Addition of Grignard Reagents to Quinolinium Salts: Evidence for a Unique Redox Reaction between a 1,4- And a 1,2-Dihydroquinoline

Full text of DOI:10.1021/jo990586b

J . Org. Chem. 1999, 64, 6911-6914
6911
conceptually different approach, Katritzky,9 and subse-
quently Akiba,10 have shown that by using pyridinium
salts containing bulky substituents that can shield the
2- and 6-positions the attack of Grignard reagents can
be forced to occur preferentially at the 4-position. To the
best of our knowledge, studies on the prospects of such
an approach in the case of quinolinium salts have not
been previously reported.11
Ad d ition of Gr ign a r d Rea gen ts to
Qu in olin iu m Sa lts: Evid en ce for a Un iqu e
Red ox Rea ction betw een a 1,4- a n d a
1,2-Dih yd r oqu in olin e
Neelakandha S. Mani,* Penghui Chen, and
Todd K. J ones†
Department of Medicinal Chemistry,
Ligand Pharmaceuticals, Inc., 10275 Science Center Drive,
San Diego, California, 92121
Though the extended conjugation in quinolines makes
nucleophilic attack at the 4-position a considerably more
difficult task, we felt that quaternized quinolinium salts
with steric shielding at the 2-position might promote
preferential attack at the 4-position. We reasoned that
the use of trialkylsilyl triflates as tunable quaternizing
agents might be suitable in this capacity mainly due to
their ease of formation (perhaps as a result of the longer
Si-N bond that reduces the peri hydrogen interaction)12
and, more importantly, due to their reduced reactivity
toward Grignard reagents.13 Thus, treatment of quinoline
with TMSOTf in dichloromethane at room temperature
afforded the quinolinium triflate 1. Treatment of this
quinolinium triflate with ethylmagnesium bromide fol-
lowed by an aqueous workup yielded a mixture of four
products (Scheme 1). These products were identified as
4-ethylquinoline (2), 2-ethylquinoline (3), 4-ethyl-1,2,3,4-
tetrahydroquinoline (4), and 2-ethyl-1,2,3,4-tetrahydro-
quinoline (5) using 1H NMR and mass spectrometry.
Structural assignments were confirmed by comparison
of spectral data with those of authentic samples.
Received April 5, 1999
Addition of nucleophilic reagents to quinolines and
acylquinolinium salts has proven to be a useful method
for the synthesis of substituted quinoline derivatives.1
In the case of organometallic reagents such as organo-
lithiums and Grignard reagents, these additions are
known to occur predominantly at the 2-position to form
2-substituted 1,2-dihydroquinolines,2 which can then be
transformed in situ to 2-substituted quinolines by oxida-
tion3 or to the corresponding 1,2,3,4-tetrahydroquinolines
by reduction.4 A limitation to the broader versatility of
this approach, however, is the lack of a suitable compli-
mentary method to regioselectively direct the attack to
the 4-position. In the context of our interest in exploring
convenient access to substituted 1,2,3,4-tetrahydroquino-
lines as useful intermediates for preparing pharmacologi-
cally active heterocyclic systems,5 we desired an efficient
entry into 4-substituted 1,2,3,4-tetrahydroquinolines
through regioselective functionalization of quinoline at
the 4-position. We wish to report herein our observations
on the addition of Grignard reagents to quinolinium salts.
In the closely related case of pyridines and acylpyri-
dinium salts, addition of organometallic nucleophiles
appears to take place preferentially at the 2-position.6
However, several successful attempts have been reported
in which nucleophilic attack at the 4-position of 1-acylpy-
ridinium salts was predominant when softer nucleophiles
such as organocopper (R2CuLi; RMgX, cat. CuI; RCu‚
BF3)7 and titanium reagents8 were employed. In a
The effect of steric bulk of silyl groups on the regiose-
lectivity was examined using several silyl triflates (Table
1). In the case of trimethylsilyl triflate, 2-ethylquinoline
resulting from attack of the Grignard reagent at the
2-position was the predominant product. In the cases of
triethylsilyl and triphenylsilyl triflates, attack at the
4-position was clearly more favorable, leading to much
better yields of 2 and 4. Interestingly, the 2-ethyl adduct
(5) was detected only in the case of trimethylsilyl triflate.
The bulkier triisopropylsilyl triflate reacted sluggishly
to form the quinolinium salt as was observed by TLC
analysis, and the resulting quinolinium gave much poorer
* To whom correspondence should be addressed. Tel: (619) 550-
7720. Fax: (619) 550-7249. E-mail: nmani@ligand.com.
† Present Address: Ontogen Corp., 2325 Camino Vida Roble, Carls-
bad, CA 92009.
(1) Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees,
C. W., Eds.; Pergamon Press: New York, 1984; Vol. 2, pp 165-315.
(2) The Chemistry of Heterocyclic Compounds; J ones, G., Ed.;
Wiley: Bristol, 1982; Vol. 32.
(3) (a) von Zeigler, K.; Zeiser, H. Liebigs Ann. Chem. 1931, 485, 174-
192. (b) Oldham, W.; J ohns, I. B. J . Am. Chem. Soc. 1939, 61, 3289-
3292.
(4) (a) Goldstein, S. W.; Dambek, P. J . Synthesis 1989, 221-222.
(b) Wee, A. G. H.; Liu, B.; Zang, L J . Org. Chem. 1992, 57, 4404-
4414. (c) Paris, D.; Cottin, M.; Demonchaux, P.; Augert, G.; Dupassieux,
P.; Lenoir, P.; Peck, M. J .; J asserand, D. J . Med. Chem. 1995, 38, 669-
685.
(5) (a) Hamann, L. G.; Mani, N. S.; Davis, R. L.; Wang, X. N.;
Marschke, K. B.; J ones, T. K. J . Med. Chem. 1999, 42, 210-212. (b)
Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52,
15031-15070.
(6) (a) Eisner, U.; Kuthan, J . Chem. Rev. 1972, 72, 1-42. (b) von
Doering, W. E.; Pasternack, V. Z. J . Am. Chem. Soc. 1950, 72, 143-
147. (c) Benkeser, R. A.; Holtar, D. S. J . Am. Chem. Soc. 1951, 73,
5861-5862. (d) Giam, C. S.; Knaus, E. E.; Pasutto, F. M. J . Org. Chem.
1974, 39, 3565-3568. (e) Giam, C. S.; Stout, J . L. J . Chem. Soc., Chem.
Commun. 1970, 478-479. (f) Frankel, G.; Cooper, J . W.; Fink, C. M.
Angew. Chem., Int. Ed. Engl. 1970, 9, 523-524. (g) Lyle, R. E.;
Marshall, J . L.; Comins, D. L. Tetrahedron Lett. 1977, 1005-1018.
(7) See, for example: (a) Piers, E.; Soucy, M. Can. J . Chem. 1974,
52, 3563-3564. (b) Comins, D. L.; Abdullah, A. H. J . Org. Chem. 1982,
47, 4315-4319. (c) Comins, D. L.; Mantlo, N. B. J . Heterocycl. Chem.
1983, 20, 1239-1243. (d) Comins, D. L., Stroud, E. D.; Herrick, J . J .
Heterocycles 1984, 22, 151-159. (e) Akiba, K.; Iseki, Y.; Wada, M.
Tetrahedron Lett. 1982, 23, 429-432.
(8) Gundersen, L.; Rise, F.; Undheim, K. Tetrahedron 1992, 48,
5647-5656.
(9) Katritzky, A. R.; Beltrami, H.; Keay, J . G.; Rogers, D. N.;
Sammes, M. P.; Leung, C. W. F.; Lee, C. M. Angew. Chem., Int. Ed.
Engl. 1979, 18, 792-793.
(10) (a) Akiba, K.-y.; Matsuoka, H.; Wada, M. Tetrahedron Lett.
1981, 22, 4093-4096. (b) Akiba, K.-y.; Iseki, Y.; Wada, M. Tetrahedron
Lett. 1982, 23, 3935-3936. (c) Akiba, K.-y.; Iseki, Y., Wada, M. Bull.
Chem. Soc. J pn. 1984, 57, 1994-1999.
(11) Report of an indirect method to prepare 4-alkylquinolines from
quinoline by the alkylation of 1-ethoxycarbonyl-1,2-dihydroquinoline-
2-phosphonate has been brought to our attention by one of the
reviewers. Akiba, K.-y.; Kasai, T.; Wada, M. Tetrahedron Lett. 1982,
23, 1709-1712.
(12) For example, the steric influence of the peri-hydrogen (8-
position) has been suggested to explain the comparative instability of
the borate complex derived from dialkylboryltriflate and lepidine.
Hamana, H.; Sugasawa, T. Chem. Lett. 1984, 1591-1594.
(13) (a) Akerman, E. Acta Chem. Scand. 1956, 10, 298-305; (b)
1957, 11, 373-381.
10.1021/jo990586b CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/30/1999

6912 J . Org. Chem., Vol. 64, No. 18, 1999
Notes
Sch em e 1
Alternatively, quenching the reaction after nondeuter-
ated EtMgBr addition with D2O followed by proton NMR
and mass spectral analysis of the products clearly
indicated formation of 4-ethyl-1,2,3,4-tetrahydroquinoline
8 with incorporation of one deuterium at the 3-position
(Figures 1b and 2b), suggesting that the initial protona-
tion of the 4-ethyl-1,4-dihydroquinoline intermediate
occurs at the 3-position. No deuterium incorporation was
detected in the 2- and 4-ethylquinolines isolated. The
4-ethyl-3,4-dihydroquinolinium derivative (12) obtained
by protonation (Scheme 3) could act as a hydride acceptor
and undergo an intermolecular redox reaction with the
2-ethyl-1,2-dihydroquinoline (10) already present in the
reaction mixture to form the observed tetrahydroquino-
line 4. 1,2-Dihydroquinolines obtained by regiocontrolled
reduction of quinoline using LAH or DIBAH have been
known to disproportionate to some extent, and the
intermediacy of 1,4-dihydroquinoline in the redox process
has been suggested.16 To verify this possibility, quinoline
deuterated at the 2-position (9) was synthesized17 and
subjected to the same reaction conditions (Scheme 3).
Analysis of mass spectra of the products formed showed
that the 4-ethyl-1,2,3,4-tetrahydroquinoline 13 formed
incorporated two deuterium atoms (Figure 1c), whereas
the 2-ethylquinoline (3) formed had no deuterium incor-
poration. Proton NMR clearly showed that the deuterium
incorporated was only at the 2-position (Figure 2c).
Incorporation of two deuterium atoms at the 2-position
thus unambiguously proved the redox reaction mecha-
nism in which the more reactive 2-ethyl-1,2 dihydro-
quinoline transfers a hydride to the iminium species 12
generated by the protonation of the 4-ethyl-1,4 dihydro-
quinoline 11.
Ta ble 1. Rea ction of Eth ylm a gn esiu m Br om id e w ith
Qu in olin iu m Tr ifla tes
yieldb (%)
entry
silyl triflate
conversiona (%)
2
3
4
5
1
2
3
4
5
Me3SiOTf
TBDMSOTf
Et3SiOTf
Ph3SiOTf
i-Pr3SiOTf
100
72
100
100
10
8
7
4
8
57
51
34
37
29
43
14
30
31
42
7
0
0
0
0
trace
a
b
Percent conversions are based on recovered quinoline. Iso-
lated yields are based upon the recovered quinolines.
Sch em e 2
In summary, our studies indicate that the addition of
Grignard reagents to quinolinium salts involving trialkyl/
arylsilyl triflates occurs at both the 2- and 4-positions.
With bulkier silyl groups, the 4-position is favored. Protic
workup of the resultant mixture of 1,2- and 1,4-dihyd-
roquinolines leads to an intermolecular redox reaction
leading to 4-alkyl-1,2,3,4-tetrahydroquinoline and 2-alkyl-
quinoline. In the case of the smaller trimethylsilyl
triflate, attack at the 2-position is favored, and the
resultant 2-ethyl-1,2-dihydroquinoline (10) undergoes
disproportionation under protic conditions to yield small
amounts of 5. Although the intermediacy of 1,4-dihy-
droquinoline in disproportionation mechanisms has been
suggested in previous studies,18 our findings for the first
time definitively establish the regiospecificity of this
intermolecular redox process between a 1,4- and a 1,2-
dihydroquinoline. The substituted tetrahydroquinoline
formed can be easily separated from the more polar
quinoline byproducts by flash column chromatography.
This reaction thus offers a one-pot method for synthesis
of 4-alkyl-1,2,3,4-tetrahyroquinolines from inexpensive
commercially available quinolines and may prove to be
of preparative utility relative to otherwise multistep
yields of products when reacted with the Grignard
reagent.
The formation of the tetrahydroquinolines was quite
unexpected. Intriguingly, some of the 4-ethyl-1,4-dihy-
droquinoline and 2-ethyl-1,2-dihydroquinoline intermedi-
ates had undergone further reduction to the correspond-
ing tetrahydroquinolines. The results in the case of
triphenylsilyl triflate eliminate the possibility of the alkyl
groups on the silyl group participating in a hydride-
transfer reduction to form the observed tetrahydroquino-
lines.
Another possible reductant could be the Grignard
reagent itself, which was used in slight excess (1.25
equiv). To rule out this possibility, the reaction was
carried out with perdeuterated ethylmagnesium bro-
mide (Scheme 2).14 Mass spectral analysis15 of the
products indicated incorporation of only five deuterium
atoms corresponding to the pentadeuterated 4-ethyl-
1,2,3,4-tetrahydroquinoline 7, clearly obviating the pos-
sibility of the Grignard reagent participating as a reduc-
ing agent.
(16) (a) Braude, E. A.; Hannah, J .; Linstead, R. J . Chem. Soc. 1960,
3249-3257. (b) Muren, J . F.; Weissman, A. J . Med. Chem. 1971, 14,
49-53. (c) Minter, D. E.; Stotter, P. L. J . Org. Chem. 1981, 46, 3965-
3970.
(14) (2H5)ethylmagnesium bromide was readily prepared from com-
mercially available (2H5)ethyl bromide by standard methods.
(15) Mass spectral fragmentation patterns clearly show that deu-
terium incorporation is on the ethyl group on the hydroaromatic system
of 1,2,3,4-tetrahydroquinoline. For mass spectra of tetrahydroquino-
lines, see: Draper, P. M.; MacLean, D. B. Can. J . Chem. 1968, 46,
1499-1505.
(17) (2-2H)Quinoline was prepared in good yields (85% after puri-
fication) by reduction of 2-chloroquinoline using zinc metal and (2H4)-
acetic acid-D2O at 0 °C. See the Supporting Information for experi-
mental details or ref 18 for an alternate method.
(18) Forrest, T. P.; Dauphine, G. A.; Deraniyagala, S. A. Can. J .
Chem. 1985, 63, 412-415.

Notes
J . Org. Chem., Vol. 64, No. 18, 1999 6913
F igu r e 1. Mass spectra from deuterium substitution experiments: (a) 4-ethyl-1,2,3,4-tetrahydroquinoline (4); (b) (3-2H)-4-ethyl-
1,2,3,4-tetrahydroquinoline (8) obtained when the reaction was quenched with deuterium oxide; (c) 2-(2H2)-4-ethyl-1,2,3,4-
tetrahydroquinoline (13) obtained when 2-deuterium substituted quinoline was used as a substrate for the reaction.
F igu r e 2. Portions of proton NMR spectra from deuterium substitution experiments: (a) 4-ethyl-1,2,3,4-tetrahydroquinoline
(4); (b) (3-2H)-4-ethyl-1,2,3,4-tetrahydroquinoline (8) obtained when the reaction was quenched with deuterium oxide; (c) 2-(2H2)-
4-ethyl-1,2,3,4-tetrahydroquinoline (13) obtained when 2-deuterium substituted quinoline was used as a substrate for the reaction.
million (ppm), and coupling constants (J ) are given in hertz (Hz).
GC-MS analyses were carried out using a Hewlett-Packard
6890 series instrument, and mass spectra were recorded at an
ionizing voltage of 70 eV. Analytical TLC was carried out on
silica gel plates. Flash column chromatography was conducted
using silica gel 60 (EM Science, 230-400 mesh).
Gen er a l P r oced u r e for th e Ad d ition of Gr ign a r d Re-
a gen t to Qu in olin iu m Tr ifla tes. Trialkyl/arylsilyl triflate
(12.5 mmol) was added to a magnetically stirred solution of
quinoline (10 mmol) in dry CH2Cl2 (20 mL) at room temperature
under nitrogen atmosphere. The reaction mixture was stirred
until TLC showed consumption of quinoline (24-48 h). The
strategies. Our studies in this direction will be the subject
of future publications.
Exp er im en ta l Section
Gen er a l Meth od s. CH2Cl2 was distilled over calcium hydride
and quinoline over KOH. The remaining commercially available
reagents and solvents were used without further purification
and were handled by using standard syringe techniques. 1H
NMR spectra were recorded at 400 or 500 MHz using CDCl3 as
solvent and TMS (0.00 ppm 1H) or CHCl3 (7.26 ppm 1H) as
internal standards. Chemical shifts (δ) are given in parts per

6914 J . Org. Chem., Vol. 64, No. 18, 1999
Notes
Sch em e 3
solution was then cooled to -78 °C, and a 1 M solution of
ethylmagnesium bromide (12.5 mL) was added dropwise. After
1-2 h, the cooling bath was removed, and the reaction mixture
was stirred for another 8-10 h while warming to room temper-
ature. The reaction mixture was then quenched by adding water
(25 mL) or dilute acid (1 N HCl, 25 mL), and the resulting
mixture was stirred for 2-4 h. The acidic mixture was neutral-
ized with saturated NaHCO3. The organic layer was separated
and the aqueous layer extracted with CH2Cl2 (3 × 25 mL). The
combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
resulting oily residue was subjected to flash column chromatog-
raphy (silica, 1:20 EtOAc/hexanes) to afford the following, in
order of elution: (i) 2-ethyl-1,2,3,4-tetrahydroquinoline (5) (ob-
served only in the case of TMSOTf), (ii) 4-ethyl-1,2,3,4-tetrahy-
droquinoline (4), (iii) 2-ethylquinoline (3), and (iv) 4-ethylquin-
oline (2). All of the above products are known compounds5 and
are easily identified by their 1H NMR and mass spectra.
Deu ter iu m Su bstitu tion Exp er im en ts. (3-2H)4-Eth yl-
1,2,3,4-tetr a h yd r oqu in olin e (8). In an experiment similar to
the one described above, triethylsilyl triflate was used as the
quaternizing agent, and the reaction was quenched with D2O
(25 mL). The products were isolated in the usual manner to
obtain the deuterium-incorporated 4-ethyl-1,2,3,4-tetrahydro-
quinoline 8: 1H NMR (400 MHz, CDCl3) δ 1.01 (3H, t, J ) 5.6),
1.51-1.82 (3H, m), 2.66 (1H, ddd, J 1 ) 4.0, J 2 ) 6.8), 3.2-3.34
(2H, m), 3.85 (1H, br), 6.5 (1H, d, J ) 6.4), 6.63 (1H, t, J ) 5.6),
6.98 (1H, t, J ) 5.6), 7.03 (1H, d, J ) 6.4); MS (70 eV) m/z 162
M+, 133 (M - CH3CH2-)+.
(2-2H2)4-Eth yl-1,2,3,4-tetr a h yd r oqu in olin e (13). In an
experiment similar to the one described in the general procedure,
(2-2H)quinoline was used as the substrate and triethylsilyl
triflate as the quaternizing agent. The products were isolated
in the usual manner to obtain the deuterated 4-ethyl-1,2,3,4-
tetrahydroquinoline 13: 1H NMR (400 MHz, CDCl3) δ 1.01 (3H,
t, J ) 5.6), 1.51-1.94 (4H, m), 2.66 (1H, m), 3.84 (1H, br), 6.5
(1H, d, J ) 6.4), 6.63 (1H, t, J ) 5.6), 6.98 (1H, t, J ) 5.6), 7.03
(1H, d, J ) 6.4); MS (70 eV) m/z 163 M+, 134 (M - CH3CH2)+.
Ack n ow led gm en t. We are grateful to Professor
Barry M. Trost, Dr. Lawrence G. Hamann, and Dr.
J ames P. Edwards for their helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure for the preparation of (2-2H)quinoline (9), 1H NMR
spectra, and mass spectra for 9. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O990586B