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4 Mechanism Problems from Reactions Give Expected Products118
and the residue was added dropwise to an ice-cold solution of KOH (168 g, 3 mol) in
water (960 mL). The reaction mixture was stirred for 6 h at 0 °C, then extracted with
diethyl ether. The aqueous phase was acidified with 4.0 M HCI (pH 5) and extracted
with diethyl ether. The combined organic layers were washed with brine (200 mL),
dried, filtered and concentrated. The afforded yellow oil was crystallized (EtOAc/
diethyl ether) which gave the title compound as colorless crystals (70 g, 63%).
MS (ESI): 159 [M + H]
+
.
(3a,6a-Cis)-tetrahydro-1H-cyclopenta[c]furan-1,3(3aH)-dione (BB2-b).
A solution of the dicarboxylic acid BB2-a (90 g, 580 mmol) in acetic anhydride
(1080 mL) was heated at reflux. After 20 h, the acetic anhydride was removed by
distillation under reduced pressure. The oily residue was distilled which gave the
title compound as a solid (55 g, 89%). MS (ESI): 141 [M + H]
+
and 158 [M + NH
4
]
+
.
(1S,2R)-2-(Methoxycarbonyl)cyclopentanecarboxylic acid (BB35-a).
Methanol (2 g, 64 mmol) was added dropwise at 65 °C to a stirred suspension
of BB2-b (3 g, 21 mmol) and quinine (7.6 g, 24 mmol) in a 1:1 mixture of toluene
and tetrachloromethane. The mixture was stirred at this temperature for 60 h, then
concentrated in vacuo to dryness. The afforded residue was dissolved in EtOAc and
the solution was washed with 2 N HCl. The organic layer was dried over Na
2
SO
4
,
filtered, and concentrated which gave the title compound (3 g, 81%). MS (ESI):
173 [M + H]
+
.
The Mechanism
Step 1: Bromination of 1.
The bromination should initially occur at the tertiary carbon in 1 in a regioselec-
tive manner to give the tertiary bromide 4a, which is easily isomerized to second-
ary bromide 4b under the acidic condition (HBr).
It is worth noting that the product is the regiomer 4a at the NBS condition [75].
Step 2: Favorskii Rearrangement [76].
Step 3: Formation of Cyclic Anhydride, Only cis-diacid Cyclizes.
Step 4: Methanolysis of the Cyclic Anhydride.
O
CO
2
Et
1
O
H
Br
Br
O
HBr
4a
OEt
O
Br
OEt
O
H
O
4a
Br
OEt
O
O
4b
Br
O
4b
Br
OEt
O
H
H
CO
2
Et
4.3 Formation of Cyclic Alkane and Derivatives 119
Problem 27: Rearrangement of Furfuryl Alcohol to 4-Hydroxy-2-cyclopen-
tenone
Furfuryl alcohol (1) is a starting material for the large-scale synthesis of the car-
bocyclic nucleoside MDL 201449A (3) which has the potential for the treatment
of multiple inflammatory diseases [77]. The first step is a rearrangement of 1 to
4-hydroxy-2-cyclopentenone (2) under acidic conditions [77, 78].
Please suggest a mechanism for this reaction.
Experimental Procedure (from Tetrahedron, 1997, 53, 1983)
A solution of furfuryl alcohol (1, 125 g, 1.27 mol) in H
2
O (3.7 L) was treated with
KH
2
PO
4
(6.3 g, 46.3 mmol). The solution was adjusted to pH = 4.1 (pH meter)
with H
3
PO
4
, then heated to 99 °C for 40 h. The cooled solution was washed with
CH
2
Cl
2
(2 × 500 mL). The combined organic layers were extracted with H
2
O (2 ×
500 mL), and the H
2
O layers combined and evaporated (70 °C, 20 mmHg) to give a
red oil. The red oil was dissolved in CH
2
Cl
2
(1 L), dried (MgSO
4
), filtered, and the
filtrate evaporated in vacuo (40 °C, 20 mmHg) to give 2 as a dark red oil, 66.5 g, 53%.
t
R
(method A) = 4.55 min;
1
HNMR (CDCl
3
) 7.61 (dd, 1H, J = 5.6, 4.8 Hz), 6.20
(d, 1H, J = 5.6 Hz), 5.0 (m, 1H), 3.6 [s(broad), 1H], 2.75 (dd, 1H, J = 18.5, 3.2 Hz).
O
CO
2
Et
Br
4b
H
–
OH
Br
KOH
KBr
O
OH
O
OEt
OEt
O
O
H
KOH
hydrolysis
CO
2
Et
O
–
HO
–
CO
2
Et
–
O
CO
2
H
HO
2
C
CO
2
–
–
O
2
C
–
O
2
C
CO
2
Et
H
3
+
O
O
–
O
O
O
H
O
O
O
O
HOAc
H
O
O
O
O
H
O
HOAc
O
O
O
O
O
O
O
H
CO
2
Me
HO
2
C
(+/–)–3
O
OH
KH
2
PO
4
H
3
PO
4
, H
2
O
98 °C, 48 h
53%
O
OH
1
2
N
N
N
N
OH
NH
2
Steps
3 (MDL 201449A)
4 Mechanism Problems from Reactions Give Expected Products120
2.26 (dd, 1H, J = 18.5, 6.0 Hz);
13
CNMR (CDCl
3
) 207.4, 164.0, 134.7, 70.1, 44.1; IR
(neat) ν
max
3387, 2974, 1711 cm
1
; EIMS m/e (% relative intensity) 98 (M
+
, 100).
Anal calcd, for C
5
H
6
O
2
•0.16 H
2
O (116.79): C, 59.47; H, 6.30. Found: C, 59.56; H, 6.52.
The Mechanism
Acid catalyzes the full process of this rearrangement. Firstly, furfuryl alcohol
(1) is rearranged to 5-methylene-2,5-dihydrofuran-2-ol (A) catalyzed by acid.
Subsequently, (A) is aromatized to 2-hydroxy-5-methylfuran (B). Addition of H
2
O
to (B) gives the 2,5-dihydroxy-2,5-dihydrofuran (C). Elimination of water generates
the ring-opened product, (Z)-4-oxopent-2-enal (D), which is equilibrium with enol
form (D′). Finally, intramolecular aldol reaction leads to the product 2.
4.3.4 Cycloheptane
Problem 28: Preparation of Homobenzylic Ketones by 1,2-shift in 1,1′-
disubstituted Olefins
Chemists from Teva pharmaceuticals developed a new method for the prepara-
tion of homobenzylic ketones by catalytic hypervalent iodine-mediated oxidation
of 1,1′-disubstituted olefins [79]. A representative reaction is shown below. The
method was applied for the synthesis of TEV-37440, a dual inhibitor of FAK and
ALK [80]. Conventionally, this transformation was performed by employing stoi-
chiometric Tl(NO
3
)
3
[81]. However, the cost and the highly toxic nature of Tl(NO
3
)
3
limit its use in the pharmaceutical industry.
Please provide a mechanism for the reaction from 1 to 3
Experimental Procedure (from Org. Lett., 2013, 15, 1650, Supporting Information)
1-Methoxy-5,7,8,9-tetrahydrobenzo[7]annulen-6-one (3c′). The general
procedure was performed by using 500 mg (2.87 mmol) of 5-methoxy-1-methylene-
1,2,3,4-tetrahydronaphthalene (1) followed by 51 mg (~10 wt%) of Triton X-405,
160 mg (0.72 mmol) of catalyst (2-iodo-5-methylbenzenesulfonic acid), 4.0 mL
of MTBE, 4.0 mL DI Water and 2.3 mL (7.5 equiv, 21.52 mmol) of isopropanol.
To the vigorously stirred mixture was charged 1.32 g (0.75 equiv, 2.15 mmol) of
Oxone and the heterogeneous mixture stirred for 24 h. After workup, the 0.85 g of
crude was dissolved in 5.1 mL of isopropanol and charged with 1.4 mL of 7 M solu-
tion of aqueous sodium bisulfite followed by 0.6 mL of DI water. After stirring for
18 hours, the slurry was cooled to 10 °C, filtered and dried for 2.5 h to result in
742 mg of bisulfite adduct 3c′.
O
HO
2
O
OH
1
H
+
O
H
H
O
H
H
O
HO
H
A
O
HO
B
O
H
H
O
C
O
H
H
H
H
O
D
O
O
D'
O
H
O
+
H
+
H
+
H
2
O, H
+
H
2
O,
H
+
O
+
4.3 Formation of Cyclic Alkane and Derivatives 121
1-Methoxy-6-methyl-5,7,8,9-tetrahydrobenzo[7]annulen-6-ol•Sodium
bisulfite salt (3c′).
1
HNMR (DMSO-d
6
, 400 MHz) δ 1.31–1.40(m, 1H), 1.71–1.75
(m, 1H), 1.97–2.09(m, 2H), 2.14(t, 1H), 3.12(d, 1H), 3.22(d, 1H), 3.26–3.29(m, 1H),
3.72(s, 3H), 4.40(s, 1H), 6.68(d, 1H), 6.77(d, 1H), 6.98(t, 1H);
13
CNMR (DMSO-d
6
,
100 MHz) δ 21.55, 24.04, 36.53, 41.06, 55.64, 84.05, 109.07, 123.89, 125.60, 130.18,
139.34, 155.59.
3c′ Was hydrolyzed according to the typical procedure to give 403 mg of 3c as an
oil in 74% yields.
1
HNMR (CDCl
3
, 400 MHz) 1.93–1.96(m, 2H), 2.49–2.53(m, 2H),
2.98–3.02(m, 2H), 3.69(s, 2H), 3.81(s, 3H), 6.75(d, 1H), 6.81(d, 1H), 7.12(t, 1H);
13
CNMR (100 MHz) 23.26(1C), 25.10(1C), 43.14(1C), 50.0(1C), 55.75(1C),
109.88(1C), 121.98(1C), 127.27(1C), 128.48(1C), 135.43(1C), 156.89(1C), 209.16(1C);
LRMS (GC-MS+) Calcd for C
12
H
15
O
2
[M + H]
+
:191.1. Found: 191.1.
The Mechanism
The reaction mechanism has been proposed in the literature [79]. The reaction is
catalyzed by hypervalent iodine species 2a which is generated by Oxone oxidation
O
I
2 (12.5%)
Oxone (0.8 eq.)
Triton X-405 (10 wt%)
MTBE - i-PrOH - H
2
O
then aq Na
2
SO
3
, 3 N NaOH
brine/H
2
O, aq. NaHSO
3
O
OH
SO
3
Na
1
MTBE/
2 N HCl
O
O
3c’
3c (74%)
Steps
O
TEV-37440
N
N
N
H
N
N
N
H
N
H
O
Cl
SO
3
H
S
I
O
O
HO
2
Oxone
S
O
O
2a
I
O
HO
OMe
1
OMe
O
+
I
OH
OMe
I
SO
3
H
OH
O
H
Proton
transfer
OMe
I
O
H
H
H
OMe
O
3
2 + H
2
O
1,2-phenyl
migration
SO
3
H
H
2
O
SO
3
–
+
4 Mechanism Problems from Reactions Give Expected Products122
of 2 in situ. Subsequently, the alkene attacks the hypervalent iodine and the ben-
zylic carbocation is captured by water. Finally, an oxocarbenium assisted 1,2-phenyl
migration under acidic conditions regenerates the precatalyst 2 and releases the
product 3.
4.4 Formation of Aromatic Compounds
Problem 29: Formation of Hexasubstituted Benzene Ring by Cyclization
Mycophenolic acid 1 is a natural product discovered in 1893. The sodium salt of
1 (mycophenolate sodium) was approved in many countries as an oral immuno-
suppressive agent for the prevention of kidney rejection during transplantation.
A reported total synthesis of 1 involved the key step for building the benzene ring
core structure as shown below [82]. In this reaction, only 33% yield of the desired
product 4 was obtained. The side products, identified as the diastereomeric ketoal-
cohols 5a and 5b, were also obtained in 62% yield in around 1:1 ratio.
Please suggest mechanisms for the formation of 4, and 5a/5b.
Experimental Procedure (from Tetrahedron, 2003, 59, 1989)
Geranyl-6-formyl-4-methoxycarbonyl-5-pivaloyloxymethyl resorcinol (4)
(3.1 g, 10mmol) of (2) was added dropwise to a suspension of NaH (60%, 13.5 mmol,
0.54 g) in dry THF (31 mL) with magnetic stirring. To the resulting solution,
4-(pivaloyloxy)-2-butynal 3 (15 mmol, 2.55 g) was added and after 2 h, the mix-
ture was poured into dilute HCl (30 mL). The organic phase was separated and
the aqueous layer was extracted with ethyl acetate. The combined organic phase
was washed with brine, dried over anhyd. Na
2
SO
4
, and concentrated. The residue
was subjected to column chromatography, the resorcinol 4 (1.47 g, 33% yield) being
eluted with 5% ethyl acetate in hexane (100 g of silica gel), and the diasteromeric
ketols 5a,b in 62% yield. 4 Mp 62–63 °C, IR (KBr) 3347, 2976, 1739, 1676, 1135 cm
1
;
1
HNMR δ ppm 1.16 (s, 9H), 1.54 (s, 3H), 1.60 (s, 3H), 1.75 (s, 3H), 1.90–2.10 (m, 4H),
3.37 (d, 2H, J = 6.3 Hz), 3.92 (s, 3H), 5.01 (t, 1H, J = 6.3 Hz), 5.18 (t, 1H, J = 7.2 Hz),
5.57 (s, 2H), 10.11 (s, 1H), 11.66 (s, 1H), 12.84 (s, 1H);
13
CNMR δ ppm 16.12 (CH
3
),
17.56 (CH
3
), 21.51 (CH
2
), 25.53 (CH
2
), 26.64 (CH
2
), 27.03 (CH
3
), 38.69 (C), 39.72
(CH
2
), 52.86 (CH
3
), 58.54 (CH
2
), 107.31 (C), 113.58 (C), 117.67 (C), 120.57 (CH),
124.34 (CH), 131.12 (C), 136.24 (C), 141.32 (C), 165.10 (C), 165.18 (C), 170.65 (C),
O
2
OPiv
OHC
3
NaH, THF, 2 h
O
O
O
OH
OH
MeO
1
O
O
O
O
–
Na
+
OH
MeO
Mycophenolate sodium (MyforticTM)
R
OH
OPiv
CHO
HO
R
4, 33%
O
OPiv
HO
R
5a + 5b, 62%
+
CO
2
Me
CO
2
Me
CO
2
Me
MeO
2
C
CO
2
Me
4.4 Formation of Aromatic Compounds 123
177.61 (C), 193.94 (CH); MS (EI) m/z (relative intensity) 446 (M
+
, 3), 344 (55), 275
(76), 243 (100), 123 (73), 57 (53). Anal. calcd for C
25
H
34
O
7
: C, 67.26; H, 7.62. Found:
C, 67.28; H, 7.59.
5a More polar. IR (neat) 3508, 2970, 1736, 1687, 1143 cm
1
;
1
HNMR δ ppm 1.21
(s, 9H), 1.57 (s, 3H), 1.65 (s, 3H), 1.66 (s, 3H), 1.92–2.10 (m, 4H), 2.57 (dd, 1H, J
gem
=
19.3 Hz, J¼7.4 Hz), 2.72–2.85 (m, 3H), 3.6–3.8 (bs, overlapping with two s, 1H, OH),
3.77 (s, 3H), 3.83 (s, 3H), 4.18 (br s, 1H), 4.79 (AB
sys
, 2H, J = 16 Hz), 4.95–5.05 (two
overlapping br t, 2H);
13
C δ ppm 16.13 (CH
3
), 17.55 (CH
3
), 25.50 (CH
3
), 26.37 (CH
2
),
27.02 (CH
3
), 29.72 (CH
2
), 33.38 (CH
2
), 38.80 (CH
3
), 39.81 (CH
2
), 52.34 (CH
3
), 52.67
(CH
3
), 62.55 (C), 63.61 (CH
2
), 68.76 (CH
2
), 117.58 (CH
2
), 123.93 (CH
2
), 131.35 (C),
131.44 (C), 139.89 (C), 153.87 (C), 165.10 (C), 172.06 (C), 177.67 (C), 190.86 (C); MS
(CI) 479 (M
+
+1, 100), 447 (8), 377 (9), 209 (9). Anal. Calcd for C
26
H
38
O
8
: C, 65.27; H,
7.94. Found: C, 65.41; H, 7.85.
5b Less polar. IR 3500, 2971, 1736, 1144 cm
1
;
1
HNMR δ ppm 1.20 (s, 9H), 1.55–
1.70 (br s overlapping with two s, 1H, OH), 1.58 (s, 3H), 1.62 (s, 3H), 1.66 (s, 3H),
1.90–2.15 m (4H), 2.56 (dd, 1H, J = 4.7 Hz, J
gem
= 19.6 Hz), 2.56–2.80 (m, 2H),
2.92 (dd, 1H, J
gem
= 19.6 Hz, J = 4.1 Hz), 3.70 (s, 3H), 3.82 (s, 3H), 4.61 (t, 1H,
J = 4.4 Hz), 4.78 (AB
sys
, 2H, J = 16 Hz), 5.03 (br t, 1H, J = 6.8 Hz), 5.25 (t, 1H, J =
7.5 Hz);
13
CNMR δ ppm 16.03 (CH
3
), 17.71 (CH
3
), 25.67 (CH
3
), 26.42 (CH
2
), 27.12
(CH
3
), 28.46 (CH
2
), 33.33 (CH
2
), 38.90 (C), 39.92 (CH
2
), 52.54 (CH
3
), 52.68 (CH
3
),
62.13 (C), 63.76 (CH
2
), 69.33 (CH), 118.19 (CH), 123.93 (CH), 131.24 (C), 131.81 (C),
139.68 (C), 153.12 (C), 165.25 (C), 169.86 (C), 177.82 (C), 191.11 (C); MS (CI) m/z
(relative intensity) 479 (M
+
+1, 100), 447 (7), 360 (16), 103 (16). Anal. calcd for
C
26
H
38
O
8
: C, 65.27; H, 7.94. Found: C, 65.43; H, 7.82.
The Mechanism
The initial step involves a Michael addition, where the enolate of 2-geranyl dimethyl
1,3-acetonedicarboxylate (2) reacts with the alkynal (3). This generates a vinyl carb-
anion intermediate (A), which is quickly protonated by the more acidic methine
proton, leading to the formation of enolate (B). Enolate (B) serves as the precursor
for the desired resorcinol (4). Despite its apparent stability, the sterically congested
nature of this intermediate facilitates its isomerization to enolate (C), which acts as
the precursor for the ketoalcohols (5a and 5b). Alternatively, enolate (C) could also
be formed directly from the vinyl carbanion (A) through protonation by the more
acidic methine proton from the opposite side.
R CO
2
Me
O
MeO
2
C
2
H
NaH
R
O
–
OPiv
OHC
3
R
O
3
OPiv
CHO
–
H
H
A
R
O
–
OPiv
CHO
H
B
MeO
O
R
OPiv
CHO
H
O
O
Enolization/
aromatization
Cyclization
OH
OPiv
CHO
HO
R
4
MeO
2
C
CO
2
Me
MeO
2
C
CO
2
Me
CO
2
Me
CO
2
Me
CO
2
Me
H
–
4 Mechanism Problems from Reactions Give Expected Products124
Problem 30: Vicarious Nucleophilic Substitution of Hydrogen in Aromatic
Nitro Compounds
Golinski and Makosza reported a “vicarious nucleophilic substitution of hydrogen
in aromatic nitro compounds [83, 84].” An o- or p-hydrogen in nitro aromatic com-
pounds can be “substituted” by chloromethyl sulfones to form corresponding meth-
ylsulfone derivatives. For example, compound 3 was prepared in 67% from 1 and
2. The scope of the reaction was explored by the same group and summarized in a
review [85].
This reaction was applied to the synthesis of a series of glucan synthase (GS)
inhibitors (4), which are potential arsenal antifungal drugs [86].
Please provide a mechanism for the formation of 3 from 1 and 2.
Experimental Procedure (from J. Org. Chem., 1984, 49, 1488)
Reaction of Nitroarenes with ɑ-Halo Sulfonyl Compounds. General
Procedure. Procedure A. To a stirred solution of nitroarene (0.01 mol) and
1-chloroalkyl phenyl sulfone or 1-chloroalkyl 4-morpholinyl sulfone (0.01 mol) in
Me
2
SO (15 mL) was added powdered KOH (4 g) and the reaction carried out at room
temperature for 1 h. The mixture was poured into 2% HCl (100 mL) and extracted
MeO
CHO
B
H
OPiv
CO
2
Me
O
–
R
O
OPiv
CO
2
Me
OMe
O
–
R
O
MeO
2
C
CHO
A
H
H
OPiv
CO
2
Me
O
O
OPiv
CO
2
Me
OMe
O
–
R
O
C
O
R
MeO
2
C
HO
OPiv
CO
2
Me
O
R
−
5a/5b
NO
2
Cl
Cl
+
S
N
O O
O
1
2
Cl
3
1. KOH, DMSO
2, H
3
+
O
75%
S
N
O
O
O
NO
2
N
N
S
Cl
O O
Ar
+
NO
2
t-BuOK
DMSO
0 °C-rt
N
N
S
O O
Ar
H
2
PtO
2
4
N
N
S
O O
Ar
NO
2
NH
2
4.4 Formation of Aromatic Compounds 125
with chloroform, and the extract was dried over MgSO
4
. A small portion of the
extract was examined by
1
HNMR or by GLC to estimate the proportion of isomers
in the crude mixture. The combined extracts were evaporated and the products were
isolated and separated by column chromatography using chloroform as eluent. The
products were purified by recrystallization.
Procedure C. Reaction and workup were completed as in Procedure A. After
evaporation of the solvent, the crude product was purified by recrystallization. (This
procedure was used when only one isomer was formed.)
Reaction of 4-Chloronitrobenzene (1) with 2. Reaction by Procedure C
gave 5-chloro-2-nitrobenzyl 4-morpholinyl sulfone (3): yield 75%; mp 172–173 °C
(AcOH).
1
HNMR 3.1 (m, 4H), 3.3–3.5 (m, 4H), 4.71 (s, 2H), 7.5–8.1 (m, 3H).
The Mechanism
The mechanism was proposed by Makosza [83, 85]. In this reaction, the Cl in
compound 2 seems replaced by the nitroarenes at ortho and para to the nitro group.
But in fact, the first stage is that σ-adduct formed from 2 and 1. Then the σ-adduct
is converted into the product by base-induced elimination of hydrogen chloride.
Finally, acidic aqueous workup releases the product 3.
Problem 31: Synthesis of Tetralone from 1-Naphthol and 1,2-Dichlorobenzene
Sertraline hydrochloride (1) is an important pharmaceutical agent for the treatment
of depression as well as dependency and other anxiety-related disorders [87]. The
reported synthesis of 1 was starting from the tetralone 2, which was prepared from
1-naphthol (3) and 1,2-dichlorobenzene (4) catalyzed by AlCl
3
[88–90].
Please propose a mechanism for the preparation of 2.
Experimental Procedure (from J. Org. Chem., 2011, 76, 10011)
4-(3,4-Dichlorophenyl)-3,4-dihydronaphthalen-1(2H)-one (2). To a stirred solu-
tion of 1-naphthol (5.0 g, 34.68 mmol), 1,2-dichlorobenzene (32 mL) and anhydrous
AlCl
3
(11.56 g, 86.70 mmol) were added. The reaction mixture was stirred at 100 °C
for 1.5 h under N
2
. The reaction mixture was then cooled to room temperature and
poured into ice and 1 N HCl (15 mL). The aqueous layer was extracted with CH
2
Cl
2
Cl S
N
O O
O
2
H
HO
–
Cl S
N
O
O
KOH
Cl
O
1
Cl S
N
O O
O
Cl
H
H
KOH
S
N
O O
O
Cl
KCl
H
3
+
O
Cl
3
S
N
O
O
O
σ-adduct
–
O
N
+
O
–
HO
–
N
+
–
O
–
O
NO
2
H
+
N
+
–
O
–
O
4 Mechanism Problems from Reactions Give Expected Products126
(2 × 100 mL). The organic layer was washed with H
2
O, stirred with celite (6.7 g)
and activated carbon (5 g), then filtered. The solvent was concentrated in vacuo.
The residue was purified by flash column chromatography (n-hexane/EtOAc =
10/1) to afford 8.2 g (82%) of 2 as a white solid: R
f
= 0.13 (n-hexane/EtOAc = 10/1);
mp 99101 °C; IR (KBr) υ 3422, 2859, 1675, 1591, 1470, 1286, 1203, 1029 cm
1
;
1
HNMR (300 MHz, CDCl
3
) δ 2.202.32 (m, 1H), 2.422.52 (m, 1H), 2.582.77
(m, 2H), 4.28 (dd, J = 8.0 and 4.6 Hz, 1H), 6.95 (dd, J = 8.4, 2.0 Hz, 2H), 7.23 (d, J =
1.9 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 7.2 Hz, 1H), 7.48 (dt, J = 7.2, 1.5 Hz, 1H),
8.13 (dd, J = 8.0 and 1.9 Hz, 1H);
13
CNMR (125 MHz, CDCl
3
) δ 31.6, 36.5, 44.5,
127.3, 127.5, 127.9, 129.2, 130.5, 130.6, 130.9, 132.6, 132.7, 133.8, 144.0, 144.8, 197.4;
LC/MS (ESI) m/z 291.0 (M + H)
+
; HRMS (EI) calcd for C
16
H
12
Cl
2
O (M)
+
290.0265,
found 290.0264.
The Mechanism
This reaction can be regarded as a Friedel-Crafts alkylation. Due to the
electron-withdrawing property of the chlorine and activated by AlCl
3
, the
1,2-dichlorobenzene can be an electrophile and attacked by 1-naphthol to give
species A. After a series of isomerization-aromatization (H-shifts), the product 2 is
produced.
4.5 Formation of Nonaromatic Heterocycles
4.5.1 Lactone
Problem 32: Preparation of Thiolactone from Lactone
Biotin (6), also referred to as vitamin B
7
or vitamin H, is a member of the B-vitamin
family. It plays a crucial role in various metabolic processes in humans and other
OH
+
Cl
Cl
3
4
AlCl
3
100 °C, 1 h
then aq. HCl
80%
O
2
Cl
Cl
Steps
H
2
+
N
(+)-1
Sertraline HCl
Cl
Cl
Cl
–
O
Cl
Cl
3
4
H
Al
Cl
Cl
Cl
Cat.
AlCl
3
O
Cl
Cl
H
H
H
A
O
Cl
Cl
H
H
B
O
Cl
Cl H
C
O
2
Cl
Cl
H-shift H-shift
H-shift
4.5 Formation of Nonaromatic Heterocycles 127
organisms, particularly in the metabolism of fats, carbohydrates, and amino acids.
A review published in 1997 outlined the synthesis of biotin [91]. Given its
commercial significance, the production methods for biotin continue to be docu-
mented in patents and scientific articles. In one such synthetic process, thiolactone
2 served as a key intermediate. This compound was synthesized by heating lactone
1 with potassium thioacetate [92]. Alongside the target product 2, several side prod-
ucts, namely 3, 4, and 5, were also isolated and identified as impurities.
Please provide mechanism for the conversion of 1 to 2 and the formation of 3
and 4.
O
NBnN
O
O
AcSK, DMF
Hydroquinone (0.01 eq.)
150 °C, 1 h
S
NBnN
O
O
1
2 (85%)
S
NHHN
O
6, biotin
CO
2
H
Steps
Ph
Ph
NBnN
O
3 (0.5–2.7%)
Ph
S
NBnN
O
O
4 (0.4–2.0%)
Ph
+
+
S
NBnN
O
O
5
Ph
+
Ph
Experimental Procedure (from Org. Process Res. Dev., 2003, 7, 272)
(3aS,6aR)-1-[(R)-1-Phenylethyl]-3-benzyltetrahydro-1H-thieno
[3,4-d]imidazol-2,4-dione (2). A mixture of 1 (100 g, 0.29 mol), hydroquinone
(0.32 g, 0.0028 mol), and potassium thioacetate (44.08 g, 0.39 mol) in 130 mL of
N,N-dimethylacetamide was stirred in a 500-mL double-walled glass reactor. The
system was nitrogen-purged three times before being heated to 150 °C under
nitrogen for exactly 1 h. The suspension became a clear-brown solution at ca.
135 °C, and beige crystals were formed when the reaction reached ca. 150 °C. The
suspension was cooled to 100 °C followed by the addition of glacial acetic acid
(1.77 mL, 0.03 mol). The suspension was cooled to 55 °C over 30 min, and 432 mL of
water was added. The suspension was stirred at 55 °C for 1 h at room temperature.
Filtration followed by a water wash (240 mL) afforded crude 2 (99.9 g, 0.28 mol) as
a light-brown/beige solid material. The crude 2 was then dissolved in 2-propanol
(675 mL) at reflux. This solution was then cooled to 0–5 °C over a period of 3–4 h.
The product was isolated by filtration and dried in a vacuum oven at 50 °C until the
loss on drying was <0.5%. 2 was obtained as a beige solid (92.4 g, 0.26 mol) in 88%
yield and with an assay of 99.1% (HPLC).
3, 4, and 5: Side Product Isolation. Approximately 1 L of plant 2-propanol
recrystallization mother liquor was concentrated at the rotary evaporator to an oil,
and a portion of this was separated on a silica gel column using ethyl acetate-hexane