Chemoselective reactions of 4,6-dichloro-2-(methylsulfonyl)pyrimidine and related electrophiles with amines

1764▌

PAPER

paper

Chemoselective Reactions of 4,6-Dichloro-2-(methylsulfonyl)pyrimidine and

Related Electrophiles with Amines

Chemoselective Reactions of 4,6-Dichloro-2-(methylsulfonyl)pyrimidine

Ramil Baiazitov, Wu Du, Chang-Sun Lee, Seongwoo Hwang, Neil G. Almstead, Young-Choon Moon*

PTC Therapeutics, Inc., 100 Corporate Ct, South Plainfield, NJ 07080, USA

Fax +1(908)2220567; E-mail: ymoon@ptcbio.com

Received: 30.03.2013; Accepted: 15.04.2013

Dedicated to Prof. Scott E. Denmark on the occasion of his 60^thbirthday

duces an extra step that may not be compatible with sen-

Abstract: Chemoselective S_NArreactions of 4,6-dichloro-2-(meth-

sitive substrates.

ylsulfonyl)pyrimidine and several related electrophiles with amines

and their derivatives are described. In the presence of weak bases

anilines and secondary aliphatic amines selectively displace the

chloride group. Deprotonated anilines and their carbonyl deriva-

tives displace the sulfone group. Sterically and electronically unbi-

ased primary aliphatic amines selectively displace the sulfone group

in 4,6-dichloro-2-(methylsulfonyl)pyrimidine; however, their reac-

tions with other electrophiles generally are less selective. Steric-

driven selectivity explanation was proposed.

Cl

6

Cl

R₂NH

Cl

N

+

N

(1)

2

4

Cl

N

Cl

N

I

NR₂

R₂N

N

II

Cl

from

2,4,6-trichloropyrimidine

Nu

Key words: pyrimidine, sulfone, chloride, heterocycles, chemose-

lectivity

Cl

N

Nu

Cl

N

+

Nu

N

III

NR₂Cl

N

IV

NR₂R₂N

Nu

N

V

Aminopyrimidines are privileged structures for drug dis-

covery and have received much attention as highlighted

by the FDA approved anti-HIV drugs Rilpivirine^1aand

Etravirine,^1band the anticancer drug Pazopanib.²Com-

pounds from these scaffolds have shown diverse bioactiv-

ity. For example, they were recently reported to be

inhibitors of various kinases,³GalR2 ligands,⁴antimalar-

ial agents,⁵γ-secrerase modulators,⁶CRF1 receptor antag-

onists,⁷and anti-HIV agents.⁸

Nu¹

N

Cl

6

Nu¹

1. [O]

2. Nu²

1. R₂NH

2. Nu¹

N

(2)

N

2

4

Cl

Nu²

NR₂

MeS

N

MeS

N

NR₂

from

4,6-dichloro-

2-(methylthio)pyrimidine

VII

VI

Recently we were interested in the preparation of a series

of 2,4,6-trisubstututed aminopyrimidines. A literature re-

view revealed that there are two principal methods for the

preparation of such compounds as shown in Scheme 1.

The first method involves the sequential substitution of

the chlorine atoms of 2,4,6-trichloropyrimidine with

amines or other nucleophiles [Scheme 1, (1)]. This elec-

trophile, while inexpensive, suffers from poor selectivity

in its reaction with nucleophiles.⁹Moreover, separation

and identification of isomers I and II may be difficult.

Further selective functionalization of I to form either III

or IV may be similarly complicated.

Scheme 1 Typical methods for preparation of aminopyrimidines

The reactions of commercially available 4,6-dichloro-2-

(methylsulfonyl)pyrimidine (1) have been much less ex-

plored than the comparative reactions with 2,4,6-trichlo-

ropyrimidine.¹¹There are only a few examples of the

reactions of 1 with various nucleophiles. For example,

alkoxides,¹²thiolates,¹³Grignard reagents,¹⁴aziridine,¹¹

and methylamine,¹⁵as well as deprotonated N(H)-

heterocycles¹⁶and a formamide,¹⁷react selectively with 1

at C2. In contrast, there is only one report of a selective,

albeit low yielding, displacement of the chloride group at

C4 of 1, using heteroaromatic amines.¹⁸Herein, we dis-

close our findings that 1 can serve as a common starting

material to selectively provide either C2- or C4-displace-

ment products by applying different reaction conditions.

The course of the reaction can be readily monitored by

LC-MS, and the isolation of the desired products is facile.

This finding leads to the efficient and divergent syntheses

of polysubstituted 2- and 4-aminopyrimidines.

Alternatively, 4,6-dichloro-2-(methylthio)pyrimidine has

been used to prepare polysubstituted pyrimidines through

nucleophilic substitution of one or both chlorine atoms,

followed by oxidation of the 2-sulfane to form a 2-sul-

fone, which can then undergo a substitution reaction at C2

[Scheme 1 (2)].¹⁰Although this method does not have se-

lectivity issues with regard to the site of the nucleophilic

substitution, the need for oxidation of the 2-sulfane intro-

SYNTHESIS 2013, 45, 1764–1784

Advanced online publication: 11.06.2013

0

3

9

-

7

8

1

4

3

7

-

2

1

0

X

DOI: 10.1055/s-0033-1338853; Art ID: SS-2013-C0253-OP

PAPER

Chemoselective Reactions of 4,6-Dichloro-2-(methylsulfonyl)pyrimidine

1765

produced 2 in high yield. As expected, in the latter case

the reaction was slower. The same trend was observed for

both electron-rich (entries 7 and 8) and electron-poor (en-

Chemoselective Displacement of Chloride in 1 with

Anilines in the Presence of Weak Base

We determined that aniline selectively displaced the chlo- tries 9–11) 4-substituted anilines. The reaction with steri-

ride at C4 from 1 (Table 1). For example, in acetonitrile cally hindered 2,6-dimethylaniline was slow but high-

when sodium hydrogen carbonate was used as the base, yielding (entry 12). N-Alkylanilines also demonstrated

the isolated yield of 2a was 95% after 48 hours (entry 1). high selectivity for reaction at C4 (entries 13 and 14).

In the presence of stronger bases, such as potassium car-

bonate (entry 2) or Hünig’s base (entry 3), the electrophile

Several heteroaromatic amines were employed and these

amines cleanly displaced the chloride in 1 (entries 15–

was consumed within five to eight hours; however, the

yield was lower due to byproduct formation.¹⁹The use of

Table 2 Chemoselective Substitution of C4–Cl in 1 with Anilines

pyridine led to rapid and extensive decomposition (entry

Cl

6

Cl

6

4);²⁰we could not identify or isolate the byproducts.

R¹R²NH

(1.1–1.3 equiv)

N

The non-nucleophilic and mild base 2,6-lutidine, on the

other hand, served as an excellent acid scavenger (entry

5). Alternative solvents, such as tetrahydrofuran, N,N-di-

methylformamide, or dimethyl sulfoxide (entries 6–8),

led to an equally high yield of product 2a. The reaction

proceeded most efficiently in dimethyl sulfoxide (entry

8). An extra equivalent of inexpensive aniline can serve as

an equally competent acid scavenger (entry 9).

2

R²

2,6-lutidine

(1.2–1.3 equiv),

DMSO (0.3 M), r.t.

4

MeO₂S

N

R¹

MeO₂S

N

1

Cl

2

Entry R¹R²NH

Time (h) Product

Yield^a(%)

1

2

PhNH₂

1

15

36

1

2a

2b

2c

2d

2e

2f

95

82

98

94

97

96

99

94

91

92

95

2-MeC₆H₄NH₂

2-ClC₆H₄NH₂

Table 1 Selective Substitution at C4 with Aniline: Solvent and Base

Screening

3

4

3-MeC₆H₄NH₂

3-ClC₆H₄NH₂

Cl

5

2

6

H₂N

(1.1 equiv)

N

6

3-O₂NC₆H₄NH₂

4-MeC₆H₄NH₂

4-MeOC₆H₄NH₂

4-ClC₆H₄NH₂

6

2

4

MeO₂S

N

MeO₂S

N

Cl

solvent (0.3 M),

H

7

1

2g

2h

2i

base (1.2 equiv), r.t.

1

2a

8

0.5

Entry

Solvent

Base

Time (h) Yield^a(%) of 2a

9

3

20

48

20

1

2

3

4

5

6

7

8

9

MeCN

THF

NaHCO₃

K₂CO₃

48

5

95

59

67

15

95

96

98

97

99

10

11

12

4-MeO₂CC₆H₄NH₂

4-NCC₆H₄NH₂

2,6-Me₂C₆H₃NH₂

2j

2k

2l

i-Pr₂NEt

8

pyridine

2

2,6-lutidine

PhNH₂

8

Me

13

14

15

1

2m

2n

2o

98

93

N

H

6

DMF

2

N

H

DMSO

1

N

0.25

0.5

^aIsolated yield.

NH₂

O

16

17

2

2p

2q

90

99

NH₂

N

These initial screening experiments identified dimethyl

sulfoxide and 2,6-lutidine (Table 1, entry 8) as the optimal

combination of solvent and base that provided the shortest

reaction time and a high yield. For consistency, these con-

ditions were also used to study the reaction scope. As data

in Table 2 show, this reaction is quite general. Reactions

with sterically hindered 2-substituted anilines (entries 2

and 3) were much slower, but they still provided the prod-

uct in high to excellent yields. Both electron-rich (entry 4)

and electron-poor (entries 5 and 6) 3-substituted anilines

N

0.2

HN

NH₂

H

N

18^b

1

2r

98

NH₂

^aIsolated yield.

^b1 (1 mmol), 1H-indol-5-amine (1 mmol), NaHCO₃(1.5 equiv),

DMF), r.t., 1 h.

Synthesis 2013, 45, 1764–1784

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R. Baiazitov et al.

PAPER

18).^{21 1}H NMR spectra of products 2o–r show broad sig- the absence of a sufficient concentration of deprotonated

nals of rotamers, which makes NMR analysis less useful aniline, side reactions take place instead.²⁷

for identification of these compounds. For the product 2q

Table 3 Chemoselective Substitution of C2–SO₂Me in 1 with

Anionic Nucleophiles

(entry 17) the existence of rotamers was confirmed by the

collapse of the ¹H NMR signals upon heating to 350 K in

DMSO-d₆.²²Although the structure of product 2r (entry

Cl

6

Cl

6

R

18) could not be unambiguously established by NMR

spectroscopy, we believe that reaction of the 5-aminoin-

dole with 1 proceeded via its NH₂group and not the indole

NH, because indole itself did not react with 1 at these con-

ditions (data not shown).²³

X

N

2

N

2

H

R

4

MeO₂S

N

1

Cl

N

Cl

conditions

Y

3

Although the reactions with anilines and some heteroaro-

matic amines were clean and followed the same general

trends, we were surprised to determine that the reactions

with many aromatic heterocyclic amines proceeded quite

different. For example, the reaction of amines such as pyr-

azole, 3,5-dimethylpyrazole, 2-aminopyridine, 2-amino-

Entry R or amine

X

Y

Product Yield^a,b(%)

1^c

2^c

H

3a

3b

3c

3d

3e

3a

3f

79

76

84

85

67

93

75

78

91

85

87

75

95

2-Cl

H

3^c

4-Cl

H

thiazole,

and

5-aminobenzimidazole

proceeded

4^c

4-Me

4-OMe

H

unselectively, displacing both the chloride and the sul-

fone, as well as forming bis-substituted and other uniden-

tified byproducts.²⁴Reaction of the 5-aminopyrimidine

and 3-aminopyridine proceeded selectively with the chlo-

ride at the early stages of the reaction (according to LC-

MS analysis of the reaction mixtures). However, the reac-

tions were slow, and multiple byproducts were formed at

completion. Some amines react not only unselectively but

also very slowly (such as indole).²³Additionally, LC-MS

analysis of the reaction mixtures suggested that the re-

leased sulfinate byproduct often was also capable of reac-

tion with 1, leading to the formation of additional

byproducts through a process described previously.^36b

5^c

H

6^d

CHO

Boc

H

7^d

2-OMe

3-OMe

4-OMe

4-Cl

H

8^d

H

3g

3e

3c

3h

3i

9^d

H

10^d

11^e

12^e

13^e

H

2-Br

3-Br

4-Cl

Boc

3j

Chemoselective Displacement of Sulfone in 1 with

Anionic Nucleophiles

14^c

15^c

16^c

H

3k

3l

84

75^f

38

N

S

NH₂

As demonstrated above, in the presence of a weak base an-

ilines and some heteroaromatic amines attack 1 at C4 with

selective displacement of the chloride moiety (Table 2).

This reactivity trend was unexpected, because previously

1 was mainly used to provide the C2-sulfone displacement

products.²⁵Because many of these examples²⁵involve an-

ionic nucleophiles, we reasoned that upon changing the

nature of the nucleophile from a neutral aniline to its de-

protonated form, the reaction selectivity may be reversed.

Indeed, we found that aniline deprotonation completely

changed the selectivity, leading to exclusive reaction at

C2 with displacement of methylsulfone and the formation

of product 3a (Table 3, entry 1). The reaction with steri-

cally and electronically deactivated 2-chloroaniline had

been slow in the presence of 2,6-lutidine (Table 2, entry

3); however, a sodium hexamethyldisilazanide²⁶promot-

ed reaction was fast and high yielding (Table 3, entry 2).

The yield was equally high with both electron-poor (entry

3) and electron-rich (entry 4) 4-substituted anilines. Prod-

uct 3e (entry 5) was isolated in lower yield. This could be

a result of the decreased acidity of p-anisidine due to the

strongly electron-donating nature of the 4-OMe group. In

NH₂

N

3m

N

^aIsolated yield.

^bReactions were not optimized.

^cNaHMDS, THF, –70 °C, 15–30 min.

^d1. NaOt-Am, THF, 0 °C–r.t., 30 min; 2. aq NaOH.

^eNaH, DMF–THF, –60 °C–0 °C, 1–2 h.

^fImpure, contains ~10% of the bis-adduct [M + H]⁺395.³⁰

As a potentially milder variant of this process, reactions of

1 with formamides in the presence of sodium tert-amylate

provided the same C2-displacement products (entries 6–

10).²⁸The intermediate formamide products (3, Y = CHO)

were partially hydrolyzed during the reactions. This hy-

drolysis could be completed by treatment with aqueous

sodium hydroxide to form the corresponding amines

3a,c,e–g. The yields of the process were high and inde-

pendent of the steric or electronic properties of the nucleo-

phile. Products of the C4-chloride displacement of 1 were

Synthesis 2013, 45, 1764–1784

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Chemoselective Reactions of 4,6-Dichloro-2-(methylsulfonyl)pyrimidine

1767

not observed under these reaction conditions. Instead of

the amide-protected anilines, Boc-protected anilines can

be used (entries 11–13).²⁹The products 3h–j were stable

and isolated unchanged. Several deprotonated heteroaro-

matic amines displaced the sulfone selectively. For exam-

ple, the reaction with 2-aminopyridine provided product

3k in 84% isolated yield (entry 14). The reaction with 2-

aminothiazole proceeded, but was complicated by further

arylation of the product 3l with 1 and its poor solubility,

which prevented its isolation (entry 15).³⁰Even though

the reaction with 3-aminopyridine was clean according to

LC-MS analysis of the reaction mixture, the product 3m

was isolated in only 38% yield, perhaps due to its instabil-

ity (entry 16).³¹

Table 4 Substitution of C4–Cl or C2–SO₂Me in 1 with Aliphatic

Amines

Cl

N

R¹

MeO₂S

N

Cl

R¹R²NH (2 equiv)

R²

4

+

2

N

Cl

N

–70 °C to 0 °C

over 30–90 min

MeO₂S

N

1

Cl

N

R¹

N

Cl

R²

5

Entry R¹R²NH

Product Yield (%) Product Yield (%)

Selective Displacement of Sulfone in 1 with Primary

Aliphatic Amines and Selective Displacement of

Chloride in 1 with Secondary Aliphatic Amines

1

2

EtNH₂

4a

4b

4c

4d

4e

4f

trace

2

5a

5b

5c

5d

5e

5f

82

92

96

77

trace

4

Ph(CH₂)₂NH₂

BnNH₂

3

Next, we examined the selectivity of the reaction between

1 and various aliphatic amines (Table 4). Because most al-

iphatic amines are more reactive than anilines, the reac-

tants were mixed at –70 °C, followed by slow warming to

~0 °C over one to two hours. However, data shown in en-

try 4 suggests that use of low temperature may be unnec-

essary and ambient temperature may be acceptable.

Reactions with some substrates at –70 °C were too slow

and required higher (ambient) temperature (entries 8–11).

An extra equivalent of the amine was used as the external

base for all of these reactions.

4^a

5

CyNH₂

MeEtNH

Et₂NH

77

6

86

7

piperidine

t-BuNH₂

4g

4h

69

5g

5h

5i

27

32

58

48

0

8^a

9^a

10^a

11^a,c

16^b

27^b

36

1-adamantylNH₂4i

CHF₂CH₂NH₂

CF₃CH₂NH₂

4j

5j

4k

58^d

5k

Interestingly, unlike the similar reactions with anilines

(Table 2), the chemoselectivity of the reactions with ali-

phatic amines depended upon the nature of the amine.

Thus, the reaction of several primary aliphatic amines

with 1 proceeded highly selectively at C2, with the forma-

tion of products 5a–d (entries 1–4).³²In contrast, several

secondary aliphatic amines preferentially displaced the

chloride at C4, forming products 4e–g (entries 5–7). The

less sterically hindered piperidine was less selective in

displacing the C4–Cl (69% vs. 29%, entry 7) compared to

highly selective diethylamine (entry 6) or N-methylethyl-

amine (entry 5). The sterically hindered primary amines

tert-butylamine and 1-adamantylamine did not displace

the sulfone as selectively as ethylamine (5/4 ~2:1, entries

8 and 9 vs. entry 1). It appears that the steric interactions

between 1 and the amine nucleophile are important in de-

termining the reaction selectivity.

^aReaction run at r.t., 0.3–2.5 h.

^bImpure.

^c1.3 equiv of amine used.

^d13% of 2,4-(dimethylsulfonyl)-6-(2,2,2-trifluoroethylamino)pyrim-

idine or its isomer was also isolated.

lectively (entry 1), the less electron-rich 2,2-difluoro-

ethylamine was less discriminating (entry 10). The even

less electron-rich 2,2,2-trifluoroethylamine did not dis-

place the sulfone at all, but it did displace the chloride in-

stead, albeit slowly (entry 11).

Attempted reactions between deprotonated secondary ali-

phatic amines and 1 were unsuccessful, and mixtures of

multiple products were formed instead as judged by LC-

MS analysis.³⁵However, deprotonated primary aliphatic

amines did displace the sulfone group selectively. For ex-

ample, when phenethylamine deprotonated with butyllith-

ium was combined with 1, the SO₂Me-displacement

product was produced, although in only 42% isolated

yield (Scheme 2). Cyclohexylamine deprotonated with

isopropylmagnesium chloride–lithium chloride complex

similarly formed the sulfone displacement product in 65%

isolated yield.

We also demonstrated that the electronic properties of the

amine affect the selectivity. For example, replacement of

the methyl group in ethylamine with an inductively

electron-withdrawing difluoromethyl or trifluoromethyl

group provides less basic³³and less nucleophilic³⁴amines,

which were also combined with 1 (entries 10 and 11).

Whereas ethylamine displaced the sulfone group very se-

Synthesis 2013, 45, 1764–1784

1768

R. Baiazitov et al.

PAPER

ment product were observed by LC-MS analysis of the

reaction mixtures. These selective displacements by ani-

lines of the chloride and not of the sulfone are consistent

with the data presented in Table 2.

Cl

N

Cl

RNH₂(2.2 equiv)

base (2.2 equiv)

N

RHN

Cl

–70 °C

MeO₂S

N

Cl

5b,d

On the other hand, primary aliphatic amines selectively

displaced the sulfone group in 2a (entries 6–8). This ob-

servation is consistent with the selective displacement by

similar amines of sulfone and not chloride in 1 (Table 4).

Formation of the alternative products (such as 6f) was ob-

served by LC-MS analysis; however, these minor prod-

ucts could not be isolated in pure form.

1

a. 5b, R = C₂H₄Ph, base = n-BuLi, 42%

b. 5d, R = Cy, base = i-PrMgCl⋅LiCl, 65%

Scheme 2 Reactions of 1 with deprotonated primary aliphatic

amines

Further Chemoselective Functionalizations of 2a

We also found that the C6-position in 2a could be selec-

tively functionalized by Suzuki reaction, providing arylat-

ed products 8a–d (Table 6). The reactions could be run at

relatively low temperatures (60 °C), which avoided com-

petitive hydrolysis of 2a or formation of other byproducts.

Additionally, we studied the selectivity of the reaction be-

tween 2a and various nucleophiles. We found that either

the sulfone or the chloride in 2a can be selectively dis-

placed. For example, heating 2a with anilines and 2,6-luti-

dine in dimethyl sulfoxide led to chloride displacement

and formation of products 6a–e (Table 5). Sterically hin-

dered (entry 2) or electronically deactivated (entry 5) ani-

lines required higher temperatures (100 °C) than did the

other anilines (80 °C). The reaction was highly chemose-

lective, and only trace amounts of the sulfone-displace-

Table 6 Substitution of C6–Cl in 2a with Arylboronates^a

R

Cl

6

a

ArylB(OH)₂

N

2

4

MeO₂S

N

NHPh

MeO₂S

N

NHPh

Table 5 Substitution of C6–Cl or C2–SO₂Me in 2a with Amines

2a

8

NHR

Entry

R

Product

Yield^b(%)

N

1

2

3

4

H

8a

8b

8c

8d

90

93

90

94

Cl

6

MeO₂S

N

6

NHPh

3-Me

4-OMe

4-F

N

2

amine

4

or

Cl

MeO₂S

N

NHPh

2a

N

^aAr-B(OH)₂(1.5 equiv), PdCl₂dppf (5 mol%), K₂CO₃(2 equiv), aq

RHN

N

NHPh

DME, 60 °C, 4 h.

7

^bIsolated yield.

Entry

RNH₂

Product Yield^aProduct Yield^a

(%)

Data presented in Table 3 illustrate that certain anionic

nucleophiles can selectively displace the sulfone group in

1. Similarly, the C2-position of 2a can also be selectively

functionalized. For example, deprotonated amides exclu-

sively displaced the sulfone from 2a (Table 7), forming

products 9. The reaction of aromatic formamides with dif-

ferent steric and electronic properties proceeded unevent-

fully (entries 1–5). The intermediate formamide products

(9, X = CHO) were partially hydrolyzed during the reac-

tions, which could be observed by LC-MS analysis of the

reaction mixtures. This hydrolysis could be completed by

treatment with aqueous sodium hydroxide to form the cor-

responding amines 9a–e. The reaction of aliphatic

phenethylformamide proceeded in a similar fashion (entry

6), providing product 9f in 91% yield upon hydrolysis. A

cyclic amide piperidone upon deprotonation also dis-

1^b

2^b

3^b

4^b

5^b

6^c

7^c

8^c

PhNH₂

6a

6b

6c

6d

6e

–

87

76

78

95

–

2-MeC₆H₄NH₂

3-MeC₆H₄NH₂

4-MeC₆H₄NH₂

4-ClC₆H₄NH₂

CyNH₂

–

7a

7b

7c

94

98

87

HOCH₂CH₂NH₂

BnNH₂

–

6f

4

^aIsolated yield.

^bRC₆H₄NH₂(2–4 equiv), 2,6-lutidine (1.2 equiv), DMSO, 80–

100 °C, 24–48 h.

^cRNH₂(3 equiv), DMSO, r.t., 24 h.

Synthesis 2013, 45, 1764–1784

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Chemoselective Reactions of 4,6-Dichloro-2-(methylsulfonyl)pyrimidine

1769

placed the methylsulfone group, providing amide product

Analysis of the Reaction Selectivity

9g in 68% yield (entry 7).

The selectivity trends described in Table 2 and Table 4 are

intriguing and deserve an explanation. A literature review

of the reactions of heterocyclic electrophiles bearing both

chloride and sulfone leaving groups reveals that chloride

is always selectively displaced by aniline or secondary al-

iphatic amine nucleophiles (neutral, not deprotonated).

Table 7 Substitution of C2–SO₂Me in 2a with Deprotonated Amides^a

Cl

6

amide,

N

2

N

conditions

4

R

MeO₂S

N

2a

NHPh

N

X

N

NHPh

For example, both aniline and dimethylamine displace

chloride from 3-chloro-6-(methylsulfonyl)pyridazine

(11b, Table 9, entry 2) to provide products 13b-1 and 13b-

2.^36aSimilar selectivity was observed for 4-chloro-6-

(methylsulfonyl)pyrimidine (11c, entry 3), which provid-

ed products 13c-1 and 13c-2.^36a

9

Entry

R

Product

X

Yield^b(%)

1

2

3

4

5

6

2-ClC₆H₄

9a

9b

9c

9d

9e

9f

H

92

87

95

99

96

91

3-ClC₆H₄

Additional examples include 4-chloro-2-(ethylsulfo-

nyl)pyrimidine,^36b4-chloro-2-(ethylsulfonyl)-6-phenyl-

pyrimidine,^36band 2,4-dichloro-6-(methylsulfonyl)pyr-

imidine.⁶The reaction of these electrophiles with anilines

or secondary aliphatic amines proceeded by chloride dis-

placement.

As the further confirmation of this trend, we found³⁷that

reaction of 2-chloro-6-(methylsulfonyl)pyrazine (11d, en-

try 4) and 4-chloro-2-(methylsulfonyl)pyrimidine (11e,

entry 5), proceeded in a similar fashion, with selective dis-

placement of chloride by either aniline or diethylamine,

providing products 13d-1, 13d-2, 13e-1, and 13e-2. 2-

Chloro-4-(methylsulfonyl)pyrimidine (11f, entry 10) be-

haved anomalously because the reaction with aniline was

not clean. In addition to the major product 13f-1, the sul-

4-ClC₆H₄

4-MeOC₆H₄

4-O₂NC₆H₄

Ph(CH₂)₂

O

7^c

9g

–

68

HN

^aReaction conditions: 1. RNHCHO, NaOt-Am (2 equiv), THF, 0 °C–

r.t., 30 min; 2. aq NaOH, r.t., 30 min.

^bIsolated yield.

^cThe hydrolysis step was omitted.

Finally, we demonstrated that organomagnesium reagents fone displacement product could also be observed by LC-

also preferentially displace the sulfone over the chloride MS analysis. In comparison, when 11f was combined with

(Table 8). At least two equivalents of the nucleophile were diethylamine, a clean and selective chloride displacement

required for this reaction, as one equivalent was con- was observed with formation of 13f-2.

sumed to deprotonate the acidic N–H present in 2a. As the

In contrast, reactions of primary aliphatic amines are less

data illustrates, both arylmagnesium reagents (entries 1–

consistent and may proceed according to one of the three

3) and alkylmagnesium reagents (entry 4) provided the

scenarios.

desired products 10a–d in high yield.

(1) Selective chloride displacement was observed when

Table 8 Substitution of C2–SO₂Me in 2a with Organomagnesium

primary aliphatic amines were combined with 3-chloro-6-

(methylsulfonyl)pyridazine 11b to provide 13b-3 (entry

2),^36aor with 2-chloro-6-(methylsulfonyl)pyrazine 11d to

provide 13d-3 (entry 4).

Reagents^a

Cl

6

RMgX

N

2

(2) Selective sulfone displacement was observed when

primary aliphatic amines were combined with 4,6-dichloro-

2-(methylsulfonyl)pyrimidine (1) to provide 12a (entry 1).

4

R

N

10

NHPh

MeO₂S

N

2a

NHPh

Entry

R

Product

Yield^b(%)

(3) In general, primary aliphatic amines react with hetero-

cyclic electrophiles less selectively. Examples include re-

actions with: (a) 4-chloro-6-(methylsulfonyl)pyrimidine

(11c, entry 3), with the formation of both products 12c-1

and 13c-3; (b) 4-chloro-2-(methylsulfonyl)pyrimidine

(11e, entry 5), with formation of both 12e-1 and 13e-3. In

each case, the sulfone displacement was preferred. Addi-

tional examples of unselective reactions include 4-chloro-

2-(ethylsulfonyl)pyrimidine,^36band 4-chloro-2-(ethylsul-

fonyl)-6-phenylpyrimidine.^36b,38In both reactions sulfone

1

2

3

Ph

10a

10b

10c

95

97

93

3-F₃COC₆H₄

4-FC₆H₄

O

4

10d

96

^aReaction conditions: RMgBr (2.5 equiv), THF, 0 °C–r.t., 1 h.

^bIsolated yield.

Synthesis 2013, 45, 1764–1784

1770

R. Baiazitov et al.

PAPER

Table 9 Selected Data on the Chemoselectivity of Reactions between Electrophiles 11a–f Containing Both Chloride and Sulfone Leaving

Groups and the Three Types of Amines: Anilines, Secondary Aliphatic Amines, and Primary Aliphatic Amines

R¹R²NH

R¹R²N

Cl

MeO₂S

NR¹R²

N

Cl

SO₂Me

¹= aryl, alkyl

²= alkyl, H

11

12

13

R

Entry Heterocycle 5^a

Product of reaction with:

Anilines

Secondary aliphatic amines Primary aliphatic amines

Cl

N

Cl

N

δ ~ + 0.53/0.57

δ ~ + 0.59

1

MeO₂S

N

NHPh

MeO₂S

N

NEt₂

EtHN

N

Cl

MeO₂S

N

Cl

12a, 82% (same as 5a)

this work

13a-1, 97% (same as 2a)

this work

13a-2, 86% (same as 4f)

this work

11a (same as 1)

N

NHPh

N

NHn-Bu

N

NMe₂

N

Cl

N

δ ~ + 0.29

MeO₂S

N

MeO₂S

δ ~ + 0.40

2

3

4

5

6

13b-1, 77%

ref. 36a

13b-2, 86%

ref. 36a

13b-3, 92%

ref. 36a

11b

N

EtHN

Cl

Br

N

δ ~ + 0.64

N

δ ~ + 0.57

12c-1, 83%

N

MeO₂S

N

H

MeO₂S

NMe₂

MeO₂S

Cl

N

13c-2, 72%

ref. 36a

13c-1, 77%

ref. 36a

11c

MeO₂S

NHEt

13c-3, 14%

this work

N

δ ~ + 0.16

δ ~ + 0.26

MeO₂S

N

MeO₂S

N

NHPh

MeO₂S

N

NEt₂

MeO₂S

Cl

13d-1, 73%

this work

13d-2, 92%

this work

13d-3, 78%

this work

11d

N

EtHN

N

Cl

N

δ ~ + 0.60

δ ~ + 0.58

12e-1, 67%

N

MeO₂S

N

MeO₂S

N

MeO₂S

N

Cl

N

13e-1, 97%

this work

13e-2, 93%

this work

11e

MeO₂S

N

NHEt

13e-3, 19%

this work

N

δ ~ + 0.75

N

δ ~ + 0.51

MeO₂S

11f

MeO₂S

N

MeO₂S

N

EtHN

N

Cl

N

Cl

13f-1^b

this work

12f-1, 79%

this work

13f-2, 94%

this work

^aPartial atomic charges are shown on the S- and Cl-bound carbon atoms.

^bThe product could not be isolated clean. Ratio of the chloride-substitution product to the sulfone-substitution product is ~3.5:1 by LC, detection

with UV 254 nm.

Synthesis 2013, 45, 1764–1784

PAPER

Chemoselective Reactions of 4,6-Dichloro-2-(methylsulfonyl)pyrimidine

1771

displacement was also slightly favored over chloride dis- This steric-driven selectivity explanation is also consis-

placement (sulfone displacement/chloride displacement tent with the less selective chloride displacement from 1

~2:1 or 4:1)

by the less hindered piperidine (Table 4, entry 7) com-

pared to diethylamine (Table 4, entry 6). Further support

for the steric origins of selectivity comes from data of Ta-

ble 4, entries 8 and 9. The sulfone displacement with these

bulky primary amines from 1 is not as selective as with the

less sterically biased ethylamine (Table 4, entry 1).

To summarize, heterocyclic electrophiles bearing both

chloride and sulfone leaving groups react with anilines

and secondary aliphatic amines by selective chloride dis-

placement. Reactions with primary aliphatic amines in

general favor sulfone displacement, although selective

chloride displacement is sometimes observed instead.

Reaction of 2-chloro-4-(methylsulfonyl)pyrimidine (11f)

with ethylamine was anomalous. The less positively

charged C(S) was attacked with formation of 12f-1. Sim-

ilarly, in 11c the less positively charged C(S) was prefer-

entially attacked by ethylamine. This anomalous behavior

suggests that there must be additional factors affecting the

selectivity of these reactions.

In order to understand what dictates the observed selectiv-

ity, we analyzed: (1) frontier molecular orbitals (FMO) of

the electrophiles; (2) partial atomic charges on the S- and

Cl-bound carbon atoms in the electrophiles;³⁹and (3) the

steric factors. We consider that the SO₂Me group has

more steric bulk the corresponding Cl; and anilines⁴⁰and

secondary aliphatic amines will have more steric bulk To summarize, we have demonstrated that 1 is a versatile

than primary aliphatic amines.

intermediate that can be used for selective synthesis of

polysubstituted pyrimidines. In the absence of a strong ex-

ternal base, anilines, some heteroaromatic amines, and

sterically unbiased secondary aliphatic amines selectively

displace the chloride group. In contrast, under the same

conditions electronically and sterically unbiased primary

aliphatic amines preferentially displace the sulfone group.

We proposed a steric-driven selectivity explanation for

the selective chloride displacement in 1 and similar elec-

trophiles (11b–f). Further, we proposed that for the reac-

tions of primary aliphatic amines, electrostatic attraction

may be equally important for the selectivity. In contrast,

anionic nucleophiles always selectively displace the sul-

fone group. The same reactivity trends apply for the reac-

tions of the advanced intermediate 2a.

First, we calculated lowest unoccupied molecular orbitals

(LUMO) in these electrophiles and determined that no

correlation exists between the atomic LUMO coefficients

and the reaction selectivity. For example, in 3-chloro-6-

(methylsulfonyl)pyridazine (11b) the LUMO is concen-

trated on the C(S); however, it is the chloride that is being

displaced from this electrophile. On the other hand, the

atomic LUMO coefficients at C(Cl) and C(S) in 1 are very

similar. Nevertheless, either carbon atom may be selec-

tively attacked by different nucleophiles.

The calculated partial atomic charges on the chlorine- and

sulfur-bound carbon atoms in these electrophiles are

shown in Table 9. We found that anilines and secondary

aliphatic amines always displace the chloride atom inde-

pendent of the position of the more positively charged

carbon atom. For example, in 3-chloro-6-(methylsulfo-

nyl)pyridazine (11b) the partial atomic charge on the

C(Cl) atom is larger than on the C(S) carbon (+0.40 vs.

+0.29). On the other hand, in 1 the charge on C(Cl) is low-

er than on C(S) (+0.53/+0.57 vs. +0.59). Nevertheless,

both electrophiles react with anilines or dialkylamines by

selective attack at C(Cl).

¹H and ¹³C NMR spectra were recorded on Bruker 500 MHz NMR

spectrometer (500 MHz ¹H, 126 MHz ¹³C) in CDCl₃, acetone-d₆, or

1

DMSO-d₆. H and ¹³C NMR assignments are corroborated by 2D

experiments (COSY, HMQC, HMBC, and NOESY) when relevant.

HRMS analysis (ESI+) was performed on an LTQ Orbitrap Discov-

ery mass spectrometer. Analytical TLC was performed on silica gel

plates with F-254 indicator. Visualization was accomplished by UV

light. Column chromatography was performed with silica gel. Melt-

ing points were determined in open capillary tubes on an OptiMelt

Because the selectivity of reactions with anilines or sec- MPA100 Automated Melting Point System. Anhydrous solvents

were purchased from Acros and used without further purification.

All commercially available reagents were purchased and used with-

out further purification unless otherwise noted. 4,6-Dichloro-2-

(methylsulfonyl)pyrimidine (1) was purchased from Accela Chem-

ondary aliphatic amines is not FMO- or charge-controlled,

we propose that it is governed by steric factors; and the

less sterically hindered C(Cl) is always attacked by these

bulkier amines.⁴¹

Bio and used without further purification.

However, primary aliphatic amines preferentially attack

6-Chloro-2-(methylsulfonyl)-N-phenylpyrimidin-4-amine (2a);

the most positively charged atom, although often unselec-

tively. Thus, in 1 the more positive C(S) is attacked by

ethylamine (entry 1), while in 11b and 11d the amines at-

tack the more positive C(Cl). However, frequently the re-

actions with primary aliphatic amines are less selective

(such as with 11c and 11e). It appears that when a primary

aliphatic amine reacts, the steric bulk may be as important

as the electrostatic attraction. In some cases (such as en-

tries 2 and 4) both steric and electronic factors match and

highly selective chloride displacement is possible. When

electronic factors predominate, selective sulfone displace-

ment is possible, such as observed with 1.

Typical Procedure

Compound 1 (227 mg, 1 mmol), 2,6-lutidine (150 μL, 1.3 mmol),

and aniline (118 μL, 1.3 mmol) were dissolved in DMSO (3 mL)

and the soln was stirred for 1 h under N₂at r.t. The reaction was

quenched with 0.1 M aq HCl (3 mL), and the resulting suspension

was stirred at 1 h at r.t. The solid product was filtered and washed

with H₂O. The wet product was dried at 50 °C under high vacuum

to give 2a as an off-white solid material; yield 270 mg (95%); mp

196–198 °C.

¹H NMR (500 MHz, DMSO-d₆): δ = 10.54 (br s, 1 H), 7.62 (br s, 2

H), 7.42 (t, J = 8.04 Hz, 2 H), 7.18 (t, J = 7.09 Hz, 1 H), 6.96 (s, 1

H), 3.36 (s, 3 H).

Synthesis 2013, 45, 1764–1784

1772

R. Baiazitov et al.

PAPER

¹³C NMR (126 MHz, DMSO-d₆): δ = 165.10, 161.44, 158.17,

137.85, 129.11, 124.34, 120.87, 107.32, 38.80.

6-Chloro-2-(methylsulfonyl)-N-(3-nitrophenyl)pyrimidin-4-

amine (2f)

Prepared according to the typical procedure for 2a, as a yellow solid

material; yield: 319 mg (97%); mp 245–246 °C.

¹H NMR (500 MHz, DMSO-d₆): δ = 10.92 (s, 1 H), 8.72 (br s, 1 H),

7.99–7.94 (m, 2 H), 7.70 (t, J = 8.2 Hz, 1 H), 7.06 (s, 1 H), 3.43 (s,

3 H).

MS (ESI): m/z (%) = 288 (1), 287 (4), 286 (36), 285 (11), 284 (100,

[M + H]⁺), 222 (2), 204 (2).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₁ClN₃O₂S: 284.0255;

found: 284.0248.

6-Chloro-2-(methylsulfonyl)-N-(o-tolyl)pyrimidin-4-amine (2b)

Prepared according to the typical procedure for 2a as a white solid

material; yield: 140 mg (95%); mp 129–130 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.48 (br s, 1 H), 7.34–7.33 (br m,

1 H), 7.28 (br m, 3 H), 6.44 (br s, 1 H), 3.31 (s, 3 H), 2.26 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 165.3, 163.4, 161.0, 134.3, 134.0,

¹³C NMR (126 MHz, DMSO-d₆): δ = 164.9, 161.2, 158.7, 148.1,

139.3, 130.5, 126.3, 118.3, 114.6, 108.4, 38.8.

MS (ESI): m/z (%) = 329 (100, [M + H]⁺), 331 (32).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₀ClN₄O₄S: 329.0111;

found: 329.0122.

6-Chloro-2-(methylsulfonyl)-N-(p-tolyl)pyrimidin-4-amine (2g)

Prepared according to the typical procedure for 2a as a yellow solid

material; yield: 285 mg (96%); mp 164–168 °C.

¹H NMR (500 MHz, DMSO-d₆): δ = 10.46 (br s, 1 H), 7.50 (br s, 2

H), 7.23 (d, J = 8.20 Hz, 2 H), 6.91 (br s, 1 H), 3.34 (s, 3 H), 2.30

(s, 3 H).

131.5, 128.1, 127.3, 125.9, 104.1, 38.8, 17.7.

MS (ESI): m/z (%) = 298 (100, [M + H]⁺), 300 (32).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₃ClN₃O₂S: 298.0417;

found 298.0427.

6-Chloro-N-(2-chlorophenyl)-2-(methylsulfonyl)pyrimidin-4-

amine (2c)

Prepared according to the typical procedure for 2a as an off-white

solid material; yield: 260 mg (82%); mp 123–126 °C.

¹H NMR (500 MHz, DMSO-d₆): δ = 10.34 (br s, 1 H), 7.70 (d, J =

7.57 Hz, 1 H), 7.61 (dd, J = 8.04, 1.42 Hz, 1 H), 7.44 (td, J = 7.65,

1.42 Hz, 1 H), 7.34 (t, J = 7.09 Hz, 1 H), 6.92 (br s, 1 H), 3.28 (s, 3

H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 166.07, 161.29, 157.61,

135.43, 133.08, 129.34, 120.43, 107.62, 38.79, 20.44.

MS (ESI): m/z (%) = 302 (2), 301 (4), 300 (37), 299 (13), 298 (100,

[M + H]⁺), 267 (1), 218 (2).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₃ClN₃O₂S: 298.0412;

found: 298.0403.

¹³C NMR (126 MHz, DMSO-d₆): δ = 170.38, 165.05, 162.54,

158.92, 133.94, 130.06, 127.95, 127.83, 127.28, 106.40, 38.68.

6-Chloro-N-(4-methoxyphenyl)-2-(methylsulfonyl)pyrimidin-

4-amine (2h)

Prepared according to the typical procedure for 2a as an off-white

solid material; yield: 310 mg (99%); mp 199–201 °C.

¹H NMR (500 MHz, DMSO-d₆): δ = 10.39 (br s, 1 H), 7.55–7.52 (br

m, 2 H), 7.01 (d, J = 8.6 Hz, 2 H), 6.89 (br, 1 H), 3.78 (s, 3 H), 3.34

(s, 3 H).

MS (ESI): m/z (%) = 323 (1), 322 (13), 321 (8), 320 (71), 319 (10),

318 (100, [M + H]⁺), 258 (1), 256 (1).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₀Cl₂N₃O₂S: 317.9865;

found: 317.9858.

6-Chloro-2-(methylsulfonyl)-N-(m-tolyl)pyrimidin-4-amine

(2d)

Prepared according to the typical procedure for 2a as a yellow solid

material; yield: 291 mg (98%); mp 129–140 °C.

¹H NMR (500 MHz, DMSO-d₆): δ = 10.27–10.56 (m, 1 H), 7.37–

7.54 (m, 2 H), 7.20–7.36 (m, 1 H), 6.97–7.04 (m, 1 H), 6.91–6.96

(m, 1 H), 3.36 (s, 3 H), 2.33 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 165.07, 161.39, 158.24,

138.39, 137.72, 128.88, 124.82, 121.05, 117.90, 107.47, 38.75,

21.06.

¹³C NMR (126 MHz, DMSO-d₆): δ = 165.2, 161.1, 157.5, 156.0,

130.9, 122.1, 114.2, 107.5, 55.2, 38.8.

MS (ESI): m/z (%) = 314 (100, [M + H]⁺), 316 (32).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₃ClN₃O₃S: 314.0366;

found: 314.0377.

6-Chloro-N-(4-chlorophenyl)-2-(methylsulfonyl)pyrimidin-4-

amine (2i)

Prepared according to the typical procedure for 2a as a white solid

material; yield: 301 mg (94%); mp 178–179 °C.

¹H NMR (500 MHz, DMSO-d₆): δ = 10.60 (br s, 1 H), 7.65 (br m,

2 H), 7.47 (d, J = 8.9 Hz, 2 H), 6.98 (s, 1 H), 3.36 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 165.0, 161.3, 158.3, 136.9,

129.0, 128.0, 122.9, 122.4, 38.8.

MS (ESI): m/z (%) = 318 (100, [M + H]⁺), 320 (63).

MS (ESI): m/z (%) = 302 (2), 301 (4), 300 (36), 299 (11), 298 (100,

[M + H]⁺), 238 (1), 236 (3), 218 (2).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₃ClN₃O₂S: 298.0417;

found: 298.0424.

6-Chloro-N-(3-chlorophenyl)-2-(methylsulfonyl)pyrimidin-4-

amine (2e)

Prepared according to the typical procedure for 2a as a yellow solid

material; yield: 298 mg (94%); mp 134–136 °C.

¹H NMR (500 MHz, DMSO-d₆): δ = 10.72 (s, 1 H), 7.85 (br s, 1 H),

7.54 (d, J = 9.14 Hz, 1 H), 7.44 (t, J = 8.04 Hz, 1 H), 7.16–7.27 (m,

1 H), 7.03 (s, 1 H), 3.37 (s, 3 H).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₀Cl₂N₃O₂S: 317.9871;

found: 317.9881.

Methyl 4-[6-Chloro-2-(methylsulfonyl)pyrimidin-4-ylami-

no]benzoate (2j)

Prepared according to the typical procedure for 2a as a yellow solid

material; yield: 310 mg (91%); mp 127–129 °C.

¹H NMR (500 MHz, DMSO-d₆): δ = 10.84 (s, 1 H), 8.01 (d, J = 9.14

Hz, 2 H), 7.80 (d, J = 8.51 Hz, 2 H), 7.08 (s, 1 H), 3.85 (s, 3 H), 3.41

(s, 3 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 164.95, 161.24, 158.38,

139.50, 133.30, 130.65, 123.76, 120.18, 118.99, 107.93, 38.80.

MS (ESI): m/z (%) = 322 (12), 321 (7), 320 (71), 319 (11), 318 (100,

[M + H]⁺), 281 (2), 267 (6), 256 (2).

¹³C NMR (126 MHz, DMSO-d₆): δ = 165.65, 164.98, 161.11,

158.57, 142.49, 130.41, 124.46, 119.72, 108.43, 51.95, 38.87.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₀Cl₂N₃O₂S: 317.9865;

found: 317.9857.

MS (ESI): m/z (%) = 346 (1), 345 (4), 344 (36), 343 (14), 342 (100,

[M + H]⁺), 312 (2), 310 (7).

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Chemoselective Reactions of 4,6-Dichloro-2-(methylsulfonyl)pyrimidine

1773

HRMS (ESI): m/z [M + H]⁺calcd for C₁₃H₁₃ClN₃O₄S: 342.0310;

found: 342.0301.

¹H NMR (500 MHz, DMSO-d₆): δ = 10.83 (s, 1 H), 8.83 (dd, J =

1.6, 4.1 Hz, 1 H), 8.30 (br d, J = 7.9 Hz, 2 H), 8.05 (d, J = 9.1 Hz, 1

H), 7.89 (app. br d, J = 8.8 Hz, 1 H), 7.52 (dd, J = 4.3, 8.4 Hz, 1 H),

7.08 (s, 1 H), 3.43 (s, 3 H).

¹³C NMR (126MHz, DMSO-d₆): δ = 165.1, 161.4, 158.5, 149.6,

145.0, 135.9, 135.6, 129.9, 128.2, 124.4, 122.0, 117.0, 107.7, 38.9.

MS (ESI): m/z (%) = 337 (37), 336 (15), 335 (100, [M + H]⁺).

HRMS (ESI): m/z [M + H]⁺calcd for C1₄H₁₂ClN₄O₂S: 335.0364;

4-[6-Chloro-2-(methylsulfonyl)pyrimidin-4-ylamino]benzoni-

trile (2k)

Prepared according to the typical procedure for 2a as an off-white

solid material; yield: 283 mg (92%); mp 219–229 °C.

¹H NMR (500 MHz, DMSO-d₆): δ = 10.90 (s, 1 H), 7.92–7.82 (m,

4 H), 7.10 (s, 1 H), 3.40 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d₆): δ =165.07, 161.26, 158.83,

found: 335.0357.

142.60, 133.63, 120.44, 119.07, 108.80, 105.61, 39.05.

N-[6-Chloro-2-(methylsulfonyl)pyrimidin-4-yl]isoxazol-3-

amine (2p)

Prepared according to the typical procedure for 2a as an off-white

solid material; yield: 247 mg (90%); mp 219–220 °C.

MS (ESI): m/z (%) = 313 (2), 312 (4), 311 (34), 310 (12), 309 (100,

[M + H]⁺), 247 (2), 229 (2), 215 (2).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₀ClN₄O₂S: 309.0208;

found: 309.0199.

¹H NMR (500 MHz, DMSO-d₆): δ = 11.6 (s, 1 H), 8.89 (s, 1 H), 7.53

(br s, 1 H), 6.82 (br s, 1 H), 3.40 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 164.9, 160.52, 160.47, 157.7,

108.3, 99.3, 39.0.

MS (ESI): m/z (%) = 255 (18), 267 (100), 275 (40, [M + H]⁺).

6-Chloro-N-(2,6-dimethylphenyl)-2-(methylsulfonyl)pyrimi-

din-4-amine (2l)

Prepared according to the typical procedure for 2a as a yellow solid

material; yield: 295 mg (95%); mp 163–169 °C.

¹H NMR (500 MHz, DMSO-d₆, mixture of two rotamers ~0.4:0.6):

δ = 10.24 (s, 0.6 H), 9.87 (s, 0.4 H), 7.20–7.29 (m, J = 3.50 Hz, 1.8

H), 7.11–7.18 (m, 1.2 H), 7.02 (s, 0.4 H), 5.88 (s, 0.6 H), 3.37 (s, 1.8

H), 3.11 (s, 1.2 H), 2.16 (s, 3.5 H), 2.14 (s, 2.5 H); see the Support-

ing Information for the spectrum.

¹³C NMR (126 MHz, acetone-d₆, signals for both rotamers): δ =

166.9, 164.9, 164.1, 164.1, 161.6, 159.8, 137.2, 136.5, 135.2, 134.1,

129.8, 129.3, 128.9, 128.2, 125.8, 107.4, 103.2, 39.7, 39.3, 38.9,

18.7, 18.2.

MS (ESI): m/z (%) = 316 (3), 315 (7), 314 (65), 312 (100, [M + H]⁺),

115 (9).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₃H₁₅ClN₃O₂S: 312.0568;

found: 312.0561.

HRMS (ESI): m/z [M + H]⁺calcd for C₈H₈ClN₄O₃S: 275.0006;

found: 274.9992.

6-Chloro-2-(methylsulfonyl)-N-(1H-pyrazol-4-yl)pyrimidin-4-

amine (2q)

Prepared according to the typical procedure for 2a as a pink amor-

phous solid; yield: 269 mg (99%).

¹H NMR (500 MHz, DMSO-d₆): δ = 12.68–13.12 (m, 1 H), 10.57

(br s, 0.8 H), 10.20 (br s, 0.2 H), 7.88–8.11 (m, 1 H), 7.50–7.82 (m,

1 H), 6.87 (br s, 0.8 H), 6.68 (br s, 0.2 H), 3.35 (s, 3 H); see VT

NMR experiments in the Supporting Information.

¹³C NMR (126 MHz, DMSO-d₆): δ = 165.4, 160.0, 157.1, 120.4,

120.4, 106.9, 38.8.

LC-MS (ESI): m/z = 274 [M + H]⁺.

6-Chloro-N-methyl-2-(methylsulfonyl)-N-phenylpyrimidin-4-

amine (2m)

Prepared according to the typical procedure for 2a as a white solid

material; yield: 292 mg (98%); mp 184–185 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.65 (s, 1 H), 7.53 (t, J = 7.5 Hz,

2 H), 7.43 (t, J = 7.5 Hz, 1 H), 7.24 (dd, J = 8.3, 1.3 Hz, 2 H), 3.55

(s, 3 H), 3.38 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 164.8, 162.8, 158.6, 142.4,

130.2, 128.1, 126.4, 104.7, 38.69, 38.66.

MS (ESI): m/z (%) = 191 (100), 298 (100, [M + H]⁺), 300 (36), 320

(28).

N-[6-Chloro-2-(methylsulfonyl)pyrimidin-4-yl]-1H-indol-5-

amine (2r)

To 1 (227 mg, 1 mmol) was added 1H-indol-5-amine (132 mg, 1

mmol), NaHCO₃(130 mg, 1.5 equiv), DMF (1 mL) and the mixture

was stirred at r.t. under N₂for 1 h. LC-MS analysis of the mixture

showed complete conversion of 1 and clean formation of the major

product (M + H = 323). AcOH (3 drops) was added, then the mix-

ture was diluted with H₂O, filtered, washed with more H₂O, then

hexane, and Et₂O, and dried in vacuo to provide 2r as a yellow

amorphous solid material; yield: 314 mg (98%).

¹H NMR (500 MHz, DMSO-d₆, mixture of rotamers): δ = 11.00–

11.39 (m, 1 H), 10.29–10.58 (m, 1 H), 7.85 (br s, 0.54 H), 7.32–7.56

(m, 2.55 H), 7.27 (br s, 0.6 H), 7.02 (br s, 0.42 H), 6.91 (br s, 0.57

H), 6.59 (br s, 0.41 H), 6.44 (br s, 1.1 H), 3.35 (s, 3 H); see the Sup-

porting Information for the ¹H NMR spectrum.

¹³C NMR not available due to signals being too weak/broad, see

HSQC spectrum in the Supporting Information for information on

some signals.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₃ClN₃O₂S: 298.0417;

found: 298.0403.

1-[6-Chloro-2-(methylsulfonyl)pyrimidin-4-yl]indoline (2n)

Prepared according to the typical procedure for 2a as an off-white

solid material; yield: 304 mg (98%); mp 222–223 °C.

¹H NMR (500 MHz, DMSO-d₆): δ = 8.40 (br s, 1 H), 7.32 (d, J =

7.3 Hz, 1 H), 7.29 (t, J = 7.8 Hz, 1 H), 7.19 (s, 1 H), 7.09 (td, J =

7.5, 0.6 Hz, 1 H), 4.14 (t, J = 8.4 Hz, 2 H), 3.42 (s, 3 H), 3.27 (t, J =

8.4 Hz, 2 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 164.3, 159.02, 158.98, 141.8,

133.1, 127.3, 125.2, 123.0, 116.7, 106.7, 48.8, 39.0, 26.8.

MS (ESI): m/z (%) = 310 (100, [M + H]⁺), 312 (36).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₃H₁₃ClN₃O₂S: 310.0417;

LC-MS (ESI): m/z = 323 [M + H]⁺.

4,6-Dichloro-N-phenylpyrimidin-2-amine (3a); Typical Proce-

dure

To aniline (279 mg, 3 mmol) in a tube with septum, stirbar, and nee-

dle for N₂was added THF (3 mL) and the soln was cooled to –70

°C (external temperature). 1 M NaHMDS in THF (5 mL, 5 mmol)

was added by syringe, followed by slow addition by cannula of a

soln of 1 [454 mg, 2 mmol in THF (3 mL)] over 2 min. UPLC anal-

ysis after 10 min showed complete conversion and after 40 min of

total reaction time the mixture was quenched with AcOH, then par-

titioned between brine and EtOAc–hexane (~1:1) mixture. The or-

ganic layer was concentrated and purified by chromatography

found: 310.0404.

N-[6-Chloro-2-(methylsulfonyl)pyrimidin-4-yl]isoquinolin-6-

amine (2o)

Prepared according to the typical procedure for 2a as a white amor-

phous solid; yield: 618 mg (93%).

Synthesis 2013, 45, 1764–1784

1774

R. Baiazitov et al.

PAPER

(silica gel, EtOAc–hexanes, gradient 0:1 to 1:5) to provide 3a as

glassy material (404 mg, 85%). The analytically pure material was

prepared through crystallization (heptane) to provide 3a as a solid

material; yield: 381 mg (79%); mp 115–117 °C (heptane).

¹H NMR (500 MHz, acetone-d₆): δ = 9.25 (br s, 1 H), 7.82–7.72 (m,

2 H), 7.41–7.31 (m, 2 H), 7.10 (tt, J = 1.1, 7.4 Hz, 1 H), 6.98 (s, 1 H).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₀Cl₂N₃O: 270.0195;

found: 270.0218.

4,6-Dichloro-N-phenylpyrimidin-2-amine (3a); Alternate Typi-

cal Procedure

Compound 1 (227 mg, 1 mmol) and N-phenylformamide (1.1

mmol) were dissolved in THF (3 mL) and the soln was cooled under

N₂to 0 °C using an ice bath. To this soln was added dropwise a soln

of 1.4 M NaOt-Am in THF (0.9 mL, 1.2 mmol). The mixture was

stirred at 0 °C for 30 min. LC-MS analysis showed consumption of

the starting material 1. Then 1 M aq NaOH (1.5 mL, 1.5 mmol) was

added and the mixture was stirred at r.t. for 30 min. LC-MS analysis

showed clean formation of the desired product 3a. The material was

extracted with EtOAc. The organic layer was collected, dried, and

evaporated. The crude product was purified by flash chromatogra-

phy to provide the 3a as white solid material; yield: 224 mg (93%).

Based on NMR and LC-MS analysis the material is identical to 3a

prepared from aniline in the presence of NaHMDS.

¹³C NMR (126 MHz, acetone-d₆): δ = 162.8, 160.8, 140.3, 130.1,

124.8, 121.4, 111.7.

MS (ESI): m/z (%) = 244 (9), 243 (8), 242 (65), 241 (12), 240 (100,

[M + H]⁺).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₀H₈Cl₂N₃: 240.0090; found:

240.0085.

4,6-Dichloro-N-(2-chlorophenyl)pyrimidin-2-amine (3b)

Prepared according to the typical procedure for 3a as a white solid

material upon crystallization (heptane); yield: 416 mg (76%); mp

112–114 °C (heptane).

¹H NMR (500 MHz, acetone-d₆): δ = 8.65 (br s, 1 H), 7.95 (dd, J =

1.7, 8.0 Hz, 1 H), 7.53 (dd, J = 1.6, 8.2 Hz, 1 H), 7.40 (dt, J = 1.6,

7.7 Hz, 1 H), 7.24 (dt, J = 1.6, 7.7 Hz, 1 H), 7.05 (s, 1 H).

¹³C NMR (126 MHz, acetone-d₆): δ = 163.2, 161.4, 136.4, 131.0,

129.0, 128.7, 127.7, 127.0, 112.5.

4,6-Dichloro-N-(2-methoxyphenyl)pyrimidin-2-amine (3f)

Prepared according to the alternate typical procedure for 3a as a

white solid material; yield: 201 mg (75%); mp 83–85 °C.

¹H NMR (500 MHz, CDCl₃): δ = 8.29 (dd, J = 7.6, 2.2 Hz, 1 H),

7.86 (br s, 1 H), 6.94–6.88 (m, 2 H), 6.77 (dd, J = 7.4, 2.2 Hz, 1 H),

6.63 (s, 1 H), 3.77 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 161.5, 158.6, 147.9, 127.5, 123.0,

120.9, 118.8, 110.8, 109.9, 55.6.

MS (ESI): m/z (%) = 270 (100, [M + H]⁺), 272 (64).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₀Cl₂N₃O: 270.0201;

MS (ESI): m/z (%) = 278 (31), 277 (8), 276 (100), 275 (11), 274 (94,

[M + H]⁺), 238 (10).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₀H₇Cl₃N₃: 273.9700; found:

273.9694.

4,6-Dichloro-N-(4-chlorophenyl)pyrimidin-2-amine (3c)

Prepared according to the typical procedure for 3a as a white solid

material; yield: 229 mg (84%); mp 172–174 °C (EtOAc–hexane).

¹H NMR (500 MHz, DMSO-d₆): δ = 10.53 (s, 1 H), 7.72–7.62 (m,

2 H), 7.44–7.36 (m, 2 H), 7.23 (s, 1 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 160.9, 158.6, 137.7, 128.6,

found: 270.0188.

4,6-Dichloro-N-(3-methoxyphenyl)pyrimidin-2-amine (3g)

Prepared according to the alternate typical procedure for 3a as a

white solid material; yield: 207 mg (78%); mp 107–108 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.45 (br s, 1 H), 7.36 (t, J = 2.3

Hz, 1 H), 7.26 (t, J = 8.2 Hz, 1 H), 7.06 (ddd, J = 8.2, 2.3, 0.7 Hz, 1

H), 6.80 (s, 1 H), 6.69 (ddd, J = 8.2, 2.3, 0.7 Hz, 1 H), 3.85 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 161.7, 160.1, 158.8, 138.9, 129.7,

112.0, 111.2, 109.3, 105.6, 55.2. MS (ESI): m/z (%) = 270 (100, [M

+ H]⁺), 272 (64).

126.7, 121.1, 110.6.

MS (ESI): m/z (%) = 278 (31), 277 (13), 276 (97), 275 (10), 274

(100, [M + H]⁺), 238 (7).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₀H₇Cl₃N₃: 273.9700; found:

273.9695.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₀Cl₂N₃O: 270.0201;

found: 270.0188.

4,6-Dichloro-N-(p-tolyl)pyrimidin-2-amine (3d)

Prepared according to the typical procedure for 3a as a light yellow

solid material; yield: 215 mg (85%); mp 114–116 °C (EtOAc–

hexane).

¹H NMR (500 MHz, DMSO-d₆): δ = 10.29 (s, 1 H), 7.54–7.48 (m,

2 H), 7.13 (s, 1 H), 7.19–7.08 (m, 2 H), 2.26 (s, 3 H).

4,6-Dichloro-N-(4-methoxyphenyl)pyrimidin-2-amine (3e)

Prepared according to the alternate typical procedure for 3a as a

white solid material; yield: 245 mg (91%); mp 139–140 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.46 (d, J = 9 Hz, 2 H), 7.29 (br s,

1 H), 6.92 (d, J = 9 Hz, 2 H), 6.75 (s, 1 H), 3.83 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 161.8, 159.3, 156.4, 130.6, 122.1,

114.2, 110.6, 55.5.

¹³C NMR (126 MHz, DMSO-d₆): δ = 160.8, 158.9, 136.1, 132.2,

129.1, 120.0, 109.8, 20.4.

MS (ESI): m/z (%) = 258 (8), 257 (7), 256 (65), 255 (12), 254 (100,

MS (ESI): m/z (%) = 115 (100), 270 (70, [M + H]⁺), 272 (47).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₀Cl₂N₃O: 270.0201;

[M + H]⁺), 218 (9).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₀Cl₂N₃: 254.0246;

found: 254.0239.

found: 270.0220.

4,6-Dichloro-N-(4-chlorophenyl)pyrimidin-2-amine (3c)

Prepared according to the alternate typical procedure for 3a as a

white solid material; yield: 232 mg (85%); mp 173–175 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.45–7.43 (m, 2 H), 7.25–7.19 (m,

2 H), 6.74 (s, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 161.9, 158.8, 136.3, 129.1, 129.0,

4,6-Dichloro-N-(4-methoxyphenyl)pyrimidin-2-amine (3e)

Prepared according to the typical procedure for 3a as an off-white

amorphous solid material; yield: 181 mg (67%).

¹H NMR (500 MHz, DMSO-d₆): δ = 10.22 (s, 1 H), 7.45–7.55 (m,

2 H), 7.09 (s, 1 H), 6.88–6.97 (m, 2 H), 3.73 (s, 3 H)

¹³C NMR (126 MHz, DMSO-d₆): δ = 160.9, 159.1, 155.5, 131.6,

121.0, 111.6.

121.8, 113.9, 109.4, 55.2

MS (ESI): m/z (%) = 274 (100, [M + H]⁺), 276 (100).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₀H₇Cl₃N₃: 273.9706; found:

MS (ESI): m/z (%) = 274 (11), 273 (8), 272 (65), 271 (12), 270 (100,

[M + H]⁺), 234 (7), 102 (8).

273.9693.

Synthesis 2013, 45, 1764–1784

PAPER

Chemoselective Reactions of 4,6-Dichloro-2-(methylsulfonyl)pyrimidine

1775

tert-Butyl 2-Bromophenyl(4,6-dichloropyrimidin-2-yl)carba-

mate (3h); Typical Procedure

¹³C NMR (126 MHz, DMSO-d₆, major signals): δ = 164.4, 162.4,

160.9, 160.4, 158.7, 156.6, 137.7, 113.8, 112.1.

To 2-bromo-N-(tert-butoxycarbonyl)aniline (272 mg, 1 mmol) in a

reaction tube with a septum, a stirbar, and a needle for N₂was added

DMF (1 mL) and THF (1.5 mL), followed by NaH (60% suspension

in oil, 80 mg, 2 mmol, GAS EVOLUTION!). After stirring at r.t. for

5 min, the mixture was cooled to –60 °C (external temperature). To

the resulting suspension was added a soln of 1 (341 mg, 1.5 mmol)

in THF (1.5 mL). The mixture quickly turned into an unstirrable

suspension, which was warmed to 0 °C over 1 h. The mixture was

quenched with AcOH (GAS EVOLUTION!) and H₂O, and extract-

ed with a mixture EtOAc–hexanes (~1:1). Upon purification by

chromatography (silica gel, gradient EtOAc–hexanes from 0:1 to

1:6) 3h was obtained as an oily viscous material, which solidified in

vacuo; yield: 365 mg (87%); mp 98–101 °C (EtOAc–hexanes).

MS (ESI): m/z (%) = 251 (13), 250 (4), 249 (69), 248 (7), 247 (100,

[M + H]⁺), 213 94), 211 (9), 102 (4).

HRMS (ESI): m/z [M + H]⁺calcd for C₇H₅Cl₂N₄S: 246.9606;

found: 246.9626.

4,6-Dichloro-N-(pyridin-3-yl)pyrimidin-2-amine (3m)

Prepared according to the typical procedure for 3a as an amorphous

white solid material after column chromatography (silica gel,

EtOAc–hexanes, gradient from 1:4 to 1:0, then to EtOAc–MeOH,

~20:1); yield: 184 mg (38%).

¹H NMR (500 MHz, DMSO-d₆): δ = 10.82 (s, 1 H), 8.94 (d, J = 2.52

Hz, 1 H), 8.38 (dd, J = 1.42, 4.89 Hz, 1 H), 8.25 (ddd, J = 1.42, 2.68,

8.51 Hz, 1 H), 7.62 (dd, J = 5.04, 8.51 Hz, 1 H), 7.35 (s, 1 H).

¹H NMR (500 MHz, acetone-d₆): δ = 7.73 (dd, J = 1.6, 8.2 Hz, 1 H),

7.50–7.43 (m, 2 H), 7.43 (s, 1 H), 7.35 (ddd, J = 0.9, 1.9, 6.9 Hz, 1

H), 1.47 (s, 9 H).

APT NMR (126 MHz, DMSO-d₆): δ = 161.1, 158.6, 141.1, 138.2,

136.6, 129.2, 124.8, 111.7.

¹³C NMR (126 MHz, acetone-d₆): δ = 163.0, 161.1, 152.2, 140.9,

134.6, 132.3, 131.2, 130.1, 124.8, 117.3, 84.1, 28.6.

MS (ESI): m/z (%) = 245 (10), 244 (6), 243 (63), 242 (9), 241 (100,

[M + H]⁺), 207 (4), 206 (1), 205 (12), 102 (3).

HRMS (ESI): m/z [M + Na]⁺calcd for C₁₅H₁₄BrCl₂N₃NaO₂:

439.9539; found: 439.9534.

HRMS (ESI): m/z [M + H]⁺calcd for C₉H₇Cl₂N₄: 241.0061; found:

241.0063.

tert-Butyl 3-Bromophenyl(4,6-dichloropyrimidin-2-yl)carba-

mate (3i)

Prepared according to the typical procedure for 3h as a white solid

material; yield: 313 mg (75%); mp 81–85 °C (EtOAc–hexanes).

¹H NMR (500 MHz, acetone-d₆): δ = 7.55–7.52 (m, 2 H), 7.51 (s, 1

H), 7.42–7.37 (m, 1 H), 7.33–7.28 (m, 1 H), 1.49 (s, 9 H)

¹³C NMR (126 MHz, acetone-d₆): δ = 163.2, 161.7, 153.4, 143.3,

132.1, 132.1, 131.7, 128.2, 123.0, 118.2, 84.3, 28.6.

HRMS (ESI): m/z [M + Na]⁺calcd for C₁₅H₁₄BrCl₂N₃NaO₂:

439.9539; found: 439.9527.

4,6-Dichloro-N-ethylpyrimidin-2-amine (5a); Typical Proce-

dure

To 1 (454 mg, 2 mmol) was added THF (3 mL) under N₂, the mix-

ture was cooled to –70 °C (i-PrOH/CO₂bath), 2 M EtNH₂in THF

(2 mL, 4 mmol) was added by syringe. The white suspension was

stirred for 1.5 h, during which time the bath temperature reached 0

°C. The mixture was diluted with hexane–EtOAc (~1:1), washed

with H₂O, and the organic layer was purified by chromatography

(silica gel, EtOAc–hexanes, gradient from 0:1 to 1:10) to provide 5a

as a white solid material; yield: 314 mg (82%); mp 96–100 °C

(EtOAc–hexane).

¹H NMR (500 MHz, DMSO-d₆): δ = 8.14 (t, J = 5.2 Hz, 1 H), 6.84

(s, 1 H), 3.25 (dq, J = 5.5, 7.2 Hz, 2 H), 1.10 (t, J = 7.3 Hz, 3 H)).

tert-Butyl 4-Chlorophenyl(4,6-dichloropyrimidin-2-yl)carba-

mate (3j)

Prepared according to the typical procedure for 3h as a white solid

material; yield: 712 mg (95%); mp 98–101 °C (EtOAc–hexanes).

APT NMR (126 MHz, DMSO-d₆): δ = 161.3, 161.1, 160.7, 107.1,

14.1.

¹H NMR (500 MHz, DMSO-d₆): δ = 7.77 (s, 1 H), 7.50–7.45 (m, 2

H), 7.32–7.27 (m, 2 H), 1.42 (s, 9 H).

MS (ESI): m/z (%) = 196 (10), 195 (4), 194 (65), 193 (6), 192 (100,

[M + H]⁺), 166 915), 164 (22), 102 (23).

¹³C NMR (126 MHz, DMSO-d₆): δ = 161.3, 159.6, 151.8, 138.9,

131.7, 129.4, 129.2, 117.0, 82.9, 27.5.

HRMS (ESI): m/z [M + H]⁺calcd for C₆H₈Cl₂N₃: 192.0104; found:

192.0090.

HRMS (ESI): m/z [M + Na]⁺calcd for C₁₅H₁₄Cl₃N₃NaO₂: 396.0044;

found: 396.0039.

4,6-Dichloro-N-phenethylpyrimidin-2-amine (5b)

Prepared according to the typical procedure for 5a as a white solid

material; yield: 490 mg (92%); mp 131–135 °C (EtOAc–hexane).

¹H NMR (500 MHz, DMSO-d₆): δ = 8.24 (t, J = 5.7 Hz, 1 H), 7.32–

7.26 (m, 2 H), 7.25–7.17 (m, 3 H), 6.86 (s, 1 H), 3.50–3.42 (m, 2 H),

2.82 (t, J = 7.4 Hz, 2 H).

4,6-Dichloro-N-(pyridin-2-yl)pyrimidin-2-amine (3k)

Prepared according to the typical procedure for 3a as an amorphous

white solid material; yield: 201 mg (84%).

¹H NMR (500 MHz, DMSO-d₆): δ = 10.70 (s, 1 H), 8.33 (dd, J =

1.89, 5.04 Hz, 1 H), 8.02 (d, J = 8.20 Hz, 1 H), 7.76–7.88 (m, 1 H),

7.27–7.34 (m, 1 H), 7.03–7.14 (m, 1 H).

APT NMR (126 MHz, DMSO-d₆): δ = 161.4, 161.1, 160.7, 139.2,

128.7, 128.3, 126.1, 107.4, 42.5, 34.4.

¹³C NMR (126 MHz, DMSO-d₆): δ = 161.0, 158.4, 151.7, 148.1,

138.1, 119.1, 113.9, 111.6.

MS (ESI): m/z (%) = 272 (11), 271 (8), 270 (64), 269 (13), 268 (100,

[M + H]⁺), 105 (77), 102 (12).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₂Cl₂N₃: 240.0090;

found: 240.0424.

MS (ESI): m/z (%) = 245 (11), 244 (6), 243 (65), 242 (1), 241 (100,

[M + H]⁺), 207 (7), 206 (2), 205 (22).

HRMS (ESI): m/z [M + H]⁺calcd for C₉H₇Cl₂N₄: 241.0061; found:

241.0042.

4,6-Dichloro-N-phenethylpyrimidin-2-amine (5b); Alternate

Typical Procedure

To 2-phenylethanamine (0.754 mL, 6 mmol) was added THF (12

mL) and the soln was cooled under N₂to –70 °C. Then 2.6 M n-

BuLi in hexane (2.1 mL, 5.5 mmol) was added by syringe. After 15

min at this temperature, to the mixture was slowly added a soln of 1

[454 mg, 2 mmol, in THF (3 mL)] by cannula. After 15 min at this

temperature, the mixture was quenched with AcOH, partitioned be-

tween H₂O and EtOAc–hexane (~1:1), and the organic layer was

concentrated and purified by chromatography (silica gel, EtOAc–

N-(4,6-Dichloropyrimidin-2-yl)thiazol-2-amine (3l)

Prepared according to the typical procedure for 3a as a white amor-

1

phous solid material, ~90% pure according to H NMR analysis;

yield: 384 mg (starting with 2.2 mmol of 1 as the limiting reagent).

¹H NMR (500 MHz, DMSO-d₆): δ = 10.70 (s, 1 H), 8.33 (dd, J =

1.89, 5.04 Hz, 1 H), 8.02 (d, J = 8.20 Hz, 1 H), 7.76–7.88 (m, 1 H),

7.27–7.34 (m, 1 H), 7.03–7.14 (m, 1 H).

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hexanes, gradient 0:1–1:10) and recrystallized (heptane) to provide

to provide 4e as a white solid material; yield: 383 mg (77%); mp

118–121 °C (EtOAc–hexane).

1

5b as an off-white solid material; yield: 226 mg (42%). The H

NMR, ¹³C NMR, and MS data match with the material prepared

¹H NMR (500 MHz, DMSO-d₆, mixture of two rotamers

~0.44:0.55): δ = 7.10 (br s, 0.44 H), 6.97 (s, 0.53 H), 3.67 (q, J = 6.1

Hz, 1.1 H), 3.53 (q, J = 6.9 Hz, 0.9 H), 3.32 (s, 3 H), 3.14 (br s, 1.3

H), 3.07 (s, 1.7 H), 1.11 (t, J = 7.1 Hz, 3 H).

¹³C NMR (126 MHz, DMSO-d₆, signals for both rotamers): δ =

164.8, 164.6, 162.0, 161.8, 158.8, 103.7, 103.5, 44.4, 44.3, 38.7,

35.4, 34.9, 11.7, 11.2.

without use of n-BuLi.

N-Benzyl-4,6-dichloropyrimidin-2-amine (5c)

Prepared according to typical procedure for 5a as a white solid ma-

terial; yield: 487 mg (96%); mp 130–133 °C.

¹H NMR (500 MHz, DMSO-d₆): δ = 8.67 (t, J = 6.3 Hz, 1 H), 7.35–

7.27 (m, 4 H), 7.27–7.21 (m, 1 H), 6.90 (s, 1 H), 4.47 (d, J = 6.3 Hz,

2 H).

MS (ESI): m/z (%) = 272 (4, [M + Na]⁺), 254 (1), 253 (3), 252 (37),

251 (8), 250 (100, [M + H]⁺), 190 (2), 188 (6), 102 (8).

APT NMR (126 MHz, DMSO-d₆): δ = 161.5, 161.1, 161.0, 138.8,

128.3, 127.1, 126.9, 107.6, 44.1.

HRMS (ESI): m/z [M + H]⁺calcd for C₈H₁₃ClN₃O₂S: 250.0412;

found: 250.0431.

MS (ESI): m/z (%) = 258 (9), 257 (7), 256 (67), 255 (11), 254 (100,

[M + H]⁺), 178 (12), 176 (19), 102 (15).

6-Chloro-N,N-diethyl-2-(methylsulfonyl)pyrimidin-4-amine

(4f) and 4,6-Dichloro-N,N-diethylpyrimidin-2-amine (5f); Typi-

cal Procedure

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₀Cl₂N₃: 254.0246;

found: 240.0262.

To 1 (454 mg, 2 mmol) was added THF (6 mL), cooled to –70 °C

under N₂and Et₂NH (0.42 mL, 4 mmol, 2 equiv) was added by sy-

ringe. After 55 min the bath temperature reached +8 °C, the mixture

was quenched with AcOH, diluted with EtOAc–toluene (~1:1), and

washed with H₂O. The organic layer was filtered through a short

plug of silica gel, concentrated, and purified by chromatography

(silica gel, EtOAc–hexanes, gradient 0:1 to 1:0). Concentration of

the less polar fractions provided 5f as a colorless oily material;

yield: 19 mg (4%). Concentration of the more polar fractions pro-

vided 4f as a white solid material; yield: 453 mg (86%).

6-Chloro-N-cyclohexyl-2-(methylsulfonyl)pyrimidin-4-amine

(4d) and 4,6-Dichloro-N-cyclohexylpyrimidin-2-amine (5d)

To 1 (313 mg, 1.38 mmol) was added THF (3 mL) then at r.t. under

N₂CyNH₂(0.32 mL, 2.8 mmol, 2 equiv) was added; after 20 min a

white precipitate formed. The mixture was diluted with CH₂Cl₂, fil-

tered through a short plug of silica gel, concentrated, and purified

by chromatography (silica gel, EtOAc–hexanes, gradient 1:50 to

1:1). Concentration of the less polar fractions provided 5d as a white

solid material; yield: 259 mg (77%). Concentration of the more po-

lar fractions provided 4d as a colorless oily material; yield: 8 mg

(2%).

2-Diethylamino Product 5f

¹H NMR (500 MHz, acetone-d₆): δ = 6.66 (s, 1 H), 3.62 (q, J = 7.3

Hz, 4 H), 1.17 (t, J = 7.1 Hz, 6 H).

2-Cyclohexylamino Product 5d

¹H NMR (500 MHz, DMSO-d₆): δ = 8.09 (d, J = 7.9 Hz, 1 H), 6.75–

6.68 (m, 1 H), 3.68–3.54 (m, 1 H), 1.88–1.74 (m, 2 H), 1.74–1.60

(m, 2 H), 1.54 (td, J = 3.8, 13.2 Hz, 1 H), 1.32–1.15 (m, 4 H), 1.15–

0.99 (m, 1 H).

APT NMR (126 MHz, acetone-d₆): δ = 162.8, 108.0, 43.6, 13.5; one

signal could not be found

2-Methylsulfonyl Product 4f

Mp 109–112 °C (EtOAc–hexanes).

APT NMR (126 MHz, DMSO-d₆): δ = 161.1, 160.7, 160.6, 106.8,

¹H NMR (500 MHz, DMSO-d₆): δ = 7.02 (s, 1 H), 3.62 (q, J = 6.7

Hz, 2 H), 3.51 (q, J = 6.8 Hz, 2 H), 3.32 (s, 3 H), 1.17–1.08 (m, 6 H).

49.6, 31.9, 25.2, 24.6

LC-MS (ESI): m/z = 246 [M + H]⁺.

¹³C NMR (126 MHz, DMSO-d₆): δ = 164.8, 161.2, 158.8, 103.4,

42.6, 42.5, 38.6, 12.3, 12.0.

2-Methylsulfonyl Product 4d

¹H NMR (500 MHz, CDCl₃): δ = 7.16–7.11 (m, 1 H), 5.59–5.43 (m,

1 H), 3.97–3.77 (m, 1 H), 3.15 (m, 3 H), 2.01 (br s, 2 H), 1.81–1.71

(m, 2 H), 1.52–1.34 (m, 2 H), 1.34–1.19 (m, 4 H).

MS (ESI): m/z (%) = 286 (4, [M + Na]⁺), 268 (1), 267 (3), 266 (36),

265 (9), 264 (100, [M + H]⁺), 202 (5), 102 (5).

LC-MS (ESI): m/z = 290 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺calcd for C₉H₁₅ClN₃O₂S: 264.0568;

found: 264.0590.

4,6-Dichloro-N-cyclohexylpyrimidin-2-amine (5d); Alternate

Preparation

4-Chloro-2-(methylsulfonyl)-6-(piperidin-1-yl)pyrimidine (4g)

and 4,6-Dichloro-2-(piperidin-1-yl)pyrimidine (5g)

Prepared according to the typical procedure for 4f and 5f. The less

polar fractions provided 5g as a white solid material; yield: 123 mg

(27%). Concentration of the more polar fractions provided 4g as a

white solid material; yield: 378 mg (69%).

To CyNH₂(0.23 mL, 2 mmol) was added THF (3 mL) and the soln

was cooled under N₂in an ice bath (0 °C). Then 1 M i-PrMgCl·LiCl

in THF (2 mL, 2 mmol) was added by syringe and after 5 min at this

temperature, the mixture was cooled to –60 °C. A soln of 1 [227 mg,

1 mmol, in THF (2 mL)] was added slowly by cannula. After 15 min

at this temperature, the reaction was continued in an ice bath for 10

min, then the mixture was quenched with AcOH, partitioned be-

tween H₂O and EtOAc–hexane, (~1:1). The organic layer was con-

centrated and purified by chromatography (silica gel, EtOAc–

hexanes, gradient 0:1–1:5) to provide 5d as a light yellow solid ma-

terial; yield: 161 mg (65%). The ¹H NMR and MS data match with

the material prepared without use of i-PrMgCl·LiCl.

2-Piperidin-1-yl Product 5g

Mp 73–79 °C (EtOAc–hexanes).

¹H NMR (500 MHz, DMSO-d₆): δ = 6.84 (s, 1 H), 3.69 (t, J = 5.7

Hz, 4 H), 1.67–1.58 (m, 2 H), 1.56–1.45 (m, 4 H).

APT NMR (126 MHz, acetone-d₆): δ = 162.8, 108.0, 43.6, 13.5; one

signal could not be found

6-Chloro-N-ethyl-N-methyl-2-(methylsulfonyl)pyrimidin-4-

amine (4e)

MS (ESI): m/z (%) = 236 (10), 235 (5), 234 (64), 233 (9), 232 (100,

[M + H]⁺), 102 (15).

To 1 (454 mg, 2 mmol) was added THF (3 mL) then the mixture was

cooled to –70 °C under N₂and MeEtNH (0.36 mL, 4.2 mmol) was

added by syringe. After 1.5 h the bath temperature reached 0 °C, the

mixture was quenched with AcOH, partitioned between H₂O and

EtOAc, and the organic layer was concentrated and purified by

chromatography (silica gel, EtOAc–hexanes, gradient 1:50 to 1:1)

HRMS (ESI): m/z [M + H]⁺calcd for C₉H₁₂Cl₂N₃: 232.0403; found:

232.0417.

2-Methylsulfonyl Product 4g

Mp 140–145 °C (EtOAc–hexanes).

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Chemoselective Reactions of 4,6-Dichloro-2-(methylsulfonyl)pyrimidine

1777

¹H NMR (500 MHz, DMSO-d₆): δ = 7.20 (s, 1 H), 3.79 (br s, 2 H),

LC-MS (ESI): m/z = 342 [M + H]⁺.

3.62 (br s, 2 H), 3.30 (s, 3 H), 1.69–1.61 (m, 2 H), 1.61–1.49 (m, 4

H).

6-Chloro-N-(2,2-difluoroethyl)-2-(methylsulfonyl)pyrimidin-4-

amine (4j) and 4,6-Dichloro-N-(2,2-difluoroethyl)pyrimidin-2-

amine (5j)

¹³C NMR (126 MHz, DMSO-d₆, signals for the two rotamers): δ =

164.8, 161.6, 159.2, 103.7, 38.7, 25.1, 23.7; additionally, two sig-

nals for the C-atoms on the piperidine, α to the N-atom are found

from HSQC (45.0, 46.2, see Supporting Information for the spec-

trum).

To 1 (297 mg, 1.31 mmol) was added THF (3 mL), then at r.t. under

N₂was added 2,2-difluoroethylamine (0.21 mL, 3 mmol, 2.2 equiv),

and the mixture was stirred at r.t. under N₂for 2.5 h. The mixture

was diluted with CH₂Cl₂, filtered through a short plug of silica gel,

which was washed with EtOAc, and the combined material was pu-

rified by chromatography (silica gel, EtOAc–hexanes, gradient 0:1–

1:0). The less polar fractions provided 5j as a white solid material;

yield: 143 mg (48%). Concentration of the more polar fractions pro-

vided 4j as a white solid material; yield: 129 mg (36%).

MS (ESI): m/z (%) = 298 (100, [M + Na]⁺), 280 (1), 279 (4), 278

(36), 277 (10), 276 (100, [M + H]⁺), 136 (2).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₀H₁₅ClN₃O₂S: 276.0568;

found: 276.0591.

N-tert-Butyl-6-chloro-2-(methylsulfonyl)pyrimidin-4-amine

(4h) and N-tert-Butyl-4,6-dichloropyrimidin-2-amine (5h)

To 1 (454 mg, 2 mmol) was added THF (3 mL) and the mixture was

cooled to –70 °C under N₂. t-BuNH₂(0.42 mL, 4 mmol, 2 equiv)

was added by syringe. After 1 h the bath temperature reached 0 °C.

The mixture was kept at this temperature for additional 30 min; the

LC-MS analysis of the mixture showed that the reaction had stalled

with ~7% of 1 remaining. The mixture was quenched with AcOH,

partitioned between H₂O and mixture EtOAc–hexane (~1:1), and

the organic layer was purified by chromatography (silica gel, EtO-

Ac–hexanes, gradient 1:20–1:1). The less polar fractions provided

5h as a white solid material; yield: 142 mg (32%). Concentration of

the more polar fractions provided still impure 4h as a colorless oily

material; yield: 83 mg (16%).

2-(2,2-Difluoroethyl)amino Product 5j

¹H NMR (500 MHz, DMSO-d₆): δ = 8.49 (t, J = 6.1 Hz, 1 H), 7.01

(s, 1 H), 6.10 (tt, J = 4.1, 55.5 Hz, 1 H), 3.68 (ddt, J = 3.9, 6.1, 15.4

Hz, 2 H).

APT NMR (126 MHz, DMSO-d₆): δ = 161.6, 161.1, 114.3 (t, J =

244.3 Hz), 108.8, 43.0 (t, J = 26.3 Hz).

LC-MS (ESI): m/z = 226, 228 [M – H]⁺.

2-Methylsulfonyl Product 4j

¹H NMR (500 MHz, DMSO-d₆, mixture of two rotamers ~4:1): δ =

8.85 (t, J = 5.4 Hz, 0.2 H), 8.77 (t, J = 4.7 Hz, 0.8 H), 7.15 (s, 0.2

H), 6.84 (s, 0.8 H), 6.20 (tt, J = 4.1, 55.8 Hz, 0.8 H), 6.17 (t, J = 55.8

Hz, 0.2 H), 3.88 (tt, J = 4.7, 15.4 Hz, 1.6 H), 3.78 (t, J = 15.1 Hz,

0.4 H), 3.33 (s, 3 H).

2-tert-Butylamino Product 5h

Mp 112–114 °C (EtOAc–hexanes).

¹H NMR (500 MHz, DMSO-d₆): δ = 7.90 (s, 1 H), 6.84 (s, 1 H), 1.34

(s, 9 H).

APT NMR (126 MHz, DMSO-d₆, only signals of the major rotamer

are shown): δ = 165.2, 164.0, 157.8, 114.2 (t, J = 240.7 Hz), 106.4,

42.6 (t, J = 26.3 Hz), 38.6.

LC-MS (ESI): m/z = 272 [M + H]⁺.

APT NMR (126 MHz, DMSO-d₆): δ = 160.7, 107.0, 50.9, 28.1; one

signal could not be found. It may be the broad signal around δ =

160.0–160.7, see the Supporting Information for the spectrum.

6-Chloro-2-(methylsulfonyl)-N-(2,2,2-trifluoroethyl)pyrimidin-

4-amine (4k)

To 1 (297 mg, 1.31 mmol) was added THF (3 mL), then at r.t. under

N₂was added 2,2,2-trifluoroethylamine (0.21 mL, 1.6 mmol, 1.3

equiv), and the mixture was stirred at r.t. under N₂for 2.5 h. The

mixture was diluted with CH₂Cl₂, filtered through a short plug of

silica gel, which was washed with EtOAc, and the combined mate-

rial was purified by chromatography (silica gel, EtOAc–hexanes,

gradient 1:2–1:0) to provide 4k as a white solid material; yield: 220

mg (58%).

¹H NMR (500 MHz, DMSO-d₆, mixture of rotamers ~4:1): δ = 9.14

(br s, 0.2 H), 8.98 (t, J = 5.8 Hz, 0.8 H), 7.32 (br s, 0.2 H), 6.89 (s,

0.8 H), 4.39–4.29 (m, 1.6 H), 4.26 (br s, 0.4 H), 3.34 (s, 3 H).

LC-MS (ESI): m/z (%) = 220 [M + H]⁺.

2-Methylsulfonyl Product 4h

¹H NMR (500 MHz, acetone-d₆): δ = 7.29 (br s, 1 H), 6.70 (s, 1 H),

3.27 (s, 3 H), 1.49 (s, 9 H).

LC-MS (ESI): m/z (%) = 264 [M + H]⁺.

N-(1-Adamantyl)-6-chloro-2-(methylsulfonyl)pyrimidin-4-

amine (4i) and N-(1-Adamantyl)-4,6-dichloropyrimidin-2-

amine (5i)

To 1 (145 mg, 0.64 mmol) was added THF (1.5 mL), adamantan-1-

amine (193 mg, 1.28 mmol, 2 equiv), and the mixture was stirred at

r.t. under N₂for 40 min. An unstirrable thick suspension was formed

and LC-MS analysis of the mixture showed that the reaction had

stalled with ~3% of 1 remaining. The mixture was diluted with

EtOAc and CH₂Cl₂, filtered through a short plug of silica gel, and

purified by chromatography (silica gel, EtOAc–hexanes, gradient

0:1–1:1). The less polar fractions provided 5i as a white solid mate-

rial; yield: 111 mg (58%). Concentration of the more polar fractions

provided still impure 4i as a white solid material; yield: 58 mg

(27%).

APT NMR (126 MHz, DMSO-d₆, major isomer): δ = 165.0, 164.0,

158.3 (q, J = 279.7 Hz), 106.7, 41.09 (q, J = 33.6 Hz), 38.6.

LC-MS (ESI): m/z = 290 [M + H]⁺.

2-(Methylsulfonyl)-N⁴,N⁶-diphenylpyrimidine-4,6-diamine

(6a); Typical Procedure

To a soln of 2a (142 mg, 0.50 mmol) and aniline (186 mg, 2.0

mmol) in DMSO (1 mL) in a capped tube was added 2,6-lutidine

(0.087 mL, 0.75 mmol) at r.t. The mixture was stirred for 24 h at 90

°C. The mixture was cooled down to r.t. and then H₂O (10 mL) was

added to precipitate the product. The product was dried over N₂to

provide 6a as an off-white amorphous solid material; yield: 148 mg

(87%)

2-(1-Adamantyl)amino Product 5i

¹H NMR (500 MHz, DMSO-d₆): δ = 7.82 (s, 1 H), 6.83 (s, 1 H),

2.07–1.97 (m, 9 H), 1.67–1.57 (m, 6 H).

¹H NMR (500 MHz, DMSO-d₆): δ = 9.69 (s, 2 H), 7.47–7.56 (m, 4

H), 7.31–7.38 (m, 4 H), 7.00–7.10 (m, 2 H), 6.25 (d, J = 2.5 Hz, 1

H), 3.33 (s, 3 H).

APT NMR (126 MHz, DMSO-d₆): δ = 160.5, 107.0, 51.4, 40.3,

35.9, 28.7; one more signal may be the broad peak around δ =

160.0–160.7, see the Supporting Information for the spectrum.

¹³C NMR (126 MHz, DMSO-d₆): δ = 164.9, 160.8, 139.4, 129.0,

122.9, 120.4, 120.3, 38.7.

LC-MS (ESI): m/z = 298 [M + H]⁺.

2-Methylsulfonyl Product 4i

MS (ESI): m/z (%) = 409 (5), 388 (2), 387 (9), 363 (8), 342 (19), 341

¹H NMR (500 MHz, DMSO-d₆): δ = 8.06 (s, 1 H), 6.70 (s, 1 H), 3.30

(s, 3 H), 2.06 (s, 9 H), 1.65 (br s, 6 H).

(100, [M + H]⁺).

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HRMS (ESI): m/z [M + H]⁺calcd for C₁₇H₁₇N₄O₂S: 341.1067;

found: 341.1059.

6-Chloro-N²-cyclohexyl-N⁴-phenylpyrimidine-2,4-diamine

(7a); Typical Procedure

A soln of 2a (142 mg, 0.50 mmol) and CyNH₂(297 mg, 3.0 mmol)

in DMSO (3 mL) in a capped tube was stirred for 24 h at r.t. The

mixture was diluted with EtOAc (50 mL) and washed with H₂O (30

mL) and then 1 M KHSO₄soln (30 mL). The organic layer was sep-

arated and concentrated under the reduced pressure. The product

was isolated by column chromatography to provide 7a as a pale yel-

low viscous oily material; yield: 142 mg (94%).

¹H NMR (500 MHz, DMSO-d₆): δ = 9.38 (br s, 1 H), 7.70 (br s, 2

H), 7.20–7.34 (m, 3 H), 6.92–7.03 (m, 1 H), 5.98 (br s, 1 H), 3.58–

3.70 (m, 1 H), 1.55–1.96 (m, 5 H), 1.21–1.35 (m, 4 H).

2-(Methylsulfonyl)-N⁴-phenyl-N⁶-(o-tolyl)pyrimidine-4,6-di-

amine (6b)

Prepared according to the typical procedure for 6a as pale yellow

viscous oily material; yield: 135 mg (76%).

¹H NMR (500 MHz, acetone-d₆): δ = 8.69 (s, 1 H), 8.22 (s, 1 H),

7.56–7.61 (m, 2 H), 7.41–7.46 (m, 1 H), 7.31–7.37 (m, 3 H), 7.28

(td, J = 7.6, 1.6 Hz, 1 H), 7.18–7.23 (m, 1 H), 7.07 (tt, J = 7.4, 1.1

Hz, 1 H), 5.88 (s, 1 H), 3.24 (s, 3 H), 2.31 (s, 3 H).

¹³C NMR (126 MHz, acetone-d₆): δ = 166.8, 163.7, 162.6, 140.5,

137.6, 134.7, 132.0, 129.9, 127.7, 127.2, 126.9, 124.1, 121.5, 85.7,

38.3, 18.2.

¹³C NMR (126 MHz, DMSO-d₆): δ = 161.6, 160.9, 158.0, 140.1,

128.6, 122.0, 119.5, 92.8, 50.1, 32.3, 25.4, 24.9.

MS (ESI): m/z (%) = 377 (11), 357 (4), 356 (20), 355 (100, [M +

MS (ESI): m/z (%) = 306 (5), 305 (33), 304 (17), 303 (100, [M +

H]⁺).

H]⁺), 223 (2), 221 (7).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₈H₁₉N₄O₂S: 355.1229;

found: 355.1215.

+

HRMS (ESI): m/z [M + H]⁺calcd for C₁₆H₂₀ClN₄: 303.1371;

found: 303.1399.

2-(Methylsulfonyl)-N⁴-phenyl-N⁶-(m-tolyl)pyrimidine-4,6-di-

amine (6c)

Prepared according to the typical procedure for 6a as pale yellow

viscous oily material; yield: 138 mg (78%).

¹H NMR (500 MHz, acetone-d₆): δ = 8.70 (s, 1 H), 8.64 (s, 1 H),

7.58 (dd, J = 8.5, 0.9 Hz, 2 H), 7.34–7.40 (m, 4 H), 7.21–7.28 (m, 1

H), 7.10 (tt, J = 7.4, 1.1 Hz, 1 H), 6.93 (dd, J = 7.3, 0.6 Hz, 1 H),

6.30 (s, 1 H), 3.28 (s, 3 H), 2.33 (s, 3 H).

¹³C NMR (126 MHz, acetone-d₆): δ = 166.8, 162.7, 140.5, 140.3,

139.8, 130.1, 130.0, 125.4, 124.6, 122.8, 122.1, 122.1, 119.3, 87.0,

39.5, 21.7.

2-[4-Chloro-6-(phenylamino)pyrimidin-2-ylamino]ethanol (7b)

Prepared according to the typical procedure for 7a as pale yellow

viscous oily material; yield: 129 mg (98%).

¹H NMR (500 MHz, DMSO-d₆): δ = 9.26–9.45 (m, 1 H), 7.67 (br s,

2 H), 7.30 (t, J = 7.7 Hz, 2 H), 7.15 (br s, 1 H), 6.93–7.03 (m, 1 H),

6.01 (br s, 1 H), 4.68 (br s, 1 H), 3.54 (br s, 2 H), 3.25–3.38 (m, 2 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 161.8, 161.6, 158.1, 140.0,

128.7, 122.2, 119.7, 119.6, 58.7, 43.6.

MS (ESI): m/z (%) = 268 (4), 267 (32), 266 (13), 265 (100, [M +

H]⁺), 249 (4), 247 (11).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₄ClN₄O⁺: 265.0851;

found: 265.0872.

MS (ESI): m/z (%) = 377 (9), 357 (3), 356 (19), 355 (100, [M + H]⁺).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₈H₁₉N₄O₂S: 355.1229;

N²-Benzyl-6-chloro-N⁴-phenylpyrimidine-2,4-diamine (7c)

Prepared according to the typical procedure for 7a as pale yellow

viscous oily material; yield: 135 mg (87%).

¹H NMR (500 MHz, DMSO-d₆): δ = 9.37 (s, 1 H), 7.93 (br s, 1 H),

7.74 (br s, 1 H), 7.48 (d, J = 3.8 Hz, 1 H), 7.26–7.35 (m, 5 H), 7.21

(br s, 2 H), 6.01 (br s, 1 H), 4.47 (d, J = 6.0 Hz, 2 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 161.7, 161.6, 140.2, 139.7,

128.6, 128.2, 126.5, 122.1, 119.7, 44.2.

MS (ESI): m/z (%) = 314 (6), 313 (33), 311 (100, [M + H]⁺).

found: 355.1216.

2-(Methylsulfonyl)-N⁴-phenyl-N⁶-(p-tolyl)pyrimidine-4,6-di-

amine (6d)

Prepared according to the typical procedure for 6a as an off-white

amorphous solid material; yield: 168 mg (95%).

¹H NMR (500 MHz, acetone-d₆): δ = 8.69 (br s, 1 H), 8.60 (br s, 1

H), 7.58 (d, J = 6.9 Hz, 2 H), 7.40–7.46 (m, 2 H), 7.36 (t, J = 7.4 Hz,

2 H), 7.18 (d, J = 7.6 Hz, 2 H), 7.06–7.12 (m, 1 H), 6.24 (s, 1 H),

3.27 (s, 3 H), 2.31 (s, 3 H).

¹³C NMR (126 MHz, acetone-d₆): δ = 166.7, 162.7, 162.5, 140.4,

137.6, 134.2, 130.5, 129.9, 124.3, 122.5, 121.9, 121.7, 86.6, 39.4,

20.9.

+

HRMS (ESI): m/z [M + H]⁺calcd for C₁₇H₁₆ClN₄: 311.1058;

found: 311.1081.

2-(Methylsulfonyl)-N,6-diphenylpyrimidin-4-amine (8a); Typi-

cal Procedure

MS (ESI): m/z (%) = 377 (8), 357 (4), 356 (19), 355 (100, [M + H]⁺).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₈H₁₉N₄O₂S: 355.1229;

A mixture of 2a (142 mg, 0.50 mmol), phenylboronic acid (91 mg,

0.75 mmol), PdCl₂(dppf) (18 mg, 5 mol%), and K₂CO₃(276 mg, 2.0

mmol) in DME (3 mL) and H₂O (0.8 mL) in a capped tube was

stirred for 4 h under N₂at 60 °C. The mixture was cooled to r.t. and

purified by column chromatography to provide 8a as an off-white

amorphous solid material; yield: 146 mg (90%).

found: 355.1216.

N⁴-(4-Chlorophenyl)-2-(methylsulfonyl)-N⁶-phenylpyrimidine-

4,6-diamine (6e)

Prepared according to the typical procedure for 6a as an off-white

amorphous solid material; yield: 177 mg (95%).

¹H NMR (500 MHz, acetone-d₆): δ = 8.88 (s, 1 H), 8.79 (s, 1 H),

7.62–7.68 (m, 2 H), 7.54–7.60 (m, 2 H), 7.35–7.41 (m, 4 H), 7.08–

7.16 (m, 1 H), 6.29 (s, 1 H), 3.29 (s, 3 H).

¹H NMR (500 MHz, DMSO-d₆): δ = 10.33 (s, 1 H), 8.02–8.11 (m,

2 H), 7.72 (d, J = 7.9 Hz, 2 H), 7.55–7.61 (m, 3 H), 7.42 (dd, J = 8.5,

7.6 Hz, 2 H), 7.38 (s, 1 H), 7.13 (s, 1 H), 3.43 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 165.5, 161.9, 161.5, 138.7,

135.4, 131.2, 129.1, 129.1, 126.7, 123.6, 120.4, 38.8.

¹³C NMR (126 MHz, acetone-d₆): δ = 166.6, 162.5, 162.2, 140.2,

139.4, 130.0, 129.8, 128.4, 124.6, 123.0, 122.1, 39.3.

MS (ESI): m/z (%) = 349 (2), 348 (13), 328 (4), 327 (18), 326 (100,

MS (ESI): m/z (%) = 399 (3), 398 (1), 397 (8), 378 (7), 377 (36), 376

[M + H]⁺).

(19), 375 (100, [M + H]⁺).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₇H₁₆N₃O₂S: 326.0958;

found: 326.0949.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₇H₁₆ClN₄O₂S: 375.0682;

found: 375.0668.

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Chemoselective Reactions of 4,6-Dichloro-2-(methylsulfonyl)pyrimidine

1779

2-(Methylsulfonyl)-N-phenyl-6-(m-tolyl)pyrimidin-4-amine

(8b)

Prepared according to the typical procedure used 8a as an off-white

amorphous solid material; yield: 157 mg (93%).

¹H NMR (500 MHz, acetone-d₆): δ = 9.30 (br s, 1 H), 7.95 (s, 1 H),

7.88–7.93 (m, 1 H), 7.74–7.81 (m, 2 H), 7.34–7.46 (m, 5 H), 7.12–

7.19 (m, 1 H), 3.38 (s, 3 H), 2.42 (s, 3 H).

¹H NMR (500 MHz, DMSO-d₆) δ = 10.30 (s, 1 H), 7.83–7.91 (m, 2

H), 7.72 (d, J = 7.9 Hz, 2 H), 7.32–7.49 (m, 5 H), 7.13 (t, J = 7.3 Hz,

1 H), 3.44 (s, 3 H), 2.42 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 162.4, 160.4, 159.0, 137.5, 135.7,

129.4, 129.1, 127.2, 125.4, 123.04, 122.99, 122.8, 121.1, 95.2.

MS (ESI): m/z (%) = 331 (100, [M + H]⁺), 333 (63).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₆H₁₃Cl₂N₄: 331.0517;

found: 331.0507.

6-Chloro-N²-(3-chlorophenyl)-N⁴-phenylpyrimidine-2,4-di-

amine (9b)

Prepared according to the typical procedure for 9a as a white solid

material; yield: 144 mg (87%); mp 147–148 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.77 (t, J = 2.1 Hz, 1 H), 7.45–7.39

(m, 2 H), 7.34 (d, J =7.6 Hz, 2 H), 7.29 (dd, J = 8.2, 1.3 Hz, 1 H),

7.25–7.15 (m, 3 H), 7.04–6.98 (ddd, J = 8.0, 2.0, 1.0 Hz, 1 H), 6.93

(br s, 1 H), 6.21 (s, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 162.4, 160.3, 159.0, 140.2, 137.4,

134.5, 129.7, 129.5, 125.4, 123.0, 122.7, 119.4, 117.5, 95.1.

MS (ESI): m/z (%) = 331 (100, [M + H]⁺), 333 (61).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₆H₁₃Cl₂N₄: 331.0517;

¹³C NMR (126 MHz, acetone-d₆): δ = 165.5, 162.0, 161.5, 138.8,

138.4, 135.4, 131.8, 129.1, 129.0, 127.2, 123.9, 123.6, 120.3, 103.8,

38.8, 21.0.

MS (ESI): m/z (%) = 363 (3), 362 (13), 342 (4), 341 (20), 340 (100,

[M + H]⁺).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₈H₁₈N₃O₂S⁺: 340.1120;

found: 340.1105.

6-(4-Methoxyphenyl)-2-(methylsulfonyl)-N-phenylpyrimidin-

4-amine (8c)

found:331.0507.

Prepared according to the typical procedure used 8a as an off-white

amorphous solid material; yield: 160 mg (90%).

¹H NMR (500 MHz, DMSO-d₆): δ = 10.22 (s, 1 H), 8.00–8.06 (m,

2 H), 7.70 (d, J = 7.9 Hz, 2 H), 7.40 (dd, J = 8.5, 7.6 Hz, 2 H), 7.28

(s, 1 H), 7.08–7.14 (m, 3 H), 3.83 (s, 3 H), 3.42 (s, 3 H).

¹³C NMR (126 MHz, acetone-d₆): δ = 165.4, 161.8, 161.6, 161.4,

138.9, 129.0, 128.4, 127.6, 123.4, 120.2, 114.4, 102.4, 55.4, 38.8.

6-Chloro-N²-(4-chlorophenyl)-N⁴-phenylpyrimidine-2,4-di-

amine (9c)

Prepared according to the typical procedure for 9a as a white solid

material; yield: 126 mg (95%); mp 180–182 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.55–7.49 (m, 2 H), 7.45–7.38 (m,

2 H), 7.37–7.31 (m, 2 H), 7.29–7.25 (m, 2 H), 7.23 (tt, J = 7.3, 1.2

Hz, 1 H), 7.00 (br s, 1 H), 6.72 (br s, 1 H), 6.20 (s, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 162.4, 160.3, 159.1, 137.6, 137.5,

129.5, 128.8, 127.7, 125.4, 123.1, 120.8, 94.9.

MS (ESI): m/z (%) = 331 (100, [M + H]⁺), 333 (63).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₆H₁₃Cl₂N₄: 331.0517;

MS (ESI): m/z (%) = 378 (8), 358 (3), 357 (19), 356 (100, [M + H]⁺).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₈H₁₈N₃O₃S: 356.1069;

found: 356.1054.

6-(4-Fluorophenyl)-2-(methylsulfonyl)-N-phenylpyrimidin-4-

amine (8d)

found:331.0508.

Prepared according to the typical procedure used 8a as an off-white

amorphous solid material; yield: 161 mg (94%).

¹H NMR (500 MHz, DMSO-d₆): δ = 10.34 (s, 1 H), 8.10–8.18 (m,

2 H), 7.71 (d, J = 7.9 Hz, 2 H), 7.39–7.45 (m, 4 H), 7.35 (s, 1 H),

7.14 (t, J = 7.4 Hz, 1 H), 3.43 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 165.5, 164.9, 163.0, 161.5,

160.8, 138.7, 131.9, 129.3, 129.2, 129.1, 123.7, 120.4, 116.2, 116.0,

38.8.

6-Chloro-N²-(4-methoxyphenyl)-N⁴-phenylpyrimidine-2,4-di-

amine (9d)

Prepared according to the typical procedure for 9a as a white solid

material; yield: 161 mg (99%); mp 148–150 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.46–7.42 (m, 2 H), 7.39–7.36 (m,

2 H), 7.32 (d, J = 7.3 Hz, 2 H), 7.19 (tt, J = 7.5, 0.9 Hz, 1 H), 6.67

(br s, 1 H), 6.94–6.83 (m, 2 H), 6.80 (br s, 1 H), 6.15 (s, 1 H), 3.81

(s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 162.4, 160.3, 159.8, 155.9, 137.8,

132.0, 129.4, 125.1, 122.8, 122.3, 114.1, 94.1, 55.6.

MS (ESI): m/z (%) = 327 (100, [M + H]⁺), 329 (32).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₇H₁₆ClN₄O: 327.1013;

MS (ESI): m/z (%) = 367 (2), 366 (12), 346 (4), 345 (19), 344 (100,

[M + H]⁺).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₇H₁₅FN₃O₂S: 344.0869;

found: 344.0855.

found:327.1004.

6-Chloro-N²-(2-chlorophenyl)-N⁴-phenylpyrimidine-2,4-di-

amine (9a); Typical Procedure

6-Chloro-N²-(4-nitrophenyl)-N⁴-phenylpyrimidine-2,4-di-

amine (9e)

Prepared according to the typical procedure for 9a as a pale yellow

solid material; yield: 131 mg (96%); mp 221–223 °C.

¹H NMR (500 MHz, DMSO-d₆): δ = 10.36 (br s, 1 H), 9.79 (br s, 1

H), 8.14 (d, J = 9.1 Hz, 2 H), 7.95 (d, J = 9.5 Hz, 2 H), 7.61 (d, J =

7.9 Hz, 2 H), 7.41 (t, J = 7.9 Hz, 2 H), 7.15 (t, J = 7.4 Hz, 1 H), 6.37

(s, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 161.7, 158.4, 157.8, 146.7, 140.6,

138.8, 128.9, 124.7, 123.6, 121.3, 118.1, 97.4.

MS (ESI): m/z (%) = 342 (100, [M + H]⁺), 344 (32).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₆H₁₃ClN₅O₂: 342.0758;

2-Chloro-N-phenylformamide (155 mg, 1 mmol) and 2a (142 mg,

0.5 mmol) were dissolved in THF (3 mL) under N₂, and the soln was

cooled to 0 °C using an ice bath. To this soln was added dropwise

1.4 M NaOt-Am in THF (0.7 mL, 1 mmol). The mixture was stirred

at 0 °C for 30 min. LC-MS analysis showed consumption of the

starting material 2a. Aq 1 M NaOH (2 mL, 2 mmol) was added and

the mixture was stirred at r.t. for 30 min. LC-MS analysis showed

clean formation of the desired product 9a. The mixture was extract-

ed with EtOAc. The organic layer was collected, dried, and concen-

trated. The product was purified by flash chromatography to

provide 9a as a white solid material; yield: 152 mg (92%); mp 108–

110 °C.

¹H NMR (500 MHz, CDCl₃): δ = 8.35 (dd, J = 8.4, 1.5 Hz, 1 H),

7.37 (br s, 1 H), 7.32–7.27 (m, 3 H), 7.23 (d, J = 8.4 Hz, 2 H), 7.17–

7.11 (m, 2 H), 6.75 (br s, 1 H), 6.14 (s, 1 H).

found: 342.0747.

6-Chloro-N²-phenethyl-N⁴-phenylpyrimidin-2,4-diamine (9f)

Prepared according to the typical procedure for 9a as an amorphous

solid material; yield: 147 mg (91%).

Synthesis 2013, 45, 1764–1784

1780

R. Baiazitov et al.

PAPER

¹H NMR (500 MHz, CDCl₃): δ = 7.38–7.35 (m, 4 H), 7.32–7.29 (m,

2 H), 7.24–7.21 (m, 3 H), 7.18–7.15 (m, 1 H), 6.77 (br s, 1 H), 6.02

(s, 1 H), 5.39 (br, 1 H), 3.66 (q, J = 6.7 Hz, 2 H), 2.89 (t, J = 6.7 Hz,

2 H).

MS (ESI): m/z (%) = 300 (100, [M + H]⁺), 302 (32).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₆H₁₂ClFN₃: 300.0704;

found: 300.0692.

¹³C NMR (126 MHz, CDCl₃): δ = 162.3, 161.8, 160.3, 139.1, 138.1,

129.3, 128.8, 128.5, 126.3, 124.6, 122.3, 92.8, 42.6, 35.8.

MS (ESI): m/z (%) = 325 (100, [M + H]⁺), 327 (32).

6-Chloro-2-[2-(1,3-dioxan-2-yl)ethyl]-N-phenylpyrimidin-4-

amine (10d)

Prepared according to the typical procedure for 10a as an amor-

phous solid material; yield: 154 mg (96%).

¹H NMR (500 MHz, CDCl₃): δ = 7.39–7.36 (m, 2 H), 7.33–7.31 (m,

2 H), 7.20–7.17 (m, 2 H), 6.51 (s, 1 H), 4.6 (t, J = 5 Hz, 1 H), 4.08

(ddd, J = 11.8, 4.9, 0.9 Hz, 2 H), 3.76–3.71 (m, 2 H), 2.86–2.83 (m,

2 H), 2.11–2.02 (m, 3 H), 1.33–1.29 (m, 1 H).

+

HRMS (ESI): m/z [M + H]⁺calcd for C₁₈H₁₈ClN₄: 325.1215;

found: 325.1240.

1-[4-Chloro-6-(phenylamino)pyrimidin-2-yl]piperidin-2-one

(9g)

Prepared according to the typical procedure for 9a as an amorphous

solid material; yield: 103 mg (68%).

¹³C NMR (126 MHz, CDCl₃): δ = 171.3, 162.1, 160.3, 137.6, 129.6,

125.4, 122.7, 101.5, 100.0, 66.9, 33.4, 33.0, 25.8.

¹H NMR (500 MHz, CDCl₃): δ = 7.71 (br s, 1 H), 7.36–7.31 (m, 4

H,), 7.16–7.13 (m, 1 H), 6.45 (s, 1 H), 3.82–3.80 (m, 2 H), 2.55 (t,

J = 6.5 Hz, 2 H), 1.93–1.85 (m, 4 H).

¹³C NMR (126 MHz, CDCl₃): δ = 171.2, 162.6, 160.3, 137.6, 129.4,

125.1, 122.3, 100.7, 48.7, 33.7, 22.9, 21.0.

MS (ESI): m/z (%) = 320 (100, [M + H]⁺), 322 (31).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₆H₁₉ClN₃O₂: 320.1166;

found: 320.1186.

4-Chloro-6-(methylsulfonyl)pyrimidine (11c)

To 4-chloro-6-(methylthio)pyrimidine (1 g, 6.2 mmol) was added

CH₂Cl₂(20 mL), and the mixture was cooled in an ice bath.

MCPBA (77% pure, 3.1 g, 13.6 mmol, 2.2 equiv) was added and the

mixture was stirred for 20 h with slow warming to r.t. To the mate-

rial was added MgSO₄, the mixture was filtered, the filtrate was

concentrated, dissolved in EtOAc, and washed with aq NaHCO₃.

The organic layer was dried (MgSO₄), filtered through a plug of sil-

ica gel, concentrated, and washed with a mixture of hexane and

Et₂O to provide 11c as an off-white solid material; yield: 855 mg

(71%); mp 125–127 °C.

MS (ESI): m/z (%) = 303 (100, [M + H]⁺), 305 (32).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₅H₁₆ClN₄O: 303.1013;

found: 303.1031.

6-Chloro-N,2-diphenylpyrimidin-4-amine (10a); Typical Pro-

cedure

Compound 2a (115 mg, 0.4 mmol) was dissolved in THF (2 mL)

under N₂and cooled to 0 °C. A 2 M soln of PhMgCl in THF (0.5

mL, 1 mmol) was added and the mixture was stirred at 0 °C for 1 h.

LC-MS analysis showed consumption of the starting material. The

mixture was quenched with brine and extracted with EtOAc. The

organic layer was dried and concentrated in vacuo. The residue was

purified by chromatography to provide 10a as a white solid materi-

al; yield: 109 mg (95%); mp 136–137 °C.

¹H NMR (500 MHz, DMSO-d₆): δ = 9.34 (d, J = 0.9 Hz, 1 H), 8.30

(d, J = 0.9 Hz, 1 H), 3.40 (s, 3 H).

¹³C NMR (126 MHz, acetone-d₆): δ = 168.1, 164.7, 160.3, 119.3,

39.9

¹H NMR (500 MHz, CDCl₃): δ = 8.41–8.39 (m, 2 H), 7.51–7.42 (m,

5 H), 7.37 (d, J = 7.4 Hz, 2 H), 7.24 (tt, J = 7.4, 1.0 Hz, 1 H), 7.04

(br s, 1 H), 6.61 (s, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 165.0, 162.2, 161.0, 137.6, 136.6,

131.1, 129.6, 128.45, 128.42, 125.5, 122.8, 100.6.

MS (ESI): m/z (%) = 282 (100, [M + H]⁺), 284 (33).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₆H₁₃ClN₃: 282.0798; found:

LC-MS (ESI): m/z = 193, 195 [M + H]⁺.

6-Chloro-N-ethylpyrimidin-4-amine (12c-1) and N-Ethyl-6-

(methylsulfonyl)pyrimidin-4-amine (13c-3)

To 4-chloro-6-(methylsulfonyl)pyrimidine (11c, 297 mg, 1.54

mmol) was added THF (2 mL), then under N₂the mixture was

cooled to –70 °C. 2 M EtNH₂in THF (1.9 mL, 3.9 mmol, 2.5 equiv)

was added by syringe, and the mixture was stirred with slow warm-

ing to r.t. under N₂for 70 min. The mixture was filtered through a

plug of silica gel, concentrated, and purified by chromatography

(silica gel, EtOAc–hexanes, gradient 1:4–1:0). The less polar frac-

tions upon concentration provided 12c-1 as a white solid material;

yield: 198 mg (83%). The more polar fractions upon concentration

provided 13c-3 as an off-white solid material; yield: 43 mg (14%).

282.0787.

6-Chloro-N-phenyl-2-[3-(trifluoromethoxy)phenyl]pyrimidin-

4-amine (10b)

Prepared according to the typical procedure for 10a as an amor-

phous solid material; yield: 71 mg (97%).

¹H NMR (500 MHz, CDCl₃): δ = 8.36 (dt, J = 7.9, 1.3 Hz, 1 H), 8.29

(s, 1 H), 7.51 (t, J = 8 Hz, 1 H), 7.46–7.45 (m, 2 H), 7.39–7.35 (m,

3 H), 7.29–7.26 (m, 1 H), 7.05 (br s, 1 H), 6.65 (s, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 163.5, 162.2, 161.0, 149.5, 138.8,

137.3, 129.8, 129.7, 126.7, 125.7, 123.4, 122.9, 121.6, 120.9, 101.1.

MS (ESI): m/z (%) = 366 (100, [M + H]⁺), 368 (31).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₇H₁₂ClF₃N₃O: 366.0621;

6-Chloro Product 12c-1

Mp 124–126 °C.

¹H NMR (500 MHz, DMSO-d₆): δ = 8.25 (br s, 1 H), 7.70 (br s, 1

H, NH), 6.47 (br s, 1 H), 3.38–3.09 (m, 2 H, CH₂), 1.11 (t, J = 7.1

Hz, 3 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 163.0, 158.5, 156.8, 103.5,

35.0, 14.3.

LC-MS (ESI): m/z = 158, 160 [M + H]⁺.

found: 366.0609.

6-Chloro-2-(4-fluorophenyl)-N-phenylpyrimidin-4-amine (10c)

Prepared according to the typical procedure for 10a as a white solid

material; yield: 56 mg (93%); mp 122–123 °C.

¹H NMR (500 MHz, CDCl₃): δ = 8.41–8.38 (m, 2 H), 7.45–7.41 (m,

2 H), 7.36 (d, J = 7.5 Hz, 2 H), 7.25 (tt, J = 7.4, 0.9 Hz, 1 H), 7.15–

7.12 (m, 2 H), 7.01 (br s, 1 H), 6.59 (s, 1 H).

6-Methylsulfonyl Product 13c-3

Mp 72–75 °C.

¹H NMR (500 MHz, acetone-d₆, mixture of rotamers ~10:1): δ =

8.55 (distorted br s, 1 H), 7.26 (distorted br s, 1 H), 7.11–6.88 (m, 1

H), 3.47 (distorted t, J = 6.6 Hz, 2 H), 3.15 (s, 3 H), 1.22 (distorted

t, J = 6.9 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 165.9, 164.0, 163.9, 162.1, 160.9,

137.4, 132.74, 132.71, 130.6, 129.6, 125.5, 122.8, 115.4, 115.3,

100.4.

¹³C NMR (126 MHz, acetone-d₆): δ = 164.7, 164.6, 160.4, 103.4,

39.8, 36.9, 15.0.

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Chemoselective Reactions of 4,6-Dichloro-2-(methylsulfonyl)pyrimidine

1781

LC-MS (ESI): m/z = 202 [M + H]⁺.

N-Ethyl-6-(methylsulfonyl)pyrazin-2-amine (13d-3)

To 2-chloro-6-(methylsulfonyl)pyrazine (11d, 193 mg, 1 mmol)

was added THF (1 mL), then the mixture was cooled under N₂to

–60 °C. 2 M EtNH₂in THF (1.1 mL, 2.2 mmol) was added by sy-

ringe and the mixture was warmed to r.t. over 3 h. After 1.5 h at r.t.

the mixture was heated to 40 °C for 3 h. At this point the LC-MS

analysis of the mixture showed only small amounts of 11d remain-

ing. The mixture was concentrated and purified by chromatography

(silica gel, EtOAc–hexane, gradient 1:2 to 1:0, then EtOAc–MeOH

~20:1) to provide 13d-3 as a white solid material; yield: 157 mg

(78%); mp 126–130 °C.

2-Chloro-6-(methylsulfonyl)pyrazine (11d)

To 2,6-dichloropyrazine (4.811 g, 32.3 mmol) was added MeCN

(30 mL), then NaSMe (5.19 g, 74 mmol, 2.3 equiv), the mixture was

stirred at r.t. under N₂for 1 h, then more NaSMe was added (~1 g).

After 30 min the mixture was heated to 60 °C for 30 min, then

cooled, diluted with a mixture of hexanes and CH₂Cl₂, filtered

through a plug of silica gel, and concentrated to provide crude 11d

as a yellow oily material (~50% pure according to ¹H NMR analy-

sis, 4.27 g). This material was dissolved in CH₂Cl₂(100 mL),

cooled in an ice bath, then MCPBA (77% pure, 13.5 g, 60 mmol)

was added in 2 portions. The mixture was stirred for 15 h with slow

warming to r.t., then concentrated, purified by chromatography (sil-

ica gel, EtOAc–hexane, gradient 1:10 to 1:1, poor separation,

streaking), and crystallization (EtOAc–hexanes) to provide 11d as

a white solid material; yield: 2.19 g (35%); mp 112–117 °C.

¹H NMR (500 MHz, acetone-d₆): δ = 8.18 (m, 2 H), 6.97 (br s, 1 H),

3.45 (dq, J = 5.4, 7.3 Hz, 2 H), 3.17 (s, 3 H), 1.25 (t, J = 7.3 Hz, 3 H).

¹³C NMR (126 MHz, acetone-d₆): δ = 155.7, 152.4, 139.4, 128.3,

40.6, 36.9, 14.9.

MS (ESI): m/z (%) = 204 (5), 203 (7), 202 (100, [M + H]⁺), 140 (1),

108 (3), 102 (9).

¹H NMR (500 MHz, DMSO-d₆): δ = 9.22 (s, 1 H), 9.19 (s, 1 H), 3.38

(s, 3 H).

HRMS (ESI): m/z [M + H]⁺calcd for C₇H₁₂N₃O₂S: 202.0645;

found: 202.0658.

¹³C NMR (126 MHz, DMSO-d₆): δ = 151.9, 149.3, 148.0, 140.3,

40.7.

2-(Methylsulfonyl)-N-phenylpyrimidin-4-amine (13e-1)

To 4-chloro-2-(methylsulfonyl)pyrimidine (11e, 192 mg, 1 mmol)

was added aniline (0.11 mL, 1.2 mmol, 1.2 equiv), 2,6-lutidine

(0.14 mL, 1.2 mmol, 1.2 equiv), and DMSO (1 mL), and the mixture

was stirred under N₂at r.t. for 7 h. At this point LC-MS analysis of

the mixture showed complete consumption of 11e. The mixture was

diluted with H₂O, extracted with CH₂Cl₂, dried (MgSO₄), concen-

trated, then purified by chromatography (silica gel, EtOAc–

hexanes, gradient 1:2 to 1:0) to provide 13e-1 as a light yellow

amorphous solid material; yield: 242 mg (97%).

¹H NMR (500 MHz, acetone-d₆): δ = 9.31 (br s, 1 H), 8.38 (d, J =

6.0 Hz, 1 H), 7.72 (d, J = 8.2 Hz, 2 H), 7.45–7.36 (m, 2 H), 7.16 (t,

J = 7.4 Hz, 1 H), 6.99 (d, J = 6.0 Hz, 1 H), 3.28 (s, 3 H).

¹³C NMR (126 MHz, acetone-d₆): δ = 167.5, 162.6, 157.4, 140.1,

130.5, 125.6, 122.4, 110.1, 39.9.

LC-MS (ESI): m/z = 193 [M + H]⁺.

6-(Methylsulfonyl)-N-phenylpyrazin-2-amine (13d-1)

To 2-chloro-6-(methylsulfonyl)pyrazine (11d, 291 mg, 1.51 mmol)

was added aniline (0.17 mL, 1.8 mmol, 1.2 equiv), 2,6-lutidine

(0.21 mL, 1.8 mmol, 1.2 equiv), and DMSO (1.5 mL), and the mix-

ture was heated under N₂at 80 °C for 26 h. Additional aniline (0.1

mL, ~0.7 equiv) was added and the mixture was heated for addition-

al 25 h. At this point LC-MS analysis of the mixture showed com-

plete consumption of 11d. The mixture was cooled to r.t., diluted

with H₂O, filtered, washed with H₂O, then Et₂O. The solid material

was dissolved in hot mixture of EtOAc–MeOH, dried (MgSO₄), fil-

tered through a plug of silica gel, concentrated, then washed with

EtOAc and then Et₂O to provide 13d-1 as a light brown amorphous

solid material; yield: 275 mg (73%).

¹H NMR (500 MHz, DMSO-d₆): δ = 10.14 (s, 1 H), 8.48 (s, 1 H),

8.40 (s, 1 H), 7.71 (dd, J = 1.1, 8.7 Hz, 2 H), 7.38 (dd, J = 7.3, 8.5

Hz, 2 H), 7.06 (tt, J = 1.3, 7.3 Hz, 1 H), 3.30 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 151.1, 149.5, 139.9, 139.4,

129.0, 128.9, 122.7, 118.8, 40.1.

MS (ESI): m/z (%) = 252 (4), 251 (11), 250 (100, [M + H]⁺), 171

(1), 170 (3), 102 (4).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₂N₃O₂S: 250.0645;

found: 250.0665.

MS (ESI): m/z (%) = 252 (4), 251 (11), 250 (100, [M + H]⁺), 102 (4).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₂N₃O₂S: 250.0645;

N,N-Diethyl-2-(methylsulfonyl)pyrimidin-4-amine (13e-2)

To 4-chloro-2-(methylsulfonyl)pyrimidine (11e, 192 mg, 1 mmol)

was added THF (1 mL), then the mixture was cooled under N₂to 0

°C (ice bath). Et₂NH (0.23 mL, 2.2 mmol) was added by syringe and

the mixture was stirred at this temperature for 1 h. At this point the

LC-MS analysis of the mixture showed almost complete consump-

tion of 11e. The mixture was diluted with EtOAc, filtered through a

plug of silica gel, concentrated, and purified by chromatography

(silica gel, EtOAc–hexane, gradient 1:2 to 1:0, then EtOAc–CHCl₃–

MeOH ~50:50:3 to 50:50:5) to provide 13e-2 as a colorless oily ma-

terial; yield: 213 mg (93%).

¹H NMR (500 MHz, acetone-d₆): δ = 8.23 (d, J = 6.3 Hz, 1 H), 6.80

(d, J = 6.3 Hz, 1 H), 3.68 (br s, 2 H), 3.59 (br s, 2 H), 3.23 (s, 3 H),

1.21 (t, J = 7.1 Hz, 6 H).

¹³C NMR (126 MHz, acetone-d₆): δ = 167.5, 162.2, 156.8, 106.4,

43.8, 39.7, 13.2.

found: 250.0655.

N,N-Diethyl-6-(methylsulfonyl)pyrazin-2-amine (13d-2)

To 2-chloro-6-(methylsulfonyl)pyrazine (11d, 193 mg, 1 mmol)

was added THF (1 mL), then the mixture was cooled under N₂to

–60 °C. Et₂NH (0.23 mL, 2.2 mmol) was added by syringe and the

mixture was warmed to r.t. over 3 h. After 1.5 h at r.t. the mixture

was heated to 40 °C for 3 h, then additional Et₂NH (0.11 mL, 1

mmol) was added and the mixture was left at r.t. for 28 h. At this

point the LC-MS analysis of the mixture showed complete con-

sumption of 11d. The mixture was concentrated and purified by

chromatography (silica gel, EtOAc–hexane, gradient 1:2 to 1:0) to

provide 13d-2 as a light yellow waxy material that partly solidified

on drying; yield: 210 mg (92%).

¹H NMR (500 MHz, acetone-d₆): δ = 8.36 (s, 1 H), 8.21 (s, 1 H),

3.67 (q, J = 7.3 Hz, 4 H), 3.18 (s, 3 H), 1.24 (t, J = 6.9 Hz, 6 H).

LC-MS (ESI): m/z = 230 [M + H]⁺.

¹³C NMR (126 MHz, acetone-d₆): δ = 153.8, 152.5, 135.9, 127.5,

44.0, 40.6, 13.4.

MS (ESI): m/z (%) = 232 (5), 231 (10), 230 (100, [M + H]⁺), 136

(2), 102 (2).

HRMS (ESI): m/z [M + H]⁺calcd for C₉H₁₆N₃O₂S: 230.0958;

found: 230.0975.

4-Chloro-N-ethylpyrimidin-2-amine (12e-1) and N-Ethyl-2-

(methylsulfonyl)pyrimidin-4-amine (13e-3)

To 4-chloro-2-(methylsulfonyl)pyrimidine (11e, 192 mg, 1 mmol)

was added THF (1 mL), then under N₂the mixture was cooled to 0

°C (ice bath). 2 M EtNH₂in THF (1.1 mL, 2.2 mmol, 2.2 equiv) was

added by syringe, and the mixture was stirred in an ice bath under

N₂for 1 h. The mixture was diluted with EtOAc, filtered through a

plug of silica gel, concentrated, and purified by chromatography

Synthesis 2013, 45, 1764–1784

1782

R. Baiazitov et al.

PAPER

(silica gel, EtOAc–hexanes, gradient 0:1–1:0). The less polar frac-

tions upon concentration provided 12e-1 as a white solid material;

yield: 105 mg (67%). The more polar fractions upon concentration

provided 13e-3 as a colorless oily material; yield: 38 mg (19%).

¹H NMR (500 MHz, DMSO-d₆): δ = 8.70 (d, J = 5.0 Hz, 1 H), 7.03

(d, J = 4.7 Hz, 1 H), 3.61 (br s, 4 H), 3.27 (s, 3 H), 1.14 (t, J = 7.1

Hz, 6 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 165.9, 161.7, 160.0, 102.4,

41.8, 38.4, 12.6.

2-Ethylamino Product 12e-1

Mp 87–89 °C.

MS (ESI): m/z (%) = 231 (9), 230 (100, [M + H]⁺), 202 (2), 186 (3),

¹H NMR (500 MHz, DMSO-d₆): δ = 8.21 (br s, 1 H), 7.64 (t, J = 5.8

Hz, 1 H), 6.63 (d, J = 5.0 Hz, 1 H), 3.26 (br s, 2 H), 1.10 (t, J = 7.1

Hz, 3 H).

169 (1), 168 915), 150 (5), 140 92), 138 (2), 122 91), 102 (1).

HRMS (ESI): m/z [M + H]⁺calcd for C₉H₁₆N₃O₂S: 230.0958;

found: 230.0976.

¹³C NMR (126 MHz, DMSO-d₆): δ = 162.1, 159.9 (br, probably 2

signals), 108.5, 35.4, 14.3.

LC-MS (ESI): m/z = 158 [M + H]⁺.

2-Chloro-N-ethylpyrimidin-4-amine (12f-1)

To 2-chloro-4-(methylsulfonyl)pyrimidine (11f, 260 mg, 1.35

mmol) was added THF (2 mL), then the mixture was cooled under

N₂to –70 °C. 2 M EtNH₂in THF (1.5 mL, 2.2 mmol) was added by

syringe and the mixture was warmed to r.t. over 3 h. The mixture

was concentrated and purified by chromatography (silica gel,

EtOAc–hexane, gradient 1:4 to 1:0) to provide 12f-1 as a white solid

material; yield: 165 mg (79%); mp 63–66 °C.

2-Methylsulfonyl Product 13e-3

¹H NMR (500 MHz, acetone-d₆, mixture of rotamers ~3:1): δ = 8.30

(br s, 0.25 H), 8.13 (br s, 0.75 H), 7.26 (br s, 0.75 H), 7.14 (br s, 0.25

H), 6.67 (d, J = 6.0 Hz, 1 H), 3.50 (br s, 1.5 H), 3.38 (br s, 0.5 H),

3.23 (br s, 3 H), 1.22 (br s, 3 H).

¹H NMR (500 MHz, acetone-d₆, mixture of rotamers ~4:1): δ =

8.11–7.79 (m, 2 H), 6.52–6.36 (m, 1 H), 3.31–3.10 (m, 2 H), 1.11 (t,

J = 7.3 Hz, 3 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 163.2, 159.9, 155.2, 105.0,

34.8, 14.1.

MS (ESI): m/z (%) = 161 (2), 160 (34), 159 (6), 158 (100, [M + H]⁺),

130 (11), 122 (4), 112 (3), 102 (2).

HRMS (ESI): m/z [M + H]⁺calcd for C₆H₉ClN₃: 158.0480; found:

158.0491.

LC-MS (ESI): m/z = 202 [M + H]⁺.

2-Chloro-4-(methylsulfonyl)pyrimidine (11f)

To 2-chloro-4-(methylthio)pyrimidine (1 g, 6.2 mmol) was added

CH₂Cl₂(10 mL), and the mixture was cooled in an ice bath.

MCPBA (77% pure, 3.15 g, 14 mmol, 2.2 equiv) was added and the

mixture was stirred for 18 h with slow warming to r.t. The mixture

was filtered, and the filtrate was washed with aq NaHCO₃. The or-

ganic layer was dried (MgSO₄), filtered, concentrated, and washed

with hexane to provide 11f as a white solid material; yield: 1.02 g

(86%).

¹H NMR (500 MHz, DMSO-d₆): δ = 9.34 (d, J = 0.9 Hz, 1 H), 8.30

(d, J = 0.9 Hz, 1 H), 3.40 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 167.3, 164.7, 160.2, 116.4,

Acknowledgment

The authors wish to thank Dr. Joseph M. Colacino, Dr. Christie

Morrill, and Prof. Scott E. Denmark, University of Illinois at Urbana-

Champaign, for helpful discussions and Jane Yang for analytical

support.

39.5.

4-(Methylsulfonyl)-N-phenylpyrimidin-2-amine (13f-1)

To 2-chloro-4-(methylsulfonyl)pyrimidine (11f, 221 mg, 1.15

mmol) was added DMSO (1.1 mL), aniline (0.13 mL, 1.4 mmol, 1.2

equiv), and 2,6-lutidine (0.16 mL, 1.4 mmol, 1.2 equiv), and the

mixture was stirred under N₂at r.t. for 21 h. At this point LC-MS

analysis of the mixture still showed presence of 11f. Additional an-

iline (0.1 mL, 1 equiv) was added, after 5 h the starting material did

not disappear; however, side-product formation became profound.

The mixture was diluted with H₂O, extracted with EtOAc–hexanes

(~1:1), dried (MgSO₄), concentrated, then purified by chromatogra-

phy (silica gel, gradient EtOAc–hexanes 1:10 to 1:1) to provide 13f-

1 as a light yellow heterogeneous oily material; yield: 204 mg,

~70% pure by UPLC–MS analysis (see below).

¹H NMR (500 MHz, acetone-d₆, major component, 13f-1): δ = 9.21

(br s, 1 H), 8.81 (d, J = 4.7 Hz, 1 H), 7.81 (dd, J = 1.1, 8.7 Hz, 2 H),

7.40–7.32 (m, 2 H), 7.31 (d, J = 4.7 Hz, 1 H), 7.07 (tt, J = 1.3, 7.3

Hz, 1 H), 3.25 (s, 3 H).

LC-MS (UV 254 nm): 9% of 11f, 70% of 13f-1 (M = 250 [M + H]⁺),

21% of 2-chloro-N-phenylpyrimidin-4-amine⁴²(M = 206 [M +

H]⁺).

Supporting Information for this article is available online at

http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi

m

tgioSrantnugIifoop

r

itmnatr

References

(1) (a) Sanford, M. Drugs 2012, 72, 525. (b) Croxtall, J. D.

Drugs 2012, 72, 847.

(2) Sonpavde, G.; Hutson, T. E.; Sternberg, C. N. Drugs Today

2009, 45, 651.

(3) (a) Sabat, M.; VanRens, J. C.; Laufersweiler, M. J.; Brugel,

T. A.; Maier, J.; Golebiowski, A.; De , B.; Easwaran, V.;

Hsieh, L. C.; Walter, R. L.; Mekel, M. J.; Evdokimov, A.;

Janusz, M. J. Bioorg. Med. Chem. Lett. 2006, 16, 5973.

(b) Gong, B.; Hong, F.; Kohm, C.; Jenkins, S.; Tulinsky, J.;

Bhatt, R.; de Vries, P.; Singer, J. S.; Klein, P. Bioorg. Med.

Chem. Lett. 2004, 14, 2303. (c) Yang, W.; AbdulHameed,

M. D. M.; Hamza, A.; Zhan, C.-G. Bioorg. Med. Chem. Lett.

2012, 22, 1629.

N,N-Diethyl-4-(methylsulfonyl)pyrimidin-2-amine (13f-2)

To 2-chloro-4-(methylsulfonyl)pyrimidine (11f, 227 mg, 1.18

mmol) was added THF (1.2 mL), then the mixture was cooled under

N₂to –60 °C. Et₂NH (0.27 mL, 2.6 mmol, 2.2 equiv) was added by

syringe and the mixture was stirred with slow warming to r.t. over

1.5 h. At this point the LC-MS analysis of the mixture showed al-

most complete consumption of 11e. The mixture was diluted with

EtOAc, filtered through a plug of silica gel, concentrated, and puri-

fied by chromatography (silica gel, EtOAc–hexane, gradient 1:10 to

1:2 to provide 13f-2 as a light yellow viscous oily material that part-

ly solidified upon standing; yield: 254 mg (94%); mp 52–56 °C.

(4) Sagi, V. N.; Liu, T.; Lu, X.; Bartfai, T.; Roberts, E. Bioorg.

Med. Chem. Lett. 2011, 21, 7210.

(5) Deng, X.; Nagle, A.; Wu, T.; Sakata, T.; Henson, K.; Chen,

Z.; Kuhen, K.; Plouffe, D.; Winzeler, E.; Adrian, F.;

Tuntland, T.; Chang, J.; Simerson, S.; Howard, S.; Ek, J.;

Isbell, J.; Tully, D. C.; Chatterjee, A. K.; Gray, N. S. Bioorg.

Med. Chem. Lett. 2010, 20, 4027.

(6) Rivkin, A.; Ahearn, S. P.; Chichetti, S. M.; Kim, Y. R.; Li,

C.; Rosenau, A.; Kattar, S. D.; Jung, J.; Shah, S.; Hughes, B.

L.; Crispino, J. L.; Middleton, R. E.; Szewczak, A. A.;

Synthesis 2013, 45, 1764–1784

PAPER

Chemoselective Reactions of 4,6-Dichloro-2-(methylsulfonyl)pyrimidine

1783

Munoz, B.; Shearman, M. S. Bioorg. Med. Chem. Lett. 2010,

20, 1269.

(20) A ¹H NMR experiment (data not shown) demonstrated that

pyridine reacts with 1 within minutes at r.t. in DMSO-d₆to

provide a complex mixture of products.

(21) The reaction is less general with these amines. Many

heteroaromatic and all heterocyclic amines that we tested

reacted unselectively, with substitution occurring at both C2

and C4, as well as forming multiple other byproducts.

Unselective examples include 2-, 3-, or 4-aminopyridine, 2-

aminothiazole, etc. Imidazole and benzimidazole

preferentially react at C2.

(7) Kumagai, T.; Okubo, T.; Kataoka-Okubo, H.; Chaki, S.;

Okuyama, S.; Nakazato, A. Bioorg. Med. Chem. 2001, 9,

1349.

(8) Gu, S.; Yang, S.; He, Q.; Ma, X.; Chen, F.; Dai, H.; De

Clercq, E.; Balzarini, J.; Pannecouque, C. Bioorg. Med.

Chem. 2011, 19, 7093.

(9) (a) Delia, T. J.; Meltsner, B. R.; Schomaker, J. M.

J. Heterocycl. Chem. 2000, 37, 1457. (b) Matsuno, T.; Kato,

M.; Sasahara, H.; Watanabe, T.; Inaba, M.; Takahashi, M.;

Yaguchi, S.; Yoshioka, K.; Sakato, M.; Kawaseima, S.

Chem. Pharm. Bull. 2000, 48, 1778. (c) Delia, T. J.;

Meltsner, B. R.; Schomaker, J. M. J. Heterocyl. Chem. 1999,

36, 1259. (d) Montebugnoli, D.; Bravo, P.; Corradi, E.;

Dettori, G.; Mioskowski, C.; Volonterio, A.; Wagner, A.;

Zanda, M. Tetrahedron 2002, 58, 2147. (e) Zanda, M.;

Talaga, P.; Wagner, A.; Mioskowski, C. Tetrahedron Lett.

2000, 41, 1757.

(10) (a) D’Atri, G.; Gomarasca, P.; Resnati, G.; Tronconi, G.;

Scolastico, C.; Sirtori, C. R. J. Med. Chem. 1984, 27, 1621.

(b) Wernert, G. T.; Winkler, D. A.; Holan, G.; Nicoletti, G.

Aust. J. Chem. 2004, 57, 77.

(11) Kopell, H. C.; Springer, R. H.; Cheng, C. C. J. Org. Chem.

1961, 26, 1884.

(12) (a) Martin, R. E.; Morawitz, F.; Kuratli, C.; Alker, A. M.;

Alanine, A. I. Eur. J. Org. Chem. 2012, 47. (b) Huang, T.-

H.; Tu, H.-Y.; Aibibu, Z.; Hou, C.-J.; Zhang, A.-D.

ARKIVOC 2011, (ii), 1.

(13) Bebbington, D.; Binch, H.; Charrier, J.-D.; Everitt, S.;

Fraysse, D.; Golec, J.; Kay, D.; Knegtel, R.; Mak, C.;

Mazzei, F.; Miller, A.; Mortimore, A.; O’Donnell, M.; Patel,

S.; Pierard, F.; Pinder, J.; Pollard, J.; Ramaya, S.; Robinson,

D.; Rutherford, A.; Studley, J.; Westcott, J. Bioorg. Med.

Chem. Lett. 2009, 19, 3586.

(22) See Supporting Information for details.

(23) When indole was combined with 1 in DMSO in the presence

of 2,6-lutidine (1.2 equiv), after 3 d at r.t. side products

started forming according to LC-MS analysis of the reaction

mixture. At that point LC-MS analysis failed to demonstrate

formation of either the C4–Cl or the C2–SO₂Me

displacement products.

(24) Preliminary data suggests that the higher acidity of

heterocyclic aromatic amines may be a reason for some of

these reactions being unselective. Both neutral and

deprotonated species may coexist and react with 1 via

different pathways.

(25) (a) With aziridine: see ref. 11. (b) With methylamine: see

ref. 15. (c) With alkoxide: see ref. 12a. (d) With thiolate: see

ref. 13. (e) With RMgX: see ref. 14. (f) With deprotonated

formamide: see ref. 17. (g) With deprotonated heterocyclic

amine: see ref. 16.

(26) Slightly lower yields were generally obtained when

PhLi/Et₂O or i-PrMgCl·LiCl/THF were used instead of

NaHMDS.

(27) One such side product was isolated and identified as V (see

Scheme 4). Its formation may be explained by the

mechanism shown in the scheme that starts with the

deprotonation of 1. Product V was the major product (38%)

isolated when cyclohexylamine was combined with

NaHMDS and 1. Analytical data for V: white solid, LC-MS

(ESI) [M + H]⁺311 (4 Cl atoms pattern); ¹H NMR (500

MHz, DMSO-d₆): δ = 8.00 (s, 2 H), 4.57 (s, 2 H); ¹³C NMR

(126 MHz, DMSO-d₆): δ = 167.5, 161.3, 120.0, 47.3.

(28) Similar reaction has been reported in ref. 8f.

(29) Reaction with Boc-protected pyridin-3-ylmethanamine did

not provide the clean product even though the reaction was

moderately clean according to the LC-MS analysis of the

reaction mixture. The product seems to be unstable.

(30) The byproduct (Figure 1) was identified as the product of

bis-arylation of the amine with 1 based on LC-MS analysis.

This reaction was not optimized.

(14) Xiao, X.-Y.; Patel, D. V.; Ward, J. S.; Bray, M. R.; Agoston,

G. E.; Treston, A. M. WO 2007041358, 2007.

(15) Medina, J. R.; Becker, C. J.; Blackledge, C. W.; Duquenne,

C.; Feng, Y.; Grant, S. W.; Heerding, D.; Li, W. H.; Miller,

W. H.; Romeril, S. P.; Scherzer, D.; Shu, A.; Bobko, M. A.;

Chadderton, A. R.; Dumble, M.; Gardiner, C. M.; Gilbert, S.;

Liu, Q.; Rabindran, S. K.; Sudakin, S.; Xiang, H.; Brady, P.

G.; Campobasso, N.; Ward, P.; Axten, J. M. J. Med. Chem.

2011, 54, 1871.

(16) Eriksen, B. L.; Hougaard, C.; Peters, D.; Christophersen, P.

WO 2010026087, 2010.

(17) Nagata, T.; Masuda, K.; Maeno, S.; Miura, I. Pest Manage.

Sci. 2004, 60, 399.

(18) Ji, M.; Zheng, Y.; Zheng, M. CN 101857589, 2010.

(19) One such byproduct was identified using LC-MS analysis as

2.1 ([M + H]⁺430, see Scheme 3). It seems that the N–H in

2a is acidic enough to be deprotonated by stronger bases

(such as aliphatic amines or K₂CO₃) and displaces the

sulfone in 1, which seems to be the preferred site of

displacement by anionic nucleophiles (vide infra).

Cl

S

N

Cl

Figure 1

N

Cl

N

(31) Unfortunately, reactions with deprotonated N-alkylanilines,

such as N-methylaniline or indoline (NaHMDS,

MeO₂S

N

Cl

Me

Ph

N

S

N

1

Me

Ph

O

TMPMgCl·LiCl, n-BuLi; various modes of addition) were

not clean. These reactions produced mixtures of products,

with displacements at C2, C4 and double C2 and C4

displacement, as well as other unidentified byproducts.

S

N

H

base

O

2

Cl

2.1

Scheme 3

Synthesis 2013, 45, 1764–1784

1784

R. Baiazitov et al.

PAPER

Cl

N

Cl

N

Cl

NaHMDS

– H⁺

1

NaHMDS

– H⁺

N

^–CH₂

Me

O

–

– MeSO₂

Cl

S

Cl

S

Cl

N

S

O

1

I

II

Cl

N

Cl

N

Cl

N

H⁺

– SO₂

N

–

N

Cl

N

Cl

O

–

O

Cl

SO₂

IV

III

V

Scheme 4

(32) The alternate products 4a–c or 5e,f could be detected by LC-

MS or ¹H NMR analysis of the reaction mixtures. However,

these minor products could be isolated only in impure form

and negligible amounts.

(33) Henne, A. L.; Stewart, J. J. J. Am. Chem. Soc. 1955, 77,

1901.

(37) See experimental section for details.

(38) Some limited information is also available on reactions with

4-chloro-6-(ethylsulfonyl)pyrimidine (see ref. 19b) and 4-

chloro-6-(propylsulfonyl)pyrimidine, see: Porter, J. R.;

Archibald, S. C.; Brown, J. A.; Childs, K.; Critchley, D.;

Head, J. C.; Hutchinson, B.; Parton, T. A. H.; Robinson, M.

K.; Shock, A.; Warrellow, G. J.; Zomaya, A. Bioorg. Med.

Chem. Lett. 2002, 12, 1595.

(34) Kanzian, T.; Nigst, T. A.; Maier, A.; Pilch, S.; Mayr, H. Eur.

J. Org. Chem. 2009, 6379.

(35) Various modes of addition and stoichiometries were tried

unsuccessfully.

(39) Calculations were conducted using Spartan software,

B3LYP 6-31G* in DMSO.

(36) (a) With 3-chloro-6-(methylsulfonyl)-1,2-diazine and 4-

chloro-6-(methylsulfonyl)pyrimidine: Nyberg, W. H.;

Cheng, C. C. J. Heterocyl. Chem. 1964, 1, 1. (b) With 4-

chloro-2-(ethylsulfonyl)-6-phenylpyrimidine and 4-chloro-

2-(ethylsulfonyl)pyrimidine: Sawayama, T.; Yamamoto, R.;

Kinugasa, H.; Nishimura, H. Heterocycles 1977, 8, 299.

(40) In anilines the NH₂-group is planarized. This may lead to

anilines being effectively bulkier compared to, for example,

CyNH₂.

(41) This conclusion is similar to the one made earlier; see ref.

19b.

(42) Assigned based on the LC-MS data.

Synthesis 2013, 45, 1764–1784

Article Doi

Chemoselective reactions of 4,6-dichloro-2-(methylsulfonyl)pyrimidine and related electrophiles with amines

DOI: 10.1055/s-0033-1338853

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Article abstract of DOI:10.1055/s-0033-1338853

Full text of DOI:10.1055/s-0033-1338853

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