Iodine-catalyzed, one-pot, three-component aza-Friedel-Crafts reaction of electron-rich arenes with aldehyde/carbamate combinations

Article abstract of DOI:10.1016/j.tetlet.2012.03.024

Iodine is shown to be an efficient catalyst for a one-step, three-component aza-Friedel-Crafts reaction of activated arenes or heteroarenes with benzyl or tert-butyl carbamates in combination with a wide variety of aldehydes in toluene under 'open-flask'

Full text of DOI:10.1016/j.tetlet.2012.03.024

Tetrahedron Letters 53 (2012) 2476–2479
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Tetrahedron Letters
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Iodine-catalyzed, one-pot, three-component aza-Friedel–Crafts reaction
of electron-rich arenes with aldehyde/carbamate combinations
Jaray Jaratjaroonphong a, , Suppachai Krajangsri a, Vichai Reutrakul b
⇑
a Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand
b Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
Iodine is shown to be an efficient catalyst for a one-step, three-component aza-Friedel–Crafts reaction of
activated arenes or heteroarenes with benzyl or tert-butyl carbamates in combination with a wide variety
of aldehydes in toluene under ‘open-flask’ and mild conditions. In the presence of 5 mol % of iodine in tol-
Received 28 January 2012
Revised 25 February 2012
Accepted 7 March 2012
Available online 13 March 2012
uene at room temperature, the reaction gives the corresponding N-CBz or N-Boc protected
a-branched
amines, selectively, in good to excellent yields.
Ó 2012 Published by Elsevier Ltd.
Keywords:
Three-components
a-Branched amines
Iodine
Aza-Friedel–Crafts
An important structural motif, which is found in various natural
products and drugs with well recognized pharmacological proper-
itations, the development of methods utilizing aromatic and het-
eroaromatic systems, amine sources, aldehydes, easily available
catalysts with high catalytic activity, and short reaction times for
the preparation of diarylmethylamine derivatives is still desirable.
Molecular iodine has been used as an efficient catalyst for sev-
eral chemical transformations.11 As part of our interest in the
employment of molecular iodine as an alternative, simple, inex-
pensive, and less toxic reagent,12 herein we report a highly efficient
one-pot, three-component aza-Friedel–Crafts reaction of electron-
rich arenes or heteroarenes, aldehydes, and benzyl or tert-butyl
carbamates under mild conditions (Scheme 1).
For initial optimization of the reaction conditions, 1,3,5-trime-
thoxybenzene (1a), benzaldehyde (2a), and benzyl carbamate
(3a) were chosen as model substrates, using 10 mol % of I2 as the
catalyst. The solvent effect was also examined. The results are
listed in Table 1. It was observed that when non-polar and weakly
polar solvents such as toluene, CH2Cl2, or THF were used, the reac-
tion gave 4a as the major product (80–81%) and only a trace
amount of double-addition product 5a (entries 1–3). The use of
polar aprotic and polar protic solvents such as CH3CN and
CH3OH, respectively, was less effective and lower product yields
of 48–71% were obtained (entries 4, 5). It should be noted that
ties, is the
for the synthesis of functionalized
a
-branched amine skeleton.1 A frequently used method
a-branched amine derivatives is
the aza-Friedel–Crafts reaction (AFCR) between electron-rich aro-
matic/heteroaromatic compounds and imine derivatives.2,3 How-
ever, most of the reported methods are multi-step processes and
require highly electrophilic imine acceptors such as those derived
from glyoxalates,4 and trifluoroacetaldehyde.5 In contrast, less acti-
vated imine substrates, such as the imines of aromatic aldehydes,
generally evolve according to a double Friedel–Crafts process to
afford symmetrical triarylmethanes due to the intrinsic instability
of the intermediate benzylamine under the acidic reaction
conditions.6
Three-component AFCRs have become an efficient and powerful
tool for the construction of the corresponding a-branched amines,
diarylmethylamines, because of the fact that the desired products
are formed in a one-pot reaction without isolation of the interme-
diates under standard reaction conditions.6b,7,8 However, most of
the examples reported to date are limited to the reactions of in-
doles or 2-naphthols, amides or urea, and non-enolizable, most
notably, aryl aldehydes.8–10 Furthermore, some of the reported
methods suffer from disadvantages such as the use of expensive
and corrosive reagents, high catalyst loading, long reaction times,
strongly acidic conditions, low yields of products, and the use of
microwave or ultrasonic irradiation.9 Therefore, to avoid these lim-
O
NHCO2R
R1
I2 (5 mol%)
toluene, rt
Ar
H
+
H2NCO2R
R = benzyl, tert-butyl
Scheme 1. I2-catalyzed three-component aza-Friedel–Crafts reaction.
+
H
R1
Ar
⇑
Corresponding author. Tel.: +66 038 10 3053; fax: +66 038 39 3494.
E-mail address: jaray@buu.ac.th (J. Jaratjaroonphong).
0040-4039/$ - see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.03.024

J. Jaratjaroonphong et al. / Tetrahedron Letters 53 (2012) 2476–2479
2477
Table 1
Model and optimization studiesa
OMe
CHO
MeO
NHCO2Bn
MeO
Ph OMe
3a
H2NCO2Bn (
)
Ph
+
+
OMe
I2, solvent
air, rt
MeO
MeO
OMe
MeO
OMe
MeO OMe
5a
4a
1a
2a
Entry
Catalyst (mol %)
Solvent
Time (h)
Products yieldb (%)
4a
5a
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
20
5
Toluene
CH2Cl2
THF
CH3CN
CH3OH
—
Toluene
Toluene
Toluene
2
2
2
2
5
12
2
2
81
80
81
71
48
51
73
87
Trace
3
3
Trace
25
Trace
Trace
Trace
c
c
0
24
—
—
a
b
c
Reaction conditions: 1a (1 mmol), 2a (1.1 mmol), 3a (1 mmol), I2, solvent (1 mL), room temperature.
Isolated yield.
No reaction based on TLC analysis.
Table 2
symmetrical triarylmethane 5a was obtained in 25% yield when
the reaction was carried out in CH3OH. This indicates accelerated
ionization of the benzyl carbamate group by the polar protic sol-
vent, resulting in the double-addition product. The reaction under
neat conditions and stirring for 12 h (entry 6) gave the desired
product 4a in moderate yield (51%). From the solvent effect study,
it was determined that toluene was the solvent of choice. We also
investigated the influence of catalyst loading on the model reaction
in toluene (entries 7–9). The results showed that the yield of the
desired product 4a increased slightly on lowering the catalyst load-
ing to 5 mol % and the reaction was generally complete within 2 h
at room temperature (entry 8).9 No side product was observed. A
control reaction in the absence of iodine gave no products and
the starting materials were recovered (entry 9).
I2-catalyzed reaction of arene 1a, benzyl or tert-butyl carbamates, and various
aldehydesa
OMe
MeO
NHCO2R2
R1
I2 (5 mol%)
toluene, rt
+
OMe
R1CHO
2 3
H2NCO2R
MeO
MeO
OMe
4
1a
2
3a: R2 = Bn
+
3b: R2 = t-Bu
MeO
R1 OMe
MeO
OMe
MeO OMe
5
The scope of the reaction under the optimized conditions was
investigated by varying the aldehyde and carbamate components
and results are summarized in Table 2.13 In the presence of
5 mol % of I2, 1,3,5-trimethoxybenzene and benzyl or tert-butyl
carbamate reacted with a number of aromatic aldehydes possess-
ing either electron-withdrawing (F, Cl, Br, and NO2) or electron-
donating (OMe) substituents to give the corresponding N-pro-
tected diarylmethylamines 4a–f and 4h–m, selectively, in good
to excellent yields (entries 1–7 and 9–14). Due to the low reactivity
of 4-nitrobenzaldehyde, increasing the catalyst loading to 10 mol %
led to a significant increase in the yield of 4e as well as 4l together
with the formation of symmetric triarylmethane 5e (entries 6 and
Entry
R1
R2
Products yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
C6H5
4-FC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
4-O2NC6H4
4-MeOC6H4
Cyclopentyl
C6H5
4-FC6H4
4-ClC6H4
4-O2NC6H4
4-O2NC6H4
4-MeOC6H4
Cyclopentyl
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
4a (87)
4b (97)
4c (82)
4d (86)
4e (50)
4e (72)c
4f (77)
4g (63)
4h (97)
4i (92)
4j (68)
4l (37)
4l (56)d
4m (80)
4n (63)
5a (trace)
5b (3)
5c (4)
5d (3)
5e (28)
5e (6)c
5f (5)
5g (—)
5a (—)
5b (—)
5c (—)
5e (16)
5e (10)d
5f (—)
13). Furthermore, the corresponding a-branched amines 4g and 4n
5g (—)
were obtained smoothly in good yields when 1,3,5-trimethoxyben-
zene and benzyl or tert-butyl carbamate were treated with cyclop-
entanecarbaldehyde (entries 8 and 15). From the results in Table 2,
it should be noted that both benzyl and tert-butyl carbamates
afforded good to excellent yields of the desired products 4a–n,
however from the tert-butyl carbamates, there was a decrease in
the formation of the double-addition adducts 5a–g.
a
Reaction conditions: 1 (1 mmol), 2 (1.1 mmol), 3 (1 mmol), I2 (5 mol %), toluene
(1 mL), room temperature.
b
Isolated yield.
c
The reaction was carried out using I2 (10 mol %) in toluene.
The reaction was carried out using I2 (10 mol %) in THF.
d
Encouraged by these results, we next investigated the three-
component AFCR with an array of arenes as well as heteroarenes,
aldehydes, and benzyl or tert-butyl carbamates. The results pre-
sented in Table 3 show that the reactions led to selective formation
(entry 1). Furthermore, 2-naphthol (1c) reacted efficiently with 4-
chlorobenzaldehyde and benzyl/tert-butyl carbamates to produce
1-carbamato-alkyl-2-naphthol derivatives 4p,q in good yields
(entries 2 and 3). It is noteworthy that compounds 4p,q can be con-
verted into important biologically active 1-aminomethyl-2-naph-
thol derivatives by carbamate hydrolysis.10 The three-component
AFCR was also successfully applied to heteroaromatic compounds
of
a-branched amines 4o–u in moderate to high yields. The reac-
tion of 1,2,4-trimethoxybenzene with benzaldehyde and tert-butyl
carbamate gave the corresponding diarylmethylamine 4o and
symmetrical triarylmethane 5h in 57% and 15% yields, respectively

2478
J. Jaratjaroonphong et al. / Tetrahedron Letters 53 (2012) 2476–2479
Table 3
I2-catalyzed reaction of various arenes with aliphatic and aromatic aldehydes and benzyl or tert-butyl carbamatea
H2NCO2R2
3
R1
NHCO2R2
R1
Ar
H
+
R1CHO
I2 (5 mol%)
toluene, rt
+
Ar
Ar
Ar
2
1b: 1,2,4-trimethoxybenzene
1c: 2-naphthol
3a; R2 = Bn
4
5
3b; R2 = t-Bu
1d: 2-methylfuran
1e: 2-ethylfuran
1f: 2-methylthiophene
Entry
1
Ar–H
R1
R2
Time (h)
Products yieldb (%)
OMe NHCO2t-Bu
OMe Ph OMe
1b
C6H5
t-Bu
2
4o (57)
5h (15)
5i (-)c
MeO
MeO
OH
OMe
OMe
OH NHCO2Bn
OMe
Ph
OMe
4p (74)c
4q (62)c
2
3
1c
1c
4-ClC6H4
Bn
18
24
Cl
OH
OH NHCO2t-Bu
OH Ph
4-ClC6H4
t-Bu
5i (-)c
Cl
OH
Ph
4
5
1d
1d
C6H5
C6H5
t-Bu
t-Bu
24
6
NHCO2t-Bu
O
CH3
4r (52)
5j (19)
4r (61)d
5j (38)d
O
O
H3C
H3C
6
7
1e
1e
C6H5
C6H5
t-Bu
t-Bu
2
2
NHCO2t-Bu
Ph
O
CH2CH3
5k (–)
5k (7)e
4s (90)
4s (65)e
O
O
H3CH2C
H3CH2C
8
9
1f
1f
C6H5
C6H5
t-Bu
t-Bu
2
2
NHCO2t-Bu
Ph
S
S
CH3
4t (27)
5l (–)
4t (40)e
5l (–)e
S
S
H3C
H3C
H3C
H3C
NHCO2t-Bu
4u (48)f
CH3
5m (–)f
10
1f
(CH3)2CH
t-Bu
2
S
S
a
b
c
d
e
f
Reaction conditions: 1 (1 mmol), 2 (1.1 mmol), 3 (1 mmol), I2 (5 mol %), toluene (1 mL), room temperature.
Isolated yield.
The reaction was carried out at using I2 (10 mol %) in CH3CN at 60 °C.
The reaction was carried out using I2 (10 mol %) in THF (1 mL) at room temperature.
The reaction was carried out using I2 (5 mol %) in THF (1 mL) at room temperature.
The reaction was carried out using I2 (20 mol %) in toluene (1 mL) at room temperature.
such as 2-methylfuran (1d), 2-ethylfuran (1e), and 2-methylthi-
ophene (1f) with benzaldehyde and tert-butyl carbamate to afford
obtained, selectively, in good to excellent yields. The use of mild
reaction conditions, low catalytic loading, and easy removal of
the N-protective group14, and one-step synthesis are advantages
of the present procedure. Further investigations on the scope and
limitations of this reaction are in progress.
the functionalized
a-branched amines 4r–t in moderate to high
yields (entries 4–9). Finally, we tested the efficiency of this reac-
tion with the aliphatic aldehyde, isobutyraldehyde (entry 10): with
2-methylthiophene and tert-butyl carbamate, the substrates were
converted smoothly into the desired product.
In summary, we have demonstrated an efficient iodine-cata-
lyzed, one-pot, three-component AFCR of arenes/heteroarenes,
benzyl/tert-butyl carbamate and a wide variety of aldehydes in tol-
uene under ‘open-flask’ and mild conditions. Typically, the corre-
Acknowledgments
We thank the Thailand Research Fund for financial support to
J.J. Financial support from the Center of Excellence for Innovation
in Chemistry (PERCH-CIC), Office of the Higher Education Commis-
sponding N-Cbz or N-Boc protected
a-branched amines were

J. Jaratjaroonphong et al. / Tetrahedron Letters 53 (2012) 2476–2479
2479
D. Ultrason. Sonochem. 2007, 14, 515–518; (c) Zhang, P.; Zhang, Z.-H. Monatsh
Chem. 2009, 140, 199–203; (d) Hajipour, A. R.; Ghayeb, Y.; Sheikhan, N.; Ruoho,
A. E. Tetrahedron Lett. 2009, 50, 5649–5651; (e) Lei, M.; Ma, L.; Hu, L.
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sion, the Ministry of Education and an Annual Grant from Burapha
University, Thailand are also gratefully acknowledged.
References and notes
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13. Typical experimental procedure: To
a toluene solution (1 mL) of arene 1
(1.0 mmol), aldehyde 2 (1.1 mmol), and carbamate 3 in a test-tube open to
air at room temperature was added molecular I2 (0.05 mmol, 5 mol %). The
reaction was stirred until completion (TLC analysis). The mixture was
quenched with aqueous Na2S2O3 (10 mL) and extracted with CH2Cl2
(2 Â 10 mL). The combined organic layer was washed with brine (10 mL),
dried over anhydrous MgSO4, concentrated, and purified by radial
chromatography (hexanes/EtOAc as eluent) to give 4 as the major product
and 5 as the minor product. Spectral data for 4a: 1H NMR (400 MHz, CDCl3): d
7.14–7.44 (10H, m), 6.69 (1H, d, J = 10.1 Hz), 6.52 (1H, d, J = 10.1 Hz), 6.15 (2H,
s) 5.19 (1H, d, J = 12.1 Hz), 5.12 (1H, d, J = 12.1 Hz), 3.82 (3H, s), 3.78 (6H, s); 13
C
NMR (100 MHz, CDCl3): d 160.1, 158.6, 156.3, 143.0, 138.6, 128.5, 128.3, 127.9,
126.3, 126.0, 110.8, 91.3, 66.8, 55.9, 55.4, 48.9; IR (Nujol): mmax 3444, 1721,
1608, 1593, 1497 cmÀ1; HRMS (EI) calcd for C24H25NO5 407.1727, found:
407.1727. 5a: 1H NMR (400 MHz, CDCl3): d 7.15 (2H, t, J = 7.4 Hz), 7.06 (3H, d,
J = 4.8 Hz), 6.22 (1H, s), 6.12 (4H, s), 3.79 (6H, s), 3.50 (12H, s); 13C NMR
(100 MHz, CDCl3): d 159.9, 159.2, 145.7, 127.8, 127.1, 124.2, 114.4, 91.9, 56.2,
55.2, 37.1; IR (Nujol): mmax 1591, 1455, 1415, 1230, 1204; HRMS (ESI-TOF)
calcd for C25H28O6Na 447.1784, found: 447.1760.
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