Tf 2 NH-Catalyzed 1,6-Conjugate Addition of Vinyl Azides with p -Quinone Methides: A Mild and Efficient Method for the Synthesis of β-Bis-Arylamides

Article abstract of DOI:10.1055/s-0036-1588546

Tf ₂ NH-catalyzed tandem 1,6-conjugate addition/Schmidt type rearrangement using vinyl azides and p -quinone methides to access a variety of β-bis-arylated amides is reported. The method is quick, efficient, mild, and high yielding with broad substrate scope.

Full text of DOI:10.1055/s-0036-1588546

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
paper
A
en
J. Rathod et al.
Paper
Synthesis
Tf2NH-Catalyzed 1,6-Conjugate Addition of Vinyl Azides with
p-Quinone Methides: A Mild and Efficient Method for the Synthesis
of β-Bis-Arylamides
Jayant Rathoda,b
Brijesh M. Sharmaa,b
Pramod S. Malic
OH
O
R1
R1
O
R1
R1
N2
Tf2NH
DCE
N
Pradeep Kumar*a,b
R3
R3
r.t., 5 min
N
a Division of Organic Chemistry, CSIR-National Chemical
Laboratory, Dr. Homi Bhabha Road, Pune-411008, India
pk.tripathi@ncl.res.in
H
R2
R2
R
R
1 = t-Bu, Me
2 = H, 4-Me, 4-t-Bu, 4-OMe, 4-Cl, 4-NO2
4-COMe, 2-Br, 2-OMe, 3,4-(OMe)2
R3 = substituted aryl, alkyl
b Academy of Scientific and Innovative Research (AcSIR),
New Delhi-110025, India
up to 97% yield
21 examples
c Central NMR Facility, National Chemical Laboratory,
Pune-411008, India
Received: 19.07.2017
Accepted after revision: 19.07.2017
Published online: 22.08.2017
NH2
OH
HO
O
O
DOI: 10.1055/s-0036-1588546; Art ID: ss-2017-n0227-op
OH
O
O
S
O
Abstract Tf2NH-catalyzed tandem 1,6-conjugate addition/Schmidt
type rearrangement using vinyl azides and p-quinone methides to ac-
cess a variety of β-bis-arylated amides is reported. The method is quick,
efficient, mild, and high yielding with broad substrate scope.
HO
N
N
H
O
HO
O
NH
NH
O
H
O
Key words vinyl azide, p-quinone methide, Brønsted acid, 1,6-conju-
gate addition, rearrangement, β-bis-arylamides
HO
Flavifloramide A
OH
Darunavir
O
O
H
HO
O
The β-bis-arylamides framework is a privileged struc-
ture embedded in various pharmaceutically active drugs
and natural products (Figure 1). The bio-significance of β-
bis-aryl amides propelled extensive endeavor towards their
synthesis and development of novel and scalable protocols.
Various synthetic approaches for β-bis-aryl amides have
been documented in the literature,1 however, the majority
of them suffer either from the use of transition metal and
expensive metal catalyst, long reaction times, harsh reac-
tion conditions, and tedious workup. Therefore, develop-
ment of mild and metal-free catalytic conditions for this re-
action is highly desirable.
OH
O
O
HO
HO
N
H
O
N
O
NH
O
O
HO
Cannabisin B
Lennoxamine
Figure 1 Privileged pharmaceutically active and naturally occurring
amides
In recent years, the p-quinone methide derivatives
gained attraction among synthetic organic chemistry, due
to its unique reactivity2 and its ability for 1,6-conjugate ad-
dition with a variety of nucleophiles.3 p-Quinone methide
motif serves as an important reactive intermediate in vari-
ous natural product syntheses4 and biosynthetic transfor-
mations.5 Recently, p-quinone methides (p-QMs) were ex-
tensively studied for addition reaction, using the Lewis acid,
organocatalytic, and transition-metal-catalyzed transfor-
mations.6 Anand and co-workers have thoroughly investi-
gated the chemistry of p-quinone methides for 1,6-conju-
gate addition with a variety of nucleophiles7 using Lewis
acid,
N-heterocyclic
carbene,
bis(amino)cyclopro-
penylidene, and transition metal as a catalyst. Fan, Tortosa,
and their co-workers including many other groups have
studied the asymmetric Michael addition of p-quinone
methides with malonates, enamines, borane thioester, and
glycine Schiff base.8,9 Lin and co-workers independently
studied the reaction of p-quinone methide10 catalyzed by
the Lewis acid for the construction of unsymmetrical tri-
arylmethanes.10a Bifunctional Pd complex and thiourea-cat-
alyzed [3 + 2] annulation of p-QMs and vinylcyclopropanes
is reported to give spirocycles with excellent diastereoselec-
tivity.10b Construction of spirocycles via tandem 1,6-addi-
tion/cyclization with vinyl p-QMs was reported by Fan and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
J. Rathod et al.
Paper
Synthesis
co-workers and also by Yao et al. using sulfonium salts,11a
and α-halo diester,11b respectively. Recently Roiser and co-
workers have reported the enantioselective spirocyclopro-
panation of p-QMs using ammonium ylides.11c
To investigate our hypothesis of the addition reaction of
vinyl azide to the p-quinone methide, simple p-quinone
methide 1a and phenyl vinyl azide (2a) were chosen as
model substrates. First the optimization of reaction condi-
tions were conducted following the literature report by Chi-
ba et al.14a for the 1,6-conjugate addition of vinyl azide and
imines using BF3·OEt2 and water as an additive in dichloro-
methane. However, the desired product 3a was obtained in
moderate yield (65%) only (Table 1, entry 1) along with oth-
er several by-products such as acetophenone and acetani-
lide. The other limitation of this method was the slow addi-
tion (5 h) of vinyl azide solution at –40 °C. In order to opti-
mize the reaction conditions, the reaction was performed
at a higher temperature like –30 °C, but the yield dropped
to 56% (entry 2) with an increase in the formation of by-
product. When the reaction was performed at 0 °C, the
yield dropped to 30%, and acetophenone was obtained as a
major by-product due to the self-hydrolysis of vinyl azide
(entry 3). When the reaction was carried out at room tem-
perature, only trace amount of the desired product was
formed along with acetophenone as the major product (en-
try 4). From these observations, we reasoned that due to
the presence of excess acid in the reaction medium, the si-
multaneous hydrolysis reaction of phenyl vinyl azide is the
main competing reaction with the addition reaction at the
higher temperature. To overcome these limitations, the re-
action was further performed by changing the addition se-
quence of vinyl azide and BF3·OEt2. Accordingly, p-quinone
methide, vinyl azide, and water were taken in dichloro-
methane followed by slow addition of BF3·OEt2 dropwise.
The results obtained were as per our expectation, affording
the desired product in 72% yield within 1 hour, with ace-
tophenone as the side product (entry 5). With these results
in hand, we further proceeded with improvement in the
yield and switched over to bis (trifluoromethanesulfo-
nyl)imide (triflimide, Tf2NH) as the Brønsted acid. Gratify-
ingly, when the reaction was performed at 0 °C in dichlo-
roethane (DCE), the reaction was complete within 30 min-
utes, and the desired product 3a was obtained in excellent
yield (82%) (entry 6). When the reaction was carried out at
room temperature, it was complete within 5 minutes as
confirmed by TLC. As per literature precedence,15 we again
examined the use of a catalytic amount of Tf2NH. It was
found that 10 mol% Tf2NH was sufficient enough to bring
out the above transformation within 5 minutes at room
temperature to afford the desired product in excellent yield
(89%) (entry 7). We further optimized the amount of vinyl
azide 2a used in the reaction as the excess amount of 2a
was always converted into acetophenone as a by-product.
To reduce the formation of by-product, the reaction was
performed with a slight excess (1.2 equiv) of vinyl azide 2a
affording the desired product in 92% yield with only minor
amount of side product (entry 9). When the temperature
was increased to 40 °C, the yield was diminished to 66%
(entry 10). The reason for the low yield may be attributed to
Vinyl azide has attracted a great deal of interest among
synthetic chemists due to its chemical properties as a pre-
cursor for the construction of new C–C bond and various ni-
trogen containing heterocycles in the presence of Lew-
is/Brønsted acid activators.12 The unique chemical reactivi-
ty of vinyl azide as an enamine type nucleophile,13 is known
to give amide via Schmidt type rearrangement.14 These re-
ports reveal that vinyl azide could serve as a good nucleo-
philic precursor for the amide under the mild reaction con-
ditions. This inspired us to explore the reactivity of vinyl
azide for conjugate addition reaction. We hypothesized that
p-quinone methide could be a good counter-motif for the
enamine type attack of vinyl azide resulting in the interest-
ing β-bis-arylamide framework.
Table 1 Optimization of Reaction Conditionsa
OH
O
t-Bu
t-Bu
O
t-Bu
t-Bu
acid
N3
O
solvent
temp
Ph
Ph
Ph
N
Ph
H
1a
2a
3a
4
Entry
Acid
Solvent
Time
Temp (°C) Yield (%)b
3a
4
1
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
Tf2NH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
5 h
5 h
–40
–30
0
65
18
25
63
78
32
43
46
39
5
2
56
30
trace
72
82
89
85
92
66
49
3
5 h
4c
5d
2 h
r.t.
r.t.
0
1 h
6d,e
7d,e
30 min
5 min
5 min
5 min
5 min
1 h
Tf2NH
DCE
r.t.
r.t.
r.t.
40
r.t.
8d,f
Tf2NH
DCE
9d,f,g
10d,f,g
11h
Tf2NH
DCE
Tf2NH
DCE
34
38
BF3·OEt2
DCE
a Unless otherwise stated, the reaction was performed with p-quinone
methide 1a (0.034 mmol, 10 mg), H2O (2 equiv), BF3·OEt2 (2 equiv), and
solvent (1 mL) by slow addition of a solution of vinyl azide 2a (2 equiv) in
solvent (2 mL).
b Isolated yields.
c Vinyl azide 2a was directly added at once.
d Addition sequence of reagent was changed, in place of vinyl azide 2a, the
acid was added dropwise and the reaction was carried out without any ad-
ditive (H2O).
e Reaction was performed with 2 equiv of Tf2NH.
f Tf2NH used: 10 mol%.
g Phenyl vinyl azide used: 1.2 equiv.
h BF3·OEt2 (10 mol%), H2O ( 2 equiv), and phenyl vinyl azide (1.2 equiv)
were used.
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C
J. Rathod et al.
Paper
Synthesis
the increase in the reaction temperature. This could result
into the acceleration of self decomposition of vinyl azide 2a
to acetophenone thus reducing its availability for nucleop-
hilic attack on p-quinone methide. In yet another reaction
with catalytic amount of BF3·OEt2 (10 mol %), the yield of
the desired product 3a was diminished to 49% with consid-
erable amount of by-product (entry 11). While preparing
this manuscript, a similar report of this reaction catalyzed
by BF3·OEt2as Lewis acid appeared in literature,16 which ex-
actly matches with our observation as made in the optimi-
zation reaction (see entry 5).
Having optimized the reaction condition, the substrate
scope was examined next by varying the substitution R2 on
p-quinone methide 1 and R3 in vinyl azide 2 (Scheme 1).
First, p-quinone methides were screened with the different
R2 substitutions. For example, various 4-substituted p-qui-
none methide reacted smoothly with phenyl vinyl azide
(2a) irrespective of the nature of substituents (electron-do-
nating or -withdrawing) to give the respective amides in ex-
cellent yields. Similarly, the reaction was compatible even
with variously substituted alkanes (Me, t-Bu), methoxy as
electron-donating and chloro, bromo, nitro, ester as elec-
tron-withdrawing groups (3a–j). Under optimized condi-
tions, the ortho, meta, and polysubstituted p-quinone
methide also gave an excellent yield of products (3e, 3f, and 3h).
Moreover, the p-quinone methide with the fused aro-
matic and heterocyclic moieties like 1- and 2-naphthyl,
thiophene, benzodioxole (Scheme 1, 3k–n) were also quite
amenable under the optimized conditions (yields 71–95%).
Besides, variously substituted phenyl vinyl azides were also
screened to examine the generality of this developed proto-
col. As shown in Scheme 1, 4-methyl-, 2-methoxy-, and 3,4-
difluoro-substituted phenyl vinyl azides reacted smoothly
to deliver the desired products in excellent yields (3o–q). To
establish the generality of the method, the reaction was
further investigated with alkyl vinyl azide, which worked
smoothly to give the products in good yields (3r, s). Inter-
estingly the reaction of dimethyl-substituted p-QM with al-
kyl/phenyl vinyl azide gave the desired products in moder-
ate to good yields (3t–u). The role of bulky substituents at 2
and 6-position of phenol such as tert-butyl group is crucial
for the stability of p-QMs. As per the literature evidences,
phenyl and methyl substituents also work well in stabiliz-
ing p-QMs. However, at our hand p-QM with these substit-
uents were found to be less stable on column chromatogra-
py.
To investigate the synthetic utility of this method, de-
tert-butylation of β-bis-arylamides was carried out
(Scheme 2). Towards this, β-bis-arylamide 3a was treated
with anhydrous AlCl3 in toluene, which smoothly delivered
the de-tert-butylated compound 4a in excellent yield (for
the detailed optimized reaction conditions, see the Sup-
porting Information). The compound 4a represents a privi-
leged pharmaceutically active and naturally occurring
structural motif.
OH
O
R1
R1
O
R1
R1
N3
Tf2NH
R3
DCE, r.t.
5 min
R3
R2
N
R2
H
1
2
3
R1 = t-Bu, Me
R2, R3 = aryl, alkyl
OH
OH
OH
t-Bu
t-Bu
OH
OH
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
O
O
O
O
O
N
N
H
5
OH
H
N
H
N
N
t-Bu
t-Bu
H
3r, 75%
3t, 61%
H
O
O
R
3a–j
3k, 81%
3m, 95%
O
OH
3a, 92% R = H
3b, 86% R = 4 -Me
N
R
H
3c, 82% R = 4 t-Bul
3d, 92% R = 4-OMe
3e, 88% R = 2-OMe
3f, 87% R = 3,4-(OMe)2
3g, 93% R = 4-Cl
OH
OH
O
OH
3o–q
3o, 93 % R = 4-Me
3p, 95 % R = 2-OMe
3q, 85 % R = 3,4-F2
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
N
5
H
O
O
O
3u, 83%
3h, 97% R = 2-Br
N
H
N
3i, 83% R = 4-NO2
3j, 87% R = 4-CO2Me
N
5
H
H
S
3l, 94%
3n, 71%
3s, 79%
Scheme 1 Synthesis of amide from p-quinone methide and vinyl azide. Reagents and conditions: 1 (0.030–0.055 mmol), 2 (1.2 equiv), Tf2NH (10 mol%),
DCE (2 mL), r.t., 5 min. Yields refer to isolated pure products.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

D
J. Rathod et al.
Paper
Synthesis
Phenylacetylene, Ag2CO3, DMSO, CH2Cl2, dichloroethane (DCE), petro-
leum ether (PE), EtOAc, BF3·OEt2, and Tf2NH were used as received
from commercial suppliers. All p-quinone methides and aryl vinyl
azides were prepared according to literature reports (see SI).
OH
OH
t-Bu
t-Bu
anhyd AlCl3
toluene, r.t.
O
O
N
N
β-Bis-Arylamides; General Procedure
H
H
The p-quinone methide 1 (15 mg, 0.030–0.055 mmol), aryl vinyl
azide 2 (1.2 equiv) in DCE (1 mL) were taken into an oven dried 5 mL
reaction vial equipped with a magnetic bar. Then, triflimide (Tf2NH,
10 mol%) dissolved in DCE (0.5 mL) was added dropwise, and the re-
action mixture was stirred at r.t. for 5 min. The completion of the re-
action was confirmed by TLC using 9:1 PE/EtOAc solvent system. The
starting material p-quinone methide was completely consumed with-
in 5 min. After the completion of the reaction, the reaction mass was
concentrated under high vacuum, and the crude product was purified
by column chromatography on silica gel 100–200 mesh to obtain the
desired product.
3a
4a 88%
Scheme 2 De-tert-butylation of β-bis-arylamides
The plausible reaction mechanism is illustrated in
Scheme 3. The p-QM is activated by H+ ion (available from
Brønsted acid Tf2NH) followed by attack of vinyl azide 2, re-
sulting in the intermediate A, which undergoes Schmidt re-
arrangement to furnish the nitrilium ion intermediate B.
Subsequent hydrolysis would afford the desired product 3.
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-N,3-diphenylpropanamide
(3a)16
OH
H
O
Yield: 13.5 mg (92%); white solid; mp 194–196 °C (Lit.16 mp 193–194
R
R
R
R
Tf2NH
°C); Rf = 0.32 (1:9 EtOAc/PE).
O
IR (CHCl3): 3635, 3283, 3196, 3071, 2958, 2921, 1653, 1599, 1547
R1
1492, 1438, 1369, 1315, 1242, 1160, 762, 697 cm–1
.
Ph
N
1a
Ph
H
3
1H NMR (500 MHz, CDCl3): δ = 7.32 (app d, J = 4.6 Hz, 4 H), 7.23 (m, 5
H), 7.08 (s, 2 H), 7.07–7.02 (m, 1 H), 6.81 (s, 1 H), 5.12 (s, 1 H), 4.51 (t,
J = 7.6 Hz, 1 H), 3.06 (d, J = 7.6 Hz, 2 H), 1.39 (s, 18 H).
R1
N
hydrolysis
R1
OH
OH
N
R
R
N
R
R
2
N
N
N
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-N-phenyl-3-(p-tolyl)pro-
panamide (3b)16
N
Ph
R1
Ph
Yield: 18.5 mg (86%); white solid; mp 208–210 °C (Lit.16 mp 211–213
B
A
N2
°C); Rf = 0.30 (1:9 EtOAc/PE).
IR (CHCl3): 3635, 3298, 2958, 1658, 1598, 1544, 1501, 1437, 1366,
Scheme 3 Plausible mechanism for the formation of β-bis-arylamides
1315, 1236, 1156, 1119, 1034, 758, 695 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.26–7.22 (m, 4 H), 7.21 (d, J = 8.0 Hz, 2
H), 7.13 (d, J = 7.6 Hz, 2 H), 7.08 (s, 2 H), 7.07–7.03 (m, 1 H), 6.79 (s, 1
H), 5.11 (s, 1 H), 4.46 (t, J = 7.6 Hz, 1 H), 3.04 (d, J = 7.6 Hz, 2 H), 2.32 (s,
3 H), 1.39 (s, 18 H).
In summary, we have developed a method for the syn-
thesis of β-bis-arylamides using Tf2NH catalyzed 1,6-conju-
gate addition of phenyl vinyl azide with p-quinone methide.
The optimized method is catalytic, highly efficient concern-
ing yields, reaction time, and the broad applicability of sub-
strate. Further studies to explore the Michael acceptor
property of p-quinone methide with other substrate are
underway in our laboratory.
3-[4-(tert-Butyl)phenyl]-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-
phenylpropanamide (3c)
Yield: 18.6 mg (82%); colorless thick liquid; Rf = 0.33 (1:9 EtOAc/PE).
IR (CHCl3): 3636, 3299, 2957, 2926, 1658, 1597, 1550, 1437, 1368,
1316, 1241, 1119, 1035, 759, 620 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.34 (app d, J = 7.9 Hz, 2 H), 7.27–7.20
(m, 4 H), 7.20–7.15 (m, 2 H), 7.11 (s, 2 H), 7.04 (t, J = 6.7 Hz, 1 H), 6.72
(s, 1 H), 5.12 (s, 1 H), 4.45 (t, J = 7.6 Hz, 1 H), 3.05 (d, J = 7.9 Hz, 2 H),
1.40 (s, 18 H), 1.30 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 169.9, 152.5, 149.3, 140.8, 137.6,
136.1, 134.0, 128.8, 127.2, 125.6, 124.2, 124.1, 119.7, 47.5, 45.5, 34.4,
31.3, 30.3.
TLC was carried out on silica gel 60 F245, precoated aluminum sheets,
and visualized by UV lamp (254 nm) and staining with the anisalde-
hyde solution. Synthesized compounds were purified by column
chromatography on silica gel (100–200 mesh). The chemicals, which
are bought commercially, were used directly for the reaction without
any purification. Melting points were measured with Buchi Melting
point B-540. 1H and 13C spectra were recorded on a Bruker AV-400
and Bruker AV-500 spectrometers. Chemical shifts are reported in
ppm, 1H NMR spectra were referenced to CDCl3 (7.27 ppm) and 13C
NMR spectra were referenced to CDCl3 (77.0 ppm). IR spectra were re-
corded on a Bruker ALPHA FTIR spectrometer. HRMS data were ob-
tained via ORBITRAP mass analyzer. Chemical nomenclature was gen-
erated using Chem Bio Draw Ultra 14.0.
HRMS (FTMS + p ESI): m/z [M + H]+ calcd for C33H44NO2: 486.3367;
found: 486.3367.
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(4-methoxyphenyl)-N-
phenylpropanamide (3d)16
Yield: 19.5 mg (92%); white solid; mp 190–192 °C (Lit.16 mp 191–192
°C); Rf = 0.46 (1:4 EtOAc/PE).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

E
J. Rathod et al.
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Synthesis
IR (CHCl3): 3791, 3301, 2956, 2925, 1658, 1600, 1547, 1511, 1483,
1312, 1248, 1178, 1155, 1120, 1035, 756 cm–1
1H NMR (500 MHz, CDCl3): δ = 7.26–7.18 (m, 6 H), 7.07 (s, 2 H), 7.06–
7.03 (m, 1 H), 6.86 (d, J = 8.4 Hz, 2 H), 6.83–6.78 (m, 1 H), 5.11 (s, 1 H),
4.46 (t, J = 7.6 Hz, 1 H), 3.79 (s, 3 H), 3.02 (d, J = 7.6 Hz, 2 H), 1.39 (s, 18
H).
13C NMR (100 MHz, CDCl3): δ = 169.1, 152.6, 142.9, 137.6, 136.1,
133.4, 132.2, 128.9, 128.1, 128.0, 127.7, 124.9, 124.5, 124.2, 119.7,
46.0, 44.2, 34.4, 30.3.
HRMS (FTMS + p ESI): m/z [M + H]+ calcd for C29H35BrNO2: 508.1846;
found: 508.1847.
.
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-N-phen-
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(2-methoxyphenyl)-N-
ylpropanamide (3i)16
phenylpropanamide (3e)
Yield: 17.5 mg (83%); white solid; mp 216–218 °C (mp was not in ac-
Yield: 18.7 mg (88%); colorless thick liquid; Rf = 0.43 (1:4 EtOAc/PE).
cordance with Lit.16 mp 108–110 °C); Rf = 0.2 (1:9 EtOAc/PE).
IR (CHCl3): 3630, 3313, 2957, 2926, 1658, 1596, 1490, 1436, 1316,
IR (CHCl3): 3629, 3252, 3197, 3138, 2959, 2867, 1654, 1599, 1547,
1242, 1118, 1035, 756 cm–1
.
1523, 1438, 1348, 1238, 1154, 1115, 759 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.26–7.18 (m, 5 H), 7.26–7.18 (m, 1 H),
7.16 (s, 2 H), 7.08–7.01 (m, 1 H), 6.99 (s, 1 H), 6.94 (t, J = 7.9 Hz, 1 H),
6.88 (d, J = 7.9 Hz, 1 H), 5.10 (s, 1 H), 4.86 (t, J = 7.6 Hz, 1 H), 3.84 (s, 3
H), 3.16–3.03 (m, 2 H), 1.40 (s, 18 H).
1H NMR (500 MHz, CDCl3): δ = 8.13 (d, J = 8.4 Hz, 2 H), 7.44 (d, J = 8.0
Hz, 2 H), 7.29 (br s, 1 H), 7.27–7.17 (m, 3 H), 7.05 (t, J = 7.1 Hz, 1 H),
6.99 (s, 2 H), 6.94 (s, 1 H), 5.14 (s, 1 H), 4.66 (t, J = 7.4 Hz, 1 H), 3.04 (d,
J = 7.2 Hz, 2 H), 1.35 (s, 18 H).
13C NMR (100 MHz, CDCl3): δ = 170.1, 156.7, 152.4, 135.9, 133.4,
132.2, 128.8, 128.0, 127.6, 124.5, 124.0, 120.8, 119.6, 110.9, 55.5, 44.0,
41.1, 34.4, 30.3.
HRMS (FTMS + p ESI): m/z [M + H]+ calcd for C30H38NO3: 460.2846;
found: 460.2837.
Methyl 4-[1-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-oxo-3-(phe-
nylamino)propyl]benzoate (3j)16
Yield: 18 mg (87%); white solid; mp 200–202 °C (Lit.16 mp 197–198
°C); Rf = 0.20 (1:9 EtOAc/PE).
IR (CHCl3): 3632, 3313, 2956, 2867, 1717, 1661, 1601, 1545, 1437,
1283, 1114, 1027, 759 cm–1
.
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(3,4-dimethoxyphenyl)-
N-phenylpropanamide (3f)16
1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 7.9 Hz, 2 H), 7.39 (d, J = 7.9
Hz, 2 H), 7.30–7.20 (m, 6 H), 7.12–7.05 (m, 1 H), 7.04 (s, 2 H), 6.90 (s, 1
H), 5.14 (s, 1 H), 4.61 (t, J = 7.3 Hz, 1 H), 3.90 (s, 3 H), 3.06 (d, J = 7.9 Hz,
2 H), 1.38 (s, 18 H).
Yield: 18 mg (87%); colorless thick liquid; Rf = 0.6 (1:1 EtOAc/PE).
IR (CHCl3): 3635, 3349, 2958, 2924, 2861, 1656, 1596, 1511, 1437,
1315, 1256, 1125, 1031, 768 cm–1
.
1H NMR (500MHz, CDCl3): δ = 7.25 (app d, J = 4.2 Hz, 4 H), 7.09 (s, 2
H), 7.07–7.02 (m, 1 H), 6.88–6.77 (m, 4 H), 5.12 (s, 1 H), 4.46 (t, J = 7.4
Hz, 1 H), 3.86 (s, 3 H), 3.83 (s, 3 H), 3.02 (d, J = 7.6 Hz, 2 H), 1.40 (s, 18
H).
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(naphthalen-2-yl)-N-
phenylpropanamide (3k)16
Yield: 16.5 mg (81%); white solid; mp 228–230 °C (Lit.16 mp 230–231
°C); Rf = 0.3 (1:9 EtOAc/PE).
IR (CHCl3): 3630, 3357, 3020, 2925, 2400, 1656, 1597, 1420, 1215,
3-(4-Chlorophenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-
phenylpropanamide (3g)
1122, 1040, 758, 669 cm–1
.
Yield: 17 mg (93%); white solid; mp 216–218 °C; Rf = 0.2 (1:9 EtO-
Ac/PE).
1H NMR (500 MHz, CDCl3): δ = 7.84–7.73 (m, 4 H), 7.51–7.40 (m, 3 H),
7.21 (app s, 4 H), 7.13 (s, 2 H), 7.08–7.00 (m, 1 H), 6.83 (s, 1 H), 5.13 (s,
1 H), 4.69 (t, J = 7.6 Hz, 1 H), 3.21–3.09 (m, 2 H), 1.39 (s, 18 H).
IR (CHCl3): 3633, 3280, 2958, 2925, 1649, 1596, 1489, 1436, 1318,
1219, 1119, 1040, 766 cm–1
.
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(naphthalen-1-yl)-N-
phenylpropanamide (3l)
1H NMR (500 MHz, CDCl3): δ = 7.31–7.21 (m, 8 H), 7.10–7.05 (m, 1 H),
7.03 (s, 2 H), 6.85 (s, 1 H), 5.14 (s, 1 H), 4.52 (t, J = 7.6 Hz, 1 H), 3.06–
2.96 (m, 2 H), 1.39 (s, 18 H).
Yield: 19.5 mg (94%); thick colorless liquid; Rf = 0.3 (1:9 EtOAc/PE).
13C NMR (125 MHz, CDCl3): δ = 169.3, 152.6, 142.5, 137.5, 136.2,
133.5, 132.2, 129.0, 128.9, 128.7, 124.3, 124.1, 119.8, 46.9, 45.0, 34.4,
30.2.
HRMS (FTMS + p ESI): m/z [M + H]+ calcd for C29H35ClNO2: 464.2351;
found: 464.2351.
IR (CHCl3): 3630, 3350, 2924, 2858, 1653, 1596, 1435, 1317, 1224,
1121, 1041, 771 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.25 (d, J = 8.4 Hz, 1 H), 7.86 (d, J = 7.6
Hz, 1 H), 7.76 (d, J = 7.6 Hz, 1 H), 7.51–7.43 (m, 4 H), 7.23 (app d, J =
4.2 Hz, 3 H), 7.15 (s, 2 H), 7.09–7.01 (m, 1 H), 6.84 (s, 1 H), 5.41–5.30
(m, 1 H), 5.09 (s, 1 H), 3.26–3.08 (m, 2 H), 1.35 (s, 18 H).
13C NMR (125 MHz, CDCl3): δ = 169.9, 152.4, 139.7, 137.6, 136.1,
134.1, 133.5, 131.5, 128.8, 128.8, 127.3, 126.2, 125.5, 125.3, 124.4,
124.1, 123.9, 123.9, 119.7, 45.5, 43.0, 34.3, 30.2.
3-(2-Bromophenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-
phenylpropanamide (3h)
Yield: 20 mg (97%); white solid; mp 226–228 °C; Rf = 0.26 (1:9
EtOAc/PE).
HRMS (FTMS + p ESI): m/z [M + H]+ calcd for C33H38NO2: 480.2897;
found: 480.2899.
IR (CHCl3): 3630, 3381, 3022, 2926, 2402, 1656, 1594, 1421, 1318
1216, 1121, 1037, 764 cm–1
.
3-(Benzo[d][1,3]dioxol-4-yl)-3-(3,5-di-tert-butyl-4-hydroxyphe-
nyl)-N-phenylpropanamide (3m)
1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 7.9 Hz, 1 H), 7.38–7.21 (m, 6
H), 7.15 (s, 2 H), 7.09–7.04 (m, 2 H), 6.95 (s, 1 H), 5.13 (s, 1 H), 5.00 (t,
J = 7.6 Hz, 1 H), 3.09 (d, J = 7.9 Hz, 2 H), 1.39 (s, 18 H).
Yield: 19.5 mg (95%); thick colorless liquid; Rf = 0.42 (1:4 EtOAc/PE).
IR (CHCl3): 3633, 3289, 3139, 2959, 2922, 1657, 1600, 1544, 1492,
1438, 1365, 1314, 1242, 1158, 1118, 1039, 934, 808, 758 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

F
J. Rathod et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3): δ = 7.29–7.23 (m, 4 H), 7.06 (s, 3 H), 6.85
(s, 1 H), 6.82–6.72 (m, 3 H), 5.92 (app d, J = 2.7 Hz, 2 H), 5.12 (s, 1 H),
4.44 (t, J = 7.6 Hz, 1 H), 3.00 (d, J = 8.0 Hz, 2 H), 1.40 (s, 18 H).
13C NMR (125 MHz, CDCl3): δ = 169.6, 152.5, 147.8, 146.1, 137.9,
137.6, 136.1, 134.1, 128.9, 124.2, 124.0, 120.5, 119.8, 108.3, 108.2,
100.9, 47.3, 45.3, 34.4, 30.3.
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-N-hexyl-3-phenylpropana-
mide (3r)
Reaction performed with p-quinone methide 1a (20 mg, 0.068 mmol)
and vinyl azide 2e (1.2 equiv); yield: 18 mg (75%); colorless thick liq-
uid; Rf = 0.34 (1:5 EtOAc/PE).
IR (CHCl3): 3356, 2945, 2833, 1657, 1450, 1415, 1114, 1032, 758 cm–1
.
HRMS (FTMS + p ESI): m/z [M + H]+ calcd for C30H36NO4: 474.2637;
found: 474.2637.
1H NMR (500 MHz , CDCl3): δ = 7.35–7.27 (m, 4 H), 7.22–7.18 (m, 1 H),
7.05 (s, 2 H), 5.16 (br s, 1 H), 5.09 (s, 1 H), 4.44 (t, J = 7.8 Hz, 1 H), 3.17–
3.00 (m, 2 H), 2.92–2.81 (m, 2 H), 1.41 (s, 18 H), 1.27–1.14 (m, 6 H),
1.13–1.06 (m, 2 H), 0.87 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 171.3, 152.3, 144.1, 135.8, 134.2,
128.5, 127.7, 126.3, 124.2, 47.7, 44.3, 39.4, 34.4, 31.4, 30.3, 29.3, 26.3,
22.5, 14.0.
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-N-phenyl-3-(thiophen-2-
yl)propanamide (3n)16
Yield: 15.5 mg (71%); white solid; mp 170–172 °C (Lit.16 mp 172–175
°C); Rf = 0.20 (1:9 EtOAc/PE).
HRMS (FTMS + p ESI): m/z [M + H]+ calcd for C29H44NO2: 438.3367;
found: 438.3363.
IR (CHCl3): 3634, 3372, 2925, 2858, 1653, 1595, 1436, 1317, 1246,
1121, 1040, 769, 696 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.26 (app s, 4 H), 7.18 (app d, J = 4.3 Hz,
1 H), 7.15 (s, 2 H), 7.07 (br s, 1 H), 6.99–6.88 (m, 2 H), 6.82 (s, 1 H),
5.15 (s, 1 H), 4.76 (t, J = 7.3 Hz, 1 H), 3.13–2.95 (m, 2 H), 1.41 (s, 18 H).
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-N-hexyl-3-(p-tolyl)propan-
amide (3s)
Reaction performed with p-quinone methide 1b (20 mg, 0.065 mmol)
and vinyl azide 2e (1.2 equiv); yield: 23 mg (79%); colorless thick liq-
uid; Rf = 0.40 (1:5 EtOAc/PE).
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-phenyl-N-(p-tolyl)pro-
panamide (3o)16
IR (CHCl3): 3357, 2945, 2833, 1655, 1453, 1415, 1113, 1026, 759 cm–1
.
Yield: 21 mg (93%); colorless thick liquid; Rf = 0.5 (1:4 EtOAc/PE).
1H NMR (500 MHz, CDCl3): δ = 7.21–7.13 (m, 2 H), 7.13–7.07 (m, 2 H),
7.04 (s, 2 H), 5.17 (br s, 1 H), 5.07 (s, 1 H), 4.38 (t, J = 7.8 Hz, 1 H), 3.16–
3.00 (m, 2 H), 2.91–2.78 (m, 2 H), 2.31 (s, 3 H), 1.40 (s, 18 H), 1.26–
1.15 (m, 6 H), 1.12–1.05 (m, 2 H), 0.86 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.4, 152.2, 141.1, 135.8, 135.8,
134.4, 129.2, 127.5, 124.1, 47.4, 44.3, 39.4, 34.3, 31.4, 30.3, 29.3, 26.3,
22.4, 20.9, 14.0.
IR (CHCl3): 3632, 3288, 2924, 2861, 1650, 1598, 1428, 1317, 1245,
1120, 1037, 816, 772 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.32 (app d, J = 4.2 Hz, 4 H), 7.24–7.19
(m, 1 H), 7.10 (d, J = 8.4 Hz, 2 H), 7.08 (s, 2 H), 7.04 (d, J = 8.4 Hz, 2 H),
6.72 (s, 1 H), 5.11 (s, 1 H), 4.51 (t, J = 7.6 Hz, 1 H), 3.04 (d, J = 7.6 Hz, 2
H), 2.28 (s, 3 H), 1.39 (s, 18 H).
HRMS (FTMS + p ESI): m/z [M + H]+ calcd for C30H46NO2: 452.3523;
found: 452.3522.
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-N-(2-methoxyphenyl)-3-
phenylpropanamide (3p)16
Reaction performed with p-quinone methide 1p (20 mg, 0.068 mmol)
and vinyl azide 2p (1.2 equiv); yield: 27 mg (95%); colorless liquid;
Rf = 0.5 (1:4 EtOAc/PE).
3-(4-Hydroxy-3,5-dimethylphenyl)-N,3-diphenylpropanamide (3t)
Reaction performed with of p-quinone methide 1o (20 mg, 0.095
mmol) and vinyl azide 2a (1.2 equiv); yield: 20 mg (61%); colorless
thick liquid; Rf = 0.38 (1:2 EtOAc/PE).
IR (CHCl3): 3634, 3372, 2926, 2859, 1656, 1594, 1533, 1457, 1424,
1319, 1251, 1121, 1038, 857, 775 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.32 (d, J = 8.0 Hz, 1 H), 7.57 (s, 1 H),
7.36–7.28 (m, 4 H), 7.22–7.19 (m, 1 H), 7.06 (s, 2 H), 6.99 (t, J = 7.2 Hz,
1 H), 6.92 (t, J = 7.4 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 1 H), 5.06 (s, 1 H), 4.56
(t, J = 7.6 Hz, 1 H), 3.76 (s, 3 H), 3.16–3.01 (m, 2 H), 1.38 (s, 18 H).
IR (CHCl3): 3356, 2945, 2833, 1657, 1450, 1416, 1114, 1032, 758 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.26 (m, 6 H), 7.23 (app d, J = 7.9
Hz, 3 H), 7.07 (br s, 1 H), 6.92 (br s, 1 H), 6.89 (s, 2 H), 4.63 (br s, 1 H),
4.50 (t, J = 7.6 Hz, 1 H), 3.04 (d, J = 7.3 Hz, 2 H), 2.20 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 169.6, 150.9, 144.1, 137.5, 135.0,
128.8, 128.7, 127.8, 127.6, 126.5, 124.3, 123.3, 120.0, 46.8, 44.6, 16.0.
HRMS (FTMS + p ESI): m/z [M + H]+ calcd for C23H24NO2: 346.1802;
found: 346.1798.
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-N-(3,4-difluorophenyl)-3-
phenylpropanamide (3q)
Yield: 20.1 mg (85%); colorless thick liquid; Rf = 0.3 (1:9 EtOAc/PE).
IR (CHCl3): 3634, 3289, 2960, 2854, 1660, 1613, 1248, 1210, 1158,
1118, 1037, 910, 865, 809, 771 cm–1
.
N-Hexyl-3-(4-hydroxy-3,5-dimethylphenyl)-3-phenylpropana-
mide (3u)
1H NMR (500 MHz, CDCl3): δ = 7.39–7.28 (m, 5 H), 7.26–7.20 (m, 1 H),
7.07 (s, 2 H), 7.00 (q, J = 8.9 Hz, 1 H), 6.76–6.66 (m, 2 H), 5.13 (s, 1 H),
4.48 (t, J = 7.8 Hz, 1 H), 3.04 (d, J = 7.6 Hz, 2 H), 1.39 (s, 18 H).
13C NMR (125 MHz, CDCl3) δ = 170.0, 152.8, 151.2, 143.9, 136.5, 134.3,
134.0, 129.0, 127.9, 126.9, 125.6, 124.4, 117.3 (d, JC,F = 19.1 Hz), 115.5,
109.8 (d, JC,F = 21.9 Hz), 48.0, 45.4, 34.7, 30.5.
Yield. 14 mg (83%); colorless thick liquid; Rf = 0.45 (1:2 EtOAc/PE).
IR (CHCl3): 3410, 2952, 2843, 1644, 1456, 1412, 1113, 1019 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.27 (app d, J = 7.2 Hz, 2 H), 7.25–7.21
(m, 2 H), 7.20–7.15 (m, 1 H), 6.84 (s, 2 H), 5.18 (br s, 1 H), 4.60 (br s, 1
H), 4.40 (t, J = 7.8 Hz, 1 H), 3.17–3.02 (m, 2 H), 2.83 (d, J = 8.0 Hz, 2 H),
2.20 (s, 6 H), 1.29–1.13 (m, 8 H), 1.11–1.04 (m, 2 H), 0.87 (t, J = 7.2 Hz,
3 H).
HRMS (FTMS + p ESI): m/z [M + H]+ calcd for C29H34F2NO2: 466.2552;
found: 466.2556.
13C NMR (125 MHz, CDCl3): δ = 171.2, 150.8, 144.3, 135.2, 128.5,
127.8, 127.6, 126.3, 123.0, 46.8, 43.8, 39.4, 31.4, 29.4, 26.3, 22.5, 16.0,
14.0.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

G
J. Rathod et al.
Paper
Synthesis
HRMS (FTMS + p ESI): m/z [M + H]+ calcd for C23H32NO2: 354.2428;
found: 354.2428.
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De-tert-butylation of β-Bis-Arylamides; 3-(4-Hydroxyphenyl)-N,3-
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In an oven-dried 50 mL round-bottomed flask, compound 3a (50 mg,
0.11 mmol) was taken in anhyd toluene (10 mL) followed by the addi-
tion of anhyd AlCl3 (94.2 mg, 0.698 mmol) at once, under an argon at-
mosphere. The reaction mixture was stirred at r.t. until the comple-
tion of reaction. The mixture was cooled to 0 °C and ice water was
added to quench the AlCl3. The mixture was extracted with EtOAc (3 ×
15 mL), the combined organic layers were dried (anhyd Na2SO4), and
concentrated under reduced pressure followed by column chromatog-
raphy purification to give 4a; yield: 13 mg (88%); colorless thick liq-
uid; Rf = 0.20 (1:2 EtOAc/PE).
IR (CHCl3): 3356, 2945, 2832, 1657, 1453, 1416, 1114, 1029,758 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 9.95 (s, 1 H), 9.28 (br s, 1 H), 7.52–
7.42 (m, J = 8.0 Hz, 2 H), 7.32–7.18 (m, 6 H), 7.18–7.03 (m, 3 H), 6.99
(app t, J = 7.2 Hz, 1 H), 6.71–6.60 (m, J = 8.0 Hz, 2 H), 4.45 (t, J = 8.0 Hz,
1 H), 3.01 (d, J = 8.0 Hz, 2 H).
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Funding Information
J. R and B. M. S thank the Council of Scientific and Industrial Research
(CSIR), New Delhi for a Senior Research Fellowship. Dr. P. R. Rajamo-
hanan [CSIR-NCL)] is thanked for NMR support, Ms. B. Santhakumari
(CSIR-NCL) for the HRMS data; P. K also thanks the Council of Scientif-
ic and Industrial Research (CSIR), New Delhi for financial support as
part of XII Five Year Plan under the title ORIGIN (CSC0108).
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Supporting information for this article is available online at
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References
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