Addition of α-lithiated nitriles to azaheterocycles

Article abstract of DOI:10.1055/s-0033-1340680

The addition of α-deprotonated nitriles to azaheteroA?-cycles followed by rearomatization is described. A simple two-step, one-pot procedure for the sequence is also presented. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340680

LETTER
▌677
lAettder dition of α-Lithiated Nitriles to Azaheterocycles
Addition of α-Lithiated Nitriles to Azaheterocycles
Corey Anderson,* Jesus Moreno, Sabine Hadida
Vertex Pharmaceuticals, 11010 Torreyana Rd., San Diego CA 92121, USA
Fax +1(858)4046726; E-mail: Corey_Anderson@vrtx.com
Received: 21.11.2013; Accepted after revision: 07.01.2014
ested in evaluating if this sequence could be extended to
other heterocyclic systems and enolates.
Abstract: The addition of α-deprotonated nitriles to azahetero-
cycles followed by rearomatization is described. A simple two-step,
one-pot procedure for the sequence is also presented.
Initially, the addition of α-lithiated nitriles6 to quinazoline
(1) was evaluated; acetonitrile, propiononitrile, and iso-
butyronitrile all added to quinazoline smoothly yielding
the desired dihydroquinazaolines 2a–c in excellent yields
(Scheme 1).
Key words: quinazoline, oxidation, nitrile, dehydrogenation,
pyrimidine
During the course of a medicinal chemistry program, we
observed that α-lithiated nitriles readily added across the
N3=C4 bond in the quinazoline (1) ring system (Scheme
1). Inspired by this observation, we felt that this reaction
could be useful for the introduction of fragments that
readily increases the fraction sp3 character1 of a molecule
and provides a handle for additional manipulation.
It is worth noting that these intermediates were stable and
readily isolated by column chromatography. With these
building blocks in hand, dehydrogenation conditions to
convert the newly substituted dihydroquinazoline into its
corresponding quinazoline were explored (Table 1).
Oxidation conditions based around bleach (NaClO),7
NaClO2,8 DDQ,2 oxone,9 or iron10 failed to provide any
dehydrogenation of the functionalized quinazoline (data
not shown). Iodine,11 hypervalent iodine reagents,12 and
CAN showed promise,13 but in some cases also caused the
cleavage of the nitrile back to the starting quinazoline (Ta-
ble 1, entries 1–5). Oxidation conditions using catalytic
copper chloride with tert-butyl hydrogen peroxide
(TBHP) gave an excellent conversion into product (Table
1, entry 6).14 Increasing the amount of the CuCl2 and
TBHP shortened the reaction time and improved the yield
(Table 1, entry 7). Manganese dioxide under microwave
conditions15 provided a fast conversion into 3, but did not
translate to a favorable isolated yield due to oxygenated
side products (Table 1, entry 8). Aqueous potassium per-
manganate in the presence of acetic acid gave an incom-
plete conversion into product (Table 1, entry 9) and
caused the undesired formation of quinazoline (1). How-
ever, stirring 2c with KMnO4 in acetonitrile at room tem-
perature provided rapid and clean conversion into 3 in a
good isolated yield (Table 1, entry 10).
N
R2
R1
R2
4
3
R1
N
N
NH
N
1
LiHMDS
THF
N
1
2a: R1 = H, R2 = H; 93%
2b: R1 = H, R2 = Me; 90%
2c: R1 = Me, R2 = Me; 92%
–78 °C to r.t.
1 h
Scheme 1 Preparation of dihydroquinazolines
The addition of organolithium and Grignard reagents
across the N1=C6 position of a pyrimidine ring, followed
by oxidation, is a well-established route to substituted al-
kyl and aryl pyrimidines.2 Addition of a tert-butyl radical3
and enolates (such as malonate) to the N3=C4 bond of
quinazoline (1) have been briefly described, but were lim-
ited to very reactive carbanions and further oxidation was
not thoroughly investigated.4 Alternatively, direct dis-
placement of 4-chloroquinazoline or 4-methoxyquinazo-
line with the sodium enolates has also been used to
synthesize similar compounds,5 but this introduces the
need to prepare the activated quinazoline ring.
Having established oxidation protocols, we wanted to
simplify the procedure by developing a one-pot addition–
oxidation sequence. In these reactions, the oxidant was
added directly to the reaction mixture after the intermedi-
ate dihydroquinazoline was formed. Slightly altered con-
ditions were evaluated to account for the lack of
purification between steps. In all cases (Table 2) the de-
sired product was formed, with the addition of two equiv-
alents of KMnO4 and acetonitrile as a cosolvent providing
results identical to the two-step sequence.
Using this optimized one-pot procedure,16 the scope of
secondary nitriles was evaluated in the reaction sequence
(Table 3). Simple nitriles performed best in this reaction
(Table 3, entries 1–3). Alkyl amines and free amino
groups were tolerated but the latter at the cost of a lower
We felt that addition of α-deprotonated nitriles to the
N3=C4 bond in the quinazoline system, followed by re-
aromatization, was an underutilized synthetic sequence
worth exploring. Our aim was to develop reaction condi-
tions that allowed the introduction of a wide variety of
nitrile inputs onto the quinazoline core followed by dehy-
drogenation to the parent heterocycle. We were also inter-
SYNLETT 2014, 25, 0677–0680
Advanced online publication: 05.02.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340680; Art ID: ST-2013-R1077-L
© Georg Thieme Verlag Stuttgart · New York

678
C. Anderson et al.
LETTER
Table 1 Evaluation of Oxidation Conditions
N
N
conditions
NH
N
N
+
N
N
N
2c
3
1
Entry
Reaction conditions
Ratio 2c/3/1a
Yield (%)b
1
2
I2 (2 equiv), MeCN, 50 °C
37:10:53
7:31:62
0:88:12
86:14:0
38:62:0
4:92:4
–
IBD (2.2 equiv), CH2Cl2, r.t., 24 h
–
3
IBX (1.1 equiv), CH2Cl2, r.t. to 80 °C, 24 h
DMP (2.2 equiv), MeCN, r.t., 3 h
–
4
–
5
CAN (3 equiv), acetone, 50 °C, 24 h
–
6
CuCl2 (0.01 equiv), TBHP (2 equiv), K2CO3 (0.1 equiv), CH2Cl2, 35 °C, 24 h
CuCl2 (0.1 equiv); TBHP (4 equiv), K2CO3 (0.3 equiv), CH2Cl2, 35 °C, 3 h
MnO2 (10 equiv), CH2Cl2, 100 °C, microwave
54
63
38
–
7
2:96:2
8
0:94:6
9
KMnO4 (1 equiv), H2O–AcOH (8:1), 60 °C, 24 h
35:48:17
0:99:1
10
KMnO4 (1 equiv), MeCN, r.t., 3 h
74
a Conversion as analyzed by LC–MS at 220.
b Isolated yield of 3.
lithiated nitrile to quinazoline. The use of secondary ben-
zylic nitriles (Table 3, entry 9) was limited by its poor ad-
dition to quinazoline (ca. 10% conversion by LC–MS
analysis) and attempted oxidation gave a mixture of over-
oxidized products.
Table 2 One-Pot Addition then Oxidation
N
N
LiHMDS, THF
N
–78 to 23 °C, 1 h
N
+
then oxidation
N
N
Heterocycles other than quinazoline were evaluated under
the one-pot reaction conditions (Table 4). Pyrimidines
with an ester or halogen gave the desired products, but in
reduced yield. LC–MS analysis of the reaction mixture
showed that the nitrile did add to the pyrimides in >80%
conversion, but oxidation generated undesired side prod-
ucts and may have caused some of the intermediate to re-
vert back to the starting heterocycle thus reducing the
yields.
3
1
Entry Conditions
Yield
(%)a
1
2
3
4
IBD (1.1 equiv), 23 °C, 8 h
43
31
66
75
CuCl2 (0.01 equiv), TBHP (2 equiv), 50 °C, 8 h
MnO2 (10 equiv), 50 °C, 7 h
The electronics of the ring system played an important
part in facilitating reactivity. Pyrimidines with multiple
electron-donating groups (Table 4, entry 6), did not react
to provide the dihydropyrimidine intermediate (via LC–
MS analysis). Conversely, heterocycles with strong elec-
tron-withdrawing groups (Table 4, entry 7) reacted readily
with the deprotonated nitrile to provide the dihydro inter-
mediate followed by dehydrogenation to the desired prod-
uct. Nitrile- and CF3-substituted pyridines were also
evaluated, but failed to undergo reaction with the α-lithi-
ated nitrile.
KMnO4 (2 equiv), MeCN, r.t., 4 h
a Isolated yield.
yield (Table 3, entries 4 and 5). Common amine protect-
ing groups such as Boc, Bn, and Cbz were unaffected in
the synthetic sequence (Table 3, entries 6–8).
In addition, both the 2-chloroquinazoline (Table 3, entry
10) and ethyl quinazoline-2-carboxylate (Table 3, entry
11) reacted likewise, but in reduced yield. In the case of
the ester, the lower yield was due to a competing side re-
action of the deprotonated nitrile with the ester to produce
a ketone; this could be minimized by not allowing the re-
action mixture to go above 0 °C during the addition of the
In addition to secondary nitriles, we were interested in be-
ing able to introduce both primary nitriles and acetonitrile
to the heterocyclic core. Compounds 2a and 2b were sub-
ject to KMnO4 dehydrogenation, but the major product in
Synlett 2014, 25, 677–680
© Georg Thieme Verlag Stuttgart · New York

LETTER
Addition of α-Lithiated Nitriles to Azaheterocycles
679
Table 3 Nitrile Inputs
O
N
N
HO
KMnO4
MeCN
N
R
LiHMDS, THF
nitrile
–78 °C to r.t.
N
NH
N
N
N
N
N
N
then KMnO4
MeCN
N
R
N
2b
4: 37%
Scheme 2 KMnO4 oxidation of 2b
Entry
1
Nitrile
R
H
Yield (%)a
94
N
N
N
N
N
termediate converted back into quinazoline after the addi-
tion of KMnO4 (Table 5, entry 5).18 Isolation of the
intermediate dihydroquinazoline was also unsuccessful.
2
3
4
5
6
H
H
H
H
H
92
76
51
82
84
In conclusion, we have shown that the lithium salts of
nitriles efficiently add to quinazolines yielding dihydro-
quinazolines. The products from the addition of secondary
nitriles undergo dehydrogenation to the desired quinazo-
line derivative with several oxidizing reagents, KMnO4
proving to be the most efficient. Pyrimidines, as well as
other enolates, also have the potential to undergo this type
O
HN
Me
N
Table 4 Heterocyclic Inputs
Cbz
N
N
R2
N
R1
LiHMDS, THF
nitrile
–78 °C to r.t.
N
N
N
R3
7
8
H
H
82
84
N
R3
Boc
then KMnO4
MeCN
X
X
N
N
Entry
Heterocyclea
Nitrile
Yield (%)b
19
Bn
O
9
H
0b
*
N
1
N
EtO
N
N
N
N
10
11
Cl
46
42
*
N
N
N
2
3
4
5
26
19
20
43
N
CO2Et
Boc
N
*
Br
a Isolated yield.
b See text.
N
N
N
Br
N
*
F
both cases was rearomatization followed by further oxida-
tion of the benzylic center. Reducing the equivalents of
KMnO4 did not stop the overoxidation. In the case of the
secondary nitrile 2b, aromatization was followed by ben-
zylic hydroxylation. A retro-Strecker-type process elimi-
nates cyanide to give the methyl ketone derivative in 37%
yield (Scheme 2).17 Although, not the desired outcome,
this represents a novel way to produce 4-keto-quinazo-
lines.
N
*
Cl
N
N
N
Boc
N
MeO
6
0c
N
N
N
*
N
OMe
*
Other nucleophiles were evaluated to expand the inputs
available to us. Deprotonated sulfones participated in the
sequence to give both quinazoline and pyrimidine deriva-
tives (Table 5).
O2N
7
21d
N
a * Denotes the position of substitution.
b Isolated yield.
The lithium enolate of ethyl isopropylester readily added
to give a dihydroquinazoline intermediate (as observed by
LC–MS analysis), but instead of dehydrogenation, the in-
c See text.
d Addition was only observed at the 6 position of the pyridine.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 677–680

680
C. Anderson et al.
LETTER
(10) Xia, J. J.; Wang, G. W. Synthesis 2005, 2379.
Table 5 Other α-Lithiated Electrophiles
(11) (a) Zeynizadeh, B.; Dilmaghani, K. A.; Roozijoy, A. J. Chin.
Chem. Soc. (Weinheim, Ger.) 2005, 52, 1001. (b) Yadav, J.
S.; Reddy, S.; Sabitha, G.; Reddy, G. S. K. K. Synthesis
2000, 1532.
(12) (a) Karade, N. N.; Gampawar, S. V.; Kondre, J. M.; Tiwari,
G. B. Tetrahedron Lett. 2008, 6698. (b) Kumar, P.; Kumar,
A.; Hussain, K. Ultrason. Sonochem. 2012, 729.
R2
R1
EWG
N
LiHMDS, THF
–78 °C to r.t.
R2
EWG
N
R3
+
R3
R1
N
then KMnO4
MeCN
N
(c) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T.
Angew. Chem. Int. Ed. 2003, 42, 4077. (d) Yadav, J. S.;
Reddy, B. V. S.; Basak, A. K.; Baishya, G.; Narsaiah, A. V.
Synthesis 2006, 45.
Entry
1
Heterocycle
R1R2CH2EWG
Yield (%)a
O
O
N
N
(13) Shanmugam, P.; Perumal, P. T. Tetrahedron 2006, 9726.
(14) Yamamoto, K.; Chen, Y. G.; Buono, F. Org. Lett. 2005, 7,
4673.
(15) Bagley, M. C.; Lubinu, M. C. Synthesis 2006, 1283.
(16) General Procedure: 1-(Quinazolin-4-yl)-
38
S
S
O
Cl
N
cyclohexanecarbonitrile (Table 3 Entry 1)
2
5
45
0b
To a solution of cyclohexanecarbonitrile (146 μL, 1.2 mmol,
1.2 equiv) in THF (5 mL) at –78 °C was added LiHMDS (1.2
mL of 1 M in THF, 1.2 mmol, 1.2 equiv) dropwise and
stirred at –78 °C for 5 min. Quinazoline (130 mg, 1.0 mmol,
1.0 equiv) was added, the cooling bath was removed, and the
reaction mixture was stirred for 1 h. Solid KMnO4 (316 mg,
2 mmol, 2 equiv) and MeCN (1 mL) were added, and the
reaction mixture was stirred at r.t. until the reaction was
complete (as judged by LC–MS analysis, in this case 4.5 h).
The reaction mixture was poured into sat. aq NaHCO3 and
extracted with EtOAc (3×). The organic layers were
combined, washed with brine, dried (Na2SO4), filtered, and
evaporated to dryness. The crude residue was purified by
silica gel flash chromatography (12 g silica, 0–40% EtOAc
in hexanes) to yield 1-(quinazolin-4-yl)cyclohexane-
carbonitrile as a white solid (222 mg, 94% yield). 1H NMR
(400 MHz, CDCl3): δ = 9.29 (s, 1 H), 8.70 (d, J = 8.6 Hz, 1
H), 8.13 (d, J = 8.2 Hz, 1 H), 7.94 (ddd, J = 8.4, 6.9, 1.3 Hz,
1 H), 7.72 (ddd, J = 8.4, 6.9, 1.3 Hz, 1 H), 2.52 (d, J = 12.3
Hz, 2 H), 2.17–2.08 (m, 2 H), 2.02–1.95 (m, 4 H), 1.93–1.87
(m, 1 H), 1.40–1.28 (m, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 166.61, 153.75, 151.05, 133.79, 130.02, 127.89,
124.73, 122.31, 121.92, 44.40, 35.58, 25.06, 22.97 ppm.
(17) Yin, Z.; Zhang, Z.; Kadow, J. F.; Meanwell, N. A.; Wang, T.
J. Org. Chem. 2004, 69, 1364.
N
O
O
N
N
EtO
a Isolated yield.
b See text.
of chemistry, but in lower yields. Future work will be di-
rected to expanding the scope of heterocycles that can par-
ticipate in this reaction along with enabling the use of
other enolates.
Acknowledgment
We would like to thank John Saunders for his encouragement and
support of this work.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
References and Notes
(18) We speculate that the ease of enolate formation may be why
dehydrogenation was not observed under these conditions
(Scheme 3). Alternatively, as pointed out by a reviewer, the
ester intermediate can adopt a six-membered transition state
that could facilitate the reverse process (Scheme 4).
(1) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009,
52, 6752.
(2) Harden, D. B.; Mokrosz, M. J.; Strekowski, L. J. Org. Chem.
1988, 53, 4137.
(3) De Bie, D. A.; Nagel, A.; Van Der Plas, H. C.; Geurtsen, G.;
Koudijs, A. Tetrahedron Lett. 1979, 649.
(4) Higashino, T.; Ito, I.; Hayashi, E. Chem. Pharm. Bull. 1972,
1544.
(5) (a) Higashino, T.; Ito, H.; Watanabe, M.; Hayashi, E.
J. Pharm. Soc. Jpn. 1973, 94. (b) Elderfield, R. C.; Serlin, I.
J. Org. Chem. 1951, 16, 1669. (c) Mizuno, Y.; Adachi, K.;
Ikeda, K. J. Pharm. Soc. Jpn. 1954, 225.
(6) (a) Klapars, A.; Waldman, J. H.; Campos, K. R.; Jensen, M.
S.; McLaughlin, M.; Chung, J. Y. L.; Cvetovich, R. J.; Chen,
C. J. Org. Chem. 2005, 70, 10186. (b) Chang, R. K.; Di
Marco, C. N.; Pitts, D. R.; Greshock, T. J.; Kuduk, S. D.
Tetrahedron Lett. 2009, 6303.
M
O
OEt
H
N
N
H
OEt
M
+
B
N
N
O
Scheme 3
OEt
(7) Stevens, R. V.; Chapman, K. T.; Weller, H. N. J. Org. Chem.
1980, 45, 2030.
(8) Liao, X.; Lin, L.; Lu, J.; Wang, C. Tetrahedron Lett. 2010,
3859.
(9) Liu, Z.; Yu, W.; Yang, L.; Liu, Z. Tetrahedron Lett. 2007,
5321.
O
H
N
N
OEt
+
N
N
O
Scheme 4
Synlett 2014, 25, 677–680
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.