Key words cycloaddition reaction - tetrachloropyrimidines - 1,3-diazadienes - intramolecular
cyclization - nucleophilic substitution
3,5-Dichloro-4,6-dimethoxy-2-(trichloromethyl)pyridine (Penclomedine)[1 ]
[2 ] and 2-(trichloromethyl)pyrimidine derivatives have attracted attention because they
have remarkable antitumor properties especially against human MX-1 mammary carcinoma.[3–5 ] Several structural variants have been designed and synthesized in an attempt to
discover related ring structures with nitrogen, oxygen, and sulfur analogues that
might exhibit better antitumor activity. A common problem in the synthesis of these
chlorinated heterocycles is how to carry out efficient preparations.[6,7 ] In this context, cycloaddition reactions employing azadienes in hetero Diels–Alder
methodology represents a straightforward and efficient approach for the construction
of a wide variety of four-, five-, and six-membered nitrogen-containing heterocycles.[8 ]
[9 ]
[10 ]
[11 ] Dienes containing two nitrogen atoms have attracted attention in heterocyclic chemistry
in recent years because of their importance in the construction of pyrimidines derivatives.[9 ]
[12 ] A variety of 1,3-diazadienes as 4π components in cycloaddition reactions have been
reported, such as [4+1] cycloaddition process with isocyanides,[13 ] the Simmons–Smith reagent;[14 ] [4+2] with acetylenic esters,[15 ]
[16 ] enamines,[17 ] oxazolinones,[18 ] sulfenes,[19 ] nitriles,[20 ] and recently with benzyne intermediates.[21 ] Particular interest has been given to the cycloaddition reactions of 1,3-diazabutadienes
with ketenes; they are reported to undergo [4+2][22 ]
[23 ]
[24 ]
[25 ] as well [2+2][26 ]
[27 ]
[28 ]
[29 ]
[30 ] cycloaddition reactions leading to several different pyrimidinones and azetidinones.
Ketenes are highly electrophilic intermediates, readily generated in solution by reaction
of acyl chlorides with non-nucleophilic bases, such as a tertiary amine.[31 ] Additionally, ketenes are generally referred to as poor nucleophiles.[32 ] In 1996, Krasodomska and Bogdanowicz-Szwed reported the reaction of 1,3-diazabutadienes
with various ketenes, including chloroketenes, for the formation of thiadiazolopyrimidines.[33 ] Although numerous examples of [4+2] cycloaddition reactions of 1,3-diazabutadiene
analogues with ketenes have been published, the majority are of little value with
regard to the generation of aromatic heterocyclic compounds.[22 ]
[23 ]
[24 ]
[25 ] In these examples, 1,3-diazabutadienes bear an alkyl or aryl substituent on N-1,
which makes the aromatization of the cycloadduct not possible. We have previously
demonstrated the synthetic utility of 1,3-diazabutadienes bearing a hydrogen on N-1
in cycloaddition reactions for the preparation of various aromatic heterocyclic compounds.[16 ]
[21 ]
[34 ]
[35 ] In connection with our studies directed at the development of new synthetic methods
to prepare 2-(trichloromethyl)pyrimidine derivatives and their potential application
in medicinal chemistry, we have been interested in studying the reactivity of these
1-unsubstituted 2-(trichloromethyl)-1,3-diazabutadienes, since these kinds of compounds
can undergo cycloaddition reactions with ketenes to produce 2-(trichloromethyl)pyrimidin-4-ones,
potential valuable intermediates to build 2-(trichloromethyl)pyrimidine derivatives.
Herein we describe our studies on the reactivity of NH -1,3-diazadienes with a variety of enolizable acyl chlorides and some reactions of
the tetrachloropyrimidine derivatives thus obtained.
2-(Trichloromethyl)-1,3-diazabuta-1,3-diene 1a and 2-(trichloromethyl)-1,3-diazapenta-1,3-diene 1b were prepared from trichloroacetamidine and the amide dimethyl acetal (commercially
available) in 90–100% yields according to our published procedure.[16 ] Initially, we believed that enolizable acyl chlorides would react under basic conditions
to form ketenes in situ, which in the presence of 2-(trichloromethyl)-1,3-diazadienes
1 would produce 2-(trichloromethyl)pyrimidin-4-one derivatives 2 involving a [4+2] cycloaddition process. Therefore, we commenced our study by using
1,3-diazabutadiene 1a as a model to evaluate this cycloaddition reaction with phenylacetyl chloride (1.2
equiv) under basic conditions (Et3 N, 1.2 equiv) at 0 °C in CH2 Cl2 solution. Unfortunately, TLC analysis showed a complex mixture containing only a
trace of the 2-(trichloromethyl)pyrimidin-4-one 2a . A range of experimental approaches were investigated, including solvent screening
as well as careful control of the reaction conditions. The best reaction conditions
for the formation of 2a were using 2.2 equivalents of phenylacetyl chloride and 2.2 equivalents of Et3 N in the presence of a catalytic amount of DMAP (10 mol%) from –10 °C to room temperature
in CH2 Cl2 solution. Under these conditions, the desired 2-(trichloromethyl)pyrimidin-4-one
2a was obtained in 57% yield after silica gel column chromatography purification (Scheme
[1 ]). However, when this procedure was applied to 2-(trichloromethyl)-1,3-diazapenta-1,3-diene
1b the 2-(trichloromethyl)pyrimidin-4-one 2b was obtained in only 36% yield. The use of this cycloaddition process utilizing acetyl
chloride as the acylating agent with both 2-(trichloromethyl)-1,3-diazadienes 1a and 1b , was much less successful. Usually, a complex mixture of products containing the
2-(trichloromethyl)pyrimidin-4-one 2c or 2d was obtained in 25% and 38% yields, respectively. We found that when propanoyl chloride
was used, the 2-(trichloromethyl)pyrimidin-4-one 2e was obtained in 40% yield together with the 4-(propanoyloxy)-2-(trichloromethyl)pyrimidine
2f in 30% yield.
Scheme 1 Synthesis of 2-(trichloromethyl)pyrimidin-4-ones 2 from acyl chlorides
We believe that this cyclization process does not involve a concerted [4+2] cycloaddition
process between the 1,3-diazadiene 1 and the ketenes because it is accelerated by DMAP. Possibly, it involves the formation
of a key intermediate the N -acyl-1,3-diazadienium A (Scheme [2 ]), followed by immediate intramolecular cyclization to form the intermediate B , which eliminates dimethylamine, which reacts with the acyl chloride to form the
corresponding N ,N -dimethylamide, to finally deliver the 2-(trichloromethyl)pyrimidin-4-one 2 and the respective 4-(acyloxy)-2-(trichloromethyl)pyrimidine.
Scheme 2 Possible mechanism in the acylation/intramolecular cyclization reaction of 2-(trichloromethyl)-1,3-diazadienes
1 with an acyl chloride
The moderate yields in the acylation/intramolecular cyclization process to produce
2-(trichloromethyl)pyrimidin-4-ones 2 are presumably due to the tedious purification of the samples, since the removal
of the excess carboxylic acid generated by the hydrolysis (work up or on the silica
gel chromatographic purification) led to material loss. Since our main interest was
the synthesis of tetrachloropyrimidines 3 , as an alternative it was though that pyrimidin-4-ones 2 might react with POCl3
[36 ] to give the corresponding tetrachloropyrimidine 3 . Therefore, we opted not to isolate the 2-(trichloromethyl)pyrimidin-4-one 2 and directly performed the chlorination reaction. Thus, the crude material obtained was reacted with POCl3 (10.0 equiv) overnight in refluxing toluene solution, to form the 4-chloro-2-(trichloromethyl)pyrimidines
3a –j (Table [1 ]). 4-Chloro-2-(trichloromethyl)pyrimidines 3a and 3b were obtained in good yields when the acyl chloride was phenylacetyl chloride (entries
1 and 2). Lower yields were obtained when acetyl chloride was used as the acylating
agent (entries 3 and 4). However, yields increased slightly when propanoyl chloride
was utilized (entries 5 and 6). Yields were generally lower when the acylating agent
was an α-haloacetyl chloride (entries 7–10), but yields were slightly higher when
the 1,3-diazadiene installed a methyl group on C-4 (entries 8 and 10).
Table 1 Synthesis of 4-Chloro-2-(trichloromethyl)pyrimidinesa
Entry
3
R1
R2
Yield (%)
1
3a
H
Ph
85
2
3b
CH3
Ph
70
3
3c
H
H
53
4
3d
CH3
H
57
5
3e
H
CH3
70
6
3f
CH3
CH3
64
7
3g
H
Cl
35
8
3h
CH3
Cl
50
9
3i
H
Br
21
10
3j
CH3
Br
40
a Reaction conditions: 1. 1 (1.0 equiv), acyl chloride (2.2 equiv), Et3 N (2.2 equiv), DMAP (10 mol%), CH2 Cl2 , –10 °C to rt; 2. POCl3 (10.0 equiv), toluene, reflux, overnight.
Table 2 Substitution Reactions
Entry
3
Nucleophile (equiv)
Solvent
Temp (°C)
4
R1
R2
R3
R4
Yield (%)
1
3a
NaOCH3 (10)
CH3 OH
rt
4a
H
Ph
CCl3
OCH3
63
2
3a
NaOCH3 (10)
CH3 OH
65
4b
H
Ph
OCH3
OCH3
86
3
3a
NaOPh (10)
THF
65
4c
H
Ph
CCl3
OPh
89
4
3a
NaSPh (2)
THF
–78
4d
H
Ph
CCl3
SPh
86[42 ]
5
3a
NaSPh (10)
THF
rt
4e
H
Ph
CH(SPh)2
SPh
83
6
3a
BuNH2 (10)
CH2 Cl2
rt
4f
H
Ph
CCl3
NHBu
86
7
3a
BuNH2 (15)
CH2 Cl2
rt
4g
H
Ph
C(O)NHBu
NHBu
81
8
3b
BuNH2 (10)
CH2 Cl2
rt
4h
CH3
Ph
CCl3
NHBu
73
9
3b
BuNH2 (20)
CH2 Cl2
rt
4i
CH3
Ph
C(O)NHBu
NHBu
65
10
3a
morpholine (10)
CH2 Cl2
rt
4j
H
Ph
CCl3
83
11
3a
morpholine (14)
CH2 Cl2
rt
4k
H
Ph
80
12
3a
BnNH2 (5)
CH2 Cl2
rt
4l
H
Ph
CONHBn
NHBn
94
13
3a
NaN3 (5)
DMF
rt
4m
H
Ph
CCl3
N3
88
14
3d
NaN3 (5)
DMF
rt
4n
CH3
H
CCl3
N3
54
15
3a
NaCH(CO2 Et)2 (5)
THF
65
4o
H
Ph
CCl3
CH(CO2 Et)2
86
16
3a
KCN (5)
DMF
rt
4p
H
Ph
CCl3
CN
57
On the other hand, the chlorine substituent at C-4 and the trichloromethyl at C-2
in this type of pyrimidines 3 should be quite reactive principally in substitution reactions and could be used
as congeners of various other pyrimidines.[37 ]
[38 ]
[39 ]
[40 ] We studied their reactivity through substitution reactions with a variety of nucleophiles
including, oxygen, sulfur, nitrogen, and carbon, giving the expected substitution
products (Table [2 ]). In all substitution reactions, we observed selective attack by the nucleophile
at the more electrophilic carbon of the heterocyclic ring (C-4) according to a SN Ar2 mechanism, at low or at room temperature, without affecting the trichloromethyl
group (entries 1, 3, 4, 6, 8, 10, and 13–16). However, when the nucleophile was oxygen
and the tetrachloropyrimidine 3a was reacted with an excess of sodium methoxide in methanol at 65 °C, dimethoxypyrimidine
4b was formed possibly by the loss of trichloromethanide (entry 2). In sharp contrast,
when sodium phenoxide is used, only the monosubstitution product 4c was formed even when the tetrachloropyrimidine 3a was heated at 65 °C overnight, this result is possibly due to its minor nucleophilic
character compared with methoxide ion (entry 3). When an excess of sodium thiophenolate
was reacted with tetrachloropyrimidine 3a at room temperature, reduction of the trichloromethyl group took place,[41 ] giving the thioketal 4e in very good yield (entry 5).
It is noteworthy that the substitution reaction of these kinds of tetrachloropyrimidine
3 using a large excess of primary or secondary amine as the nucleophile results in
the transformation of the trichloromethyl group into the respective amide, forming
4g , 4i , 4k , and 4l (entries 7, 9, 11, and 12). These products are presumably derived from the corresponding
attack by the nitrogen atom on the trichloromethyl group to give the iminium salt
C after chloride elimination, the hydrolysis of this intermediate C by the water present or on workup through the mechanism showed in Scheme [3 ] affords the corresponding amide. It is important to note, that the above reactions
could be characteristic of all tetrachloropyrimidines 3 prepared in this way and are not restricted merely to 3a or 3b .
Scheme 3 Possible mechanism on reactivity of amines with trichloromethyl group
In summary, we have developed a new methodology for the preparation of 4-chloro-2-(trichloromethyl)pyrimidines
3 in a very efficient way from simple and accessible starting materials. We believe
that this methodology is probably through acylation/intramolecular cyclization mechanism
and should be of general interest. This synthetic strategy exhibits considerable structural
flexibility that can be applied to a variety of acyl chlorides with one α-substituted
group. The reactivity of these 4-chloro-2-(trichloromethyl)pyrimidines 3 was studied with a variety of nucleophilic species to give substituted products,
which could be a useful tool for the construction of a variety of pyrimidines derivatives
containing the trichloromethyl unit. Interestingly; we observed that the second attack
depends of the nucleophile used. More reactive oxygen-derived nucleophiles (methoxide
vs phenoxide ions) react on the heterocyclic ring through an SNAr2 mechanism. While
nitrogen and sulfur nucleophiles react directly on the trichoromethyl group probably
because of the softness and hardness principle of these two elements.�
All reactions were carried out in oven-dried round-bottom flasks under N2 atmosphere. Reagents were purchased from Aldrich and used without treatment, unless
otherwise indicated. NaH 60% dispersion in mineral oil. CH2 Cl2 was distilled from CaH2 under N2 . 1 H and 13 C NMR were recorded using Bruker (300 MHz) Avance 300 and Varian (500 MHz) Avance
500 instruments; 1 H NMR relative to TMS (δ = 0.0 ppm) and 13 C NMR using CDCl3 (δ = 77.0 ppm) as internal reference. LR-MS were obtained on an Shimadzu, GCLRMS-QP20.010
Plus mass spectrometer. Melting points were measured in a Mel-Temp II instrument and
are uncorrected.
4-Chloro-2-(trichloromethyl)pyrimidines 3; General Procedure
4-Chloro-2-(trichloromethyl)pyrimidines 3; General Procedure
Under N2 atmosphere, the crude 2-(trichloromethyl)-1,3-diazadiene 1 (1.0 equiv) in anhyd CH2 Cl2 (10.0 mL) was cooled to –10 °C and Et3 N (2.2 equiv) was added. The respective acyl chloride (2.2 equiv) was added slowly
followed by DMAP (10 mol%). The mixture was stirred at this temperature for 3 h, and
then warmed to r.t. over 5 h. The reaction was quenched by the addition of sat. aq
NH4 Cl (10.0 mL) and the product was extracted with CH2 Cl2 (3 × 10.0 mL). The combined organic extracts were dried (Na2 SO4 ) and concentrated under vacuum. The crude product was suspended in toluene (10.0
mL), POCl3 (5.0 mL, 53.5 mmol) was added and the mixture was heated at reflux temperature for
12 h. The excess POCl3 was neutralized by the addition of sat. aq NaHCO3 and the product was extracted with CH2 Cl2 (3 × 30.0 mL). The combined organic extracts were dried (Na2 SO4 ) and concentrated under vacuum. The product was purified by flash chromatography
(silica gel, hexanes/EtOAc).
4-Chloro-5-phenyl-2-(trichloromethyl)pyrimidine (3a)
4-Chloro-5-phenyl-2-(trichloromethyl)pyrimidine (3a)
Purification by column chromatography (hexanes/EtOAc 9:1) gave the product (262 mg,
85%) as a white solid. Recrystallization (hexanes/CH2 Cl2 ) gave pure 3a ; mp 153–154 °C.
1 H NMR (300 MHz, CDCl3 ): δ = 8.71 (s, 1 H), 7.47–7.44 (m, 5 H).
13 C NMR (75 MHz, CDCl3 ): δ = 164.1, 160.0, 158.5, 134.7, 132.5, 129.7, 129.2, 129.0, 95.2.
MS (EI): m /z (%) = 306 (M+ , 56), 308 (M+ + 2, 70), 310 (M+ + 4, 34), 312 (M+ + 6, 8), 275 (100).
HRMS (ESI+): m /z [M + H]+ calcd for C11 H7 Cl4 N2 : 306.9363; found: 306.9356.
4-Chloro-6-methyl-5-phenyl-2-(trichloromethyl)pyrimidine (3b)
4-Chloro-6-methyl-5-phenyl-2-(trichloromethyl)pyrimidine (3b)
Purification by column chromatography (hexanes/EtOAc 95:5) gave the product (225 mg,
70%) as a white solid. Recrystallization (hexanes/CH2 Cl2 ) gave pure 3b ; mp 100–101 °C.
1 H NMR (300 MHz, CDCl3 ): δ = 7.54–7.51 (m, 3 H), 7.28–7.26 (m, 2 H), 2.46 (s, 3 H).
13 C NMR (75 MHz, CDCl3 ): δ = 170.2, 168.8, 167.0, 133.8, 133.6, 129.11, 129.06, 128.8, 95.9, 23.8.
MS (EI): m /z (%) = 320.0 (M+ , 13), 322 (M+ + 2, 16), 324 (M+ + 4, 8), 326 (M+ + 6, 2), 285 (100).
4-Chloro-2-(trichloromethyl)pyrimidine (3c)
4-Chloro-2-(trichloromethyl)pyrimidine (3c)
Purification by column chromatography (hexanes/EtOAc 9:1) gave the product (123 mg,
53%) as a yellow oil.
1 H NMR (300 MHz, CDCl3 ): δ = 8.79 (d, J = 5.4 Hz, 1 H), 7.44 (d, J = 5.4 Hz, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 166.0, 162.3, 158.7, 122.0, 92.2.
MS (EI): m /z (%) = 230 (M+ , 28), 232 (M+ + 2, 36), 234 (M+ + 4, 17), 236 (M+ + 6, 4), 197 (100).
4-Chloro-6-methyl-2-(trichloromethyl)pyrimidine (3d)
4-Chloro-6-methyl-2-(trichloromethyl)pyrimidine (3d)
Purification by column chromatography (hexanes/EtOAc 9:1) gave the product (140 mg,
57%) as a white solid. Recrystallization (hexanes/CH2 Cl2 ) gave pure 3d ; mp 58–59 °C.
1 H NMR (300 MHz, CDCl3 ): δ = 7.27 (s, 1 H), 2.65 (s, 3 H).
13 C NMR (75 MHz, CDCl3 ): δ = 170.3, 165.4, 161.8, 121.0, 95.5, 24.0.
MS (EI): m /z (%) = 244 (M+ , 21), 246 (M+ + 2, 26), 248 (M+ + 4, 13), 250 (M+ + 6, 3), 213 (100).
4-Chloro-5-methyl-2-(trichloromethyl)pyrimidine (3e)
4-Chloro-5-methyl-2-(trichloromethyl)pyrimidine (3e)
Purification by column chromatography (hexanes/EtOAc 9:1) gave the product (173 mg,
70%) as a white solid. Recrystallization (hexanes/CH2 Cl2 ) gave pure 3e ; mp 75–76 °C.
1 H NMR (300 MHz, CDCl3 ): δ = 8.66 (s, 1 H), 2.46 (s, 3 H).
13 C NMR (75 MHz, CDCl3 ): δ = 163.7, 161.8, 158.4, 131.0, 99.9, 16.3.
MS (EI): m /z (%) = 244 (M+ , 27), 246 (M+ + 2, 38), 248 (M+ + 4, 19), 250 (M+ + 6, 4), 211 (100).
4-Chloro-5,6-dimethyl-2-(trichloromethyl)pyrimidine (3f)
4-Chloro-5,6-dimethyl-2-(trichloromethyl)pyrimidine (3f)
Purification by column chromatography (hexanes/EtOAc 9:1) gave the product (167 mg,
64%) as a white solid. Recrystallization (hexanes/CH2 Cl2 ) gave pure 3f ; mp 95–96 °C.
1 H NMR (300 MHz, CDCl3 ): δ = 2.65 (s, 3 H), 2.44 (s, 3 H).
13 C NMR (75 MHz, CDCl3 ): δ = 168.5, 162.2, 161.1, 128.7, 95.6, 23.2, 15.1.
MS (EI): m /z (%) = 258 (M+ , 6), 260 (M+ +2, 7), 262 (M+ + 4, 3), 264 (M+ + 6, 2), 223 (100).
4,5-Dichloro-2-(trichloromethyl)pyrimidine (3g)
4,5-Dichloro-2-(trichloromethyl)pyrimidine (3g)
Purification by column chromatography (hexanes/EtOAc 95:5) gave the product (93 mg,
35%) as a pale yellow solid. Recrystallization (hexanes/CH2 Cl2 ) gave pure 3g ; mp 69–70 °C.
1 H NMR (300 MHz, CDCl3 ): δ = 8.83 (s, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 163.2, 159.3, 157.3, 130.7, 91.9.
MS (EI): m /z (%) = 264 (M+ , 51), 266 (M+ + 2, 77), 268 (M+ + 4, 52), 270 (M+ + 6, 16), 272 (M+ + 8, 2), 170 (100).
4,5-Dichloro-6-methyl-2-(trichloromethyl)pyrimidine (3h)
4,5-Dichloro-6-methyl-2-(trichloromethyl)pyrimidine (3h)
Purification by column chromatography (hexanes/EtOAc 95:5) gave the product (141 mg,
50%) as a pale yellow solid. Recrystallization (hexanes/CH2 Cl2 ) gave pure 3h ; mp 49–50 °C.
1 H NMR (300 MHz, CDCl3 ): δ = 2.77 (s, 3 H).
13 C NMR (75 MHz, CDCl3 ): δ = 167.8, 161.8, 159.0, 129.6, 94.9, 23.4.
MS (EI): m /z (%) = 278 (M+ , 26), 280 (M+ + 2, 38), 282 (M+ + 4, 27), 284 (M+ + 6, 9), 286 (M+ + 8, 2), 246 (100).
5-Bromo-4-chloro-2-(trichloromethyl)pyrimidine (3i)
5-Bromo-4-chloro-2-(trichloromethyl)pyrimidine (3i)
Purification by column chromatography (hexanes/EtOAc 95:5) gave the product (65 mg,
21%) as a pale yellow solid. Recrystallization (hexanes/CH2 Cl2 ) gave pure 3i ; mp 70–71 °C.
1 H NMR (300 MHz, CDCl3 ): δ = 8.94 (s, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 164.0, 160.2, 157.3, 121.0, 99.9.
MS (EI): m /z (%) = 308 (M+ , 9), 310 (M+ + 2, 21), 312 (M+ + 4, 17), 314 (M+ + 6, 8), 316 (M+ + 8, 2), 277 (100).
5-Bromo-4-chloro-6-methyl-2-(trichloromethyl)pyrimidine (3j)
5-Bromo-4-chloro-6-methyl-2-(trichloromethyl)pyrimidine (3j)
Purification by column chromatography (hexanes/EtOAc 97.5:2.5) gave the product (130
mg, 40%) as a pale yellow oil.
1 H NMR (300 MHz, CDCl3 ): δ = 2.81 (s, 3 H).
13 C NMR (75 MHz, CDCl3 ): δ = 169.9, 167.8, 162.7, 121.4, 94.9, 26.0.
MS (EI): m /z (%) = 322 (M+ , 3), 324 (M+ + 2, 6), 326 (M+ + 4, 5), 328 (M+ + 6, 2), 289 (100).
4-Methoxy-5-phenyl-2-(trichloromethyl)pyrimidine (4a)
4-Methoxy-5-phenyl-2-(trichloromethyl)pyrimidine (4a)
Under N2 atmosphere, anhyd CH3 OH (3.0 mL, 74.63 mmol) was added to a flask containing Na (128 mg, 10.0 equiv, 5.57
mmol) and the mixture was stirred for 5 min. 4-Chloro-5-phenyl-2-(trichloromethyl)pyrimidine
(3a ; 154 mg, 1.0 equiv, 0.5 mmol) was added and the mixture was stirred at rt overnight.
After completion, the mixture was neutralized with aq 5% AcOH, EtOAc (30.0 mL) was
added, the mixture was washed with sat. NH4 Cl solution, and the product was extracted with EtOAc (2 × 20.0 mL). The combined
organic extracts were dried (Na2 SO4 ) and concentrated under vacuum. Purification by column chromatography (hexanes/EtOAc
95:5) gave the product (96 mg, 63%) as a pale yellow oil.
1 H NMR (300 MHz, CDCl3 ): δ = 8.52 (s, 1 H), 7.50–7.49 (m, 2 H), 7.42–7.36 (m, 3 H), 4.04 (s, 3 H).
13 C NMR (75 MHz, CDCl3 ): δ = 166.7, 163.4, 156.1, 131.8, 129.0, 128.9, 128.6, 122.2, 96.3, 54.7.
MS (EI): m /z (%) = 302 (M+ , 28), 304 (M+ + 2, 26), 306 (M+ + 4, 9), 267 (100).
2,4-Dimethoxy-5-phenylpyrimidine (4b)
2,4-Dimethoxy-5-phenylpyrimidine (4b)
Under N2 atmosphere, anhyd CH3 OH (3.0 mL, 74.63 mmol) was added to a flask containing Na (127 mg, 10.0 equiv, 5.51
mmol) and the mixture was stirred for 5 min. 4-Chloro-5-phenyl-2-(trichloromethyl)pyrimidine
(3a ; 160 mg, 1.0 equiv, 0.52 mmol) was added and the mixture was heated to 65 °C overnight.
After completion, the mixture was neutralized with aq 5% AcOH, EtOAc (30.0 mL) was
added, the mixture was washed with sat. NH4 Cl solution, and the product was extracted with EtOAc (2 × 20.0 mL). The combined
organic extracts were dried (Na2 SO4 ) and concentrated under vacuum. Purification by column chromatography (hexanes/EtOAc
85:15) gave the product (97 mg, 86%) as a white solid; mp 57–58 °C (hexanes/CH2 Cl2 ).
1 H NMR (300 MHz, CDCl3 ): δ = 8.19 (s, 1 H), 7.43–7.41 (m, 2 H), 7.37–7.34 (m, 2 H), 7.30–7.27 (m, 1 H),
3.97 (s, 3 H), 3.95 (s, 3 H).
13 C NMR (75 MHz, CDCl3 ): δ = 168.2, 164.4, 157.5, 133.2, 128.8, 128.4, 127.7, 116.2, 54.8, 54.1.
MS (EI): m /z (%) = 216 (M+ , 100), 201 (M+ – 15, 39), 186 (M+ – 30, 70).
4-Phenoxy-5-phenyl-2-(trichloromethyl)pyrimidine (4c)
4-Phenoxy-5-phenyl-2-(trichloromethyl)pyrimidine (4c)
Under N2 atmosphere, 75% NaH (131 mg, 10.0 equiv, 4.07 mmol) was suspended in THF (5.0 mL),
85% phenol (544 mg, 10.0 equiv, 4.9 mmol) was added, and the mixture was stirred for
10 min. Subsequently, 4-chloro-5-phenyl-2-(trichloromethyl)pyrimidine (3a ; 124 mg, 1.0 equiv, 0.4 mmol) was added. The mixture was heated to 65 °C overnight.
After completion, EtOAc (30.0 mL) was added, the mixture was washed with sat. NH4 Cl solution, and the product was extracted with EtOAc (2 × 20.0 mL). The combined
organic extracts were dried (Na2 SO4 ) and concentrated under vacuum. Purification by column chromatography (hexanes/EtOAc
95:5) gave the product (130 mg, 89%) as a white solid; mp 108–109 °C (hexanes/CH2 Cl2 ).
1 H NMR (300 MHz, CDCl3 ): δ = 8.70 (s, 1 H), 7.67–7.64 (m, 2 H), 7.50–7.41 (m, 3 H), 7.38–7.32 (m, 2 H),
7.19–7.18 (m, 3 H).
13 C NMR (75 MHz, CDCl3 ): δ = 165.9, 163.4, 157.8, 152.1, 131.6, 129.4, 129.18, 129.15, 128.9, 125.7, 122.6,
121.5, 95.9.
MS (EI): m /z (%) = 364 (M+ , 70), 366 (M+ + 2, 68), 368 (M+ + 4, 27), 85 (100).
2-[Bis(phenylthio)methyl]-5-phenyl-4-(phenylthio)pyrimidine (4e)
2-[Bis(phenylthio)methyl]-5-phenyl-4-(phenylthio)pyrimidine (4e)
Under N2 atmosphere, 60% NaH (197 mg, 10.0 equiv, 4.91 mmol) was suspended in THF (10.0 mL),
thiophenol (0.55 mL, 10.0 equiv, 5.21 mmol) was added. Subsequently, 4-chloro-5-phenyl-2-(trichloromethyl)pyrimidine
(3a ; 161 mg, 1.0 equiv, 0.52 mmol) was added and the mixture was stirred at rt overnight.
After completion, EtOAc (30.0 mL) was added, the mixture was washed with sat. NH4 Cl solution, and the product was extracted with EtOAc (2 × 20.0 mL). The combined
organic extracts were dried (Na2 SO4 ) and concentrated under vacuum. Purification by column chromatography (hexanes/EtOAc
95:5) gave the product (213 mg, 83%) as a yellow solid; mp 78–79 °C (hexanes/CH2 Cl2 ).
1 H NMR (300 MHz, CDCl3 ): δ = 8.22 (s, 1 H), 7.42 (s, 5 H), 7.32–7.29 (m, 5 H), 7.26–7.22 (m, 5 H), 7.17–7.14
(m, 5 H), 5.36 (s, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 168.2, 165.8, 154.7, 152.7, 135.6, 134.1, 134.0, 132.4, 131.3, 130.7, 129.2,
129.1, 129.0, 128.89, 128.86, 128.7, 128.4, 127.7, 127.4, 124.2, 124.0, 117.8, 110.9,
62.6.
MS (EI): m /z (%) = 494 (M+ ), 384 (M+ – 110, 53), 355 (M+ – 139, 70), 274 (100).
N -Butyl-5-phenyl-2-(trichloromethyl)pyrimidin-4-amine (4f)
N -Butyl-5-phenyl-2-(trichloromethyl)pyrimidin-4-amine (4f)
Under N2 atmosphere, 4-chloro-5-phenyl-2-(trichloromethyl)pyrimidine (3a ; 156 mg, 1.0 equiv, 0.51 mmol) was dissolved in anhyd CH2 Cl2 (3.0 mL), BuNH2 (0.5 mL, 10 equiv, 5.05 mmol) was added, and the mixture was stirred at rt overnight.
After completion, CH2 Cl2 (30.0 mL) was added, the mixture was washed with sat. NaCl solution, and the product
was extracted with CH2 Cl2 (2 × 20.0 mL). The combined organic extracts were dried (Na2 SO4 ) and concentrated under vacuum. Purification by column chromatography (hexanes/EtOAc
95:5) gave the product (152 mg, 86%) as a white solid; mp 86–87 °C (hexanes/CH2 Cl2 ).
1 H NMR (300 MHz, CDCl3 ): δ = 8.06 (s, 1 H), 7.46–7.31 (m, 5 H), 5.24 (br s, 1 H), 3.46 (q, J = 6.9 Hz, 2 H), 1.51 (quint, J = 6.9 Hz, 2 H), 1.28 (sext, J = 7.2 Hz, 2 H), 0.86 (t, J = 7.2 Hz, 3 H).
13 C NMR (75 MHz, CDCl3 ): δ = 163.8, 160.1, 152.9, 133.2, 129.7, 129.0, 128.6, 118.9, 97.2, 40.9, 31.2, 20.0,
13.8.
MS (EI): m /z (%) = 343 (M+ , 32), 345 (M+ + 2, 30), 347 (M+ + 4, 12), 288 (100).
N -Butyl-4-(butylamino)-5-phenylpyrimidine-2-carboxamide (4g)
N -Butyl-4-(butylamino)-5-phenylpyrimidine-2-carboxamide (4g)
Under N2 atmosphere, to a solution of 4-chloro-5-phenyl-2-(trichloromethyl)pyrimidine (3a ; 155 mg, 1.0 equiv, 0.5 mmol) in anhyd CH2 Cl2 (3.0 mL), BuNH2 (0.75 mL, 15.0 equiv, 7.58 mmol) was added, and the mixture was stirred at rt overnight.
After completion, CH2 Cl2 (30.0 mL) was added, the mixture was washed with sat. NaCl solution, and the product
was extracted with CH2 Cl2 (2 × 20.0 mL). The combined organic extracts were dried (Na2 SO4 ) and concentrated under vacuum. Purification by column chromatography (EtOAc) gave
the product (132 mg, 81%) as a yellow oil.
1 H NMR (300 MHz, CDCl3 ): δ = 8.12 (s, 1 H), 7.97 (br s, 1 H), 7.54–7.43 (m, 3 H), 7.39–7.36 (m, 2 H), 5.18
(br s, 1 H), 3.56–3.46 (m, 4 H), 1.66–1.53 (m, 4 H), 1.47–1.33 (m, 4 H), 0.99–0.93
(m, 6 H).
13 C NMR (75 MHz, CDCl3 ): δ = 163.0, 159.7, 156.5, 153.5, 133.6, 129.5, 128.8, 128.5, 120.2, 40.7, 39.3,
31.6, 31.3, 20.0, 13.7.
MS (EI): m /z (%) = 326 (M+ ), 297 (M+ – 29, 49), 227 (M+ – 99, 75), 269 (100).
N -Butyl-6-methyl-5-phenyl-2-(trichloromethyl)pyrimidin-4-amine (4h)
N -Butyl-6-methyl-5-phenyl-2-(trichloromethyl)pyrimidin-4-amine (4h)
Under N2 atmosphere, 4-chloro-6-methyl-5-phenyl-2-(trichloromethyl)pyrimidine (3b ; 162 mg, 1.0 equiv, 0.53 mmol) was dissolved in anhyd CH2 Cl2 (3.0 mL), BuNH2 (0.5 mL, 10.0 equiv, 5.05 mmol) was added, and the mixture was stirred at rt overnight.
After completion, CH2 Cl2 (30.0 mL) was added, the mixture was washed with sat. NaCl solution, and the product
was extracted with CH2 Cl2 (2 × 20.0 mL). The combined organic extracts were dried (Na2 SO4 ) and concentrated under vacuum. Purification by column chromatography (hexanes/EtOAc
95:5) gave the product (139 mg, 73%) as a yellow oil.
1 H NMR (300 MHz, CDCl3 ): δ = 7.48–7.35 (m, 3 H), 7.19–7.15 (m, 2 H), 4.58 (br s, 1 H), 3.37 (q, J = 6.9 Hz, 2 H), 2.13 (s, 3 H), 1.42 (q, J = 7.2 Hz, 2 H), 1.26–1.18 (m, 2 H), 0.85–0.80 (t, J = 7.2 Hz, 3 H).
13 C NMR (75 MHz, CDCl3 ): δ = 163.2, 161.5, 160.8, 133.8, 129.8, 129.5, 128.6, 117.0, 97.8, 40.9, 31.4, 22.3,
19.9, 13.8.
N -Butyl-4-(butylamino)-6-methyl-5-phenylpyrimidine-2-carboxamide (4i)
N -Butyl-4-(butylamino)-6-methyl-5-phenylpyrimidine-2-carboxamide (4i)
Under N2 atmosphere, 4-chloro-6-methyl-5-phenyl-2-(trichloromethyl)pyrimidine (3b ; 125 mg, 1.0 equiv, 0.39 mmol), was dissolved in anhyd CH2 Cl2 (3.0 mL), BuNH2 (0.75 mL, 20.0 equiv, 7.58 mmol) was added, and the mixture was stirred at rt overnight.
After completion, CH2 Cl2 (30.0 mL) was added, the mixture was washed with sat. NaCl solution, and the product
was extracted with CH2 Cl2 (2 × 20.0 mL). The combined organic extracts were dried (Na2 SO4 ) and concentrated under vacuum. Purification by column chromatography (hexanes/EtOAc
1:1) gave the product (86 mg, 65%) as a yellow oil.
1 H NMR (300 MHz, CDCl3 ): δ = 7.96 (br s, 1 H), 7.47–7.37 (m, 3 H), 7.15–7.12 (m, 2 H), 4.47 (br s, 1 H),
3.45–3.33 (m, 4 H), 2.12 (s, 3 H), 1.58–1.51 (m, 2 H), 1.44–1.35 (m, 2 H), 1.26–1.18
(m, 2 H), 0.89 (t, J = 7.2 Hz, 3 H), 0.82 (t, J = 7.2 Hz, 3 H).
13 C NMR (75 MHz, CDCl3 ): δ = 163.4, 161.3, 160.4, 155.7, 133.9, 129.7, 129.4, 129.2, 128.5, 119.3, 118.4,
115.6, 40.8, 39.3, 31.6, 31.4, 22.2, 20.1, 20.0, 13.7.
MS (EI): m /z (%) = 340 (M+ ), 311 (M+ – 29, 93), 240 (M+ – 100, 67), 115 (100).
4-Morpholino-5-phenyl-2-(trichloromethyl)pyrimidine (4j)
4-Morpholino-5-phenyl-2-(trichloromethyl)pyrimidine (4j)
Under N2 atmosphere, 4-chloro-5-phenyl-2-(trichloromethyl)pyrimidine (3a ; 168 mg, 1.0 equiv, 0.55 mmol) was dissolved in anhyd CH2 Cl2 (3.0 mL), morpholine (0.5 mL, 10.0 equiv, 5.7 mmol) was added, and the mixture was
stirred at rt overnight. After completion, CH2 Cl2 (30.0 mL) was added, the mixture was washed with sat. NaCl solution, and the product
was extracted with CH2 Cl2 (2 × 20.0 mL). The combined organic extracts were dried (Na2 SO4 ) and concentrated under vacuum. Purification by column chromatography (hexanes/EtOAc
9:1) gave the product (164 mg, 83%) as a white solid; mp 101–102 °C (hexanes/CH2 Cl2 ).
1 H NMR (300 MHz, CDCl3 ): δ = 8.27 (s, 1 H), 7.51–7.40 (m, 5 H), 3.64–3.61 (m, 4 H), 3.44–3.41 (m, 4 H).
13 C NMR (75 MHz, CDCl3 ): δ = 162.9, 161.3, 158.0, 136.2, 129.2, 128.4, 127.62, 127.57, 120.1, 97.0, 66.2,
47.4.
MS (EI): m /z (%) = 357 (M+ . 42), 359 (M+ + 2, 39), 361 (M+ + 4, 15), 321 (100).
4-Morpholino-2-(morpholinocarbonyl)-5-phenylpyrimidine (4k)
4-Morpholino-2-(morpholinocarbonyl)-5-phenylpyrimidine (4k)
Under N2 atmosphere, 4-chloro-5-phenyl-2-(trichloromethyl)pyrimidine (3a ; 162 mg, 1.0 equiv, 0.53 mmol) was dissolved in anhyd CH2 Cl2 (3.0 mL), morpholine (0.65 mL, 14.0 equiv, 7.42 mmol) was added, and the mixture
was stirred at rt overnight. After completion, CH2 Cl2 (30.0 mL) was added, the mixture was washed with sat. NaCl solution, and the product
was extracted with CH2 Cl2 (2 × 20.0 mL). The combined organic extracts were dried (Na2 SO4 ) and concentrated under vacuum. Purification by column chromatography (EtOAc) gave
the product (150 mg, 80%) as a white solid; mp 112–113 °C (hexanes/CH2 Cl2 ).
1 H NMR (300 MHz, CDCl3 ): δ = 8.19 (s, 1 H), 7.46–7.39 (m, 5 H), 3.82 (br s, 4 H), 3.73–3.70 (m, 2 H), 3.60–3.58
(m, 4 H), 3.51–3.50 (m, 2 H), 3.36–3.34 (m, 4 H).
13 C NMR (75 MHz, CDCl3 ): δ = 165.7, 161.7, 159.2, 157.5, 136.7, 129.2, 128.3, 127.5, 120.7, 66.8, 66.6,
66.3, 47.4, 47.2, 42.1.
MS (EI): m /z (%) = 354 (M+ ), 183 (M+ – 171, 33), 56 (M+ – 298, 25), 241 (100).
N -Benzyl-4-(benzylamino)-5-phenylpyrimidine-2-carboxamide (4l)
N -Benzyl-4-(benzylamino)-5-phenylpyrimidine-2-carboxamide (4l)
Under N2 atmosphere, 4-chloro-5-phenyl-2-(trichloromethyl)pyrimidine (3a ; 157 mg, 1.0 equiv, 0.51 mmol) was dissolved in anhyd CH2 Cl2 (3.0 mL), BnNH2 (0.3 mL, 5.0 equiv, 2.74 mmol) was added and the mixture was stirred at rt overnight.
After completion, CH2 Cl2 (30.0 mL) was added, the mixture was washed with sat. NaCl solution, and the product
was extracted with CH2 Cl2 (2 × 20.0 mL). The combined organic extracts were dried (Na2 SO4 ) and concentrated under vacuum. Purification by column chromatography (EtOAc) gave
the product (189 mg, 94%) as a yellow solid; mp 133–134 °C (hexanes/CH2 Cl2 ).
1 H NMR (300 MHz, CDCl3 ): δ = 8.14 (s, 1 H), 7.39–7.22 (m, 15 H), 5.74 (br s, 1 H), 4.66–4.60 (m, 4 H).
13 C NMR (75 MHz, CDCl3 ): δ = 162.8, 159.3, 156.1, 153.8, 138.1, 138.0, 133.2, 129.5, 128.8, 128.5, 128.5,
128.4, 127.6, 127.3, 127.2, 127.1, 120.5, 45.0, 43.5.
MS (EI): m /z (%) = 394 (M+ ), 261 (M+ – 133, 33), 106 (M+ – 288, 24), 91 (100).
4-Azido-5-phenyl-2-(trichloromethyl)pyrimidine (4m)
4-Azido-5-phenyl-2-(trichloromethyl)pyrimidine (4m)
Under N2 atmosphere, 4-chloro-5-phenyl-2-(trichloromethyl)pyrimidine (3a ; 165 mg, 1.0 equiv, 0.54 mmol) was dissolved in anhyd DMF (3.0 mL), NaN3 (188 mg, 5.0 equiv, 2.89 mmol) was added and the mixture was stirred at rt overnight.
After completion, EtOAc (30.0 mL) was added, the mixture was washed with sat. NaCl
solution, and the product was extracted with EtOAc (2 × 20.0 mL). The combined organic
extracts were dried (Na2 SO4 ) and concentrated under vacuum. Purification by column chromatography (hexanes/EtOAc
95:5) gave the product (150 mg, 88%) as a white solid; mp 84–85 °C (hexanes/CH2 Cl2 ).
1 H NMR (300 MHz, CDCl3 ): δ = 8.70 (s, 1 H), 7.53–7.48 (m, 5 H).
13 C NMR (75 MHz, CDCl3 ): δ = 163.6, 160.1, 157.9, 131.5, 129.3, 129.0, 128.96, 128.90, 128.80, 124.5, 95.7.
MS (EI): m /z (%) = 313 (M+ , 6), 315 (M+ + 2, 5), 317 (M+ + 4, 2), 250 (100).
4-Azido-6-methyl-2-(trichloromethyl)pyrimidine (4n)
4-Azido-6-methyl-2-(trichloromethyl)pyrimidine (4n)
Under N2 atmosphere, 4-chloro-6-methyl-2-(trichloromethyl)pyrimidine (3d ; 246 mg, 1.0 equiv, 1 mmol) was dissolved in anhyd DMF (3.0 mL), NaN3 (330 mg, 5.0 equiv, 5.0 mmol) was added, and the mixture was stirred at rt overnight.
After completion, EtOAc (30.0 mL) was added, the mixture was washed with sat. NaCl
solution, and the product was extracted with EtOAc (2 × 20.0 mL). The combined organic
extracts were dried (Na2 SO4 ) and concentrated under vacuum. Purification by column chromatography (hexanes/EtOAc
95:5) gave the product (136 mg, 54%) as a colorless oil.
1 H NMR (300 MHz, CDCl3 ): δ = 6.58 (s, 1 H), 2.51 (s, 3 H).
13 C NMR (75 MHz, CDCl3 ): δ = 170.1, 164.9, 163.0, 109.3, 96.1, 24.1.
MS (EI): m /z (%) = 251 (M+ , 51), 253 (M+ + 2, 49), 255 (M+ + 4, 17), 190 (100).
Diethyl 2-[5-Phenyl-2-(trichloromethyl)pyrimidin-4-yl]malonate (4o)
Diethyl 2-[5-Phenyl-2-(trichloromethyl)pyrimidin-4-yl]malonate (4o)
Under N2 atmosphere, 60% NaH (114 mg, 10.0 equiv, 2.85 mmol) was suspended in THF (15.0 mL),
diethyl malonate (0.4 mL, 5.0 equiv, 2.62 mmol) was added and the mixture was stirred
for 10 min. Subsequently, 4-chloro-5-phenyl-2-(trichloromethyl)pyrimidine (3a ; 157 mg, 1.0 equiv, 0.51 mmol) was added. The mixture was stirred and heated to 65
°C overnight. After completion, EtOAc (30.0 mL) was added, the mixture was washed
with sat. NH4 Cl solution, and the product was extracted with EtOAc (2 × 20.0 mL). The combined
organic extracts were dried (Na2 SO4 ) and concentrated under vacuum. Purification by column chromatography (hexanes/EtOAc
95:5) gave the product (189 mg, 86%) as a white solid; mp 117–118 °C (hexanes/CH2 Cl2 ).
1 H NMR (300 MHz, CDCl3 ): δ = 8.71 (s, 1 H), 7.45–7.42 (m, 3 H), 7.27–7.24 (m, 2 H), 4.94 (s, 1 H), 4.15–4.09
(m, 4 H), 1.14 (t, J = 7.2 Hz, 6 H).
13 C NMR (75 MHz, CDCl3 ): δ = 165.8, 163.9, 160.4, 158.1, 135.1, 133.2, 129.4, 129.1, 128.9, 96.1, 62.2,
57.7, 13.9.
MS (EI): m /z (%) = 432 (M+ , 21), 434 (M+ + 2, 8), 436 (M+ + 4, 1), 358 (100).
5-Phenyl-2-(trichloromethyl)pyrimidine-4-carbonitrile (4p)
5-Phenyl-2-(trichloromethyl)pyrimidine-4-carbonitrile (4p)
Under N2 atmosphere, 4-chloro-5-phenyl-2-(trichloromethyl)pyrimidine (3a ; 162 mg, 1.0 equiv, 0.53 mmol) was dissolved in anhyd DMF (3.0 mL), and 18-crown-6
(cat.) was added. Subsequently, KCN (179 mg, 5.0 equiv, 2.74 mmol) was added and the
mixture was stirred at rt overnight. After completion, EtOAc (30.0 mL) was added,
the mixture was washed with sat. NaCl solution, and the product was extracted with
EtOAc (2 × 20.0 mL). The combined organic extracts were dried (Na2 SO4 ) and concentrated under vacuum. Purification by column chromatography (hexanes/EtOAc
9:1) gave the product (90 mg, 57%) as a white solid; mp 132–133 °C (hexanes/CH2 Cl2 ).
1 H NMR (300 MHz, CDCl3 ): δ = 9.09 (s, 1 H), 7.57–7.56 (d, J = 3.3 Hz, 5 H).
13 C NMR (75 MHz, CDCl3 ): δ = 164.6, 159.8, 138.9, 137.5, 131.0, 130.5, 129.7, 128.8, 114.4, 95.1.
MS (EI): m /z (%) = 297 (M+ , 11), 299 (M+ + 2, 10), 301 (M+ + 4, 4), 262 (100).
