Synthesis of Bis(2-arylquinolin-4-yl)amines by Lithium Bis(trimethylsilyl)amide-Mediated Cyclization of ketimines Derived from 2-(Trifluoromethyl)anilines and Aryl Methyl Ketones

Full text of DOI:10.1021/jo970101o

J . Org. Chem. 1997, 62, 4193-4196
4193
Sch em e 1
Syn th esis of Bis(2-a r ylqu in olin -4-yl)a m in es
by Lith iu m
Bis(tr im eth ylsilyl)a m id e-Med ia ted
Cycliza tion of Ketim in es Der ived fr om
2-(Tr iflu or om eth yl)a n ilin es a n d Ar yl
Meth yl Keton es
Lucjan Strekowski,* Lubomir J anda,1 and Hyeran Lee
Department of Chemistry, Georgia State University,
Atlanta, Georgia 30303
Received J anuary 21, 1997
In 1990, we reported a novel base-mediated cyclization
of o-(trifluoromethyl)-substituted ketimines such as 1
(Scheme 1) to quinolines.2 Subsequently, this and related
chemistry have been elaborated into a practical tool for
the construction of various substituted and fused quino-
lines, quinazolines, and other heterocyclic and nonhet-
erocyclic systems.3 In particular, the cyclization of 1 in
the presence of t-BuOK followed by acid hydrolysis of the
resultant 4-tert-butoxyquinoline4 yields a 4-hydroxyquin-
oline such as 2. Unfortunately, in the original paper,2 it
was also stated erroneously that the same 4-hydroxy-
quinoline 2 was produced in the reaction of 1a with
lithium bis(trimethylsilyl)amide (LHMDS) followed by
aqueous workup. This paper is a correction to the
previously published paper.5
The treatment of ketimines 1a -e with LHMDS (3.5
equiv) gave the corresponding bis(quinolyl)amines 3a -e
and silylated quinolinamines 4a -e as the major and
minor products, respectively. Compounds 3 and 4 were
easily separated by flash chromatography. A detailed
chromatographic separation of the mixtures from 1a ,b
also revealed the presence of known cyano-substituted
ketimines6 5a ,b and trace amounts of quinolinamines6
6a ,b as additional minor products with a total mass
balance for 3-6 of at least 95% in each case. These
results were confirmed by GC-MS analyses of crude
mixtures from 1a ,b. In a similar way, the GC-MS
analysis of the crude mixtures from 1c-e showed the
presence of varying amounts of two additional minor
products (not isolated in pure form by conventional
chromatography) with a molecular ion peak and frag-
mentation pattern fully consistent with the respective
structures 5c-e and 6c-e.
As expected, compounds 4 were easily and efficiently
desilylated by treatment with tetrabutylammonium fluo-
ride to give quinolin-4-amines 6. The formation of known
quinolines6 6a ,b under these conditions served as an
additional confirmation of the structure of 4a ,b. The
isolated ketimines 5a ,b were cyclized to 6a ,b by using a
previously published procedure.6
The highest yields of bis(quinolyl)amines 3 (48-73%)
were obtained with 3.0-3.5 equiv of LHMDS. The use
of 20 equiv of the reagent resulted in greatly diminished
yields of both 3 and ketimines 5, and N,N-bis(trimeth-
ylsilyl)quinolin-4-amines 4 were the major products (58-
62%). To determine whether or not products 4-6 are
precursors to bis(quinolyl)amines 3, several cross experi-
ments were conducted under standard conditions (3.5
equiv of LHMDS). The efficiency of cyclization of 1a to
3a was increased from 48% to 65% for the reaction
conducted in the presence of 1 equiv of quinolinamine
6a . As expected, a similarly increased yield of 3a was
obtained in the presence of 1 equiv of ketimine 5a
because 5a is easily cyclized to 6a under strongly basic
conditions.6 Another experiment was conducted with a
All bis(quinolyl)amines 3a -e gave a molecular ion
peak as the base peak in their mass spectra. The silyl
derivatives 4a -e are also relatively stable under electron
impact conditions. An intense molecular ion peak was
observed, and the loss of methyl from the molecular ion
accounts for the most abundant fragment ion for 4a -e.
* To whom correspondence should be addressed. Tel.: (404) 651-
0999. Fax: (404) 651-1416. E-mail: Lucjan@gsu.edu.
(1) Current address: Aldrich Chemical Co., Inc., Milwaukee, WI
53233.
(2) Strekowski, L.; Wydra, R. L; Cegla, M. T.; Czarny, A.; Harden,
D. B.; Patterson, S. E.; Battiste, M. A.; Coxon, J . M. J . Org. Chem.
1990, 55, 4777.
(3) For a review, see: Kiselyov, A. S.; Strekowski, L. Org. Prep. Proc.
Int. 1996, 28, 289.
(4) (a) J anda, L.; Nguyen, J .; Patterson, S. E.; Strekowski, L. J .
Heterocycl. Chem. 1992, 29, 1753. (b) Strekowski, L.; Patterson, S. E.;
J anda, L.; Wydra, R. L.; Harden, D.B.; Lipowska, M.; Cegla, M. T. J .
Org. Chem. 1992, 57, 196.
(5) It appears that, due to mislabeling, a sample of 2 was found to
be identical with itself.
(6) Strekowski, L.; Kong, S.-B.; Cegla, M. T.; Harden, D. B.
Heterocycles 1989, 29, 539.
S0022-3263(97)00101-1 CCC: $14.00 © 1997 American Chemical Society

4194 J . Org. Chem., Vol. 62, No. 12, 1997
Notes
Sch em e 2
mixture of ketimine 1a and quinolinamine 6b (1 equiv
each). Preparative chromatography gave an inseparable
mixture of two bis(quinolyl)amines. The mass spectrum
of this mixture showed a strong molecular ion peak for
3a at m/ z 423 and a more intense peak at m/ z 429,
which may correspond to the molecular ion of bis-
(quinolin-4-yl)amine substituted with phenyl and 2-
thienyl groups at the 2 and 2′ positions (not shown).
Ketimine 1a was also cyclized in the presence of a silyl
derivative 4b (1 equiv). Preparative chromatography
gave a mixture of 4a and 4b and pure (by 1H NMR
standard) compounds 3a , 5a , and 6a . NMR integration
of the fraction containing 4a and 4b revealed that 4b was
recovered in a 90% yield. The relative stability of
silylamines 4 under the reaction conditions was con-
firmed by conducting the reaction of 1b under standard
conditions (45 min), quenching half of the mixture, and
then quenching the second half after 1.5 h, which resulted
in only a slightly decreased yield of 4b. These results
show that (i) quinolinamines 6 are precursors to bis-
(quinolyl)amines 3 and (ii) the major pathway to 6
involves cyclization of intermediate ketimines 5 but not
desilylation of (trimethylsilyl)amines 4.
quent pathway 13 f 16 f 17 f 4 is straightforward.7
The suggested nucleophile addition to 9 is consistent with
the experimental finding that the yield of a silylamine 4
increases with increasing concentration of bis(trimeth-
ylsilyl)amide anion (up to 20 equiv).
On the other hand, the bis(quinolyl)amine 3 is formed
efficiently in the presence of 3.5 equiv of the lithium
reagent,8 and under optimized conditions the reagent is
added in portions to the mixture resulting in a low
concentration of the amide anion throughout the reaction
course. It is suggested that under these conditions the
fluoride ion-assisted desilylation of 9 competes effectively
with the nucleophile addition, the driving force being the
formation of the aromatic structure 12. Anion 14 of the
observed product 5 can be formed in two pathways: (i)
fluoride ion-mediated desilylation of 12 and elimination
of the remaining fluoride or (ii) intramolecular cyclization
of 12 (intramolecular addition of azaallyl anion to fluoro
imine) followed by fluoride-assisted desilylation and ring
opening of the resultant intermediate product 11. The
apparent driving force of both pathways is the formation
of a thermodynamically stable cyano group.9 The known
cyclization6 of 14 is followed by nucleophilic addition of
A unified mechanism for 3-6, which is consistent with
the above observations, is suggested in Scheme 2. The
initial transformations 1 f 7 f 8 f 9 are well under-
stood for a variety of strong bases/nucleophiles.2-4 While
the key intermediate product 9 can, in principle, undergo
electrocyclization to 10, a possible direct precursor to a
silylamine 4, this electrocyclization is apparently slower
than the competing nucleophilic addition of bis(trimeth-
ylsilyl)amide anion with 9 to generate 13. The subse-
(7) See refs 2 and 4b for close analogs of 17.
(8) The suggested pathway from 1 to a lithium derivative of 3
requires 3 equiv of lithium bis(trimethylsilyl)amide.
(9) The treatment of 2- or 4-(trifluoromethyl)aniline with sodium
amide in liquid ammonia gives the respective 2- or 4-aminobenzonitrile
in a low yield: Kobayashi, Y.; Kumadaki, I. Acc. Chem. Res. 1978, 11,
197. We have found (unpublished results) that 2-aminobenzonitrile is
produced in a 20% yield by the reaction of 2-(trifluoromethyl)aniline
with 3.1-3.5 equiv of lithium bis(trimethylsilyl)amide under the
general conditions of this paper. The use of an excess of the lithium
reagent (20 equiv) gave only traces of 2-aminobenzonitrile, which is
completely analogous to the reactions of 1.

Notes
J . Org. Chem., Vol. 62, No. 12, 1997 4195
(30), 654 (50), 655 (100, M+). Anal. Calcd for C34H21F8N3O2:
C, 62.29; H, 3.23; N, 6.41. Found: C, 62.21; H, 3.46; N, 6.40.
Bis[2-(2-flu or op h en yl)-6-flu or oqu in olin -4-yl]a m in e (3e):
the resultant quinolylamide anion 15 with the key
intermediate product 9 to give 18. The remaining steps
18 f 19 f 3 are self-explanatory.
1
yield 57%; mp 275-277 °C; H NMR (DMSO-d6) δ 7.26 (t, J )
In summary, we have shown that the reaction of
ketimines 1 with LHMDS gives symmetrical bis(quinolin-
4-yl)amines 3 in good yields. The proposed mechanism
is fully consistent with the experimental findings includ-
ing all isolated minor products. The method is not
practical for the synthesis of unsymmetrically substituted
amines 3 due to the formation of two amines 3 that are
difficult to separate.
8 Hz, 2 H), 7.30 (br s, exchangeable with D2O, 1 H), 7.32 (t, J )
8 Hz, 2 H), 7.48 (m, 2 H), 7.61 (s, 2 H), 7.73 (m, 2 H), 8.02 (m,
2 H), 8.16 (m, 4 H); MS m/ z 374 (40), 494 (50), 495 (100, M+).
Anal. Calcd for C30H17F4N3: C, 72.72; H, 3.46; N, 8.48. Found:
C, 72.53; H, 3.48; N, 8.42.
N,N-Bis(tr im eth ylsilyl)-2-p h en ylqu in olin -4-a m in e (4a ):
yield 26%; mp 87-89 °C; 1H NMR (CDCl3) δ 0.13 (s, 18 H), 7.43
(s, 1 H), 7.50 (m, 5 H), 7.67 (m, 1 H), 8.14 (m, 3 H); MS m/ z 349
(100), 364 (25, M+). Anal. Calcd for C21H28N2Si2: C, 69.17; H,
7.74; N, 7.68. Found: C, 69.21; H, 7.71; N, 7.61.
N,N-Bis(t r im et h ylsilyl)-2-(2-t h ien yl)q u in olin -4-a m in e
(4b): yield 7%; mp 105-106 °C; H NMR (CDCl3) δ 0.13 (s, 18
Exp er im en ta l Section
1
Melting points (Pyrex capillary) are not corrected. Proton and
13C NMR spectra were recorded at 400 and 67.8 MHz, respec-
tively. Mass spectra were determined at 70 eV.
Ketim in es 1a -f. Synthesis of 1a ,10 1b,10 1c,4a and 1e11 has
been reported previously. Ketimine 1d was obtained in a similar
fashion by condensation of 2,5-bis(trifluoromethyl)aniline with
2′-fluoro-4′-methoxyacetophenone.
N-[1-(2-F lu or o-4-m eth oxyp h en yl)eth ylid en e]-2,5-bis(tr i-
flu or om eth yl)a n ilin e (1d ): yield 65%; bp 158-159 °C/3.8
mmHg; mp 58-59 °C; 1H NMR (CDCl3) δ 2.25 (d, J HF ) 3.6 Hz,
3 H), 3.86 (s, 3 H), 6.66 (d, J HF ) 13.6 Hz, 1 H), 6.79 (d, J ) 8.6
Hz, 1 H), 7.07 (s, 1 H), 7.41 (d, J ) 7.8 Hz, 1 H), 7.78 (d, J ) 7.8
Hz, 1 H), 7.89 (t, J HF ) J HH ) 8.6 Hz, 1 H); MS m/ z 364 (100),
379 (40, M+). Anal. Calcd for C17H12F7NO: C, 53.83; H, 3.19;
N, 3.69. Found: C, 53.93; H, 3.18; N, 3.65.
H), 7.16 (dd, J ) 5.2, 3.6 Hz, 1 H), 7.35 (s, 1 H), 7.44 (t, J ) 8
Hz, 1 H), 7.47 (d, J ) 5.2 Hz, 1 H), 7.65 (t, J ) 8 Hz, 1 H), 7.69
(d, J ) 3.6 Hz, 1 H), 8.04 (d, J ) 8 Hz, 1 H), 8.06 (d, J ) 8 Hz,
1 H); MS m/ z 355 (100), 370 (30, M+). Anal. Calcd for C19H26N2-
SSi2: C, 61.56; H, 7.07; N, 7.56. Found: C, 61.62; H, 7.07; N,
7.53.
N,N-Bis(t r im et h ylsilyl)-2-p h en yl-7-(t r iflu or om et h yl)-
qu in olin -4-a m in e (4c): yield 21%; mp 101-103 °C; 1H NMR
(CDCl3) δ 0.13 (s, 18 H), 7.52 (s, 1 H), 7.54 (m, 3 H), 7.66 (d, J
) 8 Hz, 1 H), 8.15 (m, 2 H), 8.23 (d, J ) 8 Hz, 1 H), 8.45 (br s,
1 H); MS m/ z 417 (100), 432 (20, M+). Anal. Calcd for
C
22H27F3N2Si2: C, 61.07; H, 6.29; N, 6.47. Found: C, 61.00; H,
6.32; N, 6.41.
N,N-Bis(tr im eth ylsilyl)-2-(2-flu or o-4-m eth oxyp h en yl-7-
(tr iflu or om eth yl)qu in olin -4-a m in e (4d ): yield 19%; mp 82-
1
R ea ct ion of Ket im in es 1a -e w it h Lit h iu m Bis-
(tr im eth ylsilyl)a m id e: Meth od A. A solution of 1 (1.0 mmol)
in anhydrous THF (10 mL) was stirred under
83 °C; H NMR (CDCl3) δ 0.13 (s, 18 H), 3.88 (s, 3 H), 6.74 (d,
J HF ) 13 Hz, 1 H), 6.89 (d, J ) 8 Hz, 1 H), 7.56 (d, J HF ) 2.8 Hz,
1 H), 7.65 (d, J ) 8 Hz, 1 H), 8.16 (t, J HH ) J HF ) 8 Hz, 1 H),
8.22 (d, J ) 8 Hz, 1 H), 8.43 (br s, 1 H); MS m/ z 465 (100), 480
(30, M+). Anal. Calcd for C23H28F4N2OSi2: C, 57.47; H, 5.87;
N, 5.82. Found: C, 57.57; H, 5.83; N, 5.73.
a nitrogen
atmosphere at 23 °C and treated dropwise with a solution of
lithium bis(trimethylsilyl)amide in THF (1.0 M, 2.0 mL, 2.0
mmol). After 20 min, the mixture was treated with another
portion of the lithium reagent (1.5 mL, 1.5 mmol) and stirred at
23 °C for an additional 25 min. A dark-red mixture was
quenched with water (90 µL, 5 mmol), filtered, and concentrated
on a rotary evaporator, leaving a light-orange residue. Silica
gel chromatography on a chromatotron gave, in order of elution,
4, 5 (hexanes/Et3N, 9:1), 3 (hexanes/Et3N/EtOH, 6:2:2), and trace
amounts (<3%) of 6 (hexanes/Et3N/EtOH, 4:4:2). Products 4 and
5 were crystallized from hexanes and 3 from a mixture of EtOH,
THF, and hexanes.
Bis(2-p h en ylqu in olin -4-yl)a m in e (3a ): yield 48%; mp 259-
260 °C; 1H NMR (DMSO-d6) δ 7.44 (m + s, 8 H), 7.56 (t, J ) 7.8
Hz, 2 H), 7.65 (br s, exchangeable with D2O, 1 H), 7.78 (t, J )
7.8 Hz, 2 H), 8.07 (m, 6 H), 8.32 (d, J ) 7.8 Hz, 2 H); 13C NMR
(DMSO-d6) δ 107.1, 121.2, 123.3, 125.7, 127.2, 129.0, 129.7,
129.8, 130.4, 139.1, 148.2, 149.3, 156.8; MS m/ z 320 (40), 422
(70), 423 (100, M+). Anal. Calcd for C30H21N3: C, 85.07; H, 4.99;
N, 9.92. Found: C, 84.84; H, 5.02; N, 9.86.
N,N-Bis(tr im eth ylsilyl)-6-flu or o-2-(2-flu or op h en yl)qu in -
1
olin -4-a m in e (4e): yield 17%; mp 96-98 °C; H NMR (CDCl3)
δ 0.13 (s, 18 H), 7.18 (m, 1 H), 7.31 (m, 1 H), 7.44 (m, 2 H), 7.49
(d, J HF ) 2.8 Hz, 1 H), 7.73 (m, 1 H), 8.12 (m, 2 H); MS m/ z 385
(100), 400 (45, M+). Anal. Calcd for C21H26F2N2Si2: C, 62.95;
H, 6.54; N, 6.99. Found: C, 62.67; H, 6.82; N, 6.70.
2-[(1-P h en yleth ylid en e)a m in o]ben zon itr ile (5a ): yield
22%; mp 67-68 °C (lit.6 mp 68-69 °C).
2-[[1-(2-Th ien yl)eth yliden e]am in o]ben zon itr ile (5b): yield
15%; mp 86-87 °C (lit.6 mp 85-87 °C).
R ea ct ion of Ket im in es 1a ,b w it h Lit h iu m Bis(t r i-
m eth ylsilyl)a m id e: Meth od B. The lithium reagent (20
mmol) was added in one portion to a solution of 1 (1.0 mmol) in
THF (5 mL), and the resultant mixture was stirred at 23 °C for
45 min and then worked up as described in method A to give 3a
(19%), 4a (58%), 5a (10%); 3b (16%), 4b (62%), 5b (7%).
Desilylation of N,N-Bis(tr im eth ylsilyl)qu in olin -4-am in es
4a -e. A solution of a silyl derivative 4a -e (0.2 mmol) and
tetrabutylammonium fluoride hydrate (0.25 g, 0.8 mmol) in THF
(10 mL) was stirred at 23 °C under a nitrogen atmosphere for 2
h and then concentrated on a rotary evaporator. Products 6a -e
were isolated by silica gel chromatography on a chromatotron
eluting with hexanes/Et3N/EtOH (4:2:2) and then crystallized
from 95% EtOH/hexanes.
Bis[2-(2-th ien yl)qu in olin -4-yl]a m in e (3b): yield 73%; mp
1
265-267 °C; H NMR (DMSO-d6) δ 7.09 (dd, J ) 5.0, 3.8 Hz, 2
H), 7.53 (t, J ) 8.0 Hz, 2 H), 7.64 (m + s, 7 H), 7.76 (t, J ) 8.0
Hz, 2 H), 7.98 (d, J ) 8.0 Hz, 2 H), 8.28 (d, J ) 8.0 Hz, 2 H); 13
C
NMR (DMSO-d6) δ 105.7, 121.1, 123.0, 125.3, 126.3, 128.4, 129.0,
129.2, 130.3, 145.0, 147.5, 148.9, 152.3; MS m/ z 326 (20), 434
(30), 435 (100, M+). Anal. Calcd for C26H17N3S2: C, 71.69; H,
3.94; N, 9.64. Found: C, 71.52; H, 3.92; N, 9.59.
2-P h en ylqu in olin -4-a m in e (6a ): yield 94%; mp 163-164 °C
Bis[2-ph en yl-7-(tr iflu or om eth yl)qu in olin -4-yl]am in e (3c):
yield 65%; mp 236-238 °C; 1H NMR (DMSO-d6) δ 7.47 (m, 7
H), 7.84 (d, J ) 8 Hz, 2 H), 7.90 (s, 2 H), 8.14 (m, 4 H), 8.41 (s,
2 H), 8.58 (d, J ) 8 Hz, 2 H); MS m/ z 456 (50), 558 (70), 559
(100, M+). Anal. Calcd for C32H19F6N3: C, 68.67; H, 3.42; N,
7.51. Found: C, 68.85; H, 3.50; N, 7.51.
(lit.6 mp 163-165 °C).
2-(2-Th ien yl)qu in olin -4-a m in e (6b): yield 90%; mp 163-
165 °C (lit.6 mp 163-165 °C).
2-P h en yl-7-(tr iflu or om eth yl)qu in olin -4-a m in e (6c): yield
1
92%; mp 130-132 °C; H NMR (CDCl3) δ 4.80 (br s, exchange-
able with D2O, 2 H), 7.17 (s, 1 H), 7.49 (m, 3 H), 7.61 (d, J ) 8
Hz, 1 H), 7.87 (d, J ) 8 Hz, 1 H), 8.09 (m, 2 H), 8.40 (br s, 1 H);
MS m/ z 287 (80), 288 (100, M+). Anal. Calcd for C16H11F3N2:
C, 66.65; H, 3.84; N, 9.72. Found: C, 66.32; H, 4.08; N, 9.58.
2-(2-F lu or o-4-m eth oxyp h en yl)-7-(tr iflu or om eth yl)qu in -
olin -4-a m in e (6d ): yield 92%; mp 110-111 °C; 1H NMR (CDCl3/
DMSO-d6, 1:1) δ 3.87 (s, 3 H), 5.61 (br s, exchangeable with D2O,
2 H), 6.71 (d, J HF ) 16 Hz, 1 H), 6.86 (d, J ) 8 Hz, 1 H), 7.19 (d,
J HF ) 2 Hz, 1 H), 7.57 (d, J ) 8 Hz, 1 H), 8.06 (m, 2 H), 8.31 (s,
1 H); MS m/ z 273 (15), 336 (100, M+). Anal. Calcd for
Bis[2-(2-flu or o-4-m et h oxyp h en yl)-7-(t r iflu or om et h yl)-
qu in olin -4-yl]a m in e (3d ): yield 69%; mp 158-160 °C; 1H NMR
(DMSO-d6) δ 3.82 (s, 6 H), 6.92 (m, 5 H), 7.67 (s, 2 H), 7.84 (m,
2 H), 8.08 (m, 2 H), 8.36 (m, 2 H), 8.57 (m, 2 H); MS m/ z 504
(10) Strekowski, L.; Mokrosz, J . L.; Honkan, V. A.; Czarny, A.; Cegla,
M. T.; Wydra, R. L.; Patterson, S. E.; Schinazi, R. F. J . Med. Chem.
1991, 34, 1739.
(11) Strekowski, L.; J anda, L.; Patterson, S. E.; Nguyen, J . Tetra-
hedron 1996, 52, 3273.

4196 J . Org. Chem., Vol. 62, No. 12, 1997
Notes
C17H12F4N2O‚0.5H2O: C, 59.12; H, 3.79; N, 8.11. Found: C,
58.97; H, 3.83; N, 8.09.
C
15H10F2N2: C, 70.30; H, 3.93; N, 10.93. Found: C, 70.40; H,
3.97; N, 10.93.
6-F lu or o-2-(2-flu or op h en yl)qu in olin -4-a m in e (6e): yield
85%; mp 149-151 °C; H NMR (CDCl3) δ 4.64 (br s, exchange-
able with D2O, 2 H), 7.13 (d, J HF ) 2 Hz, 1 H), 7.17 (m, 1 H),
7.29 (m, 1 H), 7.39 (m, 2 H), 7.45 (m, 1 H), 8.03 (m, 1 H), 8.08
m, 1 H); MS m/ z 255 (50), 256 (100, M+). Anal. Calcd for
Ack n ow led gm en t. We thank donors of the Petro-
leum Research Fund, administered by the American
Chemical Society, for partial support of this research.
1
J O970101O