Reductive alkylation of aromatic amines with enol ethers

Article abstract of DOI:10.1055/s-2005-863704

Reductive alkylation of aromatic amines with 2-methoxypropene using 1.0 equivalent of HOAc and NaBH(OAc)₃ in 1,2-dichloroethane (DCE) at room temperature furnished N-isopropyl amines in 50-98% yields. This method was successfully extended to trimethylsilyl enol ethers. The mild reaction conditions provide a new alternative procedure for the reductive amination of electron deficient aromatic amines.

Full text of DOI:10.1055/s-2005-863704

LETTER
583
Reductive Alkylation of Aromatic Amines with Enol Ethers
R
eductive Alky
.lation of
A
ro
J
matic
A
m
a
ines gadeeswar Reddy,*1 Michael Leclair, Melanie Proulx
Virochem Pharma Inc., 275 Armand-Frappier Blvd, Laval, Quebec, H7V 4A7, Canada
Fax +1(514)4284900; E-mail: thumkunta_reddy@merck.com
Received 21 July 2004
Dedicated to Professor A. Srikrishna on the occasion of his 50th birthday.
H2N Ar
Abstract: Reductive alkylation of aromatic amines with 2-meth-
oxypropene using 1.0 equivalent of HOAc and NaBH(OAc)3 in 1,2-
dichloroethane (DCE) at room temperature furnished N-isopropyl
amines in 50–98% yields. This method was successfully extended
to trimethylsilyl enol ethers. The mild reaction conditions provide a
new alternative procedure for the reductive amination of electron
deficient aromatic amines.
H
H
N
HN
Ar
+
H2O
Ar
O
Equation 1
In connection with an effort toward anti-hepatitis C
(HCV) NS5B polymerase inhibitors, we required a safe
and convenient procedure for the large scale preparation
of methyl 3-(N-isopropyl)-amino-5-phenylthiophene-2-
carboxylate (Figure 1), a pivotal intermediate to our target
substructures.7a As the currently available methods to this
intermediate were found to be inefficient and cumber-
some, we have developed a simple, high-yielding modifi-
cation to the standard reductive amination protocol, one
that works particularly well for the preparation of N-alkyl-
ated aromatic amines.3b
Key words: reductive alkylation, aromatic amines, 2-methoxypro-
pene, trimethylsilylenol ethers, sodium triacetoxyborohydride
The amine group is regarded as one of the privileged func-
tional groups in identifying novel lead compounds for
drug discovery. Among the many methods available for
the synthesis of secondary and tertiary amines, reductive
amination, the reaction of a ketone or an aldehyde in the
presence of an amine and a mild reducing agent,2 is per-
haps the most versatile. Although this method has been
used for the preparation of a diverse range of amines, it of-
ten suffers from poor yields when applied to aromatic
amines. Gribble and co-workers3a have first described for
aromatic amines using NaBH4–HOAc, later Abdel-Magid
et al.3b has developed efficient procedure by simple mod-
ification of the reagent, NaBH(OAc)3–HOAc.3b Apodaca
et al. has used a catalytic amount of Bu2SnCl2 in combina-
NH
O
S
O
4
tion with PhSiH3 as reducing agent. These procedures
Figure 1
have widely used for direct reductive amination of aro-
matic amines. Most importantly, these procedures are of-
ten low yielding and require longer reaction time with
ketones despite using of excess reagents (up to 5 equiv).3b
In the case of unreactive amines, the equilibrium is shifted
to the left and excess carbonyl compounds will consume
the reducing agent prior to the formation of the imine
(Equation 1).3b To circumvent this problem, alternative
stepwise procedure has been developed using stochiomet-
ric amount of Ti(Oi-Pr)4 prior to adding reducing agent.
Although, this modification has been effective and it has
not been fully explored for electron deficient aromatic
amines.5,3b Moreover, operationally not simple for large
scale preparations. Recently, Park et al.6 has reported one-
pot reductive amination of acetals with aromatic amines
using decaborane (B10H14) as the reducing agent. How-
ever, it is not compatible with reducible functional groups,
e.g. ketones and basic amines.
We have hypothesized that enol ethers/mild proton source
could be used in place of ketones as no reducible groups
are present (Equation 2) and do not require excess
reagents. Moreover, the reaction rate is faster for addition
of aromatic amines to an oxonium intermediate than to
simple ketones. The highly reactive oxonium species is
generated in situ by protonation of enol ethers.
H2N Ar
H
O
MeO
MeO
Me
Ar NH
H
Equation 2
We have chosen NaBH(OAc)3 as our reducing agent as it
offers mild reaction conditions, operational simplicity and
avoids the use of toxic metals.4 Reductive alkylation of 2-
methoxypropene (5.0 equiv) using aniline with HOAc
(2.0 equiv) and NaBH(OAc)3 (3.0 equiv) in DCE at r.t. for
one hour generated a inseparable 65:35 mixture of N-iso-
propylaniline and N,N-diisopropyl anilines. In contrast,
SYNLETT 2005, No. 4, pp 0583–0586
0
4.
0
3.
2
0
0
5
Advanced online publication: 22.02.2005
DOI: 10.1055/s-2005-863704; Art ID: S07004ST
© Georg Thieme Verlag Stuttgart · New York

584
T. J. Reddy et al.
LETTER
Table 1 Reactivity of Acetone Equivalents
optimum yield and faster reaction although 20 mol%
HOAc is sufficient. 1,2-Dichloroethane is solvent of
choice compared to THF or CH2Cl2. Reductive alkylation
of aniline (2.0 mmol) with 2- methoxypropene (2.0 mmol,
1.0 equiv), HOAc (1.0 equiv) and NaBH(OAc)3 (3.0
mmol, 1.5 equiv) in DCE at room temperature for two
hours provided N-isopropyl aniline in 96% isolated yield.
R1
N
Reagent (5.0 equiv)
HOAc (2.0 equiv)
NaBH(OAc)3 (3.0 equiv)
NH2
R2
1,2-DCE, r.t., 1 h
2a: R1 = H; R2 = i-Pr
2b: R1 = R2 = i-Pr
The generality of this method was examined with a vari-
ety of functionalized hindered unreactive anilines
(Table 2). A wide range of anilines provided N-isopropyl
anilines in good to excellent yields, including weakly nu-
cleophilic and sterically hindered substrates (entries 1–3,
5 and 7). Small amount of dialkylated product was ob-
served for electron rich anilines (entries 4 and 8). The re-
action conditions are compatible with several functional
groups, e.g. CN, NO2, CO2Et, I (Table 2). Good selectiv-
ity was obtained with reducible group such as COMe
(entry 9). TFA can also be used instead of HOAc for un-
reactive anilines to facilitate the reaction rate (entry 12).
Entry
Reagent
Product(s) (%)a
(2a:2b)
65:35
100:0
15:0b
1
2
3
2-Methoxypropene
Acetone
2,2-Dimethoxypropane
a 1H NMR ratio of crude products.
b Remaining is starting material.
reaction with acetone gave N-isopropyl aniline as the sole
product. Reductive alkylation with 2-methoxypropene is
therefore much faster than with acetone and 2,2-
dimethoxypropane8 thus confirming our hypothesis
(Table 1).
The methodology was also extended to trimethylsilyl
(TMS) enol ethers in order to enhance the scope of the
reaction, as many of TMS enol ethers are commercially
available (Table 3) or easily prepared from the corre-
Reaction conditions were optimized for selective mono
N-alkylation using aniline and 2-methoxypropene. Sto-
chiometric amount of HOAc (1.0 equiv) is necessary for
Table 3 Reductive Alkylation with TMS Enol Ether
HOAc (1.0 equiv)
NaBH(OAc)3 (1.5 equiv)
H
N
R2
R1
R2
NH2
Table 2 Reductive Alkylation with 2-Methoxypropene
Ar
+
Ar
DCE, r.t.
R1
OR3
2-Methoxypropene
R2
R2
(1.5 equiv)
N
HOAc (1.0 equiv)
NH
Entrya Ar
R1
R2 R3
Yield Time
(%)b (h)
NaBH(OAc)3 (1.5 equiv)
DCE, r.t.
R1
R1
1
Ph
Ph
Ph
Ph
-(CH2)4-
-(CH2)3-
Ph
TMS 78
TMS 82
TMS 75
TMS 65
2
2
Entrya
R1
o-CN
R2
H
Yield (%)b Time (h)
2
1
2
80
65
79
97
98
96
80
98c
68
92
83
27
45
3
H
24
2
o-NO2
o-CO2Et
o-Me
o-i-Pr
o-F
H
H
H
H
H
H
H
H
H
H
Ph
49
3
2.0
N
4
3.0
3.0
3.0
3.0
96c
5
5
Ph
TMS
0
6
N
7
o-I
boc
6
7
Me
H
H
Me
Me
96
2
2
8
o-OMe
m-COMe
p-NO2
2,4-Cl2
H
27
3.0
quantd
9
Ph
CO2Me
S
10
11
12
20
2.0
166
Me
95
50
77d
2.0
CO2Me
S
a Reaction scale 2.0 mmol.
b Isolated yield.
a Reaction scale 2.0 mmol.
b Isolated yield.
c Inseparable 8:1 mixture of mono- and diisopropyl anilines.
d TFA used instead of HOAc.
c Reaction is carried out at 67 °C.
d Reaction scale 20 mmol for overnight.
Synlett 2005, No. 4, 583–586 © Thieme Stuttgart · New York

LETTER
Reductive Alkylation of Aromatic Amines
585
(8) (a) Tapia, I.; Alonso-Cires, L.; Lopez-Tudanca, P. L.;
sponding ketones. Cycloalkanone TMS enol ethers also
reacted with similar rate to 2-methoxypropene. Aceto-
phenone TMS enol ether gave good yield as conventional
reductive amination resulted in poor conversion.3b Enol
ethers carrying a basic functionality were also good sub-
strates (entry 4). Surprisingly, N-BOC piperidine failed to
react even at high temperature and longer reaction time
(entry 5). Unreactive heterocyclic amines also provided
the desired N-alkylated products in excellent yields
(entries 6 and 7). Reaction conditions are compatible with
large scale preparation as it produced quantitative yield of
methyl 3-(N-isopropyl)-amino-5-phenylthiophene-2-car-
boxylate (entry 6).
Mosquera, R.; Labeaga, L.; Innerarity, A.; Orjales, A. J.
Med. Chem. 1999, 42, 2870. (b) Schaus, J. M.; Thompson,
D. C.; Bloomquist, W. E.; Susemichel, A. D.; Calligaro, D.
O.; Cohen, M. L. J. Med. Chem. 1998, 41, 1943.
(9) For the preparation of N-methylpiperidine enol ether,
see:Wanner, K. Liebigs Ann. Chem. 1984, 1103.
(10) Few examples of preclinical drugs containing N-isopropyl
aromatic amines: (a) HCV NS-3 protease inhibitor, BILN-
2061 (b) 5-HT-4 receptor antagonists, LY353433 (c) 5-HT-
4 agonists, BIMU 8.
(11) All new compounds were fully characterized (1H NMR,
13C NMR and HRMS) and exhibited spectroscopic data
consistent with their structures. Yields refer to isolated and
chromatographically pure compounds.
Typical Experimental Procedure.
In summary, we describe a novel, and efficient method for
the preparation of N-isopropyl aromatic amines10 using 2-
methoxypropene under reductive amination conditions.
The methodology was also extended to commercially
available trimethylsilyl enol ethers. Finally, it is a method
of choice for reductive amination of weakly nucleophilic
aromatic amines and sterically hindered unreactive carbo-
nyl compounds.11
To a stirred solution of anilines (2.0 mmol) in DCE (6.0 mL)
under nitrogen was added sequentially 2-methoxypropene
(0.287 mL, 3.0 mmol), HOAc (0.114 mL, 2.0 mmol) and
NaBH(OAc)3 (636 mg, 3.0 mmol). After stirring at r.t. for
required time, then reaction mixture was quenched with aq 1
N NaOH solution and extracted with CH2Cl2 (3 × 10 mL).
The combined organic extracts were washed with brine and
dried (Na2SO4). Concentration of the extracts gave
essentially pure product. However, the crude product was
purified on small plug of silica gel using EtOAc–hexane
mixture (1:20) as an eluent produced N-isopropylaromatic
amine derivatives.
Acknowledgment
Authors thank to Drs. Oswy Pereira and Laval Chan for useful dis-
cussions. M. Leclair thanks to National Centre for Engineering and
Research Council (NCERC) for financial support.
N-Isopropyl-aniline:12 1H NMR (400 MHz, CDCl3): d =
7.16 (t, J = 8.2 Hz, 2 H), 6.66 (t, J = 7.2 Hz, 1 H), 6.58 (d,
J = 8.2 Hz, 2 H), 3.90 (br s, 1 H), 3.63 (m, 1 H), 1.21 (d,
J = 6.3 Hz, 6 H).
N,N-Diisopropylaniline:13
References
2-(Isopropylamino)benzo-nitrile:14 1H NMR (400 MHz,
CDCl3): d = 7.38–7.34 (m, 1 H), 7.37 (d, J = 7.5, 1 H), 6.68–
6.60 (m, 2 H), 4.40 (br s, 1 H), 3.72 (m, 1 H), 1.26 (d, J = 6.4
Hz, 6 H). 13C NMR (100 MHz, CDCl3): d = 149.7, 134.4,
133.1, 118.3, 116.3, 111.2, 95.8, 44.3, 22.9.
(1) Present address: Merck Frosst Canada & Co., 16711 Trans
Canada Hwy, Kirkland, Quebec, H9H 3L1, Canada.
(2) For reductive amination see review: Hutchins, R. O.;
Hutchins, M. K. Comprehensive Organic Synthesis, 1st ed.,
Vol. 8; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991,
25–78.
(3) (a) Gribble, G. W.; Lord, P. D.; Skotnicki, J.; Dietz, S. E.;
Eaton, J. T.; Johnson, J. L. J. Am. Chem. Soc. 1974, 96,
7812. (b) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849;
and references cited therein.
(4) Apodaca, R.; Xiao, W. Org. Lett. 2001, 3, 1745.
(5) For combination of Ti(OPr)4 with NaBH4 or PMHS: (a) see
ref.3b (b) Chandrasekhar, S.; Reddy, C. R.; Ahmed, M.
Synlett 2000, 1655. (c) Bhattacharya, S.; Neidigh, K. A.;
Avery, M. A.; Williamson, J. S. Synlett 1999, 1781.
(6) This method seems to require prior hydrolysis of acetals or
enol ethers to carbonyl compounds catalyzed by B10H14:
Park, E. S.; Lee, J. H.; Kim, S. J.; Yoon, C. M. Synth.
Commun. 2003, 33, 3387.
(7) (a) Chan, L.; Pereira, O.; Reddy, T. J.; Das, S. K.; Poisson,
C.; Courchesne, M.; Proulx, M.; Siddiqui, A.; Yannopoulos,
C. G.; Nguyen-Ba, N.; Roy, C.; Nasturica, D.; Moinet, C.;
Bethell, R.; Hamel, M.; L’Heureux, L.; David, M.; Nicolas,
O.; Courtemanche-Asselin, P.; Brunette, S.; Bilimoria, D.;
Bédard, J. Bioorg. Med. Chem. Lett. 2004, 14, 797. (b) For
preliminary presentation see: Reddy, T. J.; Leclair, M.;
Proulx, M.; Quebec and Ontario Mini Symposium in
Organic Synthesis November, 2002. (c) There were only
two methods available when we carried out our first
experiment, see ref. 3.
N-Isopropyl-2-nitroaniline:15 1H NMR (400 MHz, CDCl3):
d = 8.17 (d, J = 8.6 Hz, 1 H), 8.02 (br s, 1 H), 7.42 (t, J = 8.5
Hz, 1 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.61 (d, J = 8.2 Hz, 1 H),
3.84 (m, 1 H), 1.34 (d, J = 6.3 Hz, 6 H). 13C NMR (100 MHz,
CDCl3): d = 145.0, 136.4, 132.0, 127.3, 115.1, 114.4, 44.1,
22.9.
Ethyl 2-(isopropylamino)benzoate: 1H NMR (400 MHz,
CDCl3): d = 7.93 (d, J = 8.1 Hz, 1 H), 7.76 (br s, 1 H), 7.35
(t, J = 8.5 Hz, 1 H), 6.74 (d, J = 8.6 Hz, 1 H), 6.58 (t, J = 7.5
Hz, 1 H), 4.31 (q, J = 7.2 Hz, 2 H), 3.72 (br s, 1 H), 1.38 (t,
J = 7.0 Hz, 3 H), 1.28 (d, J = 6.3 Hz, 6 H). 13C NMR (100
MHz, CDCl3): d = 169.0, 150.7, 134.7, 132.0, 114.2, 111.9,
110.1, 60.4, 43.5, 23.0, 14.6. HRMS (FAB+): m/z calcd for
C12H17NO2 [M + H]+: 208.1338; found: 208.1324.
N-Isopropyl-2-methylaniline: 1H NMR (400 MHz,
CDCl3): d = 7.12 (dt, J = 1.6, 7.2 Hz, 1 H), 7.05 (d, J = 7.6
Hz, 1 H), 6.64–6.60 (m, 2 H), 3.70–3.66 (m, 1 H), 3.30 (br s,
1 H), 2.12 (s, 3 H), 1.25 (d, J = 6.3 Hz, 6 H). 13C NMR (100
MHz, CDCl3): d = 145.6, 130.5, 127.3, 121.9, 116.6, 110.5,
44.2, 23.5, 17.8. HRMS (FAB+): m/z calcd for C10H15N [M
+ H]+: 150.1283; found: 150.1283.
N,2-Diisopropylaniline: 1H NMR (400 MHz, CDCl3): d =
7.16–7.08 (m, 2 H), 6.70 (t, J = 7.3 Hz, 1 H), 6.66 (d, J = 7.9
Hz, 1 H), 3.72–3.66 (m, 1 H), 3.48 (br s, 1 H), 2.87–2.80 (m,
1 H), 1.25 (d, J = 6.7 Hz, 6 H), 1.24 (d, J = 6.3 Hz, 6 H). 13
NMR (100 MHz, CDCl3): d = 144.4, 132.2, 127.0, 125.3,
117.0, 111.4, 44.4, 27.4, 23.5, 22.6. HRMS (FAB+): m/z
calcd for C12H19N [M + H]+: 178.1596; found: 178.1596.
C
Synlett 2005, No. 4, 583–586 © Thieme Stuttgart · New York

586
T. J. Reddy et al.
LETTER
(2-Fluorophenyl)-isopropylamine: 1H NMR (400 MHz,
CDCl3): d = 7.02–6.92 (m, 2 H), 6.70 (dt, J = 8.4, 1.6 Hz, 1
H), 6.62–6.56 (m, 1 H), 3.70 (br s, 1 H), 3.67–3.61 (m, 1 H),
1.24 (d, J = 6.2 Hz, 6 H). 13C NMR (100 MHz, CDCl3): d =
151.8 (d, J = 239 Hz), 136.2, 124.8, 116.3 (d, J = 7.6 Hz),
114.7 (d, J = 19.1 Hz), 112.8, 44.3, 23.2. HRMS (FAB+):
m/z calcd for C9H12NF [M + H]+: 154.1032; found:
154.1032.
N-Cyclopentylaniline: 1H NMR (400 MHz, CDCl3): d =
7.17 (m, 2 H), 6.68 (t, J = 2.1 Hz, 1 H), 6.61 (dd, J = 8.6, 1.0
Hz, 2 H), 3.82–3.67 (m, 2 H), 2.06–1.98 (m, 2 H), 1.76–1.43
(m, 6 H). 13C NMR (100 MHz, CDCl3): d = 148.3, 129.4,
117.1, 113.4, 54.9, 33.8, 24.3. HRMS (FAB+): m/z calcd for
C11H15N [M + H]+: 162.1283; found: 162.1283.
N-(1-Phenylethyl)aniline:18 1H NMR (400 MHz, CDCl3):
d = 7.38–7.21 (m, 5 H), 7.11–7.07 (m, 2 H), 6.66 (t, J = 7.5
Hz, 1 H), 6.53 (d, J = 7.9 Hz, 2 H), 4.49 (q, J = 6.7 Hz, 1 H),
1.53 (d, J = 6.7 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d =
147.6, 145.6, 129.4, 129.0, 127.2, 126.2, 117.6, 113.6, 53.8,
25.4.
(2-Iodophenyl)-isopropylamine: 1H NMR (400 MHz,
CDCl3): d = 7.65 (d, J = 7.8 Hz, 1 H), 7.19 (t, J = 8.2 Hz, 1
H), 6.60 (d, J = 8.1 Hz, 1 H), 6.42 (t, J = 7.5 Hz, 1 H), 3.68–
3.65 (m, 1 H), 1.26 (d, J = 6.3 Hz, 6 H). 13C NMR (100 MHz,
CDCl3): d = 146.8, 139.4, 129.6, 118.4, 111.4, 86.1, 44.9,
23.2. HRMS (FAB+): m/z calcd for C9H12NI [M + H]+:
262.0094; found: 262.0093.
1-Methyl-N-phenylpiperidin-4-amine: 1H NMR (400
MHz, CDCl3): d = 7.18–7.14 (m, 2 H), 6.68 (dt, J = 7.3, 1.0
Hz, 1 H), 6.61–6.58 (m, 2 H), 3.49 (br s, 1 H), 3.29 (br s, 1
H), 2.82 (m, 2 H), 2.31 (s, 3 H), 2.17–2.05 (m, 4 H), 1.54–
1.46 (m, 2 H). 13C NMR (100 MHz, CDCl3): d = 146.5,
129.5, 117.5, 113.5, 55.0, 47.5, 33.5. HRMS (FAB+): m/z
calcd for C12H18N2 [M + H]+: 191.1548; found: 191.1548.
Methyl 3-(Isopropyl-amino)-5-phenylthiophene-2-
carboxylate: 1H NMR (400 MHz, CDCl3): d = 7.64–7.61
(m, 2 H), 7.43–7.34 (m, 3 H), 6.86 (s, 1 H), 6.71 (br s, 1 H),
3.83 (s, 3 H), 3.78–3.74 (m, 1 H), 1.29 (d, J = 6.4 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 165.4, 155.8, 149.8, 133.7,
129.0, 126.1, 112.2, 97.4, 51.0, 46.3, 43.5, 23.5. HRMS
(FAB+): m/z calcd for C15H17NO2S [M + H]+: 276.1059;
found: 276.1059.
N-Isopropyl-2-methoxyaniline:16 1H NMR (400 MHz,
CDCl3, 8:1): d = 6.86 (dt, J = 7.6, 1.5 Hz, 1 H), 6.76 (dd,
J = 7.8, 1.3 Hz, 1 H), 6.66–6.60 (m, 2 H), 4.05 (br s, 1 H),
3.84 (s, 3 H), 3.65–6.59 (m, 1 H), 1.24 (d, J = 6.3 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 147.0, 137.6, 121.5, 116.1,
110.5, 109.7, 55.6, 44.0, 23.3.
1-[3-(Isopropylamino)phenyl]-ethanone: 1H NMR (400
MHz, CDCl3): d = 7.27–7.22 (m, 2 H), 7.21–7.18 (m, 1 H),
6.83–6.79 (m, 1 H), 3.72–3.66 (m, 1 H), 2.56 (s, 3 H), 1.23
(d, J = 6.3 Hz, 6 H). 13C NMR (100 MHz, CDCl3): d = 199.0,
147.9, 138.4, 129.6, 118.2, 117.6, 112.2, 44.4, 27.0, 23.1.
HRMS (FAB+): m/z calcd for C11H15NO [M + H]+:
178.1231; found: 178.1232.
Methyl 3-(Isopropyl-amino)thiophene-2-carboxylate: 1H
NMR (400 MHz, CDCl3): d = 7.37 (d, J = 5.6 Hz, 1 H), 6.69
(d, J = 5.4 Hz, 1 H), 3.84 (s, 3 H), 3.73–3.67 (m, 1 H), 1.28
(d, J = 6.3 Hz, 6 H). 13C NMR (100 MHz, CDCl3): d = 165.5,
155.5, 98.0, 132.4, 116.4, 51.0, 46.3, 23.5. HRMS (FAB+):
m/z calcd for C9H13NO2S [M + H]+: 200.0745; found:
200.0745
N-Isopropyl-4-nitroaniline:12 1H NMR (400 MHz, CDCl3):
d = 8.08 (d, J = 9.1 Hz, 2 H), 6.50 (d, J = 8.8 Hz, 2 H), 4.40
(br s, 1 H), 3.74–3.71 (m, 1 H), 1.27 (d, J = 6.3 Hz, 6 H). 13
NMR (100 MHz, CDCl3): d = 152.9, 137.6, 126.8, 111.5,
44.5, 22.7.
C
(2,4-Dichlorophenyl)-isopropylamine: 1H NMR (400
MHz, CDCl3): d = 7.25 (m, 1 H), 7.09 (m, 1 H), 6.61 (d,
(12) Verardo, G.; Giumanini, A. G.; Strazzolini, P.; Poiana, M.
Synthesis 1993, 121.
(13) Bhaskar, J. V.; Periasamy, M. J. Org. Chem. 1993, 58, 3156.
(14) Couture, A.; Deniau, E.; Gimbert, Y.; Grandclaudon, P.
Tetrahedron 1993, 49, 1431.
J = 8.8 Hz, 1 H), 3.64–3.61 (m, 1 H), 1.25 (d, J = 6.3 Hz, 6
H). 13C NMR (100 MHz, CDCl3): d = 141.0, 127.9, 126.7,
119.6, 118.4, 111.3, 43.4, 21.8. HRMS (FAB+): m/z calcd for
C9H11NCl2 [M + H]+: 204.0348; found: 204.0347.
N-Isopropyl-N-phenylaniline: 1H NMR (400 MHz,
CDCl3): d = 7.30–7.24 (m, 4 H), 6.99 (t, J = 7.3 Hz, 2 H),
6.87–6.85 (m, 4 H), 4.37–4.30 (m, 1 H), 1.16 (d, J = 6.6 Hz,
6 H). 13C NMR (100 MHz, CDCl3): d = 146.4, 129.4, 123.1,
121.8, 48.0, 21.3. HRMS (FAB+): m/z calcd for C15H17N
[M + H]+: 212.1440; found: 212.1439.
(15) Figge, A.; Altenbach, H. J.; Brauer, D. J.; Tielmann, P.
Tetrahedron: Asymmetry 2002, 13, 137.
(16) Henke, B. R.; Aquino, C. J.; Birkemo, L. S.; Croom, D. K.;
Dougherty, R. W. Jr.; Ervin, G. N.; Grizzle, M. K.; Hirst, G.
C.; James, M. K.; Johnson, M. F.; Queen, K. L.; Sherrill, R.
G.; Sugg, E. E.; Suh, E. M.; Szewczyk, J. W.; Unwalla, R. J.;
Yingling, J.; Willson, T. M. J. Med. Chem. 1997, 40, 2706.
(17) Gasc, M. B.; Perie, J.; Lattes, A. Tetrahedron 1978, 34,
1943.
N-Cyclohexylaniline:17 1H NMR (400 MHz, CDCl3): d =
7.15 (t, J = 8.4 Hz, 2 H), 6.67 (t, J = 7.5 Hz, 1 H), 6.61 (d,
J = 8.1 Hz, 2 H), 3.28–3.23 (m, 1 H), 2.07–2.04 (m, 2 H),
1.80–1.10 (m, 8 H). 13C NMR (100 MHz, CDCl3): d = 148.0,
129.5, 117.2, 113.5, 52.0, 33.7, 26.2, 25.3.
(18) Kawakami, T.; Sugimoto, T.; Shibata, I.; Baba, A.; Matsuda,
H.; Sonoda, N. J. Org. Chem. 1995, 60, 2677.
Synlett 2005, No. 4, 583–586 © Thieme Stuttgart · New York