Mild and direct conversion of quinoline N-oxides to 2-amidoquinolines with primary amides

Article abstract of DOI:10.1021/ol060473w

A simple, one-pot procedure is described for the direct conversion of quinoline N-oxides to α-amidoquinolines with primary amides. This methodology is complimentary to the Abramovich reaction, which is limited to the introduction of secondary amides via imidoyl chlorides. Although reaction conditions are quite similar, omission of the base is key for successful reaction with primary amides, which were found not to proceed through the intermediacy of an imidoyl chloride but rather through an acyl isocyanate.

Full text of DOI:10.1021/ol060473w

ORGANIC
LETTERS
2
006
Vol. 8, No. 9
929-1932
Mild and Direct Conversion of Quinoline
N-Oxides to 2-Amidoquinolines with
Primary Amides
1
Michel Couturier,* Laurence Caron, Stephanie Tumidajski, Kris Jones, and
Timothy D. White
Chemical Research and DeVelopment, Pfizer Global Research and DeVelopment,
Eastern Point Road, P.O. Box 8013, Groton, Connecticut 06340-8013
michel.a.couturier@pfizer.com
Received February 23, 2006
ABSTRACT
A simple, one-pot procedure is described for the direct conversion of quinoline N-oxides to
r-amidoquinolines with primary amides. This
methodology is complimentary to the Abramovich reaction, which is limited to the introduction of secondary amides via imidoyl chlorides.
Although reaction conditions are quite similar, omission of the base is key for successful reaction with primary amides, which were found not
to proceed through the intermediacy of an imidoyl chloride but rather through an acyl isocyanate.
N-Acylated 2-aminoquinolines are important constituents in
of the most direct means to access 2-aminoquinolines from
quinolines is through R-amination with sodium or potassium
amide, commonly referred to as the Chichibabin reaction.4
Alternatively, conversion of quinoline N-oxides to 2-ami-
noquinolines can be achieved via 2-chloroquinolines, or more
1
pharmaceutical drug candidates, and ubiquitously present
2
in the patent literature. They also have been shown to play
3
an important role in molecular recognition processes. One
(1) For recent examples, see: (a) Inglis, S.; Jones, R.; Fritz, D.; Stojkoski,
5
directly through N-oxide activation with TsCl or dimethyl
C.; Booker, G.; Pyke, S. Org. Biomol. Chem. 2005, 3, 2543. (b) Gerster, J.
F.; Lindstrom, K. J.; Miller, R. L.; Tomai, M. A.; Birmachu, W.; Bomersine,
S. N.; Gibson, S. J.; Imbertson, L. M.; Jacobson, J. R.; Knafla, R. T.; Maye,
P. V.; Nikolaides, N.; Oneyemi, F. Y.; Parkhurst, G. J.; Pecore, S. E.; Reiter,
M. J.; Scribner, L. S.; Testerman, T. L.; Thompson, N. J.; Wagner, T. L.;
Weeks, C. E.; Andre, J.-D.; Lagain, D.; Bastard, Y.; Lupu, M. J. Med.
Chem. 2005, 48, 3481. (c) Jackson, S. A.; Sahni, S.; Lee, L.; Luo, Y.;
Nieduzak, T. R.; Liang, G.; Chiang, Y.; Collar, N.; Fink, D.; He, W.: Laoui,
A.; Merrill, J.; Boffey, R.; Crackett, P.; Rees, B.; Wong, M.; Guilloteau,
J.-P.; Mathieu, M.; Rebello, S. S. Bioorg. Med. Chem. 2005, 13, 2723. (d)
Benard, C.; Zouhiri, F.; Normand-Bayle, M.; Danet, M.; Desmaele, D.;
Leh, H.; Mouscadet, J.-F.; Mbemba, G.; Thomas, C.-M.; Bonnenfant, S.;
Le Bret, M.; d’Angelo, J. Bioorg. Med. Chem. Lett. 2004, 14, 2473. (e)
Tavares, F. X.; Boncek, V.; Deaton, D. N.; Hassell, A. M.; Long, S. T.;
Miller, A. B.; Payne, A. A.; Miller, L. R.; Shewchuk, L. M.; Wells-Knecht,
K.; Willard, D. H., Jr.; Wright, L. L.; Zhou, H.-Q. J. Med. Chem. 2004,
6
sulfate followed by displacement with ammonia. In these
previous cases, C-2 versus C-4 regioselectivity can be
M. C.; Reynolds, K.; Tatlock, M. A.; Wishart, G. Bioorg. Med. Chem. Lett.
2001, 11, 1089. (j) Colotta, V.; Catarzi, D.; Varano, F.; Cecchi, L.;
Filacchioni, G.; Martini, C.; Trincavelli, L.; Lucacchini, A. J. Med. Chem.
2000, 43, 3118.
(2) A survey of patent literature spanning from 2000 to 2005 revealed
over 90 cases.
(3) (a) Li, J.-S.; Gold, B. J. Org. Chem. 2005, 70, 8764. (b) Li, J.-S.;
Chen, F.-X.; Shikiya, R.; Marky, L. A.; Gold, B. J. Am. Chem. Soc. 2005,
127, 12657. (c) Nakatani, K.; Sando, S.; Kumasawa, H.; Kikuchi, J.; Saito,
I. J. Am. Chem. Soc. 2001, 123, 12650. (d) Nakatani, K.; Sando, S.; Saito,
I. J. Am. Chem. Soc. 2000, 122, 2172.
4
7, 588. (f) Webb, T. R.; Lvovskiy, D.; Kim, S.-A.; Ji, X.-d.; Melman, N.;
(4) For a review on the Chichibabin reaction, see: McGill, C. K.; Rappa,
A. AdV. Heterocycl. Chem 1988, 44, 1.
(5) (a) Miura, Y.; Takaku, S.; Fujimura, Y.; Hamana, M. Heterocycles
1992, 34, 1055. (b) Glennon, R. A.; Slusher, R. M.; Lyon, R. A.; Titeler,
M.; McKenney, J. D. J. Med. Chem. 1986, 29, 2375.
Linden, J.; Jacobson, K. A. Bioorg. Med. Chem. 2003, 11, 77. (g) Renau,
T. E.; Leger, R.; Yen, R.; She, M. W.; Flamme, E. M.; Sangalang, J.;
Gannon, C. L.; Chamberland, S.; Lomovskaya, O.; Lee, V. J. Bioorg. Med.
Chem. Lett. 2002, 12, 763. (h) Brzozowski, Z.; Saczewski, F. J. Med. Chem.
2
002, 45, 430. (i) Selwood, D. L.; Brummell, D. G.; Glen, R. C.; Goggin,
(6) Storz, T. Org. Proc. Res. DeV. 2004, 8, 663.
1
0.1021/ol060473w CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/31/2006

problematic, and an extra amidation step is then required to
access 2-amidoquinolines.
tization of the adduct leading to 2-benzamidoquinoline
(Scheme 2).
1
2
In a recent development program of a drug candidate, we
were seeking a more expeditious means to access 2-ami-
doquinolines. In literature precedents, Abramovich first
reported direct formation of 2-amidoquinolines from quino-
Scheme 2. Reaction Pathways
7
line N-oxides using isolated imidoyl chlorides. Merck later
developed a mild method for the generation of imidoyl
8
chlorides and their subsequent in situ reaction with N-oxides.
These methods are limited to secondary amides, as chlor-
oimidates of primary amides readily eliminate to the corre-
sponding nitrile. To the best of our knowledge, the sole report
of direct introduction of a primary amide onto quinoline
N-oxide (1) was achieved by activation of the latter in neat
benzoyl chloride at 175-180 °C in the presence of benz-
9
amide. Due to the aforementioned reasons, a milder method
to achieve this type of transformation would be highly
desirable. Herein, we report a mild and general method for
generating N-acylated quinolines from N-oxides using pri-
mary amides.
In a control experiment with the in situ imidoyl chloride
formation procedure, treatment of benzamide (2) with oxalyl
chloride in the presence of 2,6-lutidine not unexpectedly led
to dehydration to form benzonitrile. However, when this
reaction was performed in the absence of base, we found it
to generate the previously elusive 2-benzamidoquinoline (3)
in 70% yield (Scheme 1).
The generality of this reaction was then investigated. As
a matter of convenience, commercially available benzoyl
13
isocyanate (5) was employed to evaluate the substrate scope
of various pyridine N-oxide derivatives (Table 1). In the
following experiments, 2 equiv of isocyanate were used due
to the hygroscopic nature of the pyridine N-oxides partners
and the potency of the technical grade isocyanate employed.14
As anticipated from our original results, reaction of benzoyl
isocyanate (5) with quinoline N-oxide (1) proceeded in
refluxing dichloromethane and provided 2-benzamidoquino-
line (3) in 77% yield. Electron withdrawing substituted
quinolines N-oxides were also converted to their correspond-
ing 2-benzamidoquinolines in similar times and yields
Scheme 1. Mild and Regiospecific 2-Benzamidation of
Quinoline N-oxide
In essence, primary amides can be introduced onto
quinolines by using essentially the same procedure reported
for secondary amides, but in the absence of base. In contrast
to the original procedure, however, the reaction does not
proceed through the intermediacy of an imidoyl chloride.
(entries 3 and 5). However, electron-rich 6-methoxyquinoline
N-oxide (15) required more forceful conditions where 5 equiv
of isocyanate 5 were required to reach reaction completion
after 40 h at reflux. It is noteworthy that all the aforemen-
tioned reactions proceeded with the expected regiospecificity.
Isoquinoline N-oxide (7) showed increased reactivity toward
1
13
Closer inspection by H and C NMR reveals that omission
of the lutidine base changes the sequence of events such that
unstable 2-phenyloxazoline-4,5-dione hydrochloride (4) is
initially formed which then converts to benzoyl isocyanate
(
11) (a) Speziale, A. J.; Smith, L. R. J. Org. Chem. 1962, 27, 3742. (b)
Speziale, A. J.; Smith, L. R. J. Org. Chem. 1963, 28, 1805.
12) For an isolated example of reacting benzoylisocyanate with 1H-
imidazo[4,5-c]quinoline 5N-oxide, see: Gerster, J. F. U.S. Patent 5,175,296,
992.
(13) Purchased as technical grade material (90%) from Aldrich Chemical
Co.
(14) General procedure with benzoyl isocyanate: To a stirred solution
10,11
(
5).
The latter then undergoes a 1,3-dipolarcycloaddition
(
with quinoline N-oxide followed by decarboxylative aroma-
1
(
7) (a) Abramovich, R. A.; Singer, G. M. J. Am. Chem. Soc. 1969, 91,
672. (b) Abramovich, R. A.; Singer, G. M. J. Org. Chem. 1974, 39, 1795.
c) Abramovich, R. A.; Rogers, R. B. J. Org. Chem. 1974, 39, 1802. (d)
Abramovich, R. A.; Pilski, J.; Konitz, A.; Tomasik, P. J. Org. Chem. 1983,
8, 4391.
5
(
of quinoline N-oxide (5.0 mmol) in dichloromethane (15 mL) at room
temperature was added a solution of benzoyl isocyanate (10.0 mmol) in
dichloromethane (5 mL). The resulting mixture was heated to reflux except
for phenanthridine N-oxide and isoquinoline N-oxide which were kept at
room temperature. Upon reaction completion, the reaction was quenched
with methanol (500 µL), stirred for 15 min, and then concentrated under
vaccum. Unless otherwise noted (see the Supporting Information), the
residual material was purified by chromatography to yield the desired
benzamidoquinoline.
4
(
(
(
8) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2002, 4, 3127.
9) Kurbatov, Y. V.; Solekhova, M. A. Zh. Org. Khim. 1981, 17, 1121.
1
10) Compound 4: H NMR (400 MHz, CDCl3) δ 9.65 (br s, 1H), 7.93
(
d, J ) 7.5 Hz, 2H), 7.68 (t, J ) 7.5 Hz, 1H), 7.55 (t, J ) 7.5 Hz, 2H).
1
Compound 5: H NMR (400 MHz, CDCl3) δ 8.05 (d, J ) 7.5 Hz, 2H),
1
3
7
.64 (t, J ) 7.5 Hz, 1H), 7.48 (t, J ) 7.5 Hz, 2H); C NMR (100 MHz,
CDCl3) δ 165.38, 159.31, 135.02, 130.77, 129.06, 129.02.
1930
Org. Lett., Vol. 8, No. 9, 2006

required more forcing conditions (2.5 h in refluxing 1,2-
dichloroethane; entry 4).
Table 1. Direct Benzamidation of Quinoline N-oxides with
Benzoyl Isocyanate
In accordance with previous reactions, the cycloadditions/
decarboxilative rearangements were performed under reflux
with quinoline N-oxide (1) and at room temperature with
1
6
isoquinoline N-oxide (7). As exemplified in Table 2,
Table 2. Direct Amidation of Quinoline and Isoquinoline
N-Oxides with Various Amides
a
Isolated yields. b Reaction performed at room temperature. c 5 equiv
of benzoyl isocyanate required.
benzoyl isocyanate (5) as compared to quinoline N-oxide
(1) by proceeding at room temperature and reaching comple-
tion in 3 h. The compound produced in 97% yield was
identified as 1-benzamidoisoquinoline (8); none of the
3
-regioisomer was detected. Reaction with phenanthridine
a
Isolated yields. b Reaction performed at reflux. c Reaction performed
N-oxide (11) proceeded even more readily by reaching
completion within 2 min. Unfortunately, reactions with
pyridine N-oxides were nonproductive as they catalyzed the
cyclotrimerization of benzoyl isocyanate to tribenzoyl iso-
cyanurate, consistent with literature precedent.1
The substrate scope of various primary amides was then
investigated on quinoline N-oxide (1) and isoquinoline
N-oxide (7). The requisite isocyanate formations were first
monitored by C NMR to determine reaction time and
temperature required for this initial process to reach complete
conversion. Whereas benzamide (2) and substituted aryl
amides all converted to the corresponding isocyanates within
at room temperature.
reaction completion on all the cases studied was achieved
within 24 h, and provided the desired amidoquinoline in
5
(16) General amidation procedure starting from amides: To a stirred
solution of amide (10.0 mmol) in dichloromethane (10 mL) was added oxalyl
chloride (10.0 mmol) dropwise at room temperature. The reaction mixture
was stirred at room temperature, then heated to reflux until isocyanate
formation is complete. The foregoing solution was added to a solution of
quinoline N-oxide or isoquinoline N-oxide (5.0 mmol) in dichloromethane
1
3
(
10 mL). The resulting mixture was heated to reflux except for reactions
with isoquinoline N-oxide which were performed at room temperature. Upon
reaction completion, the reaction was quenched with methanol (500 µL),
stirred for 15 min, and then concentrated under vaccum. Unless otherwise
noted, the residual material was purified by chromatography to yield the
desired amidoquinoline.
1
h in refluxing dichloromethane (entries 1-3), acetamide
(15) Tsuge, O.; Mizuguchi, R. Nippon Kagaku Zasshi 1965, 86, 325.
Org. Lett., Vol. 8, No. 9, 2006
1931

generally good yields. Also, the reactions exhibited high
degrees of selectivity as no other regioisomers were detected
in the reaction mixtures.
ceutical drug candidates, this methodology should prove
useful for the synthesis of compounds bearing such sub-
structures.
In conclusion, we have developed a novel, mild, and
straightforward procedure for the regioselective introduction
of primary amides onto quinolines and derivatives via
acylisocyanates. This methodology is complimentary to the
Abramovich reaction, which is limited to the introduction
of secondary amido functionality via imidoyl chlorides. Due
to the ubiquity of N-acylated 2-aminoquinolines in pharma-
Supporting Information Available: Experimental details
1
for the synthesis of amidoquinolines with corresponding H
1
3
and C NMR. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL060473W
1932
Org. Lett., Vol. 8, No. 9, 2006