY experiments (see ESI†).
(E)-3-Bromo-N,N-diisopropyl-3-phenylprop-2-en-1-amine (5a).
Pale yellow oil, yield: 88%. IR (atr): n 3053, 2964, 2929, 1460,
1363, 1178, 844, 759, 696 cmꢁ1. MS (EI 70 eV): m/z (int. relat.):
297 (4, M + 2), 295 (4, M+), 282 (24), 280 (25), 197 (36), 195 (40),
144 (6), 115 (100), 102 (21), 70 (20), 56 (40). 1H-NMR (300 MHz,
CDCl3) d ppm 0.93 (d, 12H, J ¼ 6.5 Hz), 3.00 (hept, 2H, J ¼ 6.5
Hz), 3.08 (d, 2H, J ¼ 6.7 Hz), 6.29 (t, 1H, J ¼ 6.7 Hz), 7.25–7.38 (m,
5H). 13C-NMR (75 MHz, CDCl3) d ppm 20.6; 44.8; 48.6; 119.9;
128.1; 128.4; 128.9; 135.9; 138.6. HRMS: m/z calcd for C15H23BrN
(M + H+): 296.1014; found: 296.1008.
(E)-N-Benzyl-3-bromo-N-methyl-3-phenylprop-2-en-1-amine (5b).
Pale yellow oil, yield: 84%. IR (atr): n 3058, 3028, 2941, 2788, 1632,
1452, 1025, 699 cmꢁ1. MS (EI 70 eV): m/z (relat. int.): 317 (3), 315 (3),
236 (28), 226 (17), 224 (18), 134 (60), 115 (33), 91 (100). 1H-NMR (300
MHz, CDCl3) d ppm 2.08 (s, 3H), 3.09 (d, J ¼ 7.3 Hz, 2H), 3.36 (s,
2H), 3.68 (s, 3H), 5.18 (t, J ¼ 7.3 Hz, 1H), 6.74 (d, J ¼ 9.0 Hz, 2H),
6.89 (d, J ¼ 9.0 Hz, 2H), 7.15–7.32 (m, 8H), 7.43 (d, J ¼ 9.0 Hz, 2H).
13C-NMR (100 MHz, CDCl3) d 41.9; 56.2; 61.4; 123.0; 127.1; 128.1;
128.2; 128.6; 128.9; 128.9; 131.6; 138.3; 138.4. HRMS: m/z calcd for
C17H19BrN (M + H+): 316.0701; found: 316.0702.
(E)-3-Bromo-3-fenilprop-2-en-1-ol (5c). Colorless oil, yield:
78%. MS (EI 70 eV): m/z (relat. int.): 214 (7), 212 (8), 133 (55), 115
(54), 105 (100), 103 (85), 89 (25), 77 (51), 63 (48), 51 (80). 1H-NMR
(400 MHz, CDCl3) d ppm 1.71 (s, 1H), 4.07 (d, J ¼ 7.2 Hz, 2H),
6.42 (t, J ¼ 7.2 Hz, 1H), 7.33–7.40 (m, 5H). 13C-NMR (100 MHz,
CDCl3) d ppm 60.6; 124.7; 128.2; 128.8; 129.0; 132.5; 137.7.
HRMS: m/z calcd for C9H9BrO: 211.9837; found: 211.9850.
A mixture of HBr 1.0 M (50 mL) and 50 mmol of 3 was stirred for
10 min. Aer, the water was evaporated; the product was dis-
solved in 50 mL of CH2Cl2, dried over MgSO4 and ltered. Then,
a solution of Br2 (3.1 mL, 60 mmol) in CH2Cl2 (30 mL) was
added dropwise at 0 ꢀC during 30 min and allowed to attain
room temperature. The reaction mixture was stirred overnight
in the dark. Aer, the bromine color of the mixture was removed
by addition an excess of aq. NaHSO3 10% and the pH was raised
to 9 by addition of KOH 10%. The organic layer was then dried
(MgSO4) and the solvent was evaporated to give the crude
products. The products were crystallized in ethanol to give the
2,3-dibromo-N,N-dialkyl-3-phenylpropan-1-amines.
2,3-Dibromo-N,N-diisopropyl-3-phenylpropan-1-amine (4a).
White solid, yield: 81%, IR (atr): n 3031, 2972, 2956, 2926, 1494,
1454, 1390, 1209, 1133, 921, 765 cmꢁ1 1H-NMR (300 MHz,
.
CDCl3) d ppm 0,99 (dd, J ¼ 14.9; 6.6 Hz, 12H), 2.79 (dd, J ¼ 14.9,
9.0 Hz, 1H), 3.04 (hep, J ¼ 6.6 Hz, 2H), 3.41 (dd, J ¼ 14.9, 3.4 Hz,
1H), 4.47 (dt, J ¼ 9.0, 3.4 Hz, 1H), 5.10 (d, J ¼ 9.0 Hz, 1H), 7.20–
7.41 (m, 5H). 13C-NMR (75 MHz, CDCl3) d ppm 20.5; 48.7; 52.6;
55.5; 59.9; 128.1; 128.4; 128.6; 140.0. HRMS: m/z calcd for
C
15H24Br2N (M + H+): 376.0275; found: 376.0281.
N-Benzyl-2,3-dibromo-N-methyl-3-phenylpropan-1-amine (4b).
White crystals, yield: 77%. IR (atr): n 2959, 2927, 1495, 1456, 1213,
1
1135, 691 cmꢁ1. H-NMR (300 MHz, CDCl3) d ppm 2.37 (s, 3H),
3.03 (dd, J ¼ 13.9, 7.3 Hz, 1H), 3.20 (dd, J ¼ 13.9, 4.8 Hz, 1H), 3.70
(m, AB system, 2H), 4.67 (ddd, J ¼ 8.5, 7.3, 4.8 Hz, 1H) 5.35 (d, J ¼
8.5 Hz, 1H) 7.25–7.51 (m, 12H). 13C-NMR (75 MHz, CDCl3) d ppm
42.7; 54.4; 56.7; 62.6; 62.7; 127.2; 128.2; 128.3; 129.0; 138.4; 139.1.
HRMS: m/z calcd for C17H20Br2N (M + H+): 397.9942; found:
397.9969.
2,3-Dibromo-3-fenilpropan-1-ol(4c)
A solution of cinnamic alcohol (30 mmol) in 100 mL of CH2Cl2
was cooled to 0 ꢀC in ice bath and kept in the dark. To this
solution a mixture of 1.9 mL (36 mmol) of Br2 in 30 mL of
CH2Cl2 was added dropwise during 30 min. Aer, the reaction
was allowed to attain room temperature and the mixture was
stirred during 16 h. Aer, a solution of NaHSO3 10% was added
and the organic layer was separated, washed with brine, dried
over MgSO4, ltered and the CH2Cl2 was evaporated to give the
crude product as a yellow solid. The product was recrystallized
from a hot solution of hexane–toluene 1 : 1 furnishing white
crystals. The crystals were then washed with cold hexane and
dried under vacuum.
Suzuki coupling of 5a–c with arylboronic acids
2,3-Dibromo-3-phenylpropan-1-ol (4c):.34 White crystals, An oven-dried resealable Schlenk ask charged with 5 (2 mmol)
yield: 86%, IV (atr): n 3360, 3028, 2925, 2870, 1493, 1452, 1231, was evacuated and back-lled with argon. Then, Pd(OAc)2 (2.2
1135, 1051, 762, 692, 624, 578 cmꢁ1. MS (EI 70 eV): m/z (relat. mg, 0.01 mmol), PPh3 (5.2 mg, 0.02 mmol), arylboronic acid (2.4
int.): 295 (2), 293 (4), 291 (2), 215 (68), 213 (82), 185 (99), 183 mmol), KOH (224 mg, 4 mmol), MeOH (8 mL), and THF (8 mL)
1
(100), 133 (57), 105 (91), 91 (87). H-NMR (300 MHz, CDCl3) d were added. The reaction mixture was stirred at room temper-
ppm 2.17 (t, J ¼ 6.74, 1H), 4.21–4.36 (m, 2H), 4.70 (ddd, J ¼ 11.1, ature for 2.5 h. Aer, the solution was then taken up in Et2O
4.3, 2.7 Hz, 1H), 5.27 (d, J ¼ 11.1 Hz, 1H), 7.18–7.56 (m, 5H). (30 mL) and the Et2O layer was washed with aq. 1.0 M NaOH
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(10 mL) and brine (2 ꢂ 5 mL). The organic layer was dried CDCl3) d ppm 20.6; 21.3; 44.2; 48.6; 124.4; 126.8; 127.5; 127.7;
(MgSO4), ltered, concentrated under reduced pressure. The 127.8; 129.7; 131.4; 137.4; 140.0; 140.8; 142.4. HRMS: m/z
crude material was puried by column chromatography on calcd for C22H30N (M + H+): 308.2378; found: 308.2366.
silica gel using hexane/ethyl acetate as eluent. The E-congu-
ration of the products was assigned by 2D-NOESY of selected (11a). White solid, mp: 80 ꢀC, yield: 84%. IR (atr): n 2970, 1611,
compounds.
1491, 1379, 1287, 1201, 1180, 1023, 696 cmꢁ1. MS (EI 70 eV): m/z
(E)-N,N-Diisopropyl-3-mesityl-3-phenylprop-2-en-1-amine
(E)-N,N-Diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenyl- (relat. int.): 335 (26), 334 (16), 292 (6), 235 (100), 220 (12), 205
prop-2-en-1-amine (6a). Yellow oil, yield: 93%. MS (IE 70 eV): m/z (10), 157 (21), 129 (13), 115 (41), 91 (27). 1H-NMR (300 MHz,
(relat. int.): 337 (11, M+), 237 (70), 221 (20), 178 (32), 165 (24), CDCl3) d ppm 0.97 (d, J ¼ 6.5 Hz, 12H), 2.17 (s, 6H), 2.28 (s, 3H),
1
126 (100), 115 (51), 91 (68). H-NMR (300 MHz, CDCl3) d ppm 3.05 (hep, J ¼ 6.5 Hz, 2H), 3.44 (d, J ¼ 6.3 Hz, 2H), 5.61 (t, J ¼ 6.3
0.90 (d, J ¼ 6.5 Hz, 12H), 2.20 (s, 3H), 3.00 (hep, J ¼ 6.5 Hz, 2H), Hz, 1H), 6.86 (s, 2H), 7.14–7.31 (m, 5H). 13C-NMR (75 MHz,
3.22 (d, J ¼ 6.4 Hz, 2H), 3.43 (s, 3H), 5.84 (t, J ¼ 6.4 Hz, 1H), 6.64 CDCl3) d ppm 20.6; 20.8; 21.0; 43.8; 48.5; 126.5; 127.7; 128.2;
(d, J ¼ 8.9 Hz, 1H), 6.94 (d, J ¼ 8.9 Hz, 1H), 6.95 (s, 1H), 7.05– 129.1; 134.1; 136.0; 136.2; 138.5; 139.3; 140.6. HRMS: m/z calcd
7.24 (m, 5H). 13C-NMR (75 MHz, CDCl3) d ppm 20.7; 20.9; 43.9; for C24H34N (M + H+): 336.2691; found: 336.2678.
49.3; 55.8; 115.5; 126.1; 127.1; 128.3; 128.7; 129.3; 131.1; 132.8;
(E)-N,N-Diisopropyl-3-(4-(methylsulfonil)phenyl)-3-phenyl-
138.4; 140.5; 154.6. HRMS: m/z calcd for C23H32NO (M + H+): prop-2-en-1-amine (12a). White solid, mp: 91 C yield: 71%. IR
ꢀ
338.2484; found: 338.2474.
(atr): n 3057, 2963, 1594, 1378, 1303, 1148, 952, 771, 702 cmꢁ1
.
(E)-N,N-Diisopropyl-3-(4-methoxyphenyl)-3-phenylprop-2-en- 1H-NMR (400 MHz, CDCl3) d 0.95 (d, J ¼ 6.6 Hz, 12H), 2.95–3.08
1-amine (7a). Yellow oil, yield: 94%. IR (atr): n 3056, 2970, 2919, (m, 5H, hep + s), 3.16 (d, J ¼ 6.4 Hz, 2H), 6.29 (t, J ¼ 6.4 Hz, 1H),
1491, 1379, 1022, 860, 768, 696 cmꢁ1.1H-NMR (300 MHz, CDCl3) 7.07–7.18 (m, 2H), 7.30–7.46 (m, 5H), 7.81 (d, J ¼ 8.6 Hz, 2H).
d ppm 0.87 (d, J ¼ 6.6 Hz, 12H), 2.97 (hep, J ¼ 6.6 Hz, 2H), 3.07 13C-NMR (100 MHz, CDCl3) d 20.6; 44.2; 44.4; 48.8; 127.0; 127.4;
(d, J ¼ 6.5 Hz, 2H), 3.67 (s, 3H), 6.01 (t, J ¼ 6.5 Hz, 1H), 6.70 (d, J 127.7; 128.2; 129.5; 135.5; 138.3; 138.5; 139.0; 147.7. HRMS: m/z
¼ 8.9 Hz, 2H), 7.03–7.11 (m, 4H), 7.19–7.30 (m, 3H). 13C-NMR calcd for C22H30NO2S (M + H+): 372.1997; found: 372.2007.
(75 MHz, CDCl3) d ppm 20.7; 44.2; 48.7; 55.1; 113.3; 126.9; 127.9;
128.2; 129.7; 135.0; 140.0; 140.4; 158.6. HRMS: m/z calcd for prop-2-en-1-amine (6b). Viscous brown oil, yield: 74%. IR (atr):
22H30NO (M + H+): 324.2327; found: 324.2338.
n 3057, 3025, 2836, 1661, 1592, 1452, 1311, 1144, 1092, 1023, 772,
N,N-Diisopropyl-3,3-diphenylprop-2-en-1-amine (8a). Yellow 701 cmꢁ1. 1H-NMR (400 MHz, CDCl3) d 2.23 (s, 3H), 3.07 (s, 3H),
(E)-N-Benzyl-N-methyl-3-(4-(methylsulfonil)phenyl)-3-phenyl-
C
oil, yield: 81%. IR (atr): n 3058, 2965, 2830, 1662, 1592, 1345, 3.16 (d, J ¼ 6.7 Hz, 2H), 3.49 (s, 2H), 6.39 (t, J ¼ 6.7 Hz, 1H), 7.11–
1125, 768, 699 cmꢁ1. MS (EI 70 eV): m/z (relat. int.): 293 (9), 278 7.18 (m, 2H), 7.26–7.44 (m, 10H), 7.84 (d, J ¼ 8.5 Hz, 2H).
(13), 250 (5), 193 (100), 178 (23), 165 (11), 126 (50), 115 (5), 91 13C-NMR (75 MHz, CDCl3) d 42.6; 44.5; 56.2; 62.0; 127.0; 127.2;
(23). 1H-NMR (300 MHz, CDCl3) d ppm 0.88 (d, J ¼ 6.6 Hz, 12H), 127.6; 128.0; 128.2; 128.4; 128.9; 129.6; 130.8; 138.4; 138.8; 142.0;
2.97 (hep, J ¼ 6.6 Hz, 2H), 3.09 (d, J ¼ 6.4 Hz, 2H), 6.10 (t, J ¼ 6.4 147.6. HRMS: m/z calcd for C24H26NO2S (M + H+): 392.5419;
Hz, 1H), 6.98–7.46 (m, 10H). 13C-NMR (75 MHz, CDCl3) d ppm found: 392.5422.
20.7; 44.2; 48.6; 126.8; 127.1; 127.9; 129.7; 129.9; 131.6; 131.8;
139.9; 140.7; 142.4. HRMS: m/z calcd for C21H28N (M + H+): wax, yield: 93%. IR (atr): n 3310, 3048, 2946, 2834, 1605, 1508,
294.2222; found: 294.2212.
1441, 1247, 1177, 1016, 816, 646 cmꢁ1. MS (IE 70 eV): m/z (int.
(E)-3-(4-Methoxyphenyl)-3-phenylprop-2-en-1-ol (6c). White
(E)-3-(4-(Triuoromethyl)phenyl)-N,N-diisopropyl-3-phenyl- relat): 240 (10), 222 (100), 207(79), 197 (40), 178 (65), 165 (22),
prop-2-en-1-amine (9a). Yellow oil, yield: 83%. IR (atr): n 3057, 152 (27), 111 (12), 89 (18), 51 (21). 1H-NMR (300 MHz, CDCl3) d
3027, 2969, 1668, 1616, 1325, 1167, 1125, 1067, 840, 701 cmꢁ1
.
ppm 1.57 (s, 1H), 3.80 (s, 3H), 4.19 (d, J ¼ 6.9 Hz, 2H), 6.17 (t, J ¼
MS (EI 70 eV): m/z (relat. int.): 361 (9), 346 (24), 318 (4), 261 (100), 6.9 Hz, 1H), 6.82 (d, J ¼ 8.9 Hz, 2H), 7.14–7.22 (m, 4H), 7.32–7.41
246 (8), 183 (29), 126 (30), 115 (27), 91 (13), 361 (9), 346 (24), 318 (m, 3H). 13C-NMR (75 MHz, CDCl3) d ppm 55.3; 60.8; 113.5;
1
(4), 261 (100), 246 (8), 183 (29), 126 (30), 115 (27), 91 (13). H- 125.6; 127.5; 128.2; 128.7; 129.7; 134.3; 139.2; 143.8; 159.2.
NMR (300 MHz, CDCl3) d ppm 0.95 (d, J ¼ 6.5 Hz, 12H), 3.03 HRMS: m/z calcd for C16H17O2 (M + H+): 241.1229; found:
(hep, J ¼ 6.5 Hz, 2H), 3.17 (d, J ¼ 6.3 Hz, 2H), 6.24 (t, J ¼ 6.3 Hz, 241.1237.
1H), 7.14 (d, J ¼ 8.0 Hz, 2H), 7.29–7.46 (m, 5H), 7.50 (d, J ¼ 8.0
(E)-3-(4-(Methylsulfonil)fenil)-3-fenilprop-2-en-1-ol
(7c).
Hz, 2H). 13C-NMR (75 MHz, CDCl3) d 20.7; 44.4; 48.9; 118.9; White crystals, mp: 89 ꢀC yield: 77%. IR (atr): n 3496, 3062, 3021,
122.4; 124.9; 124.9; 125.0; 125.1; 126.0; 127.4; 128.3; 128.9; 2981, 1591, 1292, 1140, 1036, 816, 774, 701 cmꢁ1. 1H-NMR (400
129.7; 139.0; 139.7; 145.9. HRMS: m/z calcd for C22H27F3N (M + MHz, CDCl3) d 1.63 (s, 1H, OH), 3.05 (s, 3H), 4.26 (d, J ¼ 6.6 Hz,
H+): 362.4583; found: 362.4593.
2H), 6.35 (t, J ¼ 6.6 Hz, 1H), 7.09–7.19 (m, 2H), 7.39 (t, J ¼ 6.2 Hz,
(E)-N,N-Diisopropyl-3-phenyl-3-m-toluylprop-2-en-1-amine 3H), 7.43 (d, J ¼ 8.4 Hz, 2H), 7.84 (d, J ¼ 8.4 Hz, 2H). 13C-NMR
(10a). Yellow oil, yield: 92%. IR (atr): n 3021, 2966, 2924, 1665, (100 MHz, CDCl3) d 44.5; 60.5; 127.3; 128.1; 128.4; 128.6; 129.6;
1599, 1318, 1175, 785, 701 cmꢁ1. MS (EI 70 eV): m/z (relat. 130.8; 137.8; 139.1; 142.3; 147.3. HRMS: m/z calcd for C16H17O3S
int.): 307 (12), 306 (5), 292 (10), 264 (6), 207 (100), 196 (14), 165 (M + H+): 289.3751; found: 289.3752.
(8), 129 (37), 126 (64), 115 (53), 91 (14). 1H-NMR (300 MHz,
1-(4-((E)-3-Hydroxy-1-phenylprop-1-enyl)phenyl)ethanone (8c).
CDCl3) d ppm 0.88 (d, J ¼ 6.6 Hz, 12H), 2.23 (s, 3H), 2.97 (hep, White solid, yield: 86%. 1H-NMR (400 MHz, CDCl3) d 1.56 (s, 1H,
J ¼ 6.6 Hz, 2H), 3.07 (d, J ¼ 6.4 Hz, 2H), 6.07 (t, J ¼ 6.4 Hz, 1H), OH), 2.59 (s, 3H), 4.25 (d, J ¼ 6.7 Hz, 2H), 6.35 (t, J ¼ 6.7 Hz, 1H),
6.91–7.12 (m, 5H), 7.17–7.34 (m, 4H). 13C-NMR (75 MHz, 7.11–7.18 (m, 2H), 7.34 (d, J ¼ 8.5 Hz, 2H), 7.36–7.44 (m, 3H), 7.88
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(d, J ¼ 8.5 Hz, 2H). 13C-NMR (100 MHz, CDCl3) d 26.6; 60.6; 127.7; 127.0; 128.1; 128.2; 128.6; 128.8; 129.0; 130.3; 131.3; 133.5; 138.6;
127.9; 128.3; 128.4; 129.6; 129.7; 136.0; 138.3; 143.1; 146.3; 197.7. 152.1; 161.2; 196.6. HRMS: m/z calcd for C25H26NO2 (M + H+):
HRMS: m/z calcd for C17H17O2 (M + H+): 253.1229; found: 372.1964; found: 372.1954.
253.1232.
1-(4-((E)-3-Hydroxy-1-phenylprop-1-enyloxy)phenyl)ethanone
3,3-Diphenylprop-2-en-1-ol.35 (9c) Pale yellow solid, mp: (10c). Brown oil, yield: 51%. IR (atr): n 3345, 3057, 3027, 1681,
59 ꢀC, yield: 82% IR (atr): n 3316, 3052, 3023, 2918, 1598, 1441, 1601, 1359, 1267, 1023, 957, 702, cmꢁ1
.
1H-NMR (400 MHz,
1017, 759, 699 cmꢁ1. H-NMR (400 MHz, CDCl3) d 1.53 (s, 1H, CDCl3) d ppm 2.50 (s, 3H), 4.33 (d, J ¼ 7.6 Hz, 2H), 5.65 (t, J ¼ 7.6
OH), 4.14 (d, J ¼ 6.8 Hz, 2H), 6.17 (t, J ¼ 6.8 Hz, 2H), 7.09 (dd, J ¼ Hz, 1H), 7.01 (d, J ¼ 8.9 Hz, 2H), 7.29–7.39 (m, 3H), 7.42–7.48
7.8, 1.6 Hz, 2H), 7.13–7.33 (m, 8H). 13C-NMR (100 MHz, CDCl3) d (m, 2H), 7.85 (d, J ¼ 8.9 Hz, 2H). 13C-NMR (100 MHz, CDCl3) d
60.7; 127.4; 127.5; 127.6; 128.1; 128.2; 129.7; 139.0; 141.7; 144.2. ppm 26.4; 58.8; 114.7; 117.6; 128.4; 128.6; 129.3; 130.4; 131.7;
133.0; 153.8; 160.7; 196.9. HRMS: m/z calcd for C17H17O3 (M +
1
H+): 269.1178; found: 269.1155.
Copper-catalyzed Ullmann-type vinylation of phenols with 5b
and 5c
(E)-3-(4-Methoxyphenoxy)-3-phenylprop-2-en-1-ol
(11c).
White solid, yield: 74% mp: 54 ꢀC IR (atr): n 3380, 3054, 2933,
An oven-dried resealable Schlenk ask charged with 5b or 5c 1650, 1504, 1260, 1096, 982, 832, 780, 704 cmꢁ1. 1H-NMR (400
(2.0 mmol), phenol (3.0 mmol), 1,10-phenanthroline (36 mg, 0.2 MHz, CDCl3) d 3.79 (s, 3H), 4.21 (d, J ¼ 7.8 Hz, 2H), 5.19 (t, J ¼
mmol), CuI (38 mg, 0.2 mmol) and K3PO4$H2O (4.0 mmol, 920 7.8 Hz, 1H) 6.85 (d, J ¼ 9.0 Hz, 2H), 7.01 (d, J ¼ 9.0 Hz, 2H),
mg), was evacuated and back-lled with argon. Then, dioxane 7.36–7.45 (m, 3H), 7.51–7.57 (m, 2H). 13C-NMR (100 MHz,
(8 mL) was added and the reaction mixture was stirred at 100 ꢀC CDCl3) d 55.6; 59.3; 107.5; 114.7; 121.1; 128.2; 128.7; 129.06;
for 16 h. Next, the reaction mixture was cooled, ltered and 134.1; 149.1; 155.8; 158.1. HRMS: m/z calcd for C17H17O3
analysed by GC and GC-MS. Aer, the solution was taken up in (M + H+): 257.1178; found: 257.1182.
CH2Cl2 (30 mL) and the organic layer was washed with aq. 1.0 M
NaOH (to remove the phenol excess) and brine (2 ꢂ 5 mL), and
then dried over MgSO4. Finally, the solvent was evaporated and
Notes and references
the product puried by column chromatography (silica gel in
hexane/ethylacetate) and analysed by 1H-NMR and 13C-NMR.
The E-conguration of the products was assigned by 2D-NOESY
of selected compounds.
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(relat. int.): 359 (7), 358 (17), 268 (11), 251 (26), 239 (15), 161 (33),
146 (49), 134 (22), 105 (56), 91 (100). 1H-NMR (300 MHz, CDCl3)
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3H), 5.18 (t, J ¼ 7.3 Hz, 1H), 6.74 (d, J ¼ 9.0 Hz, 2H), 6.89 (d, J ¼
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126.9; 128.0; 128.1; 128.5; 128.8; 129.1; 134.5; 138.6; 149.8;
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128.6; 128.7; 129.1; 129.5; 131.2; 134.7; 153.9; 155.2. HRMS: m/z
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