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4 Mechanism Problems from Reactions Give Expected Products268
The proposed mechanism appears plausible for the formation of the side prod-
uct quinazolin-4(3H)-one (3). However, I find it less convincing in explaining the
formation of quinazoline-2,4(1H,3H)-dione (2), as several critical issues remain
unaddressed.
First, the authors did not provide evidence confirming dimethylamine as a
by-product. Dimethylamine could have been easily trapped by HCl, yet this was
not verified. Second, if a
13
C -labeled DMF
(
Me
2
N
13
CHO
)
had been used,
13
CNMR
analysis could have clarified whether the labeled
13
C was incorporated into the
product. Third, the oxidation state of the carbonyl carbon in DMF is +2, whereas
in product 2, it is +4. If DMF were the carbon source, an oxidation step must have
occurred. The authors did not elaborate on how the hydroxyl intermediate D was
oxidized to form product 2. What was the oxidant involved, and where did it orig-
inate? These unresolved questions cast doubt on the proposed mechanism for the
formation of compound 2.
I propose an alternative mechanism for the formation of compound 2, as out-
lined below. Initially, carbonic acid is activated by DMF to generate intermediate
E. Subsequently, the nitrile group is activated by E, and the carbon in the nitrile is
attacked by the hydroxyl group (HO-) from E, resulting in the formation of benz-
imidic acid F. This intermediate then undergoes isomerization to yield benzamide
G. Up to this stage, DMF and CO₂ function as catalysts. The amino group in F then
attacks the carbonyl group in E, releasing DMF and forming carbamic acid H. Finally,
cyclization occurs to produce the target compound 2. In this mechanism, CO₂ serves
as the carbon source, while DMF acts as both a catalyst and an activator. Notably, no
dimethylamine is generated during the formation of 2; dimethylamine is instead a
by-product in the formation of the side product 3. In comparison to another study
where DMF was not added, the products were still obtained in high yields (80–93%)
but under more severe conditions (14 MPa CO₂, 160 °C, 18–48 h) [314].
CO
2
+
H
2
O
HO
C
OH
O
O
N
DMF
O
C
O
O
R
N
E
N
OH
NH
2
R
H
2
O
1
NH
O
C
R
N
H
O
2
Cyclization
H
H
DMF, H
2
O
O
N
H
R
C
O
OH
CO
2
, DMF
OH
C
OO
E
E
H
O N
+
C
O
O
O
–
H
E
H
1
NH
2
O
R
F
G
NH
2
N
+
O
–
H
NH
2
NH
2
O
–
H
N
+
4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 269
Problem 109: Synthesis of 3-Alkylquinazolin-4-ones Promoted by Mukaiyama
Reagent
Quinazolinones possess a wide range of biological properties. For example,
febrifugine ( 1), isolated from the Chinese herb Dichroa febrifuga, is used as
an antimalarial drug [ 315 ]. Wacharasindhu’s group reported a synthesis of
3-alkylquinazolin-4-ones ( 4) from quinazolin-4-ones ( 2) and amines ( 3) promoted
by Mukaiyama reagent [ 316 ].
Please suggest a mechanism for this reaction.
Experimental Procedure (from Tetrahedron Lett., 2010, 51, 1713)
General Procedure: To a solution of quinazolin-4-one ( 2, 73.1 mg, 0.5 mmol) in
CH
2
Cl
2
(5 mL) at room temperature was added 2-chloro-1-methylpyridinium iodide
(255.49 mg, 1.0 mmol) followed by diisopropylethylamine (435.48 µL, 2.5 mmol).
The solution was stirred at room temperature for 1 h after which was added
n-butylamine (248 µL, 2.5 mmol). The mixture was stirred at room temperature
overnight and then concentrated and purified by column chromatography on silica
gel (eluent: EtOAc/hexanes, 50%) to give 3-butylquinazolin-4(3H)-one.
1
HNMR
(400 MHz, CDCl
3
) δ ppm 8.32 (1H, d, J = 7.96 Hz), 8.03 (1H, s), 7.81–7.65 (2H,
m), 7.51 (1H, t, J = 7.42 Hz), 4.01 (2H, t, J = 7.31 Hz), 1.87–1.70 (2H, m), 1.51–1.32
(2H, m), 0.97 (3H, t, J = 7.34 Hz).
13
CNMR (100 MHz, CDCl
3
) δ ppm 160.4, 147.6,
146.2, 133.5, 126.8, 126.6, 126.1, 121.6, 46.2, 30.9, 19.4, 13.2. HRMS [M + H
+
]: calcd
for C
12
H
13
N
2
O 203.1184, found 203.1007.
The Mechanism
The 3-NH in quinazolinone as a nucleophile attacks the Mukaiyama reagent
to form a pyridinium-quinazolinone intermediate A, in which the carbonyl is
activated. The primary amine attacks the carbonyl on the amide moiety resulting
in the ring-opening product, enamine B. Cyclization followed by elimination of
1-methylpyridin-2(1 H)-imine D gives the product 4 .
N
NH
O
R
1
2
H
2
N
R
2
+
Mukaiyama
reagent (2 eq.)
DIPEA (2 eq.)
DCM, rt
N
N
O
4
4a, R
1
=
H, R
2
=
n-Bu
yield = 78%
N
N
O
1, Febrifugine
O
N
H
HO
3
N
+
Cl
I
–
Mukaiyama
reagent
R
1
R
2
4 Mechanism Problems from Reactions Give Expected Products270
Problem 110: Dimroth Rearrangement in the Preparation of Gefitinib and
Erlotinib
The 4-anilinoquinazolines gefitinib ( 1, Iressa) and erlotinib ( 2, Tarceva) have been
launched for the treatment of non-small cell lung cancer. The final step in the syn-
thesis of 1 involves the reaction of precursor 3 with 3-chloro-4-fluoroaniline ( 4) in
hot acetic acid [ 317 ].
Please suggest a mechanism for this reaction.
Experimental Procedure (from Org. Process Res. Dev., 2007, 11, 813)
4-(3 ′-Chloro-4 ′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazo-
line (1). To a reaction flask fitted with a condenser and a Dean-Stark apparatus were
added 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile (283 g, 0.97 mol),
toluene (2.5 L), acetic acid (3 mL), and DMF-DMA (280 mL, 2.10 mol). The reaction
mixture was heated to 105 °C and stirred for 3 h. While stirring, methanol was col-
lected using the Dean-Stark apparatus. Toluene was completely stripped off under
vacuum to obtain N′-[2-cyano-5-methoxy-4-{3-(4-morpholinyl) propoxy}phenyl]-
N ,N-dimethylformamidine ( 3) as a brown liquid. IR (thin film): 864, 1010, 1118, 1384,
2214, 2812, 2950 cm
1
.
1
HNMR (CDCl
3
): δ 2.0 (m, 2H), 2.47 (m, 6H), 3.06 (s, 6H),
N
NH
O
2
N
+
Cl
N
N
O
N
Cl
HI
Trapped
by DIPEA
A
N
N
O
A
NH
2
H
2
N
3
N
N
O
R
2
N
N
HCl
Trapped
by DIPEA
H
N
N
O
N
N
H
B
C
N
N
O
HN N
+
4
D
I
–
R
2
N
+
CI
–
R
2
R
2
R
2
N
N
HN Cl
F
O
O
N
O
1 (gefitinib)
N
N
HN
O
O
O
2 (erlotinib)
O
N
CN
O
O
N
O
3
H
2
N Cl
F
4
+
N
AcOH
130 °C
70%
1
4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 271
3.72 (t, J = 4.5 Hz, 4H), 3.87 (s, 3H), 4.03 (t, J = 6.5 Hz, 2H), 6.45 (s, 1H),
6.98 (s, 1H), 7.57 (s, 1H). HRMS: calcd for C
18
H
26
N
4
O
3
(M + H) 347.2083, found
347.2081.
To the residue (3) were added acetic acid (2.5 L) and 3-chloro-4-fluoroaniline
(4, 175 g, 1.20 mol). The reaction mixture was heated to 125–130 °C and stirred
for 3 h. The reaction mixture was then cooled to 25 °C, quenched in ice water
(4 L), and adjusted pH ~9 with ammonia solution. To this reaction mass was added
ethyl acetate (1 L), and the mixture was stirred for 1 h. The solid precipitate was
filtered to obtain crude product 1. Crude material was suspended in MeOH (4 L),
and cooled to 20 °C. To this reaction mass was added concentrated HCl (190 mL)
slowly with efficient stirring. The precipitate was filtered and washed with chilled
methanol (200 mL) to give gefitinib hydrochloride. The solid was suspended in
H
2
O (5 L), stirred for 1 h at room temperature, cooled to 5 °C, filtered, and washed
with chilled water (100 mL) to obtain an off-white solid of gefitinib hydrochloride.
The solid was then suspended in water (2 L), and the suspension was adjusted to
pH ~8 using ammonia solution, filtered, and dried at 50 °C to give 1 as off-white solid
(304 g, 70% yield). Mp 193–195 °C. HPLC purity >99%.
1
HNMR (CDCl
3
, 200 MHz):
δ 2.11 (m, 2H), 2.46–2.59 (m, 6H), 3.74 (dd, J = 4.5 and 4.4 Hz, 4H), 3.98 (s, 3H),
4.17 (t, J = 6.5 Hz, 2H), 7.09 (s, 1H), 7.16 (t, J = 8.8 Hz, 1H), 7.26 (s, 1H), 7.34 (brs,
1H, exchangeable with D
2
O), 7.50–7.58 (m, 1H), 7.84–7.88 (m, 1H), 8.66 (s, 1H).
MS (m/z): 446(M
+
), 128, 100. Elemental Anal. Calcd for C
22
H
24
ClFN
4
O
3
: C, 59.19;
H, 5.38; N, 12.55. Found: C, 59.17; H, 5.21; N, 12.33.
The Mechanism
The formation of 1 from compound 3 and 3-chloro-4-fluoroaniline (4) is believed to
take place via Dimroth rearrangement. Firstly, the aniline substitutes the dimethyl-
amino and cyclizes to give the imine A. Then the pyrimidine ring is opened by acetic
acid at the C─ N
3
bond with subsequent rotation of 180° around the C
10
─ C
4
bond.
Recyclization of the molecule and elimination of acetic acid provides the product 1.
NR
2
O
R
2
O
R
1
O
R
1
O
3
H
2
N
Cl
F
4
N
N
N N
N
HN
Ar
H
N
N
Ar
NH
Me
2
NH
HO
O
AcOH
N
N
Ar
NH
OAc
H
N
N
H
Ar
NH
OAc
N
NH
HN
OAc
Ar
N
N
HN
OAc
H
Ar
AcOH
N
N
HN
Ar
1
A
4
10
3
C
4
-C
10
turn 180°
R
2
O
R
1
O
R
2
O
R
1
O
R
2
O
R
1
O
R
2
O
R
1
O
R
2
O
R
1
O
R
2
O
R
1
O
4 Mechanism Problems from Reactions Give Expected Products272
4.7.6 Thienoquinolizine
Problem 111: A [3+2] Cycloaddition Followed by Sulfur Extrusion
In order to explore novel benzodiazepine receptors, Widmer’s group synthesized
a series of dihydrothienoquinolizinone, such as compound 5. The first two steps
included the reaction from epoxide 1 and 5,6-dihydrothieno[2,3-c]pyridine-7(4H)-
thione 2 to intermediates 3 and 4 as shown below [318].
Please suggest mechanisms for the formation of 3 and 4.
Ph
+
S
1
2
DMF
rt, 2 h
N
+
3
S
Ph
–
O
78%
CO
2
Me
Toluene, reflux
90%
N
4
O
MeO
2
C
Ph
O
NC
CN
HN
S
S
S
N
5
O
Ph
S
ON
O
O
Steps
Experimental Procedure (from Helv. Chim. Acta, 1990, 73, 763)
5,6-Dihydro-2-phenylthiazolo[3.2-a] thieno[2,3-c]pyridin-4-ium 3-oxide (3).
To a solution of 4,5-dihydrothieno[2,3-c]pyridine-7(6H)-thione (2; 101.4 g, 0.6 mol)
in DMF (600 mL) under Ar, 3-phenyloxirane-2,2-dicarbonitrile (1; 122.5 g, 0.72 mol)
was added with stirring. After ca. 15 min, the product began to crystallize from the
dark red solution. After 2 h, the dark red crystals of 3 were filtered off, washed
with AcOEt, and dried at 75°/0.1 Torr. Evaporation of the mother liquor to about
half of its volume and trituration with AcOEt gave another crop of 3 (total yield:
133.2 g, 78%) which was sufficiently pure for the subsequent cycloaddition step.
Recrystallization from dioxane/MeCN afforded anal. pure 3. M.p. 225° (dec.). IR:
1615s, 1590s, 1500s, 1140m, 758m.
1
HNMR (60 MHz): 3.13 (t, J = 8.0, 2 H-C(6));
4.33 (t, J = 8.0, 2 H-C(5)); 6.98 (d, J = 5.0, H-C(7)); 7.42 (d, J = 5.0, H-C(8)); 6.90–7.50
(m, 3 arom. H); 7.75–8.05 (m, 2 arom. H). MS: 285 (100, M
+
), 121 (48).
1,3-Dipolar Cycloaddition of Mesoionic Thiuzole Derivatives with Methyl
prop-2-ynoate. Under Ar, 3 (20 mmol) in toluene (200 mL) in the presence of
methyl prop-2-ynoate (2.0 mL, 24 mmol) was heated to reflux temperature for 8 h.
The solvent was evaporated and 4 was separated by chromatography.
Methyl 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2.3-a]quinolizine-10-car-
boxylate (4). Yield 90%. M.p. 117–118° (AcOEt/(i-Pr)
2
O). IR: 1720s, 1645s, 15353,
1510s, 1270s, 1250s, 1200s, 1132s, 794m, 748m,700m.
1
H-NMR (80 MHz): 3.00 (t, J
= 7.0, 2 H-C(4)); 3.95 (s, CH
3
O); 4.47 (t, J = 7.0, 2 H-C(5)); 7.02 (d, J = 5.5, H-C(3));
7.34–7.50 (m, 3 arom. H); 7.58 (d, J = 5.5, H-C(2)); 7.75–7.88 (m, 2 arom. H); 7.90
The Mechanism
The thioamide group in compound 2 acts as a nucleophile, attacking the epoxide 1
to form the 2-hydroxymalonitrile intermediate A. This is followed by an intramo-
lecular displacement of one of the cyano (CN) groups by the nitrogen atom in the
dihydropyridine ring, resulting in the cyclized species B. Upon the elimination of
4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 273
two molecules of hydrogen cyanide (HCN), the 1,3-dipolar compound 3 is gener-
ated. Subsequently, a [3+2] cycloaddition reaction between 3 and methyl propiolate
produces the bridged compound C. Finally, the extrusion of sulfur from C yields the
product 4.
4.7.7 Pyridopyrimidine
Problem 112: An Extended Dimroth Rearrangement Catalyzed by MeONa
Trametinib, developed by GSK, is a MEK1 and MEK2 inhibitor with anticancer
activity. In May 2013, it was approved by the FDA as a single-agent for the treatment
of patients with V600E mutated metastatic melanoma. In a patent application [319],
the final step was a rearrangement of precursor 1 to trametinib catalyzed by MeONa.
Please propose a mechanism for this reaction.
Experimental Procedure (from WO 2005, 121142 A1)
Under a nitrogen atmosphere, to a solution (1.57 g) of 28% sodium methoxide in
methanol was added THF (40 mL), N-{3-[3-cyclopropyl-l-(2-fluoro-4-iodophenyl)-
6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5- ylamino]
Ph
S
1
O
NC
CN
N
S
CO
2
Me
[3+2]
cycloaddition
N
S
Ph
O
S
N
4
O
MeO
2
C
Ph
H
N
S
Ph
HO
S
CN
NC
S
Ph
HO
S
CN
H
−
CN
−
CN
−
O
−
O
HCN
S
Ph
O
S
H
HCN
N
+
S
Ph
S
3
2
S
Ph
S
S
S
Extrusion
“S”
A
B
C
CO
2
Me
MeO
2
C
N
+
N
+
N
+
N
N N
HN
F I
O
O
O
N
H
O
Trametinib
MeONa
MeOH
THF
20 °C, 4 h
95%
HN
N
N
F I
O
N
H
O
1
N
O
O
4 Mechanism Problems from Reactions Give Expected Products274
phenyl}acetamide 1 (5.00 g) obtained in Step 7, and the mixture was stirred at
room temperature for 4 h. Acetic acid (0.56 mL) was added, and the mixture was
stirred at room temperature for 30 min. Water (40 mL) was added and the mixture
was further stirred for 1 h. The crystals were collected by filtration and dried to
give N-{3-[3-cyclopropyl-5-(2-fluoro-4- iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-
3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-l-yl]phenyl}acetamide 2 (4.75 g,
yield 95%) as colorless crystals. MS ESI m/e: 616 (M + H), 614 (M-H).
1
H-NMR
(DMSO-d
6
, 400 MHz) δ 0.63–0.70 (m, 0.91–1.00 (m, 2H)), 1.25(s, 3H), 2.04(s, 3H),
2.58–2.66 (m, 1H), 3.07(s, 3H), 6.92 (t, J = 8.8 Hz, 1H), 7.00–7.05 (m, 1H), 7.36 (t, J
= 8.2 Hz, 1H), 7.52–7.63(m, 3H), 7.79 (dd, 10.4 Hz, 1H), 10.10(s, 1H), 11.08 (s, 1H).
The Mechanism
This reaction can be regarded as a Dimroth rearrangement via ring-opening,
ring-closing catalyzed by MeONa. The driving force of the reaction may be due to
the salt C which is a weaker base than salt A. This means NH in trametinib was
more acidic than the NH in 1.
4.7.8 Pyrrolopyrimidine
Problem 113: One-Pot Synthesis of 2-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)
acetates
4-(1H-Pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimi-
dine (5) is an important intermediate for synthesizing of ruxolitinib [320] and bar-
icitinib [321]. In a patent application, Qi et al. reported a new process for 5, in which
a one-pot procedure for preparation of 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetates
(4) from cyanoacetyl acetate 1, 2-bromo-1,1-diethoxyethane 2 and formimidamide
hydrochloride 3 was described [322].
N
N
N
F I
O
N
H
O
1
N
O
O
MeO
–
H
MeOH
MeONa
MeOH
N
–
N
N
F
I
O
N
H
O
A
N
O
O
MeO
–
Ring open
N
–
N
N
–
F I
O
N
H
O
O
N
O
MeO
Recyclyze
Na
+
Na
+
N
N N
N
–
F I
O
O
O
N
H
O
Na
+
B
C
MeOH
N
N N
HN
F I
O
O
O
N
H
O
Trametinib
MeONa
MeONa
MeONa
4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 275
Please suggest a mechanism for the formation of 4.
Experimental Procedure* (from CN 2019/109651424, A)
To a 500 mL four-necked flask, charged with 150 g of N,N-dimethylformamide,
were added ethyl cyanoacetate (1, 15.5 g, 0.1 mol) and 30% sodium ethoxide eth-
anol solution (27.5 g, 0.12 mol). Controlling the reaction temperature between 20
and 25 °C, bromoacetaldehyde diethyl acetal (2, 19.5 g, 0.1 mol) was added drop-
wise, and the addition was completed in about 30 minutes. Then the reaction
was stirred at 20–25 °C for 6 hours. Gas chromatography confirmed the complete
consumption of bromine acetaldehyde diethyl acetal and the formation of ethyl
1,1-diethoxy-3-cyano-4-oxo-n-hexanoate (3). Formamidine hydrochloride (10.0 g,
0.12 mol) and a 30% ethanolic sodium solution (27.5 g, 0.12 mol) were added. The
reaction mixture was stirred at 40–45 °C for 4 hours. Saturated ammonium chloride
aqueous solution (20 g) was added to the mixture and the pH value was adjusted
to 3–4. The reaction was stirred at 30–35 °C for 3 hours. Five hundred grams of
ice water was added to the reaction. The precipitates were collected by filtration to
give a filter cake. This was recrystallized from isopropanol (80 g) to obtain 18.6 g
of 2-(7-hydropyrrole[2,3-d]pyrimidin-4-yl)acetate, the HPLC purity was 99.5%, and
the yield was 90.7%.
* Translated from Chinese by the author of this book.
N
N
N
NHN
SEM
OEt
CN
O O
+
Br
OEt
OEt
EtONa, EtOH
20–25 °C
OEt
CN
O O
EtO
OEt
HN
=
CHNH
2
.HCl (3)
EtONa, EtOH
40–45 °C
N
N
N
H
CO
2
Et
90%
1
2
4
5
Steps
N
N
N
H
NN
CN
H
3
PO
4
Ruxolitinib phosphate
N
N
N
H
NN
Barcitinib
N
CN
S
O
O
1
2
3
4
3
4 Mechanism Problems from Reactions Give Expected Products276
The Mechanism
The C4-H (pK
a
~ 10) in 1 is more acidic than C2-H (pK
a
~ 11); thus, the first step
alkylation regioselectively occurs at the C4 position to give A. At the formimidam-
ide attack stage, the carbonyl is more reactive than the nitrile group, and thus pro-
vides B. Water is eliminated from B to afford C and then the formimidamide cyclizes
toward the nitrile to generate D. The produced amino group further cyclizes with
the acetal group to yield the dihydropyrrole E. Final elimination of EtOH leads to
product 4.
4.7.9 Pyrazolopyrimidine
Problem 114: Cyclization of Diazo Compound with Aldehyde
In a synthesis of SHP2 inhibitors, the core bicyclic heterocycles were prepared from
was prepared in 39% yield [324].
Please suggest a mechanism for this reaction.
Experimental Procedure (from J. Med. Chem., 2019, 62, 1781)
To a suspension of 6-((4-methoxybenzyl)diazenyl)-3-methylpyrimidine-2,4(1H,3H)-
dione (1, 0.68 g, 2.479 mmol) in DMF (8 mL) and iPrOH (4 mL) was added
2,3-dichloroisonicotinaldehyde (2, 0.436 g, 2.479 mmol) and piperidine (0.241 mL,
OEt
CN
O O
1
2
3
4
H
EtO
–
OEt
CN
O
1
2
3
4
Br
OEt
EtO
EtONa
EtOH
NaBr
O
EtO
OEt
N
HN
EtO
OEt
CO
2
Et
H
2
O
N
N
HN
HO
H
–
OEt
EtO
OEt
N
N
HN
EtO
EtO
N
N
H
2
N
EtOH
N
N
N
H
EtO
H
EtO
–
EtOH
N
N
N
H
1
2
3
4
A
B
C
D
E
CO
2
Et
CO
2
Et
CO
2
Et
H
2
N
CO
2
Et
O
–
CO
2
Et
N
N
O
H
N
N
N
Cl
N
H
N
O
H
2
N
Steps
N
H
N
O
ON
N
PMB
N
Cl
Cl
CHO
Piperidine, DMF
i-PrOH, 90 °C
N
H
N
O
N
PMBN
N
Cl
Cl
O
39%
1
2
3
SHP389
4.8 Miscellaneous 277
2.430 mmol). The resultant mixture was stirred at 85 °C for 1 h. At completion, the
reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL).
The layers were separated, and the aqueous layer was washed with ethyl acetate
(50 mL). The combined organics were washed with brine (40 mL), dried with
Na
2
SO
4
, filtered, and concentrated. The crude was purified by flash chromatography
over silica gel (010% methanol/DCM eluent) to afford 3-(2,3-dichloropyridin-
4-yl)-2-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6-(5H,7H)-
dione as a yellow solid (420 mg, 39% yield, 90% purity). LCMS: m/z 432 (M + 1)
+
,
R
t
= 1.29 min.
The Mechanism
The aldehyde 2 is activated by piperidine to form a 1-arylidenepiperidin-1-ium
hydroxide A. Then aldol reaction occurs between 1 and A to give intermediate B.
There may be three different forms of B: B-1, B-2, and B-3. Cyclization of B-3 fol-
lowed by elimination of piperidine provides the product 3.
4.8 Miscellaneous
4.8.1 Steroid
Problem 115: Formation of Cyclopropane Ring in a Nucleophile Substitution
on Steroid
Galeterone (1) is a steroidal antiandrogen used in the treatment of prostate cancer.
In an effort to explore novel analogs, Njar’s group synthesized 3β-(1H-imidazole-
1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene (galeterone 3β-imidazole (2)
in a four-step process, achieving an overall yield of 63% starting from compound 1
[325]. However, the initial results were less than optimal. When 3β-mesyl galeterone
(3) was treated with imidazole in refluxing toluene, the desired compound 2 was
obtained in only 11% yield, along with the 3α-isomer (4, 3%), the 6β-isomer of 3α, 5α
-cycloandrostane (5, 35%), and several uncharacterized elimination products [326].
Please suggest a mechanism for the formation of 2, 4, and 5.
Ar
HO
–
N
N
O
ON
N
PMB
H
N
N
O
ON
N
PMB
Ar
H
N
H
N
O
ON
N
PMB
N
N
H
N
O
O
N
N
PMB
Ar
A
O
Ar
H
Piperidine
2
N
B-1
3
Piperidine
B-2
H
2
O
H
Ar
N
H
N
O
ON
N
H
PMB
N
B-3
Ar
N
H
N
O
O
N
N
PMB
Ar
N
H
1
N
+