Sequential and selective Buchwald-Hartwig amination reactions for the controlled functionalization of 6-bromo-2-chloroquinoline: Synthesis of ligands for the Tec Src homology 3 domain

Article abstract of DOI:10.1021/jo801808r

(Chemical Equation Presented) Src homology 3 (SH3) domains are highly conserved protein-protein interaction domains that mediate important biological processes and are considered valuable targets for the development of therapeutic agents. In this paper, we report the preparation of a range of new 6-heterocyclic substituted 2-aminoquinolines using Buchwald-Hartwig chemistry. 6-Heterocyclic substitution of the 2-amino-quinoline has provided ligands with increased binding affinity for the SH3 domain relative to the lead compound, 2-aminoquinoline, that are the highest affinity ligands prepared to date. The key step in the synthesis of these compounds required a selective Buchwald-Hartwig amination of an aryl bromide in the presence of an activated heteroaryl chloride. The optimization of reaction conditions to achieve the selective amination is discussed and has allowed for cross-coupling with a range of cyclic amines. Introduction of the amino functionality of the 6-heterocyclic 2-aminoquinolines involved additional Buchwald-Hartwig chemistry utilizing lithium bis(trimethylsilyl)amide as an ammonia equivalent.

Full text of DOI:10.1021/jo801808r

Sequential and Selective Buchwald-Hartwig Amination Reactions
for the Controlled Functionalization of 6-Bromo-2-chloroquinoline:
Synthesis of Ligands for the Tec Src Homology 3 Domain
Jessica A. Smith,† Rhiannon K. Jones,† Grant W. Booker,‡ and Simon M. Pyke*,†
Discipline of Chemistry, School of Chemistry and Physics, and Discipline of Biochemistry, School of
Molecular and Biomedical Science, The UniVersity of Adelaide, Adelaide, South Australia 5005, Australia
simon.pyke@adelaide.edu.au
ReceiVed August 12, 2008
Src homology 3 (SH3) domains are highly conserved protein-protein interaction domains that mediate
important biological processes and are considered valuable targets for the development of therapeutic
agents. In this paper, we report the preparation of a range of new 6-heterocyclic substituted
2-aminoquinolines using Buchwald-Hartwig chemistry. 6-Heterocyclic substitution of the 2-amino-
quinoline has provided ligands with increased binding affinity for the SH3 domain relative to the lead
compound, 2-aminoquinoline, that are the highest affinity ligands prepared to date. The key step in the
synthesis of these compounds required a selective Buchwald-Hartwig amination of an aryl bromide in
the presence of an activated heteroaryl chloride. The optimization of reaction conditions to achieve the
selective amination is discussed and has allowed for cross-coupling with a range of cyclic amines.
Introduction of the amino functionality of the 6-heterocyclic 2-aminoquinolines involved additional
Buchwald-Hartwig chemistry utilizing lithium bis(trimethylsilyl)amide as an ammonia equivalent.
Introduction
of substituted 2-aminoquinolines has allowed for the develop-
ment of a model for the mechanism of binding of these
compounds to the Tec SH3 domain. This model involves π-π
stacking of the quinoline with the side chain of the tryptophan
residue (W215) and a salt bridge between the positively charged
ligand and the negatively charged aspartate residue (D196) under
physiological conditions (Figure 1A).6
The highest affinity ligands identified to date (2-4) contain
acetal functionality at the 6-position of the quinoline ring system
and have equilibrium binding dissociation constants (Kd) in the
range of 20-50 µM (Figure 2).5 The acetal functionality of these
ligands, however, is not suitable for use in therapeutic agents
as the acetals hydrolyze to carbonyl compounds under physi-
ological aqueous conditions.5 We envisaged that replacement
of the biologically labile acetal with an alternate heterocyclic
substituent, as in 5, would provide ligands with increased
stability and may also provide ligands with similar or increased
affinity for the SH3 domain relative to ligands 2-4 (Figure 2).
Additionally, such ligands would provide information as to
Src homology 3 (SH3) domains are small, highly conserved
protein-protein interaction domains. The function of the SH3
domain is to mediate the assembly of large multiprotein
complexes by binding to specific proline-rich sequences in target
proteins. Protein complexes containing SH3 domains are found
in a variety of signaling pathways controlling processes such
as cell proliferation, apoptosis, and gene expression.1-3 Proteins
containing SH3 domains have been identified in deregulated
signaling pathways associated with human diseases including
cancer and osteoporosis, therefore making these domains
valuable therapeutic targets. Previously, we have reported that
a range of substituted 2-aminoquinoline derivatives display weak
to moderate binding affinity with the Tec SH3 domain.4-6 SAR
information provided from 2-aminoquinoline (1) and a number
* To whom correspondence should be addressed. Phone: +61 8 83035358.
† School of Chemistry and Physics.
‡ School of Molecular and Biomedical Science.
(1) Mayer, B. J. J. Cell Sci. 2001, 114, 1253–1263.
(2) Ren, R.; Mayer, B. J.; Cicchetti, P.; Baltimore, D. Science 1993, 259,
1157–1161.
(5) Inglis, S.; Jones, R.; Fritz, D.; Stojkoski, C.; Booker, G.; Pyke, S. Org.
Biomol. Chem. 2005, 3, 2543–2557.
(6) Inglis, S. R.; Stojkoski, C.; Branson, K. M.; Cawthray, J. F.; Fritz, D.;
Wiadrowski, E.; Pyke, S. M.; Booker, G. W. J. Med. Chem. 2004, 47, 5405–
5417.
(3) Vidal, M.; Gigoux, V.; Garbay, C. Crit. ReV. Oncol. Hematol. 2001, 40,
175–186.
(4) Inglis, S. R.; Jones, R. K.; Booker, G. W.; Pyke, S. M. Bioorg. Med.
Chem. Lett. 2006, 16, 387–390.
8880 J. Org. Chem. 2008, 73, 8880–8892
10.1021/jo801808r CCC: $40.75 2008 American Chemical Society
Published on Web 10/25/2008

Functionalization of 6-Bromo-2-chloroquinoline
SCHEME 1. Retrosynthesis of 6-Substituted
2-Aminoquinolines
process is described using Buchwald-Hartwig chemistry and
lithium bis(trimethylsilyl)amide (LHMDS) as an ammonia
equivalent. The binding affinity of the prepared compounds with
the Tec SH3 domain is also reported and the new SAR
information discussed.
FIGURE 1. (A) Model for the mechanism of binding of 1 to the Tec
SH3 domain and regions predicted to make contacts with substituents
attached to the 2-aminoquinoline backbone on the “left” and “right”
sides of the binding site. (B) Equilibrium binding dissociation constant
(Kd) of 1.6
Results and Discussion
Synthesis of 6-Heterocyclic 2-Aminoquinolines. To prepare
6-heterocyclic 2-aminoquinolines of the general structure 5,
6-bromo-2-chloroquinoline (7) was envisaged as the key
intermediate (see Scheme 1). 7 can be prepared according to
methods previously described6 and contains halide functionality,
allowing for the introduction of a heterocyclic substituent at
the 6-position using Buchwald-Hartwig chemistry, producing
6-heterocyclic 2-chloroquinolines of the general structure 6.
Although there are two potential sites on 7 for palladium-
catalyzed coupling (i.e., 6-Br vs 2-Cl), it was anticipated that
selectivity for the 6-postion could be achieved in the presence
of the activated chlorine at the 2-position. Once the heterocyclic
substituent is introduced, the required 2-amino functionality can
be subsequently incorporated utilizing the method of Ko´ro´di.11
Introducing the Heterocyclic Substituent: Buchwald-Hart-
wig Amination. Initial exploration into the Buchwald-Hartwig
reaction of 7 involved an investigation into the palladium
catalytic system. Biphenyl-based “Buchwald ligands” 12,13 9-14
were examined due to their high prevalence in palladium-
catalyzed reactions (see Table 1).14-16 These ligands are notable
for being both bulky, which accelerates reductive elimination,
and electron rich, which facilitates oxidative addition.17 They
also offer increased air stability relative to traditional
phosphine ligands, and the development of such biphenyl
ligandshasexpandedthesubstratescopeofBuchwald-Hartwig
aminations.13,16
The biphenyl ligands were examined in combination with
Pd(OAc)2 and KOtBu in toluene at 110 °C overnight employing
a as the model cyclic amine. Of these ligands, CyJohnPhos (13)
was the most effective ligand and afforded a moderate conver-
sion of the starting material to the desired product 6a (54%).
In addition to the desired product, however, substitution at the
2-position was also observed to produce compound 8a under
these conditions (see Table 1; formation of 8a was observed
with all the biphenyl ligands, excluding 14). Ligands XPhos
(10) and SPhos (11) demonstrated a reduced ability to afford
the desired product 6a under the reaction conditions employed.
FIGURE 2. Equilibrium binding dissociation constants (Kd) of some
2-aminoquinolines reported previously.5
whether the nature of the heteroatom and its location in the
heterocycle at the 6-position are important for increased binding
affinity.
The preparation of 5 requires the formation of a C-N bond
at the 6-position of the 2-aminoquinoline. Traditional methods
for the synthesis of arylamines, such as nucleophilic aromatic
substitution and Ullmann-type couplings, are typically conducted
using relatively harsh reaction conditions and have limited
generality.7,8 On the other hand, the palladium-catalyzed C-N
bond formation of arylamines (Buchwald-Hartwig amination)
can be conducted under relatively mild conditions, is regiose-
lective, and does not require activating groups.9,10 Buchwald-
Hartwig chemistry is a rapidly developing field of interest due
to the importance of amino-substituted aryl derivatives and
would allow for the synthesis of the target 2-aminoquinoline
compounds. The use of Buchwald-Hartwig chemistry, however,
requires the proper choice of catalyst (Pd source, ligand choice),
base, and solvent, which is crucial for the success of a given
amination reaction.
In this paper we report the synthesis of a range of new
6-heterocyclic substituted 2-aminoquinolines. The general ap-
proach employed was the synthesis of 2-chloroquinolines with
appropriate 6-heterocyclic substitution introduced by Buchwald-
Hartwig chemistry in the key step. A detailed investigation of
the conditions for introducing substitution at the 6-position in
the presence of an activated heteroaryl halide at the 2-position
was conducted, and general reaction conditions for the selective
cross-coupling with a range of cyclic amines are provided.
Conversion of the 2-chloroquinolines to the corresponding
2-aminoquinolines was initially carried out using the method
of Ko´ro´di.11 In addition, an improved method for this amination
(12) Huang, X.; erson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 6653–6655.
(13) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722–9723.
(7) Belfield, A. J.; Brown, G. R.; Foubister, A. J. Tetrahedron 1999, 55,
13285–13300.
(8) Lindley, J. Tetrahedron 1984, 40, 1433–1456.
(9) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125–
146.
(14) Bedford, R. B.; Cazin, C. S. J.; Holder, D. Coord. Chem. ReV. 2004,
248, 2283–2321.
(15) Mayssam, H. A.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2560–2565.
(16) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J.
Org. Chem. 2000, 65, 1158–1174.
(10) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046–2067.
(11) Ko´ro´di, F. A. Synth. Commun. 1991, 21, 1841–1846.
(17) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 9550–9561.
J. Org. Chem. Vol. 73, No. 22, 2008 8881

Smith et al.
TABLE 1. Buchwald-Hartwig Amination of 7 with a Range of
use of 15 as a superior catalyst for C-N bond formation in
the present context, specifically with improved selectivity for
bromine, was explored again with a as the model amine. The
reaction of 7 and a in the presence of 15 according to the
method of Organ et al.18,19 afforded 2-tert-butoxy-6-bromo-
quinoline (18) in almost quantitative yield in 1.5 h. However,
repetition of this reaction with no catalyst produced a similar
result. This indicates that 15 did not facilitate the desired
C-N bond formation required and therefore was not suitable
for this particular amination reaction.
Catalytic Systemsa
Further studies on the Buchwald-Hartwig reaction of 7
utilized the CataCXium A ligand (16).20 This class of sterically
demanding phosphine ligands has been reported to be suitable
for a range of palladium-catalyzed reactions,20-22 including
Buchwald-Hartwig aminations.23 The use of 16 was examined
using conditions reported by Tewari et al.23 involving Pd(OAc)2
and KOtBu in toluene at 120 °C under pressure overnight
employing a as the amine for comparison (see Table 1). The
use of 16 under these reaction conditions led to a slight
improvement in the conversion of starting material to 6a (57%;
cf. 54% with 13). In addition, a reduction in the amount of 8a
was also observed. The results of the ligand screen therefore
indicated that ligand 16 was the most appropriate of the ligands
tested for use in this particular Buchwald-Hartwig reaction and
was employed for the preparation of a range of 6-substituted
2-chloroquinolines.
The use of 16/Pd(OAc)2 in the Buchwald-Hartwig reaction
of 7 using the conditions above allowed for the amination of 7
with a number of cyclic amines, a-m, and afforded compounds
6a-m in varying yields (1-94%) (see Table 2). In addition to
the desired products, however, substitution at the 2-position was
also observed to produce compounds 8. In the reactions with
heterocycles c and l, the expected reactivity was observed, with
6 predominating in good yields and none of 8 observed (see
Table 2). However, in the reactions with heterocycles b, d-f,
h-k, and m, low to moderate yields of 6 were obtained. In
these reactions notable amounts of 8 were observed, and in many
cases 8 was isolated in significant yield. In the case of
heterocycle g only a trace amount of the desired product 6
was observed, and for heterocycle m, 8 was the only isolated
product. The competing amination at chlorine and the
resulting formation of compounds 8 in the presence of the
more reactive bromine are due to the activation of the chlorine
substituent from the adjacent quinoline nitrogen, which makes
the 2-position more susceptible to nucleophilic attack. This also
results in the formation of compounds 17 and 18, which are
seen in varying amounts and result from the displacement of
the chloride by the base. In addition, in the reaction with a
product 19 was observed, and in the reaction with g products
20 and 21 were also observed. The formation of these side
products causes a reduction in the yield of the desired product
and additionally complicates the purification process. In a
number of cases the desired products were unable to be separated
from the unwanted side products.
a Reaction conditions: 7 (1 equiv), 4-methylpiperidine (a; 1.2 equiv),
KOtBu (1.2 equiv), Pd(OAc)2 (0.5 mol %), and ligand (1 mol %) in
toluene at 110 °C. Yields were determined by 1H NMR analysis of the
crude material. The reaction employing 16 was carried out under
pressure at 120 °C. b Pd(OAc)2 was used as the source of palladium in
all cases except for 15. c Only 18 isolated.
t
Interestingly, BuXPhos (12) and JohnPhos (14) were unsuc-
cessful in affording any 6a.
Use of the N-heterocyclic carbene (NHC) palladium
complex PEPPSI (pyridine-enhanced precatalyst preparation
stabilization and initiation, 15) was also explored as it
reportedly offers a number of advantages over traditional
palladium complexes. It is stable to air and moisture and
has been reported to have activity better than or comparable
to that of known palladium catalysts in a range of coupling
reactions including Buchwald-Hartwig aminations.18,19 The
(19) Organ, M. G.; Abdel-Hadi, M.; Avola, S.; Dubovyk, I.; Hadei, N.;
Kantchev, E. A. B.; O’Brien, C. J.; Sayah, M.; Valente, C. Chem.sEur. J. 2008,
14, 2443–2452.
(20) Beller, M.; Zapf, A.; Riermeier, T. Spec. Chem. 2004, 24, 22–24.
(21) Ehrentraut, A.; Zapf, A.; Beller, M. J. Mol. Catal. A 2002, 515, 182–
183.
(22) Torborg, C.; Zapf, A.; Beller, M. ChemSusChem 2008, 1, 91–96.
(23) Tewari, A.; Hein, M.; Zapf, A.; Beller, M. Tetrahedron 2005, 61, 9705–
9709.
(18) Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Aldrichimica Acta
2006, 39, 97–111.
8882 J. Org. Chem. Vol. 73, No. 22, 2008

Functionalization of 6-Bromo-2-chloroquinoline
a
TABLE 2. Buchwald-Hartwig Amination of 7 with 16/Pd(OAc)2 and a Range of Cyclic Amines Showing the Distribution of Products
a Reaction conditions: 7 (1 equiv), amine (1.2 equiv), KOtBu (1.2 equiv), Pd(OAc)2 (0.5 mol %), and 16 (1 mol %) in toluene at 120 °C under
pressure. b Yields were determined by 1H NMR analysis of the crude material. c Isolated yield after chromatography. d Indicates isolated as a mixture
which could not be separated; yields refer to individual components. e Observed by 1H NMR analysis but not isolated. f 17 was also observed by 1H
g
1
NMR analysis but was not isolated. 18 was also observed by H NMR analysis but was not isolated.
Having prepared a range of 6-heterocylic 2-chloroquinoline
compounds in significantly varied yields using this method,
we turned our attention to improving the selectivity of this
reaction for the 6-position. An initial attempt aimed at
improving the selectivity involved replacement of the bromine
atom at C-6 with an iodine atom, compound 22, as the iodine
equivalent should be more reactive (see Scheme 2). The
Buchwald-Hartwig reaction with a using Pd(OAc)2/16/
NaOtBu in toluene afforded the desired product 6a in only
38% yield, together with the corresponding 2-substituted
compound 23 in 13% yield. This demonstrated that the
reaction was less selective for the 6-position when 22 was
employed as the aryl halide (cf. 44% yield with 7), despite
the anticipated increased reactivity of the iodine relative to
bromine. This observation is consistent with several reports
that show that aryl iodides are often less effective than their
J. Org. Chem. Vol. 73, No. 22, 2008 8883

Smith et al.
TABLE 4. Effect of Base on Buchwald-Hartwig Amination of 7a
SCHEME 2. Buchwald-Hartwig Amination of 21 with
a
16/Pd(OAc)2
base
yield of 6a (%)
yield of 8a (%)
KOtBu
NaOtBu
Cs2CO3
57
60
30
14
11
0
a Reaction conditions: 7 (1 equiv), a (1.2 equiv), base (1.2 equiv),
Pd(OAc)2 (0.5 mol %), and 16 (1 mol %) in toluene at 120 °C under
pressure. Yields were determined by 1H NMR analysis of the crude
material.
a Reaction conditions: 22 (1 equiv), a (1.2 equiv), NaOtBu (1.2 equiv),
Pd(OAc)2 (0.5 mol %), and 16 (1 mol %) in toluene at 120 °C under
pressure.
Microwave-assisted organic synthesis has become increas-
ingly popular over the past 20 years due to the potential
improvements that can be achieved in chemical reaction times,
yields, reaction purities, and selectivities. The use of microwave
heating in palladium-catalyzed reactions, including Buchwald-
Hartwig aminations, has been reported and has provided
improvements in the yields and reaction times in many
instances.28,29 The Buchwald-Hartwig reaction was therefore
investigated with the use of microwave irradiation using the
catalytic system of 16/Pd(OAc)2 and c as a model cyclic amine
in this instance. The reaction of 7 and c in toluene in the
presence of NaOtBu afforded the desired product 6c in 80%
yield. Incomplete conversion of the starting material was
observed and is likely a consequence of the inability of the
reaction mixture to reach the required temperature of 150 °C
in a short period of time.30 Due to the poor heating ability of
toluene for use in microwave reactions a number of alternate
solvents were investigated including DME, DMF, DMF/water,
and (trifluoromethyl)benzene. The reactions employing DMF
and DMF/H2O as the solvent lead to the formation of complex
mixtures of products, with minor amounts of the desired product
being observed. The use of DME, however, predominantly leads
to the recovery of starting material. The use of (trifluorometh-
yl)benzene as a solvent has been shown to be effective in
microwave-assisted Buchwald-Hartwig reactions as it could
be heated rapidly and provided moderate to good yields of the
desired coupled products.31 The reaction of 7 with c was
therefore examined with (trifluoromethyl)benzene as the solvent
at 150 °C under microwave irradiation (see Table 5). The use
of (trifluoromethyl)benzene allowed for rapid heating of the
reaction mixture (typically 1 min) and for the consumption of
all starting material. The reaction afforded the desired product
6c in higher yield than the corresponding reaction in toluene
(95%; cf. 80% in toluene). The yield obtained was also
equivalent to the reaction of 7 with c conducted under thermal
conditions in toluene; however, the reaction time was signifi-
cantly reduced to 15 min. The reaction of 7 with other cyclic
amines was also successful and provided the compounds 6e,f,h
in good to high yield. All of the yields obtained are improve-
ments on the thermal reactions in toluene and were achieved in
20 min or less of microwave irradiation. It should be noted that
these yields have not been optimized.
TABLE 3. Comparison of Buchwald-Hartwig Amination of 7
with CuBr Cocatalysisa
yield of 6 (%), yield of 8 (%), yield of 6 (%), yield of 8 (%),
amine
no CuBr
no CuBr
with CuBr
with CuBr
a
f
h
j
57
50
34
57
39
30
10
22
26
11
72
58
78
9
6
47
0
50
45
k
45
a Reaction conditions: 7 (1 equiv), amine (1.2 equiv), KOtBu (1.2
equiv), Pd(OAc)2 (0.5 mol %), 16 (1 mol %), and CuBr (10 mol %) (if
required) in toluene at 120 °C under pressure. Yields were determined
1
by H NMR analysis of the crude material.
bromide equivalents and display significantly different re-
activities in amination reactions.15,24
A number of authors have reported that coupling reactions
of this type can be improved by the addition of a copper(I) salt
as a cocatalyst.25-27 The specific role of the copper in these
reactions is not known, but it has been suggested that the copper
may facilitate the transmetalation step.25 We have investigated
the effect of copper in the reaction of 7 with selected cyclic
amines through the addition of CuBr (10 mol %) using the
reaction conditions described for the preparation of compounds
6a-m. The addition of Cu(I) improved the amount of 6
substantially when a and h were used as the amine and slightly
in the cases of f and k (Table 3). In the case of j, a substantial
decrease in the production of 6 was observed. In these reactions,
the addition of Cu(I) decreased the amount of 8 substantially
when a and h were used as the amine; however, in the cases of
f, j, and k a substantial increase in the amount of 8 was observed.
The use of Cu(I) in this particular palladium-catalyzed reaction
therefore appeared to be inconsistent across the amines used.
The addition of Cu(I), however, prevented the formation of
corresponding compounds 17 and 18, and little to none of these
compounds were observed in all of the reactions involving CuBr.
The absence of these side products is likely to be the main
contribution to the improvement in the formation of 6 and 8
where they are observed.
A brief investigation of the effects of the base employed in
these reactions involved a comparison of KOtBu with NaOtBu
and Cs2CO3. In toluene, it was found that NaOtBu was effective
for the amination reaction of 7, displaying amounts of both 6a
and 8a similar to those obtained when KOtBu was used as the
base (see Table 4). The weak base Cs2CO3, on the other hand,
was less effective in this reaction and resulted in a substantially
lower yield of 6a being obtained. It is however worth noting
that in this case no 8a was observed.
Due to the success of (trifluoromethyl)benzene as a solvent
for the microwave reactions, the use of this solvent for thermal
Buchwald-Hartwig aminations was considered (see Table 6).
(28) Majetich, G.; Hicks, R. Res. Chem. Intermed. 1994, 20, 61–77.
(29) Maes, B. U. W.; Loones, K. T. J.; Hostyn, S.; Diels, G.; Rombouts, G.
Tetrahedron 2004, 60, 11559–11564.
(24) Bolm, C.; Hildebrand, J. J. Org. Chem. 2000, 65, 169–175.
(25) Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5369–5364.
(26) Gomez-Bengoa, E.; Echavarren, A. M. J. Org. Chem. 1991, 56, 3497–
3501.
(27) Tamayo, N.; Echavarren, A. M.; Paredes, M. C. J. Org. Chem. 1991,
56, 6488–6491.
(30) The reaction mixture reached a maximum of 130 °C after 15 min at
maximum power (120 0W) in a MARS (CEM) microwave system. Differences
in the heating profiles of common solvents and their use in various microwave
systems have been investigated.31
(31) Loones, K. T. J.; Maes, B. U. W.; Rombouts, G.; Hostyn, S.; Diels, G.
Tetrahedron 2005, 61, 10338–10348.
8884 J. Org. Chem. Vol. 73, No. 22, 2008

Functionalization of 6-Bromo-2-chloroquinoline
TABLE 5. Comparison of Buchwald-Hartwig Amination of 7
Using C6H5CF3 with Microwave Irradiation and C6H5CH3 under
Thermal Conditionsa
TABLE 7. Comparison of Methods for Amination of
2-Chloroquinolines
yield of 5 (%)
yield of 6 (%)
6
Ko´ro´di amination
Pd-catalyzed amination
97b,a
amine
C6H5CH3
C6H5CF3
a
b
c
d
e
f
h
i
j
40
56
32
64
40
25
11
26
46
4a
c
e
f
94
44
40
32
95
50
78
50
98b
h
a Reaction conditions: 7 (1 equiv), amine (1.2 equiv), NaOtBu (1.2
equiv), Pd(OAc)2 (0.5 mol %), and 16 (1 mol %). The reaction in
toluene was conducted at 120 °C under pressure. The reaction in
(trifluoromethyl)benzene was conducted at 150 °C with microwave
irradiation for 15-20 min. Yields are not optimized and refer to isolated
yields.
90b
96b
88b
k
l
47
a Purified on C18 preparative TLC plates. b Yields were determined
by H NMR analysis of the crude material.
1
TABLE 6. Effect of Solvent on the Buchwald-Hartwig Amination
of 7 under Thermal Conditionsa
SCHEME 4. Amination of 6 Using LHMDS as an Ammonia
Equivalenta
yield of 6 (%)
amine
C6H5CH3
C6H5CF3
a
c
e
f
h
j
57
98
62
50
34
57
39
93
95
80
88
80
91
90
a Reaction conditions: 6 (1 equiv), LHMDS (2.2 equiv), Pd2(dba)3 (1
mol %), and 8 (1.2 mol %) in dioxane at 100 °C under pressure.
k
a Reaction conditions: 7 (1 equiv), amine (1.2 equiv), NaOtBu (1.2
equiv), Pd(OAc)2 (0.5 mol %), and 16 (1 mol %) in toluene at 120 °C
or (trifluoromethyl)benzene at 100 °C under pressure. Yields were
aryl halides to prepare simple anilines.32-34 It was envisaged
that this methodology could be applied to compounds such as
6 in the preparation of 2-aminoquinolines 5 (see Scheme 4).
The reaction of a number of 2-chloroquinolines using the method
described by Lee et al.33 involving Pd2(dba)3 and DavePhos
(9) in dioxane at 100 °C under pressure verified the usefulness
of LHMDS for this type of amination process (see Table 7). In
all instances 5 was obtained from workup of the reaction with
only trace amounts of impurities observed (less than 2%
impurities by NMR analysis in the cases of 5a,c,j,k and less
than 5% impurities by NMR analysis in the case of 5h). 5 was
afforded in high yield (88-98%) with an average improvement
in yield of 70% compared to those of the corresponding Ko´ro´di
reactions. This method is therefore a significant improvement
on the Ko´ro´di reaction, which gave a complex mixture of
products and low yields of 5. In addition, this method provides
an alternate pathway for the preparation of 2-aminoquinolines
using palladium chemistry.
Binding Studies of 6-Substituted 2-Aminoquinolines
with Murine Tec IV SH3 Domain. The 6-substituted 2-ami-
noquinolines 5a-f,h-k35 prepared were assayed for binding
to the Tec SH3 domain by NMR chemical shift perturbation
analysis utilizing (1H, 15N) heteronuclear single-quantum coher-
ence (HSQC) experiments with uniformly 15N-labeled SH3
protein, in the presence of the 2-aminoquinoline ligand. Changes
in the chemical shifts for protein-ligand mixtures relative to
the free protein indicate binding and allow for Kd values to be
calculated. The use of this method for binding information of
2-aminoquinolines has been reported previously.6
1
determined by H NMR analysis of the crude material.
SCHEME 3. Amination of 6 Using the Ko´ro´di11 Methoda
a Reaction conditions: 6 (1 equiv), NH2COCH3 (20-40 equiv), and
K2CO3 (20 equiv) at 200 °C for 1-3 h.
Gratifyingly, employing (trifluoromethyl)benzene as a solvent
in the amination of 7 with NaOtBu produced substantial
increases in the yields of compounds 6 with a range of cyclic
amines (see Table 6). In all instances, the conversion of starting
material to 6 was 80% or greater (80-95%) and only minor of
amounts 8 were observed. In addition, in most cases none of
compound 17 or 18 was observed. These reaction conditions
were therefore the optimal conditions for selectively aminating
at the 6-bromine in the presence of the activated 2-chlorine and
allowed for the preparation of compounds 6 in high yield.
Introducing the 2-Amino Functionality. Previous studies
have utilized the method of Ko´ro´di11 to convert 2-chloroquino-
lines to 2-aminoquinolines.5,6 Using this method, the 2-chlo-
roquinolines prepared in this study (6a-f,h-l) were converted
to 2-aminoquinolines 5a-f,h-l (see Scheme 3). The yields
obtained, however, varied substantially and in many cases were
poor (see Table 7). A complex mixture of products was generally
formed during these reactions and contributed to the low yields
displayed in most cases. The complex mixture of products that
was obtained from the Ko´ro´di reactions also caused considerable
difficulties in the purification process. Due to these difficulties
and low yields an alternate method for amination was desirable.
The binding affinities of ligands 5 are shown in Table 8. All
of the ligands 5 bound the Tec SH3 domain surface with
(32) Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417–3419.
(33) Lee, S.; Jorgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729–2732.
(34) Harris, M. C.; Huang, X.; Buchwald, S. L. Org. Lett. 2002, 4, 2885–
2888.
(35) 5b was not assayed due to its instability. 5l was not assayed due to its
insolubility in the assay medium.
Recently, a few reports have described the use of LHMDS
as an ammonia equivalent for palladium-catalyzed coupling of
J. Org. Chem. Vol. 73, No. 22, 2008 8885

Smith et al.
TABLE 8. Equilibrium Dissociation Binding Constants (Kd) of 5
with the Tec SH3 Domain As Determined by NMR Chemical Shift
Perturbation Experiments
%), ligand precursor (1 mol %), and base (1.2 equiv) under a
nitrogen atmosphere. Anhydrous toluene was added, followed by
7 (1 equiv) and the amine (1.2 equiv). The tube was evacuated,
backfilled with nitrogen, and sealed, and then the mixture was stirred
for 18-26 h at 120 °C. After cooling, the mixture was diluted with
an organic solvent and washed with water and/or brine. The organic
phase was dried over MgSO4 or Na2SO4, and then the solvent was
removed under reduced pressure. The product was isolated by flash
chromatography on silica gel with appropriate solvent mixtures.
General Procedure 2: Buchwald-Hartwig Amination in
(Trifluoromethyl)benzene and 1,4-Dioxane.23,31 General proce-
dure 1 was employed with either (trifluoromethyl)benzene or 1,4-
dioxane as the solvent except that the reaction was heated at 100
°C for the specified time. The product was isolated by flash
chromatography on silica gel with appropriate solvent mixtures,
a
ligand 5
Kd (µM)
a
c
d
e
f
h
i
12 ( 2
27 ( 3
91 ( 9
22 ( 4
9 ( 1
67 ( 18
28 ( 6
31 ( 5
28 ( 8
j
k
a Quoted values are the mean ( standard deviation over residues
where 1H (H-N) chemical shift changes of the SH3 domain were at
least 0.1 ppm at or near saturation binding of the ligand.
1
or alternatively quantitative determinations were obtained by H
NMR analysis of the crude material.
General Procedure 3: Buchwald-Hartwig Amination in
the Presence of CuBr.27 General procedure 1 was employed with
KOtBu as the base and with the addition of CuBr (10 mol %).
Quantitative determinations of product yields were obtained by 1H
NMR analysis of the crude material.
General Procedure 4: Buchwald-Hartwig Amination with
Microwave Irradiation.31 A high-pressure microwave vessel was
loaded with 7 (1 equiv) and amine (1.2 equiv) in anhydrous toluene
or (trifluoromethyl)benzene. Pd(OAc)2 (0.5 mol %), 16 (1 mol %),
and NaOtBu (1.2 equiv) were added, and then the vessel was
evacuated, backfilled with nitrogen, and sealed. The mixture was
heated at the temperature and power indicated for 15-20 min
(including the ramp time). After cooling, the mixture was filtered
through Celite, and the solvent was removed under reduced
pressure. The product was isolated by flash chromatography on
silica gel with appropriate solvent mixtures.
General Procedure 5: Ko´ro´di Amination of 2-Chloroquino-
lines.11 The 2-chloroquinoline (1 equiv) was treated with acetamide
(20-40 equiv) and potassium carbonate (20 equiv) and heated at
200 °C for 1-3 h. After cooling, water was added and the mixture
extracted with either ethyl acetate or a solution of chloroform/2-
propanol (3:1). The organic layers were washed with brine and dried
over Na2SO4 and the solvent removed under reduced pressure. The
product was isolated by flash chromatography with appropriate
solvent mixtures.
improved affinity relative to the lead compound 1 (Kd ) 125
µM). Introduction of a simple piperidine substituent, 5d,
displayed a small improvement in binding affinity (Kd ) 90
µM). Further extension on the piperidine substituent in ligands
5a, 5e, and 5f led to a greater improvement (6-10-fold, Kd )
9-22 µM) in binding relative to 1. The incorporation of an
oxygen in ligand 5c displayed a similar improvement in binding
affinity (Kd ) 27 µM). Incorporation of piperazine in 5h (Kd )
67 µM) gave an approximately 2-fold improvement in binding,
with extension on the piperazine substituent similarly improving
the binding affinity further (Kd ) 28-31 µM). Ligands 5a and
5f are the highest affinity ligands for the Tec SH3 domain
prepared to date.
The SAR information provided from the assay results suggests
that the appended heterocycle makes an additional hydrophobic
contact with the protein surface, which provides an improvement
in binding affinity of compounds 5 relative to 1. Extension on
the heterocyclic substituent may provide a further contact with
the protein surface, leading to a greater improvement in binding.
The assay results also indicate that the second nitrogen in the
piperazine ring appears to reduce the binding affinity of these
compounds. Extension on the piperazine, however, regains some
of the lost binding affinity presumably by making an additional
contact with the protein surface.
The binding affinities of compounds 5 were compared to those
of 2-4 (Kd ) 40, 52, and 22 µM, respectively). Of the ligands
assayed 5d and 5h displayed a reduced affinity for the Tec SH3
domain relative to ligands 2-4. 5c, 5e, and 5i-k showed affinity
simlar to that of the acetal-substituted ligands, while 5a and 5f
had improved affinities. The overall similarity of the binding
affinities of ligands 5 with 2-4 is consistent with our prediction
that the acetal functionality could be replaced with an alternate
heterocycle. The replacement of the acetal with the above-
mentioned heterocycles affords compounds with increased
chemical stability and provides improvements in binding affinity
relative to 1.
General Procedure 6: Buchwald-Hartwig Amination of
2-Chloroquinolines Using LHMDS.33 A pressure tube was loaded
with Pd2(dba)3 (1 mol %), 9 (1.2 mol %), and the 2-chloroquinoline
derivative (1.0 equiv). Dry 1,4-dioxane was added followed by
lithium bis(trimethylsilyl)amide solution (1.0 M in THF, 2.2 equiv).
The pressure tube was evacuated, backfilled with nitrogen, and
sealed and the mixture stirred for 18-24 h at 100 °C. After being
cooled to room temperature, the mixture was quenched with 1 M
HCl and stirred for 10 min. The solution was then basified by the
addition of NaOH. The aqueous phase was extracted with a solution
of chloroform/2-propanol (3:1), washed with water, and dried over
Na2SO4 and the solvent removed under reduced pressure. Quantita-
1
tive determinations of product yields were obtained by H NMR
analysis.
General Procedure 7: Preparation of Maleate Salts. The
2-aminoquinoline (1.0 equiv) was dissolved in acetone, and a
solution of maleic acid (1.0 equiv) in acetone was added dropwise
at room temperature. The reaction mixture was then stirred at 0 °C
for 1 h. The resulting precipitate was filtered and recrystallized from
ethanol/water to afford the corresponding maleate salt.
2-Chloro-6-(4-methylpiperidin-1-yl)quinoline (6a). Synthesis
Method i. Using general procedure 1, 7 (520 mg, 2.13 mmol) and
a (300 µL, 2.56 mmol) were added to a mixture of Pd(OAc)2 (2.4
mg, 10.6 µmol), 16 (7.6 mg, 21.3 µmol), and KOtBu (287 mg,
2.56 mmol) in toluene (3 mL). The reaction mixture was heated
for 21 h. Extraction with ethyl acetate and chromatographic
separation eluting with CH2Cl2/ethyl acetate (50:1) afforded the
Experimental Section
General Considerations. Compounds 76 and 226,36 were
‡
synthesized as previously described. Indicates an unresolved J
coupling.
General Procedure 1: Buchwald-Hartwig Amination in
Toluene.23 A pressure tube was loaded with Pd(OAc)2 (0.5 mol
(36) Alabaster, C. T.; Bell, A. S.; Campbell, S. F. P. E.; Henderson, C. G.;
Roberts, D. A.; Ruddock, K. S.; Samuels, G. M.; Stefaniak, M. H. J. Med. Chem.
1988, 31, 2048–2056.
8886 J. Org. Chem. Vol. 73, No. 22, 2008

Functionalization of 6-Bromo-2-chloroquinoline
title compound as a 5:1 mixture with 2-tert-butoxy-6-(4-methylpi-
peridin-1-yl)quinoline (17a) (combined yield 297 mg; 6a, 44%; 17a,
9%). 6-Bromo-2-(4-methylpiperidin-1-yl)quinoline (8a) (yellow
crystals, mp 76-80 °C, 140 mg, 25%) and 2-(4-methylpiperidin-
1-yl)quinoline (19) (yellow oil, 71 mg, 15%) were also isolated.
(2H, s, H7, H8), 7.81 (1H, d, J ) 2.7 Hz, H5), 7.83 (1H, d, J )
9.0 Hz, H4); 13C NMR (150 MHz, CDCl3) δ 28.7 (C(CH3)3), 80.7
(C(CH3)3), 116.2 (C3), 116.9 (C6), 125.9 (C4a), 129.4 (C5), 129.5
(C8), 132.4 (C7), 137.1 (C4), 145.3 (C8a), 162.3 (C2); IR (CH2Cl2
solution) ν/cm-1 3384, 1667, 1613, 1602, and 1561; MS (EI) m/z
225 ([81Br], 100), 223 ([79Br], 100), 197 ([81Br], 40), 195 ([79Br],
40), 116 (75), 97 (20), 89 (45), 57 (30), 44 (35); HRMS (EI+) m/z
found 280.0332, C13H1479BrNO + H requires 280.0332.
Method v: Synthesis of 6a Employing Aryl Halide 22. Using
general procedure 1, 22 (100 mg, 0.35 mmol) and a (35 µL, 0.41
mmol) were added to a mixture of Pd(OAc)2 (0.4 mg, 1.8 µmol),
16 (1.2 mg, 3.5 µmol), and NaOtBu (40 mg, 0.41 mmol) in toluene
(3 mL). The reaction mixture was heated for 21 h. Extraction with
ethyl acetate and chromatographic separation eluting with CH2Cl2/
ethyl acetate (50:1) afforded the title compound 6a as a yellow
solid (35 mg 38%). Data are as above. 6-Iodo-2-(4-methylpiperidin-
1-yl)quinoline (23) was also isolated (yellow glass, 16 mg, 13%):
1H NMR (300 MHz, CDCl3) δ 1.00 (3H, d, J ) 6.3 Hz, CH3),
1.28 (2H, dq, J2′/6′eq,3′5′ax ) 3.0 Hz, J2′/6′ax,3′5′ax ) J3′/5′ax,3′5′eq ) J3′5′ax,4′
) 12.3 Hz, 2 CH, H(3′/5′ax)), 1.69 (1H, br m, CH, H(4′)), 1.80
(2H, br d‡, J3′/5′ax,3′5′eq ) J2′/6′eq, 3′5′eq ) 12.3 Hz, 2 CH, H(3′/5′eq)),
3.00 (2H, br t‡, J ) 12.6 Hz, 2 CH, H(2′/6′ax)), 4.54, (2H, br d‡,
J2′/6′ax,2′6′eq ) J2′/6′eq,3′5′eq )12.3 Hz, 2 CH, H(2′/6′eq)), 6.98 (1H, br
d, J ) 6.3 Hz, H3), 7.59 (1H, br d, J ) 7.2 Hz, H8), 7.71-7.76
(2H, m, H4, H7), 7.92 (1H, d, J ) 1.5 Hz, H5); IR (Nujol mull)
ν/cm-1 1646, 1615, 1598, 1560, and 1500; MS (EI) 352 (M•+, 100),
254 (30); HRMS (EI+) m/z found 352.0435, C15H17IN2 requires
352.0436.
1
Data for 6a: H NMR (600 MHz, CDCl3) δ 0.99 (3H, d, J ) 6.6
Hz, CH3), 1.37 (2H, dq, J2′/6′eq,3′5′ax ) 2.4 Hz, J2′/6′ax,3′5′ax ) J3′/
5′ax,3′5′eq ) J3′5′ax,4′ ) 12.6 Hz, 2 CH, H(3′/5′ax)), 1.56 (1H, br m,
CH, H(4′)), 1.77 (2H, br d‡, J3′/5′ax,3′5′eq ) J2′/6′eq,3′5′eq ) 12.6 Hz, 2
CH, H(3′/5′eq)), 2.79 (2H, dt, J2′/6′ax,3′5′eq ) 2.4, J2′/6′ax,2′6′eq ) J2′/
6′ax,3′5′ax ) 12.6 Hz, 2 CH, H(2′/6′ax)), 3.77 (2H, br d‡, J2′/6′ax,2′6′eq
)
J2′/6′eq,3′5′eq )12.6 Hz, 2 CH, H(2′/6′eq)), 6.97 (1H, d, J ) 2.4 Hz,
H5), 7.24 (1H, d, J ) 9.0 Hz, H3), 7.47 (1H, dd, J ) 2.4, 9.0 Hz,
H7), 7.84 (1H, d, J ) 9.0 Hz, H8), 7.87 (1H, d, J ) 9.0 Hz, H4);
13C NMR (150 MHz, CDCl3) δ 27.7 (CH3), 30.6 (C4′), 33.8 (C3′/
5′), 49.6 (C2′/6′), 108.6 (C5), 122.2 (C3), 123.5 (C7), 128.1(C4a),
128.9 (C8), 137.3 (C4), 142.8 (C8a), 147.0 (C2), 150.0 (C6); IR
(Nujol mull) ν/cm-1 1654, 1616, 1600, and 1578. MS (EI) m/z
262 (M + H•+ [37Cl], 30), 261 (M•+ [37Cl], 40), 260 (M + H•+
[35Cl], 100), 259 (M•+ [35Cl], 100), 164 (6), 162 (18); HRMS (EI+)
m/z found 259.1000, C15H1735ClN2 - H requires 259.1002. Data
1
for 8a: H NMR (600 MHz, CDCl3) δ 0.98 (3H, d, J ) 6.6 Hz,
CH3), 1.27 (2H, m, 2 CH, H(3′/5′ax)), 1.69 (1H, br m, CH, H(4′)),
1.78 (2H, br d‡, J3′/5′ax,3′5′eq ) J2′/6′eq,3′5′eq ) 12.6 Hz, 2 CH, H(3′/
5′eq)), 2.98 (2H, br s‡, 2 CH, H(2′/6′ax)), 4.53, (2H, br s‡, 2 CH,
H(2′/6′eq)), 6.73 (1H, d, J ) 9.0 Hz, H3), 7.26 (1H, d, J ) 1.2 Hz,
H5), 7.39 (1H, br d‡, J ) 9.0 Hz, H7), 7.68 (1H, d, J ) 9.0 Hz,
H8), 7.78 (1H, d, J ) 9.0 Hz, H4); IR (Nujol mull) ν/cm-1 1642,
1615, 1598, 1546, and 1493; MS (EI) m/z 306 (M•+ [81Br], 50),
304 (M•+ [79Br], 50), 277 (30), 263 (35), 261 (35), 249 (100), 237
(50), 235 (50), 224 (40), 222 (40), 208 (50), 127(50); HRMS (EI+)
m/z found 304.0575, C15H1779BrN2 requires 304.0575. Data for 17a:
1H NMR (600 MHz, CDCl3) δ 0.99 (3H, d, J ) 6.6 Hz, CH3),
1.37 (2H, dq, J2′/6′eq,3′5′ax ) 2.4 Hz, J2′/6′ax,3′5′ax ) J3′/5′ax,3′5′eq ) J3′5′ax,4′
) 12.6 Hz, 2 CH, H(3′/5′ax)), 1.56 (1H, br m, CH, H(4′)), 1.66
(9H, s, tBu), 1.77 (2H, br d‡, J3′/5′ax,3′5′eq ) J2′/6′eq,3′5′eq ) 12.6 Hz, 2
CH, H(3′/5′eq)), 2.73 (2H, m, 2 CH, H(2′/6′ax)), 3.67, (2H, br d‡,
J2′/6′ax,2′6′eq ) J2′/6′eq,3′5′eq )12.6 Hz, 2 CH, H(2′/6′eq)), 6.73 (1H, d,
J ) 9.0 Hz, H3), 7.26(1H, d, J ) 1.2 Hz, H5), 7.39 (1H, br d‡, J
) 9.0 Hz, H7), 7.68 (1H, d, J ) 9.0 Hz, H8), 7.78 (1H, d, J ) 9.0
2-Chloro-6-(pyrrolidin-1-yl)quinoline (6b). Using general pro-
cedure 1, 7 (140 mg, 0.58 mmol) and pyrrolidine (b; 58 µL, 0.69
mmol) were added to a mixture of Pd(OAc)2 (0.65 mg, 2.9 µmol),
16 (2.1 mg, 5.8 µmol), and KOtBu (79 mg, 0.70 mmol) in toluene
(2 mL). The mixture was heated for 20 h. Extraction with diethyl
ether and chromatographic separation eluting with CH2Cl2/hexane
(4:1) afforded the title compound as a brown solid which
1
decomposed above 250 °C (70 mg, 52%): H NMR (200 MHz,
CDCl3) δ 2.07 (4H, tt, J ) 3.3, 6.6 Hz, 2 CH2, H(3′/4′)), 3.39 (4H,
t, J ) 6.6 Hz, 2 CH2, H(2′/5′)), 6.60 (1H, d, J ) 2.7 Hz, H5), 7.17
(1H, dd, J ) 2.7, 9.0 Hz, H7), 7.22 (1H, d, J ) 8.7 Hz, H3), 7.83
(1H, d, J ) 9.0 Hz, H8), 7.86 (1H, d, J ) 8.7 Hz, H4); 13C NMR
(150 MHz, CDCl3) δ 25.8 (C3′/4′), 48.3 (C2′/5′), 104.0 (C5), 119.8
(C3), 122.5 (C7), 128.7 (C4a), 129.3 (C8), 136.9 (C4), 143.2 (C8a),
149.2 (C2), 152.5 (C6); IR (Nujol mull) ν/cm-1 3270, 1658, 1616,
1563, and 1517; MS (EI) m/z 234 (M•+ [37Cl], 25), 233 (M - H•+
[37Cl], 25), 232 (M•+ [35Cl], 80), 231 (M - H•+ [35Cl], 100), 176
(35); HRMS (EI+) m/z found 232.0761, C13H1335ClN2 requires
232.0767. Anal. Calcd for C13H13ClN2: C, 67.10; H, 5.63; N, 12.04.
Found: C, 67.05; H, 5.63; N, 12.10.
2-Chloro-6-morpholinoquinoline (6c). Synthesis Method i.
Using general procedure 1, 7 (102 mg, 0.42 mmol) and morpholine
(c; 44 µL, 0.51 mmol) were added to a mixture of Pd(OAc)2 (0.5
mg, 2.2 µmol), 16 (1.5 mg, 4.2 µmol), and KOtBu (57 mg, 0.51
mmol) in toluene (1 mL). The mixture was heated for 20 h.
Extraction with ethyl acetate and chromatographic separation eluting
with CH2Cl2 afforded the title compound as a yellow solid, mp
88-91 °C (98 mg, 94%): 1H NMR (600 MHz, CDCl3) δ 3.26 (4H,
br t, J ) 4.8 Hz, 2 CH2, H(2′/6′)), 3.90 (4H, br t, J ) 4.8 Hz, 2
CH2, H(3′/5′)), 6.98 (1H, d, J ) 2.7 Hz, H5), 7.27 (1H, d, J ) 8.7
Hz, H3), 7.45 (1H, d, J ) 2.7, 9.6 Hz, H7), 7.88 (1H, d, J ) 9.6
Hz, H8), 7.91 (1H, d, J ) 8.7 Hz, H4); 13C NMR (150 MHz,
CDCl3) δ 49.1 (C2′/6′), 66.7 (C3′/5′), 110.4 (C5), 122.4 (C7), 122.5
(C3), 127.9 (C4a), 128.2 (C8), 137.1 (C4), 143.2 (C8a), 147.6 (C2),
149.5 (C6); IR (Nujol mull) ν/cm-1 1652, 1621, 1563, and 1503;
MS (EI) m/z 250 (M•+ [37Cl], 15), 248 (M•+ [35Cl], 50), 192 (30),
190 (100), 162 (20), 127 (20), 40 (30); HRMS (EI+) m/z found
248.0707, C13H1335ClN2O requires 248.0716. Anal. Calcd for
C13H13ClN2O: C, 62.78; H, 5.27; N, 11.26. Found: C, 62.80; H,
5.23; N, 11.26.
1
Hz, H4); MS (EI) m/z 242 (M•+ - C4H8, 100). Data for 19: H
NMR (600 MHz, CDCl3) δ 1.00 (3H, d, J ) 6.6 Hz, CH3), 1.27
(2H, dq, J2′/6′eq,3′5′ax ) 2.4 Hz, J2′/6′ax,3′5′ax ) J3′/5′ax,3′5′eq ) J3′5′ax,4′
)
12.6 Hz, 2 CH, H(3′/5′ax)), 1.68 (1H, br m, CH, H(4′)), 1.77 (2H,
br d‡, J3′/5′ax,3′5′eq ) J2′/6′eq,3′5′eq ) 12.6 Hz, 2 CH, H(3′/5′eq)), 2.95
(2H, dt, J2′/6′ax,3′5′eq ) 2.4, J2′/6′ax,2′6′eq ) J2′/6′ax,3′5′ax ) 12.6 Hz, 2
CH, H(2′/6′ax)), 4.53, (2H, br d‡, J2′/6′ax,2′6′eq ) J2′/6′eq,3′5′eq )12.6
Hz, 2 CH, H(2′/6′eq)), 7.00 (1H, d, J ) 9.0 Hz, H3), 7.20 (1H, dt,
J ) 0.9, 7.8 Hz, H6), 7.39 (1H, dt, J ) 1.5, 7.8 Hz, H7), 7.58 (1H,
br d‡, J ) 7.8 Hz, H8), 7.70 (1H, br d‡, J ) 7.8 Hz, H5), 7.86 (1H,
d, J ) 9.0 Hz, H4); IR (Nujol mull) ν/cm-1 3051, 1675, 1619,
1603, 1556, and 1505. MS (EI) m/z 226 (M•+, 100).
Synthesis Method ii. Using general procedure 2, the title
1
compound was obtained in 93% yield as determined by H NMR
analysis. Data are as above.
Synthesis Method iii. Using general procedure 3, the title
1
compound was obtained in 72% yield as determined by H NMR
analysis. Data are as above.
Method iv: Attempted Synthesis of 6a Using PEPPSI
Catalyst.18,19 7 (50 mg, 0.21 mmol) was dissolved in dry DME
and added to a reaction vessel loaded with KOtBu (35 mg, 0.32
mmol) and 15 (3 mg, 4.4 µmol) in DME under argon. a (27 µL,
0.23 mmol) was added dropwise, and then the solution was stirred
at 50 °C for 1.5 h. After being cooled to room temperature, the
mixture was extracted with a mixture of chloroform/2-propanol (3:
1) and then washed with water and brine. The organic phase was
dried over Na2SO4 and the solvent removed under reduced pressure
1
to afford 18 as a pink glass (50 mg, 87%): H NMR (300 MHz,
t
CDCl3) δ 1.69 (9H, s, Bu), 6.76 (1H, d, J ) 9.0 Hz, H3), 7.65
J. Org. Chem. Vol. 73, No. 22, 2008 8887

Smith et al.
Synthesis Method ii. Using general procedure 2, the title
compound was obtained in 95% yield as determined by H NMR
Synthesis Method ii. Using general procedure 2, the title
compound was obtained in 80% yield as determined by H NMR
1
1
analysis. Data are as above.
analysis. Data are as above.
Synthesis Method iii. Using general procedure 4, 7 (45 mg, 0.19
mmol) and e (37 mg, 0.23 mmol) were combined in (trifluorom-
ethyl)benzene (2 mL). Pd(OAc)2 (0.2 mg, 1.0 µmol), 16 (0.8 mg,
2.1 µmol), and NaOtBu (22 mg, 0.23 mmol) were added, and then
the vessel was evacuated, backfilled with nitrogen, and sealed. The
mixture was heated at 150 °C at 300 W in a Discover system for
17 min (including a 1 min ramp time). Chromatographic separation
eluting with CH2Cl2/ethanol (48:1) afforded the title compound as
a cream solid (30 mg, 50%). Data are as above.
Synthesis Method iii. Using general procedure 4, 7 (200 mg,
0.82 mmol) and c (86 µL, 0.98 mmol) were combined in toluene
(10 mL). Pd(OAc)2 (1.0 mg, 4.1 µmol), 16 (3.0 mg, 8.2 µmol),
and NaOtBu (94 mg, 0.98 mmol) were added, and then the vessel
was evacuated, backfilled with nitrogen, and sealed. The mixture
was heated at 130 °C at 1200 W in a MARS microwave system
for 15 min (including a 5 min ramp time). Chromatographic
separation eluting with CH2Cl2 afforded the title compound as a
yellow solid (195 mg, 80%). Data are as above.
2-Chloro-6-(4-benzylpiperidin-1-yl)quinoline (6f). Synthesis
Method i. Using general procedure 1, 7 (600 mg, 2.47 mmol) and
4-benzylpiperidine (f; 530 µL, 2.98 mmol) were added to a mixture
of Pd(OAc)2 (2.8 mg, 12.4 µmol), 16 (8.9 mg, 24.7 µmol), and
KOtBu (335 mg, 2.99 mmol) in toluene (5 mL), and the reaction
was heated for 16 h. Extraction with chloroform/2-propanol (3:1)
and chromatographic separation eluting with CH2Cl2/hexane (4:1)
afforded the title compound as a 6:1 mixture with 2-tert-butoxy-
6-(4-benzylpiperidin-1-yl)quinoline (17f) (yellow solid; combined
yield 390 mg; 6f, 40%; 17f, 7%). An analytical sample of 6f was
Synthesis Method iv. Using general procedure 4, 7 (45 mg, 0.19
mmol) and c (20 µL, 0.23 mmol) were combined in (trifluorom-
ethyl)benzene (2 mL). Pd(OAc)2 (0.2 mg, 1.0 µmol), 16 (0.8 mg,
2.1 µmol), and NaOtBu (22 mg, 0.23 mmol) were added, and then
the vessel was evacuated, backfilled with nitrogen, and sealed. The
mixture was heated at 150 °C at 300 W in a Discover system for
15 min (including a 1 min ramp time). Workup afford the title
compound as a yellow solid (45 mg, 95%). Data are as above.
2-Chloro-6-(piperidin-1-yl)quinoline (6d). Using general proce-
dure 1, 7 (600 mg, 2.47 mmol) and piperidine (d; 300 µL, 3.03
mmol) were added to a mixture of Pd(OAc)2 (2.8 mg, 12.5 µmol),
16 (9.1 mg, 25.4 µmol), and KOtBu (341 mg, 3.04 mmol) in toluene
(2 mL). The reaction mixture was heated for 24 h. Extraction with
ethyl acetate and chromatographic separation eluting with CH2Cl2/
hexane (3:2) afforded the title compound as an orange solid, mp
127-130 °C (330 mg, 54%): 1H NMR (300 MHz, CDCl3) δ 1.60
(2H, m, CH2, H4′), 1.74 (4H, br qn, J ) 5.4 Hz, 2 CH2, H(3′/5′)),
3.27 (4H, t, J ) 5.4 Hz, 2 CH2, H(2′/6′)), 6.99 (1H, br s, H5), 7.24
(1H, d, J ) 8.4 Hz, H3), 7.48 (1H, dd, J ) 2.7, 9.3 Hz, H7), 7.84
(1H, d, J ) 9.3 Hz, H8), 7.88 (1H, d, J ) 8.4 Hz, H4); 13C NMR
(75 MHz, CDCl3) δ 24.4 (C4′), 25.8 (C3′/5′), 50.5 (C2′/6′), 109.0
(C5), 122.4 (C3), 123.7 (C7), 128.3 (C4a), 129.1 (C8), 137.5 (C4),
143.1 (C8a), 147.3 (C2), 150.4 (C6); IR (Nujol mull) ν/cm-1 3280,
1685, 1620, 1583, and 1500; MS (EI) m/z 248 (M•+ [37Cl], 25),
247 (M - H•+ [37Cl], 100), 246 (M•+ [35Cl], 80), 245 (M - H•+
[35Cl], 100), 190 (25); HRMS (EI+) m/z found 246.0915,
C14H1535ClN2 requires 246.0924. Anal. Calcd for C14H15ClN2: C,
68.15; H, 6.13; N, 11.35. Found: C, 68.13; H, 6.07; N, 11.52.
2-Chloro-6-(4-phenylpiperidin-1-yl)quinoline (6e). Synthesis
Method i. Using general procedure 1, 7 (600 mg, 2.47 mmol) and
4-phenylpiperidine (e; 480 mg, 2.98 mmol) were added to a mixture
of Pd(OAc)2 (2.8 mg, 12.4 µmol), 16 (8.9 mg, 24.7 µmol), and
KOtBu (332 mg, 2.96 mmol) in toluene (5 mL). The reaction
mixture was heated for 20 h. Extraction with chloroform/2-propanol
(3:1) and chromatographic separation eluting with CH2Cl2/hexane
(4:1) afforded the title compound as a cream powder, mp 165-167
°C (346 mg, 44%). 6-Bromo-2-(4-phenylpiperidin-1-yl)quinoline
(8e) was also observed in the crude material but was not isolated.
Data for 6e: 1H NMR (600 MHz, CDCl3) δ 1.94 (2H, dq, J2′/6′eq,3′5′ax
) 3.6, J2′/6′ax,3′5′ax ) J3′/5′ax,3′5′eq ) 12.0 Hz, 2 CH, H(3′/5′ax)), 2.03
(2H, br d‡, J2′/6′eq,3′5′eq ) J3′/5′ax,3′5′eq ) 12.0 Hz, 2 CH, H(3′/5′eq)),
2.73 (1H, m, CH, H(4′)), 2.95 (2H, dt, J2′/6′ax,3′5′eq ) 2.4, J2′/6′ax,2′6′eq
) J2′/6′ax,3′5′ax ) 12.0 Hz, 2 CH, H(2′/6′ax)), 3.96, (2H, br d‡, J2′/6′eq,
3′5′eq ) J2′/6′eq,2′6′ax ) 12.0 Hz, 2 CH, H(2′/6′eq)), 7.06 (1H, d, J )
2.4 Hz, H5), 7.23 (1H, tt, J ) 1.8, 7.2 Hz, H4′′), 7.26-7.29 (3H,
m, H3, H(3′′/5′′), 7.34 (2H, tt, J ) 1.8, 7.2 Hz, H(2′′/6′′), 7.55
(1H, dd, J ) 3.0, 9.6 Hz, H7), 7.89 (1H, d, J ) 9.6 Hz, H8), 7.93
(1H, d, J ) 8.4 Hz, H4); 13C NMR (150 MHz, CDCl3) δ 33.1
(C3/5′), 42.4 (C4′), 50.2 (C2′/6′), 109.0 (C5), 122.4 (C3), 123.7
(C7), 126.4 (C4′′), 126.8 (C3′′/5′′), 128.2 (C4a), 128.6 (C2′′/6′′),
129.1 (C8), 137.4 (C4), 143.0 (C8a), 145.7 (C1′′), 147.4 (C2), 150.0
(C6); IR (Nujol mull) ν/cm-1 1618, 1574, and 1500; MS (EI) m/z
324 (M•+ [37Cl], 35), 322 (M•+ [35Cl], 100), 266 (20), 217 (50),
189 (40). Anal. Calcd for C20H19ClN2: C, 74.41; H, 5.93; N, 8.68.
Found: C, 74.57; H, 5.94; N, 8.62.
1
obtained by recrystallization from hexane, mp 114-117 °C: H
NMR (600 MHz, CDCl3) δ 1.44 (2H, dq, J2′/6′eq,3′5′ax ) 4.2, J2′/
6′ax,3′5′ax ) J3′/5′ax,3′5′eq ) 12.6 Hz, 2 CH, H(3′/5′ax)), 1.74 (1H, m,
CH, H(4′)), 1.80 (2H, br d‡, J2′/6′eq,3′5′eq ) J3′/5′ax,3′5′eq ) 12.6 Hz, 2
CH, H(3′/5′eq)), 2.60 (2H, d, J ) 7.2 Hz, CH2), 2.77 (2H, dt, J2′/
6′ax,3′5′eq ) 4.2, J2′/6′ax,2′6′eq ) J2′/6′ax,3′5′ax ) 12.6 Hz, 2 CH, H(2′/
6′ax)), 3.80, (2H, br d‡, J2′/6′eq,3′5′eq ) J2′/6′eq,2′6′ax ) 12.0 Hz, 2 CH,
H(2′/6′eq)), 6.98 (1H, d, J ) 3.0 Hz, H5), 7.18 (2H, d, J ) 7.8 Hz,
H(2′′/6′′)), 7.22 (1H, t, J ) 7.2 Hz, H4′′), 7.26 (1H, d, J ) 8.4 Hz,
H3), 7.31 (2H, t, J ) 7.8 Hz, H(3′′/5′′)), 7.48 (1H, dd, J ) 3.0, 9.6
Hz, H7), 7.85 (1H, d, J ) 9.6 Hz, H8), 7.90 (1H, d, J ) 8.4 Hz,
H4); 13C NMR (150 MHz, CDCl3) δ 28.7 (C4′), 31.8 (C3′/5′), 43.1
(CH2) 49.7 (C2′/6′), 108.8 (C5), 122.3 (C3), 123.6 (C7), 126.0
(C4′′), 128.2 (C4a), 128.3 (C3′′/5′′), 129.0 (C8), 129.1 (C2′′/6′′),
137.4 (C4), 140.3 (C1′′), 142.9 (C8a), 147.2 (C2), 150.4 (C6); IR
(Nujol mull) ν/cm-1 3330, 1653, 1558, and 1505; MS (EI) m/z
338 (M•+ [37Cl], 30), 336 (M•+ [35Cl], 100), 302 (20), 162 (16);
HRMS (EI+) m/z found 336.1388, C21H2135ClN2 requires 336.1393.
Anal. Calcd for C21H21ClN2: C, 74.88; H, 6.28; N, 8.32. Found: C,
75.05; H, 6.59; N, 8.08. Data for 17f: 1H NMR (600 MHz, CDCl3)
δ 1.47 (2H, dq, J2′/6′eq,3′5′ax ) 4.2, J2′/6′ax,3′5′ax ) J3′/5′ax,3′5′eq ) 12.6
Hz, 2 CH, H(3′/5′ax)), 1.72 (1H, m, CH, H(4′)), 1.80 (2H, br d‡,
J2′/6′eq,3′5′eq ) J3′/5′ax,3′5′eq ) 12.6 Hz, 2 CH, H(3′/5′eq)), 2.60 (2H, d,
J ) 7.2 Hz, CH2), 2.68 (2H, dt, J2′/6′ax,3′5′eq ) 4.2, J2′/6′ax,2′6′eq
)
J2′/6′ax,3′5′ax ) 12.6 Hz, 2 CH, H(2′/6′ax)), 3.69, (2H, br d‡, J2′/6′eq,3′5′eq
) J2′/6′eq,2′6′ax ) 12.6 Hz, 2 CH, H(2′/6′eq)), 6.72 (1H, d, J ) 8.4
Hz, H3), 6.99 (1H, d, J ) 3.0 Hz, H5), 7.18 (2H, d, J ) 7.8 Hz,
H(2′′/6′′)), 7.22 (1H, t, J ) 7.2 Hz, H4′′), 7.31 (2H, t, J ) 7.8 Hz,
H(3′′/5′′)), 7.36 (1H, dd, J ) 3.0, 9.6 Hz, H7), 7.67 (1H, d, J )
9.6 Hz, H8), 7.77 (1H, d, J ) 8.4 Hz, H4); 13C NMR (150 MHz,
CDCl3) δ 28.7 (C4′), 30.9 (CH3), 32.1 (C3′/5′), 43.1 (CH2), 50.9
(C2′/6′), 80.0 ((CH3)3C), 110.9 (C5), 115.0 (C3), 123.6 (C7), 125.0
(C4a), 125.9 (C4′′), 128.0 (C8), 128.1 (C3′′/5′′), 129.1 (C2′′/6′′),
137.1 (C4), 140.5 (C1′′), 141.5 (C8a), 147.5 (C6), 161.2 (C2); MS
(EI) m/z 374 (M•+, 7), 318 (100), 144 (30).
Synthesis Method ii. Using general procedure 2, the title
1
compound was obtained in 88% yield as determined by H NMR
analysis. Data are as above.
Synthesis Method iii. Using general procedure 3, the title
1
compound was obtained in 58% yield as determined by H NMR
analysis. Data are as above.
Synthesis Method iv. Using general procedure 4, 7 (45 mg, 0.19
mmol) and f (41 µL, 0.23 mmol) were combined in (trifluorom-
ethyl)benzene (2 mL). Pd(OAc)2 (0.2 mg, 1.0 µmol), 16 (0.8 mg,
2.1 µmol), and NaOtBu (22 mg, 0.23 mmol) were added, and then
the vessel was evacuated, backfilled with nitrogen, and sealed. The
mixture was heated at 150 °C at 300 W in a Discover system for
8888 J. Org. Chem. Vol. 73, No. 22, 2008

Functionalization of 6-Bromo-2-chloroquinoline
20 min (including a 1 min ramp time). Chromatographic separation
eluting with CH2Cl2 afforded the title compound as a yellow solid
(50 mg, 78%). Data are as above.
Synthesis Method ii. Using general procedure 2, the title
compound was obtained in 80% yield as determined by H NMR
analysis. Data are as above.
1
Synthesis Method iii. Using general procedure 3, the title
Methyl 1-(2-Chloroquinolin-6-yl)piperidine-4-carboxylate (6g).
Using general procedure 1, 7 (509 mg, 2.10 mmol) and methyl
isonipecotate (g; 361 mg, 2.52 mmol) were added to a mixture of
Pd(OAc)2 (2.3 mg, 10.5 µmol), 16 (7.5 mg, 21.0 µmol), and KOtBu
(283 mg, 2.52 mmol) in toluene (2 mL). The reaction mixture was
heated for 22 h. Extraction with chloroform/2-propanol (3:1) and
chromatographic separation on C18 silica eluting with water/
methanol (1:1) afforded 6-bromo-2-methoxyquinoline (20), mp
96-98 °C (lit.37 mp 98 °C) (200 mg, 40%). The title compound
was isolated as an impure mixture with methyl 1-(2-methoxyquino-
lin-6-yl)piperidine-4-carboxylate (21) (combined yield 20 mg; 6g,
1
compound was obtained in 78% yield as determined by H NMR
analysis. Data are as above.
Synthesis Method iv. Using general procedure 4, 7 (45 mg, 0.19
mmol) and h (26 µL, 0.23 mmol) were combined in (trifluorom-
ethyl)benzene (2 mL). Pd(OAc)2 (0.2 mg, 1.0 µmol), 16 (0.8 mg,
2.1 µmol), and NaOtBu (22 mg, 0.23 mmol) were added, and then
the vessel was evacuated, backfilled with nitrogen, and sealed. The
mixture was heated at 150 °C at 300 W in a Discover system for
20 min (including a 1 min ramp time). Chromatographic separation
eluting with CH2Cl2/ethanol (49:1) afforded the title compound as
a yellow solid (26 mg, 50%). Data are as above.
1
1%; 21, 2%). Data for 6g: H NMR (600 MHz, CDCl3) δ 1.94
2-Chloro-6-(4-ethylpiperazin-1-yl)quinoline (6i). Using general
procedure 1, 7 (502 mg, 2.06 mmol) and 1-ethylpiperazine (i; 314
µL, 2.47 mmol) were added to a mixture of Pd(OAc)2 (2.3 mg,
10.3 µmol), 16 (7.4 mg, 20.6 µmol), and KOtBu (279 mg, 2.47
mmol) in toluene (2 mL). The reaction mixture was heated for 20 h.
Extraction with ethyl acetate and chromatographic separation eluting
with CH2Cl2/hexane (4:1) afforded the title compound as a 2.5:1
mixture with 6-bromo-2-(4-ethylpiperazin-1-yl)quinoline (8i) (com-
bined yield 480 mg; 6i, 58%; 8i, 30%). Pure 8i was also isolated,
mp 140-144 °C (40 mg, 7%), along with 2-tert-butoxy-6-(4-
ethylpiperazin-1-yl)quinoline (17i), mp 107-109 °C (63 mg, 10%).
(2H, m, 2 CH, H(3′/5′ax)), 2.07 (2H, m, 2 CH, H(3′/5′eq)), 2.53
(2H, m, CH, H(4′)), 2.93 (2H, dt, J2′/6′ax,3′5′eq ) 3.0, J2′/6′ax,2′6′eq
)
J2′/6′ax,3′5′ax ) 12.6 Hz, 2 CH, H(2′/6′ax)), 3.77, (2H, m, 2 CH, H(2′/
6′eq)), 4.03 (3H, s, OCH3), 7.01 (1H, d, J ) 3.0 Hz, H5), 7.27 (1H,
d, J ) 9.0 Hz, H3), 7.49 (1H, dd, J ) 3.0, 9.6 Hz, H7), 7.87 (1H,
d, J ) 9.0 Hz, H8), 7.91 (1H, d, J ) 8.4 Hz, H4); 13C NMR (150
MHz, CDCl3) δ 27.9 (C3′/5′), 40.8 (C4′), 48.9 (C2′/6′), 109.2 (C5),
122.4 (C3), 123.7 (C7), 128.1 (C4a), 129.2 (C8), 137.4 (C4), 143.1
(C8a), 147.5 (C2), 149.7 (C6); IR (Nujol mull) ν/cm-1 3310, 1694,
1602, and 1503; MS (EI) m/z 306 (M•+ [37Cl], 100), 304 (M•+ [35Cl],
30), 269 (25); HRMS (EI+) m/z found 304.0974, C16H1735ClN2O2
1
Data for 6i: H NMR (600 MHz, CDCl3) δ 1.16 (3H, t, J ) 7.2
1
requires 304.0978. Data for 20: H NMR (600 MHz, CDCl3) δ
Hz, CH3), 2.52 (2H, m, CH2), 2.67 (4H, br t, J ) 4.8 Hz, 2 CH2,
H(3′/5′)), 3.36 (4H, br t, J ) 4.8 Hz, 2 CH2, H(2′/6′)), 7.00 (1H, d,
J ) 3.0 Hz, H5), 7.27 (1H, d, J ) 9.0 Hz, H3), 7.49 (1H, dd, J )
2.4, 9.0 Hz, H7), 7.87 (1H, d, J ) 9.0 Hz, H8), 7.92 (1H, d, J )
9.0 Hz, H4); 13C NMR (150 MHz, CDCl3) δ 11.9 (CH3), 48.8 (C2′/
C6′), 52.4 (CH2), 52.6 (C3′/5′), 108.7 (C5), 122.4 (C3), 123.0 (C7),
128.2 (C4a), 129.2 (C8), 137.1 (C4), 143.1 (C8a), 147.5 (C2), 149.6
(C6); IR (Nujol mull) ν/cm-1 1650, 1618, 1600, 1582, and 1500;
MS (EI) m/z 277 (M+· [37Cl], 30), 275 (M•+ [35Cl], 85), 262 (20),
260 (60), 192 (15), 190 (35), 97 (40), 84 (100); HRMS (EI+) m/z
4.06 (3H, s, OCH3), 6.91 (1H, d, J ) 8.7 Hz, H3), 7.67 (1H, dd,
J ) 2.1, 8.7 Hz, H7), 7.72 (1H, d, J ) 8.7 Hz, H8), 7.85 (1H, d,
J ) 2.1 Hz, H5), 7.87 (1H, d, J ) 8.7 Hz, H4); 13C NMR (75
MHz, CDCl3) δ 53.5 (OCH3), 114.1 (C3), 117.1 (C6), 126.3 (C4a),
129.0 (C8), 129.5 (C5), 132.7 (C7), 137.6(C4), 145.3 (C8a), 162.6
(C2); IR (Nujol mull) ν/cm-1 1614, 1597, and 1567. Data for 21:
1H NMR (600 MHz, CDCl3) δ 1.94 (2H, m, 2 CH, H(3′/5′ax)),
2.07 (2H, m, 2 CH, H(3′/5′eq)), 2.48 (2H, m, CH, H(4′)), 2.84 (2H,
dt, J2′/6′ax,3′5′eq ) 3.0, J2′/6′ax,2′6′eq ) J2′/6′ax,3′5′ax ) 12.6 Hz, 2 CH,
H(2′/6′ax)), 3.70, (2H, m, 2 CH, H(2′/6′eq)), 4.03 (3H, s, OCH3),
6.83 (1H, d, J ) 8.4 Hz, H3), 7.04 (1H, d, J ) 2.4 Hz, H5), 7.40
(1H, dd, J ) 2.4, 9.6 Hz, H7), 7.73 (1H, d, J ) 9.6 Hz, H8), 7.84
(1H, d, J ) 8.4 Hz, H4); 13C NMR (150 MHz, CDCl3) δ 28.2
(C3′/5′), 40.9 (C4′), 49.9 (C2′/6′), 53.2 (OCH3), 111.2 (C5), 113.0
(C3), 123.7 (C7), 125.7 (C4a), 128.1 (C8), 137.8 (C4), 143.1 (C8a),
148.1 (C6), 161.2 (C2), 175.0 (CdO); MS (EI) m/z 300 (M•+,100),
285 (20), 269 (9); HRMS (EI+) m/z found 300.1471, C17H20N2O3
requires 300.1474.
2-Chloro-6-(4-methylpiperazin-1-yl)quinoline (6h). Synthesis
Method i. Using general procedure 1, 7 (601 mg, 2.47 mmol) and
1-methylpiperazine (h; 330 µL, 2.96 mmol) were added to a mixture
of Pd(OAc)2 (2.8 mg, 12.5 µmol), 16 (8.8 mg, 24.7 µmol), and
KOtBu (334 mg, 2.96 mmol) in toluene (2 mL). The reaction
mixture was heated for 20 h. Extraction with chloroform/2-propanol
(3:1) and chromatographic separation eluting with CH2Cl2 afforded
the title compound as a 6:1 mixture with 7 (combined yield 241
mg; 6h, 32%; 7, 5%). Data for 6h: 1H NMR (600 MHz, CDCl3) δ
2.40 (3H, s, CH3), 2.65 (4H, br t, J ) 4.8 Hz, 2 CH2, H(3′/5′)),
3.36 (4H, br t, J ) 4.8 Hz, 2 CH2, H(2′/6′)), 7.01 (1H, d, J ) 3.0
Hz, H5), 7.29 (1H, d, J ) 9.0 Hz, H3), 7.49 (1H, dd, J ) 3.0, 9.0
Hz, H7), 7.88 (1H, d, J ) 9.0 Hz, H8), 7.92 (1H, d, J ) 9.0 Hz,
H4); 13C NMR (150 MHz, CDCl3) δ 46.0 (CH3), 48.8 (C2′/C6′),
54.8 (C3′/5′), 108.9 (C5), 123.1 (C3), 123.3 (C7), 128.0 (C4a), 129.2
(C8), 137.8 (C4), 143.2 (C8a), 147.6 (C2), 149.5 (C6); IR (Nujol
mull) ν/cm-1 3150, 1654, 1616, 1600, and 1578; MS (EI) m/z 263
(M•+ [37Cl], 7), 261 (M•+ [35Cl], 20), 245 (30), 243 (100), 241 (70),
208 (50), 208 (50); HRMS (EI+) m/z found 261.1042, C14H1635ClN3
requires 261.1033.
found 275.1186, C15H1835ClN3 requires 275.1189. Data for 8i: H
1
NMR (600 MHz, CDCl3) δ 1.16 (3H, t, J ) 7.2 Hz, CH3), 2.52
(2H, m, CH2), 2.59 (4H, br t, J ) 4.8 Hz, 2 CH2, H(3′/5′)), 3.80
(4H, br t, J ) 4.8 Hz, 2 CH2, H(2′/6′)), 6.97 (1H, d, J ) 9.3 Hz,
H3), 7.57 (1H, d, J ) 9.0 Hz, H8), 7.57 (1H, dd, J ) 1.8, 9.0 Hz,
H7), 7.71 (1H, d, J ) 1.8 Hz, H5), 7.80 (1H, d, J ) 9.3 Hz, H4);
13C NMR (150 MHz, CDCl3) δ 11.9 (CH3), 45.0 (C2′/C6′), 52.3
(CH2) 54.5 (C3′/5′), 110.7 (C3), 115.2 (C6), 124.2 (C4a), 128.3
(C5), 129.1 (C8), 132.6 (C7), 137.1 (C4), 146.6 (C8a), 157.3 (C2);
IR (Nujol mull) ν/cm-1 1617, 1597, and 1542. MS (EI) m/z 321
(M•+ [81Br], 100), 319 (M•+ [79Br], 100), 306 (13), 304 (13); HRMS
(EI+) m/z found 319.0689, C15H1879BrN3 requires 319.0684. Data
1
for 17i: H NMR (200 MHz, CDCl3) δ 1.16 (3H, t, J ) 7.2 Hz,
CH3), 1.68 (9H, s, tBu), 2.49 (2H, q, J ) 7.2 Hz, CH2), 2.67 (4H,
t, J ) 4.8 Hz, 2 CH2, H(3′/5′)), 3.28 (4H, t, J ) 4.8 Hz, 2 CH2,
H(2′/6′)), 6.75 (1H, d, J ) 8.8 Hz, H3), 7.01 (1H, d, J ) 2.8 Hz,
H5), 7.37 (1H, dd, J ) 2.8, 9.0 Hz, H7), 7.70 (1H, d, J ) 9.0 Hz,
H8), 7.80(1H, d, J ) 8.8 Hz, H4); MS (EI) m/z 313 (40), 257 (100),
242 (60), 173 (20), 84 (65), 57 (45).
2-Chloro-6-(4-phenylpiperazin-1-yl)quinoline (6j). Synthesis
Method i. Using general procedure 1, 7 (501 mg, 2.06 mmol) and
1-phenylpiperazine (j; 375 µL, 2.47 mmol) were added to a mixture
of Pd(OAc)2 (2.3 mg, 10.3 µmol), 16 (7.4 mg, 20.6 µmol), and
KOtBu (279 mg, 2.47 mmol) in toluene (2 mL). The reaction
mixture was heated for 20 h. Extraction with ethyl acetate and
chromatographic separation eluting with CH2Cl2/hexane (4:1)
afforded the title compound as a yellow solid, mp 182-185 °C
(yield 290 mg, 44%). 6-Bromo-2-(4-phenylpiperazin-1-yl)quinoline
(8j) was also isolated as a yellow solid, mp 155-159 °C (yield
1
110 mg, 15%). Data for 6j: H NMR (300 MHz, CDCl3) δ 3.39
(4H, br t, J ) 4.8 Hz, 2 CH2, H(3′/5′)), 3.47 (4H, br t, J ) 4.8 Hz,
2 CH2, H(2′/6′)), 6.92 (1H, t, J ) 7.2 Hz, H4′′), 7.01 (2H, d, J )
(37) Osborne, A. G.; Miller, L. A. D. J. Chem. Soc., Perkin Trans. 1 1993,
2 (19), 81–184.
J. Org. Chem. Vol. 73, No. 22, 2008 8889

Smith et al.
7.8 Hz, H(2′′/6′′)), 7.06 (1H, d, J ) 2.4 Hz, H5), 7.31 (3H, m, H3,
H(3′′/5′′)), 7.54 (1H, dd, J ) 3.0, 9.0 Hz, H7), 7.91 (1H, d, J )
9.0 Hz, H8), 7.85 (1H, d, J ) 8.4 Hz, H4); 13C NMR (75 MHz,
CDCl3) δ 49.2 (C2′/C6′), 49.3 (C3′/5′), 109.1 (C5), 116.4 (C2′′/
C5′′), 120.3 (C4′′), 122.5 (C3), 123.2 (C7), 128.0 (C4a), 129.2 (C8),
129.3 (C3′′ /C5′′), 137.5 (C4), 143.2 (C8a), 147.7 (C2), 149.5 (C1′′),
151.0 (C6); IR (Nujol mull) ν/cm-1 1669, 1615, 1600, and 1574;
MS (EI) m/z 325 (M•+ [37Cl], 15), 323 (M•+ [35Cl], 50), 190 (30),
157 (50), 132 (100), 105 (50), 77 (25); HRMS (EI+) m/z found
323.1185, C19H1835ClN3 requires 323.1189. Anal. Calcd for
C19H18ClN3: C, 70.47; H, 5.60; N, 12.98. Found: C, 70.37; H, 5.77;
N, 12.62. Data for 8j: 1H NMR (600 MHz, CDCl3) δ 3.46 (4H, br
t, J ) 4.8 Hz, 2 CH2, H(3′/5′)), 3.93 (4H, br t, J ) 4.8 Hz, 2 CH2,
H(2′/6′)), 6.92 (1H, t, J ) 7.2 Hz, H4′′), 7.01 (2H, d, J ) 8.1 Hz,
H(2′′/6′′)), 7.06 (1H, d, J ) 9.3 Hz, H3), 7.32 (2H, t, J ) 8.1 Hz,
H(3′′/5′′)), 7.62 (2H, br s, H7, H8), 7.76 (1H, br s, H5), 7.82 (1H,
d, J ) 9.3 Hz, H4); 13C NMR (150 MHz, CDCl3) δ 45.2 (C2′/
C6′), 49.4 (C3′/5′), 110.5 (C3), 115.4 (C6), 116.5 (C2′′/C6′′), 120.3
(C4′′), 124.4 (C4a), 128.5 (C5), 129.2 (C8), 129.4 (C3′′/C5′′), 132.9
(C7), 136.7 (C4), 146.7 (C8a), 151.3 (C1′′), 157.4 (C2); IR (Nujol
mull) ν/cm-1 1608, 1594, and 1545; MS (EI) 369 (M•+ [81Br], 10),
367 (M•+ [79Br], 10), 235 (100), 145 (20), 132 (30), 104 (25), 77
(20); HRMS (EI+) m/z found 367.0677, C19H1879BrN3 requires
367.0684.
(6H, m, H7, Ph), 7.70 (1H, d, J ) 9.0 Hz, H8), 7.80 (1H, d, J )
9.0 Hz, H4); IR (Nujol mull) ν/cm-1 1654, 1597, 1560, and 1505.
Synthesis Method ii. Using general procedure 2, the title
compound was obtained in 90% yield as determined by H NMR
analysis. Data are as above.
1
Synthesis Method iii. Using general procedure 3, the title
1
compound was obtained in 45% yield as determined by H NMR
analysis. Data are as above.
tert-Butyl 4-(2-Chloroquinolin-6-yl)piperazine-1-carboxylate (6l).
Using general procedure 1, 7 (510 mg, 2.10 mmol) and tert-butyl
piperazine-1-carboxylate (l; 472 mg, 2.52 mmol) were added to a
mixture of Pd(OAc)2 (2.3 mg, 10.5 µmol), 16 (7.5 mg, 21.0 µmol),
and KOtBu (284 mg, 2.53 mmol) in toluene (3 mL). The reaction
mixture was heated for 20 h. Extraction with ethyl acetate and
chromatographic separation eluting with CH2Cl2 afforded the title
compound as a yellow glass (580 mg, 80%). tert-Butyl 4-(2-tert-
butoxyquinolin-6-yl)piperazine-1-carboxylate (17l) was also isolated
1
as a brown solid, mp 119-122 °C (52 mg, 7%). Data for 6l: H
t
NMR (600 MHz, CDCl3) δ 1.50 (9H, s, Bu), 3.27 (4H, br t, J )
4.8 Hz, 2 CH2, H(2′/6′)), 3.64 (4H, br t, J ) 4.8 Hz, 2 CH2, H(3′/
5′)), 7.03 (1H, br s, H5), 7.30 (1H, d, J ) 9.0 Hz, H3), 7.48 (1H,
br d, J ) 9.0 Hz, H7), 7.90 (1H, d, J ) 9.0 Hz, H8), 7.93 (1H, d,
J ) 9.0 Hz, H4); 13C NMR (150 MHz, CDCl3) δ 28.4 (C(CH3)3),
43.2 (C3′/5′), 49.2 (C2′/6′), 80.1 (C(CH3)3), 109.6 (C5), 122.5 (C3),
123.4 (C7), 127.9 (C4a), 129.3 (C8), 137.5 (C4), 143.3 (C8a), 147.9
(C2), 149.4 (C6), 154.6 (CdO); IR (Nujol mull) ν/cm-1 3310, 1694,
1602, and 1503; MS (EI) m/z 349 (M•+ [37Cl], 15), 347 (M•+ [35Cl],
15), 293 (15), 291 (50), 247 (20), 219 (10), 217 (30), 207 (30),
205 (100), 190 (20), 57 (20); HRMS (EI+) m/z found 347.1397,
C18H22ClN3O2 requires 347.1401. Data for 17l: 1H NMR (600 MHz,
Synthesis Method ii. Using general procedure 2, the title
1
compound was obtained in 91% yield as determined by H NMR
analysis. Data are as above.
Synthesis Method iii. Using general procedure 3, the title
1
compound was obtained in 9% yield as determined by H NMR
analysis. Data are as above.
t
t
DMSO) δ 1.42 (9H, s, Bu), 1.62 (9H, s, Bu), 3.12 (4H, br t, J )
4.8 Hz, 2 CH2, H(2′/6′)), 3.48 (4H, br t, J ) 4.8 Hz, 2 CH2, H(3′/
5′)), 6.76 (1H, d, J ) 9.0 Hz, H3), 7.14 (1H, d, J ) 2.4 Hz, H5),
7.43 (1H, dd, J ) 2.4, 9.0 Hz, H7), 7.57 (1H, d, J ) 9.0 Hz, H8),
7.96 (1H, d, J ) 9.0 Hz, H4); 13C NMR (150 MHz, DMSO) δ
28.0 (C(CH3)3), 28.3 (C(CH3)3), 43.2 (C3′/5′), 49.0 (C2′/6′), 79.0
(C(CH3)3), 78.9 (C(CH3)3), 110.5 (C5), 114.6 (C3), 122.2 (C7),
124.8 (C4a), 127.4 (C8), 137.7 (C4), 140.6 (C8a), 147.3 (C6), 153.8
(CdO), 159.9 (C2); IR (Nujol mull) ν/cm-1 3295, 1706, 1694, and
1602.
6-(4-Benzylpiperazin-1-yl)-2-chloroquinoline (6k). Synthesis
Method i. Using general procedure 1, 7 (500 mg, 2.06 mmol) and
1-benzylpiperazine (k; 428 µL, 2.47 mmol) were added to a mixture
of Pd(OAc)2 (2.3 mg, 10.3 µmol), 16 (7.4 mg, 20.6 µmol), and
KOtBu (277 mg, 2.47 mmol) in toluene (3 mL). The reaction
mixture was heated for 20 h. Extraction with ethyl acetate and
chromatographic separation eluting with CH2Cl2 afforded the title
compound as a 2.5:1 mixture with 2-(4-benzylpiperazin-1-yl)-6-
bromoquinoline (8k) (combined yield 260 mg; 6k, 26%; 8k, 11%).
2-tert-Butoxy-6-(4-benzylpiperazin-1-yl)quinoline (17k) was also
isolated as a dark yellow solid, mp 127-131 °C (50 mg, 6%). Data
for 6k: 1H NMR (600 MHz, CDCl3) δ 2.66 (4H, br t, J ) 4.8 Hz,
2 CH2, H(3′/5′)), 3.32 (4H, br t, J ) 4.8 Hz, 2 CH2, H(2′/6′)), 3.60
(2H, s, CH2), 6.96 (1H, d, J ) 2.4 Hz, H5), 7.25 (1H, d, J ) 9.0
Hz, H3), 7.38 (5H, m, Ph), 7.42 (1H, dd, J ) 2.4, 9.0 Hz, H7),
7.85 (1H, d, J ) 9.0 Hz, H8), 7.92 (1H, d, J ) 9.0 Hz, H4); 13C
NMR (150 MHz, CDCl3) δ 48.8 (C2′/C6′), 52.8 (C3′/5′), 62.9
(CH2), 108.7 (C5), 122.3 (C3), 123.0 (C7), 127.2 (C4′′), 128.0
(C4a), 128.3 (C3′′/C5′′), 129.1 (C2′′/C6′′), 129.2 (C8), 137.4 (C4),
137.6 (C1′′), 143.0 (C8a), 147.4 (C2), 149.6 (C6); IR (Nujol mull)
ν/cm-1 1650, 1615, 1576, and 1503; MS (EI) m/z 339 (M•+ [37Cl],
30), 337 (M•+ [35Cl], 90), 193 (25), 191 (70), 119 (20), 91 (100);
HRMS (EI+) m/z found 337.1345, C20H2035ClN3 requires 337.1346.
Data for 8k: 1H NMR (600 MHz, CDCl3) δ 2.58 (4H, br t, J ) 4.8
Hz, 2 CH2, H(3′/5′)), 3.58 (2H, s, CH2), 3.75 (4H, br t, J ) 4.8
Hz, 2 CH2, H(2′/6′)), 6.93 (1H, d, J ) 9.0 Hz, H3), 7.28 (5H, m,
Ph), 7.53 (1H, d, J ) 9.0 Hz, H8), 7.55 (1H, dd, J ) 2.4, 9.0 Hz,
H7), 7.69 (1H, d, J ) 2.4 Hz, H5), 7.73 (1H, d, J ) 9.0 Hz, H4);
13C NMR (150 MHz, CDCl3) δ 44.8 (C2′/C6′), 52.8 (C3′/5′), 62.9
(CH2), 110.2 (C3), 115.0 (C6), 124.1 (C4a), 127.2 (C4′′), 128.3
(C3′′/C5′′), 129.1 (C5), 129.2 (C2′′/C6′′), 129.2 (C8), 132.5 (C7),
136.3 (C4), 137.6 (C1′′), 146.6 (C8a), 157.3 (C2); MS (EI) 383
(M•+ [81Br], 10), 381 (M•+ [79Br], 10), 237 (30), 235 (30), 159
(50), 146 (90), 119 (20), 91 (100); HRMS (EI+) m/z found
381.0842, C20H2079BrN3 requires 381.08412. Data for 17k: 1H NMR
(300 MHz, CDCl3) δ 1.67 (9H, s, C(CH3)3), 2.77 (4H, br s, 2 CH2,
H(3′/5′)), 3.33 (4H, br s, 2 CH2, H(2′/6′)), 3.70 (2H, s, CH2), 6.75
(1H, d, J ) 9.0 Hz, H3), 7.01 (1H, d, J ) 2.4 Hz, H5), 7.31-7.42
Attempted Synthesis of 2-Chloro-6-(4-(2-hydroxy)ethylpiper-
azin-1-yl)quinoline (6m). Using general procedure 1, 7 (507 mg,
2.10 mmol) and 1-(2-hydroxyethyl)piperazine (m; 310 µL, 2.52
mmol) were added to a mixture of Pd(OAc)2 (2.3 mg, 10.5 µmol),
16 (7.5 mg, 21.0 µmol), and KOtBu (287 mg, 2.56 mmol) in toluene
(2 mL). The reaction mixture was heated for 22 h. Extraction with
chloroform/2-propanol (3:1) and chromatographic separation on C18
silica eluting with water/methanol (2:3) did not afford the title
compound; however, 6-bromo-2-(4-(2-hydroxy)ethylpiperazin-1-
yl)quinoline (8m) was obtained, mp 75-80 °C (241 mg, 37%): 1H
NMR (200 MHz, CDCl3) δ 2.58 (4H, br t, J ) 4.4 Hz, 2 CH2,
H(3′/5′)), 2.84 (2H, t, J ) 6.0 Hz, CH2N), 2.93 (4H, br t, J ) 4.4
Hz, 2 CH2, H(2′/6′)), 4.62 (2H, t, J ) 6.0 Hz, CH2OH), 6.94 (1H,
d, J ) 8.7 Hz, H3), 7.68 (2H, br s, H7, H8), 7.86 (1H, br s, H5),
7.88 (1H, d, J ) 8.7 Hz, H4); 13C NMR (75 MHz, CDCl3) δ 44.8
(C2′/C6′), 52.4 (C3′/5′), 53.1 (2 CH2), 57.2 (CH2N), 63.3 (CH2OH),
114.4 (C3), 117.4 (C6), 126.4 (C4a), 129.1 (C5), 129.6 (C8), 132.9
(C7), 137.9 (C4), 145.2 (C8a), 162.1 (C2); IR (Nujol mull) ν/cm-1
3455, 3379, 3236, 1659, 1613, 1597, and 1567; MS (EI) m/z 225
([81Br], 20), 223 ([79Br], 20), 210 (20), 208 (20), 140 (20), 127
(40), 112, (100), 99 (80), 84 (30), 70 (100), 56 (60), 42 (20); HRMS
(EI+) m/z found 336.0714, C15H1879BrN3O + H requires 336.0706.
6-(4-Methylpiperidin-1-yl)quinolin-2-amine (5a). Synthesis Method
i. Using general procedure 5, impure 6a (290 mg, 0.93 mmol) was
treated with acetamide (1.31 g, 22.2 mmol) and potassium carbonate
(760 mg, 5.55 mmol) for 2 h. Extraction with chloroform/2-propanol
(3:1) and chromatographic separation eluting with ethanol/CH2Cl2
(1:19) afforded the title compound as a pale orange solid, mp
1
166-174 °C (90 mg, 40%): H NMR (600 MHz, CDCl3) δ 0.99
8890 J. Org. Chem. Vol. 73, No. 22, 2008

Functionalization of 6-Bromo-2-chloroquinoline
(3H, d, J ) 6.6 Hz, CH3), 1.41 (2H, dq, J2′/6′eq,3′5′ax ) 2.4 Hz, J2′/
6′ax,3′5′ax ) J3′/5′ax,3′5′eq ) J3′5′ax,4′ ) 12.6 Hz, 2 CH, H(3′/5′ax)), 1.52
(1H, m, CH, H4′), 1.78 (2H, m, Hz, 2 CH, H(3′/5′eq)), 2.71 (2H,
dt, J2′/6′ax,3′5′eq ) 2.4, J2′/6′ax,2′6′eq ) J2′/6′ax,3′5′ax ) 12.6 Hz, 2 CH,
H(2′/6′ax)), 3.66, (2H, br d‡, J2′/6′ax,2′6′eq ) J2′/6′eq,3′5′eq )12.6 Hz, 2
CH, H(2′/6′eq)), 4.66 (2H, br s, NH2), 6.67 (1H, d, J ) 8.7 Hz,
H3), 6.97 (1H, d, J ) 2.4 Hz, H5), 7.38 (1H, dd, J ) 2.4, 9.0 Hz,
H7), 7.58 (1H, d, J ) 9.0 Hz, H8), 7.76 (1H, d, J ) 9.0 Hz, H4);
13C NMR (150 MHz, CDCl3) δ 21.9 (CH3), 30.7 (C4′), 34.2 (C3′/
5′), 50.8 (C2′/6′), 111.1 (C5), 111.6 (C3), 123.6 (C7), 124.2 (C4a),
126.4 (C8), 137.3 (C4), 142.2 (C8a), 147.8 (C6), 155.2 (C2); IR
(Nujol mull) ν/cm-1 3441, 3295, 3105, 2354, 1645, 1600, 1557,
and 1505; MS (EI) m/z 241 (M•+ 100), 171 (40); HRMS (EI+)
found 241.1572, C15H19N3 requires 241.1579. 5a was converted to
the corresponding maleate salt, mp 190-200 °C, using general
procedure 7 for the purpose of obtaining an elemental analysis.
Anal. Calcd for C19H23N3O4 ·0.5H2O: C, 62.28; H, 6.60; N, 11.47.
Found: C, 62.32; H, 6.58; N, 11.39.
in THF, 460 µL) was added, and then the reaction was heated for
22 h. Workup afforded the title compound (47 mg, 98%). Data are
as above.
6-(Piperidin-1-yl)quinolin-2-amine (5d). Using general procedure
5, 6d (300 mg, 1.2 mmol) was treated with acetamide (1.42 g, 24.0
mmol) and potassium carbonate (830 mg, 6.0 mmol) for 1.5 h.
Extraction with ethyl acetate and chromatographic separation eluting
with ethyl acetate/CH2Cl2 (2:3) afforded the title compound as a
pale brown solid, mp 120-122 °C (175 mg, 64%): 1H NMR (300
MHz, CDCl3) δ 1.59 (2H, br d,‡ J ) 4.8 Hz, CH2, H4′), 1.72 (4H,
br d‡, J ) 4.8 Hz, 2 CH2, H(3′/5′)), 3.16 (4H, br t, J ) 4.8 Hz, 2
CH2, H (2′/6′)), 5.82 (2H, br s, NH2), 6.83 (1H, d, J ) 8.7 Hz,
H3), 6.97 (1H, d, J ) 2.7 Hz, H5), 7.38 (1H, dd, J ) 2.7, 9.0 Hz,
H7), 7.60 (1H, d, J ) 9.0 Hz, H8), 7.82 (1H, d, J ) 9.0 Hz, H4);
13C NMR (75 MHz, CDCl3) δ 25.7 (C4′), 29.6 (C3′/5′), 51.0 (C2′/
6′), 111.4 (C5), 113.1 (C3), 120.8 (C8), 122.6 (C4a), 124.1 (C7),
134.3 (C8a), 139.7 (C4), 148.9 (C6), 154.2 (C2); IR (Nujol mull)
ν/cm-1 3400, 3210, 1685, and 1618; MS (EI) m/z 227 (M•+, 100),
171 (50), 143 (30), 116 (20); HRMS (EI+) m/z found 227.1428,
C14H17N3 requires 227.1422.
6-(4-Phenylpiperidin-1-yl)quinolin-2-amine (5e). Using general
procedure 5, 6e (132 mg, 0.41 mmol) was treated with acetamide
(486 mg, 8.23 mmol) and potassium carbonate (283 mg, 2.05 mmol)
for 2 h. Extraction with chloroform/2-propanol (3:1) and chro-
matographic separation eluting with ethanol/CH2Cl2 (1:19) afforded
the title compound as a pale yellow powder, mp 187-194 °C (50
mg, 40%): 1H NMR (600 MHz, CDCl3) δ 1.95 (2H, dq, J2′/6′eq,3′5′ax
) 3.0, J2′/6′ax,3′5′ax ) J3′/5′ax,3′5′eq ) 12.0 Hz, 2 CH, H(3′/5′ax)), 2.01
(2H, br d‡, J2′/6′eq,3′5′eq ) J3′/5′ax,3′5′eq ) 12.0 Hz, 2 CH, H(3′/5′eq)),
2.65 (1H, m, CH, H4′), 2.85 (2H, dt, J2′/6′ax,3′5′eq ) 3.0, J2′/6′ax,2′6′eq
) J2′/6′ax,3′5′ax ) 12.0 Hz, 2 CH, H(2′/6′ax)), 3.84, (2H, br d‡, J2′/
6′eq,3′5′eq ) J2′/6′eq,2′6′ax ) 12.0 Hz, 2 CH, H(2′/6′eq)), 4.66 (2H, br s,
NH2), 6.69 (1H, d, J ) 9.0 Hz, H3), 7.03 (1H, d, J ) 3.0 Hz, H5),
7.22 (1H, t, J ) 7.2 Hz, C4′′), 7.27 (2H, m, C3′′/5′′), 7.32 (2H, t,
J ) 7.2 Hz, C2′′/6′′), 7.42 (1H, dd, J ) 3.0, 9.0 Hz, H7), 7.60
(1H, d, J ) 9.0 Hz, H8), 7.79 (1H, d, J ) 9.0 Hz, H4); 13C NMR
(150 MHz, CDCl3) δ 33.4 (C3′/5′), 42.5 (C4′), 51.4 (C2′/6′), 111.4
(C5), 111.7 (C3), 123.6 (C7), 124.2 (C4a), 126.3 (C4′′), 126.5 (C8),
126.9 (C3′′/5′′), 128.5 (C2′′/6′′), 137.4 (C4), 142.4 (C8a), 146.0
(C1′′), 147.6 (C6), 155.3 (C2); IR (Nujol mull) ν/cm-1 1618, 1574,
and 1500; MS (EI) m/z 303 (M•+, 100), 198 (30), 171 (40), 143
(20); HRMS (EI+) m/z found 303.173, C20H21N3 requires 303.174.
5e was converted to the corresponding maleate salt, mp 197-207
°C, using general procedure 7 for the purpose of obtaining an
elemental analysis. Anal. Calcd for C24H25N3O4 ·H2O: C, 65.89;
H, 6.22; N, 9.60. Found: C, 65.45; H, 6.01; N, 9.35.
Synthesis Method ii. Using general procedure 6, Pd2(dba)3 (1.9
mg, 2.1 µmol), 9 (1.0 mg, 2.5 µmol), and 6a (55 mg, 0.21 mmol)
were combined in 1,4-dioxane (1 mL). LHMDS solution (1.0 M
in THF, 460 µL) was added, and then the reaction was heated for
22 h. Workup afforded the title compound (49 mg, 97%). Data are
as above.
6-(Pyrrolidin-1-yl)quinolin-2-amine (5b). Using general proce-
dure 6b (160 mg, 0.66 mmol) was treated with acetamide (3.34 g,
56.60 mmol) (note the deviation in the amount of acetamide used
in this reaction) and potassium carbonate (477 mg, 3.45 mmol) for
1.5 h. Extraction with ethyl acetate and chromatographic separation
eluting with ethanol/CH2Cl2 (1:9) afforded the title compound as a
1
yellow solid (79 mg, 56%): H NMR (300 MHz, CDCl3) δ 2.04
(4H, t, J ) 6.6 Hz, 2 CH2, H(3′/4′)), 3.32 (4H, t, J ) 6.6 Hz, 2
CH2, H(2′/5′)), 6.42 (2H, br s, NH2), 6.56 (1H, d, J ) 2.4 Hz, H5),
6.88 (1H, d, J ) 9.0 Hz, H3), 7.02 (1H, dd, J ) 2.4, 9.0 Hz, H7),
7.58 (1H, d, J ) 9.0 Hz, H8), 7.82 (1H, d, J ) 9.0 Hz, H4); 13C
NMR (75 MHz, CDCl3) δ 25.78 (C3′/4′), 48.1 (C2′/5′), 105.8 (C5),
112.5 (C3), 119.3 (C7), 122.5 (C4a), 124.1 (C8), 133.3 (C4), 139.7
(8a), 145.2 (C6), 153.3 (C2); IR (Nujol mull) ν/cm-1 3392, 1673,
1618, and 1523; MS (EI) m/z 213 (M•+, 100), 170 (20), 157 (20),
143 (20), 87 (20), 71 (20), 57 (30), 47 (30); HRMS (EI+) m/z found
213.1260, C13H15N3 requires 213.1266. This compound decomposed
at room temperature and was therefore unable to be assayed for
binding to the Tec SH3 domain by NMR chemical shift perturbation
analysis utilizing (1H, 15N) HSQC experiments with uniformly 15N-
labeled SH3 protein.
6-Morpholinoquinolin-2-amine (5c). Synthesis Method i. Using
general procedure 5, 6c (370 mg, 1.49 mmol) was treated with
acetamide (1.76 g, 29.8 mmol) and potassium carbonate (1.03 g,
7.4 mmol) for 2.5 h. Extraction with ethyl acetate and chromato-
graphic separation eluting with ethanol/CH2Cl2 (1:9) afforded the
title compound as a pale orange solid, mp 224-228 °C (111 mg,
6-(4-Benzylpiperidin-1-yl)quinolin-2-amine (5f). Using general
procedure 5, an impure mixture of 6f (390 mg, 1.0 mmol) was
treated with acetamide (1.20 g, 20.3 mmol) and potassium carbonate
(698 mg, 5.0 mmol) for 2.5 h. Extraction with chloroform/2-
propanol (3:1) and chromatographic separation eluting with CH2Cl2
afforded the title compound as a yellow/brown solid, mp 169-174
1
1
32%): H NMR (300 MHz, CDCl3) δ 3.20 (4H, t, J ) 4.8 Hz, 2
°C (78 mg, 25%): H NMR (600 MHz, CDCl3) δ 1.47 (2H, dq,
CH2, H(2′/6′)), 3.90 (4H, t, J ) 4.8 Hz, 2 CH2, H(3′/5′)), 5.46 (2H,
br s, NH2), 6.71 (1H, d, J ) 9.0 Hz, H3), 6.97 (1H, d, J ) 2.4 Hz,
H5), 7.33 (1H, dd, J ) 2.4, 9.0 Hz, H7), 7.61 (1H, d, J ) 9.0 Hz,
H8), 7.80 (1H, d, J ) 9.0 Hz, H4); 13C NMR (75 MHz, CDCl3) δ
50.2 (C2′/6′), 66.9 (C3′/5′), 110.8 (C5), 112.1 (C3), 122.5 (C7),
124.0 (C4a), 126.1 (C8), 137.7 (C4), 141.7 (C8a), 147.1 (C6), 155.4
(C2); IR (Nujol mull) ν/cm-1 3379, 3300, 3154, 1661, 1603, and
1567; MS (EI) m/z 229 (M•+, 60), 171 (100); HRMS (EI+) m/z
found 229.1208, C13H15N3O requires 229.1215. 5c was converted
to the corresponding maleate salt, mp 194-200 °C, using general
procedure 7 for the purpose of obtaining an elemental analysis.
Anal. Calcd for C17H19N3O5 ·0.5H2O: C, 57.62; H, 5.69; N, 11.86.
Found: C, 57.47; H, 5.39; N, 11.66.
J2′/6′eq,3′5′ax ) 4.2, J2′/6′ax,3′5′ax ) J3′/5′ax,3′5′eq ) 12.6 Hz, 2 CH, H(3′/
5′ax)), 1.70 (1H, m, CH, H(4′)), 1.79 (2H, br d‡, J2′/6′eq,3′5′eq ) J3′/
5′ax,3′5′eq ) 12.6 Hz, 2 CH, H(3′/5′eq)), 2.60 (2H, d, J ) 7.2 Hz,
CH2), 2.69 (2H, dt, J2′/6′ax,3′5′eq ) 4.2, J2′/6′ax,2′6′eq ) J2′/6′ax,3′5′ax
)
12.6 Hz, 2 CH, H(2′/6′ax)), 3.68, (2H, br d‡, J2′/6′eq,3′5′eq ) J2′/6′eq,2′6′ax
) 12.0 Hz, 2 CH, H(2′/6′eq)), 4.59 (2H, br s, NH2), 6.66 (1H, d, J
) 9.0 Hz, H3), 6.95 (1H, d, J ) 2.4 Hz, H5), 7.18 (1H, t, J ) 7.2
Hz, C4′′), 7.21 (2H, m, C2′′/6′′), 7.30 (2H, t, J ) 7.2 Hz, C3′′/5′′),
7.35 (1H, dd, J ) 2.4, 9.0 Hz, H7), 7.56 (1H, d, J ) 9.0 Hz, H8),
7.76 (1H, d, J ) 9.0 Hz, H4); 13C NMR (150 MHz, CDCl3) δ 32.1
(C3′/5′), 37.8 (C4′), 43.2 (CH2), 50.8 (C2′/6′), 111.2 (C5), 111.7
(C3), 123.6 (C7), 124.3 (C4a), 125.9 (C4′′), 126.5 (C8), 128.2 (C3′′/
5′′), 129.2 (C2′′/6′′), 137.3 (C4), 140.5 (C1′′), 142.5 (C8a), 147.7
(C6), 155.3 (C2); IR (Nujol mull) ν/cm-1 3456, 3309, 3120, 1650,
Synthesis Method ii. Using general proceedure 6, Pd2(dba)3 (1.9
mg, 2.1 µmol), 9 (1.0 mg, 2.5 µmol) and 6c (52 mg, 0.21 mmol)
were combined in 1,4-dioxane (3 mL). LHMDS solution (1.0 M
1601, 1566, and 1502; MS (EI) m/z 317 (M
•+, 100), 224 (40), 198
(20), 172 (30), 71 (30), 170 (30), 143 (20); HRMS (EI+) m/z found
J. Org. Chem. Vol. 73, No. 22, 2008 8891

Smith et al.
317.1884, C21H23N3 requires 317.1892. 5f was converted to the
corresponding maleate salt, mp 188-195 °C, using general
procedure 7 for the purpose of obtaining an elemental analysis.
Anal. Calcd for C25H27N3O4 ·0.5H2O: C, 67.86; H, 6.38; N, 9.50.
Found: C, 67.69; H, 6.38; N, 9.33.
m/z found 304.1682, C19H20N4 requires 304.1688. Anal. Calcd for
C19H20N4 ·0.5H2O: C, 72.82; H, 6.75; N, 17.88. Found: C, 72.56;
H, 6.63; N, 17.42.
Synthesis Method ii. Using general proceedure 6, Pd2(dba)3 (1.4
mg, 1.5 µmol), 9 (0.7 mg, 1.8 µmol), and 6j (50 mg, 0.15 mmol)
were combined in 1,4-dioxane (1 mL). LHMDS solution (1.0 M
in THF, 330 µL) was added, and then the reaction was heated for
18 h. Workup afforded the title compound (44 mg, 96%). Data are
as above.
6-(4-Methylpiperazin-1-yl)quinolin-2-amine (5h). Synthesis
Method i. Using general procedure 5, impure 6h (200 mg, 0.77
mmol) was treated with acetamide (912 mg, 15.3 mmol) and
potassium carbonate (527 mg, 3.84 mmol) for 2.5 h. Extraction
with chloroform/2-propanol (3:1) and chromatographic separation
on C18 silica eluting with water/methanol (2:3) afforded the title
compound as a pale yellow powder, mp 171-181 °C (20 mg, 11%):
1H NMR (600 MHz, CDCl3) δ 2.39 (3H, s, CH3), 2.64 (4H, t, J )
4.8 Hz, 2 CH2, H(3′/5′)), 3.26 (4H, t, J ) 4.8 Hz, 2 CH2, H(2′/6′)),
4.94 (2H, br s, NH2), 6.70 (1H, d, J ) 8.6 Hz, H3), 6.98 (1H, d,
J ) 2.6 Hz, H5), 7.36 (1H, dd, J ) 2.6, 9.0 Hz, H7), 7.60 (1H, d,
J ) 9.0 Hz, H8), 7.79 (1H, d, J ) 8.6 Hz, H4); 13C NMR (150
MHz, CDCl3) δ 46.1 (CH3), 49.8 (C2′/6′), 55.1 (C3′/5′), 111.0 (C5),
111.9 (C3), 122.9 (C7), 124.0 (C4a), 126.0 (C8), 137.8 (C4), 141.5
(C8a), 147.1 (C6), 155.2 (C2); IR (Nujol mull) ν/cm-1 3299, 3181,
1603, and 1505; MS (EI) m/z 242 (M•+, 20), 144 (100), 117 (50);
HRMS (EI+) m/z found 242.1531, C14H18N4 requires 242.1531.
Synthesis Method ii. Using general proceedure 6, Pd2(dba)3 (1.7
mg, 1.9 µmol), 9 (0.9 mg, 2.2 µmol), and 6h (65 mg, 0.19 mmol)
were combined in 1,4-dioxane (1 mL). LHMDS solution (1.0 M
in THF, 420 µL) was added, a nd then the reaction was heated for
24 h. Workup afforded the title compound (41 mg, 90%). Data are
as above.
6-(4-Benzylpiperazin-1-yl)quinolin-2-amine (5k). Synthesis Method
i. Using general procedure 5, impure 6k (575 mg, 1.71 mmol) was
treated with acetamide (2.0 g, 34.1 mmol) and potassium carbonate
(1.18 g, 8.5 mmol) for 2.0 h. Extraction with chloroform/2-propanol
(3:1) and chromatographic separation on C18 silica eluting with
water/methanol (1:4) afforded the title compound as an impure
mixture (90 mg). Additional attempts to purify the product on C18
preparative plates afforded a small amount of the title pure
1
compound as a cream powder, mp 194-196 °C (20 mg, 4%): H
NMR (600 MHz, CDCl3) δ 2.64 (4H, m, 2 CH2, H(3′/5′)), 3.23
(4H, t, J ) 4.8 Hz, 2 CH2, H(2′/6′)), 3.58 (2H, s, CH2), 4.66 (2H,
br s, NH2), 6.66 (1H, d, J ) 9.0 Hz, H3), 6.94 (1H, d, J ) 3.0 Hz,
H5), 7.25-7.37 (6H, m, H (C7, Ph)), 7.57 (1H, d, J ) 9.0 Hz,
H8), 7.75 (1H, d, J ) 9.0 Hz, H4); 13C NMR (150 MHz, CDCl3)
δ 49.9 (C2′/6′), 53.1 (C3′/5′), 63.0 (CH2), 110.8 (C5), 112.8 (C3),
121.9 (C7), 124.2 (C4a), 126.7 (C8), 127.1 (C4′′), 128.3 (C2′′/
C6′′), 129.1 (C3′′/C5′′), 137.9 (C4), 138.15 (C1′′), 142.8 (C8a),
147.0 (C6), 155.5 (C2); IR (Nujol mull) ν/cm-1 3439, 3301, 2354,
1647, 1599, and 1560; MS (EI) m/z 318 (M•+, 100), 172 (70), 146
(30), 91 (50); HRMS (EI+) m/z found 318.1847, C20H22N4 requires
318.1844.
6-(4-Ethylpiperazin-1-yl)quinolin-2-amine (5i). Using general
procedure 5, impure 6i (220 mg, 0.80 mmol) was treated with
acetamide (946 mg, 16.0 mmol) and potassium carbonate (553 mg,
4.0 mmol) for 2.5 h. Extraction with chloroform/2-propanol (3:1)
and chromatographic separation on C18 silica eluting with water/
methanol (2:3) afforded the title compound as a pale yellow powder,
mp 166-169 °C (17 mg, 8%). Additional product was also isolated
as a mixture that could not be purified further (combined yield 45
Synthesis Method ii. Using general proceedure 6, Pd2(dba)3 (2.6
mg, 2.8 µmol), 9 (1.3 mg, 3.3 µmol), and 6k (96 mg, 0.15 mmol)
were combined in 1,4-dioxane (1 mL). LHMDS solution (1.0 M
in THF, 620 µL) was added, a nd then the reaction was heated for
24 h. Workup afforded the title compound (80 mg, 88%). Data are
as above.
1
tert-Butyl 4-(2-Aminoquinolin-6-yl)piperazine-1-carboxylate (5l).
Using general procedure 5, 6l (200 mg, 0.58 mmol) was treated
with acetamide (685 mg, 11.6 mmol) and potassium carbonate (400
mg, 2.9 mmol) for 1.5 h. Extraction with chloroform/2-propanol
(3:1) and chromatographic separation eluting with ethanol/CH2Cl2
(1:9) afforded the title compound as a green-brown solid, mp
mg; 5i, 18%). Data for 5i: H NMR (600 MHz, CDCl3) δ 1.15
(3H, t, J ) 7.2 Hz, CH3), 2.51 (2H, q, J ) 7.2 Hz, CH2), 2.67 (4H,
t, J ) 4.8 Hz, 2 CH2, H(3′/5′)), 3.27 (4H, t, J ) 4.8 Hz, 2 CH2,
H(2′/6′)), 4.68 (2H, br s, NH2), 6.68 (1H, d, J ) 9.0 Hz, H3), 6.97
(1H, d, J ) 2.4 Hz, H5), 7.36 (1H, dd, J ) 2.4, 9.0 Hz, H7), 7.59
(1H, d, J ) 9.0 Hz, H8), 7.78 (1H, d, J ) 9.0 Hz, H4); 13C NMR
(150 MHz, CDCl3) δ 11.9 (CH3), 49.9 (C2′/6′), 52.3 (CH2), 52.9
(C3′/5′), 110.9 (C5), 111.8 (C3), 122.8 (C7), 124.2 (C4a), 126.5
(C8), 137.4 (C4), 142.4 (C8a), 147.1 (C6), 155.3 (C2); IR (Nujol
mull) ν/cm-1 3466, 3730, 3210, 1639, and 1601; MS (EI) m/z 256
(M•+, 100), 241 (50), 172 (40), 84 (40), 57 (30); HRMS (EI+) m/z
found 256.1688, C15H20N4 requires 256.1688.
1
220-228 °C (90 mg, 47%): H NMR (600 MHz, CDCl3) δ 1.26
(9H, s, C(CH3)3), 3.22 (4H, t, J ) 4.8 Hz, CH2, H(2′/6′)), 3.66
(4H, t, J ) 4.8 Hz, 2 CH2, H(3′/5′)), 5.17 (2H, br s, NH2), 6.74
(1H, d, J ) 8.4 Hz, H3), 6.97 (1H, d, J ) 2.4 Hz, H5), 7.35 (1H,
dd, J ) 2.4, 9.0 Hz, H7), 7.62 (1H, d, J ) 9.0 Hz, H8), 7.81 (1H,
d, J ) 8.4 Hz, H4); 13C NMR (150 MHz, CDCl3) δ 29.7 (C(CH3)3),
41.4 (C3′/5′), 49.9 (C2′/6′), 80.10 (C(CH3)3), 111.9 (C5), 112.2
(C3), 123.4 (C7), 123.8 (C4a), 125.9 (C8), 135.1 (C4), 138.0 (C8a),
146.8 (C6), 155.4 (C2), 169.0 (CdO); IR (Nujol mull) ν/cm-1 3336,
6-(4-Phenylpiperazin-1-yl)quinolin-2-amine (5j). Synthesis Method
i. Using general procedure 5, impure 6j (150 mg, 0.46 mmol) was
treated with acetamide (550 mg, 9.3 mmol) and potassium carbonate
(320 mg, 2.3 mmol) for 1.5 h. Extraction with chloroform/2-
propanol (3:1) and chromatographic separation eluting with ethanol/
CH2Cl2 (1:19) afforded the title compound as a yellow powder,
t
3157, 1658, 1621, and 1604; MS (EI) m/z 270 (M+ - Bu, 90),
198 (100), 185 (30), 170 (50) 143 (30), 83 (30), 56 (30); HRMS
(EI+) m/z found 328.1895, C18H24N4O2 requires 328.1899.
1
mp 233-240 °C (65 mg, 46%): H NMR (600 MHz, CDCl3) δ
Acknowledgment. We thank the Australian Government for
the provision of Australian Postgraduate Awards (J.A.S. and
R.K.J.).
3.39 (8H, br s, 4 CH2), 5.38 (2H, br s, NH2), 6.70 (1H, d, J ) 9.0
Hz, H3), 6.92 (1H, t, J ) 7.2 Hz, H4′′), 7.00 (2H, d, J ) 8.1 Hz,
H(2′′/6′′)), 7.05 (1H, d, J ) 2.7 Hz, H5), 7.29 (2H, m, H(3′′/5′′)),
7.43 (1H, dd, J ) 2.7, 9.0 Hz, H7), 7.65 (1H, d, J ) 9.0 Hz, H8),
7.87 (1H, d, J ) 9.0 Hz, H4); 13C NMR (150 MHz, CDCl3) δ 49.7
(C2′/6′), 50.4 (C3′/5′), 111.5 (C3), 112.1 (C4′′), 116.6 (C2′′/C6′′),
120.3 (C5), 123.3 (C7), 124.3 (C4a), 126.7 (C8), 129.4 (C3′′/C5′′),
142.5 (C4), 142.5 (C8a), 147.3 (C6), 151.5 (C1′′), 155.6 (C2); IR
(Nujol mull) ν/cm-1 3435, 3301, 3112, 1646, and 1602; MS (EI)
m/z 304 (M•+, 100), 171 (60), 132 (60), 105 (30); HRMS (EI+)
Supporting Information Available: General experimental
considerations and NMR spectra for characterization of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO801808R
8892 J. Org. Chem. Vol. 73, No. 22, 2008