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 Products88
Experimental Procedure (from Tetrahedron Lett., 1994, 35, 5081)
In a typical experiment, an alcohol (1 mmol) and HA (the nucleophile, 1.5 mmol)
were successively dissolved in dry benzene (5 mL) with stirring under an argon
atmosphere, and CMBP (1.5 mmol) was added all at once, using a syringe. The reac-
tion mixture was heated at 100 °C for 24 h with stirring in a sealed tube. The product
was purified by silica gel column chromatography after evaporation of the solvent
in vacuum.
(from Tetrahedron Lett., 2018, 59, 1708)
N
NH
O
B
O
HO
O
N
N
O
O
+
CMBP (2 eq.)
dioxane, microwave
150 °C, 30 min
N
N
O
O
B
O
O
Br
Pd(dppf)Cl
2
K
2
CO
3
, dioxane-H
2
O
120 °C, 20 min
69%, 2 steps
Typical experimental procedure: (1) (Cyanomethylene)tributylphosphorane
(262 µL, 1.00 mmol) was added to a solution of (tetrahydrofuran-3-yl)methanol
(51 mg, 0.50 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(97 mg, 0.5 mmol) in degassed 1,4-dioxane (2 mL) sealed in a microwave tube at rt
under nitrogen. The solution was heated to 150 °C for 30 min in the microwave
reactor and cooled to rt. 2) 1-Bromo-4-methoxybenzene (94 mg, 0.50 mmol),
potassium carbonate (207 mg, 1.50 mmol), and [1,1-Bis(diphenylphosphino)
ferrocene]dichloropalladium(II) complex with CH
2
Cl
2
(40.8 mg, 0.05 mmol) were
added to the solution. The tube was sealed, evacuated, and backfilled with nitrogen.
Degassed water (1 mL) was added under nitrogen. The resulting mixture was stirred
at 120 °C for 20 min. The reaction mixture was diluted with EtOAc (25mL) and water
(15 mL), the layers were separated, and the aqueous layer was extracted with EtOAc
(15 mL). The combined organic layers were washed with saturated brine (15 mL).
The organic layer was dried with MgSO
4
, filtered, and evaporated to afford the crude
product. The crude product was purified by preparative HPLC (Waters XSelect CSH
C18 ODB column, 5 m silica, 30 mm diameter, 100 mm length), using decreasingly
polar mixtures of water (containing 1% by volume NH
4
OH (28–30% in H
2
O)) and
MeCN as eluents to afford 4-(4-methoxyphenyl)-1-((tetrahydrofuran-3-yl)methyl)-
1H-pyrazole (89 mg, 69%) as a beige solid.
The Mechanism
The CH in CMBP is a good nucleophile and a strong base. It gains a proton from
even relatively weaker nucleophilic acid (H─Nu) to form the ions pair A. Then the
alcohol oxygen attacks the phosphine and releases acetonitrile. The deprotonated
4.1 Formation of Noncyclic Compounds 89
nucleophile (Nu
) attacks the alcoholic carbon to provide the product and tribu-
tylphosphine oxide.
Problem 11: Preparation of Arylacetonitriles from Arylbromides
In 2011, Velcicky et al. reported a preparation of arylacetonitriles (3) from aryl-
bromides (1) through Suzuki coupling and base-induced fragmentation as shown
below [30]. The arylacetonitrile unit is found as a structural motif in several impor-
tant drugs, including verapamil, isoaminile, anastrozole, and cilomilast [31].
Could you please provide a mechanism for the reaction without checking the
reference?
Experimental Procedure (from J. Am.Chem. Soc., 2011, 133, 6948, Supporting
Information)
Representative Procedure for the Cyanomethylation of Aryl Halides:
(2-Naphthalen-2-yl)acetonitrile (3) according to Table 1, entry 25). A silicon/
PTFE screw-capped vial containing boronate 1 (40.0 mg, 0.205 mmol, 1.2 equiv),
2-bromonaphthalene 2 (35.0 mg, 0.171 mmol, 1eq) in dimethyl sulfoxide (DMSO)
(1.21 mL, 0.017 mmol, 0.1 M) was charged with potassium fluoride (30.0 mg,
0.513 mmol, 3 equiv) and pure water (0.51 mL, 0.513 mmol, 3 equiv). After 5 min
degassing in an ultrasonic bath under argon atmosphere, PdCl
2
dppf (14.0 mg,
0.017 mmol, 10 mol%) was added. The vial was sealed and flushed with argon
once again. After stirring in an aluminum block at 130 °C for 16 h, the crude reac-
tion mixture was cooled to room temperature and filtered over Celite. NaCl (satu-
rated solution, 25 mL) was added to the dark solution. After extraction with EtOAc
(5 × 25 mL), the organic phase was dried (Na
2
SO
4
) and concentrated under reduced
pressure. The residue was purified by flash chromatography on silica gel (EtOAc/
CycHex = 1:9) to provide compound 3 (24.4 mg, 88%). The characteristic data of 3
were identical with those described below.
Bu
3
P
N
1, CMBP
N
–
H Nu
N
H
H
H
H
O
R
O
R
Nu-
Nu
R
A
Bu
3
+
P
Bu
3
+
P
Nu
–
Bu
3
PO
CH
3
CN
Bu
3
+
P
H
O
O
Br
+
N
O
BPin
PdCl
2
dppf (10 mol%)
KF (3 eq., 1 M in water)
DMSO (0.1 M), 130 °C, 16 h
84%
O
O
CN
1 2
3
BH
3
-THF
78%
O
O
4, Dopamine
Steps
O
O
CN
N
O
O
5, Verapamil
NH
2
4 Mechanism Problems from Reactions Give Expected Products90
Beige solid, R
f
= 0.49 (EtOAc/CycHex = 1:2);
1
HNMR: δ
H
(300 MHz, CDCl
3
) =
3.92 (s, 2H), 7.38 (dd, J = 8.4 Hz, J = 1.5 Hz, 1H), 7.49 – 7.56 (m, 2H), 7.82 – 7.87 (m);
13
CNMR: δ
C
(75 MHz, CDCl
3
) = 23.9, 118.0, 125.5, 126.5, 126.8, 126.9, 127.2, 127.7,
127.8, 129.1, 132.7, 133.4; IR-ATR: v
max
(film) = 2250 (m, -CN), 1597 (m), 1507 (m),
1408 (s), 1365 (m), 960 (m), 927 (m), 861 (s), 825 (s), 755 (s); MS (EI, 70 eV): m/z (%) =
167 (100) [M
+
], 139 (49), 126 (8), 115 (17), 99 (3), 83 (10), 74 (14), 63 (16), 51 (9), 39 (8);
HRMS (EI, 70 eV): determined mass: 167.073 u, exact mass: 167.0735 u.
The Mechanism
The reaction begins from a Suzuki coupling between 1 and 2 to give A. Then the
isoxazole ring is opened by F
to release the aldehyde B. Retro-aldol reaction of B
provides the product 3.
Problem 12: Transformation of Aromatic Bromides into Aromatic Nitriles
Aromatic nitrile subunit exists in many drugs, such as citalopram hydrobro-
mide, periciazine, fadrozole, letrozole, bicalutamide and etravirine [32]. In 2011,
Togo’s group reported a one-pot preparation of aromatic nitriles (2) from aromatic
bromides (1) by the following reaction [33].
Could you please provide a mechanism for the reaction without checking the
reference?
Experimental Procedure (from Tetrahedron Lett., 2011, 52, 2404)
Typical Experimental Procedure for the Transformation of Aromatic
Bromides into Aromatic Nitriles: To a flask containing Mg turnings (0.28 g,
14 mmol) was added p-bromotoluene (1.38 g, 8.0 mmol) in THF (8 mL) at room
temperature. After stirring for 2 h, DMF (1.3 mL, 12 mmol) was added to the reac-
tion mixture. The obtained mixture was stirred for 2 h at room temperature. Then,
aq NH
3
(7 mL, 28–30%) and I
2
(4.06 g, 1.6 mmol) were added to the reaction mix-
ture. After stirring overnight, the reaction mixture was poured into aq sat. Na
2
SO
3
solution and extracted with CHCl
3
(3 × 30 mL). The organic layer was dried over
O
O Br
+
N
O
PinB
Suzuki
O
O
N
O
H
HO H
O
O
CN
OH
H
2
O, F
–
H
2
O
O
O
CN
Retro-aldol
1
2
3
O
O
CN
–
A
B
F
–
HO
–
HO
–
HO
–
HCO
2
H
Br
1. Mg, THF, rt, 2 h
2. DMF, rt, 2 h
3. I
2
, NH
3
, rt, 16 h
67%
1
CN
2
4.1 Formation of Noncyclic Compounds 91
Na
2
SO
4
and filtered. After the solvent was removed, the residue was purified by
short column chromatography on silica gel (eluent: hexane /ethyl acetate = 9:1, v/v)
to provide pure p-tolunitrile (0.77 g) in 67% yield. Most aromatic nitriles mentioned
in this work are commercially available and were identified by comparison with the
authentic samples.
4-Methylbenzonitrile: Mp 26–28 °C (commercial, Mp 26–28 °C); IR: 2227 cm
1
;
1
HNMR (CDCl
3
: 500 MHz) δ = 2.41 (s, 3H), 7.26 (d, J = 8.1 Hz, 2H), 7.52 (d, J =
8.1 Hz, 2H);
13
CNMR (125 MHz, CDCl
3
) δ = 21.7, 109.2, 119.1, 129.7, 131.9, 143.6.
The Mechanism
The first stage is the formylation of the Grignard reagent with DMF to give the
aldehyde A. Then addition of ammonia to the aldehyde, after elimination of H
2
O,
provides imine B. Finally, the imine B is oxidized by I
2
to yield the nitrile product 2.
Br
Mg
THF
MgBr
N
O
NMe
2
OMgBr
H
2
O
HOMgBr
O
H
HNMe
2
O
NH
O
H
H
N
H
H
I I
HI
N
H
I
HI
N
1
2
A
B
C
NMe
2
H
2
O
NH
3
Problem 13: Preparation of Nitriles from Carboxylic Acid by Smiles
Rearrangement
In the pursuit of developing novel ionophores capable of effectively and selectively
complexing and separating metal cations, Huber and Bartsch synthesized a series of
lariat ethers 2, where X represents an alkyl, perfluoroalkyl, or aryl group [34]. The
synthesis began with the conversion of carboxylic acid 1 into its corresponding acyl
chloride using oxalyl chloride. This acyl chloride was then reacted with a sulfon-
amide, which had been pre-treated with potassium hydride (KH) in THF, to yield
the desired N-sulfonyl carboxamide [35].
Interestingly, when 2,4-dinitrobenzenesulfonamide (DNBSA) was used as the sul-
fonamide, the expected lariat ether 3 was not obtained. However, when trimethyl-
amine was employed as the base instead, lariat ether 3 was produced, albeit in low
yield (<25%), while the corresponding nitrile 4 was isolated in 52% yield. This unex-
pected outcome led to the development of a new method for synthesizing nitriles
directly from carboxylic acids using DNBSA.
4-Methoxybenzonitrile (5) was prepared in 76% yield by using this method, which
is an important starting material for synthesis of a series of ROCK1 inhibitors, such
as 6 [35].
4 Mechanism Problems from Reactions Give Expected Products92
Please provide a mechanism for the preparation of nitriles from carboxylic acids.
Experimental Procedure (from Tetrahedron, 1998, 54, 9281)
General Procedure for Conversion of Carboxylic Acids into the
Corresponding Nitriles. Oxalyl chloride (0.6 mL, 6.20 mmol) was added to
a mixture of carboxylic acid (1.0 mmol) in benzene (25 mL). The mixture was
stirred at room temperature under nitrogen for 6 h and evaporated in vacuo. The
acid chloride was dissolved in THF (15 mL) and a solution of DNBSA (0.30 g,
1.20 mmol) and TEA (1.4 mL, 16 mmol) was added in dry THF (10 mL). The
resulting orange mixture was refluxed under nitrogen for 24 h. EtOAc (50 mL)
was added and the resulting solution was washed with 1 N HCl (2 × 25 mL) and
aq. 10% K
2
CO
3
(2 × 25 mL). The dark organic solution was dried over MgSO
4
and evaporated in vacuo to give a red residue which was purified by column
chromatography.
The Mechanism
This is a special Smiles rearrangement. Acylation of sulfonamide DNBSA with the
acid chloride provides the sulfonylbenzamide A in which the hydrogen on the NH is
deprotonated to form anion B. Due to the strong electron-withdrawing property of
the dinitro group, anion B is readily cyclized to the spirobicyclic intermediate C. The
five-membered ring in C is opened at basic conditions to produce the sulfenate D.
Final ɑ-elimination of the sulfenate D affords products 4-methoxybenzonitrile (5),
SO
2
, and 2,4-dinitrophenol (next page).
Problem 14: Synthesis of Disubstituted Malononitriles
Arylmalononitriles serve as crucial intermediates in the synthesis of JAK2 inhibi-
tors [36]. Additionally, disubstituted malononitriles have been utilized as antipara-
sitic agents in mammals [37]. Mills and Rousseaux developed an efficient one-pot
synthesis method for both arylmalononitriles and disubstituted malononitriles [38].
In this process, primary nitriles are first treated with a Grignard reagent, followed
O
O
O
O
O
R O CO
2
H
1
1. (COCl)
2
, benzene
rt, 6 h
2. H
2
NSO
2
X, KH, THF
rt, 3–12 h
O
O
O
O
O
R O
2, X
=
CF
3
3, X
=
2,4-(NO
2
)
2
C
6
H
3
N
H
O
S
X
O O
O
O
O
O
O
R O CN
4
2. or DNBSA, TEA
THF, reflux
MeO
O
Cl
+
S
O
O
DNBSA
THF, TEA
reflux, 24 h
76%
MeO
CN
5
Steps
MeO
6
N
H
N
H
N
N
H
N
F
Cl
O
H
2
N
NO
2
NO
2
4.1 Formation of Noncyclic Compounds 93
by the addition of dimethylmalononitrile (DMMN). After an aqueous workup,
monosubstituted malononitriles are obtained in high yields. If an electrophile is
introduced before the aqueous workup, the reaction yields disubstituted malononi-
triles as the final product.
Please provide mechanism for those transformations.
Experimental Procedure (from Tetrahedron, 2019, 75, 4298)
General Procedure A: Synthesis of malononitriles from primary nitriles using
MeMgBr Step 1: To an 8-mL culture tube with stir bar was added lithium chlo-
ride (1.1 equiv) and the flask was flame-dried under vacuum and cooled under
an atmosphere of N
2
. THF (1.0 M) was added, followed by the appropriate nitrile
(1.0 equiv). While stirring, methylmagnesium bromide (1.1 equiv of a solution in
Et
2
O) was added dropwise at room temperature, and the solution was stirred at
room temperature for 30 min under an atmosphere of N
2
. A 1.1 M stock solution
of DMMN or dibenzylmalononitrile in THF was prepared and added at room tem-
perature (1.1 equiv of a 1.1 M solution in THF, reaction volume ¼ 0.50 M with
respect to nitrile starting material). The reaction was stirred at 80 °C for 6 h under
an atmosphere of N
2
. Step 2: The reaction was cooled to room temperature and
DMF was added to bring the reaction solvent to a 1:1 THF/DMF ratio (0.25M of a
1:1 THF/DMF mixture with respect to nitrile starting material). The desired elec-
trophile (1.2 equiv) was added in a single portion. If the electrophile was a solid,
MeO
Cl
O
S
H
2
N
O
O
HCl
S
H
N
O
O
Ar
Ar
O
S
O
O
Ar
O
N
S
N
O
O
Ar
O
OAr
N
S
O
ArCN +
+
O
O
5
A
B
C
D
DNBSA
NO
2
NO
2
Et
3
N
Et
3
N.HCI
NO
2
NO
2
Et
3
N
Et
3
N
+
H
N
+
O
–
N
–
NO
2
NO
2
NO
2
O
–
SO
2
NO
2
NO
2
O
–
NO
2
O
–
Ph
CN
MeMgBr (1.1 eq.)
LiCl (1.1 eq.)
THF, rt, 30 min
then DMMN (1.1 eq.)
80 °C, 6 h
Ph
CN
CN
NC
CN
DMMN
2 (99%)
1
Ph
CN
Ph
NC CN
3 (99%)
Ph
NC
MgBr
CN
PhCH
2
Br (1.2 eq.)
THF/DMF (1:1)
Ph
1
MeMgBr (1.1 eq.)
LiCl (1.1 eq.)
THF, rt, 30 min
then DMMN (1.1 eq.)
80 °C, 6 h
80 °C, 16 h
4 Mechanism Problems from Reactions Give Expected Products94
it was added with the DMF as a 0.60M stock solution. The reaction was stirred at
80 °C for 16 h, or until complete conversion was achieved as judged by TLC. The
reaction was cooled to room temperature, opened to air, quenched with 1M aq.
HCl, and extracted with EtOAc ( ×3). The organic fractions were combined, dried
over MgSO
4
, and concentrated. The crude residue was purified by flash column
chromatography to yield the desired malononitrile.
2-Benzyl-2-phenylmalononitrile (2d). According to General Procedure A ,
2d was prepared using the following amounts of reagent: Step 1: lithium chloride
(19 mg, 0.44 mmol, 1.1 equiv), THF (0.40 mL), benzyl cyanide (46 mL, 0.40 mmol,
1.0 equiv), methylmagnesium bromide (0.21 mL of a 2.1 M solution in Et
2
O,
0.44 mmol, 1.1 equiv), and DMMN (0.40 mL of a 1.1 M solution in THF, 0.44 mmol,
1.1 equiv). Step 2: DMF (0.80 mL; total reaction solvent ¼ 1.6 mL of a 1:1 DMF/
THF mixture, 0.25 M) and benzyl bromide (57 mL, 0.48 mmol, 1.2 equiv). The crude
residue was purified by flash column chromatography (gradient of 0–15% EtOAc/
hexanes) to yield 2d as a white solid (93 mg, 0.40 mmol, 99%). Analytical data:
1
HNMR (400 MHz, CDCl
3
, 298K): δ
H
7.52–7.43 (m, 5H), 7.39–7.26 (m, 3H), 7.17–7.10
(m, 2H), 3.46 (s, 2H) ppm;
13
CNMR (100 MHz, CDCl
3
, 298 K): δ
C
131.7, 131.6, 130.6,
130.1, 129.7, 129.0, 128.8, 126.3, 114.8, 48.7, 44.2 ppm; R
f
(9:1 hexanes/EtOAc): 0.41.
The Mechanism
Due to the acidity of the benzylic proton in 2-phenzyl acetonitrile 1, it is deprot-
onated by methyl magnesium bromide and then the carbanion adds to the nitrile
group in DMMN to form intermediate A. After eliminative transnitrilation, A
would be cleaved to 2-phenylmalonitrile ( 2) and Grignard species B. As 2 is even
more acidic than 1, anion exchange would quickly take place between 2 and B, to
give isobutyronitrile ( C) and tertiary Grignard species D. Protonation of D at acidic
aqueous condition will provide the product 2. Adding an electrophile such as benzyl
bromide before the aqueous workup leads to the coupling product 3 .
Ph
CN
H
MeMgBr
Ph
CN
–
Mg
+
Br
N
CN
Ph
CN
N
CN
MgBr
Ph
CN
CN
+
BrMg
CN
Anion
exchange
Ph
CN
CN
+
H
CN
MgBr
PhCH
2
Br
Ph
CN
CN
Ph
NC CN
transnitrilation
Ph
3
2
1
H
MgBr
2
Mg(OH)Br
DMMN
A
2
D
B
C
CH
4
H
2
O
4.1 Formation of Noncyclic Compounds 95
Problem 15: Preparation of 2-Arylacetonitriles from Aromatic Ketones
2-(3,4-Dimethoxyphenyl)-3-methylbutanenitrile (2) is a key intermediate for syn-
thesizing verapamil, a calcium channel blocker medication. The preparation of 2
from aromatic ketone 1 was described in a patent by a telescoped process as shown
below [39].
Could you please propose a stepwise mechanism for the reactions?
The Experimental Procedure (from US 5,097,058, 1992)
EXAMPLE 6. ɑ-(1-Methylethyl)-3,4-dimethoxybenzeneacetonitrile. 26 g
(0.125 moles) of isobutyryl-3,4-dimethoxybenzene are put into 100 mL of toluene
and then 35 g (0.31 moles) of potassium tert-butoxide are added. After cooling to
10 °C, the reaction mixture is added with 33.3 mL (0.31 moles) of ethyl chlo-
roacetate in about 2 h. Subsequently, the temperature is raised to the value of
the room temperature and after another 2 h, the reaction mixture is added with
a solution containing 22 g (0.35 moles) of 90% potassium hydroxide (KOH) in
100 mL of methanol and is kept under stirring for 6 h. The reaction mixture is
then added with 10 mL of acetic acid, and subsequently with 8.68 g (0.125 moles)
of hydroxylamine hydrochloride dissolved in 20 mL of water. The reaction mix-
ture is heated to 60 °C for 1 h, then it is acidified to pH 4 by means of concen-
trated aqueous hydrochloric acid, kept another hour at 60 °C and finally added
with water until complete dissolution of the undissolved salts. The layers are sep-
arated, the aqueous phase is extracted three times with 50 mL of toluene and then
is discarded. The organic phase, together with the toluene extracts, is washed with
water, dried over anhydrous sodium sulfate and evaporated to dryness. The oily
residue is dissolved in 80 mL of glacial acetic acid and added, under nitrogen
atmosphere, with 19.5 mL (0.20 moles) of acetic anhydride. After about 30 min,
the reaction mixture is added with 10 g (0.122 moles) of anhydrous sodium acetate
and is heated to 75 °C for 6 hours. The acetic acid is evaporated under vacuum
and the residue is treated with a mixture of 100 mL of water and 100 mL of tol-
uene. The mixture is brought to pH 9 by means of a 30% (w/w) aqueous solution
of sodium hydroxide, then the layers are separated and the aqueous phase is twice
extracted with 75 mL of toluene and then is discarded. The organic phase is added
with the toluene extracts and then is twice washed with 100 mL of water, dried
over anhydrous sodium sulfate, filtered and evaporated to dryness under vacuum.
The obtained oily residue is distilled under vacuum obtaining 22.3 g of pure nitrile
with a yield of 81.4% of the theoretical.
O
O
O
1. t-BuOK, toluene, −10 °C
ClCH
2
CO
2
Et, rt, 2 h
2. KOH, MeOH, rt, 6 h
3. HOAc
4. NH
2
OH.HCl, 60 °C, 1 h
5. HOAc, Ac
2
O, NaOAc
75 °C, 6 h
O
O
CN
2, 81%
1
Steps
O
O
NC
N
O
O
Verapamil
4 Mechanism Problems from Reactions Give Expected Products96
The Mechanism
Step 1. The first step should be a Darzens reaction to form an epoxide A.
Step 2. The second step should be the hydrolysis of the ester, then decarboxylation
followed by rearrangement to give the aldehyde B.
Step 3. Reaction of hydroxylamine with aldehyde B provides oxime C.
Step 4. The final step is a dehydration of the oxime, assisted by Ac
2
O, to produce
nitrile 2.
By using the Van Leusen reaction, the arylacetonitrile 4 could be prepared in a
single step [40].
Cl
OEt
O
H
H
t-BuO
–
Cl
OEt
Ar O
R
Cl
OEt
O
Ar
R
t-BuOH
KCl
OEt
O
Ar
O
R
1
A
K
+
K
+
O
−
K
+
O
−
OEt
O
Ar
O
KOH
OK
O
Ar
O
EtOH
HOAc
KOAc
Ar
O
O
H
O
CO
2
Ar
OH
Ar
O
R
R
R
R
R
B
Ar
O
R
Ar
N
R
OH
NH
2
OH
Ar
OH
R
N
OH
H
C
NH
2
OH.HCI
H
2
O
HOAc
Ar
N
R
OH
Ac
2
O
H
Ar
N
R
H
OO
HOAc
Ar
N
R
O
O
CN
C
2
F
Cl
O
TOSMIC (1.5 eq.)
t-BuOK (2 eq.)
t-BuOH, dioxane
0 °C - rt, overnight
4, 69%
O
Br
F
Cl
CN
O
Br
3
4.1 Formation of Noncyclic Compounds 97
Problem 16: Synthesis of Aminophosphonate by Birum–Oleksyszyn
Reaction
UAMC-00050 (1) was recently developed at the University of Antwerp as a new
treatment of dry eye disease [41]. The core aminophosphonate structure in the key
intermediate 2 was assembled by the one-pot three-component Birum–Oleksyszyn
reaction [42] from aldehyde 3, benzyl carbamate 4, and phosphite 5, using yttrium
triflate as the catalyst. [41] Please suggest a mechanism for this reaction.
The Experimental Procedure (from Org. Process Res. Dev., 2022, 26, 2937)
tert-Butyl(4-(2-(((benzyloxy)carbonyl)amino)2(bis-(4acetamidophenoxy)
phosphoryl)ethyl)phenyl) carbamate (2). To a 500 mL flask equipped with a
magnetic stirrer compound 3 (10.0 g, 0.043 mol, 1.0 equiv), yttrium triflate (2.30 g,
4.3 mmol, 0.1 equiv) dissolved in dry-MeCN (130.0 mL) (water content <0.001%),
benzyl carbamate (4) (6.50 g, 0.043 mol, 1.0 equiv), tris(4- acetamidophenyl)
phosphite (5) (23.00 g, 0.043 mol, 1.0 equiv), dry THF (130.0 mL) (water content
<0.005%), and trifluoroacetic anhydride (5.98 mL, 0.043 mol, 1.0 equiv) were added
under argon. The mixture was stirred for 4 h at 2025 °C. The solvent was removed,
and the residue was dissolved in a solution of ethyl acetate/ethanol (4:1 v/v)
(500 mL). The organic phase was washed with NaOH 0.5 M (4 × 500 mL) and brine
(500 mL). The organic layers were collected together and dried on Na
2
SO
4
(300g), and
the solvent was removed with vacuum. A silica pad with silica gel (200 g) was packed
in a 500-mL glass filter. The residue was dissolved in ethyl acetate/ethanol (3:1 v/v),
celite (20 g) was added, and the solvent was removed. The solid mixture was placed
on top of the filter and washed with ethyl acetate/heptane (2:1 v/v) (2000 mL) to
collect fraction 1, the collection flask was changed, the silica pad was washed with
ethyl acetate/ethanol (3:1 v/v) (1000 mL) to collect fraction 2, and the solvent was
removed from fraction 2 to give a yellow foamy solid. The crude product was dissolved
in acetone (100 mL), and a solution of NaHCO
3
0.5% (200 mL) was added dropwise.
The solid was filtered, washed with methyl tert-butyl ether (MTBE) (100 mL), and
dried in vacuum overnight. The dry solid was suspended in ethyl acetate/acetone
(19:1 v/v) (300 mL), stirred for 24 h, filtered, washed with ethyl acetate (100 mL), and
dried in vacuum (5 mbar) overnight to get a white solid with a yield of 44%. 98.2% AN
by HPLC. HRMS (ESI+): m/z calculated for C
37
H
41
N
4
O
9
PNa [M + Na]
+
: 739.2509,
found 739.2519.
1
HNMR (400 MHz, DMSO-d
6
) δ: 10.00 (s, 2H), 9.32 (s, 1H), 8.11
(d, J = 8 Hz, 1H), 7.57 (m, 4H), 7.39 (d, J = 8Hz, 2H,), 7.30 (m, 3H), 7.19 (d, J = 8Hz, 2H),
7.12 (m, 6H), 4.97 (dd, J = 32, 12Hz, 2H), 4.42 (q, J = 12 Hz, 1H), 3.18 (d, J = 12Hz, 1H),
O
P
O
O
NHCbz
NHAc
AcHN
2
2 steps
1 (UAMC-00050)
NHBoc
O
3
Cbz
H
2
N
+
4
O
NHAc
P
5
+
Y(OTf)
3
MeCN
-THF
TFAA, rt
44%
3
BocHN
O
P
O
O
NHCbz
NHAc
AcHN
N
H
NH
.HCl
H
2
N