Novel palladium-free synthesis of a key quinazolinap precursor

Article abstract of DOI:10.1055/s-0030-1259507

A novel, short synthetic route has been successfully developed for a key precursor of Quinazolinap ligands. The key step is a Friedel-Crafts-type reaction between 2-naphthol and 4-chloroquinazoline, with moderate to quantitative yields recorded. A variation of this reaction allows for the introduction of an amine group on the naphthalene unit. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1259507

LETTER
383
Novel Palladium-Free Synthesis of a Key Quinazolinap Precursor
N
ovel Palladium
u
-
Free Synth
d
esis of
a
K
ey
o
Q
uinazolin
v
a
p
Precursoric Milhau, Patrick J. Guiry*
Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
Fax +353(1)7162501; E-mail: p.guiry@ucd.ie
Received 13 December 2010
phthalazin-1(2H)-one synthesis.9 They relied on a
Friedel–Crafts-type reaction in order to react 1,4-dichlo-
rophthalazine with various aromatic compounds, notably
2-naphthol (3). They found that the reaction was tolerant
Abstract: A novel, short synthetic route has been successfully de-
veloped for a key precursor of Quinazolinap ligands. The key step
is a Friedel–Crafts-type reaction between 2-naphthol and 4-chloro-
quinazoline, with moderate to quantitative yields recorded. A vari-
ation of this reaction allows for the introduction of an amine group to free hydroxyl groups, and that 2-naphthol (3) was sub-
on the naphthalene unit.
stituted exclusively in the 1-position. This idea was ap-
plied to the development of the PINAP class of ligands by
Carreira and co-workers, which were used with impres-
sive results in the field of alkyne additions.10
Key words: arylation, Lewis acids, ligands, quinazolines, phenols
The expansion of the scope of catalytic asymmetric syn-
thesis relies heavily on the design, preparation and evalu-
ation of chiral ligands for transition metal complexes.1
Chiral P–N ligands have proven over the years to form a
synthetically useful class of ligands,2 in which QUINAP
(1) holds a central place. Developed by Brown in 1993, it
opened the way to a class of atropisomeric chiral P–N
ligands.3 Today, applications exist in most of the fields of
organometallic catalysis (hydroboration,4 alkyne addi-
tion,5 diboration,6 and azomethine cycloaddition7). Our
group has since then developed our own series of atropi-
someric P–N ligands, Quinazolinap (2; Figure 1) which
has been successfully applied to the rhodium-catalysed
hydroboration of vinylarenes and palladium-catalysed al-
lylic alkylation, with enantiomeric excesses up to 99% in
the former application.8
R1 = Me or Bn
1. protection
2. bromination
B(OH)2
OR1
3. Li–Br exchange
4. reaction with borate
5. hydrolysis
OH
3
4
O
R2
NH2
NH2
1. cyclisation
2. chlorination
Cl
+
R2
NH
condensation
O
NH2
O
O
5
6
7
1. deprotection
2. triflation
N
R2
2a
2b
2c
2d
2e
2f
R = H
Me
N
R
3. Ni coupling
4. resolution
(3 steps)
N
R2
Suzuki
coupling
N
i-Pr
t-Bu
Cy
N
N
N
2
OR1
4
PPh2
PPh2
Cl
Ad
2g
2h
2i
Ph
Bn
CF3
8
9
Scheme 1
QUINAP (1)
Quinazolinap (2)
Figure 1
In addition, the reaction of 4-chloroquinazoline 8 and 2,4-
dichloroquinazoline with 1-naphthol to afford 4-(4-hy-
droxynaphthalen-1-yl)quinazoline and 2,4-bis(4-hydroxy-
naphthalen-1-yl)quinazoline, respectively, has been
reported in the patent literature.11 The reaction was selec-
tive for substitution at the 4-position of 1-naphthol. Simi-
lar conditions have been used recently with 2-naphthol (3)
and 2,4-dichloroquinazoline, and afforded the expected
product (substitution at the 1-position).12
However, one of the obstacles to the widespread use of the
Quinazolinap (2) ligands is the length of their synthesis.
Overall fifteen steps were required to obtain the resolved
ligand 2 (Scheme 1).8 One of the key steps is the attach-
ment of the upper and lower rings systems by a Suzuki–
Miyaura reaction between a 4-chloroquinazoline 8 and a
2-alkoxynaphthalen-1-yl boronic acid 4.
A first hint to a possible alternative route was given by
Pal, Yeleswarapu and co-workers with their 4-substituted
The reaction conditions employed in the later process (3
equiv Lewis acid at 80 °C in DCE for 3.5 h) were tested
on 4-chloroquinazoline (8a) and 2-naphthol (3) and we
were pleased to obtain a good yield of 70% of the required
product 9a (Table 1, entry 1). The use of two equivalents
of Lewis acid only slowed the reaction; whereas the use of
SYNLETT 2011, No. 3, pp 0383–0385
x
x.
x
x.
2
0
1
1
Advanced online publication: 25.01.2011
DOI: 10.1055/s-0030-1259507; Art ID: D31910ST
© Georg Thieme Verlag Stuttgart · New York

384
L. Milhau, P. J. Guiry
LETTER
four equivalents had no beneficial effect (entries 2 and 3).
Replacing AlCl3 by other Lewis acids or the use of other
solvents gave either no reaction (entry 4) or lowered the
yield of the reaction (32–53%, entries 5–8).
Table 2 Reaction of 2-Naphthol (3) and Various 4-Chloroquinazo-
lines 8
N
R
OH
N
R
AlCl3
DCE
N
+
N
Table 1 Reaction of 4-Chloroquinazoline (8a) and 2-Naphthol (3)
OH
3
N
8
Cl
N
N
9
Lewis acid
(3 equiv)
N
Cl
8a
Entry
R
Product
9a
Yield (%)
70
solvent
[1 mol/L]
80 °C, 3.5 h
OH
+
1
2
3
4
5
6
7
8
9
H
OH
Me
i-Pr
t-Bu
Cy
Ad
Ph
9b
55
9a
3
9c
58
Entry
Lewis Acid
Solvent
DCE
Yield (%)
9d
85
1
AlCl3
AlCl3
AlCl3
BF3·Et2O
FeCl3
AlCl3
AlCl3
AlCl3
70
43
68
0
9e
100
100
51
2a
3b
4
DCE
9f
DCE
9g
DCE
Bn
CF3
9h
100
100
5
DCE
49
32
46
53
9i
6
DMSO
Toluene
CH2Cl2
substrate with our optimised arylation protocol
(Scheme 2). However, despite variations of solvents,
Lewis acid and temperatures, this did not allow for the
formation of QUINAP precursor 11. Reports of arylation
between 2-naphthol (3) and 2- and 3-position substituted
1-chloroquinazoline do exist, but in these cases the reac-
tion was promoted by UV irradiation.14
7
8
a 2 equiv of Lewis acid were used.
b 4 equiv of Lewis acid were used.
As expected, the selectivity was excellent for the 1-posi-
tion of the naphthalene unit and no other substitution pat-
tern was observed. Moreover, no alkoxidation product
was observed even though reports of such reactions exist
with 4-chloroquinazolines, but neutral or basic conditions
and high temperatures are required for the nucleophilic ar-
omatic substitution to occur.13
N
AlCl3 (3 equiv)
N
DCE
Cl
10
80 °C, 3.5 h
OH
+
OH
Compounds 8a–h were obtained from anthranilamide and
the corresponding acid chloride, followed by chlorination
with phosphorus oxychloride according to the established
procedure.8
11
3
Scheme 2
The trifluoromethyl-substituted analogue 8i was obtained
in 74% yield starting with anthranilamide and trifluoro-
acetic anhydride. Biaryls 9a–i were then prepared using
the optimum conditions from Table 1, entry 1, in yields
ranging from 55% to quantitative.
A preliminary study on the scope of our arylation protocol
extended the substrates to 2-naphthylamines. The desired
product 13a was not obtained when 2-naphthol (3) was re-
placed by 2-aminonaphthalene (12a; Scheme 3). A mix-
ture of compounds was obtained, and no single
component could be isolated for identification. However,
a benzyl-protected amine 12b afforded compound 13b in
67% yield. It was then successfully deprotected by palla-
dium-catalysed hydrogenation to give the primary amine
13a in 87% yield. Furthermore, this approach avoids the
handling of 2-aminonaphthalene (12a) which is a known
carcinogen.
Steric hindrance appears to play an important role as the
yields increase with the size of the R groups (Table 2, en-
tries 2–6). Electronic effects seem also to play a role as
substituents of similar size gave better results when they
were more electron-withdrawing (Table 2, compare en-
tries 2 and 9).
In an attempt to extend this methodology to the synthesis
of QUINAP (1), 1-chloroisoquinoline (10) was tested as a
Synlett 2011, No. 3, 383–385 © Thieme Stuttgart · New York

LETTER
Novel Palladium-Free Synthesis of a Key Quinazolinap Precursor
385
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N
Ph
N
Ph
N
N
Cl
+
AlCl3 (3 equiv)
DCE
8g
NHR
80 °C, 3.5 h
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NHR"
13a R = H
0%
H2, Pd/C
87%
13b R = Bn 67%
12a R = H
12b R = Bn
Scheme 3
In conclusion, a robust new method has been developed to
obtain the Quinazolinap scaffold.15 Overall, five steps
have been removed from the previous synthetic route as
the nucleophilic component of the Suzuki reaction, the
boronic acid, is no longer required because the biaryl is
formed directly from 2-naphthol. The 2-trifluoromethyl-
substituted intermediate 5i is currently being progressed
to give a novel Quinazolinap ligand. The approach report-
ed herein is now the favoured method for the preparation
of this class of ligand.
(9) Pal, M.; Batchu, V. R.; Parasuraman, K.; Yeleswarapu, K. R.
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US Patent, 20050277772, 2005.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
procedures and spectroscopic data for previously unreported com-
pounds 8i, 9i, 13a and 13b.
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Acknowledgment
Ludovic Milhau acknowledges the award of an IRCSET Enterprise
Partnership Scheme scholarship co-funded by Eli Lilly.
References and Notes
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(15) Typical Procedure: 2-Naphthol (1 mmol), 4-chloroquinaz-
oline (1 mmol) and AlCl3 (3 mmol) were suspended in DCE
(3 mL) in a Schlenk tube under a nitrogen atmosphere. The
mixture was heated at 80 °C for 3.5 h and then diluted with
CH2Cl2 (15 mL). The mixture was washed with 1 M NaOH
solution (15 mL), sat. NH4Cl solution (15 mL), H2O (15
mL), brine (15 mL), dried over MgSO4, filtered and eva-
porated under reduced pressure. The crude product could be
directly used in the subsequent steps of the synthesis without
significant loss of yield compared to the use of pure
compound. Nevertheless, purification was achievable by
column chromatography using silica gel and CH2Cl2 as
eluent. Compounds were identical to known samples.
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Synlett 2011, No. 3, 383–385 © Thieme Stuttgart · New York

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