An efficient and economical synthesis of 5,6-diethyl-2,3-dihydro-1H-inden- 2-amine hydrochloride

Article abstract of DOI:10.1021/op0502093

An efficient and economical synthesis of 5,6-diethyl-2,3-dihydro-1H-inden- 2-amine hydrochloride (1) utilizing 2-aminoindan as a cheap and commercially readily available starting material is described. The newly developed synthesis involves six-steps with 49% overall yield, and it introduces two ethyl groups at the 5- and 6-positions via sequential regioselective Friedel-Crafts acetylations and hydrogenations of N-protected-2-aminoindan. The Friedel-Crafts acetylations can be carried out neat with high regioselectivity using acetyl chloride as the reagent as well as the solvent, thus avoiding the use of halogenated solvents.

Full text of DOI:10.1021/op0502093

Organic Process Research & Development 2006, 10, 135−141
An Efficient and Economical Synthesis of
5,6-Diethyl-2,3-dihydro-1H-inden-2-amine Hydrochloride
Mahavir Prashad,* Bin Hu, Denis Har, Oljan Repicˇ, and Thomas J. Blacklock
Process R&D, Chemical and Analytical DeVelopment, NoVartis Pharmaceuticals Corporation,
One Health Plaza, East HanoVer, New Jersey 07936, U.S.A.
Olivier Lohse
Process R&D, Chemical and Analytical DeVelopment, NoVartis Pharma AG, CH-4002 Basel, Switzerland
Abstract:
acidic conditions involving Friedel-Crafts acetylation and
An efficient and economical synthesis of 5,6-diethyl-2,3-dihydro-
1H-inden-2-amine hydrochloride (1) utilizing 2-aminoindan as
a cheap and commercially readily available starting material
is described. The newly developed synthesis involves six-steps
with 49% overall yield, and it introduces two ethyl groups at
the 5- and 6-positions via sequential regioselective Friedel-
Crafts acetylations and hydrogenations of N-protected-2-ami-
noindan. The Friedel-Crafts acetylations can be carried out
neat with high regioselectivity using acetyl chloride as the
reagent as well as the solvent, thus avoiding the use of
halogenated solvents.
readily removed under basic conditions afterwards.
The protection of the amino group in 2-aminoindan (2)
with trifluoroacetyl group was first carried out with trifluo-
roacetic anhydride. However, ethyl trifluoroacetate is the
preferred choice because it is easier to handle on a large
scale in the pilot plant. The reaction of 2 with ethyl
trifluoroacetate in isopropyl acetate at 0-10 °C followed by
addition of heptane afforded N-(2,3-dihydro-1H-inden-2-yl)-
2,2,2-trifluoroacetamide (3) as a crystalline solid in 83.4%
yield (Scheme 2).
The Friedel-Crafts acetylation of 2-acetamidindan was
reported in patent literature3 using AlCl3 (0.8 equiv) and
acetyl chloride (0.48 equiv) in 1,2-dichloroethane to afford
very low yield (30%) of 2-acetamide-5-acetylindan.
We first focused on optimizing the amounts of AlCl3 and
acetyl chloride using dichloromethane as the solvent for the
regioselective 5-acetylation of 3. The reaction of 3 was
incomplete with less than 2 equiv of AlCl3, while it was
complete with 2.5 equiv or more. Thus, 2.5 equiv of AlCl3
was determined to be optimum. The amount of acetyl
chloride was optimized to be 3.0 equiv. AlCl3 (2.5 equiv)
was first added to dichloromethane at room temperature
followed by a slow addition of acetyl chloride (3.0 equiv)
at 0-5 °C. Finally, solid 3 was added in five equal portions
at 0-5 °C to afford a solution. The reaction was highly
regioselective as only 5-6% of the 4-regioisomer was
detected. The desired regioisomer 4 was isolated in 88.7%
yield without a significant amount of the undesired 4-re-
gioisomer. After the addition of substrate 3, the reaction was
stirred at 0-5 °C for additional 1 h. If the reaction was stirred
at room temperature for prolonged period of time, it turned
dark and resulted in a retro-Friedel-Crafts, liberating starting
material 3, due to deacetylation.
Introduction
5,6-Diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride
(1) serves as an important intermediate in the synthesis of
indacaterol (QAB149), a potent once-a-day â2-agonist.1 The
original synthesis1 of this intermediate possessed several
shortcomings and was not suitable for large-scale production.
Our goal was to develop an efficient and economical
synthesis of 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hy-
drochloride (1) suitable for scale-up in the pilot plant. In
this paper we describe an efficient and economical six-step
synthesis of 1 from 2-aminoindan (Scheme 1).
Results and Discussion
Our approach to 5,6-diethyl-2,3-dihydro-1H-inden-2-
amine hydrochloride (1) was based on utilizing 2-aminoindan
as a cheap ($189/kg) and commercially available starting
material (Scheme 1). Utilizing an acetyl group as a synthon
for the ethyl group, we rationalized that a sequence of
regioselective Friedel-Crafts acetylations and hydrogena-
tions starting with N-protected-2-aminoindan would furnish
the desired 5,6-diethyl-2-aminoindan in an efficient manner.
We previously reported2 regioselective bromination of
2-aminoindan at the 5-position. The trifluoroacetyl group was
chosen as the protecting group because it will be stable under
It was desirable to eliminate the use of dichloromethane
as the solvent in this reaction. Friedel-Crafts acetylation of
3 using acetic anhydride as the acetylating agent in aceto-
nitrile in the presence of catalytic Sc(OTf)3 was not suc-
cessful.4
* To whom correspondence should be addressed.
(1) Cuenoud, B.; Bruce, I.; Fairhurst, R.; Beattie, D. WO 00/75114, December
14, 2000.
(3) Nunokawa,Y.; Nakatsuka, T.; Saitoh, M.; Abe, K. EP 1018514A1, July
12, 2000.
(2) Prashad, M.; Hu, B.; Har, D.; Repicˇ, O.; Blacklock, T. J.; Acemoglu, M.
AdV. Synth. Catal. 2001, 343, 461-472.
(4) Kawada, A.; Mitamura, S.; Matsuo, J.; Tsuchiya, T.; Kobayashi, S. Bull.
Chem. Soc. Jpn. 2000, 73, 2325-2333.
10.1021/op0502093 CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/14/2005
Vol. 10, No. 1, 2006 / Organic Process Research & Development
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135

Scheme 1
Scheme 2
We next decided to investigate the Friedel-Crafts acety-
We examined the hydrogenation of 4 in ethanol and ethyl
acetate. Both solvents gave satisfactory results. Ethyl acetate
was selected for initial development. Degussa catalyst E101
NE/W, which is 10% Pd on carbon (50% wet), was used
for the hydrogenation. The amount of catalyst, 10% of weight
of the substrate 4, was optimized for this hydrogenation. The
reaction worked well under atmospheric pressure and at room
temperature. Due to the operational difficulty of removing
the oxygen in the headspace of the reactor by hydrogen at
atmospheric pressure in the pilot plant, we decided to conduct
this hydrogenation at 40 psig. The reaction was complete in
4 h. The corresponding alcohol intermediate was observed
in the beginning of the reaction, but it was not detectable at
the end of the reaction. To achieve maximum throughput,
the reaction was performed in 3.5 mL of ethyl acetate per
gram of 4. At room temperature, 4 was not completely
soluble in this amount of ethyl acetate. However, a complete
solution was obtained as the reaction progressed. After the
hydrogenation and removal of the catalyst by filtration, the
solvent was switched to heptane, and the resulting suspension
was stirred at 40 °C for 30 min and then slowly cooled to
room temperature with efficient stirring. Product 5 was
isolated by filtration in 91% yield with 99.8% HPLC purity.
Any undesired 4-regioisomer of 5 was not efficiently
removed in this process. It was mainly purified during the
isolation of 7 in the second hydrogenation step.
lation using acetyl chloride both as the acetylating agent as
well as the solvent. When the usual amounts of AlCl3 (2.5
equiv), acetyl chloride (3.0 equiv), and 3 (1.0 equiv) were
used for the reaction, the initial slurry became a solution,
and then it solidified. On the other hand, with more acetyl
chloride (g6.0 equiv), the reaction proceeded well, and it
remained a solution. Therefore, the amount of acetyl chloride
was optimized to be 6.0 equiv and that of AlCl3 2.5 equiv.
Thus, AlCl3 was added to cooled acetyl chloride (0-5 °C)
in four equal portions. After the addition of AlCl3, substrate
3 was added in five equal portions to obtain a clear solution.
After stirring at 0-5 °C for 1 h, the reaction mixture was
diluted with heptane and reverse-quenched into a mixture
of 1 N HCl and isopropyl acetate. The mixture was stirred
at room temperature for 1 h and at 40-45 °C for 45 min.
The product was isolated by cooling the mixture to room
temperature and filtration. The yield of 4 was 90% with
undetectable amounts of the undesired 4-regioisomer. The
product contained 0.5% of aluminum. A use-test showed that
it had no effect on the next hydrogenation step and was
removed in the workup. To assess tolerability of the
undesired 4-regioisomer in 4 on the quality of 1, we observed
that 4, containing 3% of the undesired 4-regioisomer,
afforded 1 of the desired purity. The 4-regioisomer can also
be removed by reslurrying the crude 4 in isopropyl acetate
and heptane (1/4.6) at 72-75 °C for 3 h.
The hydrogenation of 4 in ethanol was then carried out
with a lesser amount of 5% Pd on carbon. The product was
crystallized from a mixture of ethanol and water to afford 5
in 95.9% yield with no detectable amounts of the undesired
regioisomer.
With successful regioselective Friedel-Crafts acetylation
conditions in hand, our next goal was to reduce the acetyl
group to the ethyl group. Such a conversion was reported in
a patent by hydrogenation over Pd-C in THF.5
Similar to the previous Friedel-Crafts acetylation of 3
to 4, the acetylation of 5 was first carried out in dichlo-
(5) Patsidis, K.; Palackal, S. J.; Alt, H. G. U.S. Patent 5,393,911, February 28,
1995.
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romethane. The ratio of the desired regioisomer 6 to the
undesired regioisomer was ∼90 to 10 in the crude reaction
mixture. Again, prolonged reaction at higher temperature
(room temperature) resulted in a dark reaction mixture and
decomposition. Thus, acetyl chloride (3.0 equiv) was added
slowly at 0-5 °C to a mixture of AlCl3 (2.5 equiv) in
dichloromethane. Then, solid 5 was added in five equal
portions at 0-5 °C to obtain a solution. The desired
regioisomer 6 was obtained in 94% yield containing 6-7%
of the undesired regioisomer. Since the undesired regioisomer
was lowered to 1.2% during the isolation of 7 in the next
hydrogenation step, crude 6 was used as such. However, 6
could be recrystallized from a mixture of dichloromethane
and heptane (1:4 v/v) to achieve higher purity (<1.5% of
the undesired regioisomer), but the yield was significantly
lower (85%).
Similar to previous Friedel-Crafts acetylation, dichlo-
romethane was eliminated by using acetyl chloride as a
reagent as well as the solvent. While 2.5 equiv of AlCl3 was
satisfactory, 12.0 equiv of acetyl chloride had to be used.
The reaction mixture was again quenched into a mixture of
1 N HCl and isopropyl acetate, and the product 6 was isolated
in 94% yield by the addition of heptane, and it contained
9% of the undesired regioisomer.
The reduction of the acetyl group in 6 to the ethyl group
was achieved by hydrogenation using 10% Pd/C catalyst in
ethyl acetate. However, in this case we observed that the
conversion of the alcohol intermediate to the ethyl group
was much slower, and it required ∼14 h to convert the
alcohol intermediate to 7 at room temperature under 40 psig
of hydrogen. We, therefore, decided to examine this hydro-
genation at higher temperature. We found that the conversion
of the alcohol intermediate to the product 7 was complete
in 3 h at 50 °C. Thus, we optimized the reaction conditions
that involved the hydrogenation first at the room temperature
for 2 h, and then at 50 °C for 2.5 h, which converted all the
alcohol intermediate to the product 7. The workup was also
similar to the previous hydrogenation. A solvent switch to
heptane was carried out by concentrating the filtrate after
removing the catalyst. The heptane suspension was stirred
at 50-60 °C for 3 h. This procedure was highly efficient to
remove the undesired regioisomer in the mother liquor. The
reaction mixture containing 10% undesired regioisomer could
be purified to give 7 with <2.5% of the regioisomer in 85%
or higher yield.
We found that a homogeneous mixture of 6 N NaOH and
ethanol (1:1 v/v) at reflux led to a fast (1 h) and clean
deprotection under nitrogen. After workup, a solution of the
free base of 1 was obtained, which was concentrated to
remove residual H2O azeotropically. The free base of 1 was
converted to the HCl salt by a slow addition of the free base
solution to 1.43 equiv of a 2 N solution of HCl gas in
isopropyl acetate at 20-30 °C. The salt formation can also
be carried out using HCl gas above the surface rather than
a solution. The crude 1 still contained some of the undesired
regioisomer carried over from 6. The crude product was then
recrystallized from a mixture of ethanol and isopropyl acetate
to afford pure 1 with no detectable regioisomeric impurity.
Thus, 2.5% of the undesired regioisomer was efficiently
removed to nondetectable amounts.
In summary, an efficient and economical synthesis of 5,6-
diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (1) uti-
lizing 2-aminoindan as a cheap and commercially readily
available starting material is described (Scheme 2).6 The
newly developed synthesis involves six steps with 49%
overall yield, and it introduces two ethyl groups at the 5-
and 6-positions via sequential regioselective Friedel-Crafts
acetylations and hydrogenations of N-protected-2-aminoin-
dan. The Friedel-Crafts acetylations can be carried out neat
with high regioselectivity using acetyl chloride as the reagent
as well as the solvent, thus avoiding the use of halogenated
solvents.
Experimental Section
Melting points were measured on a Buchi 535 melting
point apparatus. 1H and 13C NMR spectra were recorded on
a Bruker 300 instrument.
N-(2,3-Dihydro-1H-inden-2-yl)-2,2,2-trifluoroaceta-
mide (3). A 1-L, three-necked, round-bottomed flask,
equipped with a mechanical stirrer, digital thermometer,
cooling bath, and nitrogen inlet-outlet, was charged with
2-aminoindan (2, 104.0 g, 781.0 mmol) and isopropyl acetate
(200.0 mL). The solution was cooled to an internal temper-
ature at 0-5 °C, and ethyl trifluoroacetate (133.0 g, 936.0
mmol) was added over 40 min while maintaining the internal
temperature at 0-10 °C. The thick slurry was stirred at 0-10
°C for 2 h and then warmed to 20-25 °C over 30 min.
Heptane (60.0 mL) was added, and the stirring was continued
for an additional 30 min. The solids were collected by
filtration, and washed with heptane (3 × 50.0 mL) or until
the filtrate was colorless. The solids were dried at 60-65
°C in vacuo to afford N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-
trifluoroacetamide (3, 149.2 g, 83.4%): mp 153-155 °C;
1H NMR (CDCl3, δ) 2.89 (dd, 2H, J ) 4.4 and 16.4 Hz),
3.38 (dd, 2H, J ) 7.1 and 16.4 Hz), 4.76 (m, 1H), 6.54 (br,
1H), 7.19-7.24 (m, 4H); 13C NMR (CDCl3, δ) 39.97, 51.62,
125.30, 127.59, 140.24; Calc for C11H10F3NO: C, 57.64; H,
4.40; N, 6.11; F, 24.87. Found: C, 57.55; H, 4.22; N, 6.07;
F, 24.94.
The hydrogenation of 6 in ethanol was then carried out
with a lesser amount of 5% Pd on carbon. The product was
crystallized from a mixture of ethanol and water to afford 7
in 82.5% yield.
Having introduced the two ethyl groups at the 5- and
6-positions of 2-aminoindan, the final step was the depro-
tection of the trifluoroacetyl group. The deprotection of the
trifluoroacetyl protecting group in 7 was studied under basic
conditions. No significant hydrolysis was observed with
NaOMe in refluxing methanol. In a biphasic solvent system
using aqueous NaOH and an organic solvent, such as
isopropyl acetate or toluene, the hydrolysis was incomplete,
even in the presence of a phase-transfer catalyst (Bu4NBr).
N-(5-Acetyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoro-
acetamide (4). Procedure 1: RegioselectiVe Friedel-Crafts
Acetylation of 3 in Dichloromethane. A 1-L, four-necked,
(6) Prashad, M.; Lohse, O.; Hu, B. WO 03/076387, March 7, 2003.
Vol. 10, No. 1, 2006 / Organic Process Research & Development
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137

round-bottomed flask (rinsed with dichloromethane), equipped
with a mechanical stirrer, digital thermometer, cooling bath,
and nitrogen inlet-outlet, was charged with aluminum
chloride (102.0 g, 765.0 mmol) and dichloromethane (280.0
mL) at 20-25 °C. The slurry was cooled to an internal
temperature at 0-5 °C, and acetyl chloride (72.0 g, 917.0
mmol) was added over 20 min while maintaining the
temperature at 0-5 °C. The white suspension was stirred at
0-5 °C for 15 min and N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-
trifluoroacetamide (3, 70.0 g, 305.0 mmol) was added in five
equal portions (14.0 g each) at 5-min intervals (total time )
25 min) while maintaining the internal temperature at 0-7
°C. Dichloromethane (20.0 mL) was added to wash off any
solids sticking to the wall of the flask. The resulting tan
solution was stirred at 0-5 °C for 1 h and then added to 1
N HCl (500.0 mL, precooled to 0-5 °C) in a 2-L, three-
necked, round-bottomed flask, equipped with a mechanical
stirrer, digital thermometer, and a cooling bath, while
maintaining the temperature at 0-25 °C. The 1-L, round-
bottomed flask and the transferring tube were rinsed with
dichloromethane (40.0 mL) and the dichloromethane added
to the reaction mixture. The biphasic reaction mixture was
warmed to 20-25 °C. The layers were separated, and the
organic layer was washed with water (100.0 mL).
temperature at 0-10 °C. The resulting tan solution was
stirred at 0-5 °C for 1 h. To the solution was added heptane
(400.0 mL) at 0-5 °C. The resulting biphasic mixture was
added to a precooled (0 to -5 °C) mixture of 1 N HCl (650.0
mL) and isopropyl acetate (125.0 mL) in a 5-L, three-necked,
round-bottomed flask, equipped with a mechanical stirrer,
digital thermometer, and a cooling bath, over a period of 20
min while maintaining the internal temperature at 0-25 °C.
The 1-L round-bottomed flask was rinsed with acetyl chloride
(20.0 mL), followed by heptane (110.0 mL), and the rinses
were added to the batch. The reaction mixture was warmed
to 22-24 °C over a period of 30 min, then heated to an
internal temperature at 40-45 °C, and stirred at 40-45 °C
for 1 h. The slurry was cooled to 21-25 °C and stirred for
1 h. The solids were collected by filtration, washed with
heptane (2 × 200.0 mL), followed by 1 N HCl (350.0 mL)
and deionized water (2 × 200.0 mL). The solids were dried
at 60-65 °C in vacuo to afford N-(5-acetyl-2,3-dihydro-1H-
inden-2-yl)-2,2,2-trifluoroacetamide (4, 106.1 g, 90.0%).
N-(5-Ethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoro-
acetamide (5). Procedure 1: Hydrogenation of 4 in Ethyl
Acetate. A 1-L Buchi reactor was charged with N-(5-acetyl-
2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (4, 100.0
g, 368.7 mmol), 10% Pd-C (10.0 g, 50% water), and ethyl
acetate (350.0 mL) to obtain a suspension. The reactor was
sealed and pressurized with N2 to 40 psig. The N2 was vented
and the process repeated two more times. The reactor was
again repressurized with N2 to 40 psig, and agitation was
started at 300 rpm. The reaction mixture was heated to 25
°C and held for 10 min to stabilize the temperature. Agitation
was stopped, and the N2 was vented. The reactor was
pressurized with H2 to 40 psig, which was then vented. This
process was repeated two more times and the reactor was
repressurized with H2 to 40 psig. The in-line pressure
regulator was set to maintain 40 psig of H2 inside the reactor,
and the hydrogen supply valve was opened. Agitation was
started at 450 rpm. The heterogeneous reaction mixture was
stirred at 23-25 °C and 450 rpm for 4 h. The hydrogen
supply valve was closed, and the H2 was vented. The reactor
was purged three times with N2, the reaction mixture was
filtered over a pad of Celite (15.0 g), and the filtrate was
saved. The reactor vessel was rinsed with ethyl acetate (210.0
mL) and filtered through the Celite pad. The cake was
washed with ethyl acetate (210.0 mL).
The organic layer was transferred to a 2-L, four-necked,
round-bottomed flask, equipped with a mechanical stirrer,
digital thermometer, addition funnel, nitrogen inlet-outlet,
a reflux condenser, and a heating mantle. The solution was
warmed to an internal temperature at 40 ( 3 °C to achieve
gentle refluxing. Heptane (1.2 L) was added slowly over a
period of 50 min while maintaining the temperature at 40-
55 °C to maintain a gentle reflux. The resulting slurry was
stirred at 55-58 °C for an additional 30 min. The suspension
was cooled to 20-25 °C over a period of 30 min with
efficient stirring and stirred at 20-25 °C for an additional 2
h. The solids were collected by filtration, washed with a
mixture of dichloromethane/heptane (2 × 100.0 mL, 20:80
v/v), and dried at 60-65 °C in vacuo to afford N-(5-acetyl-
2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (4, 73.4
1
g, 88.7%): mp 112-114 °C; H NMR (CDCl3, δ) 2.52 (s,
3H), 2.94-3.01 (m, 2H), 3.36-3.44 (m, 2H), 4.80 (m, 1H),
7.23 (br, 1H), 7.27-7.32 (m, 1H), 7.74-7.77 (m, 2H); 13C
NMR (CDCl3, δ) 26.98, 39.44, 39.97, 51.58, 125.01, 125.25,
128.17, 136.75, 141.17, 143.36, 198.46; Calc for C13H12F3-
NO2: C, 57.57; H, 4.46; N, 5.16; F, 21.01. Found: C, 57.45;
H, 4.48; N, 5.07; F, 20.93.
Procedure 2: RegioselectiVe Friedel-Crafts Acetylation
of 3 in Acetyl Chloride. A 1-L, three-necked, round-bottomed
flask, equipped with a mechanical stirrer, digital thermom-
eter, cooling bath, and nitrogen inlet-outlet, was charged
with acetyl chloride (205.5 g, 2.62 mol) and cooled to an
internal temperature of 0-5 °C. Aluminum chloride (145.5
g, 1.09 mol) was added in four equal portions (36.4 g each)
at such a rate to maintain the internal temperature below 15
°C. The slurry was cooled to 0-5 °C and stirred for 15 min.
N-(2,3-Dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (3,
100.0 g, 0.436 mol) was added in five equal portions (20.0
g each) at 10-min intervals while maintaining the internal
The filtrates were combined and transferred to a 2-L, four-
necked, round-bottomed flask, equipped with a mechanical
stirrer, digital thermometer, addition funnel, nitrogen inlet-
outlet, and heating mantle. The combined filtrates were
concentrated in vacuo at 35-40 °C to collect approximately
670 mL of solvent to obtain approximately 100 mL of a
suspension. Heptane (870.0 mL) was added and the solution
was concentrated to collect approximately 270 mL of solvent
to obtain approximately 700 mL of a slurry. Heptane (270.0
mL) was added, and the suspension was concentrated to
collect approximately 270 mL of solvent to obtain ap-
proximately 700 mL of a slurry. Heptane (270.0 mL) was
added to obtain approximately 1000 mL of a suspension.
The suspension was stirred at 35-40 °C for 30 min. The
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suspension was cooled to 20-25 °C over a period of 30
min with efficient stirring. Stirring was continued at this
temperature for an additional 2 h. The solids were collected
by filtration, washed with heptane (100.0 mL) in two equal
portions of 50 mL each, and dried at 60-65 °C in vacuo to
afford N-(5-ethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluo-
roacetamide (5, 87.0 g, 91.0%): mp 112-114 °C; 1H NMR
(CDCl3, δ) 1.23 (t, 3H, J ) 7.5 Hz), 2.63 (q, 2H, J ) 7.5
Hz), 2.80-2.88 (m, 2H), 3.29-3.38 (m, 2H), 4.75 (m, 1H),
6.63 (br, 1H), 7.04-7.09 (m, 2H), 7.16 (d, 1H, J ) 7.7 Hz);
13C NMR (CDCl3, δ) 16.25, 29.12, 39.68, 40.01, 51.80,
124.77, 125.09, 127.29, 137.42, 140.41, 143.96; Calc for
C13H14F3NO: C, 60.70; H, 5.49; N, 5.37. Found: C, 60.67;
H, 5.48; N, 5.44.
wall of the flask. The solution was stirred at 0-5 °C for an
additional 1 h.
A 3-L, four-necked, round-bottomed flask, equipped with
a mechanical stirrer, digital thermometer, addition funnel,
nitrogen inlet-outlet, and heating cooling bath, was charged
with 1 N hydrochloric acid (1.0 L) and cooled to an internal
temperature at 0-5 °C. The reaction mixture was added to
hydrochloric acid solution over a period of 45 min while
maintaining the internal temperature below 25 °C. Dichlo-
romethane (2 × 90.0 mL) was used to rinse the reaction
flask and the transferring pipe and was then added to the
quenched mixture. The organic layer was separated and
saved. The aqueous layer was extracted with dichloromethane
(150.0 mL). The organic layers were combined and washed
with water (500.0 mL).
Procedure 2: Hydrogenation of 4 in Ethanol. A reactor
was charged with N-(5-acetyl-2,3-dihydro-1H-inden-2-yl)-
2,2,2-trifluoroacetamide (4, 108.5 g, 400.0 mmol) and ethanol
(94%; 542.0 mL). After inertizing the suspension with N2,
5% Pd-C (5.42 g, 50% water) was added. After inertizing
with N2 the reactor was pressurized with H2 to 3 bar at 25
°C internal temperature. The reaction mixture was hydro-
genated until no H2 was consumed. The hydrogen was
replaced with N2, the reaction mixture was filtered, and the
filtrate was saved. The reactor vessel was rinsed with ethanol
(109.0 mL) and filtered to wash the cake. The filtrates were
combined and transferred to another flask. The reactor was
washed with ethanol (50.0 mL). The combined filtrates were
concentrated at 95-105 °C (jacket temperature) and 70-80
°C (internal temperature) to collect approximately 290.0 mL
of solvent. Water (260.0 mL) was added at 70-80 °C
(internal temperature) within 30-60 min. The clear solution
was cooled to 65 °C and seeded at this temperature with 5.
The mixture was then cooled to 0-5 °C in 1 h, and stirred
at this temperature for additional 2 h. The solids were
collected by filtration, washed with a precooled (0 °C)
mixture of ethanol and water (1:1 v/v; 102.0 mL), and dried
at 50 °C in vacuo (20 mbar) for 20 h to afford N-(5-ethyl-
2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (5, 98.6
g, 95.9%).
N-(5-Acetyl-6-ethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-
trifluoroacetamide (6). Procedure 1: RegioselectiVe Friedel-
Crafts Acetylation of 5 in Dichloromethane. A 2-L, four-
necked, round-bottomed flask, equipped with a mechanical
stirrer, digital thermometer, addition funnel, nitrogen inlet-
outlet, and heating cooling bath, was charged with aluminum
chloride (194.4 g, 1457.7 mmol) and dichloromethane (525.0
mL). The mixture was stirred to give a suspension which
was cooled to an internal temperature at 0 ( 5 °C over a
period of 15 min. Acetyl chloride (137.3 g, 1749.2 mmol)
was added over a period of 30 min while maintaining the
internal temperature at 0 ( 5 °C. A suspension was obtained,
which was stirred at this temperature for an additional 15
min. N-(5-Ethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoro-
acetamide (5, 150.0 g, 583.1 mmol) was added in five equal
portions (30.0 g each) while maintaining the internal tem-
perature at 0 ( 5 °C. A solution was obtained when about
half of the starting material was added. Dichloromethane
(75.0 mL) was added to wash off any solids sticking on the
The organic layer was transferred to a 2-L, four-necked,
round-bottomed flask, equipped with a mechanical stirrer,
digital thermometer, addition funnel, nitrogen inlet-outlet,
and heating mantle. The organic layer was concentrated at
atmospheric pressure at 40 ( 3 °C to collect approximately
700 mL of solvent to obtain approximately 340 mL of
solution. Heptane (1.125 L) was added over a period of 15
min while maintaining the internal temperature at 40-50
°C (gentle refluxing) with efficient stirring. A solid precipi-
tated out. The resulting suspension was stirred at 55 ( 3 °C
(gentle refluxing) for an additional 30 min. The suspension
was cooled to an internal temperature at 20-25 °C over a
period of 1 h with efficient stirring. The suspension was
stirred at 20-25 °C for an additional 2 h. The solids were
collected by filtration, washed with a mixture of heptane/
dichloromethane (2 × 100.0 mL, 5:1, v/v), and dried at
60-65 °C in vacuo to afford N-(5-acetyl-6-ethyl-2,3-di-
hydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (6, 165.1 g,
94.0%): mp 124-127 °C; 1H NMR (CDCl3, δ) 1.18 (t, 3H,
J ) 7.5 Hz), 2.53 (s, 3H), 2.79-2.94 (m, 4H), 3.34-3.42
(m, 2H), 4.79 (m, 1H), 6.73 (br, 1H), 7.15 (s, 1H), 7.47 (s,
1H); 13C NMR (CDCl3, δ) 16.43, 23.72, 27.45, 30.32, 39.48,
39.99, 51.67, 125.64, 127.19, 137.65, 137.74, 144.07, 144.12,
202.50; Calc for C15H16F3NO2: C, 60.20; H, 5.39; N, 4.68;
F, 19.04. Found: C, 60.04; H, 5.54; N, 4.47; F, 18.89.
Procedure 2: RegioselectiVe Friedel-Crafts Acetylation
of 5 in Acetyl Chloride. A 250-mL, four-necked, round-
bottomed flask, equipped with a mechanical stirrer, digital
thermometer, cooling bath, and nitrogen inlet-outlet, was
charged with acetyl chloride (37.68 g, 480 mmol) and cooled
to an internal temperature at 0 ( 5 °C. Aluminum chloride
(13.33 g, 100 mmol) was added in four equal portions (3.33
g each) while maintaining the internal temperature below
15 °C. The resulting solution was cooled to 0 ( 5 °C and
stirred for 5 min. N-(5-Ethyl-2,3-dihydro-1H-inden-2-yl)-
2,2,2-trifluoroacetamide (5, 10.29 g, 40 mmol) was added
in five equal portions (2.06 g) at 10 min intervals while
maintaining the internal temperature at 0-10 °C. The tan
solution was stirred at 0 ( 5 °C for an additional 30 min.
The reaction mixture was added to a precooled (0-5 °C)
mixture of 1 N HCl (120.0 mL) and isopropyl acetate (13.0
mL) in a 500-mL, three-necked, round-bottomed flask,
equipped with a mechanical stirrer, digital thermometer, and
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a cooling bath, over a period of 20 min while maintaining
the internal temperature at 0-25 °C. The 250-mL round-
bottomed flask was rinsed with acetyl chloride (3.0 mL)
followed by heptane (13.0 mL) and added to the batch. The
resulting slurry was warmed to 40-45 °C over a period of
30 min and then stirred for additional 1 h. Heptane (39.0
mL) was added, and the slurry was stirred at 40-45 °C for
an additional 15 min. The slurry was cooled to 20-25 °C
and stirred for 1 h. The solids were collected by filtration,
washed with a mixture of heptane/isopropyl acetate (2 ×
10.0 mL, 80:20 v/v), followed by 1 N HCl (36.0 mL) and
deionized water (2 × 25 mL). The solids were dried at 60-
65 °C in vacuo to afford N-(5-acetyl-6-ethyl-2,3-dihydro-
1H-inden-2-yl)-2,2,2-trifluoroacetamide (6, 11.3 g, 94.0%).
N-(5,6-Diethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trif-
luoroacetamide (7). Procedure 1: Hydrogenation of 6 in
Ethyl acetate. A 1-L Buchi reactor was charged with N-(5-
acetyl-6-ethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroac-
etamide (6, 160.0 g, 534.6 mmol), 10% Pd-C (16.0 g, 50%
water), and ethyl acetate (560.0 mL) to obtain a suspension.
The reactor was sealed and pressurized with N2 to 40 psig,
which was then vented. This process was repeated two more
times. The reactor was repressurized with N2 to 40 psig, and
agitation was started at 650 rpm. The reaction mixture was
heated to 25 °C and held for 10 min to stabilize the
temperature. Agitation was stopped, and the N2 was vented.
The reactor was pressurized with H2 to 40 psig and then
vented. This process was repeated two more times. The
reactor was repressurized with H2 to 40 psig and the in-line
pressure regulator set to maintain 40 psig of H2. The
hydrogen supply valve was opened, and agitation was started
at 650 rpm. The heterogeneous reaction mixture was stirred
at 20-25 °C and 650 rpm for 2 h. The reaction mixture was
heated to an internal temperature at 45-50 °C over a period
of 30 min. The mixture was stirred at this temperature for
an additional 3 h. The reaction mixture was cooled to 20-
25 °C over a period of 30 min. The hydrogen supply valve
was closed, and the H2 was vented. The reactor was purged
three times with N2. The reaction mixture was filtered over
a pad of Celite (24.0 g). The filtrate was saved. The reactor
was rinsed with ethyl acetate (336.0 mL) which was filtered
through the Celite pad. The cake was washed with ethyl
acetate (336.0 mL). The filtrates were combined and
transferred to a 5-L, four-necked, round-bottomed flask,
equipped with a mechanical stirrer, digital thermometer,
addition funnel, nitrogen inlet-outlet, and heating mantle.
The filtrates were concentrated in vacuo at 35-40 °C to
collect approximately 1140 mL of solvent to obtain ap-
proximately 240 mL of a suspension. Heptane (1.4 L) was
added, and the suspension was concentrated in vacuo at 35-
40 °C to collect approximately 680 mL of solvent to obtain
approximately 960 mL of a slurry. Heptane (1.6 L) was
added to obtain approximately 2,560 mL of a suspension.
The suspension was stirred at an internal temperature at 45-
50 °C for 3 h. The suspension was cooled to an internal
temperature at 20-25 °C over a period of 1 h with efficient
stirring and stirred at this temperature for additional 2 h. The
solids were collected by filtration, washed with heptane (2
× 250.0 mL), and dried at 60-65 °C in vacuo to afford
N-(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroac-
etamide (7, 133.5 g, 87.5%): mp 155-156 °C; H NMR
(CDCl3, δ) 1.21 (t, 6H, J ) 7.5 Hz), 2.63 (q, 4H, J ) 7.5
Hz), 2.82 (dd, 2H, J ) 3.9 and 16.2 Hz), 3.33 (dd, 2H, J )
7.1 and 16.2 Hz), 4.75 (m, 1H), 6.53 (br, 1H), 7.06 (s, 2H);
13C NMR (CDCl3, δ) 15.86, 25.85, 39.87, 51.79, 125.10,
137.80, 141.31; Calc for C15H18F3NO: C, 63.15; H, 6.36;
N, 4.91; F, 19.98. Found: C, 63.02; H, 6.30; N, 4.85; F,
19.64.
1
Procedure 2: Hydrogenation of 6 in Ethanol. A reactor
was charged with N-(5-acetyl-6-ethyl-2,3-dihydro-1H-inden-
2-yl)-2,2,2-trifluoroacetamide (6, 119.72 g, 400.0 mmol) and
ethanol (94%; 912.0 mL). After inertizing the suspension
with N2, 5% Pd-C (5.99 g, 50% water) was added. After
inertizing with N2 the reactor was pressurized with H2 to 3
bar. The reaction mixture was hydrogenated at 40 °C (internal
temperature) until no H2 was consumed. The hydrogenation
was then continued at 50 °C for an additional 1 h. The
hydrogen was replaced with N2, the reaction mixture was
filtered at 40-50 °C, and the filtrate was saved. The reactor
vessel was rinsed with ethanol (158.0 mL) at 40 °C and
filtered to wash the cake. The filtrates were combined and
transferred to another flask at >35 °C. The reactor was
washed with hot (40-50 °C) ethanol (70.0 mL). The
combined filtrates were heated to 75-78 °C (internal
temperature), and water (456.0 mL) was added at 70-80
°C (internal temperature) within 30-60 min. The slightly
cloudy solution was cooled to 60 °C (the product started
crystallizing out as flakes). The mixture was stirred at 60
°C for 30 min and then heated to 65-67 °C (internal
temperature). Stirring was continued at 65-67 °C for
additional 1 h (during this time a homogeneous suspension
was formed). The mixture was then cooled to 50 °C in 1 h,
and then to 20 °C as quickly as possible. The mixture was
stirred at this temperature for additional 2 h. The solids were
collected by filtration, washed with a mixture of ethanol (89.0
mL) and water (35.5 mL), and dried at 55-60 °C in vacuo
(20 mbar) for 20 h to afford N-(5,6-diethyl-2,3-dihydro-1H-
inden-2-yl)-2,2,2-trifluoroacetamide (7, 94.15 g, 82.5%).
5,6-Diethyl-2,3-dihydro-1H-inden-2-amine Hydrochlo-
ride (1). A 2-L, four-necked, round-bottomed flask, equipped
with a mechanical stirrer, digital thermometer, addition
funnel, nitrogen inlet-outlet, and heating cooling bath, was
charged with N-(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)-
2,2,2-trifluoroacetamide (7, 100.0 g, 350.5 mmol), 200-proof
ethanol (500.0 mL), and 6 N NaOH (500.0 mL). The mixture
was stirred under nitrogen to give a solution and heated to
an internal temperature at 78 ( 3 °C over a period of 30
min to achieve gentle refluxing. The solution was stirred at
this temperature for an additional 1 h. The solution was
cooled to an internal temperature at 30-35 °C and concen-
trated in vacuo at 35 ( 5 °C to collect approximately 520
mL of solvent to obtain approximately 485 mL of a biphasic
mixture (an oil layer floating on top of the aqueous layer).
This mixture was cooled to 20-25 °C, and isopropyl acetate
(500.0 mL) was added. After stirring for 5 min the organic
layer was separated and saved. The aqueous layer was
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extracted with isopropyl acetate (500.0 mL). The organic
layers were combined and washed with water (300.0 mL).
The organic layer was concentrated in vacuo at 35 ( 5
°C to collect approximately 230 mL of solvent to obtain
approximately 800 mL of a solution. This solution was added
to a solution of HCl gas in isopropyl acetate (250.0 mL, 2
N, prepared by dissolving 18.3 g of hydrogen chloride gas
in 250.0 mL of isopropyl acetate) over a period of 40 min
while maintaining an internal temperature at 25 ( 5 °C.
Solids formed immediately. The suspension was stirred at
20-25 °C for 2 h. The solids were collected by filtration,
washed with isopropyl acetate (2 × 100.0 mL), and dried at
60-65 °C in vacuo to afford crude 5,6-diethyl-2,3-dihydro-
1H-inden-2-amine hydrochloride (1, 78.3 g).
A 2-L, four-necked, round-bottomed flask, equipped with
a mechanical stirrer, digital thermometer, addition funnel,
nitrogen inlet-outlet, and a heating/cooling bath, was
charged with 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hy-
drochloride (78.0 g) and 200-proof ethanol (624.0 mL). The
suspension was stirred and heated to an internal temperature
at 78 ( 3 °C to achieve gentle refluxing. To the resulting
solution was added isopropyl acetate (624.0 mL) at a rate to
maintain the internal temperature at 78 ( 3 °C. A precipitate
formed. The resulting suspension was stirred at this tem-
perature for an additional 1 h. The suspension was cooled
to an internal temperature at 20-25 °C over a period of 2 h
with efficient stirring, and the stirring was continued for an
additional 2 h. The solids were collected by filtration, washed
with a mixture of isopropyl acetate/ethanol (2 × 100.0 mL,
70:30 v/v), and dried at 60-65 °C in vacuo to afford pure
5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (1,
1
70.8 g, 89.0%): mp >250 °C; H NMR (CD3OD, δ) 1.18
(t, 6H, J ) 7.5 Hz), 2.63 (q, 4H, J ) 7.5 Hz), 2.98 (dd, 2H,
J ) 4.5 and 16.4 Hz), 3.34 (dd, 2H, J ) 7.1 and 16.4 Hz),
4.06 (m, 1H), 4.87 (br, 3H), 7.08 (s, 2H); 13C NMR (CD3-
OD, δ) 16.57, 26.88, 38.89, 53.31, 126.21, 138.24, 142.72;
Calc for C13H20ClN: C, 69.15; H, 8.93; N, 6.20; Cl, 15.70.
Found: C, 69.08; H, 8.80; N, 6.12; Cl, 15.75.
Acknowledgment
We thank Raeann Wu and Hanspeter Schilling for their
help.
Received for review October 19, 2005.
OP0502093
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