Reductive cyclization of o-nitrophenyl propargyl alcohols: Facile synthesis of substituted quinolines

Article abstract of DOI:10.1021/ol0710921

Reduction of secondary and tertiary o-nitrophenyl propargyl alcohols followed by acid-catalyzed Meyer-Schuster rearrangement gave 2-substituted and 2,4-disubstituted quinolines, respectively. Tertiary propargyl alcohols gave excellent yields of the quinoline derivative, while the yields of quinolines were slightly reduced when secondary propargyl alcohol derivatives were utilized.

Full text of DOI:10.1021/ol0710921

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3209-3212
Reductive Cyclization of o-Nitrophenyl
Propargyl Alcohols: Facile Synthesis of
Substituted Quinolines†
Matthew J. Sandelier and Philip DeShong*
Department of Chemistry and Biochemistry, UniVersity of Maryland,
College Park, Maryland 20742
deshong@umd.edu
Received May 10, 2007
ABSTRACT
Reduction of secondary and tertiary o-nitrophenyl propargyl alcohols followed by acid-catalyzed Meyer−Schuster rearrangement gave 2-substituted
and 2,4-disubstituted quinolines, respectively. Tertiary propargyl alcohols gave excellent yields of the quinoline derivative, while the yields of
quinolines were slightly reduced when secondary propargyl alcohol derivatives were utilized.
The synthesis of the quinoline ring system has been
extensively studied since its discovery by Gerhardt in 1842.1
The quinoline ring system is found in a variety of compounds
including dyes, organic materials, and pharmaceuticals.
Among the pharmaceuticals, quinoline derivatives have been
employed for treatment of parasitic infections such as
malaria2 and leishmaniasis,3 as well as being present in
antitumor agents such as streptonigrin,4 luotonin A,5 dyne-
micin A,6 and camptothecin.7 In addition, natural product
isolations and biological activity assays continue to identify
new, potentially useful quinoline alkaloids from both plant
and marine animal sources.8
In our studies on the synthesis of streptonigrin (1, Figure
1), McElroy developed an efficient route to the functionalized
CD pyridyl triflate intermediate 2.9 The initial strategy for
the synthesis of streptonigrin was to couple triflate 2 to an
AB quinoline ring system precursor affording the intact
carbon skeleton of the natural product. Since direct aryl-
aryl cross coupling to form 2-(2′-pyridyl)quinolines met with
limited success,10 an alternative method for the synthesis of
quinoline was investigated.
† The views expressed in this article are those of the author and do not
reflect the official policy or position of the United States Air Force,
Department of Defense, or the U.S. Government.
Previous streptonigrin syntheses have utilized classical
Friedla¨nder11 or Borsche12 methodology to prepare the
(1) Manske, R. H. F. Chem. ReV. 1942, 30, 113-144.
(2) Foley, M.; Tilley, L. Pharmacol. Ther. 1998, 79, 55-87.
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J. Am. Chem. Soc. 1997, 119, 6072-6094.
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1994, 59, 5120-5121. (b) Shen, W.; Coburn, C. A.; Bornmann, W. G.;
Danishefsky, S. J. J. Org. Chem. 1993, 58, 611-617.
(8) Michael, J. P. Nat. Prod. Rep. 2003, 20, 476-493.
(9) McElroy, W. T.; DeShong, P. Tetrahedron 2006, 62, 6945-6954.
(10) (a) Deshayes, K.; Broene, R. D.; Chao, I.; Knobler, C. B.; Diederich,
F. J. Org. Chem. 1991, 56, 6787-6795. (b) Godard, A.; Rovera, J. C.;
Marsais, F.; Ple, N.; Queguiner, G. Tetrahedron 1992, 48, 4123-4134. (c)
Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron Lett. 1993,
34, 2937-2940. (d) Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G.
Tetrahedron 1993, 49, 3325-3342. (e) Godard, A.; Fourquez, J. M.;
Tamion, R.; Marsais, F.; Queguiner, G. Synlett 1994, 235-236. (f) Kimber,
M.; Anderberg, P. I.; Harding, M. M. Tetrahedron 2000, 56, 3575-3581.
(g) Nguyen, T.; Wicki, M. A.; Snieckus, V. J. Org. Chem. 2004, 69, 7816-
7821.
10.1021/ol0710921 CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/24/2007

derivatives. Propargylic alcohols are at the same oxidation
state as enones and rearrange to enones under acidic
conditions (Meyer-Schuster rearrangement),14 and we pro-
posed to study the viability of this approach. We were
heartened by the observation by Choudhury and co-workers15
of the propensity of tertiary propargyl alcohols to form
quinolines during deprotection of an o-aniline derivative.
Although a quinoline was an undesired byproduct in
Choudhury’s work, the mild conversion of o-anilinopropargyl
alcohols to quinolines seemed to be a potential solution to
the introduction of the quinoline required in the streptonigrin
synthesis. Analogously, propargyl alcohols have been utilized
in the synthesis of quinolines by Jiang, via Zn(II)-mediated
alkynylation of o-trifluoroacetylanilines;16 by Cho, via
Sonogashira coupling to o-iodoanilines;17 and by Flynn, via
6-endo-digonal iodocyclization.18
Our approach to the synthesis of quinolines is outlined in
Scheme 1, starting from readily available o-nitrobenzalde-
hyde 9. Addition of lithium or magnesium acetylides to
aldehyde 9 provided o-nitrophenyl propargyl alcohols 7 or
8, respectively. The required reduction and rearrangement
necessary to convert o-nitrophenyl propargyl alcohol 7 to
o-aminochalcone 4 could be accomplished in either 7 f 5
f 4 or 7 f 6 f 4 order. However, repeated attempts to
promote acid-catalyzed Meyer-Schuster (M-S) rearrange-
ment of nitrochalcones (7 f 5, Ar ) phenyl) were typically
unsuccessful and gave very low yields of the desired enone.
Analogous studies of M-S rearrangements have been
reported by Engel and Dudley19 via gold(III) catalysis,
however, only in moderate yield with secondary propargyl
alcohols.
Figure 1. Retrosynthesis of streptonigrin (1).
quinoline AB ring system. In Weinreb’s synthesis, a
Wadsworth-Emmons-Horner condensation produced a ni-
trochalcone intermediate that gave the quinoline AB ring
following reduction. Kende’s synthesis employed condensa-
tion of an iminoaniline with a 2-methyl ketone functionalized
CD ring intermediate to form the AB quinoline system.
While both strategies were effective, they required consider-
able modifications to their CD ring systems before the AB
rings could be introduced. Our goal was to develop a
Friedla¨nder-like method that would minimize modification
of the McElroy CD intermediate (2), allow facile attachment
to a functionalized A-ring substrate, and undergo quinoline
formation using mild conditions.
The development of a new quinoline synthesis (Scheme
1) depended on the well-precedented transformation of
We anticipated that reduction of the nitro group prior to
M-S rearrangment would increase the electron density of
the phenyl ring, hopefully facilitating the M-S rearrange-
ment 6 f 4. Once 4 is produced, quinolines are expected to
be formed following spontaneous ring closure and aroma-
tization. This strategy had several appealing features, the
major one being that introduction of the CD-fragment (Ar
in Scheme 1) could be accomplished either prior to forma-
tion of the propargylic alcohol (9 f 7) with an aryl acetylide
or after the nucleophilic addition of the acetylide func-
tionality via Sonogashira coupling of terminal propargyl
alcohol 8.
Scheme 1. Retrosynthesis of 2-Arylquinolines
In practice, lithium acetylides of 1-hexyne and phenyl-
acetylene added to o-nitroacetophenone providing the pro-
pargyl alcohols 10a and 10b, respectively, in excellent yield.
Reduction of the nitroarenes, followed by in situ Meyer-
Schuster rearrangement provided the desired quinolines. A
(13) (a) Han, R.; Chen, S.; Lee, S. J.; Qi, F.; Wu, X.; Kim, B. H.
Heterocycles 2006, 68, 1675-1684. (b) Shi, D.; Rong, L.; Wang, J.; Zhuang,
Q.; Wang, X.; Tu, S.; Hu, H. J. Chem. Res. (S) 2003, 342-343. (c) Barros,
A. I. R. N. A.; Silva, A. M. S. Tetrahedron Lett. 2003, 44, 5893-5896. (d)
Wang, X.; Zhang, Y. Synth. Commun. 2002, 32, 3617-3620. (e) Fischer,
F.; Arlt, W. Z. Chem. 1964, 4, 100-101.
(14) Meyer, K. H.; Schuster, K. Chem. Ber. 1922, 55, 819.
(15) Choudhury, A.; Pierce, M. E.; Confalone, P. N. Synth. Commun.
2001, 31, 3707-3714.
nitrochalcones (5) to quinoline by reduction (the Friedla¨nder
method).13 Our synthetic plan diverged from classical ap-
proaches, however, in the preparation of nitrochalcone
(11) Weinreb, S. M.; Basha, F. Z.; Hibino, S.; Khatri, N. A.; Kim, D.;
Pye, W. E.; Wu, T.-T. J. Am. Chem. Soc. 1981, 104, 536-544.
(12) Kende, A. S.; Lorah, D. P.; Boatman, R. J. J. Am. Chem. Soc. 1981,
103, 1271-1273.
(16) Jiang, B.; Si, Y.-G. J. Org. Chem. 2002, 67, 9449-9451.
(17) Cho, C. S. J. Organomet. Chem. 2005, 690, 4094-4097.
(18) Hessian, K. O.; Flynn, B. L. Org. Lett. 2006, 8, 243-246.
(19) Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027-4029.
3210
Org. Lett., Vol. 9, No. 17, 2007

number of reduction methods were investigated, including
Fe/HCl,20 Zn/NH4Cl,21 TiCl3/HCl,22 and SnCl2/HCl.23 In each
case, o-anilinopropargyl alcohols were not observed as
intermediates; the quinolines 11a and 11b were formed
directly. It was observed that Zn-, Fe-, and Sn-reductions
generally gave excellent yields, while TiCl3 reduction gave
a poor yield of the desired product (Table 1).
Table 2. 2-Alkyl and 2-Aryl Quinolines
Table 1. Reduction/Rearrangement/Heteroannulation
entry
R
[H]
Fe
H+
yield,a %
1
2
3
4
5
n-butyl
n-butyl
n-butyl
n-butyl
phenyl
HCl
AcOH
HCl
HCl
HCl
95
95
91
<40b
82
Zn
SnCl2
TiCl3
Fe
a Isolated. b By GC.
For application in the streptonigrin project, a 2-substituted
quinoline is desired and this required preparation from a
secondary propargylic alcohol derivative. To demonstrate the
generality of this technique, a series of secondary propargyl
alcohol derivatives were converted to quinolines and the
results are summarized in Table 2. Entries 1 and 5 are
analogous to the n-butyl and phenyl tertiary propargyl alcohol
analogues in Table 1. Both quinolines 13a and 13e were
obtained in good yield, although the yield was slightly lower
than their tertiary counterparts. Entries 2, 3, and 4 examine
the electronic effects of substituents on the A ring in the
cyclization and will be similar to the effects anticipated in
the synthesis of streptonigrin. The presence of electron-
donating substituents on the A-ring had minimal effect on
the yield of quinoline (entry 2), unless the substituent was
in the ortho position. For example, the yield of quinoline
was dramatically reduced for the methoxy-substituted alcohol
13d (entry 4). Propargyl alcohol 12f (entry 6) also gave a
low yield of 2-alkenylquinoline 13f under the reduction
conditions; however, the diminished yield in this case appears
to result from difficulty isolating the sensitive product rather
than inherent limitations with the reaction in question. It is
important to note that the purification of these quinolines
(13a-f) was done by a combination of acid-base extractions
and/or bulb-to-bulb distillation since these low molecular
weight quinolines were generally unstable to either silica or
florisil chromatography. In most cases the NMR spectra of
prior crude product indicated the presence of the desired
quinoline in high purity; however, significant mass loss
occurred during purification (see the Supporting Information
for experimental details).
Despite repeated attempts, the transformation of pyridyl-
substituted alcohol 12g into the quinoline derivative (entry
7) corresponding to the ABC-ring system of streptonigrin
did not occur as expected. Treatment of pyridine 12g under
reducing conditions gave quinolone 13g, not the expected
quinoline derivative, as the only product isolated from the
reductive cyclization reaction. This was the only reaction
that produced quinolone, rather than the quinoline deriva-
tive. In addition, formation of a quinolone is not mechan-
istically consistent with the quinolines produced in this
study. Further studies will be conducted to examine the
mechanism of this novel transformation. The proposed
mechanism of quinoline formation is depicted in Scheme 2.
Acid-catalyzed Meyer-Schuster rearrangement of tertiary
propargyl alcohols is well precedented;24 however, the
analogous rearrangement of secondary substrates is known
(20) Liu, Y.; Lu, Y.; Prashad, M.; Repic, O.; Blacklock, T. J. AdV. Synth.
Catal. 2005, 347, 217-219.
(21) Tsukinoki, T.; Tsuzuki, H. Green Chem. 2001, 3, 37-38.
(22) Somei, M.; Kato, K.; Inoue, S. Chem. Pharm. Bull. 1980, 28, 2515-
2518.
(23) Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839-842.
Org. Lett., Vol. 9, No. 17, 2007
3211

Scheme 2. Proposed Mechanism: Resonance-Stabilized Meyer-Schuster Rearrangement/Heteroannulation
to result in lower yields of enone. This result is consistent
with the observations that are reported above in Tables 1
and 2. Even so, the conversion of secondary propargylic
alcohols provided acceptable yields of the desired quinoline
derivatives in most instances.
nigrin, lavendamycin, and related natural products is under-
way and the results of these studies will be reported in due
course.
Acknowledgment. M.J.S. acknowledges the Air Force
Institute of Technology and the U.S. Air Force Academy
for their financial support. The generous financial support
of the University of Maryland is acknowledged. We thank
Dr. Yiu-Fai Lam and Mr. Noel Whittaker (University of
Maryland) for their assistance obtaining NMR and mass
spectral data, respectively.
In conclusion, the facile reductive cyclization of o-
nitrophenyl propargyl alcohol derivatives provided 2-aryl-
and 2-alkylquinolines in good to excellent yield. The
methodology is tolerant of both electron-donating and
electron-withdrawing functionality on the A-ring and to
substitution on the alkyne. Attempts to prepare model
systems for the ABC-pyridyl-quinoline ring system of
streptonigrin led to formation of quinolone derivatives
resulting from an aberrant cyclization pathway. Applica-
tion of this methodology to the total synthesis of strepto-
Supporting Information Available: Detailed experi-
mental procedures and full characterization for all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(24) Swaminathan, S.; Narayanan, K. V. Chem. ReV. 1971, 71, 429-
438.
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