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4 Mechanism Problems from Reactions Give Expected Products78
({N-[(9H-fluoren-9-ylmethoxy) carbonyl] glycyl} amino) methyl acetate (0.65 g) and
stirred at room temperature for about 1 hour. Water (6.5 L) was added dropwise,
cooled to 0–5 °C. and stirred for about 3 hours. The precipitate was filtered off and
the filtered powder was washed with cold 30 (v / v)% aqueous THF (2.6 L). The
obtained powder was dried at 40 °C under reduced pressure, and ({N-[(9H-fluoren-
9-ylmethoxy) carbonyl] glycyl} amino) methyl acetate (4, 617.1 g, 1.675 mol, yield
91.3% Got).
1
HNMR (400 MHz, CDCl
3
) δ 2.06 (3H, s), δ 3. 90 (2H, d, 4.9 Hz), 4.23 (1H, t,
6.7 Hz), 4.45 (2H, d, 6.7 Hz), 5.25 (2H, d, 7.3 Hz), 5.39 (1H, brs), 7.05 (1H, brs),
7.30–7.34 (2H, m)), 7.41 (2H, t, 7.3 Hz), 7.59 (2H, d, 7.3 Hz), 7.77 (2H, d, 7.3 Hz).
13
CNMR (100 MHz, CDCl
3
) δ 20.8, 44.4, 47.0, 63.9, 67.2, 120.0, 125.0, 127.1, 127.7,
141.3, 141.3 143.6, 156.6, 169.8, 171.7.
MS (ESI) (m/z): 369 ([M + H
+
]).
The Mechanism
The reaction mechanism was studied by Threadgill’s group [13]. The results
indicated that the process involved initial ligand exchange at lead, followed by
N-acetoxylation, decarboxylation, elimination, and a final re-addition of acetic acid
to N-aroylimines to yield the products.
Ar N
H
O
OH
O
1
AcO
Pb(OAc)
3
HOAc
Ar
N
O
O
O
Pb
AcO
AcO
OAc
H
Ar
N
O
O
O
O
Ac
H
CO
2
HOAc
Ar N
O
Ar N
H
O
OAc
2
HOAc
Ligand exchange
N-acetoxylation
Decarboxylation
elimination
Addition
HOAc
Pb(OAc)
4
Pb(OAc)
2
OH
+
1 (1 eq.)
2 (1.2 eq.)
Ph
3
P (1.2 eq.)
DDQ (1.2 eq.)
CH
2
Cl
2
, rt, 1 min
86%
N
N
H
2
N
O
3
N
N
H
N
O
Please propose a mechanism for this reaction.
Problem 5: Preparation of Aromatic Amines Promoted by DDQ and Ph
3
P
Amide and amine formation are the current most frequently used synthetic reactions
in medicinal chemistry [17]. In 2009, Iranpoor et al. reported selective mono- and
di-N-alkylation of aromatic amines with alcohols and acylation of aromatic amines
using Ph
3
P/DDQ [18]. A representative reaction is shown below.
4.1 Formation of Noncyclic Compounds 79
Experimental Procedure (from Tetrahedron, 2009, 65, 3893)
Typical Procedure for N-benzylation of 4-amino-2,3-dimethyl-1-phenyl-
3-pyrazolin-5-one. To a flask containing a stirred mixture of Ph
3
P (1.2 mmol,
0.314 g) and DDQ (1.2 mmol, 0.272 g) in DCM (5 mL) was added 4-amino-
2,3-dimethyl-1-phenyl-3-pyrazolin-5-one (1.2 mmol, 0.244 g) at room tempera-
ture. Benzyl alcohol (1.0 mmol, 0.1 mL) was then added to the reaction mixture.
Thin-layer chromatography (TLC) monitoring showed the completion of the
reaction after 1 min. The solvent was evaporated and the residue was chroma-
tographed on a silica gel column using n-hexane/ethyl acetate (4:1) as eluent.
4-(N-Benzylamino)-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one was obtained in
86% yield (0.30 g). IR (neat) 3403, 3054, 2986, 2928, 1662, 1594, 1455, 1359 cm
1
;
1
HNMR (250 MHz, CDCl
3
): δ (ppm) = 1.86 (3H, s), 2.06 (1H, s), 2.60 (3H, s),
5.18 (2H, s), 7.07–7.42 (10H, m);
13
CNMR (62.9 MHz, CDCl
3
): δ (ppm) = 9.75,
36.32, 57.81, 113.45, 123.34, 126.04, 126.82, 127.65, 127.93, 128.10, 128.82, 129.00,
139.83, 154.59. Anal. Calcd for C
18
H
19
N
3
O: C, 73.69; H, 6.53; N, 14.32%. Found:
C, 73.46; H, 6.57; N, 14.22%.
The Mechanism
The authors [18] proposed a mechanism to account for this transformation. Initially,
the known quaternary phosphonium salts (i) are formed via the addition of Ph
3
P to
DDQ. The negatively charged oxygen in the hydroquinone moiety of this adduct
can function as a base, deprotonating the amine without the need for an additional
base, thereby facilitating the generation of an amine anion. The resulting complex
(ii) then reacts with the alcohol to yield the alkoxyphosphonium salt (iii), which
undergoes an SN-type displacement to produce the desired alkylated amine.
I think the above mechanism is implausible. Firstly, species (i) is not a strong
base—its conjugated acid, the phenol, is relatively acidic. For example, picric acid is
a similar phenol; its pK
a
is 0.38. On the other hand, the pK
a
of an aniline is around
30. Consequently, deprotonation of an aniline by species (i) is impossible. Secondly,
O
O
CN
CN
Cl
Cl
DDQ
PPh
3
O
O
–
CN
CN
Cl
Cl
(i)
Ph
N
R
H
O
OH
CN
CN
Cl
Cl
Ph
N
–
R
H
O Rʹ
O
OH
CN
CN
Cl
Cl
Ph
R
H
O
+
Rʹ
(ii)
PhNHR
(iii)
PhNRRʹ +
O
OH
CN
CN
Cl
Cl
H
O
O
OH
CN
CN
Cl
Cl
H
+
PPh
3
O
PPh
3
P
+
Ph
3
P
+
Ph
3
R’OH
PPh
3
PPh
3
N
–
4 Mechanism Problems from Reactions Give Expected Products80
even if species (ii) were formed, the protonated alkyl-phosphine ether would be
very acidic. I predict its pK
a
to be in the range of 6 ~ 0. It would likely be immedi-
ately deprotonated by the strong base PhN
R, resulting in the release of free aniline.
The aniline anion (PhN
R) had no chance to attack the alcoholic carbon in (iii).
Furthermore, that mechanism could not explain that amides were less active than
amines, since amides are more acidic than amines and should be easier to be depro-
ponated than amines.
Based on above considerations, I propose a different mechanism as shown below.
The first step is still the addition of Ph
3
P to DDQ to form onium salt (A). Then
the oxygen of the hydroxyl in the alcohol as a nucleophile attacks the quaternary
phosphonium and gives the protonated phosphonyl ether (B). The proton on the
ethereal oxygen would be quickly transferred to the phenolic oxygen to generate
the neutral molecule (C). Thus, the alcohol is activated by forming a phospho-
nate, which is a good leaving group. Finally, aniline as a nucleophile attacks the
activated carbon to provide the product along with triphenylphosphine oxide and
4,5-dichloro-3,6-dihydroxyphthalonitrile. This mechanism is similar to the mecha-
nism of Mitsunobu reaction, in which the DDQ plays the role of diethyl azodicar-
boxylate (DEAD).
However, this mechanism still cannot explain the results from the paper [18],
which indicated that alkylamines (no reaction) were less reactive than arylamines.
Obviously, the results and the mechanism are contradictory.
Problem 6: Conversion of Alkyl Aryl Ketones to ɑ-Arylalkanoic Acids
Using DPPA
In 1978, Shioiri and Kawai reported a preparation of ɑ-arylalkanoic acids (4) from
alkyl aryl ketones (1) by using pyrrolidine and diphenylphosphoryl azide (DPPA) [19].
The reactions are illustrated as follows in three steps. The method was successfully
applied to the synthesis of ibuprofen, the anti-inflammatory drug.
OH
OH
CN
CN
Cl
Cl
O
O
CN
CN
Cl
Cl
H
O Rʹ
RʹOH
O
O
CN
CN
Cl
Cl
DDQ
O
OH
CN
CN
Cl
Cl
PPh
3
Ph
H
N
R
O
Rʹ
A
C
PhNHR
Ph
N
R
Rʹ
O
CN
CN
Cl
Cl
RʹH
transfer
+ +
B
PPh
3
PPh
3
P
+
Ph
3
PPh
3
H
+
O
–
O
–
Ph
3
P
O
+
4.1 Formation of Noncyclic Compounds 81
Please provide mechanisms for those transformations.
Experimental Procedure (from J. Org. Chem., 1978, 43, 2936)
A typical procedure is as follows. DPPA (4.95 g) was added with stirring to pyr-
rolidine enamine 2 (3.05 g) in THF (45 mL). The mixture was stirred at room
temperature for 1 h, at 40 °C for 1 h, and then refluxed for 2 h. After dilution with
ethyl acetate and benzene (1:1, 150 mL), the mixture was successively washed
with 5% aqueous citric acid, water, saturated aqueous sodium chloride, satu-
rated aqueous sodium bicarbonate, water, and saturated aqueous sodium chlo-
ride. The dried solution was evaporated and the residue was purified by column
chromatography on silica gel with ethyl acetate and benzene (1:5) to give the
N-phosphorylated amidine 3 (5.68 g, 80%).
The Mechanism
The first reaction is the conversion of alkyl aryl ketones 1 to pyrrolidine enamine 2.
Then 1,3-dipolar/[3+2] cycloaddition of DPPA to enamine 2 followed by aryl migration
with concomitant evolution of nitrogen from labile triazoline provides intermediate 3.
Finally, hydrolysis of the resulting N-phosphorylated amidine 3 yields the product 4.
Ph
O
1
OH
O
4
Ph
Ph
N
H
2
Pyrrolidin
benzene, reflux
DPPA, THF
rt- reflux
N
N
Ph
PO(OPh)
2
3
KOH, glycol
reflux
79%
80%
91%
O
1. Pyrrolidine, benzene, reflux
2. DPPA, THF, rt- reflux
3. KOH, glycol, reflux
overall yield 62%
5
Ibuprofen
HO
O
Ph
O
1
Ph
N
HN
H
2
O
2
N
N
+
N
–
(PhO)
2
OP
DPPA
Pyrrolidine
[3+2]
cycloaddition
N
N
N
Ph
N
N
N
Ph
3
KOH
hydrolysis
OH
O
4
Ph
HO
–
N
Ph
N
–
O
H
N
Ph
–
HN
O
P
O
PhO
OPh
N
Ph
HN
P
O
OPh
O
KOH
hydrolysis
PO(OPh)
2
PO(OPh)
2
PO(OPh)
2
N
2
PhO
–
4 Mechanism Problems from Reactions Give Expected Products82
Problem 7: Synthesis of -Aryl-α-Keto Acid from Benzaldehyde and
Hydantoin
Rupintrivir (1, AG-7088) is a peptidomimetic antiviral drug that acts as a 3C and
3CL protease inhibitor [20]. (R)-3-(4-fluorophenyl)-2-hydroxy propionic acid (2) is
one of the building blocks for synthesizing 1. The compound 3, precursor of 2, is
prepared from 4-fluorobenzaldehyde (4) and hydantoin (5) by the reaction shown
below [21].
Please provide a mechanism for this reaction.
Experimental Procedure (from Org. Process Res. Dev., 2002, 6, 520)
Sodium 3-(4-fluorophenyl)-2-oxo-propionate (3). 4-Fluorobenzaldehyde (4)
(3.72 kg, 30 mol), hydantoin (5) (3.00 kg, 30 mol), 1-amino-2-propanol (225 g,
3.0 mol), and water (7.5 L) were added to a 50-L reactor equipped with a temper-
ature probe, reflux condenser, agitator, and cooling coils. The resulting mixture
was heated and refluxed for approximately 10 h. The reaction was monitored by
1
HNMR and was deemed complete upon disappearance of the hydantoin (5) proton
signal at δ 3.9 (s, 2H, CH
2
) and the appearance of condensed intermediate olefin
proton δ 6.4 (s, 2H, CH). Aqueous sodium hydroxide (6.00 kg in 30.0 L) was then
added to the bright yellow slurry, and reflux continued until completion as shown
by high-performance liquid chromatography (HPLC), leading to a transparent
orange solution. The mixture was cooled to 20 ± 5 °C, and sodium chloride (3.51 kg,
60.0 mol) was added with agitation. The pH of the mixture was adjusted to 8.0 using
concentrated HCl and the suspension was stirred for 4 h until a pale yellow slurry
was obtained. The solids were filtered off and purified via slurrying in methanol
(30.0 L), followed by filtration. Upon drying under house vacuum at ambient tem-
perature for 4 days, 5.47 kg of solids (6) was obtained with a yield of 82% and HPLC
purity above 80%.
1
HNMR (D2O): 4.72 (s, 2H), 7.02–7.19 (m, 4H). Anal. Calcd for
C
9
H
6
O
3
FNa•H
2
O: C, 48.66; H, 3.63; Found: C, 48.64, H 3.74.
N
H
N
H
N
O
O
O
O
NH
O
H
CO
2
Et
F
Rupintrivir (1, AG-7088, Rupinavir)
HO
OH
O
F
2
O
OH
O
F
3
O
F
4
+
HN
NH
O
O
5
1. H
2
O
1-amino-2-propanol
reflux
2. NaOH, reflux
23 kg, 77–82%
O
ONa
O
F
6 (Na
+
salt)
4.1 Formation of Noncyclic Compounds 83
The Mechanism
A similar reaction was reported previously [22]. The first step is a condensation of
the 4-flourobenzaldehyde 4 and hydantoin 5 catalyzed by the aminoalcohol. Then
hydrolysis of the formed 4-flourobenzalhydantoin A at basic condition yields the
sodium salt of 6.
Another possible mechanism for the hydrolysis of A could be as follows. The
hydroxyl anion adds to the C═C bond via a Michael addition followed by hydrolysis
of the amide in hydantoin B to form mono substituted urea C. Subsequently, elim-
ination of the urea yields the epoxide D which would rearrange to the product 6.
Problem 8: α-Amination of Amides
α-Amino acids and peptides are becoming an increasing subset of commercialized
drugs [23, 24]. Therefore, developing synthetic methods for non-natural α-amino
acids is an attractive area for medicinal chemistry. Maulide’s group reported a ste-
reoselective α-amination of amides with azides under mild conditions [25]. One
example is shown below.
Please provide a mechanism for the reaction.
O
F
4
NH
2
OH
N
H
NH
O
O
5
N
H
NH
O
O
F
N
OH
H
F
N
H
OH
NH
HN
O
O
H
OH
F
NH
HN
O
O
HO
–
NaOH
F
NH
O
O
NaOH
A
NaO
F
NH
O
O
NaOH
urea
NaO
HO
F
OH
O
ONa
3 (Na
+
salt)
H
2
O
NH
2
NH
2
HO
–
Na
+
H
2
O
NH
2
−
F
NH
HN
O
O
HO
−
NaOH
A
F
NH
HN
O
NaO
HO
NaOH
F
NH
HN
O
O
B
HO
NaOH
F
NH
O
O
NaO
HO
urea
F
O
ONa
O
H
F
O
ONa
O
6 (Na
+
salt)
H
2
O
NH
2
4 Mechanism Problems from Reactions Give Expected Products84
Experimental Procedure (from J. Am. Chem. Soc., 2016, 138, 8348, Supporting
Information)
General Procedure for -Amination of Amides. To a mixture of amide
(0.3 mmol) and 2-fluoropyridine (0.6 mmol, 2 equiv, 58.3 mg, 51.6 L) in DCM
(1 mL), triflic anhydride was added dropwise (0.6 mmol, 2 equiv, 84 mg, 51 µL) at
0 °C under Ar. The mixture was stirred for 15 minutes at this temperature. Then a
solution of azide (0.6 mmol, 2 equiv) in 0.5 mL of DCM was added and the mix-
ture was brought to room temperature. N
2
release was observed after addition of
the azide. After 30 min, 2 mL of a saturated solution of NaHCO
3
was added and
the mixture was further stirred for 1 h. The biphasic mixture was then diluted with
DCM and washed with a 20 mL of NaHCO
3
. The combined organic layers were
dried over MgSO
4
and the solvent removed under reduced pressure. Purification
through column chromatography DCM/dimethylamine (DMA) (0–60% DMA)
afforded the products.
2-(Phenethylamino)-1-(pyrrolidin-1-yl)butan-1-one (3ba).
1
HNMR (400MHz,
CDCl
3
) δ = 7.30–7.26 (m, 2H), 7.22–7.19 (m, 3H), 3.57–3.39 (m, 4H), 3.31 (t, J =
6.5 Hz, 1H), 2.89–2.80 (m, 2H), 2.78–2.73 (m, 1H), 2.29–2.65 (m, 1H), 1.93 (dd, J=
12.9 and 6.5 Hz, 2H), 1.85 (dd, J = 12.9 and 6.4 Hz, 2H), 1.62 (dt, J = 14.8, 7.3 Hz,
2H), 0.94 (t, J = 7.5 Hz, 3H) ppm.
13
CNMR (100 MHz, CDCl
3
) δ = 172.2, 140.1, 128.9,
128.5, 126.3, 61.5, 50.1, 46.4, 45.9, 37.0, 26.6, 26.3, 24.3, 10.5 ppm. HRMS (ESI) m/z cal-
culated for [M + H
+
] = 261.1961, found 261.1967. Attenuated total reflectance (ATR)-
FTIR (cm
1
): 3502, 3297, 3026, 2875, 1633, 1428, 1340, 1226, 1150, 1031, 751, 700.
The Mechanism
The amide 1, in its enol form, is first transformed into the triflate A. Following
this, the triflate group (TfO) is substituted with 2-fluoropyridine, yielding the
reactive intermediate B. Notably, density functional theory calculations indi-
cate the participation of a distinct keteniminium species C in this process. This
intermediate C undergoes nucleophilic attack by the azide 2, leading to the
formation of intermediate D. Subsequently, a molecule of N
2
is eliminated, result-
ing in the aziridinium intermediate E. Finally, an aqueous workup step liberates
the product 3.
In Maulide’s paper, one special case was reported. Treatment of mixed adipic acid
ester/amide 4 with azide 2 led to the bicyclic product 5.
The mechanism is shown as follows.
1. T f
2
O (1 eq.), 2-F-Py (2 eq.)
DCM, 0 °C - rt, 1 h
N
O
2. aq. NaHCO
3
85%
N
O
NH
+
Ph
N
3
Ph
3
1
2
2 eq.
4.1 Formation of Noncyclic Compounds 85
Could you predict the products of the reaction below?
Problem 9: α-Oxidation of Amides
In 2017, Maulide’s group reported an ɑ-oxidation of amide by using 2,6-lutidine
N-oxide (LNO) in the presence of Tf
2
O [ 26 ]. The method was applied to the syn-
thesis of the antitumor active compound 5 [ 26 , 27 ].
N
O
Tf
2
O
2-F-Py
N
OTf
F
H
TfO
–
Ph
N
N
N
N
N
Ph
Ph
HO H
N
N
Ph
O H
N
O
NH
Ph
aq.
workup
H
Tf
O
S
CF
3
O
O
1
2
3
A
D
E
N
F
N
B
F
2-F-Py
C
TfOH
C
N
+
TfO
–
N
+
N
+
N
–
N
+
TfO
–
N
+
TfO
–
N
2
TfO
–
N
+
1. T f
2
O, 2-F-Py
DCM
N
O
2. aq. NaHCO
3
+
Ph
N
3
5 (34%)
MeO
O
N
O
MeO
Ph
TfO
–
4
2
N
+
N
O
+
Ph
N
3
MeO
O
Tf
2
O
2-F-Py
N
N
N
+
TfO
–
N
Ph
O
O
Me
N
N
O
Me
Ph
N
O
MeO
Ph
4
2
5
O
+
TfO
–
N
2
TfO
–
N
+
1. T f
2
O, 2-F-Py
DCM
N
O
2. aq. NaHCO
3
+
Ph
N
3
N
O
6
2
?
4 Mechanism Problems from Reactions Give Expected Products86
Please provide a mechanism for this oxidation.
Experimental Procedure (from J. Am. Chem. Soc., 2017, 139, 6758, Supporting
Information)
‐Ketoamides from LNO‐adduct. To a solution of the amide (1 equiv) and LNO
(2.2 equiv) in DCM (0.1 M) with activated molecular sieves (3 Å) at 0 °C was added
Tf
2
O (1.1 equiv) and the resulting mixture was allowed to warm to room tempera-
ture over the course of 3 h. After this, the molecular sieves were removed by filtra-
tion and an aqueous solution of sodium hydroxide (1 M, 3.0 equiv) was added. The
biphasic mixture was vigorously stirred at room temperature for 30 min, after which
saturated aqueous ammonium chloride was added and the phases were separated.
The aqueous phase was extracted with DCM and the combined organic phases were
dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate
was concentrated under reduced pressure on a rotary evaporator. The crude residue
was purified by flash column chromatography on silica gel (heptane/ethyl acetate)
to afford the title compounds.
Methyl 8,9‐dioxo‐9‐(pyrrolidin‐1‐yl)nonanoate (2g).(63%).
1
HNMR(400MHz,
CDCl
3
): δ 3.66 (s, 3H), 3.59 (t, J = 6.8 Hz, 2H), 3.51 (t, J = 6.8Hz, 2H), 2.83 (t, J = 7.4 Hz,
2H), 2.30 (t, J = 7.5 Hz, 2H), 1.98–1.83 (m, 4H), 1.67–1.57 (m, 4H), 1.39–1.30 (m, 4H);
13
C-NMR (100 MHz, CDCl
3
): δ201.1, 174.3, 163.2, 51.6, 47.4, 46.4, 39.3, 34.1, 29.0,
28.9, 26.5, 24.9, 23.8, 23.0; IR (neat) ν
max
: 2923, 2855, 1736, 1716, 1635, 1438, 1366,
1200, 1171; HRMS (ESI+): exact mass calculated for [M + Na]
+
(C
14
H
23
NO
4
Na)
requires m/z 292.1519, found m/z 292.1515.
The Mechanism
The dipolar form of the amide is triflated to give the O-triflate as the salt A. Due to
the excellent leaving ability of the TfO group, it is substituted by LNO to generate the
intermediate B, which could be isomerized to the enol form. The second LNO adds
to the ɑ-position, with elimination of 2,6-lutidine to yield C. Deprotonation of the
ɑ-H at basic condition provides D, and finally elimination of another 2,6-lutidine
affords the ɑ-ketoamide 2.
R
1
NR
2
2
O
1. T f
2
O (1.1 eq.), LNO (2.2 eq.)
DCM, MS 3A, 0 - 23 °C, 3 h
2. NaOH (1 M, 3 eq.), 23 °C, 30 min
O
O
2, 37–78%
1
N
BnO
PMB
O
O
N
BnO
PMB
O
O
O
Steps
62%
N
H
N
H
O
O
O
N
S
MeO
3
4
5, antitumor active
NR
2
2
R
1
4.1 Formation of Noncyclic Compounds 87
Problem 10: Tsunoda Reagent for Mitsunobu Reaction
In 1994, Tsunoda’s group reported 2-(tributylphosphoranylidene)acetonitrile or cya-
nomethylenetributylphosphorane (CMBP, 1) as a novel reagent for Mitsunobu reac-
tion. This reagent works better than normal azodicarboxylates such as DEAD and
diisopropyl azodicarboxylate when nucleophiles have a weak acidity. For example,
benzylation of N-benzyl-2,2,2-trifluoroacetamide ( 3, p K
a
13.6) by benzyl alcohol ( 2 )
under the normal Mitsunobu condition provided the desired product 3 in only 3%
yield. Whereas, a good yield of 4 (77%) was reached by using CMBP [ 28 ].
Recently, in a medicinal chemistry project, chemists from AstraZeneca needed to
prepare a series of N-alkylated pyrazoles. By employing the classic Mitsunobu con-
ditions, the reaction failed. While, by employing the Tsunoda reagent (CMBP), the
desired product 7 was obtained in 79% yield [ 29 ].
Please propose a mechanism for this reaction.
S
O
S
O
OO
O
N
+
R
2
2
O
S
O O
LNO
R
1
O
2,6-lutidine
O
O
H
NaOH
O
O
O
2,6-lutidine
+ TfONa
1b
2
A
B
C
D
R
1
NR
2
2
O
H
1a
O
H
B
LNO
TfOH
F
3
C CF
3
Tf
2
O
R
1
O
–
TfO
–
O
–
N
+
TfO
–
CF
3
2TfO
–
N
+
R
1
R
1
N
+
R
2
2
NR
2
2
N
+
O
–
N
+
TfO
–
HO
–
N
+
N
+
R
2
2
NR
2
2
TfO
–
R
1
R
1
N
+
NR
2
2
TfO
–
O
–
Na
+
NR
2
2
R
1
Ph OH
F
3
C
H
N Ph
O
+
N Ph
O
Ph
2
3 (pK
a
~13.6)
DEAD, Ph
3
P, THF
3%
CMBP, benzene, rt
77%
4
P
N
1, CMBP
F
3
C
O
N
NH
5 (pK
a
~14)
N
O
OH
+
6
DIAD, Ph
3
P, THF
O
N
N
7
N
O
CMBP, dioxane
rt, 16 h, 79%
or microwave, 150 °C
40 min, 79%