Concise preparation of amino-5,6,7,8-tetrahydroquinolines and amino-5,6,7,8-tetrahydroisoquinolines via catalytic hydrogenation of acetamidoquinolines and acetamidoisoquinolines

Article abstract of DOI:10.1021/jo026258k

A method to prepare amino-substituted 5,6,7,8- tetrahydroquinolines and 5,6,7,8-tetrahydroisoquinolines via catalytic hydrogenation of the corresponding acetamido-substituted quinolines and isoquinolines followed by acetamide hydrolysis is described. The

Full text of DOI:10.1021/jo026258k

was justified by experimentation; initial attempts to
selectively reduce amino-substituted quinolines using
catalytic amounts of PtO2 in trifluoroacetic acid (TFA)
at room temperature led to substantial hydrogenolysis
of the amine substituents.
Con cise P r ep a r a tion of
Am in o-5,6,7,8-tetr a h yd r oqu in olin es a n d
Am in o-5,6,7,8-tetr a h yd r oisoqu in olin es via
Ca ta lytic Hyd r ogen a tion of
Aceta m id oqu in olin es a n d
To circumvent this problem, a series of N-protected
8-aminoquinoline substrates were prepared and sub-
jected to the hydrogenation conditions. While we were
gratified to find that the N-pivaloyl, N-methanesulfonyl,
and N-acetyl groups were stable to hydrogenolysis (com-
pared to the N-trifluoroacetyl group which was cleaved
under the reaction conditions), only moderate selectivity
was observed, with significant amounts (30-40%) of the
1,2,3,4-tetrahydroquinolines being isolated in addition to
the desired 5,6,7,8-tetrahydro products. Of the substrates
investigated, 8-acetamidoquinoline (1g) showed the best
selectivity for formation of the 5,6,7,8-THQ product.
Unfortunately, selectivity was not improved by the choice
of heterogeneous catalyst or solvent. Using 8-acetami-
doquinoline as a representative substrate, we found that
Rh/C, Pd/C, Ru/C, or Raney-Ni gave either starting
material or decomposition products, whereas alternative
solvents gave either poor selectivity (HCl/MeOH, concd
H2SO4, H2SO4/HOAc), or resulted in cleavage of the
acetamide (12 N HCl, 12 N HCl/EtOH, 12 N HCl/HOAc,
phosphoric acid). Varying catalyst loading and hydrogen
pressure also had little effect on product distribution.
However, we were pleased to find that carrying out the
reduction at higher temperature favored formation of the
5,6,7,8-tetrahydro product. For example, reduction of
8-acetamidoquinoline 1g (Table 1, entry 7) with PtO2 in
trifluoroacetic acid at room temperature gave the 5,6,7,8-
and 1,2,3,4-tetrahydroquinoline products 2g and 3g in a
1.6:1 ratio, respectively. When the temperature of this
reaction was elevated to 60 °C (entry 8), the selectivity
of the reaction was improved, giving 2g and 3g in a ratio
of 4.4:1. Equally significant from a practical perspective
was the fact that the reduction proceeded to completion
more rapidly at higher temperature, requiring only 2.5
h at 60 °C (entry 8) compared to 7 h at ambient
temperature (entry 7). With this information in hand, the
selective hydrogenation of a series of substituted quino-
lines was undertaken; the results of this study are
summarized in Table 1.
Aceta m id oisoqu in olin es
Krystyna A. Skupinska, Ernest J . McEachern,*
Renato T. Skerlj, and Gary J . Bridger
AnorMED Inc., #200-20353 64th Avenue, Langley, BC,
Canada V2Y 1N5
emceachern@anormed.com
Received J uly 29, 2002
Abstr a ct: A method to prepare amino-substituted 5,6,7,8-
tetrahydroquinolines and 5,6,7,8-tetrahydroisoquinolines via
catalytic hydrogenation of the corresponding acetamido-
substituted quinolines and isoquinolines followed by aceta-
mide hydrolysis is described. The yields of the products are
good when the acetamido substituent is present on the
pyridine ring and moderate with the acetamido substituent
on the benzene ring. This method has also been applied to
the regioselective reduction of quinoline substrates bearing
other substituents (R ) OMe, CO2Me, Ph).
As part of our medicinal chemistry research program,
we required an efficient synthetic approach to a series
of amino-5,6,7,8-tetrahydroquinolines and amino-5,6,7,8-
tetrahydroisoquinolines. The 5,6,7,8-tetrahydroquinoline
moiety is found as a subunit in numerous medicinally
interesting compounds,1 but concise methods to access
usefully functionalized 5,6,7,8-tetrahydroquinolines are
scarce in the literature. To our knowledge, no general
method for the synthesis of amino-5,6,7,8-tetrahydro-
quinolines or amino-5,6,7,8-tetrahydroisoquinolines has
been described.
It is well-known that catalytic hydrogenation of quino-
lines at neutral and weakly acidic pH (e.g., in MeOH or
acetic acid) generally takes place at the pyridine ring,
generating 1,2,3,4-tetrahydroquinolines.2 It has also been
shown that when the hydrogenation is performed in a
strongly acidic medium (CF3COOH, 12 N HCl) the
selectivity of the saturation is reversed in favor of 5,6,7,8-
tetrahydroquinolines.3 We were cognizant of the fact,
however, that the intermediate amine formed during the
reduction of aminoquinolines using these conditions may
be benzylic or allylic (during stepwise reduction) and
therefore susceptible to hydrogenolysis, providing the
unsubstituted 5,6,7,8-tetrahydroquinoline.4 This concern
The results for the reduction of a series of N-acetyl-
amino-substituted quinolines are shown in entries 1-9,
with moderate to good yields of the desired 5,6,7,8-THQ
isomers being isolated in each case. The highest yields
of the desired acetamido-5,6,7,8-tetrahydro products
(63-78%) were obtained with substrates 1a -c, which
bear substituents on the pyridine ring (Table, entries
1-3); in these cases, the 5,6,7,8-THQ products 2a ,5 2b,6
and 2c were formed almost exclusively, with only trace
amounts of the 1,2,3,4-THQ isomers detected. For sub-
* To whom correspondence should be addressed. Tel: +1 (604) 530-
1057. Fax: +1 (604) 530-0976.
(1) (a) Sucheck, S. J .; Greenber, W. A.; Tolbert, T. J .; Wong, C.-H.
Angew. Chem., Int. Ed. 2000, 39, 1080-1084. (b) Bosch, J .; Roca, T.;
Perez, C. G.; Montanari, S. Bioorg. Med. Chem. Lett. 2000, 10, 563-
566. (c) Glase, S. A.; Corbin, A. E.; Pugsley, T. A.; Heffner, T. G.; Wise,
L. D. J . Med. Chem. 1995, 38, 3132-3137.
(2) Rylander, R. N. Catalytic Hydrogenation over Platinum Metals;
Academic Press: New York, 1967; p 385.
(3) (a) Vierhapper, F. W.; Eliel, E. L. J . Am. Chem. Soc. 1974, 96,
2256-2257. (b) Vierhapper, F. W.; Eliel, E. L. J . Org. Chem. 1975, 40,
2729-2734. (c) Vierhapper, F. W.; Honel, M. Monat. Chem. 1984, 115,
1219-1228.
(4) Hydrogenolysis of other quinoline heterosubstituents (F, OH,
OMe) has been reported under similar conditions: Vierhapper, F. W.;
Honel, M. J . Chem. Soc., Perkin Trans. 1 1980, 1933-1939.
(5) Vijn, R. J .; Arts, H. J .; Maas, P. J .; Castelijns, A. M. J . Am. Chem.
Soc. 1992, 58, 887-891.
(6) Kato, K.; Terauchi, J .; Mori, M.; Suzuki, N.; Shimomura, Y.;
Takekawa, S.; Ishihara, Y. Takeda Chemical Industires Ltd. J apan;
PCT Int. Appl. WO 20010211577; J P 2002003370, 2001.
10.1021/jo026258k CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/03/2002
7890
J . Org. Chem. 2002, 67, 7890-7893

TABLE 1. Hyd r ogen a tion of Su bstitu ted Qu in olin es
substitution on the pyridine group renders the ring less
susceptible to reduction compared to the phenyl ring,
thereby improving selectivity (entries 1-3), whereas
substitution on the phenyl ring makes this ring less
susceptible to reduction (relative to the pyridine ring),
thereby diminishing selectivity (entries 4-9). This ob-
servation is consistent with previous reports suggesting
that catalytic hydrogenation of naphthalenes is sensitive
to steric factors, with the less sterically encumbered ring
generally being preferentially reduced;12 it is also con-
sistent with previous reports of hydrogenation of simple
alkyl-substituted quinolines.3a,b
1a -n a
reaction yield of yield of
entry compnd
R
time (h)
2 (%)
3 (%)
1
2
3
4
1a
1b
1c
1d
1e
1f
1g
1g
1h
1i
1j
1k
1l
1m
1n
2-NHAc
3-NHAc
4-NHAc, 2-Me
5-NHAc
6-NHAc
7-NHAc
8-NHAc
8-NHAc
8-NHAc, 2-Me
3-MeO
18
3.5
20
4.5
5
18
7
2.5
3
4
5
4
5
5
69
63
78
45
49
25
53
62
57
65
68
51
70
30
36
0
1
0
27
28
20
34
14
15
0d
10
20
11
39
28e
At this point, we examined a number of other sub-
strates in an effort to probe the general utility of this
reaction (entries 10-15). Functional groups that are
tolerated under the reaction conditions include methoxy
(entry 10), phenyl (entry 11), and methyl carboxylate
(entries 12-15). Interestingly, in these cases substrates
bearing substituents on the pyridine ring (1i-l) also
exhibit higher selectivity for the 5,6,7,8-THQ isomers
than those bearing groups on the phenyl ring (1m , 1n ).
Correspondingly, the isolated yields for the pyridine-
substituted products 2i, 2j,13 2k ,14 and 2l range from 51
to 70% (entries 10-13), while yields for the 6- and
8-substituted esters 2m and 2n 15 are 30% and 36%,
respectively (entries 14-15).16 The results from this
series of substrates indicate that electronic factors may
also influence the selectivity of the hydrogenation. For
example, substrates 1b and 1i, bearing electron-donating
NHAc and MeO groups at the 3-position (entries 2 and
10), exhibit almost complete selectivity for the 5,6,7,8-
THQ isomers; conversely, substrate 1l, which bears an
electron-withdrawing methyl carboxylate17 at the 3-posi-
tion, exhibits a selectivity of 6.4:1. This appears to be a
general observation within our data set: substrates
bearing electron-donating groups on the pyridine ring
(entries 1-3, 10) exhibit better selectivity for formation
of 5,6,7,8-THQ products compared to substrates bearing
electron-withdrawing groups on the same ring (entries
11-13). Presumably, the explanation for this trend is
that the positive inductive capacity of the electron-
releasing substituents renders the pyridine ring less
susceptible to reduction and suppresses formation of the
1,2,3,4-THQ products. Thus, for reduction of quinoline
derivatives using these reaction conditions, the combined
effects of electron donating groups on the pyridine ring
and an unsubstituted phenyl ring lead almost exclusively
to the 5,6,7,8-THQ isomer.18
5
6b
7c
8
9
10
11
12
13
14
15
2-Ph
2-COOMe
3-COOMe
6-COOMe
8-COOMe
2
a
Unless otherwise noted, all reactions were performed with
0.8-1.5 mmol of 1 at 0.3 M in TFA using 5 mol % PtO2 at 60 °C
under 1 atm hydrogen. The progress of each reaction was moni-
tored by GC and/or TLC. Yields are for isolated, purified product.
b
Yields are approximate as the reaction was performed on a small
scale (30 mg 1f) with 20% PtO2. c The reaction was carried out at
d
room temperature. Trace amounts (∼2%) of hydrogenolyzed
products were detected (quinoline, 1,2,3,4-THQ, 5,6,7,8-THQ).
e 16% recovered starting material was isolated from this reaction.
strates bearing the acetamido substituent on the phenyl
ring (1d , 1e, 1f, and 1g) (entries 4-6, 8) selectivity for
the 5,6,7,8-THQ isomer was diminished to the range 1.3-
4.4:1, a fact reflected in the commensurately lower yields
9
for the respective products 2d 7, 2e,8 2f, and 2g.10 It
should be noted, however, that the desired 5,6,7,8-THQ
isomer was still the major product in each case, and
isolated yields for 2d , 2e, and 2g were in the range of
45-62%.11 While previous studies have indicated that
methyl substitution in the 2-position favors formation of
5,6,7,8-tetrahydro products,3a,c the effect was not appar-
ent in this case (compare entries 8 and 9).
The results obtained with the acetamido-substituted
substrates (entries 1-9) suggest that steric factors play
a dominant role in determining the selectivity of the
hydrogenation. That is, the steric hindrance provided by
(7) Dukat, M.; Fiedler, M.; Dumas, D.; Damaj, I.; Martin, B. R.;
Rosecrans, J . A.; J ames, J . R.; Glennon, R. A Eur. J . Med. Chem. 1996,
31, 875-888.
(12) Siegel, S. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 8, p 438.
(13) Chelucci, G.; Cossu, S.; Soccolini, F. J . Heterocycl. Chem. 1986,
23, 1283-1286.
(8) Adachi, J .; Nomura, K.; Yamamoto, S.-I.; Mitsuhashi, Chem.
Pharm. Bull. 1976, 24, 2876-2980.
(9) Preparation of 7-amino-5,6,7,8-tetrahydroquinoline via a differ-
ent route has been described: Cliffe, I. A.; Ifill, A. D.; Mansell, H. L.;
Todd, R. S.; White, A. C. Tetrahedron Lett. 1991, 32, 678-692.
(10) Preparation of enantiomerically pure 8-amino-5,6,7,8-tetrahy-
droquinoline has recently been described: Uenishi, J .; Hamada, M.
Synthesis 2002, 5, 625-630.
(11) The 1,2,3,4-tetrahydro products 3d , 3e, and 3g are known
compounds: (a) Bigge, C. F.; Malone, T. C.; Boxer, P. A.; Nelson, C.
B.; Ortwine, D. F.; Schelkun, R. M.; Retz, D. M.; Lescosky, L. J .;
Borosky, S. A.; Vartanian, M. G.; Schwarz, R. D.; Campbell, G. W.;
Robichaud, L. J .; Watjen, F. J . Med. Chem. 1995, 38, 3720-3740. (b)
Reich, S. H.; Fuhry, M. A.; Nguyen, D.; Pino, M. J .; Welsh, K. M.;
Webber, S.; J anson, C. A.; J ordan, S. R.; Matthews, D. A.; Smith, W.
W.; Bartlett, C. A.; Booth, C. L. J .; Herrmann, S. M.; Howland, E. F.;
Morse, C. A.; Ward, R. W.; White, J . J . Med. Chem. 1992, 35, 847-
858. (c) Richardson, A.; Amstutz, E. D. J . Org. Chem. 1960, 25, 1138.
(14) Renslo, A. R.; Danheiser, R. L. J . Org. Chem. 1998, 63, 7840-
7850.
(15) An alternative, more efficient synthesis of 2n has been re-
ported: Crossley, R.; Curran, A. C. W.; Hill, D. G. J . Chem. Soc., Perkin
Trans. 1 1976, 977-982.
(16) The 1,2,3,4-tetrahydro products 3j, 3k , 3l, and 3m are known
compounds: (a) Gogte, V. N.; El-Namaky, H. M.; Salama, M. A.; Tilak,
B. D. Tetrahedron Lett. 1969, 39, 3319-3322. (b) Rao, V. A.; J ain, P.
C.; Anand, N. Indian J . Chem. 1972, 10, 1134-1135. (c) Rasetti, V.;
Rueeger, H.; Maibaum, J .; Mah, R., Gruetter, M.; Cohen, N. C. Ciba-
Geigy A.-G., Switzerland. Eur. Pat. Appl. EP 702004, 1996. (d) Oku,
T.; Kayakiri, H.; Satoh, S.; Abe, Y.; Sawada, Y.; Inoue, T.; Tanaka, H.
PCT Int. Appl. WO 9604251, 1996.
(17) Methyl 5-carboxylate-5,6,7,8-tetrahydroisoquinoline was pre-
pared via this method: Paivio, E.; Berner, M.; Tolvanen, A.; J okela,
R. Heterocycles 2000, 53, 2241-2246.
J . Org. Chem, Vol. 67, No. 22, 2002 7891

SCHEME 1
desired 5,6,7,8-tetrahydroquinoline isomer in the cata-
lytic reduction step is improved by the presence of an
electron donating substituent on the pyridine ring, and
diminished by the presence of sterically bulky substitu-
ents on the phenyl ring.
Exp er im en ta l Section
SCHEME 2
1
Gen er a l Meth od s. H NMR and 13C NMR were recorded at
300 and 75 MHz, respectively, in CDCl3 as a solvent. Proton
and carbon chemical shifts were referenced to residual solvent
protons and the solvent, respectively. Flash chromatography was
carried out on silica gel (230-400 mesh). Unless otherwise noted,
materials were obtained from commercial suppliers and were
used without further purification. Trifluoroacetic acid (99%) was
purged with argon prior to use in hydrogenation reactions.
Acetamides 1a -e,g,h and 5a ,b were prepared from com-
mercially available amines. 7-Acetamidoquinoline (1f) was
obtained by acetylation of 7-aminoquinoline prepared by the
reduction of 7-nitroquinoline.21 3-Methoxyquinoline (1i)22 was
prepared from commercially available 3-bromoquinoline by the
method of Baker and Duke.23 Methyl carboxylates 1k -n were
prepared from commercially available acids. All new products
(2c, 2f, 3f, 2g, 2h , 3h , 2i, 2l, 2m , 3n , 6a , 6b, 7a ) were
characterized by 1H NMR, 13C NMR, and mass spectrometry.
Rep r esen ta tive P r oced u r e for Sm a ll-Sca le Hyd r ogen a -
tion Rea ction s. To a two-neck, 250 mL round-bottom flask
containing a stir bar were added 8-acetamidoquinoline 1g (186.1
mg, 0.999 mmol) and platinum oxide (11.5 mg, 0.0506 mmol, 5
mol %). Trifluoroacetic acid (3.4 mL, 0.3 M) was added via a
plastic syringe into the reaction flask under an atmosphere of
nitrogen. The stirred reaction mixture was flushed and the flask
filled with hydrogen gas from a balloon. The reaction flask was
sealed, and the reaction mixture was warmed to 60 °C for 2.5 h.
The progress of the reaction was monitored by GC and/or TLC.
The reaction mixture was cooled to rt, and aqueous saturated
sodium hydroxide was added until the mixture was basic (or
saturated sodium bicarbonate for methyl carboxylate substrates).
The mixture was then extracted with CH2Cl2 (3 × 30 mL). The
extracts were dried (MgSO4), filtered, and concentrated in vacuo.
The products 2g and 3g were separated by flash chromatography
using 5-15% MeOH in EtOAc. Compound 2g was obtained as
an off-white solid (118.3 mg, 62%) that displayed: 1H NMR δ
1.59-1.70 (m, 1H), 1.86-1.95 (m, 2H), 2.08 (s, 3H), 2.56-2.64
(m, 1H), 2.79-2.84 (m, 2H), 4.85-4.95 (m, 1H), 6.52 (br s, 1H),
7.14 (dd, 1H, J ) 5, 7 Hz), 7.43 (d, 1H, J ) 7 Hz), 8.41 (d, 1H,
J ) 5 Hz); 13C NMR δ 20.3, 24.1, 28.6, 29.8, 51.5, 122.8, 133.4,
137.5, 147.2, 155.7, 170.8; MS m/z: 213 (M + Na+). Anal. Calcd.
for C11H14N2O: C, 69.44; H, 7.43; N, 14.72. Found: C, 69.23; H,
7.56; N, 14.74. Compound 3g11c was isolated as a pale yellow
solid (26.7 mg, 14%).
The methods described herein were readily amenable
to the preparation of amino-5,6,7,8-tetrahydroquinolines
in multigram quantities (see the Experimental Section
for procedure). For example, reduction of 7 g of 1e
afforded the acetamide 2e in 43% yield (Scheme 1);
subsequent acid-mediated hydrolysis of the acetamide (6
N HCl, reflux) furnished 6-amino-5,6,7,8-tetrahydro-
quinoline 4 in 86% yield.
Finally, we applied this hydrogenation method to two
acetamidoisoquinoline systems, 5a and 5b (Scheme 2).
We obtained a good yield of 1-acetamido-5,6,7,8-tetrahy-
droisoquinoline 6a along with some of the 1,2,3,4-tet-
rahydro product 7a . The reaction of 5-acetamidoisoquin-
oline 5b provided 6b in 43% yield, albeit with the
expected lower selectivity (20% of 7b19 was isolated).
Amino-5,6,7,8-tetrahydroisoquinolines were also readily
accessible via this protocol using the deprotection condi-
tions described above.
As a point of general interest, it should be emphasized
that the use of an acetamido-protected amino group
overcomes the major limitation inherent to the previous
methodology, namely, hydrogenolysis of heterosubstitu-
ents.20 Until the present time, the use of this hydrogena-
tion procedure has been confined to simple alkyl-
substituted quinolines and isoquinolines, given the poor
yields obtained when heterosubstituents are present. The
ability to perform this reaction in the presence of a
protected amine represents an important advance, par-
ticularly in light of the fact that many of these amino-
5,6,7,8-tetrahydroquinolines and isoquinolines are not
readily available via other routes, and several have not
been reported previously. Moreover, the amino function
can serve as a useful synthetic handle for subsequent
functionalization (e.g., diazotization), which gives this
new procedure a broad range of synthetic applicability.
In conclusion, we report a practical and concise method
for the preparation of amino-substituted 5,6,7,8-tetrahy-
droquinolines and amino-5,6,7,8-tetrahydroisoquinolines
by catalytic reduction of the N-acetylamino protected
parent quinoline and isoquinoline systems at 60 °C,
followed by hydrolysis. In general, the selectivity for the
Using the representative procedure for small scale reactions,
1a (164 mg, 0.881 mmol) provided 2a 5 (114 mg, 69%), 1b (138
mg, 0.741 mmol) provided 2b6 (89 mg, 63%), 1d (158 mg, 0.849
mmol) provided 2d 7 (72 mg, 45%) and 3d 11a (44 mg, 27%), 1e
(143 mg, 0.768 mmol) provided 2e8 (71 mg, 49%) and 3e11b (40
mg, 28%), and 1j (162 mg, 0.781 mmol) provided 2j13 (111 mg,
68%) and 3j16a (20 mg, 10%). Reaction of 1k (160 mg, 0.855
mmol) following the representative procedure using saturated
NaHCO3 in place of NaOH in the workup provided 2k 14 (83 mg,
51%) and 3k 16b (33 mg, 20%).
N-(2-Meth yl-5,6,7,8-tetr a h yd r oqu in olin -4-yl)a ceta m id e
(2c). Reaction of N-(2-methylquinolin-4-yl)acetamide (1c) (136
mg, 0.679 mmol) using the general procedure for small-scale
hydrogenations provided 2c (109 mg, 78%): 1H NMR δ 1.83-
1.90 (m, 4H), 2.21 (s, 3H), 2.47 (s, 3H), 2.46-2.2.53 (m, 2H),
2.84-2.87 (m, 2H), 7.18 (br s, 1H), 7.82 (br s, 1H); 13C NMR δ
(18) For
a detailed discussion on the mechanism of quinoline
hydrogenation see: Okazaki, H.; Onishi, K.; Soeda, M.; Ikefuji, Y.;
Tamura, R.; Mochida, I. Bull. Chem. Soc. J pn. 1990, 63, 3167-3174;
refs 4 and 3c.
(19) Bailey, Denis M.; DeGrazia, C. George; Lape, Harlan E.;
Frering, Richard; Fort, Dorothy; Skulan, Thomas. J . Med. Chem. 1973,
16, 151-156.
(20) The authors acknowledge this, stating “The synthetic possibili-
ties are severely diminished by this hydrogenolysis”; ref 4.
(21) Sharma, K. S.; Kumari, S.; Singh, R. P. Synthesis 1981, 316-
318.
(22) Baker, J . T.; Duke, C. C. Aust. J . Chem. 1976, 29, 1023-1030.
(23) Keegstra, M. A.; Peters, T. H. A.; Brandsma, L. Tetrahedron
1992, 48, 3633-3652.
7892 J . Org. Chem., Vol. 67, No. 22, 2002

22.7, 22.8, 23.5, 24.6, 25.3, 33.1, 112.3, 117.3, 143.7, 156.4, 157.3,
169.0; MS m/z 205 (M + H+).
δ 21.2, 28.2, 41.6, 51.7, 108.8, 113.9, 122.4, 129.8, 134.1, 148.8,
169.6; MS m/z 192 (M + H+).
N-(5,6,7,8-Tetr ah ydr oisoqu in olin -1-yl)acetam ide (6a). Re-
action of N-(isoquinol-1-yl)acetamide (5a ) (159 mg, 0.854 mmol)
using the general procedure for small-scale hydrogenations
provided 6a (96 mg, 59%): 1H NMR δ 1.74-1.76 (m, 4H), 2.16-
2.19 (m, 3H), 2.60-2.70 (m, 2H), 2.70-2.76 (m, 2H), 6.86 (d, 1H,
J ) 5 Hz), 8.03 (d, 1H, J ) 5 Hz); 13C NMR δ 22.3, 22.8, 23.8,
25.1, 29.6, 122.9, 144.4 (2C), 149.5, 150.2, 170.6; MS m/z 213
(M + Na+). N-(1,2,3,4-Tetrahydroisoquinolin-1-yl)acetamide (7a )
was also isolated (16 mg, 11%): 1H NMR δ 2.28 (m, 3H), 2.96-
3.01 (m, 2H), 3.56-3.61 (m, 2H), 7.20 (d, 1H, J ) 8 Hz), 7.33-
7.38 (m, 1H), 7.44-7.49 (m, 1H), 8.27 (d, 1H, J ) 8 Hz); 13C
NMR δ 27.2, 28.7, 29.7, 39.3, 127.3, 127.5, 128.0, 132.6, 137.9,
162.8, 188.0; MS m/z 191 (M + H+).
N-(5,6,7,8-Tetr ah ydr oisoqu in olin -5-yl)acetam ide (6b). Re-
action of N-(isoquinol-5-yl)acetamide (5b) (171 mg, 0.918 mmol)
using the general procedure for small-scale hydrogenations
provided 6b (79 mg, 45%): 1H NMR δ 1.60-1.70 (m, 1H), 1.70-
1.09 (m, 2H), 1.98 (s, 3H), 1.98-2.08 (m, 1H), 2.65-2.68 (m, 2H),
5.03-5.11(m, 1H), 6.63 (br d, 1H), 7.08 (d, 1H, J ) 5 Hz), 8.17
(s, 1H), 8.20 (d, 1H, J ) 5 Hz); 13C NMR δ 20.7, 23.7, 26.4, 30.1,
47.1, 122.9, 133.3, 146.3, 147.5, 150.7, 170.1; MS m/z 191 (M +
H+). N-(1,2,3,4-Tetrahydroisoquinolin-5-yl)acetamide (7b)19 was
also isolated (35 mg, 20%).
Rep r esen ta tive P r oced u r e for La r ge-Sca le Hyd r ogen a -
tion Rea ction a n d Hyd r olysis Rea ction . To a three-neck, 500
mL round-bottom flask containing a stir bar was added 6-ac-
etamidoquinoline (1e) (6.80 g, 36.5 mmol) and platinum(IV)
oxide (414 mg, 5 mol %). The flask was equipped with two Teflon
cannulae: one for purging of the reaction flask with nitrogen
gas and introduction of hydrogen, and the other leading to a
flask connected to a bubbler. Trifluoroacetic acid (110 mL) was
added to the reaction flask under an atmosphere of nitrogen.
The stirred reaction mixture was flushed with nitrogen gas and
warmed to 60 °C. Hydrogen gas was bubbled through the stirred
reaction for 5 h. The progress of the reaction was monitored by
GC and/or TLC. The reaction mixture was cooled to rt and
purged with nitrogen gas, and the catalyst was filtered through
a pad of Celite and washed with CH2Cl2 (100 mL). The solvent
was removed in vacuo and the residue was basified with
saturated NaOH. The mixture was then extracted with CH2Cl2
(3 × 250 mL). The organic extracts were dried (MgSO4), filtered,
and concentrated. The crude material was purified by flash
chromatography using 1% MeOH in EtOAc. Compound 2e8 was
obtained as an off-white solid (3.01 g, 43%), while compound
3e11b was isolated as a yellow oil (1.86 g, 26%).
6-Acetamido-5,6,7,8-tetrahydroquinoline (2e) (2.76 g, 14.5
mmol) was dissolved in 6 N HCl (50 mL). The mixture was
heated at reflux for 1 h, and the progress of the reaction was
monitored by GC. Upon completion, the reaction mixture was
cooled to rt, basified with saturated NaOH and extracted with
chloroform (5 × 100 mL). The organic extracts were dried
(MgSO4) and concentrated. The crude material was purified by
distillation (bp 113-115 °C at 0.20 mmHg) to yield 6-amino-
5,6,7,8-tetrahydroquinoline (4) as a clear liquid (1.85 g, 86%)
that displayed: 1H NMR δ 1.40 (br s, 2H), 1.62-1.76 (m, 1H),
2.03-2.07 (m, 1H), 2.55 (dd, 1H, J ) 16.2, 9.3 Hz), 2.88-3.17
(m, 3H), 3.19-3.26 (m, 1H), 6.98-7.03 (m, 1H), 7.32 (d, 1H, J )
7.5 Hz), 8.33 (d, 1H, J ) 3.9 Hz); 13C NMR δ 31.3, 33.1, 38.9,
47.1, 121.4, 130.7, 137.4, 147.5, 156.7; MS m/z 149 (M + H+).
Anal. Calcd for C9H12N2‚0.3H2O: C, 70.37; H, 8.27; N, 18.24.
Found: C, 70.09; H, 8.11; N, 18.36.
N-(5,6,7,8-Tetr a h yd r oqu in olin -7-yl)a ceta m id e (2f). Reac-
tion of N-(quinol-7-yl)acetamide (1f) (33 mg, 0.177 mmol) using
the general procedure for small-scale hydrogenations provided
2f (8.3 mg, 25%): 1H NMR δ 1.72-1.83 (m, 1H), 1.99 (s, 3H),
2.04-2.20 (m, 2H), 2.72-2.95 (m, 3H), 3.25 (dd, 1H, J ) 5, 17
Hz), 4.29-4.40 (m, 1H), 5.72 (br s, 1H), 7.05 (dd, 1H, J ) 4, 8
Hz), 7.38 (d, 1H, J ) 8 Hz), 8.35 (d, 1H, J ) 4 Hz); 13C NMR δ
23.9, 26.5, 28.7, 39.0, 45.6, 121.9, 131.4, 137.0, 147.7, 154.8,
170.1; MS m/z 213 (M + Na+). N-(1,2,3,4-Tetrahydroquinolin-
7-yl)acetamide (3f) was also isolated (6.5 mg, 20%): 1H NMR δ
1.24-1.28 (s, 1H), 1.87-1.95 (m, 2H), 2.70 (dd, 2H, J ) 6, 6 Hz),
3.28 (dd, 2H, J ) 5, 5 Hz), 6.46 (d, 1H, J ) 8 Hz), 6.84 (d, 1H,
J ) 8 Hz), 6.93 (s, 1H), 7.03 (br s, 1H); 13C NMR δ 22.1, 24.7,
26.6, 37.9, 105.6, 108.3, 117.6, 129.6, 136.5, 145.1, 168.1; MS
m/z 213 (M + Na+).
N-(2-Meth yl-5,6,7,8-tetr a h yd r oqu in olin -8-yl)a ceta m id e
(2h ). Reaction of N-(2-methyl-quinol-8-yl)acetamide (1h ) (159
mg, 0.795 mmol) using the general procedure for small-scale
hydrogenations provided 2h (92 mg, 57%): 1H NMR δ 1.57-
1.66 (m, 1H), 1.77-1.86 (m, 2H), 2.02 (s, 3H), 2.44 (s, 3H), 2.43-
2.57 (m, 1H), 2.68-2.73 (m, 2H), 4.67-4.74 (m, 1H), 6.79 (br s,
1H), 6.92 (d, 1H, J ) 8 Hz), 7.24 (d, 1H, J ) 8 Hz); 13C NMR δ
21.6, 25.4, 25.8, 29.6, 31.0, 53.0, 123.4, 131.4, 139.2, 155.9, 157.2,
172.2; MS m/z 227 (M + Na+). N-(2-Methyl-1,2,3,4-tetrahydro-
quinolin-8-yl)acetamide (3h ) was also isolated (25 mg, 15%) as
a tautomeric mixture of acyclic and cyclized isomers in an
approximately 1:2 ratio which exhibited the following data: 1H
NMR δ 1.21-1.25 (m), 1.45-1.61 (m), 1.90 (s), 1.90-1.95 (m),
2.20 (s), 2.71-2.91 (m), 3.32-3.43 (m), 4.00 (br s), 6.56 (dd, J )
8, 8 Hz), 6.63 (dd, J ) 8, 8 Hz), 6.66 (br s), 6.83 (d, J ) 8 Hz),
6.87 (d, J ) 8 Hz), 6.94 (d, J ) 8 Hz), 7.02 (d, J ) 8 Hz), 7.06 (br
s); MS m/z 205 (M + H+).
3-Met h oxy-5,6,7,8-t et r a h yd r oq u in olin e (2i). Reaction of
3-methoxyquinoline (1i) (181 mg, 1.16 mmol) using the general
procedure for small-scale hydrogenations provided 2i (127 mg,
65%): 1H NMR δ 1.74-1.93 (m, 4H), 2.75 (dd, 2H, J ) 6, 6 Hz),
2.85 (dd, 2H, J ) 6, 6 Hz), 3.82 (s, 3H), 6.88 (d, 1H, J ) 3 Hz),
8.06 (d, 1H, J ) 3 Hz); 13C NMR δ 23.0, 23.7, 29.4, 32.0, 55.9,
121.5, 132.9, 134.9, 149.8, 154.1; MS m/z 164.1 (M+H+). A
mixture (5 mg) of hydrogenolyzed products (quinoline, 1,2,3,4-
tetrahydroquinoline and 5,6,7,8-tetrahydroquinoline as deter-
mined by GC analysis by comparison with commercial samples)
was also obtained.
5,6,7,8-Tetr a h yd r oqu in olin e-3-ca r boxylic Acid Meth yl
Ester (2l). Reaction of quinoline-3-carboxylic acid methyl ester
(1l) (170 mg, 0.908 mmol) using the general procedure (workup
with saturated NaHCO3 in place of NaOH) for small-scale
hydrogenations provided 2l (121 mg, 70%): 1H NMR δ 1.80-
1.95 (m, 4H), 2.79-2.83 (m, 2H), 2.94-2.99 (m, 2H), 3.91 (s, 3H),
7.95 (s, 1H), 8.93 (s, 1H); 13C NMR δ 22.8, 23.1, 28.9, 33.1, 52.5,
123.7, 132.5, 138.0, 148.2, 162.6, 166.5; MS m/z 192 (M + H+).
1,2,3,4-Tetrahydroquinoline-3-carboxylic acid methyl ester (3l)16c
was also isolated (19 mg, 11%).
5,6,7,8-Tetr a h yd r oqu in olin e-6-ca r boxylic Acid Meth yl
Ester (2m ). Reaction of quinoline-6-carboxylic acid methyl ester
(1m ) (170 mg, 0.908 mmol) using the general procedure (workup
with saturated NaHCO3 in place of NaOH) for small-scale
hydrogenations provided 2m (49 mg, 30%): 1H NMR δ 1.91-
2.05 (m, 1H), 2.25-2.34 (m, 1H), 2.74-2.84 (m, 1H), 2.90-3.11
(m, 4H), 3.74 (s, 3H), 7.06 (dd, 1H, J ) 4, 8 Hz), 7.39 (d, 1H, J
) 8 Hz), 8.37 (d, 1H, J ) 4 Hz); 13C NMR δ 26.1, 31.2, 31.7,
39.6, 52.3, 121.6, 130.5, 137.2, 147.6, 156.3, 175.7; MS m/z 214
(M + Na+). 1,2,3,4-Tetrahydroquinoline-6-carboxylic acid methyl
ester (3m )16d was also isolated (66 mg, 39%).
Reaction of quinoline-8-carboxylic acid methyl ester (1n ) (156
mg, 0.833 mmol) using the general procedure (workup with
saturated NaHCO3 in place of NaOH) for small-scale hydrogena-
tions provided 2n 15 (58 mg, 36%). 1,2,3,4-Tetrahydroquinoline-
8-carboxylic acid methyl ester (3n ) was also isolated (45 mg,
28%): 1H NMR δ 1.87-1.96 (m, 2H), 2.76-2.81 (m, 2H), 3.40-
3.45 (m, 2H), 3.83 (s, 3H), 6.43 (dd, 1H, J ) 7, 8 Hz), 7.03 (d,
1H, J ) 7 Hz), 7.69 (d, 1H, J ) 8 Hz), 7.76 (br s, 1H); 13C NMR
Ack n ow led gm en t. We thank NSERC of Canada for
an Industrial Research Fellowship to K.A.S. as well as
Lucita Ramos and Roger Sun for analytical support.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of compounds 2c, 2f, 3f, 2h , 3h , 2i, 2l, 2m , 3n ,
6a , 6b, and 7a . This material is available free of charge via
the Internet at http://pubs.acs.org.
J O026258K
J . Org. Chem, Vol. 67, No. 22, 2002 7893