Preparation of polyfunctionalized 2,6-dimethoxypyrimidine derivatives via chemo- and regioselective direct zinc insertion

Article abstract of DOI:10.1055/s-2007-983885

The functionalization at the C4 and/or C5 positions of 2,6- dimethoxypyrimidine derivatives via direct chemo- and regioselective zinc insertions is described. The insertion of commercially available zinc dust into C-I and C-Br bonds, in the presence of Li

Full text of DOI:10.1055/s-2007-983885

PRACTICAL SYNTHETIC PROCEDURES
3915
Preparation of Polyfunctionalized 2,6-Dimethoxypyrimidine Derivatives via
Chemo- and Regioselective Direct Zinc Insertion
Preparation of
P
oly
a
functionali
r
zed 2, 6-
u
D
imethoxyp
n
yrimidines ee Soorukram, Nadège Boudet, Vladimir Malakhov, Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13,
Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: paul.knochel@cup.uni-muenchen.de
Received 5 April 2007; revised 9 May 2007
PSP
No105
Abstract: The functionalization at the C4 and/or C5 positions of 2,6-dimethoxypyrimidine derivatives via direct chemo- and regioselective
zinc insertions is described. The insertion of commercially available zinc dust into C–I and C–Br bonds, in the presence of LiCl, proceeded
under mild reaction conditions. The reactions of the resulting organozinc reagents with electrophiles gave the expected products in good
yields. This procedure represents a new method for the polyfunctionalization of uracil derivatives.
Key words: insertion, organozinc compounds, zinc, pyrimidine, uracil
Procedure 1
O
OMe
N
OMe
OMe
N
1. CuCN·2LiCl (0.5 equiv)
–30 °C, 30 min
6
Zn dust (3 equiv)
I
LiCl·ZnI
1
2
t-Bu
N
5
4
LiCl (2 equiv), THF
50 °C, 1 h
2. pivaloyl chloride (1.3 equiv)
–30 °C to r.t.
N
OMe
OMe
N
3
OMe
N
OMe
1a
2a: 95%
3a: 84%
I
Procedure 2
OMe
N
OMe
N
EtO2C
Zn dust (3 equiv)
(1.2 equiv)
N
N
OMe
LiCl (2 equiv), THF
50 °C, 2 h
Pd(dba)2 (5 mol%)
P(o-furyl)3 (10 mol%)
THF, reflux, 4 h
LiCl·ZnI
N
OMe
I
N
OMe
EtO2C
1b
2b: 96%
3b: 82%
Procedure 3
CO2Et
OMe
N
OMe
OMe
N
Br
EtO2C
EtO2C
Zn dust (3 equiv)
(1.1 equiv)
EtO2C
EtO2C
N
LiCl (2 equiv), THF
25 °C, 1 h
CuCN·2LiCl (cat.)
0 °C, 1 h
N
OMe
I
N
OMe
LiCl·ZnI
N
OMe
1c
2c: 98%
3c: 94%
Procedure 4
EtO2C
I
OMe
OMe
OMe
N
I
LiCl·ZnI
Cl
Zn dust (3 equiv)
(1.2 equiv)
EtO2C
N
N
LiCl (2 equiv), THF
50 °C, 3 h
Pd(dba)2 (5 mol%)
P(o-furyl)3 (10 mol%)
THF, 25 °C, 2 h
Cl
N
OMe
Cl
N
OMe
N
OMe
OMe
1d
2d: 96%
3d: 91%
Procedure 5
O
OMe
N
OMe
OMe
N
1. CuCN·2LiCl (0.5 equiv)
–30 °C, 30 min
I
Zn dust (1.5 equiv)
LiCl·ZnI
I
N
LiCl (1.5 equiv), THF
50 °C, 3 h
R
I
N
OMe
2.
COCl
R
I
N
OMe
N
3e: R = Ph: 83%
3f: R = F: 81%
1e
2e: 98%
(1.1 equiv), –30 °C to 25 °C
I
Procedure 6
NC
OMe
OMe
N
OMe
N
Zn dust (1.5 equiv)
Br
LiCl·ZnBr
Br
NC
N
(1.2 equiv)
LiCl (1.5 equiv), THF
25 °C, 12 h
Pd(dba)2 (5 mol%)
P(o-furyl)3 (10 mol%)
THF, reflux, 2 h
Br
N
1f
OMe
N
OMe
Br
N
OMe
2f: 95%
3g: 86%
Scheme 1
SYNTHESIS 2007, No. 24, pp 3915–3922
x
x.
x
x
.
2
0
0
7
Advanced online publication: 29.08.2007
DOI: 10.1055/s-2007-983885; Art ID: T06707SS
© Georg Thieme Verlag Stuttgart · New York

3916
D. Soorukram et al.
PRACTICAL SYNTHETIC PROCEDURES
3b was obtained in 82% yield. The zinc insertion into 4-
iodo-2,6-dimethoxypyrimidine-5-carboxylic acid ethyl
Introduction
Organozinc compounds are important organometallic in- ester required milder reaction conditions (Procedure 3).
termediates in modern organic synthesis. They tolerate a Thus, treatment of the iodoester 1c14 with zinc dust (3
wide range of functional groups and display an excellent equiv) in the presence of LiCl (2 equiv) in THF gave the
reactivity in the presence of appropriate catalysts (Pd, Cu, corresponding zinc reagent 2c after stirring at 25 °C for 1
Ti…).1 The direct insertion of zinc into organic halides is hour. A copper-catalyzed allylation [CuCN·2LiCl (5
the most general method for the preparation of functional- mol%)] with ethyl (2-bromomethyl)acrylate (1.1 equiv,
ized organozinc halides. The zinc insertion into an sp2 C– 0 °C, 1 h) led to the diester 3c in 94% yield. Starting from
X bond is more difficult than into an sp3 C–X bond and re- 4-chloro-5-iodo-2,6-dimethoxypyrimidine (1d),14 the
quires either the use of polar solvents2 (such as hexameth- zinc insertion provided 4b in 98% yield (Procedure 4). A
ylphosphoramide, N,N-dimethylformamide, dimethyl Negishi cross-coupling reaction with ethyl 4-iodoben-
sulfoxide, acetonitrile or tetramethylurea), elevated reac- zoate [Pd(dba)2 (5 mol%), P(o-furyl)3 (10 mol%), THF,
tion temperatures, or the use of highly activated zinc 25 °C, 2 h] led to the desired functionalized pyrimidine 3d
(Rieke zinc).3
in 91% yield.
Recently, we have found that LiCl considerably acceler- Various electrophiles such as aryl iodides, acyl chlorides
ates the bromine–magnesium exchange reaction on aryl and 3-iodo-2-cyclohexenone, react with the organozinc
and heteroaryl bromides.4 We have reported a protocol for derivative 2d, and a variety of polyfunctionalized 2,6-
the preparation of functionalized aryl- and alkylzinc com- dimethoxypyrimidines could be prepared in moderate to
pounds by the direct insertion of commercially available high yields (45–96%, entries 1–5, Table 1). The palladi-
Zn powder in the presence of LiCl in THF.5 This method um-catalyzed cross-coupling15 with 4-iodobenzonitrile
allows a simple, high yielding preparation of a broad provided the expected product 3h in 89% yield (entry 1).
range of functionalized aryl- and heteroarylzinc reagents. The acylation reactions in the presence of CuCN·2LiCl
These results encouraged us to study the zinc insertion (0.5 equiv) led to the products 3i–k in moderate to good
with various uracil derivatives. This class of heterocycles yields (entries 2–4). The 1,4-addition-elimination of 2d
is present in DNA and related natural products.6 General- with 3-iodocyclohex-2-en-1-one16 gave the expected
ly, the functionalization of uracil derivatives requires pro- product 3l in 96% isolated yield (entry 5). Interestingly,
tection steps and functional groups are implemented by the zinc insertion into dihalogenated 2,6-dimethoxypyri-
directed lithiation7 or bromine–lithium exchange midine displays an excellent regioselectivity. Thus, treat-
reaction8 starting from 2,6-dialkoxy-5-halogenopyrim- ment of 4,5-diiodo-2,6-dimethoxy-pyrimidine (1e)14 with
idines. Recently, we also reported a chemo- and regiose- Zn/LiCl (1.5 equiv, 50 °C, 3 h, Procedure 5, Scheme 1)
lective functionalization of uracil derivatives at C4 and C5
positions, starting from 5-bromo-4-halogeno-2,6-
F
dimethoxypyrimidines by a LiCl-catalyzed Br–Mg ex-
change reaction using i-PrMgCl·LiCl.9
O
I
OMe
N
Zn powder
(3 equiv)
OMe
N
Herein, we wish to describe our results for the preparation
of zincated uracil derivatives by direct regioselective zinc
insertion starting from halogenated 2,6-dimethoxypyrim-
idines, as well as the reactions of the resulting organozinc
reagents with electrophiles.
LiCl (2 equiv),
THF
F
N
OMe
O
25 °C, 1 h
LiCl·ZnI
N
OMe
2g: 96%
3f
R
Results and Discussion
Br
(1.1 equiv)
First, we treated 5-iodo-2,6-dimethoxypyrimidine10 (1a,
Procedure 1, Scheme 1) with commercial zinc dust (3
equiv)11 in the presence of LiCl (2 equiv) in THF. After 1
hour at 50 °C, a full conversion12 of 1a was observed and
the corresponding organozinc compound 2a was obtained
in 95% yield.13 Subsequently, the transmetalation with
CuCN·2LiCl (0.5 equiv) and the reaction with pivaloyl
chloride (1.3 equiv, –30 to 25 °C) gave cleanly the expect-
ed ketone 3a in 84% yield. The zinc insertion into 4-iodo-
2,6-dimethoxypyrimidine (1b)14 was performed at 50 °C
for 2 hours (Procedure 2) to give the zinc organometallic
2b in 96% yield. After a palladium-catalyzed cross-
coupling15 with ethyl 4-iodobenzoate (1.2 equiv), under
reflux conditions (4 h), the expected biphenyl derivative
CuCN·2LiCl (cat.)
0 °C, 1 h
O
OMe
N
F
N
OMe
R
3o: R = CO2Et: 80%
3p: R = H: 95%
Scheme 2
Synthesis 2007, No. 24, 3915–3922 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Polyfunctionalized 2,6-Dimethoxypyrimidines
3917
Table 1 Preparation of Functionalized 2,6-Dimethoxypyrimidines via Direct Zinc Insertion
Entry
1
Zinc reagent Yield (%)a
Electrophile
Product Yield (%)b
NC
OMe
OMe
I
ClLi·IZn
N
N
NC
Cl
N
OMe
Cl
N
OMe
3h: 89c
2d: 96
F
O
OMe
N
F
F
F
F
COCl
F
2
2d: 96
Cl
N
OMe
F
F
F
F
3i: 86d
O
OMe
N
COCl
3
4
2d: 96
2d: 96
F
F
Cl
N
OMe
3j: 83d
OMe
O
OMe
N
OMe
COCl
Cl
N
OMe
MeO
3k: 45d
O
OMe
O
OMe
N
5
2d: 96
I
Cl
3l: 96e
EtO2C
N
OMe
OMe
N
OMe
ClLi·IZn
CO2Et
6
7
N
Br
I
N
OMe
I
N
OMe
3m: 87f
2e: 98
OMe
OMe
N
ClLi·BrZn
N
Br
Br
N
OMe
Br
N
OMe
2f: 92
3n: 81f
a Yield estimated after titration with I2.
b Yield of analytically pure product.
c Pd(Ph3P)4 (5 mol%) was added.
d CuCN·2LiCl (0.5 equiv) was added.
e CuCN·2LiCl (1 equiv) was added.
f CuCN·2LiCl (5 mol%) was added.
resulted only in an insertion into the C–I bond at position (12 h, 25 °C, Procedure 6). The corresponding zinc re-
5 to give the zinc reagent 2e. Treatment of 2e with acid agent 2f reacted, by a Negishi cross-coupling,15 with 4-io-
chlorides in the presence of CuCN·2LiCl (0.5 equiv) pro- dobenzonitrile to give the polyfunctional 4-bromo-2,6-
vided the products 3e and 3f in 83 and 81%, respectively. dimethoxypyrimidine (3g) in 86% yield. Furthermore, the
After a transmetalation using catalytic amount of zinc reagent 2f was easily allylated in the presence of cat-
CuCN·2LiCl (5 mol%) followed by the reaction with eth- alytic amount of CuCN·2LiCl (5 mol%) furnishing the ex-
yl (2-bromomethyl)acrylate, the product 3m was obtained pected product 3n in 81% isolated yield (entry 7).
in 87% yield (entry 6). A regioselective zinc insertion at
Starting from 4,5-diiodo-2,6-dimethoxypyrimidine (1e),
two successive zinc insertion reactions were performed
(Scheme 2). Thus, 5-substituted 4-iodo-2,6-dimethoxypy-
position C5 into 4,5-dibromo-2,6-dimethoxypyrimidine
(1f)9 was also obtained under milder reaction conditions
Synthesis 2007, No. 24, 3915–3922 © Thieme Stuttgart · New York

3918
D. Soorukram et al.
PRACTICAL SYNTHETIC PROCEDURES
tion of CuCN·2LiCl in THF (1 M, 0.5 equiv) was added and the
mixture was stirred at –30 °C for 30 min. Pivaloyl chloride (145 mg,
1.3 equiv, 1.2 mmol) was then added at –30 °C. The mixture was
stirred at –30 °C for 1 h and then slowly warmed to 25 °C. The mix-
ture was quenched with sat. aq NH4Cl (10 mL), and the aqueous lay-
er was extracted with EtOAc (4 × 10 mL). The combined organic
extracts were dried (Na2SO4) and concentrated in vacuo. The crude
residue was purified by column chromatography (20% EtOAc–pen-
tane) to give 3a (169 mg) in 84% yield as a colorless oil.
rimidine 3f was subjected into the second insertion to give
the corresponding zinc intermediate 2g. A copper(I)-cata-
lyzed allylation reactions provided the products 3o and 3p
in 80 and 95% isolated yields, respectively (Scheme 2).
In summary, we have developed a synthetic method to se-
lectively functionalize halogenated 2,6-dimethoxypyrim-
idines using a direct zinc insertion in the presence of LiCl.
The zinc insertion proceeds within a practical temperature
range (25–50 °C). Further extensions of this work con-
cerning the large-scale preparation are currently under-
way in our laboratories.
IR (neat): 1694 (m), 1586 (s), 1554 (s), 1468 (s), 1458 (s), 1382 (s),
1320 (m), 1265 (m), 1200 (s), 1173 (m), 1074 (m), 1011 (m), 944
cm–1 (m).
1H NMR (CDCl3, 300 MHz): d = 8.13 (s, 1 H), 4.02 (s, 3 H), 4.00
(s, 3 H), 1.23 (s, 9 H).
13C NMR (CDCl3, 75 MHz): d = 208.8, 167.8, 165.5, 156.5, 116.9,
All reactions were carried out under an argon atmosphere in dried
glassware. THF was continuously refluxed and freshly distilled
from sodium benzophenone ketyl under N2. Yields refer to isolated
compounds estimated to be >95% pure as determined by 1H NMR
and capillary GC analysis.
55.3, 54.3, 45.5, 26.8 (3 C).
MS (EI, 70 eV): m/z (%) = 224 (M+, 3), 167 (100), 124 (3), 72 (2),
59 (5).
HRMS (EI): m/z calcd for C11H16N2O3 [M+]: 224.1161; found:
224.1168.
Zinc Reagent 2a; Procedure 1
Anhyd LiCl (169 mg, 4 mmol) was placed in an argon-flushed flask
and dried for 30 min at 150 °C on high vacuum (1 mbar). After cool-
ing to r.t. under argon, Zn powder (393 mg, 6 mmol) was added and
the heterogeneous mixture of Zn and LiCl was dried again for 30
min at 150 °C on high vacuum (1 mbar). After cooling to r.t. under
argon, the reaction flask was evacuated and refilled with argon three
times. Anhyd THF (5 mL) was added and the zinc powder was ac-
tivated by treatment first with BrCH2CH2Br (25 mL, 5 mol%) and
then with chlorotrimethylsilane (1 mol%). A solution of 5-iodo-2,6-
dimethoxypyrimidine (1a, 532 mg, 2 mmol) in THF (2 mL) was
added and the mixture was heated at 50 °C. The insertion reaction
was complete after 1 h (checked by GC analysis of reaction aliquots,
the conversion was higher than 98%). The organozinc reagent 2a
was titrated using iodine13 showing ca. 0.95 M concentration of 2a
in THF. The solution of 2a was decanted and carefully separated
from the remaining zinc powder using a syringe and transferred to
another dry argon-flushed flask.
4-(2,6-Dimethoxypyrimidin-4-yl)benzoic Acid Ethyl Ester (3b)
A flame-dried round-bottomed flask was charged with Pd(dba)2 (27
mg, 5 mol%), P(o-furyl)3 (22 mg, 10 mol%), and THF (0.9 mL).
The mixture was stirred at 25 °C for 10 min and then transferred to
the reaction flask which was charged with an organozinc solution of
2b, prepared according to Procedure 2 (0.9 mmol), and ethyl 4-io-
dobenzoate (304 mg, 1.2 equiv, 1.1 mmol). The mixture was re-
fluxed for 4 h and then quenched with sat. aq NH4Cl (25 mL). The
aqueous layer was extracted with EtOAc (4 × 25 mL). The com-
bined organic extracts were dried (Na2SO4) and concentrated in
vacuo. The crude residue was purified by column chromatography
(40% Et2O– pentane) to give 3b (213 mg) in 82% yield as a white
solid; mp 116.0–118.2 °C.
IR (neat): 1714 (m), 1597 (m), 1578 (m), 1559 (s), 1467 (m), 1350
(s), 1274 (s), 1217 (m), 1104 (s), 1013 (m), 825 (s), 771 (s), 703
cm–1 (s).
1H NMR (CDCl3, 300 MHz): d = 8.16–8.06 (m, 4 H), 6.82 (s, 1 H),
4.41 (q, J = 7.5 Hz, 2 H), 4.09 (s, 3 H), 4.02 (s, 3 H), 1.41 (t, J = 7.1,
3 H).
13C NMR (CDCl3, 75 MHz): d = 172.7, 166.1, 165.6, 164.8, 140.7,
132.2, 129.9, 126.9, 98.0, 61.2, 54.9, 54.1, 14.3.
Zinc Reagents 2b–e; Procedures 2–6
The zinc reagents were prepared from the corresponding iodides or
bromide as described above and using the following conditions.
Zinc Reagent 2b; Procedure 2
Time and temperature of the insertion: 2 h at 50 °C.
MS (EI, 70 eV): m/z (%) = 288 (M+, 100), 258 (49), 243 (30), 143
(10), 99 (10).
Zinc Reagent 2c; Procedure 3
Time and temperature of the insertion: 1 h at 25 °C.
HRMS (EI): m/z calcd for C15H16N2O4 [M+]: 288.1110; found:
288.1097.
Zinc Reagent 2d; Procedure 4
Time and temperature of the insertion: 3 h at 50 °C.
4-(2-Ethoxycarbonylallyl)-2,6-dimethoxypyrimidine-5-carbox-
ylic Acid Ethyl Ester (3c)
The resulting organozinc solution of 2c from Procedure 3 in THF
(0.7 mmol) was transferred into a dry and argon-flushed flask and
cooled to –20 °C. Ethyl (2-bromomethyl)acrylate (149 mg, 1.1
equiv, 0.77 mmol) was added at –20 °C, followed by a solution of
CuCN·2LiCl in THF (cat., ca. 5 drops). The resulting mixture was
stirred at 0 °C for 1 h and then quenched with sat. aq NH4Cl (25
mL). The aqueous layer was extracted with EtOAc (4 × 25 mL).
The combined organic extracts were dried (Na2SO4) and concentrat-
ed in vacuo. The crude residue was purified by column chromatog-
raphy (40% Et2O–pentane) to give 3c (214 mg) in 94% as a
colorless oil.
Zinc Reagent 2e; Procedure 5
Time and temperature of the insertion: 3 h at 50 °C (in this case only
1.5 equiv of Zn and LiCl were used).
Zinc Reagent 2f; Procedure 6
Time and temperature of the insertion: 12 h at 25 °C (in this case
only 1.5 equiv of Zn and LiCl were used).
All zinc reagents were used as solutions in THF.
1-(2,4-Dimethoxypyrimidin-5-yl)-2,2-dimethylpropan-1-one
(3a)
The organozinc solution of 2a in THF (0.9 mmol) was decanted and
carefully transferred from the rest of Zn powder using a syringe to
the new dry and argon-flushed flask and cooled to –30 °C. A solu-
IR (neat): 1715 (s), 1559 (s), 1483 (m), 1459 (m), 1375 (s), 1360 (s),
1256 (s), 1058 cm–1 (s).
Synthesis 2007, No. 24, 3915–3922 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Polyfunctionalized 2,6-Dimethoxypyrimidines
3919
1H NMR (CDCl3, 200 MHz): d = 6.22–6.18 (m, 1 H) 5.48–5.44 (m,
1 H), 4.28 (dq, J = 1.3, 7.1 Hz, 2 H), 4.12 (dq, J = 1.5, 7.1 Hz, 2 H),
3.93 (d, J = 1.5 Hz, 3 H), 3.88 (d, J = 1.3 Hz, 3 H), 3.77–3.73 (m, 2
H), 1.28 (dt, J = 1.3, 7.0 Hz, 3 H), 1.17 (dt, J = 1.5, 7.0 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 169.5, 169.0, 166.8, 165.7, 164.7,
137.2, 127.0, 108.3, 61.7, 61.0, 55.2, 54.7, 38.0, 14.4, 14.3.
MS (EI, 70 eV): m/z (%) = 324 (M+, 30), 295 (100), 279 (40), 251
(53), 223 (24), 205 (14).
HRMS (EI): m/z calcd for C15H20N2O6 [M+]: 324.1321; found:
324.1330.
(4-Chloro-2,6-dimethoxypyrimidin-5-yl)pentafluorophenyl-
methanone (3i)
The organozinc solution of 2d in THF (1.1 mmol) was decanted and
carefully transferred from the rest of Zn powder using a syringe to
a dry argon-flushed flask and cooled to –30 °C. A solution of
CuCN·2LiCl (1 M in THF, 0.5 equiv) was added and the mixture
was stirred at –30 °C for 30 min. Pentafluorobenzoyl chloride (323
mg, 1.3 equiv, 1.4 mmol) was then added at –30 °C. The mixture
was stirred at –30 °C for 1 h and then slowly warmed to 25 °C. The
mixture was quenched with sat. aq NH4Cl (10 mL), and the aqueous
layer was extracted with EtOAc (4 × 10 mL). The combined organ-
ic extracts were dried (Na2SO4) and concentrated in vacuo. The
crude residue was purified by column chromatography (30% Et2O–
pentane) to give 3i (349 mg, 86%) as a white solid; mp 120.3–
122.9 °C.
4-(4-Chloro-2,6-dimethoxypyrimidin-5-yl)benzoic Acid Ethyl
Ester (3d)
A flame-dried round-bottomed flask was charged with Pd(dba)2 (24
mg, 5 mol%), P(o-furyl)3 (20 mg, 10 mol%), and THF (0.9 mL).
The mixture was stirred at 25 °C for 10 min, and then transferred to
the reaction flask containing an organozinc solution of 2d (0.85
mmol, prepared according to Procedure 4) and ethyl 4-iodoben-
zoate (282 mg, 1.2 equiv, 1.02 mmol). The mixture was stirred at
25 °C for 2 h, then quenched with sat. aq NH4Cl (25 mL), and the
aqueous layer was extracted with EtOAc (4 × 25 mL). The com-
bined organic extracts were dried (Na2SO4) and concentrated in
vacuo. The crude residue was purified by column chromatography
(30% Et2O–pentane) to give 3d (250 mg, 91%) as a white
solid; mp 101.4–103.0 °C.
IR (neat): 1693 (m), 1571 (s), 1521 (s), 1490 (s), 1464 (s), 1395 (m),
1367 (m), 1334 (m), 1309 (m), 1219 (s), 1192 (m), 1081 (s), 1030
(s), 976 (s), 937 cm–1 (s).
1H NMR (CDCl3, 300 MHz): d = 4.00 (s, 3 H), 3.90 (s, 3 H).
13C NMR (CDCl3, 75 MHz): d = 181.0, 169.8, 164.7, 159.9, 147.1,
145.4, 143.6, 142.0, 139.5, 136.1, 113.7, 56.2, 55.7.
MS (EI, 70 eV): m/z (%) = 368 (M+, 100), 338 (32), 201 (68), 195
(47), 167 (25), 117 (11), 76 (26).
HRMS (EI): m/z calcd for C13H6ClF5N2O3 [M+]: 367.9987; found:
367.9965.
IR (neat): 1717 (s), 1587 (m), 1538 (s), 1461 (m), 1375 (s), 1271 (s),
1092 (s), 1022 (s), 937 cm–1 (m).
1H NMR (CDCl3, 300 MHz): d = 8.06–8.00 (m, 2 H), 7.34–7.27 (m,
2 H), 4.33 (q, J = 7.1 Hz, 2 H), 3.98 (s, 3 H), 3.87 (s, 3 H), 1.33 (t,
J = 7. 1 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 169.7, 166.5, 163.7, 159.7, 136.8,
130.7 (2 C), 130.5, 129.7 (2 C), 113.7, 61.3, 55.7, 55.3, 14.6.
MS (EI, 70 eV): m/z (%) = 322 (M+, 100), 293 (15), 277 (63), 234
(14), 199 (8), 177 (7), 170 (8), 114 (9).
HRMS (EI): m/z calcd for C15H15ClN2O4 [M+]: 322.0720; found:
322.0697.
(4-Chloro-2,6-dimethoxypyrimidin-5-yl)(4-fluorophenyl)meth-
anone (3j)
The organozinc solution of 2d in THF (1.1 mmol) was decanted and
carefully transferred from the rest of Zn powder using a syringe to
a dry argon-flushed flask and cooled to –30 °C. A solution of
CuCN·2LiCl (1 M in THF, 0.5 equiv) was added and the mixture
was stirred at –30 °C for 30 min. 4-Fluorobenzoyl chloride (222 mg,
1.3 equiv, 1.4 mmol) was then added at –30 °C. The mixture was
stirred at –30 °C for 1 h and then slowly warmed to 25 °C. The mix-
ture was quenched with sat. aq NH4Cl (10 mL), and the aqueous lay-
er was extracted with EtOAc (4 × 10 mL). The combined organic
extracts were dried (Na2SO4) and concentrated in vacuo. The crude
residue was purified by column chromatography (30% Et2O–pen-
tane) to give 3j (271 mg, 83%) as a white solid; mp 102.2–104.7 °C.
4-(4-Chloro-2,6-dimethoxypyrimidin-5-yl)benzonitrile (3h)
A flame-dried round-bottomed flask was charged with Pd(dba)2 (24
mg, 5 mol%), P(o-furyl)3 (20 mg, 10 mol%), and THF (0.9 mL).
The mixture was stirred at 25 °C for 10 min, and then transferred to
the reaction flask containing an organozinc solution of 2d (0.85
mmol, prepared according to the Procedure 4) and 4-iodobenzoni-
trile (234 mg, 1.2 equiv, 1.02 mmol). The mixture was stirred at
25 °C for 2 h, then quenched with sat. aq NH4Cl (25 mL), and the
aqueous layer was extracted with EtOAc (4 × 25 mL). The com-
bined organic extracts were dried (Na2SO4) and concentrated in
vacuo. The crude residue was purified by column chromatography
(50% Et2O–pentane) to give 3h (208 mg, 89%) yield as a white sol-
id; mp 144.9–146.4 °C.
IR (neat): 1667 (m), 1578 (s), 1536 (s), 1464 (m), 1379 (s), 1268 (s),
1157 (m), 1018 (s), 912 cm–1 (m).
1H NMR (CDCl3, 200 MHz): d = 7.83–7.75 (m, 2 H), 7.13–7.03 (m,
2 H), 4.00 (s, 3 H), 3.87 (s, 3 H).
13C NMR (CDCl3, 75 MHz): d = 189.3, 169.6, 168.4, 165.0, 164.6,
158.4, 133, 132, 116.5, 116.2, 112.7, 56.0, 55.4.
MS (EI, 70 eV): m/z (%) = 296 (M+, 84), 266 (10), 201 (100), 187
(10), 123 (60), 95 (31), 76 (14).
HRMS (EI): m/z calcd for C13H10ClFN2O3 [M+]: 296.0364; found:
296.0345.
IR (neat): 1589 (s), 1535 (m), 1488 (s), 1463 (s), 1394 (s), 1378 (s),
1304 (m), 1244 (m), 1194 (m), 1094 (m), 1019 (s), 993 (m), 938
cm–1 (s).
1H NMR (CDCl3, 300 MHz): d = 7.69–7.61 (m, 2 H), 7.40–7.33 (m,
2 H), 3.98 (s, 3 H), 3.88 (s, 3 H).
13C NMR (CDCl3, 75 MHz): d = 169.5, 163.9, 159.7, 137.1, 132.2
(2 C), 131.6 (2 C), 118.8, 112.9, 112.3, 55.8, 55.4.
MS (EI, 70 eV): m/z (%) = 275 (M+, 100), 260 (12), 245 (32), 240
(17), 210 (16), 182 (12), 175 (12), 140 (16), 114 (8), 102 (6).
(4-Chloro-2,6-dimethoxypyrimidin-5-yl)(2,6-dimethoxyphe-
nyl)methanone (3k)
The organozinc solution of 2d in THF (1.1 mmol) was decanted and
carefully transferred from the rest of Zn powder using a syringe to
a dry argon-flushed flask and cooled to –30 °C. A solution of
CuCN·2LiCl (1 M in THF, 0.5 equiv) was added and the mixture
was stirred at –30 °C for 30 min. 2,6-Dimethoxybenzoyl chloride
(281 mg, 1.3 equiv, 1.4 mmol) was then added at –30 °C. The mix-
ture was stirred at –30 °C for 1 h and then slowly warmed to 25 °C.
The mixture was quenched with sat. aq NH4Cl (10 mL), and the
aqueous layer was extracted with EtOAc (4 × 10 mL). The com-
bined organic extracts were dried (Na2SO4) and concentrated in
HRMS (EI): m/z calcd for C13H10ClN3O2 [M+]: 275.0462; found:
275.0438.
Synthesis 2007, No. 24, 3915–3922 © Thieme Stuttgart · New York

3920
D. Soorukram et al.
PRACTICAL SYNTHETIC PROCEDURES
vacuo. The crude residue was purified by column chromatography
(50% Et2O–pentane) to give 3k (168 mg) in 45% yield as a white
solid; mp 127.9–129.7 °C.
13C NMR (CDCl3, 150 MHz): d = 190.2, 165.0, 161.1, 144.6, 137.3,
131.9, 128.0 (2 C), 126.7 (2 C), 126.1, 125.2 (2 C), 125.0 (2 C),
124.3, 118.9, 53.3, 52.5.
IR (neat): 1673 (m), 1580 (s), 1541 (s), 1472 (s), 1371 (m), 1257 (s),
1242 (s), 1108 (s), 1032 (s), 927 cm–1 (s).
MS (EI, 70 eV): m/z (%) = 446 (M+, 100), 345 (15), 293 (37), 181
(49), 152 (31).
1H NMR (CDCl3, 300 MHz): d = 7.32 (t, J = 8.8 Hz, 1 H), 6.54 (d,
J = 8.8 Hz, 2 H), 4.02 (s, 3 H), 3.92 (s, 3 H), 3.74 (s, 6 H).
HRMS (EI): m/z calcd for C19H15IN2O3 [M+]: 446.0127; found:
446.0109.
13C NMR (CDCl3, 75 MHz): d = 189.5, 169.9, 163.6, 159.1 (2 C),
(4-Fluorophenyl)(4-iodo-2,6-dimethoxypyrimidin-5-yl)meth-
anone (3f)
158.6, 132.7, 119.3, 116.4, 104.4 (2 C), 56.4 (2 C), 55.7, 55.2.
MS (EI, 70 eV): m/z (%) = 338 (M+, 31), 303 (82), 202 (35), 165
(100).
HRMS (EI): m/z calcd for C15H15ClN2O5 [M+]: 338.0670; found:
338.0652:
The organozinc solution of 2e in THF (0.9 mmol) was decanted and
carefully transferred from the rest of Zn powder using a syringe to
a dry argon-flushed flask and cooled to –30 °C. A solution of
CuCN·2LiCl (1 M in THF, 0.5 equiv) was added and the mixture
was stirred at –30 °C for 30 min. 4-Fluorobenzoyl chloride (190 mg,
1.3 equiv, 1.2 mmol) was then added at –30 °C. The mixture was
stirred at –30 °C for 1 h and then slowly warmed to 25 °C for 14 h.
The mixture was quenched with sat. aq NH4Cl (10 mL) and the
aqueous layer was extracted with EtOAc (4 × 10 mL). The com-
bined organic extracts were dried (Na2SO4) and concentrated in
vacuo. The crude residue was purified by column chromatography
(50% Et2O–pentane) to give 3f (283 mg, 81%) as a white solid;
mp 142.6–144.7 °C.
3-(4-Chloro-2,6-dimethoxypyrimidin-5-yl)cyclohex-2-enone
(3l)
The resulting organozinc solution of 2d in THF (0.80 mmol) was
transferred into a dry argon-flushed flask and cooled to –30 °C. A
solution of CuCN·2LiCl (1 M in THF, 1 equiv) was added and the
mixture was stirred at –30 °C for 30 min. 3-Iodocyclohex-2-en-1-
one (195 mg, 1.1 equiv, 0.88 mmol) was then added at –30 °C. The
mixture was stirred at –30 °C for 1 h, then slowly warmed to –10 °C
for 15 h, and quenched with sat. aq NH4Cl (25 mL). The aqueous
layer was extracted with EtOAc (4 × 25 mL). The combined organ-
ic extracts were dried (Na2SO4) and concentrated in vacuo. The
crude residue was purified by column chromatography (50% Et2O–
pentane) to give 3l (206 mg) in 96% as a white solid; mp 120.9–
122.5 °C.
IR (neat): 1669 (m), 1595 (m), 1566 (s), 1525 (s), 1506 (m), 1475
(m), 1455 (m), 1381 (s), 1364 (s), 1312 (s), 1255 (s), 1245 (s), 1225
(s), 1158 (s), 1076 (s), 1015 (s), 920 cm–1 (s).
1H NMR (CDCl3, 400 MHz): d = 7.83–7.77 (m, 2 H), 7.12–7.05 (m,
2 H), 3.98 (s, 3 H), 3.83 (s, 3 H).
13C NMR (CDCl3, 100 MHz): d = 191.6, 167.9, 167.4, 165.3, 163.7,
132.6, 132.3, 126.9, 121.1, 116.5, 116.3, 55.9, 55.1.
MS (EI, 70 eV): m/z (%) = 388 (M+, 55), 358 (5), 293 (30), 136 (37),
123 (100), 95 (81), 75 (28).
IR (neat): 1672 (s), 1581 (s), 1536 (s), 1461 (s), 1388 (s), 1344 (s),
1236 (m), 1190 (m), 1088 (s), 1028 (s), 940 cm–1 (m).
1H NMR (CDCl3, 300 MHz): d = 5.93 (s, 1 H), 3.95 (s, 3 H), 3.92
(s, 3 H), 2.48–2.39 (m, 4 H), 2.15–2.02 (m, 2 H).
13C NMR (CDCl3, 75 MHz): d = 199.2, 168.8, 163.8, 158.3, 154.1,
131.8, 113.5, 55.7, 55.3, 37.6, 29.6, 23.1.
HRMS (EI): m/z calcd for C13H10FIN2O3 [M+]: 387.9720; found:
387.9734.
MS (EI, 70 eV): m/z (%) = 268 (M+, 100), 240 (87), 225 (28), 197
(31), 177 (24), 77 (7).
HRMS (EI): m/z calcd for C12H13ClN2O3 [M+]: 268.0615; found:
268.0591.
2-(4-Iodo-2,6-dimethoxypyrimidin-5-ylmethyl)acrylic Acid
Ethyl Ester (3m)
The resulting organozinc solution of 2e in THF (0.7 mmol) was
transferred into a dry argon-flushed flask and cooled to –20 °C. Eth-
yl (2-bromomethyl)acrylate (149 mg, 1.1 equiv, 0.77 mmol) was
added at –20 °C, followed by a solution of CuCN·2LiCl (cat., ca. 5
drops). The resulting mixture was stirred at 0 °C for 1.5 h and then
quenched with sat. aq NH4Cl (25 mL). The aqueous layer was ex-
tracted with EtOAc (4 × 25 mL). The combined organic extracts
were dried (Na2SO4) and concentrated in vacuo. The crude residue
was purified by column chromatography (40% Et2O–pentane) to
give 3m (230 mg, 87%) as a white solid; mp 49.7–51.5 °C.
Biphenyl-4-yl(4-iodo-2,6-dimethoxypyrimidin-5-yl)methanone
(3e)
The organozinc solution of 2e in THF (0.9 mmol) was decanted and
carefully transferred from the rest of Zn powder using a syringe to
a dry argon-flushed flask and cooled to –30 °C. A solution of
CuCN·2LiCl (1 M in THF, 0.5 equiv) was added and the mixture
was stirred at –30 °C for 30 min. Biphenyl-4-carbonyl chloride (260
mg, 1.3 equiv, 1.2 mmol) was then added at –30 °C. The mixture
was stirred at –30 °C for 1 h and then slowly warmed to 25 °C for
14 h. The mixture was quenched with sat. aq NH4Cl (10 mL) and
the aqueous layer was extracted with EtOAc (4 × 10 mL). The com-
bined organic extracts were dried (Na2SO4) and concentrated in
vacuo. The crude residue was purified by column chromatography
(50% Et2O–pentane) to give 3e (333 mg, 83%) as a white solid;
mp 152.3–154.7 °C.
IR (neat): 1705 (s), 1575 (s), 1534 (s), 1456 (s), 1375 (s), 1221 (s),
1129 (s), 1077 (s), 1015 (s), 944 cm–1 (m).
1H NMR (CDCl3, 300 MHz): d = 6.14–6.10 (m, 1 H), 5.07–5.03 (m,
1 H), 4.20 (q, J = 7.2 Hz, 2 H), 3.91 (s, 3 H), 3.86 (s, 3 H), 3.57–3.54
(m, 2 H), 1.27 (t, J = 7.2 Hz, 2 H).
13C NMR (CDCl3, 75 MHz): d = 168.0, 166.9, 162.8, 136.8, 135.5,
124.5, 117.4, 61.2, 55.5, 54.9, 33.9, 14.5.
IR (neat): 1664 (m), 1600 (m), 1570 (s), 1526 (s), 1460 (m), 1384
(s), 1369 (s), 1311 (s), 1261 (s), 1200 (m), 1075 (s), 1008 (s), 916
cm–1 (s).
1H NMR (CDCl3, 600 MHz): d = 7.85 (d, J = 8.2 Hz, 2 H), 7.63 (d,
J = 8.2 Hz, 2 H), 7.57 (d, J = 7.1 Hz, 2 H), 7.42–7.37 (m, 2 H),
7.36–7.31 (m, 1 H), 3.99 (s, 3 H), 3.84 (s, 3 H).
MS (EI, 70 eV): m/z (%) = 321 [(81Br) – M+, 100], 304 (12), 291
(26), 240 (18), 210 (28), 182 (22), 168 (16), 140 (37).
HRMS (EI): m/z calcd for C13H1081BrIN3O2 [M+]: 320.9936; found:
320.9911.
4-(4-Bromo-2,6-dimethoxypyrimidin-5-yl)benzonitrile (3g)
A flame-dried round-bottomed flask was charged with Pd(dba)2 (24
mg, 5 mol%), P(o-furyl)3 (20 mg, 10 mol%), and THF (0.9 mL).
The mixture was stirred at 25 °C for 10 min and then transferred to
Synthesis 2007, No. 24, 3915–3922 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Polyfunctionalized 2,6-Dimethoxypyrimidines
3921
the reaction flask containing the organozinc solution 2f (0.85 mmol,
prepared according to the Procedure 6) and 4-iodobenzonitrile
(234 mg, 1.2 equiv, 1.02 mmol). The mixture was refluxed for 2 h
and then quenched with sat. aq NH4Cl (25 mL). The aqueous layer
was extracted with EtOAc (4 × 25 mL). The combined organic ex-
tracts were dried (Na2SO4) and concentrated in vacuo. The crude
residue was purified by column chromatography (40% Et2O–pen-
tane) to give 3g (234 mg, 86%) as a white solid; mp 149.1–
150.6 °C.
2-[5-(4-Fluorobenzoyl)-2,6-dimethoxypyrimidin-4-ylmeth-
yl]acrylic Acid Ethyl Ester (3o)
The resulting organozinc solution of 2g in THF (0.7 mmol) was
transferred into a dry argon-flushed flask and cooled to –20 °C. Al-
lyl bromide (93 mg, 1.1 equiv, 0.77 mmol) was added at –20 °C,
followed by a solution of CuCN·2LiCl (cat., ca. 5 drops). The re-
sulting mixture was stirred at 0 °C for 1 h and then quenched with
sat. aq NH4Cl (25 mL). The aqueous layer was extracted with
EtOAc (4 × 25 mL). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo. The crude residue was purified
by column chromatography (50% Et2O–pentane) to give 3o (210
mg, 80%) as a colorless oil.
IR (neat): 2228 (w), 1587 (m), 1531 (m), 1460 (m), 1376 (s), 1324
(m), 1196 (m), 1094 (m), 1019 (m), 992 (m), 936 (m), 832 (m), 790
(m), 741 cm–1 (m).
IR (neat): 1714 (m), 1665 (m), 1575 (s), 1557 (s), 1480 (m), 1458
(m), 1367 (s), 1262 (s), 1144 (s), 1082 (s), 916 (s), 852 cm–1 (m).
1H NMR (CDCl3, 200 MHz): d = 7.89–7.79 (m, 2 H), 7.17–7.07 (m,
2 H), 6.25–6.21 (m, 1 H), 5.58–5.54 (m, 1 H), 4.10 (q, J = 7.3 Hz, 2
H), 3.98 (s, 3 H), 3.86 (s, 3 H), 3.62–3.59 (m, 1 H), 1.20 (t, J = 7.3
Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 192.8, 169.1, 168.3, 168.1, 166.6,
164.9, 164.7, 136.8.
MS (EI, 70 eV): m/z (%) = 374 (M+, 87), 359 (31), 345 (26), 329
1H NMR (CDCl3, 300 MHz): d = 7.70 (d, J = 8.6 Hz, 2 H), 7.40 (d,
J = 8.6 Hz, 2 H), 4.04 (s, 1 H), 3.92 (s, 1 H).
13C NMR (CDCl3, 75 MHz): d = 168.6, 163.4, 152.3, 138.4, 132.0,
131.3, 118.6, 115.6, 112.1, 104.7, 55.6, 55.1.
MS (EI, 70 eV): m/z (%) = 321 (M+, 100), 304 (12), 289 (28), 240
(18), 225 (24), 210 (29), 189 (23), 168 (16), 140 (38).
HRMS (EI): m/z calcd for C13H1081BrN3 [M+]: 318.9936; found:
320.9911.
(23), 313 (15), 301 (81), 287 (18), 275 (71), 123 (100), 95 (35).
HRMS (EI): m/z calcd for C19H19FN2O5 [M+]: 374.1278; found:
374.1285.
5-Allyl-4-bromo-2,6-dimethoxypyrimidine (3n)
The resulting organozinc solution of 2f in THF (1 mmol) was trans-
ferred into a dry argon-flushed flask and cooled to –20 °C. Allyl
bromide (144 mg, 1.2 equiv, 1.2 mmol) was added at –20 °C, fol-
lowed by a solution of CuCN·2LiCl (cat., ca. 5 drops). The resulting
mixture was stirred at 0 °C for 5 h and then quenched with sat. aq
NH4Cl (25 mL). The aqueous layer was extracted with EtOAc
(4 × 25 mL). The combined organic extracts were dried (Na2SO4)
and concentrated in vacuo. The crude residue was purified by col-
umn chromatography (20% Et2O–pentane) to give 3n (210 mg,
81%) as a colorless oil.
(4-Allyl-2,6-dimethoxypyrimidin-5-yl)(4-fluorophenyl)meth-
anone (3p)
The resulting organozinc solution of 2g in THF (0.7 mmol) was
transferred into a dry argon-flushed flask and cooled to –20 °C.
Neat ethyl (2-bromomethyl)acrylate (149 mg, 1.1 equiv, 0.77
mmol) was added at –20 °C, followed by a solution of CuCN·2LiCl
(cat., ca. 5 drops). The resulting mixture was stirred at 0 °C for 1 h
and then quenched with sat. aq NH4Cl (25 mL). The aqueous layer
was extracted with EtOAc (4 × 25 mL). The combined organic ex-
tracts were dried (Na2SO4) and concentrated in vacuo. The crude
residue was purified by column chromatography (40% Et2O–pen-
tane) to give 3p (201 mg, 95%) as a colorless oil.
IR (film): 3081 (w), 2957 (w), 1639 (w), 1586 (m), 1542 (s), 1459
(m), 1370 (s), 1223 (m), 1079 (m), 1026 cm–1 (s).
1H NMR (CDCl3, 400 MHz): d = 5.87–5.77 (m, 1 H), 5.02 (2 dd,
3Jtrans = 13.2 Hz, Jgem and 3Jcis = 1.7 Hz, 2 H), 3.98 (s, 3 H), 3.97 (s,
3 H), 3.35 (dt, 3J = 6.1 Hz, 4J = 1.5 Hz).
13C NMR (75 MHz, CDCl3, 25 °C): d = 170.08, 162.61, 159.98,
133.39, 115.93, 110.71, 55.14, 54.82, 29.57.
IR (neat): 1666 (m), 1556 (s), 1480 (m), 1457 (m), 1367 (s), 1261
(s), 1237 (s), 1155 (m), 1078 (m), 1056 (m), 920 cm–1 (s).
1H NMR (CDCl3, 200 MHz): d = 7.78–7.69 (m, 2 H), 7.09–6.99 (m,
2 H), 5.92–5.76 (m, 1 H), 4.94–4.83 (m, 2 H), 3.96 (d, J = 1.5 Hz, 3
H), 3.79 (d, J = 1.8 Hz, 3 H), 3.32–3.23 (m, 2 H).
MS (EI, 70 eV): 260.0 (98), 258.0 (100), 245.0 (23), 243.0 (22),
231.0 (41), 179.0 (25), 163.0 (14).
13C NMR (CDCl3, 75 MHz): d = 192.9, 169.1, 168.9, 168.0, 165.1,
164.6, 134.2, 133.6, 132.3, 132.1, 118.0, 116.2, 115.9, 113.0, 55.2,
54.4.
HRMS (EI): m/z calcd for C9H11BrN2O2: 258.0004; found:
258.0023.
Zinc Reagent 2g
MS (EI, 70 eV): m/z (%) = 302 (M+, 100), 287 (79), 273 (10), 247
Anhyd LiCl (203 mg, 4.8 mmol) was placed in an argon-flushed
flask and dried 30 min at 150 °C on high vacuum (1 mbar). After
cooling to r.t. under argon, Zn powder (471 mg, 7.2 mmol) was add-
ed, and the heterogeneous mixture of Zn and LiCl was dried again
30 min at 150 °C on high vacuum (1 mbar). After cooling to r.t. un-
der argon, the reaction flask was evacuated and refilled with argon
three times. Anhyd THF (5 mL) was added, and the Zn powder was
activated by treating it first with BrCH2CH2Br (30 mL, 5 mol%) fol-
lowed by chlorotrimethylsilane (1 mol%). Then a solution of (4-flu-
orophenyl)(4-iodo-2,6-dimethoxypyrimidin-5-yl)methanone (3f;
931 mg, 2.4 mmol) in THF (1 mL) was added and the mixture was
stirred at 25 °C. The insertion reaction was complete after 1 h
(checked by GC analysis of reaction aliquots, the conversion was
(6), 207 (8), 191 (12), 123 (56), 95 (26).
HRMS (EI): m/z calcd for C16H15FN2O3 [M+]: 302.1067; found:
302.1076.
Acknowledgment
We thank the Fonds der Chemischen Industrie and the DFG for
financial support. We also thank Chemetall GmbH (Frankfurt),
Degussa GmbH (Hanau), and BASF AG (Ludwigshafen) for the
generous gift of chemicals.
13
higher than 98%). The organozinc reagent 2g was titrated using I2
References
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was carefully separated from the remaining Zn powder using a sy-
ringe and transferred to another dry argon-flushed flask.
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Synthesis 2007, No. 24, 3915–3922 © Thieme Stuttgart · New York

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D. Soorukram et al.
PRACTICAL SYNTHETIC PROCEDURES
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