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 Products188
The Mechanism
Methanolysis of the thioacetate group by methoxide anion in 3 leads to a thiolate
anion which takes part in an addition-elimination process to give cinnamonitrile A.
Under basic conditions, the anionic cyclization is potentially autocatalytic, possibly
because the proposed nitrile anion B is sufficiently basic to deprotonate A, thereby
propagating the catalytic cycle. This rationale explains why only 1.5 equivalents of
sodium methoxide were added (based on 100% of 1 converted to 3). Final intramo-
lecular cyclization and aqueous workup produces the product 5.
4.6.4 Pyrrol-2-one
Problem 66: Preparation of Spiro 1H-Pyrrol-2(5H)-ones by One-Pot
Multicomponent Reaction
1H-Pyrrol-2(5H)-ones 1 represent important heterocycles with a variety of pharma-
ceutical uses. For example, pulchellalactam (2) is a CD45 protein tyrosine phos-
phatase inhibitor [179]. Commeiras and coworkers reported new multicomponent
synthesis of either γ-hydroxy-γ-butyrolactams 3 or various γ-lactam motifs 4–6 from
(Z)-3-iodoacrylic acids or (E)-2,3-dihalogenoacrylic acids 7, terminal alkynes 8, and
primary amines 9 in the presence of a copper(I) catalyst [180, 181].
The following is a representative example [181]. One-pot, two-step reaction of 7a,
8a, and 9a under the specified conditions afforded the desired product 5a along with
a side product 10a.
Please suggest mechanisms for the formation of 5a and 10a.
N
O
N
H
O
1 2
Pulchellalactam
X CO
2
H
X
CuI, K
2
CO
3
i-PrOH
7
8
9
N
O
X
HO
3
or
or
or
N
O
4
X
N
O
6
Nu
N
O
5
Nu
H
2
N
R
3
R
3
R
2
R
2
R
2
R
3
R
2
R
3
R
2
R
3
R
1
R
1
R
1
R
1
R
1
R
1
R
5
R
2
R
3
R
4
I CO
2
H
NH
2
1. CuI (20%)
K
2
CO
3
(2 eq.)
i-PrOH, 45 °C, 12 h
7a
8a
9a
N
O
5a (43%)
N
H
NH
2. 6 M HCl
50 °C, 1 h
+
10a (9%)
N
H
O
O
+
+
4.6 Formation of Monocyclic Aromatic Heterocycles 189
Experimental Procedure (from Org. Biomol. Chem., 2017, 15, 3304, supplemen-
tary information)
(Z)-3-Substituted-3-iodoprop-2-enoic acid derivative 7 (0.5 mmol, 1 equiv) was dis-
solved in iPrOH (1.75 mL) in oven-dried-Schlenk tube. K
2
CO
3
(139 mg, 1.0 mmol,
2 equiv) was then added to the solution and the suspension was stirred for 10 min
under argon. The mixture was then degassed at 78 °C for 2 × 10 min and the
vessel was back filled with argon. After warming to room temperature, terminal
alkyne 8 (1.0 mmol, 2 equiv), primary amine 9 (2.0 mmol, 4 equiv), and CuI (19 mg,
0.1 mmol, 0.2 equiv) were respectively added into the mixture. The mixture was
then rapidly degassed and the vessel was back filled with argon. The sealed Schlenk
tube was placed in the preheated oil bath (45 °C) and was stirred overnight. The
reaction mixture was cooled to 0 °C, then 1.7 mL of a solution of hydrochloric acid
(6 M, 20 equiv) was added dropwise. The reaction was then heated at 50 °C until the
disappearance of the γ-hydroxybutyrolactam checked by TLC. The reaction mix-
ture was cooled to 0 °C, then filtered through a pad of Celite®. The aqueous phase
was extracted with ethyl acetate and the combined organic layers were washed with
brine, dried over Na
2
SO
4
, and concentrated under reduced pressure. The crude
product was then purified by flash chromatography on silica gel using petroleum
ether: ethyl acetate as eluent.
1′-Butyl-3′-methyl-2,3,4,9-tetrahydrospiro[carbazole-1,2′-pyrrol]-5′
(1′H)-one (5a). Purification: flash chromatography on silica gel (PE/EtOAc: from
8/2 to 6/4). Yield: 43% (66 mg). Physical appearance: white solid; m.p. (crystal):
105 °C;
1
HNMR (CDCl
3
, 400 MHz): δ (ppm) 0.81 (3H, CH
3
, t, J = 7.3 Hz), 1.15–1.25
(2H, CH
2
, m), 1.30–1.41 (1H, CH
2
, m), 1.53–1.63 (1H, CH
2
, m), 1.81 (3H, CH
3
, br
d, J = 1.5 Hz), 2.01–2.17 (4H, 2 x CH
2
, m), 2.74–2.81 (1H, CH
2
, m), 2.88–2.98 (2H,
2 x CH
2
, m), 3.29 (1H, CH
2
, ddd, J = 15.9, 10.5 and 5.4 Hz), 5.91 (1H, CH, br q,
J = 1.5 Hz), 7.12 (1H, HAr, br dd, J = 8.0 and 7.1 Hz), 7.20 (1H, HAr, br dd, J = 8.0
and 7.1 Hz), 7.26–7.30 (1H, HAr, m), 7.55 (1H, HAr, d, J = 8.0 Hz), 7.96 (1H, NH,
br s);
13
CNMR (CDCl
3
, 100 MHz): δ (ppm) 13.8 (CH
3
), 14.2 (CH
3
), 20.6 (CH
2
), 20.8
(CH
2
), 21.5 (CH
2
), 31.5 (CH
2
), 32.6 (CH
2
), 41.0 (CH
2
), 67.9 (C), 111.6 (CHAr),115.8
(CAr), 118.6 (CHAr),119.2 (CHAr), 122.0 (CH), 122.7 (CHAr), 127.0 (CAr), 129.1
(CAr),136.9 (CAr), 163.1 (C), 171.3 (C); IR (nujol): 3178, 2931, 1672, 1641, 1407,
1228, 779, 729 cm
1
; HRMS (ESI-MS) calcd for C
20
H
25
N
2
O[M + H]
+
309.1961,
found 309.1962.
The Mechanism
A plausible mechanism involving a Sonogashira-type coupling without the use of
palladium has been proposed in the literature [180, 182]. The process is thought
to begin with the oxidative addition of copper(I) into the C─I bond of compound
A, forming the copper(III) intermediate B. Subsequent steps likely include the
π-coordination of alkyne 8a, followed by the formation of complex D through
base-mediated deprotonation of the terminal acetylenic proton. Reductive elimina-
tion of intermediate D then yields intermediate E.
At this stage, the pathway diverges: a 6-endo-dig cyclization [183] facilitated by
copper(I) could lead to the formation of side product 10a (path b), while a 5-exo-dig
4 Mechanism Problems from Reactions Give Expected Products190
cyclization [ 183 ] assisted by copper(I) would generate lactone F (path a) via pro-
todemetalation. The primary amine 9a then undergoes nucleophilic addition onto
lactone F, producing hydroxylactam 3a through intermediate G. Subsequent elimi-
nation of water from 3a results in the formation of lactam 4a .
The addition of excess HCl to the mixture ultimately provides the final product
5a [ 181 ]. It is proposed that the mechanism involves the cyclization of 3a via acyli-
minium chloride H to yield the spiro product 5a .
At the stage of intermediate H, there is a second possible cyclization, namely C-3
addition, to give the spiro compound intermediate I. The latter would undergo rear-
rangement to give J, followed by β-elimination to furnish the final product 5a .
I CO
2
H
7a
8a
9a
N
O
5a
Bu
N
H
NH
N
H
O
O
K
2
CO
3
KHCO
3
I CO
2
–
K
+
A
CuI
Oxidative
addition
Cu
B
I
O
O
KI
Cu
C
I
O
O
N
H
H
KI
Cu
D
O
O
N
H
KI
Reductive
elimination
O
O
E
N
H
a
b
path b
10a
Cu
I
CuI
path a
CuI
O
O
HN
F
Protodemetalation
Protodemetalation
O
HN
G
O
NHBu
N
O
HN
3a
HO
Bu
N
O
HN
4a
Bu
HCl
O
H
Bu
N
H
HCl
2
2
2
2
2
N
Bu
N
H
O
C-2 addition
2
3
K
2
CO
3
KHCO
3
H
2
N
H
2
O
H
2
O
CI
–
N
+
−
K
+
N
O
5a
Bu
NH
N
+
O
H
Bu
N
H
HCl
2
C-3 addition
2
3
N
N
O
Bu
H
+
catalyzed
rearrangement
N
O
Bu
NH
H
I
β-elimination
J
CI
–
H
+
+
H
4.6 Formation of Monocyclic Aromatic Heterocycles 191
4.6.5 Pyridine
Problem 67: A General Preparation of Pyridines via the Annulation of
Ketones
In 2001, chemists from Merck reported a general preparation of pyridines via the
annulation of ketones [184]. A representative example is shown as the preparation
of nicotinate 3, which is a key building block for the synthesis of a c-Met kinase
inhibitor 4 [185]. The methodology was also applied for the synthesis of COX-2
specific inhibitor Etoricoxib [186].
Please suggest a mechanism for this reaction.
Experimental Procedure (from J. Org. Chem., 2001, 66, 4194)
General Experimental Procedure for the Annulation of Ketones. To a
suspension of the ketone (1, 25 mmol) in dry THF (50 mL) at 0 °C was added drop-
wise a 20 wt % solution of t-BuOK in THF (16.4 mL, 26.3 mmol, 1.05 equiv). The
slurry was stirred at room temperature for 45 min, and the vinamidinium hexafluo-
rophosphate salt (2, 11.5 g, 37.5 mmol, 1.5 equiv) was added in one portion. The
resulting mixture was stirred at 45 °C for 3 h (in the presence of 1.0 equiv of DABCO
when specified), and ammonium acetate (2 equiv) was added in one portion. The
resulting dark solution was heated at reflux for 6 h and concentrated under reduced
pressure. The residue was directly purified by chromatography on silica gel (CH
2
Cl
2
or CHCl
3
/MeOH was used as eluent). Alternatively, the residue after evaporation of
the THF can be extracted with ethyl acetate and washed with water and saturated
sodium chloride solution prior to the purification.
O
MeO
O
+
N
+
N
Cl
PF
6
–
PF
6
–
1
2 (1.5 eq.)
1. t-BuOK (1.05 eq.)
THF, 0 °C - rt, 45 min
2. 2 (1.5 eq.), 45 °C, 3 h
3. NH
4
OAc (2 eq.)
reflux, 6 h
N
Cl
MeO
O
3 (84%)
Steps
N
N
N
O
H
N
S
N
O
O
O
O
4
N
Cl
2 (1.5 eq.)
1. t-BuOK, THF
2. HOAc
3. NH
4
OAc
reflux
97%
O
N
MeO
2
S
5
N
6 (Etoricoxib)
N
Cl
+
MeO
2
S
N
+
4 Mechanism Problems from Reactions Give Expected Products192
2-Methyl-5-chloro Methylnicotinate (3). Mp 186–187 °C.
1
HNMR (400 MHz,
CDCl
3
): δ 8.58 (d, J = 2 Hz, 1H), 8.18 (d, J = 2 Hz, 1H), 3.94 (s, 3H), 2.81 (3H).
13
CNMR (100 MHz, CDCl
3
): δ 165.6, 157.9, 150.5, 137.7, 129.1, 125.9, 52.4, 24.1. IR
(cm
1
): 3074, 3036, 3000, 2957, 2925, 2858, 1732. Anal. Calcd for C
8
H
8
ClNO
2
: C,
51.77; H, 4.34; N, 7.55. Found: C, 51.98; H, 4.43; N, 7.44.
The Mechanism
The reaction mechanism, investigated by Merck scientists [184], can be succinctly
summarized in the following scheme. The ketone must possess an active CH
2
or
CH
3
group at the α-position, enabling the generation of enolate A using t-BuOK.
The reaction of enolate A with the vinamidinium salt 2 can proceed through two
distinct transition state models—1,2-addition or 1,4-addition—both leading to the
same enamine intermediate B. This enamine B is stabilized by the presence of an
electron-withdrawing substituent at the β-position (R
3
), facilitating its partial tau-
tomerization to form C. Typically, the adduct B/C undergoes elimination of dimeth-
ylamine to yield the corresponding dienamine D, which is stable and can be isolated
and characterized. The cyclization of intermediate D in the presence of ammonium
acetate proceeds through the formation of dienamine intermediate E, accompa-
nied by the release of dimethylamine. Notably, there is no evidence suggesting that
ammonia attacks the ketone moiety in D during the final cyclization step.
Problem 68: Conversion of Benzenes to Pyridines by ipso-selective Nitrene
Internalization
The pyridine moiety serves as a significant isostere of benzene in medicinal chem-
istry research. However, the absence of direct carbon-to-nitrogen replacement tech-
niques means that performing a nitrogen scan typically necessitates the bottom-up
synthesis of each azine isomer. The synthetic approach for these isomers often dif-
fers considerably from that of their benzene counterparts. Specific nitrogen scans
O
R
2
O
N
PF
6
–
PF
6
–
1
2
N
O
3
t-BuOK
O
–
K
+
O
K
+
PF
6
–
t-BuOH
NH
4
OAc
(NH
3
)
NH
3
O
O
A
N
N
N
O
O
H
1,2-addition
1,4-addition
O
A
B
N
O
O
H
C
N
O
O
Me
2
NH
Me
2
NH
H
2
O
H
2
N
D
E
R
1
R
2
R
2
R
1
R
1
R
3
R
3
R
2
R
1
R
3
R
3
R
3
R
2
R
2
R
2
R
2
R
1
R
1
R
1
R
1
R
3
R
3
O
–
K
+
N
+
N
+
N
+
4.6 Formation of Monocyclic Aromatic Heterocycles 193
have played a crucial role in the discovery of several recently approved pharma-
ceuticals, including FDA-approved drugs such as imatinib, selpercatinib, sotorasib,
and omidenepag, as well as flumatinib, which were approved by China’s National
Medical Products Administration.
A recent breakthrough by Levin’s group at the University of Chicago introduced an
innovative approach for aromatic nitrogen scanning through ipso-selective nitrene
internalization [187]. In a representative example, 1-azido-3-(tert-butyl)benzene
(1) and ethylaminoethanol (2) in acetonitrile were irradiated using a 427 nm LED.
This was followed by treatment with 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) and
N-bromocaprolactam (NBC) in dioxane at 80 °C, yielding the corresponding pyr-
idine product 4 in 32% yield. This method was successfully applied to synthesize
a potential 5α-reductase inhibitor, 7, an estrone pyridine analog, demonstrating
significantly improved efficiency compared to previously reported synthetic routes
[188].
Please suggest a mechanism for the transformation from 1 to 4.
N
N
N
H
N
H
N
N
N
O
Imatinib
Anticancer
FDA-approved 2001
N
N
N
H
N
N
H
N
N
N
O
Flumatinib
Anticancer
NMPA-approved 2019
CF
3
N
N
N
O
N
N
NMeO
Selpercatinib
Anticancer
FDA-approved 2020
N
N N
N
NO
F
OH
F
O
N
Sotorasib
Anticancer
FDA-approved 2021
N
N
H
HO
2
C
N
S
O
O
N
N
N
Omidenepag
For glaucoma
FDA-approved 2022
HO
N
3
t-Bu
N
H
OH
MeCN
427 nm LED
1.
DBU, dioxane
80 °C
1
2
N
N
HO
t-Bu
3a (1:1)
+
N
N
HO
3b
t-Bu
N
t-Bu
4 (32%)
N
O
Br
(NBC)
2.
H
H H
O
HO
H
H H
OH
O
H
OH
N
3
Nitrene
internalization
3 steps
10% overall
N
H
H H
O
Glaxo 1994
10 steps
3% overall
(5) Estrone
$6/g
6 (19-nor-testosterone)
$182/g
7
4 Mechanism Problems from Reactions Give Expected Products194
Experimental Procedure (from Science, 2023, 381, 1474, Supplementary Materials)
General Procedure: A 2 dram vial was charged with 0.3 mmol of aryl azide (1),
0.3 mmol ethylaminoethanol (2), 3 mL MeCN, and a stir bar. The vial was sealed
under a septum cap under air and subjected to photolysis using a 427 nm LED
lamp while cooling to room temperature with a fan. After TLC indicated consump-
tion of starting material, the solvent was removed under a stream of nitrogen. The
atmosphere was then replaced with dry N
2
and then 3 mL dry, degassed dioxane
was added. Then, 1.0 eq. (0.3 mmol) DBU was added, and the reaction was warmed
to 80 °C. Separately, a solution of 115 mg (0.6 mmol, 2 eq.) of NBC was prepared in
1 mL dioxane (note: degassing of this latter solution was found experimentally not
to significantly impact yields) and added dropwise to the reaction at 80 °C over the
course of 2 minutes. The reaction was then concentrated under a stream of nitrogen
and the residue purified by column chromatography on silica gel.
3-(tert-Butyl)-pyridine (4). Synthesized according to the general procedure
from 1-azido-3-(tert-butyl) benzene (1, 52.5 mg, 0.3 mmol). The title compound was
obtained as a yellow oil in 32% yield (12.9 mg) after purification by silica gel chro-
matography.
1
HNMR (400 MHz, CDCl
3
) δ 8.70 – 8.65 (m, 1H), 8.43 (dd, J = 4.8
and 1.6 Hz, 1H), 7.69 (ddd, J = 8.1, 2.6, and 1.6 Hz, 1H), 7.23 (ddd, J = 8.0, 4.8, and
0.8 Hz, 1H), 1.35 (s, 9H). Spectra match those previously reported.
The Mechanism
Benzene ring enlargement by photolysis of phenylazide was reported by Doering
and Odum in 1966 [189]. Under the irradiation of an LED, the starting azide 1 gives
the intermediate nitrene A. Nitrene A then rearranges to form azepine B or C, both
of which are electrophilic at the carbon where the azide was originally attached.
Nucleophilic addition of amine 2 to azepines B or C provides the intermediate 3a
or 3b. Cyclization of 3a provides the spiro azepine oxazolidine D. The azepine D
is then brominated by NBC to yield the bromide E. Elimination of one molecule
of HBr by DBU from E affords azaheptatriene F. 3,3-Sigma tropic rearrangement
of F provides the azanorcaradiene G. Due to the instability of the aziridine ring,
it cleaves to the zwitterionic intermediate H. Aromatization of H by extrusion of
carbene I leads to the pyridine product 4.
C
N
t-Bu
C (azepine)
C
N
–
t-Bu
1
N
Photolysis
N
2
C
Nt-Bu
A (nitrene)
N
N
C
t-Bu
B (azepine)
N
H
OH
2
N
C N
HO
t-Bu
3a
N
C N
HO
3b
t-Bu
HNR2
C
t-Bu
HNR2
N
H
OH
2
N
+
4.6 Formation of Monocyclic Aromatic Heterocycles 195
Following the similar manner, another intermediate 3b could also undergo cycli-
zation to give J. Due to the steric hindrance of the t-butyl group, the following
bromination with NBC occurs at C-4 rather than at C-6. Thus, the corresponding
product is still 4.
The fate of carbene I is eventually oxidized to the N-ethyl oxazolidinone R. This
oxidation can occur either from adventitious dioxygen to dioxirane P, which is an
oxidant and oxidizing another carbene I to give two molecules of oxazolidinone R.
The carbine I could be also oxidized by Br
+
(from NBC) and forming the oxazolidi-
none
R through hydrolysis upon aqueous workup.
Due to the tension of the enamine (azepine C) in seven-membered ring and its
high reactivity, in the presence of ethylaminoethanol (2), there would be no chance
to tautomerize to azepine C′ via a 1,3-H shift. Consequently, the corresponding regi-
omeric product S was not observed.
N
C
t-Bu
N
O
N
O
Br
H
DBU
DBU.HBr
N
C
t-Bu
N
O
N
t-Bu
C
N
O
C
N
O
N
t-Bu
4
D
F
G
I (carbene)
t-Bu
C
N
+
O
H
From
3a
NBC
NH
O
N
C
t-Bu
N
O
Br
H
DBU
E
NBC
N
–
N
C
N
HO
3b
N
C
N
O
N
O
Br
H
J
from
3b
t-Bu
N
C
N
O
Br
t-Bu
Steric hindrance
K
N
C
N
O
t-Bu
Br
H
N
C
N
O
t-Bu
M
N
C
t-Bu
N
O
N
–
t-Bu
C
O
L
C
N
O
N
4
I (carbene)
DBU
DBU.HBr
NBC
t-Bu
N
O
1
3
4
6
t-Bu
N
+
4 Mechanism Problems from Reactions Give Expected Products196
It is worth to note that, before finding NBC as a suitable oxidant, Levin’s group
tried NBS as an oxidant [187]. However, treatment of 8 with DBU and NBS led to the
exclusive formation of the succinimide trapped oxidation product 9, which further
decomposed on heating.
The phenomenon can be explained as follows. NBS is a stronger oxidizing Br
+
equivalent than NBC, it will brominate compound 8 to the bromide T. Subsequently,
the succinimide anion displaces the Br to lead the product 9.
Since caprolactam (pK
a
~ 22) is a much weaker acid than succinimide (pK
a
~ 9.5),
it is not deprotonated by DBU (pK
a
of DBUH
+
~ 13.5) and thereby a strong nucle-
ophile caprolactam anion is not generated. The amide substituted analog U is not
formed. Therefore, replacing NBS with NBC directs the reaction along the desired
pathway.
C
N
O
I (carbene)
O O
O
2
C
N
O
OO
H
2
O
C
N
O
O
O
H
O
H
C
N
O
O
P (dioxirane)
NBC
C
N
O
I (carbene)
N
Br
O
N
N
O
Br
C
N
O
Br
O
H
HBr
HN
O
DBU
DBU.HBr
C
N
O
OO
C
N
O
I
C
N
O
O
2
R
R
Q
H
2
O
H
2
O
2
H
2
O
–
O
C
+
H
+
C
N
C
t-Bu
C (azepine)
H
C
N
C
t-Bu
Cʹ (azepine)
H
C
N
t-Bu
S
1,3-H shift
Not observed
N
C N
8
t-Bu
NBS, DBU
CDCl
3
N
C N
9
OH
OH
H
N
O O
86%
80 °C
Decomposed
t-Bu
4.6 Formation of Monocyclic Aromatic Heterocycles 197
Problem 69: Synthesis of Multisubstituted Pyridines via HFIP Catalyzed
Cyclization
Methoxatin ( 4), a natural product, has demonstrated the ability to mitigate damage
caused by ischemia-reperfusion injury, which occurs during heart attacks or strokes.
Although it is not currently classified as a vitamin, it is marketed as a dietary sup-
plement due to its potential benefits [ 190 ]. Glinkerman and Boger developed a
synthetic method for preparing di- and tetrahydroquinolines by reacting triazine ( 1 )
with an enamine, such as compound 2, in hexafluoroisopropanol (HFIP) [ 191 ]. The
resulting product ( 3) was subsequently converted into methoxatin ( 4) with a high
overall yield.
Please suggest a mechanism for the formation of 3 from 1 and 2 .
Experimental Procedure (from J. Am. Chem. Soc., 2016, 138, 12408)
Cycloaddition: A vigorously stirred solution of freshly prepared enamine 2
(0.965 mmol) in HFIP (9.65 mL) at 23 °C was treated with 1,2,3-triazine 1 (435 mg,
1.93 mmol). The vessel was sealed and heated at 60 C for 24 h. After 24 h, the reac-
tion mixture was concentrated on a rotary evaporator and the residue was puri-
fied by preparative TLC (SiO
2
, 50% EtOAc/hexanes) to provide 3 as a light yellow
solid (356 mg, 95%): mp 97–99 °C;
1
HNMR (CDCl
3
, 600 MHz) δ 11.72 (s, 1H),
N
C N
8
t-Bu
N
C N
9
t-Bu
OH
OH
H
N
O O
N
C N
8
OH
H
H
Br
N
O
O
N
C N
OH
Br
T
N
–
O
O
DBU
NBS
DBU
DBUH
+
DBU.HBr
t-Bu
t-Bu
Br
–
DBUH
+
N
–
O
N
C N
8
t-Bu
OH
H
Br
N
O
N
C N
OH
Br
DBU
NBC
DBU (cat)
Caprolactam
not good nucleophile
O
Not formed
N
C N
t-Bu
OH
U
N
O
+
DBUH
+
Fast
NH
O
+
DBU
t-Bu
N
−