Gold(I)-catalyzed unprecedented rearrangement reaction between 2-aminobenzaldehydes with propargyl amines: An expedient route to 3-aminoquinolines

Article abstract of DOI:10.1002/chem.201103668

Access to aminoquinolines: A gold(I)-catalyzed unprecedented rearrangement reaction between 2-aminobenzaldehydes with propargyl amine was studied. The study provided, for the first time, direct access to 3-aminoquinolines in one step starting from readily available starting materials (see scheme). Elegantly designed experiments were employed to unravel the mechanism of this unprecedented rearrangement, which are corroborated by DFT calculations.

Full text of DOI:10.1002/chem.201103668

DOI: 10.1002/chem.201103668
Gold(I)-Catalyzed Unprecedented Rearrangement Reaction Between
2-Aminobenzaldehydes with Propargyl Amines: An Expedient Route to
3-Aminoquinolines
Nitin T. Patil,*[a] Vivek S. Raut,[a] Valmik S. Shinde,[a] Gaddamanugu Gayatri,[b] and
G. Narahari Sastry[b]
A great number of novel transformations have appeared
during the last decade based on the gold-catalyzed activa-
tion of alkynes.[1] A historical retrospect on the progress in
this area reveals that gold–alkyne chemistry is based on
three pillars: addition reactions,[1g,v] substitution reactions,[1a]
and rearrangement reactions. Of particular interest is the re-
arrangement reaction, which enables the generation of un-
usual intermediates and therefore products. Such reactions
have attained considerable success only in the case of cycloi-
somerization[1o] and Au–vinylidene chemistry.[1s] Clearly, for
the further development of gold–alkyne chemistry, a search
for new type of rearrangement reaction is highly desirable.
The quinoline ring system is a privileged scaffold in me-
dicinal chemistry and is found in numerous natural products
and pharmaceuticals.[2] One of the most important subclass
of quinolines is the aminoquinolines, which exhibit many
pharmacological properties.[3] Of particularly importance are
the 3-aminoquinolines, which have been extensively studied
against different biological targets such as anti-obesity,[4]
efflux-pump inhibitors,[5] antibacterial,[6] platelet aggregation
inhibitors,[7] cancer chemotherapy,[8] anti-proliferative activi-
ty against leukemia cell lines,[9] and antagonist properties
against vanilloid[10] and d-opioid receptors.[11] In addition, 3-
aminoquinolines have been known to be useful in the struc-
ture elucidation of biopolymers by using matrix-assisted
laser desorption/ionization (MALDI) techniques.[12] Al-
though this class of compounds holds great potential, a care-
ful examination of the literature revealed a lack of efficient
methods for their preparation. Conventionally, 3-aminoqui-
nolines are prepared from reaction between nitroarenes and
protected ethyl aminocrotonate,[13] 3-bromoquinolines,[14] 3-
nitroquinolines[15] and a condensation reaction between 2-
aminobenzaldehydes and 1-(2-ethoxycarbonyl-2-oxoethyl)-
pyridinium bromide salt.[16] All these methods suffer from
considerable drawbacks, such as the use of strong acids, ele-
vated temperatures and some of them involve multistep pro-
cesses. To our knowledge, there have been no reports of the
direct preparation of 3-aminoquinolines from easily avail-
able starting materials. Herein, we report a gold(I)-catalyzed
one-pot method for the synthesis of 3-aminoquinolines from
readily available 2-aminobenzaldehydes with propargyl
amine.
In designing new transition-metal-catalyzed approaches
toward nitrogen-containing heterocycles,[17] we became inter-
ested in searching for a novel route for the synthesis of qui-
nolines. In this regard, we recently reported a cooperative
catalytic system, consisting of CuI and pyrrolidine, toward
an efficient synthesis of 2-substituted quinolines
(Scheme 1a).[18] As a further extension, we postulated that
Scheme 1. Unexpected rearrangement: Formation of 3-aminoquinolines.
this rudimentary mechanism could be adapted for the syn-
thesis of synthetically valuable 2-aminomethylquinolines[19]
by replacing simple terminal alkyne with propargyl amine
(Scheme 1b). Our initial attempt to accomplish this transfor-
mation employed 2-aminobenzaldehyde 1a (R1, R2 =-
OCH2O-) and propargyl amine in the presence of CuI
(10 mol%) and pyrrolidine (20 mol%) following previously
established conditions.[18] Unfortunately, this reaction failed
to provide the desired 2-aminomethylquinoline and instead
gave an intractable mixture of unidentified products. Inter-
estingly, in the absence of pyrrolidine, 2-methyl-3-aminoqui-
noline was obtained in 65% yield (Scheme 1c). The forma-
[a] Dr. N. T. Patil, V. S. Raut, V. S. Shinde
CPC Division
CSIR–Indian Institute of Chemical Technology,
Hyderabad, 500 607 (India)
Fax : (+91)40-27193382
E-mail: nitin@iict.res.in
[b] Dr. G. Gayatri, Dr. G. N. Sastry
Molecular Modeling Group
CSIR–Indian Institute of Chemical Technology,
Hyderabad, 500 607 (India)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103668.
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Chem. Eur. J. 2012, 18, 5530 – 5535

COMMUNICATION
tion of this product was very encouraging and therefore we
decided to optimize the reaction further.
At the outset of this study, our efforts were directed to-
wards finding an appropriate metal catalyst and suitable re-
action conditions. As shown in Table 1, we began probing
To demonstrate the scope of this rearrangement reaction,
a variety of 2-aminobenzaldehydes were examined under
the optimized reaction conditions. As shown in Table 2, the
reactions proceeded quite well and the desired 3-aminoqui-
nolines were obtained in moderate to good yields. The 2-
aminobenzaldehydes 1b–c on reaction with propargyl amine
gave expected products in 70–88% yields (Table 2, en-
tries 1–3). The various halogen containing 2-aminobenzalde-
hydes on reaction with propargyl amine gave 2e–i in 60–
72% yields (Table 2, entries 4–8). As can be judged from
Table 2, entries 9 to 11, the presence of an electron-with-
drawing substituent on 2-aminobenzaldehyde was tolerated;
however, the products were obtained in lower yields. The 2-
aminobenzaldehydes bearing electron-donating substituents
such as -OMe and -OPh furnished 2m and 2n in 80 and
34% yields, respectively (Table 2, entries 12 and 13). Even
a thiophenyl substituent on 2-aminobenzaldehyde was toler-
ated to give 2o in 43% yield (Table 2, entry 14). Interesting-
ly, when 1-amino-2-naphthaldehyde was reacted with prop-
argyl amine, benzo[h]quinoline 2p was obtained in 55%
yield (Table 2, entry 15).
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Solvent
T
[8C]
t
Yield
[%][b]
[h]
1
2
3
4
5
6
7
8
Cul
Cul
Cul
Cul
Cul
CH3CN
MeOH
1,4-dioxane
neat
100
100
100
100
100
100
100
100
100
100
100
50
12
12
12
12
12
12
12
12
12
12
12
20
36
20
65
trace
22
60
34
32
44
27
82
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Cu
N
AuCl
Ph3PAuNTf2
Ph3PAuOTf
Ph3PAuSbF6
Ph3PAuBF4
Ph3PAuOTf
Ph3PAuOTf
Ph3PAuOTf
9
10
11
12
13
14
54
47
To further explore the scope of the reaction, 3-phenylpro-
pargyl amine was treated with 1a in presence of Ph3PAuOTf
(3 mol%) in CH3CN at 508C for 20 h. Very interestingly, in-
stead of the expected product, 2-phenylquinoline 3 was ob-
tained in 52% yield (reaction (1)). The formation of this un-
expected product could be accounted on the basis of gold
85
25
50
58[c]
87[d]
[a] Reactions were performed employing 1a (0.60 mmol), propargyl
amine (1.20 mmol), catalyst (10 mol%), and solvent (3.0m) under an
argon atmosphere for 12 h. [b] Isolated product yields. [c] Starting mate-
rial 1a was recovered in 20% yield. [d] Reaction was carried out with
Ph3PAuOTf (3 mol%) for 20 h.
À
À
catalyzed C C and C N bond cleavage (see below).
the reaction between 2-aminobenzaldehyde 1a and proparg-
yl amine using CuI catalyst and various solvents (Table 1,
entries 1–5). The results revealed that CH3CN is the
best solvent for this transformation. As can be seen
Table 2. Generality and scope study.[a]
from Table 1 (entry 6), the catalyst CuACTHNURGTNEUNG(OTf)2 was
not efficient. With the reasoning that a more alky-
nophilic catalyst would display greater reactivity
toward this unprecedented rearrangement, we
screened various gold(I) catalysts such as AuCl,
Ph3PAuNTf2, Ph3PAuSbF6, and Ph3PAuBF4 (Table 1,
entries 7–11). Out of the several salts examined, the
catalyst Ph3PAuOTf was found to be the best
(Table 1, entry 9). When the temperature of reac-
tion was decreased up to 508C, a slight increase in
reaction time (20 h) was found to be necessary for
obtaining 2a in 85% yield (Table 1, entry 12). Low-
ering the temperature further had adverse effect
and 2a was isolated only in 58% yield (Table 1,
entry 13). We finally found that 2a could be ob-
tained in almost comparable yield (Table 1, entry 9)
when the catalyst loading was lowered from 10 to
3 mol% (Table 1, entry 14). It should be noted that
neither the gold salt Ph3PAuCl, nor the silver salt
AgOTf was a suitable catalyst for this unprecedent-
ed transformation.
Entry
1
2
Yield Entry
[%][b]
1
2
Yield
[%][b]
65[c]
1
2
3
4
5
6
7
8
1b R1 =R2 =R3 =H
2b 88
2c 73
2d 70
2e 60
2 f 67
2g 72
2h 72
9
1j R1 =COOMe,
R2 =R3 =H
2j
1c R1 =Me,
R2 =R3 =H
1d R1 =R3 =Me,
R2 =H
10
11
12
13
14
15
1k R1 =R3 =H,
R2 =COOMe
1l R1 =R3 =H,
R2 =CN
2k 55[c]
30[c]
2l
1e R1 =Cl,
R2 =R3 =H
1 f R1 =R3 =H,
R2 =Cl
1m R1 =R2 =OMe, 2m 80
R3 =H
1n R1 =PhO,
R2 =R3 =H
2n 34
2o 43
2p 55
1g R1 =Cl, R2 =H,
R3 =Me
1o R1 =PhS,
R2 =R3 =H
1h R1 =Br,
R2 =R3 =H
1p R1 =H,
R2 =R3 =-(C4H4)-
1i R1 =I, R2 =R3 =H 2i 68
[a] A solution of 1 (0.60 mmol), propargyl amine (1.20 mmol), Ph3PAuOTf (3 mol%)
in CH3CN (3.0m) was heated at 508C for 20 h. [b] Isolated product yields. [c] Reaction
time 28 h.
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N. T. Patil et al.
and product(Pr)s. Propargyl amine
amine (Ph-yne) attack on aminobenzaldehyde (1a)/phenyl
aminobenzaldehyde (1b) in the presence of AuP(CH3)3 cat-
ACHTUNGERTN(NUNG H-yne)/phenyl propargyl
AHCTUNGTRENNUNG
alyst is considered for the study. The reaction profiles along
with the optimized structures for H-yne and Ph-yne attacks
are depicted in Figure 1 and Figure 2, respectively. The ini-
tial attack of H-yne on 1a can either be AuPACHTNUGTRNEG(UN CH3)3-cata-
lyzed or non-catalyzed. The non-catalyzed attack forms an
endothermic product, imine (2-In1, 5.4 kcalmolÀ1), which
has a propensity to undergo bond rotation isomerisation (2-
In2, 0.6 kcalmolÀ1). The subsequent union with catalyst is
highly exothermic (2-In3, À15.6 kcalmolÀ1). Alternatively,
H-yne···AuPACTHNUTRGNEUNG(CH3)3 attack results in an exothermic inter-
mediate 2-In1-C (À9.4 kcalmolÀ1), which in turn undergoes
bond rotation isomerisation and forms 2-In3 (À0.1 kcal
molÀ1), thereby suggesting the attack of the H-yne···AuP-
AHCTUNGTREN(NGUN CH3)3 complex on 1a to be more favored. Furthermore, 2-
In3 undergoes ring closure resulting in the formation of 2-
In4 (À16.6 kcalmolÀ1) via 2-TS1 (2.5 kcalmolÀ1). This is fol-
lowed by the conversion of -CH of the alkyne group to
-CH3, which is mediated through two proton-migration steps
as demonstrated computationally. The proton transfer TSs
in the present study are considered to be counterion (OTf)-
mediated and previous reports have shown the role of coun-
terion during proton migration.[24] As the couterion-mediat-
ed TSs could not be obtained at B3LYP level, all the TfOÀ-
mediated proton-transfer TSs are optimized at the HF level
Scheme 2. Plausible mechanism.
Whereas a precise mechanism of the present reaction
awaits further studies,[20] a plausible proposal for the forma-
tion of 2b/3 is presented in Scheme 2. At first, condensation
between 1a and propargyl amine would occur to provide
imine 4, which would be interconvertible as E and Z isomers
under the influence of a catalyst. The Z isomer would un-
dergo gold-catalyzed exo-dig cyclization (see 5) and subse-
quent isomerization to form benzodiazepine 6 (cycle A).[21]
The intermediate 6 would then
using the LanL2DZ basis set for Au and 6-31+GACHTNUTRGNE(UNG d,p) basis
set for all other atoms (TSs depicted in Figure 1 and
Figure 2 in bold font with a superscript a). The nature of the
stationary point obtained at HF level has been verified also
at B3LYP level by performing frequency calculations. The
rearrange to Au-cordinated
azirinoquinoline 7, which, after
subsequent skeletal rearrange-
ment, affords 2b (cycle B). The
formation of 3 from 1a and 3-
phenylpropargyl amine is pre-
sumably similar and explained
in cycles C and D. The underly-
ing difference[22] could be the
endo-dig cyclization of anili-
noalkyne 4 (see 8) and subse-
quent protodeauration to form
benzodiazocine 9 (cycle C). The
skeletal rearrangement, in 9, in-
À
volving cleavage of C C and
[23]
À
C N bonds
with the expul-
sion of methanimine (see 10)
would produce 3 (cycle D).
To unravel the mechanistic
aspects of Au-catalyzed reac-
tion, quantum chemical calcula-
tions were performed on the re-
actants, proposed intermedia-
te(In)s, transition state(TS)s Figure 1. Plot showing the reaction profile of the Au-catalyzed reaction involving H-yne.
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Chem. Eur. J. 2012, 18, 5530 – 5535

An Expedient Route to 3-Aminoquinolines
COMMUNICATION
Figure 2 depicts a similar re-
action profile for Ph-yne as ob-
served in H-yne. Analogous to
H-yne, the initial attack of Ph-
yne on 1b can either be AuP-
AHCTUNTGREG(NUNN CH3)3-catalyzed or non-cata-
lyzed. The non-catalyzed attack
forms an imine (3-In1, 5.4 kcal
molÀ1) in the first step and un-
dergoes bond rotation isomeri-
sation (3-In2, 0.7 kcalmolÀ1) in
the next step. This is followed
by the AuPACHTNUGTRNEGNU(CH3)3 attack, which
results in the formation of 3-In3
(À12.1 kcalmolÀ1). The Ph-
yne···AuPACHTNUGTRNEGNU(CH3)3 attack results
in an exothermic intermediate
3-In1-Cb
which in turn undergoes bond
(À6.5 kcalmolÀ1),
rotation
isomerisation
and
forms 3-In3 (0.6 kcalmolÀ1).
The energy values thus suggest
the initial Ph-yne···AuPACHTUNGTRENNUNG(CH3)3
attack. Furthermore, 3-In3 pro-
Figure 2. Plot showing the reaction profile of the Au-catalyzed reaction involving Ph-yne.
ceeds through a ring closure TS
3-TS1
(8.3 kcalmolÀ1)
and
forms 3-In4 (0.1 kcalmolÀ1).
proton-transfer steps proceed through the initial counterion
attack. The TfOÀ counteranion abstracts proton from nitro-
gen forming 2-In5 (5.2 kcalmolÀ1) via 2-TS2 (5.7 kcalmolÀ1).
Subsquently, the abstracted proton being transfered to the
terminal carbon of alkyne forming 2-In6 (À39.5 kcalmolÀ1)
via 2-TS3 (0.8 kcalmolÀ1). Again, TfOÀ abstracts proton
from CH2 forming 2-In7 (38.1 kcalmolÀ1) via 2-TS4
(40.5 kcalmolÀ1). The abstracted proton is then transferred
to the alkyne carbon thereby forming 2-In8 (NC/C) via 2-
TS5 (2.0 kcalmolÀ1). In this process, the catalyst either gets
detached (2-In8-NC, À15.1 kcalmolÀ1) or remains intact
with the intermediate (2-In8-C, À36.0 kcalmolÀ1). The
energy values, thus, delineate the role of catalyst during the
course of reaction. Furthermore, 2-In8-C can proceed
through three different routes, 2-In10–1, 2-In10–2, and 2-
In10–3. Two out of the three possibilities, 2-In10–1 and 2-
In10–3, are 23.8 and 14.8 kcalmolÀ1 higher in energy than 2-
In8-C and are highly endothermic in nature, whereas the
third one, 2-In10–2, is 1.2 kcalmolÀ1 higher in energy. The
reason for the lower stability of 2-In10–1 compared with 2-
In10–2 and 2-In10–3 can be traced to its zwitterionic nature.
The strain that develops due to the formation of the three-
membered ring in 2-In10–3 might be the reason for its lower
stability compared with 2-In10–2. Thus, the formation of 2-
In10–2 from 2-In8-C proceeds through 2-In9 (28.5 kcal
molÀ1). The seven-membered ring in 2-In10–2 then under-
goes cyclization resulting in three-membered and six-mem-
bered rings forming 2-In11 (À1.5 kcalmolÀ1). The formation
of 2 from 2-In11 is exothermic by about 10.1 kcalmolÀ1.
The proton migration to carbon adjacent to the terminal
carbon of alkyne proceeds in two steps. Initially, TfOÀ ab-
stracts a proton from nitrogen to give 3-In5 (8.1 kcalmolÀ1)
via 3-TS2 (12.6 kcalmolÀ1). It then transfers the proton to
the alkyne carbon, which leads to 3-In6ACTHNUGRTENUNG(NC/C) via 3-TS3
(5.3 kcalmolÀ1). During this process, analogous to the H-yne
attack, the catalyst has a propensity to either leave the reac-
tion (3-In6-NC, À19.7 kcalmolÀ1) or remain intact with the
intermediate (3-In6-C, À36.7 kcalmolÀ1), which in turn sug-
gests the effect of the catalyst on the reaction. Out of the
three different possibilities, namely 3-In8–1, 3-In8–2 and 3-
In8–3 from 3-In6-C, the former and the latter are 10.2 and
19.5 kcalmolÀ1 higher in energy compared to 3-In6-C and
are highly endothermic in nature, whereas 3-In8–2 is 3.7 kcal
molÀ1 higher in energy. The stability of 3-In8–2 compared
with 3-In8–1 and 3-In8–3 can be explained based on the
zwitterionic nature of the former and the presence of
a strained four-membered ring in the later. Thus, the forma-
tion of 3-In8–2 (À27.0 kcalmolÀ1) from 3-In6-C proceeds via
3-In7, 30.7 kcalmolÀ1). The eight-membered ring in 3-In8–2
then cyclizes to form four- and six-membered rings (3-In9,
À18.4 kcalmolÀ1) through 3-TS4 (27.4 kcalmolÀ1). The for-
mation of 3 from 3-In9 proceeds through a concerted [2+2]
bond cleavage TS (3-TS5, 39.1 kcalmolÀ1). The transition
state 3-TS5 could not be obtained at the B3LYP level but
could be obtained at mPW1K level in combination with
LanL2DZ basis set on Au and 6-31G(d) basis set on all
other atoms (TS in Figure 2 are depicted in bold with a su-
perscript b). However frequency calculations at B3LYP
level on mPW1K optimized geometry of 3-TS5 correspond
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N. T. Patil et al.
CatChem 2010, 2, 493–497; j) S. Md. Abu Sohel, R.-S. Liu, Chem.
Soc. Rev. 2009, 38, 2269–2281; k) A. Fꢂrstner, Chem. Soc. Rev.
2009, 38, 3208–3221; l) D. J. Gorin, B. D. Sherry, F. D. Toste, Chem.
Rev. 2008, 108, 3351–3378; m) Z. Li, C. Brouwer, C. He, Chem. Rev.
2008, 108, 3239–3265; n) A. Arcadi, Chem. Rev. 2008, 108, 3266–
3325; o) E. Jimꢁnez-NfflÇez, A. M. Echavarren, Chem. Rev. 2008,
108, 3326–3350; p) A. S. K. Hashmi, M. Rudolph, Chem. Soc. Rev.
2008, 37, 1766–1775; q) A. Fꢂrstner, P. W. Davies, Angew. Chem.
2007, 119, 3478–3519; Angew. Chem. Int. Ed. 2007, 46, 3410–3449;
r) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180–3211; s) E. Jimꢁnez-
NfflÇez, A. M. Echavarren, Chem. Commun. 2007, 333–346; t) L.
Zhang, J. Sun, S. A. Kozmin, Adv. Synth. Catal. 2006, 348, 2271–
2296; u) A. S. K. Hashmi, G. J. Hutchings, Angew. Chem. 2006, 118,
8064–8105; Angew. Chem. Int. Ed. 2006, 45, 7896–7936; v) R. A.
Widenhoefer, X. Han, Eur. J. Org. Chem. 2006, 4555–4563.
[2] For reviews, see: a) J. P. Michael, Nat. Prod. Rep. 2007, 24, 223–246;
b) V. V. Kouznetsov, L. Y. V. Mꢁndez, C. M. M. Gómez, Curr. Org.
Chem. 2005, 9, 141–161; c) J. Wiesner, R. Ortmann, H. Jomaa, M.
Schlitzer, Angew. Chem. 2003, 115, 5432–5451; Angew. Chem. Int.
Ed. 2003, 42, 5274–5293.
to the concerted [2+2] pericyclic reaction. The intermediate
3-In9 results in the formation of 3, which is endothermic by
about 13.5 kcalmolÀ1. Thus, the computational studies clear-
ly demonstrate the role of catalyst in making the reaction
feasible. There are several plausible mechanistic routes for
the reaction, which are depicted in Figures 1 and 2; the most
preferred route in both cases among the various possible
ones is represented with a thick black line.
In summary, we have discovered the gold-catalyzed rear-
rangement reaction between 2-aminobenzaldehydes and
propargyl amines to give synthetically valuable 3-aminoqui-
nolines; a class of compounds that to date are not easily ac-
cessible. The mechanism of the reaction was established by
carefully conducted experimental and computational studies.
In combination with subsequent literature-known meth-
ods,[25] this protocol enables the rapid synthesis of useful
synthetic building blocks that can be advanced to functional-
ized quinolines.
[3] For reviews, see: a) M. Rudrapall, D. Chetia, Der Pharmacia Lettre
2011, 3, 29–36; b) M. Foley, L. Tilley, Pharmacol. Ther. 1998, 79,
55–87. Similarly, several drugs exist that share aminoquinoline moi-
eties, for example, primaquine, pamaquine, chloroquine, hydroxy-
chloroquine amodiaquine, piperaquine, and so on.
Experimental Section
[4] A. Moreno, S. Pꢁrenz, S. Galiano, L. Juanenea, O. Erviti, C. Frígola,
I. Aldana, A. Monge, Eur. J. Med. Chem. 2004, 39, 49–58.
General procedure: 2-Aminobenzaldehydes 1 (0.6 mmol) and propargyl
amines (1.2 mmol) were dissolved in dry CH3CN (3.0m) under argon at-
mosphere in a screw-cap vial (2.5 mL) containing a stirrer bar. Ph3PAuCl
(3 mol%) and AgOTf (3 mol%) were then added successively to the so-
lution. The reaction vial was fitted with cap and heated at 508C for 20 h.
The reaction mixture was allowed to cool to ambient temperature. Then
the reaction mass was diluted with ethyl acetate and filtered through
a plug of celite. The filtrate was concentrated under reduced pressure
and the resulting residue was purified by column chromatography on
silica gel with ethyl acetate/hexane (1:1) as eluent to afford products 2/3.
[5] a) W. J. Watkins, Y. Landaverry, R. Lꢁger, R. Litman, T. E. Renau,
N. Williams, R. Yen, J. Z. Zhang, S. Chamberland, D. Madsen, D.
Griffith, V. Tembe, K. Huie, M. N. Dudley, Bioorg. Med. Chem.
Lett. 2003, 13, 4241–4244; b) T. E. Renau, R. Lꢁger, R. Yen, M. W.
She, E. M. Flamme, J. Sangalang, C. L. Gannon, S. Chamberland, O.
Lomovskaya, V. J. Lee, Bioorg. Med. Chem. Lett. 2002, 12, 763–766;
c) T. E. Renau, R. Lꢁger, E. M. Flamme, M. W. She, C. L. Gannon,
K. M. Mathias, O. Lomovskaya, S. Chamberland, V. J. Lee, T. Ohta,
K. Nakayama, Y. Ishida, Bioorg. Med. Chem. Lett. 2001, 11, 663–
667; d) T. E. Renau, R. Lꢁger, E. M. Flamme, J. Sangalang, M. W.
She, R. Yen, C. L. Gannon, D. Griffith, S. Chamberland, O. Lomov-
skaya, S. J. Hecker, V. J. Lee, T. Ohta, K. Nakayama, J. Med. Chem.
1999, 42, 4928–4931.
Computational methods: The density functional theory method B3LYP
was employed in combination with LanL2DZ basis set on Au and 6–
31G(d) basis set on all other atoms. Optimizations and frequency calcula-
tions have been performed on all the systems by employing the PCM
method using acetonitrile as solvent at 373 K. All the calculations were
performed using the G09 programme package.[26]
[6] a) T. Lꢂbbers, P. Angehrn, H. Gmꢂnder, S. Herzig, Bioorg. Med.
Chem. Lett. 2007, 17, 4708–4714; b) M. Tabart, G. Picaut, M. Lav-
ergne, S. Wentzler, J.-L. Malleron, S. Dutka-Malen, N. Berthaut,
Bioorg. Med. Chem. Lett. 2003, 13, 1329–1331.
[7] D. L. Selwood, D. G. Brummell, R. C. Glen, M. C. Goggin, K. Rey-
nolds, M. A. Tatlock, G. Wishart, Bioorg. Med. Chem. Lett. 2001, 11,
1089–1092.
Acknowledgements
[8] a) A. S. Kiselyov, E. L. Piatnitski, A. V. Samet, V. P. Kisliy, V. V. Se-
menov, Bioorg. Med. Chem. Lett. 2007, 17, 1369–1375; b) T. Suzuki,
A. Kouketsu, Y. Itoh, S. Hisakawa, S. Maeda, M. Yoshida, H. Naka-
gawa, N. Miyata, J. Med. Chem. 2006, 49, 4809–4812; c) S.-K. Anan-
dan, J. S. Ward, R. D. Brokx, M. R. Bray, D. V. Patel, X.-X. Xiao,
Bioorg. Med. Chem. Lett. 2005, 15, 1969–1972.
We gratefully acknowledge financial support by Department of Science
and Technology (DST), India. V.S.R. and V.S.S. thank UGC, India for
their fellowships.
Keywords: 3-aminoquinolines · alkynes · density functional
calculations · gold · rearrangement
[9] T. Y. H. Wu, C. Hassig, Y. Wu, S. Ding, P. G. Schultz, Bioorg. Med.
Chem. Lett. 2004, 14, 449–453.
[10] D. M. Swanson, A. E. Dubin, C. Shah, N. Nasser, L. Chang, S. L.
Dax, M. Jetter, J. G. Breitenbucher, C. Liu, C. Mazur, B. Lord, L.
Gonzales, K. Hoey, M. Rizzolio, M. Bogenstaetter, E. E. Codd,
D. H. Lee, S.-P. Zhang, S. R. Chaplan, N. I. Carruthers, J. Med.
Chem. 2005, 48, 1857–1872.
[11] Y. Fujita, Y. Tsuda, T. Li, T. Motoyama, M. Takahashi, Y. Shimizu,
T. Yokoi, Y. Sasaki, A. Ambo, A. Kita, Y. Jinsmaa, S. D. Bryant,
L. H. Lazarus, Y. Okada, J. Med. Chem. 2004, 47, 3591–3599.
[12] For a review, see: a) A. Tholey, E. Heinzle, Anal. Bioanal. Chem.
2006, 386, 24–37. For recent publications, see: b) K. Kaneshiro, Y.
Fukuyama, S. Iwamoto, S. Sekiya, K. Tanaka, Anal. Chem. 2011, 83,
3663–3667; c) M. Rohmer, B. Meyer, M. Mank, B. Stahl, U. Bahr,
M. Karas, Anal. Chem. 2010, 82, 3719–3726.
[1] Selected recent reviews: a) B. Biannic, A. Aponick, Eur. J. Org.
Chem. 2011, 6605–6617; b) A. Corma, A. Leyva-Pꢁrez, M. J. Sabat-
er, Chem. Rev. 2011, 111, 1657–1712; c) H. A Wegner, M. Auzias,
Angew. Chem. 2011, 123, 8386–8397; Angew. Chem. Int. Ed. 2011,
50, 8236–8247; d) M. Bandini, Chem. Soc. Rev. 2011, 40, 1358–1367;
e) N. T. Patil, R. D. Kavthe, Y. Yamamoto, Advances in Heterocyclic
Chemistry 2010, 101, 75–95; f) S. Ma, Handbook of Cyclization Re-
actions, Wiley-VCH, 2010, Chapter 10; g) A. S. K. Hashmi, M.
Bꢂhrle, Aldrichimica Acta 2010, 43, 27–33; h) A. S. Dudnik, N.
Chernyak, V. Gevorgyan, Aldrichimica Acta 2010, 43, 37–46; i) P.
Garcia, M. Malacria, C. Aubert, V. Gandon, L. Fensterbank, Chem-
5534
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 5530 – 5535

An Expedient Route to 3-Aminoquinolines
COMMUNICATION
[13] a) R. Bujok, A. Kwast, P. Cmoch, Z. Wróbel, Tetrahedron 2010, 66,
698–708.
A. Muruganantham, G. Rajaraman, H. Wadepohl, M. Zajaczkowski,
Chem. Eur. J. 2008, 14, 5313–5328.
[14] a) A. A. Trabanco, J. A. Vega, M. A. Fernµndez, J. Org. Chem. 2007,
72, 8146–8148; b) F. Lang, D. Zewge, I. N. Houpis, R. P. Volante,
Tetrahedron Lett. 2001, 42, 3251–3254.
[21] C. Z. Ding, S-H Kim, J. T. Hunt, T. Mitt, R. Bhide, K. Leftheris,
N. J. Skillman, (Bristol-Myers Squibb, Princeton, NJ) US-
6011029A1, 2000.
[15] P. Magnus, S. A. Eisenbeis, R. A. Fairhurst, T. Iliadis, N. A. Magnus,
D. Parry, J. Am. Chem. Soc. 1997, 119, 5591–5605.
[16] Y. D. Wang, D. H. Boschelli, S. Johnson, E. Honores, Tetrahedron
2004, 60, 2937–2942.
[22] For exo/endo cyclization dependant on terminal/internal alkyne, see:
C. Ferrer, C. H. Amijs, A. M. Echavarren, Chem. Eur. J. 2007, 13,
1358–1373.
À
À
[23] For metal catalyzed cleavage of C C and C X bonds, see: a) S.
Sabiah, C.-S. Lee, W.-S. Hwang, I. J. B. Lin, Organometallics 2010,
29, 290–293 and reference cited therein; b) C.-H. Jun, Chem. Soc.
Rev. 2004, 33, 610–618.
[17] a) N. T. Patil, V. Singh, Chem. Commun. 2011, 47, 11116–11118;
b) N. T. Patil, A. K. Mutyala, P. G. V. V. Lakshmi, B. Gajula, B. Srid-
har, G. R. Pottireddygari, T. P. Rao, J. Org. Chem. 2010, 75, 5963–
5975; c) N. T. Patil, P. G. V. V. Lakshmi, V. Singh, Eur. J. Org. Chem.
2010, 4719–4731; d) N. T. Patil, R. D. Kavthe, V. S. Shinde, B. Srid-
har, J. Org. Chem. 2010, 75, 3371–3380; e) N. T. Patil, A. K. Mutya-
la, P. G. V. V. Lakshmi, P. V. K. Raju, B. Sridhar, Eur. J. Org. Chem.
2010, 1999–2007; f) N. T. Patil, R. D. Kavthe, V. S. Raut, V. S.
Shinde, B. Sridhar, J. Org. Chem. 2010, 75, 1277–1280; g) N. T. Patil,
R. D. Kavthe, V. S. Raut, V. V. N. Reddy, J. Org. Chem. 2009, 74,
6315–6318.
[18] N. T. Patil, V. S. Raut, J. Org. Chem. 2010, 75, 6961–6964.
[19] For importance of 2-aminomethylquinolines, see: a) D. Moffat, S.
Patel, F. Day, A. Belfield, A. Donald, M. Rowlands, J. Wibawa, D.
Brotherton, L. Stimson, V. Clark, J. Owen, L. Bawden, G. Box, E.
Bone, P. Mortenson, A. Hardcastle, S. van Meurs, S. Eccles, F. Ray-
naud, W. Aherne, J. Med. Chem. 2010, 53, 8663–8678; b) J. R.
Quinn, S. C. Zimmerman, J. Org. Chem. 2005, 70, 7459–7467; c) S.
Zahn, J. W. Canary, J. Am. Chem. Soc. 2002, 124, 9204–9211;
d) T. A. Shepherd, L. N. Jungheim, A. J. Baxter, Bioorg. Med.
Chem. Lett. 1994, 4, 1391–1396; e) K. C. Langry, Org. Prep. Proc.
Int. 1994, 26, 429–438.
[20] It also possible that 2-aminomethylquinoline (Scheme 1, b) forms
first, which then rearranges to 3-amino-2-methylquinoline
(Scheme 1, c) in the presence of Au salts. To ascertain this possibili-
ty, 2-aminomethylquinoline was treated under Au-catalyzed stan-
dard conditions. However, the formation of product was not ob-
served and the starting material was recovered in quantitative yield.
This led us to conclude that the 2-aminomethylquinoline is not the
intermediate of the present reaction. The 2-Aminomethylquinoline
used in this study was prepared using a procedure reported by
Comba and co-workers, see: P. Comba, C. Lang, C. L. de Laorden,
[24] A. S. Dudnik, Y. Xia, Y. Li, V. Gevorgyan, J. Am. Chem. Soc. 2010,
132, 7645–7655.
[25] a) E.-H. Cho, S.-G. Chung, S.-H. Lee, H.-S. Kwon, J.-E. Lee, D.-.
Kang, J.-H. Joo, Y.-H. Lee (Samjin Pharmaceutical Co. Ltd., Seoul,
Republic of Korea), US-6028195A1, 2000; b) H. Sashida, A. Fujii, T.
Tsuchiya, Chem. Pharm. Bull. 1987, 35, 4110–4116; c) A. Godard,
G. Queguiner, J. Heterocycl. Chem. 1980, 17, 465–473; d) S. Rachlin,
E. Bramm, I. Ahnfelt-Rønne, E. Arrigoni-Martelli, J. Med. Chem.
1980, 23, 13–20; e) G. R. Clemo, G. A. Swan, J. Chem. Soc. 1945,
867–870.
[26] Gaussian 09, Revision A.02, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V.
Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X.
Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-
nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven,
J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J.
Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J.
Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar,
J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A.
Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O.
Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian,
Inc., Wallingford CT, 2009.
Received: November 21, 2011
Published online: March 20, 2012
Chem. Eur. J. 2012, 18, 5530 – 5535
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5535