Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5262_Библиотеки_им_академика_М_И_Перельмана.pdf
4 Mechanism Problems from Reactions Give Expected Products218
General Procedure for the Synthesis of Benzisoxazoles. Powdered NaOH
(0.8 g, 20 mmol, 10 equiv) was stirred with ethanol (10 mL) at room temperature for
20 min. A mixture of 4 (500 mg, 2 mmol) and arylacetonitrile 2 (3–4 mmol, 1.5–2
equiv) was added, and the mixture was stirred in a closed reaction flask at room tem-
perature for the given time (1–2 h) and then poured into water (70 mL). The crude
product was extracted into EtOAc (3 × 30 mL). The combined organic phase was
washed with saturated NH
4
Cl (20 mL), dried and the solvent was removed under
reduced pressure. Flash chromatography using silica gel (EtOAc–PE) provided pure
products.
3-Phenyl-5-(pentafluorosulfanyl)benzo[c]isoxazole (5). A white solid (66%
yield); mp 129–130 °C; R
f
0.40 (EtOAc–PE, 4:96); IR (film) ν
max
3128, 3090, 3050,
1631, 1547, 1521, 1495, 1466, 1447, 1368, 1144, 1064, 935, 839;
1
HNMR (500 MHz,
CDCl
3
) δ
H
7.56–7.64 (m, 3H), 7.65 (dd, 1H,
4
J
HH
= 9.8Hz,
4
J
HH
= 1.8Hz), 7.67
(br d, 1H,
3
J
HH
= 9.8Hz), 7.98 (m, 2H), 8.31 (br dd, 1H,
4
J
HH
= 1.8Hz,
4
J
HH
= 0.8Hz
);
13
CNMR (125.7 MHz, CDCl
3
) δ
C
112.4, 116.3, 121.3 (quint.,
3
J
CF
= 5.3Hz), 127.0,
127.2, 127.5 (quint.,
3
J
CF
= 4.1Hz), 129.6, 131.5, 150.4 (quint.,
2
J
CF
= 18.1Hz), 156.4,
168.6;
19
FNMR (470.3 MHz, CDCl
3
) δ
F
62.8 (d, 4F,
2
J
FF
= 150.4Hz), 83.6 (quint.,
1F,
2
J
FF
= 150.4Hz); MS (EI) m/z (rel. int.) 322 (32), 321 (100) [M]
+
, 213 (55), 194
(24), 185 (35), 184 (21), 166 (55), 140 (21), 139 (32), 105 (18), 77 (70), 51 (19); HRMS
(EI) m/z calcd for C
13
H
8
F
5
NOS [M]
+
321.0247, found 321.0244.
The Mechanism
The reaction necessitates one equivalent of KOH, leading to the elimination of one
equivalent of potassium cyanide (KCN) and two equivalents of H
2
O. The mecha-
nism of this transformation was elucidated by Davis and Pizzini [225]. According
to their interpretation, the process initiates with the condensation of nitrobenzene
(1) and phenylacetonitrile (2), wherein the phenylacetonitrile anion attacks the
ortho position relative to the nitro group, generating intermediate I. Following this,
water is eliminated under basic conditions, producing the nitroso intermediate II.
Deprotonation of II yields the potassium salt III, which can subsequently rearrange
to form IV. Finally, ring closure, potentially via salt V, results in the formation of
the product 3.
Cl
O
O
−
Ph
CN
–
Cl
Ph
CN
OH
H
1
Ph
CN
H
2
I
N
Cl
O
Ph
CN
II
H
KOH
N
Cl
O
Ph
CN
III
N
Cl
Ph
CN
IV
KCN
O
N
Ph
Cl
3
KOH
O
Ph
Cl
CN
V
N
+
K
+
K
+
HO
−
O
−
N
−
K
+
K
+
K
+
HO
−
H
2
O
H
2
O
K
+
H
2
O
O
−
N
+
HO
−
K
+
−
4.6 Formation of Monocyclic Aromatic Heterocycles 219
The reaction can be facilitated by potassium methoxide, although this is not the
critical factor. I believe the process might follow a different sequence. Specifically, I
propose that after the deprotonated phenylacetonitrile reacts with nitrobenzene, the
intermediate I is likely the potassium salt A, as illustrated below. Under strong basic
conditions, the salt A has little opportunity to be protonated to form intermediate
I. The sodium salt of phenylnitromethane was previously synthesized in ethanol
through the reaction of phenylnitromethane with sodium ethoxide [229]. However,
the anionic oxygen serves as a potent nucleophile, displacing the CN group (with
the elimination of KCN) to generate the cyclized intermediate B. Following aro-
matization and a hydrogen shift, the neutral species C is formed. Finally, the
base-catalyzed elimination of one molecule of H
2
O yields the product 3.
Problem 81: Preparation of Isoxazoles from Nitro Compounds and Oxetanes
Isoxazoles has been used as a functional moiety in the synthesis of polo-like kinase
1 (Plk1) binding inhibitors [230]. Carreira’s group reported a facile synthesis of isox-
azoles by base-mediated rearrangement of substituted oxetanes [231].
Please propose a mechanism for this reaction.
Experimental Procedure (from Angew. Chem. Int. Ed., 2011, 50, 5379, Supporting
Information)
General Procedure for the One-Pot Reaction Sequence. In a 10 mL oven-dried
cone-shaped flask were mixed under Ar the nitro compound (0.75 mmol,
1.0 equiv), and oxetan-3-one (0.98 mmol, 1.3 equiv), and the mixture was cooled
to 0 °C. Et
3
N (0.15 mmol, 0.2 equiv) was added, and the reaction mixture was
stirred at 0 °C for 10 min, warmed to room temperature and stirred for 90 min.
Cl
Ph
CN
H
O
MeO
−
Ph
CN
–
Cl
Ph
CN
MeOH
H
KCN
Cl
H
O
Ph
Cl
O
N
Ph
OH
H
O
N
Ph
Cl
A
B
C
3
1
2
−
OMe
Cat.
MeO
−
K
+
MeOH
+
KOH
MeOK
+
H
2
O
MeOH
+
KOH
N
+
K
+
K
+
MeOK
+
H
2
O
N
+
O
−
O
−
O
−
O
−
N
+
K
+
O
O
+
O
2
N
R
1. Et
3
N (0.2 eq.)
2. MsCl (1.1 eq.)
Et
3
N (2.0 eq.)
3. DIPEA (1.0 eq.)
O
N
R
CHO
3, 58–85%
1
2
4 Mechanism Problems from Reactions Give Expected Products220
In most cases, formation of a solid was observed. The reaction mixture was diluted
with THF (7.5 mL). Et
3
N (1.5 mmol, 2.0 equiv) was added and the solution was
cooled to 78 °C. MsCl (0.83 mmol, 1.1 equiv) was added dropwise and the mix-
ture was stirred at 78 °C for 30 min, then allowed to slowly warm to room temper-
ature over 60 min. iPr
2
NEt (0.75 mmol, 1.0 equiv) was added and the mixture was
stirred at room temperature for 12 h. It was diluted with CH
2
Cl
2
(15 mL), quenched
with H
2
O (5 mL), and the aqueous phase was extracted with CH
2
Cl
2
(3 × 5 mL).
The combined organic phases were washed with brine (10 mL), dried (Na
2
SO
4
), fil-
tered, and concentrated in vacuo. The pure product was obtained after purification
by flash column chromatography on silica gel.
3-Benzylisoxazole-4-carbaldehyde (3a). Following the general procedure
using (2-nitroethyl)benzene (113 mg, 0.75 mmol, 1.0 equiv), oxetan-3-one (70 mg,
0.98 mmol, 1.3 equiv), Et
3
N (21 µL, 0.15 mmol, 0.2 equiv), then Et
3
N (0.21 mL,
1.5 mmol, 2.0 equiv), MsCl (64 µL, 0.83 mmol, 1.1 equiv), and iPr
2
NEt (130 µL,
0.75 mmol, 1.0 equiv). The crude product was purified by FC (SiO
2
; hexanes: EtOAc
8:1) to afford the pure title compound. Yield: 112 mg (0.60 mmol, 80%). Colorless
oil. TLC: R
f
= 0.34 (hexanes: EtOAc 4:1; UV, DNP);
1
H-NMR (400 MHz, CDCl
3
):
δ = 9.92 (s, 1H), 8.91 (s, 1H), 7.52–6.91 (m, 5H), 4.29 (s, 2H);
13
C-NMR (101 MHz,
CDCl
3
): δ = 182.7, 165.5, 160.5, 136.2, 129.4, 129.0, 127.4, 121.4, 31.4; IR (neat):
3099, 3039, 1689, 1575, 1455, 1421, 1392, 1129, 874, 744, 720, 694, 671 cm
1
; HRMS
(EI): exact mass calculated for C
11
H
9
NO
2
(M
+
), 187.0628; found 187.0629.
The Mechanism
The first step is a Henry reaction between nitroalkane (2) and the oxetan-3-one (1)
to give the β-nitroalcohol A. The next elimination is promoted by adding MsCl, via
formation of the mesylate B, to afford the , β-unsaturated nitro compound C. In the
O
O
N R
O
O
H
NEt
3
N R
O
–
O
HN
+
Et
3
O
N R
O
O
Et
3
N
O
HO
N R
O
O
H
N R
O
O
O
H
N(i-Pr)
2
Et
N R
O
O
O
N
R
O
HN
+
iPr
2
Et
O
N
R
O
O
–
DIPEA
MsOH
O
N
R
O
OH
H
H
2
O
Ms Cl
MsCl
HCl
Et
3
N
+
HCl
–
Et
3
N
O
O
N R
O
O
H
Ms
Et
3
N
+
HO
–
Ms
A
B
C
D
E
F
G
3
O
N
R
O
HN
+
Et
3
–
O
Et
3
N
–
O
O
–
HN
+
iPr
2
Et
Et
3
N
HN
+
iPr
2
Et
4.6 Formation of Monocyclic Aromatic Heterocycles 221
presence of base, DIPEA, C is isomerized to D, which is readily cyclized to isoxazole
E/F. Finally, one molecule of H
2
O is eliminated to yield the product 3.
4.6.8 Thiazole
Problem 82: Preparation of Thiazole by Thiourea
Compound 4 is a TRPV1 inhibitor developed by Johnson & Johnson. The key pro-
cess to build-up the thiazolo[5,4-d]pyrimidine core is shown by the following reac-
tion [232].
Please suggest the mechanism for this reaction.
Experimental Procedure (from Org. Process Res. Dev., 2011, 15, 382)
2-(2,6-Dichlorobenzyl)-N-(4-(trifluoromethyl)phenyl)thiazolo[5,4-d]
pyrimidin-7-amine (4). 2,6-Dichlorophenylaceticacid (1, 62.5 g, 0.305 mol, 1.17
equiv) and DMF (1.60 mL) were dissolved in toluene (160 mL). Thionyl chlo-
ride (26.6 mL, 0.36 mol, 1.38 equiv) was added slowly over 10 min. The reac-
tion mixture was stirred at 20 °C for 18 h, then added over 1.5 h to a solution of
6-chloro-N
4
-(4-trifluoromethyl-phenyl)pyrimidine-4,5-diamine hemihydrochloride
(2, 80.0 g, 0.261 mol, 1.00 equiv) in DMA (80 mL). The reaction was stirred at 20 °C
for 2 h. Thiourea (31.6 g, 0.416 mol, 1.60 equiv) was added in one batch, followed by
HCl in 2-propanol (5–6 M, 504 mL, ~2.77 mol, ~10.6 equiv) over 1 h via an addition
funnel. The resulting solution was heated to 80 °C for 4 h. Water (340 mL) was added
over 20 min and the resulting suspension was cooled to room temperature. The pre-
cipitate was collected by filtration and washed with ethanol (500 mL) to afford crude
4 (90 g, 76%) as a light-pink solid.
Final Purification of 4. A suspension of crude 2-(2,6-dichlorobenzyl)-N-(4-
(trifluoromethyl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (4, 98.0 g, 0.215 mol) in
N N
Cl
NHO
Cl
Cl
N
H
3
3. thiourea, HCl
i-PrOH, 80 °C, 5 h
4. H
2
O trituration
N N
N
H
4 (90 g)
S
N
Cl
Cl
OHO
Cl
Cl
1
N N
Cl
NH
2
N
H
CF
3
2
1. SOCl
2
, DMF
toluene, rt, 18 h
2.
Two-pot process
76% overall
CF
3
CF
3
4 Mechanism Problems from Reactions Give Expected Products222
acetone (1.55 L) was heated to reflux and filtered. The filtrate was heated to reflux
again. Water (620 mL) was added over 5 min, and the suspension was cooled to
20 °C over 4 h. The solid was collected by filtration and dried in a vacuum oven at
50 °C overnight to give 4 as a white crystalline solid (91.5 g, 93% yield).
1
HNMR
(400 MHz, d
6
-DMSO, δ): 10.43 (s, 1H), 8.58 (s, 1H), 8.19 (d, J = 8.4 Hz, 2H), 7.71 (d, J
= 8.5 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.48 (t, J = 8.1 Hz, 1H), 4.83 (s, 2H);
13
CNMR
(126 MHz, d
6
-DMSO, δ): 165.7, 162.8, 153.5, 152.4, 142.7, 135.4, 132.4, 130.8, 130.8,
128.9, 125.6 (q, J = 3.7 Hz), 124.4 (q, J = 271.2 Hz), 123.0 (q, J = 37.0 Hz), 121.1, 36.0;
MS (ESI
+
): calculated for C
19
H
12
Cl
2
F
3
N
4
S [M + H]
+
, 455.0; m/z found, 455.1; HPLC
retention time: 6.076 min; Anal. Calculated for C
19
H
11
Cl
2
F
3
N
4
S: C, 50.12; H, 2.44; N,
12.31; found: C, 49.92; H, 2.27; N, 12.23.
The Mechanism
At first, the pyrimidine in 3 is activated by HCl and then attacked by thiourea to
give the adduct A. Elimination of HCl from A provides the SN
Ar
intermediate B.
Subsequently, isopropanol as a nucleophile attacks the carbamimidothioate in C to
release the thiopyridine C and isopropyl carbamimidate, which should be the HCl
salt. Cyclization of the thiol with the amide moiety affords D. Finally, water is elim-
inated to yield the thiazole product 4.
Another example for this kind of thiazole formation is described in a patent appli-
cation [233].
N N
Cl
NHO
N
H
Ar
1
3
H
+
H
2
N
HN
S
H
N N
Cl
NHO
N
H
HN
S
H
HCl
N N
NHO
N
H
HN
S
Addition
thiourea
i-PrOH
i-Pr O
NH
2
NH
N N
NHO
N
H
HS
N N
N
H
S
N
HO
H
H
2
O
N N
N
H
CF
3
4
S
N
Cl
Cl
A
B
C
D
H
2
N
Ar
2
Ar
1
Ar
2
H
2
N
Ar
1
Ar
2
Ar
1
Ar
2
Ar
1
Ar
2
N
N
Cl
Thiourea
HCO
2
H, EtOH
85 °C, 15 h
Cl
NH
O
N
N OH
N
S
78%
4.6 Formation of Monocyclic Aromatic Heterocycles 223
Problem 83: Preparation of Thiazole from Sulfoxide During Ceftibuten
Synthesis
In 1970, Cooper and Jose reported a novel rearrangement of penicillin V sulfoxide
(1) to a thiazole product 2 [234]. Treatment of 1 with trimethyl phosphite in reflux-
ing benzene for 30 hours provided 2 in high yield (>80%). The mechanism of this
reaction was also briefly discussed. This reaction has been applied to the synthesis
of ceftibuten [235], seco-isopenicillin N [236], intermediates of cefaclor [237] and
cefovecin [238].
Please suggest a mechanism for this reaction.
Experimental Procedure (from CN111763221 A, 2020*)
4-Nitrobenzyl (R)-2-((1R,5R)-3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]
hept-2-en-6-yl)-3-methylbut-3-enoate (6b). To the reaction vessel was added
anhydrous toluene (450 kg) followed by 5b (100 kg). The addition port was rinsed
with anhydrous toluene (20 kg). The mixture was heated to 90–100 °C and stirred
N
S
H
N
O
O
PhO
O
P(OMe)
3
benzene
reflux, 30 h
>80%
1
N
O
SN
OPh
O
O
OO CCl
3
CCl
3
Ref. 2
steps
N
O
S
H
N
O
CO
2
H
N
S
H
2
N
Ceftibuten
N
S
H
N
O
O
Ph
O
P(OMe)
3
toluene
reflux
3
N
CO
2
CHPh
2
O
4
SN
Ph
N
SH
H
N
O
O
H
2
N
Seco-isopenicillin N
Ref. 3
steps
CO
2
H
CO
2
H
CO
2
H
CO
2
CHPh
2
N
S
H
N
O
O
Ph
O
O
O
X
5a, X
=
OMe
5b, X
=
NO
2
Ref. 5
steps
N
CO
2
R
O
SN
Ph
6a, X
=
4-MeOC
6
H
4
CH
2
6b, X
=
4-NO
2
C
6
H
4
CH
2
N
O
S
H
N
O
N
OMe
N
S
H
2
N
Cefovecin
O
Ref. 4
steps
N
O
S
CO
2
H
H
N
O
Ph
NH
2
Cefaclor
CO
2
H
4 Mechanism Problems from Reactions Give Expected Products224
to form a clear solution. Trimethyl phosphite (51.1 kg) was added. The reaction
temperature was controlled between 90 and 100 °C till the reaction was completed.
The mixture was cooled to 30 °C under the atmosphere of nitrogen. Then trieth-
ylamine (27 kg) was added while the reaction temperature was controlled below
30 °C. The mixture was stirred by avoiding light till reaction completed. Aqueous
HCl (5%, 200 kg) was added and the mixture was stirred for 5 minutes. The mix-
ture was left to stand until layers formed. The layers were separated. The aqueous
layer was extracted with DCM (250 kg). Aqueous was discarded. The combined
organic solutions were washed with aqueous NaCl (12.5%, 150 kg). The solvents
were evaporated under reduced pressure to give the crude product. This was crys-
tallized from methanol, after being dried, to yield the product, 74.4 kg, yield 80%,
theoretical yield 92.99 kg.
* Translated from Chinese by the author of this book.
The Mechanism
The ring of sulfoxide 1 is opened to the sulfenic acid A through a reversible rear-
rangement. Then sulfenic acid A is reduced by trimethyl phosphite to the thiol D
via B and C. The final stage is a condensation of the thiol with the amido side chain,
eliminating one molecule of water, to give the thiazoline ring 2.
4.6.9 Pyrazole
Problem 84: Synthesis of Trifluoromethylpyrazoles
A regioselective synthesis of trifluoromethylpyrazoles was developed by Zhu and
Jiang’s group [239]. As shown below, 5-phenyl-3-(trifluoromethyl)-1H-pyrazole
(3) was prepared from benzaldehyde (1), 4-methylbenzenesulfonohydrazide, and
2-bromo-3,3,3-trifluoroprop-1-ene (BTP) (2) in 88% yield. Notably, the reactions
were successfully carried out on a 100 mmol scale, efficiently yielding the key inter-
mediates necessary for the synthesis of celecoxib [240], SC-560 [241], and AS-136A
[241].
Please suggest a mechanism for this reaction.
N
H
N
O
O
1
H
N
S
H
N
O
O
OH
P(OMe)
3
A
N
S
H
N
O
O
B
N
S
–
H
N
CO
2
R
2
O
O
P
+
(OMe)
3
C
O
H
(MeO)
3
PO
N
SH
HN
O
D
O
H
2
O
N
O
2
SN
R
1
CO
2
R
2
CO
2
R
2
R
1
R
1
S
+
O
–
R
1
CO
2
R
2
CO
2
R
2
P(OMe)
3
R
1
R
1
HO
–
P
+
(OMe)
3
CO
2
R
2
4.6 Formation of Monocyclic Aromatic Heterocycles 225
Experimental Procedure (from Org. Lett., 2020, 22, 809, Supporting Information)
General Procedure for the Synthesis of 3-Trifluoromethylpyrazole. To a
25 mL round bottom flask equipped with a magnetic stirring bar and a refluxing
condenser was added aldehyde 1 (1 mmol), 4-methylbenzenesulfonohydrazide
(1.2 mmol), toluene (6 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3 mmol),
and 2-bromo-3,3,3-trifluoropropene (2, 2 mmol). The resulting mixture was vigor-
ously stirred at 60 °C for 6 h. Then water was added to the mixture (15 mL) and
extracted with EtOAc (15 mL × 3). The combined organic phases were dried over
anhydrous Na
2
SO
4
, filtered and concentrated in vacuo. The obtained crude product
was then purified by flash column chromatography on silica gel (eluting with petro-
leum ether/ethyl acetate = 6/1) to provide the product 3.
5-Phenyl-3-(Trifluoromethyl)-1H-Pyrazole (3a). 186.6 mg, 88% yield; yellow
solid, mp: 112113 °C;
1
HNMR (400 MHz, CDCl
3
) δ 13.25 (brs, 1H), 7.507.52 (m,
2H), 7.337.39 (m, 3H), 6.60 (s, 1H);
13
CNMR (100 MHz, CDCl
3
) δ 145.3, 143.4
(q,
2
J
F−C
= 38.0 Hz), 129.4, 129.2, 127.8, 125.5, 121.1 (q,
1
J
F−C
= 267.2 Hz), 100.8;
19
FNMR (376 MHz, CDCl
3
) δ − 62.0 (s, 3F); IR (KBr): 3127, 2881, 1592, 1498, 1437,
1271, 1158 cm
1
; HRMS (ESI, m/z): [M + H]
+
Calcd. for C
10
H
7
F
3
N
2
+ H, 213.0634;
found, 213.0635.
The Mechanism
The condensation of benzaldehyde 1 with p-toluenesulfonyl hydrazide generates
N-tosylhydrazone A, which then decomposes to diazo compound B in the presence
of bases. The regioselective [3 + 2] cycloaddition of diazo compound B with BTP
Ph
O
+
TsNHNH
2
+
CF
3
Br
HN
N
Ph
DBU, toluene
60 °C, 6 h
88%
N
N
S
O O
H
2
N
Celecoxib
COX-2 inhibitor
N
N
Cl
O
SC-560
COX-2 inhibitor
measles virus inhibitor
N
N
H
N
O
S
N
O O
AS-136A
1
2
3
CF
3
CF
3
CF
3
CF
3
Ph
O
H
2
NNHTs
H
2
O
Ph
N
N
Ts
DBU
DBUH
+
Ph
N
N
−
S
Ph
N
–
Ph
N
–
Br
N
N
Ph
Br
H
HBr
N
N
Ph
H-shift
HN
N
Ph
CF
3
Ph
N
H
N
Ts
OH
H
H
To l
O
O
STo l
O
A
B
C
1
2
H
3
D
[3+2]
O
−
DBUH
+
CF
3
CF
3
CF
3
N
+
N
+
4 Mechanism Problems from Reactions Give Expected Products226
(2) affords intermediate C, which is further converted to trifluoromethylated diazo
intermediate D via the elimination of HBr in the presence of base. Finally, D rear-
ranges to the conjugated pyrazole product 3.
Problem 85: Preparation of Pyrazole by Sulfur Extrusion
In 1977, Bulka’s group reported preparation of 5-aminopyrazoles (2) via sulfur
extrusion from 2,3-dihydro-6H-1,3,4-thiazine (1) in high yield [242]. That method
was applied to the synthesis of a CB
1
antagonist CE-178,253 [243], and to the syn-
thesis of p38 mitogen-activated protein kinase inhibitors [244, 245].
Please suggest a mechanism for this reaction from compounds 3 and 4 to 5.
Experimental Procedure (from Tetrahedron, 2009, 65, 3292)
3-(2-Chlorophenyl)-4-(4-chlorophenyl)-1H-pyrazol-5-amine (5). Bromoketone
3 (3.41 g, 9.95 mmol) and 4-benzhydrylthiosemicarbazide (4) (2.58 g, 10.0 mmol)
were added to EtOH (120 mL) at 0 °C. The suspension was allowed to warm to
room temperature overnight. HBr (2 mL of a 48% aqueous solution) was added
and the reaction mixture was heated to 80 °C for 4 h. HCl (10 mL of a 6 N solu-
tion) was added and heating was continued for 16 h. The mixture was cooled to
room temperature and concentrated. The residue was partitioned between EtOAc
(100 mL) and 2 N NaOH (50 mL). The mixture was filtered and the layers were
separated. The organic layer was concentrated and the crude product purified by
chromatography on silica gel (4:1 EtOAc/hexanes) to afford 3-(2-chlorophenyl)-4-
(4-chlorophenyl)-1Hpyrazol-5-amine (5) as a slightly tan solid (2.10 g, 70%), mp
156–157 °C. IR (thin film) cm
1
3425, 1603, 1563, 1347, 1175, 1125, 865, 780, 630.
1
HNMR (400 MHz, CDCl
3
): δ 7.40 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H),
7.16–7.30 (m, 5H), 7.09 (d, J = 9 Hz, 2H).
13
CNMR (100 MHz, CDCl
3
): δ 133.8,
N
N
O
O
Br
F
H
N
H
N
S OH
OBn
6
7
KH
2
PO
4
, EtOH-H
2
O
40 °C, 22 h
N
N
O
F
8 (30.6 kg)
N
NH
HN
OBn
OH
Steps
N
N
O
F
9.HBr (16.7 kg)
p38 MAPK inhibitor
N
N
HN
OH
S
N
N
Ph
Ph
N
EtONa
EtOH, reflux
N
H
N
Ph
Ph
N
R
2
1 2
10 examples
yield 81–96%
O
Br
3
Cl
Cl
H
2
N
H
N
H
N
S
Ph
Ph
4
1. EtOH, 0 °C
2. 48% HBr, 80 °C
70%
5
Cl
Cl
N
NH
NH
2
Steps
CE-178,253–26
Cl
Cl
N
N
N
N
N
O
EtHN
R
1
H
2
N
NH
2
R
2
R
1
4.6 Formation of Monocyclic Aromatic Heterocycles 227
133.1, 132.7, 132.6, 132.5, 130.7, 130.5, 130.2, 130.0, 129.9, 129.7, 129.2, 128.6, 128.3,
127.4. Anal. Calcd for C
15
H
11
Cl
2
N
3
: C, 59.23; H, 3.65; N, 13.81. Found: C, 58.98; H,
3.57; N, 13.61.
The Mechanism
The reaction sequence likely begins with the substitution of the bromine atom by
a sulfur atom, yielding intermediate A and releasing one equivalent of HBr. This
intermediate can be isolated as the HBr salt. The charge distribution in A makes the
terminal NH
2
group of the hydrazine the most nucleophilic site, facilitating cycli-
zation with the ketone to form aminal B. Subsequent dehydration of B generates
the 5,6-diaryl-6 H-1,3,4-thiadiazin-2-amine C, which may also exist in its tautomeric
form D. The benzhydryl protecting group plays a crucial role by introducing steric
effects that enhance regioselectivity. Upon further addition of HBr, sulfur extrusion
from C and/or D via intermediate E leads to the formation of protected aminopyr-
azole F. Finally, the benzhydryl group is removed in the presence of aqueous HCl to
yield the desired product 5 .
Other sulfur extrusion examples were also reported [ 246 , 247 ].
Problem 86: Synthesis of 4-(3-Aminopropyl)-5-amino-1-methylpyrazole
FR259647 ( 1) shows superiority to current carbapenems in the antibacte-
rial activity against P. aeruginosa and also strong resistance to β-lactamase.
4-(3-Aminopropyl)-5-amino-1-methylpyrazole ( 2a), the side chain of 1, was syn-
thesized from 3-cyanopyridine ( 3) via an intermediate, 1,4,5,6-tetrahydro-pyridine-
3-carbonitrile ( 4), and N-methylhydrazine [ 248 ]. The ratio of the amino pyrazole
products 2a /2b influenced by the equivalents of HCl used. For example, 1 equivalent
of HCl provided 2a /2b in a 90:9.5 ratio, while 2 equivalents of HCl gave 2a /2b in
around 1:1.
Please provide a mechanism for the transformation from 4 to 2a / 2b .
Cl
O
Br
3
4
Ar1
=
Ar2
=
NH
2
N
HN
S
Ph
H
HBr
NH
S
Ar
1
Ar
2
NHR
O
N
N
S
OH
NHR
H
H
2
O
N
N
S
NHR
R
=
N
N
S
NHR
H
N
N
S
NHR
E
H
S
N
H
N
N
NH
NH
2
5
Cl
Ph
A
B
C
D
F
Ph
Ph
HBr
Ph
Ph
Br
H
H
HCl
HBr
Br
–
Br
–
Ar
1
Ar
2
Ar
1
Ar
2
Ar
1
Ar
2
Ar
1
Ar
2
Ar
1
Ar
2
Ar
1
Ar
2
N
+
+
NH
2