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4 Mechanism Problems from Reactions Give Expected Products168
phases were combined, and solvent (900 L) was distilled off under vacuum, maximum
base temperature 22 °C. The resulting concentrate was cooled to 8 °C (pH 10.3) and then
pH-adjusted to 4.3 by the addition of 12% v/v aqueous sulfuric acid solution (177 L),
taken from a bulk solution of concentrated sulfuric acid (340 kg) and demineralized
water (1500 L). The temperature was allowed to rise to a maximum of 17 °C. The mix-
ture was stirred for 5 min, and the phases were allowed to separate for 15 min. The
phases were separated, and the organic phase was discarded. The aqueous phase was
diluted with demineralized water (150 L) and then basified to pH 11.7 with 50% w/w
sodium hydroxide solution (110 kg). Compound 4 was extracted into ethyl acetate
(270 kg), and the mixture was warmed to 27 °C. The aqueous phase was separated
off and extracted with further ethyl acetate (135 kg), maintaining the temperature at
25–30 °C, and then discarded. The organic phases were combined.
A solution of dimethylacetylene dicarboxylate (86 kg, 605 mol) in ethyl acetate
(90 kg) was added over 1 h with cooling applied, allowing the temperature to rise to
a maximum of 29 °C. The head tank and transfer lines were washed through with
ethyl acetate (9.0 kg). The reaction mixture was stirred at 23–24 °C for 40 min. The
mixture was cooled to 4 °C, and demineralized water (50 L) was charged, followed by
ethyl acetate (180 kg). The pH was adjusted from 10.9 to 2.6 by the careful addition
of 12% v/v aqueous sulfuric acid (45 L), maintaining the temperature between 0 and
5 °C. The mixture was stirred for 5 min, and the phases were allowed to separate for
15 min. The aqueous phase was separated off and discarded, and the organic phase
washed with an aqueous solution of sulfuric acid and sodium sulfate (135 kg), taken
from a bulk solution of sodium sulfate (50 kg), concentrated sulfuric acid (9.0 kg),
and demineralized water (650 L), maintaining the temperature between 0 and 5 °C.
The head tank and transfer lines were washed through with demineralized water
(10 L). The mixture was stirred for 5min, and the phases were allowed to separate for
15 min. The aqueous phase was separated off and discarded and the organic phase
washed twice with 10% w/w sodium bicarbonate solution (2 × 125 kg), allowing the
N
CO
2
Me
5
NO
2
OH
2
(i)
OMs
3
(ii)
NHMe
4
(iii)
N
6
(iv)
7
(v)
8
(vi)
N
H
N
N
H
N
O
9
(vii)
N
H
N
O
Steps
N
H
N
O
N
O
HN
1 (SB-214857-A, lotrafiban)
Reagents: (i) MeSO
2
Cl, Et
3
N, THF; (ii) aq MeNH
2
; (iii) dimethyl acetylenedi-carboxylate (DMAD), EtOAc;
(iv) cyclohexene, Pd-C, or H
2
, Raney Ni; (v) AcOH, MeOH; (vi) DBU, or NaOMe, MeOH;
(vii) NH
4
HCO
2
or Pd-C, MeOH, H
2
O.
NO
2
NO
2
CO
2
Me
NO
2
CO
2
Me
CO
2
Me
CO
2
Me
CO
2
Me
CO
2
Me
NH
2
MeO
2
C
HO
2
C
4.5 Formation of Nonaromatic Heterocycles 169
temperature to rise to 7 °C. After addition of the second bicarbonate wash, the head
tank and transfer lines were washed through with demineralized water (10 L).
Ten percent palladium on charcoal (Pd─C), 59% water wet (30 kg, source Johnson
Matthey, 87 L) was charged and the mixture heated to 66 °C. Cyclohexene (240 kg,
2921 mol) was added over 35 min, maintaining reflux. The head tank and transfer
lines were washed through with ethyl acetate (9 kg). The reaction mixture was
stirred at reflux (68 °C) for 4.5 h, and then the water was separated off by Dean-Stark
distillation over a further 4 h 20 min. The total volume of water collected was 54 L.
The mixture was cooled to 25 °C and filtered, washing the filters and lines through
with ethyl acetate (89 kg). A mixture of ethyl acetate and unreacted cyclohexene was
distilled off at atmospheric pressure (950 L), the temperature rising to a maximum
of 82 °C. The remaining contents of the vessel were cooled to 62 °C, and methanol
(550 kg) was added. The distillation was continued at atmospheric pressure until
a further 200 L of solvent had been distilled out (maximum temperature 65 °C).
Glacial acetic acid (2.1 kg, 35 mol) was charged, washing through with methanol
(8 kg), and the mixture stirred at reflux for 1.5 h.
A 30% solution of sodium methoxide in methanol (19.7 kg, 109 mol) was added,
maintaining reflux, and the head tank and lines were washed through with methanol
(8 kg). The mixture was stirred at reflux for 2 h. The mixture was cooled to 33 °C and
the pH (10.0) adjusted to 7.7 by the addition of glacial acetic acid (5.1 kg, 85 mol). The
mixture was stirred at 30–35 °C for 33 min (final pH 7.5). Ten percent Pd-C, 59% water
wet (15 kg, source Johnson Matthey 87 L) was charged, and a solution of sodium bo-
rohydride in demineralized water containing sodium hydroxide [sodium borohydride
(20.0 kg, 528.7 mol) in demineralized water (265 L) containing sodium hydroxide
(0.12 kg)] was added over 2 h 45 min, allowing the temperature to rise from 33 °C and
maintaining at 40–45 °C. The head tank and transfer lines were washed through with
demineralized water (5 L). The mixture was stirred at 40–42 °C for 55 min.
The pH was adjusted from 9.6 to 7.0 by the addition of glacial acetic acid (25 kg,
416 mol). The head tank and transfer lines were washed through with demineralized
water (10 L). DCM (930 kg) was added and the slurry (35 °C) filtered to a clean vessel.
The filters and lines were washed through with DCM (266 kg) at 30 °C. A mixture of
DCM and methanol was distilled off at atmospheric pressure to a base temperature
of 50 °C (volume of distillate 800 L). The distillation was continued under vacuum
to a base temperature of 53 °C (volume of distillate 511 L). Demineralized water
(500 L) was added to the concentrate and the mixture cooled to 20 °C to crystallize
the product. After stirring the slurry for 1 h at 17–2 °C, the product was filtered off in
a filter drier, washed with demineralized water (200 L), and dried at 35–40 °C under
vacuum for 14 h to give 9 as a white solid, 117 kg 70% from 2-nitrobenzyl alcohol, 9:
mp 174–176 °C;
1
HNMR (400 MHz, CDCl
3
) δ 7.07 (td, 1H, J = 7.7 and 1.4 Hz), 6.93
(dd, 1H, J = 7.5 and 1.1 Hz), 6.67 (td, 1H, J = 7.4 and 1.0 Hz), 6.57 (dd, 1H, J =
8.1 and 0.9 Hz), 5.42 (d, 1H, J = 16.3 Hz), 5.00 (q, 1H, J = 6.1 Hz), 4.09 (d, 1H,
J = 5.4 Hz), 3.73 (s, 3H), 3.72 (d, 1H, J = 16.4 Hz), 3.07 (s, 3H), 2.98 (dd, 1H,
J = 16.0 and 6.8 Hz), 2.65 (dd, 1H, J = 16.0 and 6.5 Hz);
13
CNMR (100 MHz, CDCl
3
)
δ 171.9, 169.6, 145.1, 129.5, 129.0, 119.8, 118.2, 117.5, 53.3, 51.9, 51.8, 35.9, 34.6; IR
(neat, cm
1
) 1728, 1650; LRMS (CI + ve) m/z 249 (M
+
+ H).
4 Mechanism Problems from Reactions Give Expected Products170
The Mechanism
The first reaction is a selective hydrogenation of the nitro to give the aniline 6. Then
Michael addition (cyclization) of the amino to the C═C double bond yields the
intermediate 7. At the basic condition, the heterocycle can be opened to the diamino
compound A which in turn cyclizes via amidation to produce the seven-membered
product 8. The , β-unsaturated double bond of the ester should be Z-form due to
the intra molecule hydrogen bond.
Although it is less likely, another possibility is, at the second stage, the amino add-
ing to the C-3 of the double bond in 6 to form B. Subsequently, the reaction follows
ring-opening-ring-close process to lead to product 8.
4.5.10 Trioxane
Problem 56: Formation of 1,2,4-Trioxanes from Cyclic Peroxides and Carbonyl
Compounds
1,2,4-Trioxane core structure in artemisinin is proven to be the active site for its
anti-malaria activity. In 1983, Jefford’s group reported that when cyclic peroxide 2
was treated with acetaldehyde in the presence of Amberlyst-15, a 1,2,4-trioxane 4 was
obtained in 13% yield as a pair of epimers. Meanwhile, 1,4-dimethoxynaphthalene
(1) (24%) and naphthalene-1,4-dione (3) (37%) were also obtained [151].
More stable 1,4-endoperoxide 7 was subjected to the same reaction with acet-
aldehyde, the epimeric mixture of cis-fused 1,2,4-trioxanes 8 were obtained in
quantitative yield. Ketones proved less reactive with 7. Catalyzed by trimethylsilyl
trifluoromethanesulfonate (TMSOTf) in DCM, the yield of product 9 was improved
to 83% [152].
Please provide mechanism for the formation of products 1, 3, and 4.
N
CO
2
Me
5
H
2
, Ni
NH
2
N
6
2
3
N
H
N
H
MeO
–
Cat.
HOAc
7
Cat.
MeONa
N
H
N
H
OMe
O
MeOH
N
N
O
8
A
H
O
O
CO
2
Me
NO
2
MeO
2
C
CO
2
Me
CO
2
Me
CO
2
Me
CO
2
Me
N
6
2
3
CO
2
Me
Cat.
HOAc
N
H
N
H
MeO
–
B
Cat.
MeONa
N
H
N
A
H
OMe
O
MeOH
N
H
N
O
MeO
2
C
8
CO
2
Me
NH
2
CO
2
Me
CO
2
Me
MeO
2
C
4.5 Formation of Nonaromatic Heterocycles 171
Experimental Procedure (from J. Chem. Soc., Chem. Commun., 1984, 523)
The peroxide (0.2 mmol) is mixed with an excess of carbonyl compound (200 µL
for acetaldehyde and acetone and 60 µL for cyclopentanone) in dry DCM (2 mL).
To this solution at 78 °C, TMSOTf (0.3–8.4 equiv) is added with stirring under
nitrogen. Once the reaction is complete (ca. 1.5 h), a portion of trimethylamine (half
the volume of TMSOTf used) is added and the resulting mixture is diluted with
DCM (20 mL). The organic layer is washed with water (3 times) and dried (MgSO
4
).
After evaporation of solvent, the 1,2,4-trioxane is preparatively isolated by layer
chromatography over silica gel (thickness 2 mm).
The Mechanism
Due to the thermal instability of 2, a retro Diels-Alder reaction gives product 1 and
singlet oxygen. Acid-catalyzed hydrolysis of 2 provides the quinone 3. Protonation
of 2 has generated the hydroperoxide 5 as the crucial first step for the formation
O
O
O
H
H
O
O
Artemisinin
(Qinghaosu)
OMe
OMe
1
O
2
OMe
OMe
O
O
CH
3
CHO
Amberlyst-15
THF
O
O
O
O
H
MeO
O
O
+
3 (37%)
1
2
OMe
OMe
1 (24%)
+
4 (13%)
Amberlyst-15
THF
O
O
O
Me
H
Me
Me
Me
O
O
R
Me
O
+
Me
R
8, R
=
H, 100%
9, R
=
Me, 30%
10, R
=
CO
2
Me, 31%
7
OMe
OMe
O
O
OMe
MeO
O
+
O
H
O
O
O
O
OMe
H
MeO
OMe
OMe
O
O
2
CH
3
CHO
H
3
+
O
MeOH
O
O
O
O
H
MeO
4
H
2
O
MeO
MeO
O
O
H
OH
Retro
D-A reaction
3
2MeOH
H
2
O
2
5 6
O
O
OMe
OMe
1
H
+
H
+
H
3
+
O
1
O
2
4 Mechanism Problems from Reactions Give Expected Products172
of the trioxane 6. Normally, its hydrolysis is easy, giving 1,4-naphthoquinone (3).
However, 5 has the chance to nucleophilically attack the acetaldehyde molecule,
which in turn cyclizes to give the 1,2,4-trioxane ring, which is cis-fused for reasons
of geometry control. The resulting product 6 is hydrolyzed in situ to 4, which con-
sists of a pair of epimers.
Problem 57: Synthesis of 1,2,4-Trioxanes from 4-Alkylphenols and Aldehydes
The 1,2,4-trioxane moiety appears to be a key pharmacophore in combating malaria
[153]. M. W. George’s group reported a continue flow synthesis of 1,2,4-trioxanes (such
as 4) from 4-alkylphenols (such as 1) and aldehydes (such as 3) by photo-generated
singlet oxygen via the peroxyquinol intermediate 2 [154]. An example is shown below.
Please suggest a mechanism for the transformation from 1 to 4.
Experimental Procedure (from Org. Process Res. Dev., 2021, 25, 1873, Supporting
Information)
Procedure for the Synthesis of para-peroxyquinol Derivatives: The desired
concentration of starting material was pumped into the rig by organic pump 1 at
the desired flow rate; a second pump delivered more solvent after the photo reactor
to avoid the blockage in the bicyclic peroxy radical (BPR). The para-peroxyquinol
derivatives crude could be collected after BPR, ready to be isolated using flash chro-
matography and identified.
Procedure for the Synthesis of 1,2,4-Trioxane Derivatives: As described in
the procedure for the synthesis of para-peroxyquinol derivatives, instead of pump-
ing the pure solvent from the second pump, the desired aldehyde dissolved in the
solvent was pumped at the same flow rate as organic pump 1.
Procedure in Batch Experiments. In a round bottle flask, 1 mmol of para-cresol
(1) was dissolved in the desired solvent to prepare 0.067 M of the solution. To this
solution, 0.05–0.1 mol% of TPFPP to 1 was added. Oxygen was provided from a
balloon loaded with pure oxygen at atmospheric pressure. The mixture was irradi-
ated by white light-emitting diode (LED) light at room temperature for a time period
of 4–5 h. The crude was purified using cyclohexane/EtOAc to eluent products using
automatic flash chromatography after removing the solvent. For the reaction with
co-catalyst, 0.5 equivalent co-catalyst was added into the solution before irradiation.
4-Hydroperoxy-4-methylcyclohexa-2,5-dien-1-one (2). The product was puri-
fied using flash chromatography column and eluted with a mixture of EtOAc/cyclo-
hexane (1:1). White solid.
1
HNMR (400 MHz, CDCl
3
) δ 8.34 (s, 1H), 6.94 – 6.87
(m, 2H), 6.33 – 6.26 (m, 2H), 1.42 (s, 3H).
13
CNMR (101 MHz, CDCl
3
) δ 185.5, 149.7,
130.5, 78.7, 22.9. HRMS (ESI, m/z): calc for C
7
H
8
O
3
[M]
+
: 140.0473, found: 140.0472.
HO
1
O
2
, TPFPP, hν
supercritical CO
2
EtOAc, HFIP
40 °C, 120 bar
O
O
O
H
1
2
95%
CHO
Amberlyst-15
88%
O
O
O
O
H
3
4
4.5 Formation of Nonaromatic Heterocycles 173
3-Cyclohexyl-8a-methyl-4a,8a-dihydrobenzo[e][1,2,4]trioxin-6(5H)-one
(4). The product was purified using flash chromatography column and eluted with
a mixture of EtOAc/cyclohexane (1:4). White solid.
1
HNMR (400 MHz, CDCl
3
)
δ 6.84 (dd, J = 10.4 and 2.8 Hz, 1H), 6.07 (dd, J = 10.3 and =, 0.9 Hz, 1H), 5.02 (d,
J = 5.4 Hz, 1H), 4.14 (q, J = 3.0 Hz, 1H), 2.70 (t, J = 2.9 Hz, 2H), 1.74 – 1.58 (m, 6H),
1.33 (s, 3H), 1.22 – 0.98 (m, 5H).
13
CNMR (101 MHz, CDCl
3
) δ 195.3, 151.3, 129.7,
106.7, 78.0, 76.5, 41.2, 40.5, 27.1, 26.3, 25.8 (2×C), 20.7.
The Mechanism
4-Methylphenol (1) undergoes regioselective oxidation at the 4-position by singlet
oxygen, yielding the peroxyquinol intermediate 2. Upon the addition of aldehyde 3
to the system, it is activated by the solid acid catalyst, amberlyst-15. The hydroper-
oxyl group in 2 acts as a nucleophile, attacking the aldehyde group of 3 to form the
adduct A. Subsequently, an intramolecular Michael addition takes place between
the newly generated hydroxyl group and the quinone moiety in A, leading to the
formation of the cyclized 1,2,4-trioxane product 4.
Problem 58: A Key Step for Industrial-Scale Synthesis of Artemisinin
(Qinghaosu)
Artemisinin 2 (Qinghaosu) and its derivatives, including dihydroartemisinin, arte-
mether, and artesunate, are critical components of modern malaria treatment. This
natural compound was discovered by Chinese scientists, most notably Tu Youyou,
who was jointly awarded the 2015 Nobel Prize in Physiology or Medicine alongside
William C. Campbell and Satoshi Ōmura for her groundbreaking work. Artemisinin
is industrially extracted from the plant Artemisia annua, commonly known as
sweet wormwood. In 2014, researchers at Sanofi developed a synthetic route for
the industrial-scale production of artemisinin [155]. The key steps in this process
involve the Schenck ene reaction and Hock cleavage, as illustrated below.
Please propose a detailed mechanism for the conversion of compound 1 to
compound 2.
O
1
H
O O
O
O
O H
2
O
1
O
2
O
O
O
O
H
A
O
O
O
O
H
4
+
H
H
H
OEtO
O O
Hg lamp, TPP, air
DCM, TFA
−10 °C - rt
59%
O
O
O
H
H
O
O
2, Qinghaosu
1, Mixed anhydride of
dihydroartemisinic acid
H
H
HO
O
2 steps
Artemisinic acid
H
H
4 Mechanism Problems from Reactions Give Expected Products174
Experimental Procedure (from Org. Process Res. Dev., 2014, 18, 417)
The process started with 600 kg of artemisinic acid in Step 1.
Step 3: Photooxidation of Mixed Anhydride (dihydroartemisinic acid ester
mixed anhydride (DHAEMC)) to Artemisinin. To the solution of DHAEMC were
added 2570 kg DCM and 300 g tetraphenylporphyrin before the solution was
exposed to light irradiation using photoreactors containing mercury vapor lamps
and ambient air bubbling at about 10 to 15 °C. In the beginning of the irradia-
tion, 132 kg TFA was added to the reaction mixture. The reaction was monitored
by HPLC. As soon as the reaction was completed, the solution was treated twice
with 720 L aqueous solution of sodium bicarbonate and was subsequently washed
with 1440 kg water. The washed organic phase was treated with 30 kg activated
charcoal and filtered. Before the crystallization step, the ADT24h of the reaction
mixture was checked.
Step 4: Crystallization of Artemisinin. By the organic solution of artemisinin
coming from the photooxidation, DCM was partially removed by distillation under
vacuum, while 2700 kg n-heptane was added in order to maintain a constant
volume in the reactor. During the solvent switch, artemisinin was crystallized. The
n-heptane suspension of artemisinin was added with 180 kg ethanol, and then it
was cooled at about 20 °C to accomplish the crystallization. The wet product was
isolated by centrifugation, and washed twice with 1200 kg mixture of n-heptane/
ethanol. The artemisinin was dried under reduced pressure at a temperature not
exceeding 36 °C. About 370 kg of artemisinin as crystalline white powder was typi-
cally obtained for a batch size of 600 kg of artemisinic acid.
Analytical Data of Semisynthetic Artemisinin. Optical Rotation: [α]
20
D
= +7478
[10 mg/mL in ethanol]. The melting point of the crystalline artemisinin was
found to be about 159 °C. The theoretical mass of [M + H]
+
is 283.1545 amu. The
high-resolution mass spectrum shows the [M + H]
+
at m/z = 283.1557 amu. This mea-
sured mass is consistent with the [M + H]
+
formula C
15
H
22
O
5
within a deviation of
4.2 ppm. (amu: atomic mass unit) Data acquisition of all NMR spectra was achieved
using a spectrometer operating at a proton resonance frequency of 600 MHz and a
carbon 13 resonance frequency of 150 MHz (see Table 1). The NMR spectra were
recorded using a solution in deuterated dimethyl sulfoxide (DMSO-d
6
). Calibration
was performed using the residual solvent signal.
1
HNMR δ 0.93 (d), 1.08 (d),
1.15 (dq), 1.34 (m), 1.36 (s), 1.54 (m), 1.65 (m), 1.73 (dq), 1.79 (dt), 1.94 (m), 2.06 (m),
2.28 (m), 3.17 (m), 6.11 (s).
13
CNMR δ 12.30 (CH
3
), 19.46 (CH
3
), 22.36 (CH
2
), 24.28
(CH
2
), 24.85 (CH
3
), 32.44 (CH), 33.07 (CH
2
), 35.42 (CH
2
), 36.02 (CH), 43.85 (CH),
49.43 (CH), 77.48 (C), 93.20 (CH), 104.62 (C), 171.34 (C═O).
The Mechanism
It is assumed that a regioselective Schenck ene reaction [156] between singlet
oxygen and the double bond in 1 takes place to form intermediate A. Then a Hock
cleavage [157] occurs to produce intermediate C via B. Subsequently, a free radical
oxygenation of C occurs with triplet oxygen to generate intermediate D. Finally, cas-
cade cyclization of D leads to Qinghaosu 2.
4.6 Formation of Monocyclic Aromatic Heterocycles 175
4.6 Formation of Monocyclic Aromatic Heterocycles
4.6.1 Oxathiolane
Problem 59: Synthesis of Substituted 1,3-Oxathiolane
Apricitabine (5, ATC, 2-(R)-hydroxymethyl-4-(R)-(cytosin-10-yl)-1,3-oxathiolane) is
classified as a deoxycytidine analog nucleoside reverse transcriptase inhibitor and
is in phase III clinical development for the treatment of HIV infection. In 2011,
Australian chemists reported a three-step process of ATC as shown below [158].
Please suggest a mechanism for the reaction from 2 and 3 to 4.
Experimental Procedure (from Org. Process Res. Dev., 2011, 15, 763)
2-(R)-Benzoyloxymethyl-4-(R)-(N-benzoylcytosin-1-yl)-1,3-oxathiolane (4 -
4c). 2-(R,S)-Benzoyloxymethyl-1,3-oxathiolane-S-oxide (2, 2a) (12.0 g, 0.050 mol)
was dissolved in DCM in a 500-mL three-neck flask and this was cooled to 50 °C.
To this was added triethylamine (15.3 mL, 0.110 mol), followed by iodotrimethyl-
silane (21.4 mL, 0.150 mol) via a dropping funnel, dropwise, at a rate so that the
internal temperature was between 30 °C and 50 °C. The resulting light yellow
solution was stirred for 45 min while maintaining the temperature between 40 and
50 °C. To the reaction mixture was added copper(II) chloride (1.3 g, 0.010 mol);
after 5 more minutes was added N-benzoylcytosine (3) (10.1 g, 0.047 mol). The
resulting mixture was stirred at 50 °C for 15 min and then was allowed to warm
to 0 °C over 1 h. The reaction mixture was stirred at this temperature overnight.
After overnight stirring, the reaction was stirred at room temperature for 1 h, cooled
again in ice, and quenched with the addition of water (100 mL) followed by 5%
ammonia (100 mL). This was stirred for 5 min, diluted with DCM (50 mL), and fil-
tered through a Celite plug. The plug was washed with additional DCM (2 × 50 mL),
H
H
OEtO
O O
H
OEtO
O O
HOO
H
+
H
O
O O
O
H
H
EtO
Hock
cleavage
H
O
O O
EtO
O
+
O O
H
O
O
O
EtO
O
O
H
H
O
O
O
OEt
O
O
O
O
H
H
O
O
O
O
O
OEt
O
O
H
O
O
O
H
H
O
O
2, Qinghaosu
H
O
O
OEt
O
O
O
H
.O
O.
1
O
2
(singlet oxygen)
Schenck ene reaction
3
O
2
(triplet oxygen)
(free radical reaction)
1
A
B
C
D
E
H
2
O
CO
2
EtOH
O
+
H
2
O
– H
+
4 Mechanism Problems from Reactions Give Expected Products176
and the combined filtrates were poured into a separating funnel. The organic layer
was separated, washed with 2% phosphoric acid (2 × 60 mL) and again with 2.5%
ammonia (2 × 100 mL). The combined aqueous layers were re-extracted with DCM
(100 mL). The combined organic layers were dried with magnesium sulfate, fil-
tered, and evaporated to give a light yellow/brown thick oil 17.8 g (86% recovery).
This crude mixture consisted of cis-3 and trans-4 combined coupled product at 62%
purity (NMR) and with a cis-/trans-isomer ratio 2.86:1 (NMR).
Recrystallization of the crude 2-(R,S)-benzoyloxymethyl- 4-(R,S)-
(N-benzoylcytosin-1-yl)-1,3-oxathiolane (4, 4a, 4b, 4c) to give pure
2-(R)-benzoyloxymethyl-4-(R)-(N-benzoylcytosin-1-yl)-1,3-oxathiolane
(4). To the crude (R,S)-benzoyloxymethyl-4-(R,S)-(N-benzoylcytosin-1-yl)-
1,3-oxathiolane (4, 4a, 4b, 4c) (17.8 g) in a 500-ml round bottom flask was added
14.5 times (by volume) methanol (258 mL), and the mixture was refluxed until a
clear solution could be seen. This was then allowed to cool to room temperature
gradually and was left standing overnight. The resulting crystallized product was fil-
tered, followed by washing with methanol (2 × 100 mL) and drying under vacuum.
The resulting slightly colored, feathery, crystalline solid on analyzing with NMR
showed that it is 99.1% cis-(2R,4R)-isomer 4, with 0.9% of cis-(2S,4S)-isomer 4c,
isolated yield, 7.2 g (35% yield for the isomer).
1
HNMR (CDCl
3
): δ 8.5 (br s, 1H),
O
S
BzO
HN
N
O
NHBz
1
O
S
O
BzO
2
H
2
O
2
(aq. 35%)
HOAc
40 °C, 1 h
90%
3
1. TMSI (3 eq.), TEA (2.2 eq.)
DCM, –50 °C, 45 min
2. CuCl
2
(0.2 eq.), then 3
–50 to 0 °C, 1 h
O
S
BzO
N
N
O
NHBz
4, cis-R,R
2 M NH
3
MeOH
94%
O
S
HO
N
N
O
NH
2
5, ATC
O
S
BzO
N
N
O
NHBz
4a, trans-S,R
O
S
BzO
N
N
O
NHBz
4c, cis-S,S
O
S
BzO
N
N
O
NHBz
4b, trans-R,S
4.6 Formation of Monocyclic Aromatic Heterocycles 177
8.25 (d, 1H), 8.0 (d, 2H), 7.8 (d, 2H), 7.6 (m, 2H), 7.45 (m, 4H) 7.3 (poorly resolved d,
1H), 6.6 (d, 1H) 5.5(t, 1H), 4.8 (m, 2H), 4.5 (d, 1H), 4.05 (dd, 1H). Chiral HPLC for
cis-(2R,4R) isomer (4) R
t
12.14 min. Melting point 163–165 °C.
The Mechanism
The reaction proceeds through an initial activation of (2) undergoing a sila-Pummerer
rearrangement [159]. The TMSI is activated by CuCl
2
and then attacked by 2 to form
the active electrophile A. Addition of 3 to A provides the major isomer 4 and minor
isomers 4a, 4b, and 4c.
4.6.2 Pyrrole
Problem 60: Preparation of Pyrrole-2-Aldehyde from Pyrrole-2-t-butyl ester
Sunitinib (3) is an anticancer drug for the treatment of renal cell carcinoma. In a
synthesis of 3, pyrrole aldehyde (2) is an important intermediate. It was produced by
the following process from 1 [160, 161].
Please provide a mechanism for this reaction.
Experimental Procedure (from US2004/266843, A1)
3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester
(1, 80.1 g, 0.3 mol) and 400 mL of TFA were stirred for 5 minutes in a 2-L 3-neck
round bottom flask equipped with mechanical stirring and warmed to 40 °C in an
oil bath. The mixture was then cooled to 5 °C and triethyl orthoformate (67.0 g,
0.45 mol) was added all at once. The temperature increased to 15 °C. The mixture
O
S
BzO
N
N
O
NHBz
TMSOH
4 (major isomer)
O
S
O
BzO
I
Cl
Cu
Cl
Me
3
SiI
+
CuCl
2
O
BzO
O
O
BzO
H
2
CuICl
I
–
Et
3
N-HCl
O
BzO
TMSO
–
N
N
O
NHBz
3
H
A
Halo-exchange
Me
3
Si
CI
–
S
+
S
+
O
–
Me
3
Si
S
+
CI
–
NEt
3
N
H
OEt
O
O
O
1
1. TFA, 40 °C
2. CH(OEt)
3
–5 to 15 °C, 1 h
N
H
OEt
O
O
2
Steps
F
N
H
N
H
NH
O
N
O
3 (Sunitinib)
81%