Multiple regioselective functionalizations of quinolines via magnesiations

Article abstract of DOI:10.1021/ol702494k

A wide range of polyfunctionalized quinolines was prepared via chemo- and regioselective magnesiation reactions using appropriate Mg reagents, such as i-PrMgCl-LiCl, MesMgBr·LiCl, Mes₂Mg·2LiBr, TMPMgCl·LiCl, and TMP₂Mg·2LiCl. An application to the total synthesis of the biologically active compound talnetant was performed (six steps, 28%).

Full text of DOI:10.1021/ol702494k

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5525-5528
Multiple Regioselective
Functionalizations of Quinolines via
Magnesiations
Nade`ge Boudet, Jennifer R. Lachs, and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse
5-13, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received October 12, 2007
ABSTRACT
A wide range of polyfunctionalized quinolines was prepared via chemo- and regioselective magnesiation reactions using appropriate Mg
reagents, such as i-PrMgCl LiCl, MesMgBr LiCl, Mes2Mg 2LiBr, TMPMgCl LiCl, and TMP2Mg 2LiCl. An application to the total synthesis of the
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‚
‚
‚
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biologically active compound talnetant was performed (six steps, 28%).
The preparation of polyfunctionalized quinolines is of great
interest since this structural unit (Figure 1) is found in various
lithiation of quinolines via Br/Li exchange reactions or by
using a lithium base has been reported.4 Mongin and
Que´guiner described also Br/Mg exchange5 on monobromi-
nated quinolines using Bu3MgLi.6 These approaches are often
complicated by a lack of regioselectivity and the propensity
of lithium or magnesium reagents to undergo nucleophilic
substitution at the C2 position. Recently, we have found that
Br/Mg exchange reactions7 or the use of TMPMgCl‚LiCl
(TMP ) 2,2,6,6-tetramethylpiperidyl)8 allows an efficient
(3) Duffour, J.; Gourgou, S.; Desseigne, F.; Debrigode, C.; Mineur, L.;
Pinguet, F.; Poujol, S.; Chalbos, P.; Bressole, F.; Ychou, M. Cancer
Chemother. Pharmacol. 2007, 60, 283.
(4) (a) Comins, D. L.; Nolan, J. M. I.; Bori, D. Tetrahedron Lett. 2005,
46, 6697. (b) Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4059. (c)
Comins, D. L.; Hong, H.; Saha, J. K.; Jianhua, G. J. Org. Chem. 1994, 59,
5120. (d) Arzel, E.; Rocca, P.; Marsais, F.; Godard, A.; Que´guiner, G.
Tetrahedron 1999, 55, 12149. (e) Marull, M.; Schlosser, M. Eur. J. Org.
Chem. 2003, 1569. (f) Marull, M.; Schlosser, M. Eur. J. Org. Chem. 2004,
1008. (g) For review, see: Schlosser, M. Angew. Chem., Int. Ed. 2005, 44,
376.
Figure 1. Drugs containing the quinoline skeleton.
drugs such as mefloquine (1), an antimalarial,1 talnetant (2),2
a potential NK3 receptor antagonist developed by GSK, or
irinotecan (3),3 an anticancer drug, marketed by Pfizer. The
(5) Dumouchel, S.; Mongin, F.; Tre´court, F.; Que´guiner, G. Tetrahedron
Lett. 2003, 44, 2033.
(1) Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Angew. Chem.,
Int. Ed. 2003, 42, 5274.
(2) Elliott, J. M.; Carling, R. W.; Chambers, M.; Chicchi, G. G.; Hutson,
P. H.; Jones, A. B.; MacLeod, A.; Marwood, R.; Meneses-Lorente, G.;
Mezzogori, E.; Murray, F.; Rigby, M.; Royo, I.; Russell, M. G. N.; Sohal,
B.; Tsao, K. L.; Williams, B. Bioorg. Med. Chem. Lett. 2006, 16, 5748.
(6) Kitagawa, K.; Inoue, A.; Shinokubo, H.; Oshima, K. Angew. Chem.,
Int. Ed. 2000, 39, 2481.
(7) (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
3333. (b) Boudet, N.; Knochel, P. Org. Lett. 2006, 8, 3737.
(8) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int.
Ed. 2006, 45, 2958.
10.1021/ol702494k CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/21/2007

direct magnesiation of various heterocycles. Herein, we wish
to report chemo- and regioselective magnesiation of quino-
lines using Mg reagents (Scheme 1) such as i-PrMgCl‚LiCl
Table 1. Regioselective Magnesiation via Br/Mg Exchange of
Polybromoquinolines of Type 9 and Trapping with Electrophiles
Scheme 1. Synthesis of the Magnesiation Reagents 5, 6, 7,
and 8
(4),9 MesMgBr‚LiCl (5, Mes ) mesityl), Mes2Mg‚2LiBr (6),
TMPMgCl‚LiCl (7),8 and TMP2Mg‚2LiCl (8),10 starting from
readily available polybrominated quinolines. The new Grig-
nard reagents MesMgBr‚LiCl and Mes2Mg‚2LiBr were
readily prepared as indicated in Scheme 1. They proved to
be highly selective for challenging Br/Mg exchanges.
Thus, the reaction of 2,3-dibromoquinoline (9a) with
i-PrMgCl‚LiCl (4, 1.1 equiv, -50 °C, 2 h, Scheme 2)
Scheme 2. Regioselective Br/Mg Exchange Reactions on
Polybrominated Quinolines of Type 9
a X ) Cl‚LiCl or Br‚LiCl. b Isolated yield of analytically pure product.
c Reaction performed after transmetalation with CuCl‚2LiCl (1.2 equiv).
d Ar ) Mes‚LiBr. e Reaction performed after transmetalation with ZnCl2.
f 2 mol % of Pddba2 and 4 mol % of P-(o-furyl)3 were added.
addition of 4 (1.1 equiv, -78 °C, 2 h) gave the corresponding
4-magnesiated 2-bromoquinoline (10b). In contrast, the
reactions of 2,3,4-tribromoquinoline (9c) or 3,4-dibromo-
quinoline (9d)14 with iPrMgCl‚LiCl (4) were not selective
and provided regioisomeric mixture of Grignard reagents.
Related selectivity problems have been observed with
dibromopyridines.15,16 However, using the sterically more
demanding MesMgBr‚LiCl (5, 1.1 equiv, -10 °C, 3 h), a
complete regioselective magnesiation at the C3 position was
observed for the 2,3,4-tribromoquinoline (9c), providing the
corresponding intermediate 10c (Table 1). The Grignard
provided quantitatively11 and regioselectively12 the corre-
sponding 3-magnesiated 2-bromoquinoline (10a, Table 1).
Similarly, starting from 2,4-dibromoquinoline (9b),13 the
(9) (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
3333. (b) The reagent 4 was directly used from commercial sources such
as Chemetall GmbH.
(10) Clososki, G. C.; Rohbogner, C. J. Angew. Chem., Int. Ed. 2007,
46, 7681.
(11) The completion of the Br/Mg exchange reaction was checked by
GC analysis of a reaction of aliquots quenched with saturated NH4Cl
(aqueous).
(12) The regioselectivity of the Br/Mg exchange reaction was checked
by 1H NMR of the crude product quenched with saturated NH4Cl (aqueous).
(13) Osborne, A. G.; Buley, J. M.; Clarke, H.; Dakin, R. C. H.; Price, P.
I. J. Chem. Soc., Perkin Trans. 1 1993, 22, 2747.
(14) Steck, E. A.; Hallock, L. L.; Holland, A. J. J. Am. Chem. Soc. 1946,
68, 1241.
(15) Tre´court, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.;
Que´guiner, G. Tetrahedron 2000, 56, 1349.
(16) Mallet, M.; Que´guiner, G. Tetrahedron 1986, 42, 2253.
5526
Org. Lett., Vol. 9, No. 26, 2007

reagent 5 was not reactive enough to perform an exchange
in the case of the 3,4-dibromoquinoline (9d). However, by
using the corresponding dimesitylmagnesium‚2LiBr (1.1
equiv of 6, 1.1 equiv of TMEDA,17 -10 °C, 6 h), a smooth
regioselective magnesiation furnished the diaryl magnesium
reagent 10d (Table 1).
(1.1 equiv, -50 °C, 12 h) and led after quenching with
PhSO2SMe to the 3,4-functionalized 2-bromoquinoline 12
in 87% yield.
A third Br/Mg exchange was performed on 12 using Mes2-
Mg‚2LiBr (6, 1.2 equiv, 0 °C, 12 h), and a copper-catalyzed
allylation with ethyl (2-bromomethyl)acrylate21 afforded the
highly functionalized quinoline 13 in 70% yield. This last
exchange reaction completed the sequence of successive
functionalization at C4, C3, and C2 positions.
The Grignard compounds 10a-d were trapped with
various electrophiles as shown in Table 1. Thus, the C3-
magnesiated 2-bromoquinoline 10a was quenched with tosyl
cyanide or propionaldehyde and gave 3-cyano-2-bromo-
quinoline (11a, 84%) or the corresponding alcohol (11b,
76%) (entries 1 and 2). Similarly, the Grignard intermediate
10b afforded after quenching with PhSO2SPh18 or tosyl
cyanide the corresponding phenylsulfanyl quinoline (11c,
91%) or 4-cyano-2-bromoquinoline (11d, 85%) (entries 3
and 4). Interestingly, the transmetalation of the C4-magne-
siated 2-bromoquinoline 10b using CuCl‚2LiCl (1.2 equiv,
-50 °C, 1 h) followed by the addition of LiHMDS (2 equiv,
-60 °C, 1 h) provided the corresponding amidocuprate19
which was oxidized using chloranil (1.2 equiv,
-78 °C, 12 h) and then deprotected with TBAF (2.0 equiv,
25 °C, 15 min) leading to the 4-amino-2-bromoquinoline
(11e, entry 5) in 75% yield. The reaction with C4-magne-
siated 2,3-dibromoquinoline (10c) and tosyl cyanide afforded
the corresponding quinoline 11f (88%, entry 6). The Grignard
intermediate 10c was also quenched with ethyl cyanoformate
giving the quinoline ester 11g (90%, entry 7). The C3-
magnesiated 4-bromoquinoline (10d) provided after trapping
with PhSO2SMe20 the thioether 11h (entry 8, 79% yield).
Interestingly, the diarylmagnesium reagent 10d underwent,
after transmetalation with ZnCl2, a Pd-catalyzed Negishi
cross-coupling with 4-iodobenzonitrile and furnished the
coupling product (11i) in 71% yield (entry 9). Remarkably,
multiple selective exchanges can also be performed starting
with the tribromoquinoline 9c. Thus, the reaction of MesMgBr‚
LiCl (5, 1.1 equiv, -10 °C, 3 h) with 9c provided, after
quenching with benzyl bromide, the corresponding benzy-
The direct magnesiation of quinolines using TMPMgCl‚
LiCl (7) and TMP2Mg‚2LiCl (8) further enhanced both the
flexibility for regioselective magnesiations as well as the
tolerance toward sensitive functional groups such as ketones
or esters. Thus, successive magnesiations in positions C2,
C3, and C4 could be achieved. Commercially available
3-bromoquinoline (14, Scheme 4) underwent a C2-deproto-
Scheme 4. Successive Regioselective Magnesiations at the
C2, C3, and C4 Positions
nation using TMPMgCl‚LiCl (7, 1.1 equiv, -20 °C, 2 h)8
and was quenched with 1,2-dibromo-1,1,2,2-tetrachloro-
ethane, giving the 2,3-dibromoquinoline 9a in 65% yield.
The treatment of 9a with iPrMgCl‚LiCl (4) provided, after
reaction with ethyl cyanoformate, the 2-bromoquinoline-3-
carboxylic acid ethyl ester 11k in 88% yield. Addition of
TMPMgCl‚LiCl (7) to 11k gave regioselectively the C4-
magnesiated intermediate under mild conditions (0 °C, 3 h).
Then, a smooth carboxylation in the presence of CuCN‚2LiCl
led to the quinoline 15 in 84% yield. Thus, the sequence of
functionalization C2 > C3 > C4 was accomplished. The
pertinent combination of Br/Mg exchanges and direct meta-
lations allowed a regioselective functionalization of up to
three new positions of the 2,4-dibromoquinoline (9b).
Performing a Br/Mg exchange on 9b using i-PrMgCl‚LiCl
(4, -78 °C, 2 h, Scheme 5) led, after reaction with ethyl
cyanoformate, to the quinoline 11l in 92% yield. Then, the
regioselective deprotonation of 11l at the C3 position using
7 (-10 °C, 3 h) followed by a copper-mediated acylation
using pivaloyl chloride gave the quinoline derivative 16 in
81% yield. Remarkably, a second regioselective deprotona-
Scheme 3. Successive Regioselective Br/Mg Exchange
Reactions at the C3, C4, and C2 Positions
lated quinoline 11j in 89% yield (Scheme 3). This product
11j underwent a second Br/Mg exchange reaction using 4
(18) Fujiki, K.; Tanifuji, N.; Sasaki, Y.; Yokoyama, T. Synthesis 2002,
343.
(19) del Amo, V.; Dubbaka, S. R.; Krasovskiy, A.; Knochel, P. Angew.
Chem., Int. Ed. 2006, 45, 7838.
(20) Stoll, A. H.; Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed.
2006, 45, 606.
(17) (a) Without the addition of TMEDA, the C3/C4 regioselectivity was
found to be 19:1, whereas using TMEDA (1.1 equiv), it was 99:1. (b) For
the use of TMEDA, see also: Wang, X. J.; Xu, Y.; Zhang, L.; Krishna-
murthy, D.; Senanayake, D. H. Org. Lett. 2006, 8, 3141.
(21) Villieras, J.; Rambaud, M. Org. Synth. 1988, 66, 220.
Org. Lett., Vol. 9, No. 26, 2007
5527

cross-coupling of PhZnCl with 18 gave the corresponding
functionalized boronic ester 19 in 76% yield. A basic
oxidation using LiOH (6 equiv) and aq H2O2 (3 equiv) in
MeOH (rt, 15 h) afforded the quinoline salicylic acid 20 in
89% yield. Treatment25 of 20 with NEt3 in acetonitrile (rt,
30 min) using CDI (1.1 equiv, 50 °C, 5 h) and (S)-1-
phenylpropylamine (1.1 equiv, 50 °C to rt, 12 h) gave
talnetant (2) in 84% yield.
Scheme 5. Successive Regioselective Magnesiations at the
C4, C3, and C8 Positions
By this method, we obtained a new sequence of functional-
ization, C4 > C3 > C2, and have found an alternative
method to the Pfitzinger synthesis.26
In summary, we have described various versatile regiose-
lective functionalizations of quinolines using a combination
of Br/Mg exchange reaction27 and direct magnesiations.
Several sensitive functionalities are tolerated such as an ester
and a ketone. This approach opens a new route for the direct
preparation of highly functionalized quinolines. Further
extensions of this work are currently underway in our
laboratories.
tion on the quinoline 16 was performed at the C8 position
(N-coordination), using the magnesium bisamide TMP2Mg‚
2LiCl (8, Scheme 1)22 under mild conditions (0 °C, 20 h).
After transmetalation with ZnCl2, the corresponding dior-
ganomagnesium species underwent a Pd-catalyzed Negishi
cross-coupling using ethyl 4-iodobenzoate, furnishing the
highly functionalized quinoline 17 in 71% yield.
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the DFG, Merck Research Laboratories (MSD),
Chemetall GmbH (Frankfurt), and BASF AG (Ludwig-
shafen) for financial support and generous gift of chemicals.
We thank also Sanofi-Aventis (Frankfurt) for a fellowship
to N.B.
As an application to our methodology, the total synthesis
of talnetant 2 was performed (Scheme 6). The treatment of
Supporting Information Available: Experimental pro-
cedures and full characterization of all compounds. This
material is available free of charge via Internet at http:
//pubs.acs.org
Scheme 6. Successive Regioselective Functionalizations at the
C4, C3, and C2 Positions
OL702494K
(23) Ethyl pinacol borate was preferentially used instead of commercially
available isopropyl pinacol borate because of a transesterification side
reaction.
(24) Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988,
29, 2631.
(25) Labaw, C. S.; Liu, P. PCT Int. Appl. WO 2007016609, 2007.
(26) Kaila, N.; Janz, K.; Huang, A.; Moretto, A.; DeBernardo, S.; Bedard,
P. W.; Tam, S.; Clerin, V.; Keith, J. C., Jr.; Tsao, D. H. H.; Sushkova, N.;
Shaw, G. D.; Camphausen, R. T.; Schaub, R. G.; Wang, Q. J. Med. Chem.
2007, 50, 21.
(27) Typical procedure. Synthesis of 2-bromo-3-cyanoquinoline (11a).
A dry and argon flushed 10 mL flask, equipped with a magnetic stirrer and
a septum, was charged with a solution of 2,3-dibromoquinoline (9a) (1.23
g, 4.3 mmol) in dry THF (4 mL). i-PrMgCl‚LiCl (4, 1.05 M in THF, 4.7
mmol, 1.1 equiv) was added slowly at -50 °C, and the resulting mixture
was stirred for 2 h to complete the bromine-magnesium exchange (checked
by GC-MS analysis of reaction aliquots). Tosyl cyanide (1.02 g, 1.3 equiv)
was then added dropwise at -50 °C. The reaction mixture was warmed to
rt for 12 h and was quenched with saturated aqueous NH4Cl solution. The
aqueous phase was extracted with ethyl acetate (3 × 10 mL). The organic
fractions were dried (Na2SO4) and concentrated in vacuo. Purification by
flash chromatography (n-pentane/diethyl ether ) 7:3) yielded 837 mg (84%
yield) of 11a as a colorless solid (mp 176.6-177.4 °C).
the 4-carbethoxy-2-bromoquinoline 11l with TMPMgCl‚LiCl
(7, -10 °C, 3 h) followed by quenching with ethyl pinacol
borate23 (1.5 equiv, -10 °C to rt, 12 h) and acidic workup
(1.2 equiv of HCl24 in Et2O) furnished the corresponding
pinacol boronic ester 18 in 71% yield. The Pd(0)-catalyzed
(22) TMPMgCl‚LiCl (7) was found to be ineffective for this metalation.
5528
Org. Lett., Vol. 9, No. 26, 2007