Synthesis of 3-Sulfonylamino Quinolines from 1-(2-Aminophenyl) Propargyl Alcohols through a Ag(I)-Catalyzed Hydroamination, (2 + 3) Cycloaddition, and an Unusual Strain-Driven Ring Expansion

Article abstract of DOI:10.1021/acs.orglett.5b00832

We describe herein a silver-catalyzed conversion of 1-(2-aminophenyl)-propargyl alcohols to 4-substituted 3-tosylaminoquinolines using TsN₃ as an amino surrogate. Controlled reactions reveal the pathway consisting of Ag(I)-catalyzed 5-exo-dig cyclization, catalyst-free (2 + 3) cycloaddition, and ring-expansive rearrangement via nitrogen expulsion. As a support study, we show that the cyclic enamines in similar conditions produce amidines via a C - C bond migration. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b00832

Letter
pubs.acs.org/OrgLett
Synthesis of 3‑Sulfonylamino Quinolines from 1‑(2-Aminophenyl)
Propargyl Alcohols through a Ag(I)-Catalyzed Hydroamination, (2 +
3) Cycloaddition, and an Unusual Strain-Driven Ring Expansion
Yalla Kiran Kumar,† Gadi Ranjith Kumar,†,∥ Thota Jagadeshwar Reddy,‡ Balasubramanian Sridhar,§
and Maddi Sridhar Reddy*,†,∥
†Medicinal & Process Chemistry Division and ‡SAIF Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram
Extension, Sitapur Road, Post Office Box 173, Lucknow 226031, India
§X-ray Crystallography Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
∥Academy of Scientific and Innovative Research, New Delhi 110001, India
S
* Supporting Information
ABSTRACT: We describe herein a silver-catalyzed conversion
of 1-(2-aminophenyl)-propargyl alcohols to 4-substituted 3-
tosylaminoquinolines using TsN3 as an amino surrogate.
Controlled reactions reveal the pathway consisting of Ag(I)-
catalyzed 5-exo-dig cyclization, catalyst-free (2 + 3) cyclo-
addition, and ring-expansive rearrangement via nitrogen
expulsion. As a support study, we show that the cyclic enamines
in similar conditions produce amidines via a C−C bond
migration.
Scheme 1. Electrophilic Cyclizations of 1-(2-Aminophenyl)
Propargyl Alcohols
minoquinolines represent an important class of bioactive
molecules that display a broad spectrum of pharmaceutical
A
activities.1 Although facile access is well-documented in the
literature for the amino group insertion at C2 and C4 of
quinoline2 via nucleophilic displacement utilizing the electron
deficiency at the respective positions, the synthesis of their C3
counterpart is highly underinvestigated because the same
concept is unadoptable. This could have been one of the
reasons for not undertaking the extensive evaluation of the
biological activities of 3-aminoquinolines.3 As part of our
ongoing program of unveiling the novel reactivities of alkynes
activated by electrophiles,4 we herein present the synthesis of 4-
substituted 3-tosylaminoquinolines from 1-(2-aminophenyl)-
propargyl alcohols using TsN3 as an amino surrogate.
1-(2-Aminophenyl)-propargyl alcohols have been identified
as ready precursors for the synthesis of various benzo-fused six-
or five-membered heterocycles (Scheme 1). When R1 ≠ H
(Scheme 1, eq 1), the substrates take a 6-endo-dig- or 5-exo-dig-
cyclization pathway,5 depending on the N protection, reagent,
and conditions, to give quinoline or indole derivatives,
respectively. However, the substrates with R1 = H (Scheme 1,
eq 2) always undergo a 5-exo-dig cyclization6 to afford indole
derivatives. Herein, we present a rare example of the conversion
of substrates with R1 = H (Scheme 1, eq 3) to 6-cyclized
products, i.e., quinolines. The reaction is, however, identified to
go through a 5-exo-dig cyclization followed by an unprece-
dented strain-driven ring-expansive rearrangement.
It was a serendipitous observation that occurred during an
attempt at the outset for the conversion of 2a (obtained by the
addition of ethynylmagnesium bromide to 2-aminobenzophe-
none (1a)) to 4 via 5-exo-dig cyclization and (2 + 3)
cycloaddition with TsN3 (3) followed by a known diazo-
methane expulsion.7 Intermediate B instead undertook a rare
C−N bond migratory approach with the expulsion of nitrogen
(Scheme 2). C subsequently underwent a tautomerization and
Received: March 21, 2015
Published: April 15, 2015
© 2015 American Chemical Society
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Letter
Scheme 2. Conversion of 2a to Amino Quinoline 5a via 6
Scheme 3. Synthesis of 3-Tosylaminoquinolines (5) from
Various Aminophenyl Propargyl Alcohols (2)
dehydration processes to reveal 4-phenyl-3-tosylamino quino-
line (5a). The formation of 5-exo adduct A and its slow
conversion to the product was clearly observed by TLC.
In the absence of TsN3, tautomerized adduct (6) of 5-exo
adduct A was exclusively isolated. To clearly establish the
pathway, intermediate 6 was separately treated with TsN3 in
DMSO in the absence of silver catalyst. As expected, 6 was
cleanly converted to product 5a, demonstrating that the
reaction is going through a cascade involving Ag-catalyzed 5-
exo-dig cyclization, catalyst-free (2 + 3) cycloaddition, and C−
N bond migration. Although the yield of the product was
moderate, no other considerable byproduct formation was
observed. We attribute this to the unstable nature of A (or 6).
Considering the underdevelopment of 3-amino quinolines
synthesis,3 we immediately turned to explore the generality of
this new reaction. A variety of 2-aminophenyl propargyl
alcohols (2) were synthesized (few from readily available 2-
aminophenyl ketones (1) and others from 2-amino benzoni-
triles;8 see Supporting Information for details) and subjected to
the standard reaction conditions (see the Supporting
Information for optimization studies). As evident from
Schemes 3 and 4, the reaction is applicable over a wide range
of substrates to produce the products in moderate to good
yields. Initially, we synthesized various C4-aryl adducts using
this cascade process. Halogen groups like Br, Cl, and F were
tolerated on the C4-aryl group as well as on the quinoline
nucleus as in case of the products 5ba−ka. Products with
halogen on the quinoline core were obtained with slightly lower
yields (44−50% compared to 53−62%). A naphthyl group
could also be introduced at C4 of aminoquinoline (5la) with
the equal ease. Electron-rich substrates with methyl/ethyl
(2m−q), methoxy (2r), and methylenedioxy (2s−t) sub-
stituents afforded the products in slightly better yield, whereas
electron-deficient, nitro-substituted substrate 2u did not yield
any product (starting material recovered after 24 h). We then
focused on introducing alkyl groups at C4 of aminoquinoline
adducts using substrates obtained from 2-aminophenyl alkyl
ketones. Thus, 2v−z with a methyl group and 2a′−c′ with n-
propyl, i-propyl, and n-pentyl groups, respectively, along with a
variety of other substitutions were successfully converted to the
corresponding products (5va−c′a) in moderate to good yields
(48−65%). In these cases, formation of traces (5−10%) of
amidine byproducts relevant to 4 was observed.
a
Reaction conditions: TsN3 (1.2 mmol), 2 (1.0 mmol), Ag2CO3 (0.02
b
c
mmol), DMSO (4 mL), 50 °C, open air. Isolated yield. Starting
material recovered.
the reaction with 2v to produce corresponding products 5vb−
vg in practically considerable yields (47−59%). Electronic
variation in the phenyl group of sulfonyl azides (electron-poor
nitrophenyl sulfonyl azides 3h−i and electron-rich t-butylphen-
Next, we evaluated the scope of the reaction with respect to
sulfonyl azides. Like toluenesulfonyl azide, unsubstituted and
halosubstituted phenyl sulfonyl azides also participated well in
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Scheme 4. Scope of Sulfonyl Azides
Scheme 5. Synthesis of N-Tosylamidines from Enamines
a
Reaction conditions: R3SO2N3 (1.2 mmol), 2v (1.0 mmol), Ag2CO3
b
(0.02 mmol), DMSO (4 mL), 50 °C, open air. Isolated yield.
a
Reaction conditions: (a) 7 (2 mmol), 8 (2 mmol), PhMe (2 mL),
120 °C, 12 h. (b) TsN3 (1.2 mmol), DMSO (4 mL), 50 °C, 8 h, open
yl sulfonyl azide 3j) did not show any impact on the reaction,
producing the products in almost similar yields (45−65%).
Unlike aryl azide, methane sulfonyl azide led to corresponding
product 5vk in moderate yield of 35%.
b
air. Isolated yield.
To get insight into the intriguing rearrangement in the above
cascade, we wanted to conduct some experiments where
sulfonyl azide similarly adds on to enamine but the enamine
now with the nonstrained C−N bond. For that, we prepared a
Schiff base (E, from cyclohexanone aniline in refluxing toluene)
which can in situ tautomerise to F during the reaction process.
Unlike in the case of intermediate B in Scheme 2, where the
C−N bond is part of a spirocyclic system, the NHAr would be
freely flanking outside of the probable bicyclic triazole G from
enamine F and thus may not receive the same force to migrate.
Thus, as expected, when F was treated (in the same RB flask
after removal of toluene) with TsN3 in DMSO at 50 °C, the
C−C bond in G migrated in preference to a C−N bond to
produce amidine 9 with ring-contracted cycle.9 To the best of
our knowledge, this catalyst/reagent-free in situ cycloaddition
and rearrangement is hitherto not reported in the literature. For
this reason and because of the importance of amidine products
in medicinal and biological fields,10 we aimed to explore its
generality. Thus, cyclohexanone, cycloheptanone, and cyclo-
octanone (with aniline) furnished the corresponding amidine
products in excellent yields (75−85%). The scope of the
reaction with respect to aniline was also verified with variety of
substituted anilines to obtain products 9ab−ae in good to
excellent yields (67−80%).
A structure from each category of compounds (5va, 5vb, and
9ca from Schemes 3−5, respectively) was unambiguously
confirmed by X-ray crystallography, as depicted in Figure 1.
In summary, an efficient synthesis of hitherto formidable 3-
amino quinoline derivatives from readily accessible 2-amino-
phenyl propargylic alcohols is described. The reaction offers a
rare 6-endo-dig product via common 5-exo-dig cyclization and
an unusual rearrangement. A very catalytic amount of Ag2CO3
is sufficient to execute this cascade, and the reaction is found to
have a broad substrate scope with respect to both the propargyl
alcohols and the sulfonyl azides. Furthermore, we also
Figure 1. X-ray crystal structures of 5va, 5vb, and 9ca.
demonstrated the catalyst/reagent-free and effective conversion
of cycloalkanones to cycloalkyl amidines (with the reduced ring
size) via another cascade involving enamine formation,
regioselective (2 + 3) cycloaddition, and C−C bond migration.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and copies of H and 13C spectra for
1
compounds 2, 5, 6, and 9. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: msreddy@cdri.res.in.
Notes
The authors declare no competing financial interest.
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Letter
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ACKNOWLEDGMENTS
■
Y.K.K. and G.R.K. thank CSIR for the fellowships. We thank
SAIF division CSIR-CDRI for the analytical support. We
gratefully acknowledge the financial support by CSIR-Network
project BSC0104 (CSIR-CDRI-SPLENDID) and by DST
under Fast Track Proposal Scheme for Young Scientists (SB/
FT/CS-102/2012). CDRI Communication No. 8957.
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