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5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products368
Since the formation of impurities 2 and 4 is attributed to the use of isopropanol
as the solvent, replacing it with the more sterically hindered t-BuOH is expected
to suppress side product formation. Indeed, when the reaction was carried out in
t-BuOH, the desired product 1b was obtained from 1c in 97% yield.
5.6.4 Naphthyridine
Problem 148: Unexpected Formation of a Dibenzo[c,f]-2,7-naphthyridine-
3,6-diamine
10,11-Dimethoxy-4-methyldibenzo[c,f]-2,7-naphthyridine-3,6-diamine (1) was
identified as a potent compound with favorable biological profile. This compound
was discovered accidently from a side product of the following reaction. The
chemists from Wyeth wanted to prepare 4-((3-amino-2-methylphenyl)amino)-
6,7-dimethoxyquinoline-3-carbonitrile (4) from 4-chloro-6,7-dimethoxyquinoline-
3-carbonitrile (2) and 2-methylbenzene-1,3-diamine (3), an unexpected product 1
was also obtained as a side product. A reliable high yielding (80%) procedure for
preparation of 1 was identified through the use of DoE [57].
Please suggest a mechanism for the formation of 1.
NH
N
O
n-Pr
O
B
O O
–
O
– DBACO
+
DBACO
NH
N
O
n-Pr
O
O OH
O
C
1b
N
N
O
n-Pr
O
2
N
N
O
n-Pr
O
N
N
O
n-Pr
O
O)
2
3
4
O
O O
O
i-PrOH
H
i-PrOH
H
2
O
H
1b, CO
2
H
2
O
HCO
3
–
CO
2
DBACOH
+
N
N
MeO
MeO
NMeO
MeO
CN
Cl
NH
NMeO
MeO CN
NH
2
+
+
Py.HCl
ethoxyethanol
30 °C
1 (65%)
4
2
3
NH
2
NH
2
NH
2
NH
2
5.6 Formation of Bicyclic Aromatic Heterocycles 369
Experimental Procedure (from Org. Process Res. Dev., 2007, 11, 450)
10,11-Dimethoxy-4-methyldibenzo[c,f]-2,7-naphthyridine-3,6-diamine (1)
Method A. A stirred mixture of 4-chloro-6,7-dimethoxyquinoline-3-
carbonitrile 2 (25 mg, 0.10 mmol), 2,6-diaminotoluene 3 (49 mg, 0.40 mmol), and
pyridine hydrochloride (58 mg, 0.50mmol) (catalyst) in 2 mL of 2-ethoxyethanol was
heated at 130 °C for 8 h. 10,11-Dimethoxy-4-methyldibenzo[c,f]-2,7-naphthyridine-
3,6-diamine 1 was formed in 65% yield (based on LC/MS analysis).
Method B. A stirred mixture of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile 2
(25 mg, 0.10 mmol), 2,6-diaminotoluene 3 (24 mg, 0.20 mmol), and pyridine hydro-
chloride (12 mg, 0.10 mmol) in 2 mL of 2-ethoxyethanol was heated in a sealed
tube at 210 °C in a microwave oven (Biotage, Initiator) for 1 h using a power limit of
300 W and a pressure inside the reaction vessel of less than 20 psi. 10,11-Dimethoxy-
4-methyldibenzo[c,f]-2,7-naphthyridine-3,6-diamine 1 was formed in 80% yield
(based on LC/MS analysis). The reaction mixture was concentrated under reduced
pressure, diluted with ethyl acetate, and washed with brine. The organic layer was
collected, dried over sodium sulfate, and concentrated. The crude product was puri-
fied by flash column chromatography using silica gel. Isolated yield: 72%. HPLC:
R
t
) 2.13 min; MS (ES
+
): m/z 335.1 [M + H]. HRMS: 335.15122 [M + H]; 335.15026
[calculated];
1
HNMR (DMSO-d
6
): δ 9.4 (1H, s), 8.4 (1H, d), 8.2 (1H, s), 7.5 (1H, s),
6.9 (1H, br), 6.8 (1H, d), 5.4 (2H, br), 4.0 (3H, s), 3.9 (1H, s), 2.4 (3H, s); IR (cm
−1
).
Cyano group’s absorption around 2200 cm
−1
is not observed.
4-[(3-Amino-2-methylphenyl)amino]-6,7-dimethoxyquinoline-3-carboni-
trile (4):
1
HNMR (DMSO-d
6
): δ 9.3 (1H, s), 8.3 (1H, d), 7.8 (1H, s), 7.3 (1H, s), 6.9
(1H, m), 6.6 (1H, d), 6.5 (1H, d), 5.0 (2H, br), 4.0 (3H, s), 3.9 (1H, s), 1.9 (3H, s),
HRMS: 335.14954 [M + H]; 335.15026 [calculated]; IR (cm
−1
). Cyano group’s
absorption around 2200 cm
−1
.
The Mechanism
This reaction can be regarded as a Friedel-Crafts acylation. Usually, the reaction of
4-chloropyridines with anilines yields diarylamines [58], as seen in the formation
of product 4 in this case. However, due to the presence of a second amino group on
the benzene ring, 2,6-diaminotoluene (3) exhibits high reactivity as a nucleophile
in Friedel-Crafts acylation. At the same time, the 4-chloro-3-cyanoquinoline 2 is
a good electrophile owing to the electron-withdrawing cyano group. The C4 posi-
tion is further activated by pyridinium chloride, allowing nucleophilic attack by
the C-3 position of compound 3 to form intermediate A. Subsequent cyclization
between the amino and the cyano groups, followed by aromatization, leads to the
final product 1.
You can also draw the mechanism as shown below—it’s basically the same as the
one above.
Another possibility is that the amino group in 3 first attacks the cyano group in 2,
followed by the adjacent carbon acting as a nucleophile and attacking the quinoline
moiety.
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products370
5.6.5 Pteridine
Problem 149: Formation of Two Pteridine Impurities During a Synthesis of
Dexrazoxane
Dexrazoxane (1) has been used to protect the heart against the cardiotoxic side
effects of chemotherapeutic drugs such as daunorubicin, doxorubicin, or other che-
motherapeutic agents. In a process-related impurity study of dexrazoxane synthesis
[59], two new impurities—present at levels ranging from 0.5% to 5%—were isolated
by preparative HPLC. Their structures were identified as compounds 3 and 4 by
IR,
1
H,
13
C, 2D NMR, and mass spectrometry. Their structures were finally con-
firmed by comparison with synthetic standards.
Please suggest mechanisms for the formation of 3 and 4.
NMeO
MeO
CN
Cl
2
Py.HCl
N
+
MeO
MeO CN
Cl
H
HN
NH
2
3
H
3
NMeO
MeO
CN
Cl
H
NH
H
Py
HCl
Py
Py.HCl
HCl
NMeO
MeO
N
A
N
N
NH
MeO
MeO
H
N
N
MeO
MeO
1
CI
–
NH
2
NH
2
NH
2
NH
2
NH
2
NH
2
N
+
MeO
MeO
CN
Cl
H
NH
2
3
NMeO
MeO
CN
Cl
H
NH
H
HCl
Py
Py.HCl
HCl
NMeO
MeO
N
A
1
H
N
H
3
CI
–
NH
2
NH
2
NH
2
NMeO
MeO
NH
2
N
3
2
Cl
N
MeO
MeO
NH
NH
Cl
NH
H
HCl
N
N
NH
NH
MeO
MeO
H
Cl H
H
1
NH
2
5.6 Formation of Bicyclic Aromatic Heterocycles 371
Experimental Procedure (from Org. Process Res. Dev., 2017, 21, 11)
5-(2-(3-Oxopiperazin-1-yl) propyl)-5,6-dihydropteridin-7(8H)-one (Impurity 3)
M.p: 252.09 °C.
1
HNMR (DMSO-d
6
, 400 MHz): δ
H
0.95 (3H, d, H4), 3.09–3.23
(2H, m, H2), 3.29–3.49 (5H, m, H14, H11, and H3), 3.94–4.04 (2H, m, H5), 8.14
(1H, s, H8), 8.02 (1H, s, H9).
13
CNMR (DMSO-d
6
, 100 MHz): δ
C
50.54 (C2), 54.33
(C3), 11.28 (C4), 52.31 (C5), 166.81 (C6), 147.15 (C7), 128.95 (C8), 135.96 (C9), 147.07
(C10), 51.93 (C11 and C14), 172.41 (C12 and C13); HRMS (ESI) calcd for C
13
H
17
O
3
N
6
:
305. 13338 ([M + H]
+
), found; 305.13566([M + H]
+
). IR (KBr, cm
−1
): 3248.13 (NH),
2970.38 & 2931.80 (CH), 1705.07 & 1689.64 (C═O), 1564.27 (NH bending), 1512.19
(C═N).
4-(2-(7-Oxo-7,8-dihydropteridin-5(6H)-yl)propyl)piperazine-2,6-dione
(Impurity 4) M.p: 242.98 °C.
1
HNMR (DMSO-d
6
, 400 MHz): δ
H
1.07 (3H, d, H4), 4.16
(2H, dd, H9, J = 6.4 Hz, 15.6 Hz), 3.73–3.82 (2H, m, H5), 3.31–3.42 (3H, m, H3, H5
and H8),2.76 (2H, dd, H2, J = 8.4 Hz, 12.8 Hz), 8.17 (1H, s, H13), 8.15 (1H, s, H14).
13
CNMR (DMSO-d
6
, 100 MHz,): δ
C
45.12 (C2), 47.84 (C3), 13.53 (C4), 55.57 (C5
and C8), 171.82 (C6 and C7), 56.64 (C9), 167.33 (C10), 147.75 (C11), 147.39 (C12),
136.88 (C13), 128.95 (C14). HRMS (ESI) calcd for C
13
H
17
O
3
N
6
:305. 13334 ([M + H]
+
),
found; 305.13566 ([M + H]
+
). IR (KBr, cm
−1
): 3227.51 (NH), 2993.72 and 2920.23
(CH), 1703.14 (C═O), 1571.77 (NH bending), 1523.76 (C═N).
The Mechanism
Tautomerization of product 1 at ring B gives A, which attacks the formamide car-
bonyl group to form B. Then the condensation of B with another molecule of form-
amide gives C. An intramolecular cyclocondensation produces the corresponding
N
N
2 (tetra acid)
HCONH
2
toluene
160 °C, 17 h
N
N
1 (dexrazoxane)
HN
NH
O
O
O
O
+
N
N
3, R
1
=
Me, R
2
=
H
4, R
1
=
H, R
2
=
Me
HN
NH
O
O
O
N N
HO
2
C
HO
2
C
CO
2
H
CO
2
H
R
2
R
1
N
N
1 (dexrazoxane)
HN
NH
O
O
O
O
N
N
HN
NH
O
O
O
O
H
O H
NH
2
N
N
HN
NH
O
O
O
O
HCONH
2
HO
O H
HCONH
2
N
N
HN
NH
O
O
O
O
HO
HN
OH
N
N
HN
NH
O
O
O
HO
HN
OH
NH
OH
3
N
N
HN
NH
O
O
O
N N
3
A
B
B
B
B
B
B
A
B
C
D
NH
2
NH
2
H
2
O
NH
2
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products372
bicyclic ring D and finally aromatization occurs by dehydration to lead the impurity 3 .
Following the same principle, tautomerization occurs at ring-A in 1 leads to the
formation of impurity 4 .
The mechanism for the formation of the desired product 1 from 2 is shown below.
5.7 Miscellaneous
5.7.1 Steroid
Problem 150: Formation of Impurity F of Clobetasol Propionate
Clobetasol propionate ( 1) is a corticosteroid used to treat skin conditions such
as eczema, contact dermatitis, seborrheic dermatitis, and psoriasis. Impurity F ( 2 )
is one of the impurities [ 60 ] during the production [ 61 , 62 ]. During a stability study
of clobetasol propionate ( 1), compound 2 was identified as a major degradant under
acidic conditions at a level up to 1.39% [ 62 ]. As shown below, forced degradation
experiments generated 2 in 2.7%. It has a relative retention time (RRT) on HPLC of
0.49 compared to clobetasol propionate.
Please propose a mechanism for the formation of impurity F ( 2) from clobetasol
propionate under acidic conditions.
Experimental Procedure (from https://doi.org/10.26434/chemrxiv.11809077.v1)
Preparation and Purification of RRT 0.49 Impurity from Forced Degradation .
To prepare a suitable amount of pure RRT 0.49 impurity for NMR structural elucida-
tion, a forced degradation of clobetasol propionate was designed to enrich and iso-
late RRT 0.49 impurity. Hence, a solution containing clobetasol propionate (5.0 g),
O
HO
H
F H
O
Cl
O
O
Clobetasol propionate (1)
O
HO
H
F H
CO
2
H
Impurity F (2)
2.7%
i-PrOH-H
2
O (4:1)
AcOH (0.13%)
80 °C, 10 days
N
N
2 (tetra acid)
N
N
1
HN
NH
O
O
O
O
HCONH
2
O
OH
H
O
R
R
N
N
HO
O
O
OH
H
O
H
R
N
NH
OH
O
OH
R
N
O
O
OH
N
NH
O
O
R
Same process
for the left part
H
HO
2
C
HO
2
C
CO
2
H
H
2
N
HCO
2
H
NH
2
H
2
O
5.7 Miscellaneous 373
isopropanol (200 mL), water (50 mL), and acetic acid (0.33 mL) was heated at 80 °C
for 10 days, during which period RRT 0.49 impurity grew to 2.7%. RRT 0.49 impu-
rity was then isolated from a portion of the forced degradation sample solution by
semipreparative HPLC, which was performed on a Shimadzu LC-8A system (Model
XXI-4563) with a Waters Xterra RP18, 150 mm × 19 mm, 5 μm semipreparative
HPLC column. The separation was carried out at room temperature, and the same
mobile phase system as used in LC-PDA/UV-MSn analyses was utilized as per the
gradient according to the following program: 0 min (40% B), 30 min (40% B), 35 min
(55% B), 35.1 min (80% B), and 41 min (80% B). The HPLC separation was run at a
flow rate of 9 mL/min with an injection volume of 1.8 mL and the detection wave-
length for fraction collection was set at 240 nm. Approximately 20 mg of purified
RRT 0.49 impurity was obtained with an HPLC purity of ~96%.
1
HNMR (DMSO-d
6
,
400 MHz): δ
H
7.29 (1H, d, J = 10.2 Hz), 6.21 (1H, d, J = 10.2 Hz), 6.00 (1H, s), 5.50
(1H, brs), 5.33 (1H, s), 4.14 (H, brs), 2.63 (1H, td, J = 13.2 and 5.7 Hz), 2.47 (1H,
m), 2.32 (1H, dd, J = 13.5 and 3.3 Hz), 2.05 (1H, m), 1.93 (1H, m), 1.86 (1H, d, J =
12.8 Hz), 1.86 (1H, m), 1.49 (3H, s), 1.42 (1H, d, J = 13.3 Hz), 1.34 (1H, m), 1.26
(1H, m), 1.23 (1H, d, J = 7.0 Hz), 1.18 (1H, m), 1.10 (3H, s).
13
CNMR (DMSO-d
6
,
100 MHz): δ
C
185.2, 177.5, 167.4, 152.6, 129.1, 124.2, 109.6, 101.6 (d, J = 175.5 Hz), 70.4
(d, J = 36.5 Hz), 66.8, 47.9 (d, J = 22.0 Hz), 45.3, 40.5, 33.2 (d, J = 19.8 Hz), 32.9, 30.1,
27.0, 22.5 (d, J = 5.4 Hz), 21.3, 19.7, 5.9. HRMS (ESI) calcd for C
22
H
28
FO
4
: 375.1972
([M + H]
+
), found: 375.1967 ([M + H]
+
).
The Mechanism
Typical Favorskii rearrangement is catalyzed by base [63]. This is a case where
impurity F (2) forms from clobetasol propionate (1) via an acid-catalyzed Favorskii
rearrangement. In this particular circumstance the propionate is the leaving group
rather than a typically halogen.
Problem 151: Formation of a 24-Methylene Steroidal Impurity
In a homologation study of cholanic acid derivatives to 25-hydroxy vitamin D and
congeners, demethoxycarbonylation of malonate 1 was carried out in DMSO with
O
HO
H
F H
O
Cl
O
O
Clobetasol propionate (1)
O
HO
H
F H
Impurity F (2)
Enolization
O
Cl
O
O
H
H
+
H
+
O
Cl
Cl
O
O H
H
HCl
H
OH
2
CO
2
H
EtCO
2
H
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products374
sodium chloride under reflux conditions. This reaction yielded the desired ester 2
(80% yield) along with trace amounts of 24-methylene derivative 3 [64].
Please suggest a mechanism for the formation of 3.
Experimental Procedure (from Org. Process Res. Dev., 1998, 2, 290)
Methyl 3 -Acetoxy-23a-homo-5-cholen-24-oate (2). A mixture of diester 1
(72 g, 143 mmol), sodium chloride (11 g, 188 mmol), and water (11 g, 611 mmol)
in DMSO (1.2 L) was heated at 170–180 °C for 2.5 h. The mixture was poured into
water (2 L) and left overnight. The precipitate was filtered off, rinsed with water, and
dissolved in ethyl acetate. The solvent was removed and homoester 2 was obtained
as yellow oil. Filtration over alumina (400 g) in toluene (2 L) gave homoester 2 (69 g)
as a creamy white solid. Crystallization from methanol/benzene (1:1) gave colorless
crystals (66 g, 80%), mp 110–112 °C;
[
R
]
D
25
) −45 (c 0.3) {ref 5, 110–112.5 °C, from
methylene chloride-methanol;
[
α
]
D
25
− 45 (c 1, CHCl
3
); IR 2940, 1730, 1375, 1261,
1049;
1
HNMR (200 MHz) δ 0.68 (3H, s, 18-CH
3
), 0.93 (3H, d, J) 6 Hz, 21-CH
3
), 1.02
(3H, s, 19-CH
3
), 2.03 (3H, s, COCH
3
), 3.7 (3H, s, −COOCH
3
), 4.6 (1H, m, 3α-H), 5.37
(1H, br s, 4-H); EIMS m/z (rel intensity) 384 (M
+
− 60, 100), 369 (17), 353 (5), 342
(3), 276 (8), 263 (22), 255 (17), 213 (10), 147 (19); HRMS calcd for C
26
H
40
O
2
(M −
AcOH) 384.3028, found 384.3029. Anal. Calcd for C
28
H
44
O
4
: C, 75.6; H, 10.0. Found:
C, 75.6; H, 10.2%.
Silica gel (300–400 mesh, 6 g) flash chromatography of an aliquot of mother
liquors (300 mg) using ethyl acetate (0.4–3.6%) in hexane gave unchanged homoes-
ter 2 (61 mg) and ene ester 3 (less polar by-product, 32 mg) as a white solid: UV λ
max
208 nm; IR 2940, 1725, 1629, 1367, 1244, 1041;
1
HNMR (200 MHz) δ 0.68 (3H, s,
18-CH
3
), 0.98 (3H, d, J) 6 Hz, 21-CH
3
), 1.02 (3H, s, 19-CH
3
), 2.03 (3H, s, COCH
3
), 3.7
(3H, s, −COOCH
3
) 4.6 (1H, m, 3α-H), 5.38 (1H, br s, 4-H), 5.5, 6.1 (1H and 1H, br s
and br s, 26-CH
2
); EIMS m/z (rel intensity) 396 (M
+
– 60, 100), 381 (15), 354 (3), 275
(12), 255 (14), 213 (10), 145 (13); HRMS calcd for C
27
H
40
O
2
(M - AcOH) 396.3028,
found 396.3013.
The Mechanism
The possible mechanism might involve the attack of dimethyl sulfoxide on the ester
group that would generate intermediate A. The acidic proton at the malonate would
be deprotonated to form ionic pair B, which would rearrange to ionic intermediate C.
Finally, decarboxylation and elimination of methanethiol lead to the side product 3.
DMSO
NaCl, H
2
O
170–180 °C
CO
2
Me
3
24
24a
+
2 (80%)
AcO
CO
2
Me
CO
2
Me
CO
2
Me
5.7 Miscellaneous 375
5.7.2 Terramycin
Problem 152: An Unusual Reaction of Terramycin with Methyl Iodide
Terramycin (1), a broad-spectrum antibiotic treatment for eye infections, was pat-
ented in 1949 and came into commercial use in 1950. During 1953–1954, Woodward
and Zimmerman performed a methylation of terramycin 1 with methyl iodide, and
a decomposition product 2 was identified. The results were published in 1981 [65].
Could you please propose a mechanism for the formation of 2?
Experimental Procedure (from Tetrahedron, 1981, 37, 311)
Formation of Lactone 2. Terramycin (1, 50 g) was dissolved in 3500 mL analyt-
ical grade acetone and to this solution was added 200 mL MeI. The mixture was
kept in a stoppered 4-L dark brown vessel. At the end of several days, crystals of
tetramethylammonium iodide began to separate. The mixture was allowed to stand
at room temp for a least 10 days. The best yield of 2 was obtained when the reaction
was run for 14 days. One run, which lasted 50 days, gave a lower yield of product.
At the end of the reaction period, the solution was filtered free of 7.1 g tetrameth-
ylammonium iodide. The filtrate was concentrated in cucuo
vacuum to leave a tan
glass. This was dissolved in 300 mL acetone and then treated with 1500 mL dry ether
to give a yellow ppt, which was removed by centrifugation. The ether ppt fraction
weighed 41.6 g. The ether filtrate was concentrated under vacuum to leave 14.08 g
of brownish-yellow solid, which was dissolved in 150 mL acetone and treated with
1600 mL benzene. The ppt that formed was filtered off and the filtrate was con-
centrated in vacuo. The residue was extracted with three 70-mL portions of hot
CO
2
Me
O O
S
H
O
DMSO
MeOH
O
O
S
H
O
A
DMSO
O
O
S
OH
B
–
O
O O
–
C
S
H
3
24
24a
1
Me
2
S
CO
2
Me
CO
2
Me
Me
2
+
S
CO
2
Me
CO
2
DMSO
MeSH
MeO
2
C
Me
2
+
S
OH
OH
O
NMe
2
OH
OH
HO
OH
O
O
MeI, acetonert,
several days
OOH
O
O
O
2 (12.7%)
1
A
B
C
D
1
2
3
4
56
NH
2
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products376
EtOAc and the remaining solid was taken up in 20 mL hot acetone. Crystalline 2
was separated from all four extracts on cooling. The mother liquors yielded more
2 on concentration. The lactone was recrystallized from EtOAc containing a little
acetone. Slow crystallization by evaporation of solvent from a saturated solution at
room temperature proved most effective. The yield of product averaged 1.5 g; the
highest yield was 2.9 g (12.7%). The ether-precipitated fraction isolated from short
runs could be redissolved in acetone and treated with Mel to yield more 2.
Lactone 2 decomposed at 148° turning green. The IR spectrum of 2 in dioxane
showed maxima at 5.60, 5.85 m, 6.04, 6.20, and 6.32 μ. The spectrum gave much
more detail in the 7–14 μ region but was very similar at shorter wavelengths except
that the CO absorption band at 5.84 μ was considerably more intense. The UV spec-
trum in 0.001 N HCl in EtOH exhibited maxima at 267.5 (logε = 3.86) and 339.0
(3.67) nm. The lactone was sublimed in high vacuum before analysis. (Found: C,
63.62; H, 4.30. Calc. for C
12
H
10
O
5
: C, 63.41: H, 4.09%.)
Lactone 2 readily formed a yellow 2,4-dinitrophenylhydrazone: m.p. 257-8° after
extraction with boiling EtOH and recrystallization from EtOAc (Found: N. 12.90.
Calc. for C
19
H
14
O
8
N
4
: N, 13.14%).
The Mechanism
Alkylation of the tertiary amine provides the quaternary ammonium salt A.
Elimination of trimethylamine with β-eliminations of the C-5 carbinol group yields
an aldehyde B, in which the enol is isomerized to the ketone C. This intermediate
can readily aromatize by β-diketone fission occasioned by intramolecular attack of
the tertiary OH group of ring C on the CO group of ring B to release lactone 2 and
2,3,6-trihydroxybenzamide 3.
Compound 3 was not isolated.
5.7.3 Cephem
Problem 153: Degradation of Cephem Intermediate
BMS-247243 (1) is an antimethicillin-resistant Staphylococcus aureus cephem. In a
process chemistry of BMS-247243, the deprotection of the diester 2 to the diacid 3 is
a key step. Treatment of 2 with aqueous TFA provided 3 in 70–80% yield along with
a degradation product 4 in 3–10% yield [66]. The degradation of diester 2 to diacid
O
OH
O
OH
OH OH
OH
O O
H
O
OH
O
OH
OH OH
OH
O O
O
OH
O
OH
OH O
OH
O O
MeI
OOH
O
O
O
HO
OH O
OH
+
2 (12.7%)
3 (not separated)
MeI
A
B
C
OH
OH
O
NMe
2
OH
OH
HO
OH
O
O
1
A
B
C
D
1
2
3
4
56
HI
NH
2
NH
2
Me
3
N
N
+
Me
3
I
–
Me
4
N
+
I
–
NH
2
NH
2
NH
2
5.7 Miscellaneous 377
4 was caused by the presence of water in the TFA. Diester 2 actually was converted
with 20% aqueous TFA to diacid 4 in over 70% yield.
Please provide a mechanism for the formation of 4.
Experimental Procedure (from Org. Process Res. Dev., 2000, 4, 488, Supplementary
material)
(E)-(3-(4-((2-((carboxymethyl)amino)-2-oxoethyl)thio)-2,5-dichlorophenyl)
acryloyl)glycine (4).
1
HNMR (DMSO-d
6
, 270 MHz) δ, 3.80 (d, J = 6.0 Hz, 2H),
3.89 (d, J = 6.0 Hz, 2H), 3.90 (d, J = 6.0 Hz, 2H), 6.80 (d, J = 15.8 Hz, 1H), 7.52
(s, 1H), 7.60 (d, J = 15.8 Hz, 1H), 7.79 (s, 1H), 8.40 (t, J = 6.0 Hz, 1H), 8.60 (t, J =
6.0 Hz, 1H).
13
CNMR (DMSO-d
6
, 68 MHz) δ, 35.8, 42.1, 42.2, 126.2, 128.3, 128.5,
130.4, 131.5, 133.7, 134.0, 140.4, 165.9, 168.6, 172.0, 172.2. MS (high resolution)
exact mass = 419.99.
The Mechanism
The degradation of diester 2 to diacid 4 was caused by the presence of water in the
TFA. Diester 2 was actually converted with 20% aqueous TFA to diacid 4 in over 70%
CO
2
–
O
N
H
Cl
Cl S
H
N
O
N
O
S
S
BMS-247243 (1)
O
N
H
Cl
Cl S
H
N
O
N
O
S
Cl
O
3 (70–80%)
aq. TFA
t-BuO
2
C
N
H
Cl
Cl S
H
N
O
N
O
S
Cl
O
2
N
H
Cl
Cl S
O
H
N
O
4 (3–10%)
CO
2
–
N
+
N
+
CO
2
H
CO
2
CHPh
2
CO
2
H
CO
2
H
CO
2
H
CO
2
H
CO
2
H
N
H
Cl
Cl S
N
O
H
N
O
S
Cl
O
R=
3
N
N
S
HCl
O
O
R
A
N
S
B
N
O
OH
R
OH
+
C
H
O
H
H
N
O
R
HO
OH
N
H
Cl
Cl S
O
H
N
O
R
4
CO
2
H
+
H
CO
2
H
OH
2
H
3
+
O
CO
2
H
CO
2
H
H
2
O