Metallation of 2,4-dialkoxy-5-bromopyrimidine and formylation with dimethylformamide: Isolation of 2,6-dialkoxy-5-dimethylaminopyrimidine-4- carboxaldehyde

Article abstract of DOI:10.1080/00397910903175397

Direct metallation of 2,4-dialkoxy-5-bromopyrimidine with lithium diisopropylamide and consequent trapping by dimethylformamide resulted unexpectedly in the formation of 2,6-dialkoxy-5-dimethylaminopyrimidine-4- carboxaldehyde via displacement of bromine by dimethylamine moiety of dimethylformamide. Copyright

Full text of DOI:10.1080/00397910903175397

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Metallation of 2,4-Dialkoxy-5-
bromopyrimidine and Formylation with
Dimethylformamide: Isolation of 2,6-
Dialkoxy-5-dimethylaminopyrimidine-4-
carboxaldehyde
Soumita Mukherjee a & Binay K. Ghorai a
a Department of Chemistry , Bengal Engineering and Science
University , Shibpur, Howrah, West Bengal, India
Published online: 08 Jun 2010.
To cite this article: Soumita Mukherjee & Binay K. Ghorai (2010) Metallation of 2,4-Dialkoxy-5-
bromopyrimidine and Formylation with Dimethylformamide: Isolation of 2,6-Dialkoxy-5-
dimethylaminopyrimidine-4-carboxaldehyde, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 40:13, 1939-1943, DOI:
10.1080/00397910903175397
To link to this article: http://dx.doi.org/10.1080/00397910903175397
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Synthetic Communications1, 40: 1939–1943, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903175397
METALLATION OF 2,4-DIALKOXY-5-
BROMOPYRIMIDINE AND FORMYLATION
WITH DIMETHYLFORMAMIDE: ISOLATION OF
2,6-DIALKOXY-5-DIMETHYLAMINOPYRIMIDINE-4-
CARBOXALDEHYDE
Soumita Mukherjee and Binay K. Ghorai
Department of Chemistry, Bengal Engineering and Science University,
Shibpur, Howrah, West Bengal, India
Direct metallation of 2,4-dialkoxy-5-bromopyrimidine with lithium diisopropylamide and
consequent trapping by dimethylformamide resulted unexpectedly in the formation of
2,6-dialkoxy-5-dimethylaminopyrimidine-4-carboxaldehyde via displacement of bromine
by dimethylamine moiety of dimethylformamide.
Keywords: 2,4-Dialkoxy-5-bromopyrimidine; formylation; metallation
Reactions involving halogen substituted heterocycles with strong bases are of great
importance in organic synthesis. These reactions proceed via several competing
mechanisms, described in several comprehensive reviews.[1,2] One of these reaction
pathways is the elimination–addition (EA) mechanism, where the position ortho
to the halogen atom is first deprotonated or metallated prior to elimination of halide
or metal halide. The resulting aryne can then add a nucleophile, affording the pro-
duct. In the case of 5-bromopyrimidine, the existence of 4-lithio-5-bromopyrimidine
was established by Kress, and trapping of that lithiated product by several carbonyl
compounds was also demonstrated.[3]
Here we conducted the metallation of 2,4-dialkoxy-5-bromopyrimidine by
using lithium diisopropylamide (LDA) and trapped the lithiated derivative with
dimethylformamide (DMF). Analogous results were obtained after formylation of
the corresponding lithiated intermediates. In each case, after formylation the bro-
mine atom was replaced by a dimethyl amino moiety. Our detailed study of this kind
of reaction is confined to 2,4-dimethoxy-5-bromopyrimidine (1a), where, after
formylation, two products were obtained. One was the expected aldehyde
[2,6-dimethoxy-5-bromopyrimidine-4-carboxaldehyde (2a)], and the other one was
an unexpected product [2,6-dimethoxy-5-dimethylaminopyrimidine-4-carboxaldehyde
(3a)]. We examined the reaction conditions where the formation of the anomalous
Received March 25, 2009.
Address correspondence to Binay K. Ghorai, Department of Chemistry, Bengal Engineering and
Science University, Shibpur, Howrah 711 103, West Bengal, India. E-mail: bkghorai@yahoo.co.in
1939

1940
S. MUKHERJEE AND B. K. GHORAI
Scheme 1. Reaction of 2,4-dialkoxy-5-bromopyrimidines with LDA and DMF: a, R ¼ Me; b, R ¼ Et; c,
R ¼ nPr.
product (3a) can be diminished with the expected bromo aldehyde (2a) as the major
product (Scheme 1, Table 1). Previous literature gives no report of replacement of a
bromine atom by a dimethyl amine group during formylation with dimethylforma-
mide. Numata et al.[4] had performed the metallation by lithium diisopropylamide in
the case of bromopyridines, followed by electrophilic substitution of the lithiated
Table 1. Synthesis of 2,6-dialkoxy-5-dimethylaminopyrimidine-4-carboxaldehyde
Product yieldb (%)
Entry
Starting materials
Conditionsa
2
3
1
2
3
4
5
6
1a
1a
1a
1a
1b
1c
A
B
2a (6)
2a (22)
2a (25)
2a (52)
—
3a (70)
3a (37)
3a (38)
3a (28)
3b (51)
3c (59)
C
D
A
A
—
aCondition A: t1 ¼ 10 min, t2 ¼ 1 h, quenched at rt; condition B: t1 ¼ 30 min, t2 ¼ 15 min,
quenched at ꢀ78 ꢁC; condition C: t1 ¼ 30 min, t2 ¼ 1 h, quenched at ꢀ78 ꢁC; condition D:
t1 ¼ 2 h, t2 ¼ 2 h, quenched at ꢀ78 ꢁC; where t1 is time of addition of DMF after adding
starting material and t2 is time of stirring after DMF addition at ꢀ78 ꢁC.
bIsolated yield.
Scheme 2. Reaction pathway to 2,6-dialkoxy-5-dimethylaminopyrimidine-4-carboxaldehyde.

METALLATION OF 2,4-DIALKOXY-5-BROMOPYRIMIDINE
1941
derivative with DMF, but replacement of bromine by dimethyl amine moiety of
DMF was not reported. This reaction behavior was found to be generalized to other
alkoxy substituted pyrimidines (e.g., 1b, 1c).
A reasonable reaction pathway for this reaction is depicted in Scheme 2. The
initial step is the lithiation of the pyrimidine derivative 1 to form lithio compound
4, which is subsequently formylated by DMF to give the expected bromo aldehyde
2. The bromine atom adjacent to the aldehyde undergoes nucleophilic substitution
by the dimethylamine anion present in the reaction medium via intermediate 5 to
give dimethylamino aldehyde 3.
These results indicate that the formation of the unexpected aldehydes 3a–c by
this mechanism increases when the reaction mixture was quenched at room tempera-
ture. The yield of desired aldehyde 2a can be increased if quenching is done at ꢀ78ꢁC.
EXPERIMENTAL
All melting points are uncorrected. Unless otherwise noted, all reactions were
carried out under an inert atmosphere in flame-dried flasks. Solvents and reagents
were dried and purified by distillation before use as follows: tetrahydrofuran
(THF) from sodium benzophenone ketyl; DMF and diisopropylamine from CaH2;
and alcohols (methanol, ethanol, and n-propanol) by refluxing over magnesium turn-
ings. After drying, organic extracts were evaporated under reduced pressure, and the
residue was column chromatographed on silica gel (Spectrochem, particle size
100–200 mesh), using an ethyl acetate–petroleum ether (60–80ꢁC) mixture as eluent.
General Procedure for Preparation of 2,4-Dialkoxy-5-
bromopyrimidine[5]
Sodium metal (350 mg, 15.2 mmol) was added to dry alcohol (15 mL). When all
the sodium metal was dissolved, 2,4-dichloro-5-bromopyrimidine (750 mg,
5.03 mmol) [prepared by refluxing 5-bromouracil (1.0 g), phosphorus oxychloride
(14 mL), and dimethylaniline (0.5 mL) for 4 h] was added and refluxed for 2 h. The
reaction mixture was cooled to room temperature, excess alcohol was removed under
reduced pressure, and saturated NH4Cl solution (5 mL) was added. The mixture was
extracted with diethyl ether (3 ꢂ 10 mL), washed with brine (3 mL), and dried over
anhydrous Na2SO4. Removal of the solvent gave 1a–c.
2,4-Dimethoxy-5-bromopyrimidine (1a)[5]
Mp 62–64 ꢁC, white prisms; IR (KBr, cmꢀ1): 1095 (C-Br); 1H NMR (400 MHz,
CDCl3): d 8.28 (s, 1H, ArH), 4.03 (s, 3H, OCH3), 3.97 (s, 3H, OCH3); MS: m=e (rela-
tive intensity): 219, 221 (Mþ, Mþ þ 2, 55, 55), 204, 206 (Mþ-Me, Mþ þ 2-Me, 12, 12),
188 (100), 102 (35).
2,4-Diethoxy-5-bromopyrimidine (1b)[5]
Mp 72–73 ꢁC, white prisms; IR (KBr, cmꢀ1): 1085 (C-Br); 1H NMR (300 MHz,
CDCl3): d 8.28 (s, 1H, ArH), 4.49 (q, 2H, J ¼ 6.9 Hz, OCH2CH3), 4.37 (q, 2H,

1942
S. MUKHERJEE AND B. K. GHORAI
J ¼ 6.9 Hz, OCH2CH3), 1.44 (t, 3H, J ¼ 6.9 Hz, OCH2CH3), 1.41 (t, 3H, J ¼ 6.9 Hz,
OCH2CH3); MS: m=e (relative intensity): 247, 249 (Mþ, Mþ þ 2, 20, 20), 219, 221
(35, 35), 191, 193 (100, 100), 169 (15), 141 (5), 102 (10), 91 (30).
2,4-Dipropoxy-5-bromopyrimidine (1c)
Yellow oil, Rf (10% EtOAc=petroleum ether) 0.52; IR (KBr, cmꢀ1): 1092
1
(C-Br); H NMR (300 MHz, CDCl3): d 8.27 (s, 1H, ArH), 4.37 (t, 2H, J ¼ 6.6 Hz,
OCH2), 4.28 (t, 2H, J ¼ 6.6 Hz, OCH2), 1.90–1.70 (m, 4H, 2-CH2CH3), 1.02 (t,
3H, J ¼ 7.5 Hz, ꢀCH2CH3), 1.00 (t, 3H, J ¼ 7.5 Hz, ꢀCH2CH3); 13C NMR
(75 MHz, CDCl3): d 166.2, 163.7, 158.8, 97.7, 69.4, 69.1, 21.9, 21.7, 10.2, 10.1;
MS: m=e (relative intensity): 275, 277 (Mþ, Mþ þ 2, 5, 5), 233, 235 (18, 18), 191,
193 (100, 96), 141 (55), 122 (30), 117 (52). Anal. calcd. for C10H15BrN2O2: C,
43.65; H, 5.50; N, 10.18. Found: C, 43.84; H, 5.64, N, 10.11.
General Procedure for Metallation of 2,4-Dimethoxy-5-
bromopyrimidine
A solution of 1 (1.60 mmol) in THF (2 mL) was added dropwise to a LDA sol-
ution, prepared from n-butyllithium (1.6 M hexane solution, 4.0 mmol) and diisopro-
pylamine (4.8 mmol) in THF (10 mL) at ꢀ78 ꢁC for 1 h under an argon atmosphere,
and the mixture was stirred at ꢀ78 ꢁC for time t1. After addition of DMF (3.2 mmol),
the mixture was stirred for time t2. The solution was then quenched with saturated
aqueous NH4Cl solution (2 mL). The mixture was extracted with diethyl ether
(3 ꢂ 10 mL). The ether layer was washed with brine (2 mL) and dried over anhydrous
Na2SO4. The compound was purified by column chromatography (silica gel, ethyl
acetate=petroleum ether 1:9).
2,6-Dimethoxy-5-bromopyrimidine-4-carboxaldehyde (2a)
White needles, mp 106–108 ꢁC; Rf (10% EtOAc=petroleum ether) 0.43; IR
(KBr, cmꢀ1): 2860 (HꢀCO), 1695 (C¼O), 1076 (CꢀBr); 1H NMR (400 MHz,
CDCl3): d 10.22 (s, 1H, CHO), 4.10 (s, 3H, OCH3), 4.08 (s, 3H, OCH3); 13C
NMR (125 MHz, CDCl3): d 186.8, 171.0, 164.6, 157.3, 110.9, 56.1, 55.5; MS: m=e
(relative intensity): 247, 249 (Mþ, Mþ þ 2, 100, 97), 219, 221 (20, 20), 167, 169,
(Mþ-Br, Mþ þ 2-Br, 5, 4), 141 (12), 110 (12). Anal. calcd. for C7H7BrN2O3: C,
34.03; H, 2.86; N, 11.34. Found: C, 33.83; H, 2.75, N, 11.51.
2,6-Dimethoxy-5-dimethylaminopyrimidine-4-carboxaldehyde (3a)
White needles; mp 117–118 ꢁC; Rf (10% EtOAc=petroleum ether) 0.41; IR
1
(KBr, cmꢀ1): 2906, 2813 (HꢀCO), 1664 (C¼O); H NMR (400 MHz, CDCl3): d
10.02 (s, 1H, CHO), 4.00 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 3.09 [s, 6H,
N(CH3)2]; 13C NMR (100 MHz, CDCl3): 183.7, 174.5, 163.9, 163.5, 95.4, 54.1,
53.9, 40.7 (2C); MS: m=e (relative intensity): 234 (Mþþ Na, 11), 212 (MHþ, 100),
182 (45), 169 (5), 130 (5). Anal. calcd. for C9H13N3O3: C, 51.18; H, 6.20; N,
19.89. Found: C, 51.31; H, 6.34, N, 19.81.

METALLATION OF 2,4-DIALKOXY-5-BROMOPYRIMIDINE
1943
2,6-Diethoxy-5-dimethylaminopyrimidine-4-carboxaldehyde (3b)
White needles; mp 54–56 ꢁC; Rf (15% EtOAc=petroleum ether) 0.53, IR (KBr,
1
cmꢀ1): 2857, 2778 (HꢀCO), 1667 (C¼O); H NMR (500 MHz, CDCl3): d 10.06 (s,
1H, CHO), 4.48 (q, 2H, J ¼ 6.9 Hz, OCH2), 4.39 (q, 2H, J ¼ 6.9 Hz, OCH2), 3.10
[s, 6H, N(CH3)2], 1.41 (t, 3H, J ¼ 6.9 Hz, ꢀCH2CH3), 1.40 (t, 3H, J ¼ 6.9 Hz,
ꢀCH2CH3); 13C NMR (125 MHz, CDCl3): d 184.7, 174.8, 164.2, 164.1, 96.0, 63.5,
63.2, 41.2 (2C), 14.4, 14.3; MS: m=e (relative intensity): 240 (MHþ, 87), 225 (22),
212 (100), 184 (90), 156 (17), 102 (10). Anal. calcd. for C11H17N3O3: C, 55.22; H,
7.16; N, 17.56. Found: C, 55.54; H, 7.11, N, 17.51.
2,6-Dipropoxy-5-dimethylaminopyrimidine-4-carboxaldehyde (3c)
White solids; mp 38–39 ꢁC; Rf (20% EtOAc=petroleum ether) 0.60, IR (KBr,
1
cmꢀ1): 2875, 2778 (H–CO), 1666 (C¼O); H NMR (300 MHz, CDCl3): d 10.06 (s,
1H, CHO), 4.37 (t, 2H, J ¼ 6.6 Hz, OCH2), 4.28 (t, 2H, J ¼ 6.6 Hz, OCH2), 3.10 [s,
6H, N(CH3)2], 1.90–1.70 (m, 4H, 2-CH2CH3), 1.02 (t, 3H, J ¼ 7.5 Hz, ꢀCH2CH3),
1.00 (t, 3H, J ¼ 7.5 Hz, ꢀCH2CH3); 13C NMR (75 MHz, CDCl3): d 184.6, 174.9,
164.3, 164.1, 96.0, 69.3, 68.9, 41.2 (2C), 22.1, 22.0, 10.5, 10.4; MS: m=e (relative
intensity): 268 (MHþ, 33), 227 (7), 226 (57), 184 (100). Anal. calcd. for
C13H21N3O3: C, 58.41; H, 7.92; N, 15.72. Found: C, 58.17; H, 7.95, N, 15.78.
ACKNOWLEDGMENTS
We are grateful to the Council for Scientific and Industrial Research, New
Delhi [No. 01(2215)=08=EMR-II], for financial support of this work. The University
Grants Commission, New Delhi, is also thanked for the award of a junior research
fellowship to S. M.
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1971, 10, 20–33.
3. Kress, T. J. Direct metalation of pyrimidine: Synthesis of some 4-substituted pyrimidines.
J. Org. Chem. 1979, 44, 2081–2083.
4. Numata, A.; Kondo, Y.; Sakamoto, T. General synthetic method for naphthyridines and
their N-oxides containing isoquinolinic nitrogen. Synthesis 1999, 306–311.
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