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3 General Terms and Concepts in Medicinal Chemistry68
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Drawing from my research and professional experience in medicinal chemistry,
as well as the literature I have reviewed, this chapter compiles 121 cases of reac-
tion mechanisms pertinent to synthesis in medicinal chemistry. These mecha-
nisms are both intriguing and challenging. Given that most mechanism problems
encompass multiple reactions, categorizing them by reaction type proves difficult.
Consequently, the mechanisms are organized based on the structure of the reaction
products. In the experimental and compound structural characterization sections of
each problem, unless otherwise stated, the compound numbers have been renum-
bered to align with the layout of this book. This same approach has been applied to
Chapter 5 as well.
4.1 Formation of Noncyclic Compounds
Problem 1: t-BuOK Promoted Isomerization of Terminal Alkyne to Internal
Alkyne
AMG-3969 was discovered as a compound capable of disrupting the interaction bet-
ween glucokinase and glucokinase regulatory protein (GK-GKRP), showing poten-
tial for use in diabetes treatment in humans [1]. During the scale-up synthesis of
AMG-3969, a crucial step involved the isomerization of terminal alkyne 2 to alkyne 3
using t-BuOK [2].
Please suggest a mechanism for this reaction.
Experimental Procedure (from J. Org. Chem., 2014, 79, 3684)
(3S)-1-Benzyl-3-(1-propyn-1-yl)piperazine (3). To a solution of (3S)-1-benzyl-3-
(propan-2-yl)piperazine (2, 38.8 g, 181 mmol) in tetrahydrofuran (THF) (200 mL)
was added potassium tert-butoxide (40.6 g, 362 mmol) portionwise. After the
addition was complete, the reaction mixture was stirred at room temperature for
30 min and then quenched with water (500 mL) and diluted with EtOAc (1 L).
The organic phase was dried (Na
2
SO
4
), filtered, and concentrated to give a solid.
Purification via silica gel chromatography (07% MeOH in CH
2
Cl
2
) followed by
4
Mechanism Problems from Reactions Give Expected
Products
4 Mechanism Problems from Reactions Give Expected Products72
recrystallization from 100% hexanes provided (3S)-1-benzyl-3-(propan-2-yl)pipera-
zine 3 (26.0 g, 67%) as tan crystalline solid:
1
HNMR (400 MHz, CDCl
3
) δ 7.367.18
(m, 5 H), 3.59 (br d, J = 8.8 Hz, 1 H), 3.51 (s, 2 H), 2.98 (d, J = 11.9 Hz, 1 H),
2.882.76 (m, 2 H), 2.65 (d, J = 11.0 Hz, 1 H), 2.222.05 (m, 2 H), 1.841.76 (s, 3 H),
1.73 (br s, 1 H);
13
C NMR (101 MHz, CD
3
OD) δ 138.5, 130.7, 129.5, 128.5, 80.3, 78.9,
64.0, 59.8, 53.8, 48.0, 45.5, 3.2; HRMS (ESI-TOF) m/z [M + H]
+
calcd for C
14
H
19
N
2
215.1548, found 215.1551; mp 6568 °C,
[
α
]
D
20
= −55.4 (c = 2.9, MeOH).
The Mechanism
It is well-known that a nonterminal alkyne can isomerize into a terminal alkyne
under strong basic conditions—a process known as the alkyne zipper reaction [3].
The current case isomerization can be understood as a retro-alkyne zipper reaction.
Similar rearrangement was also observed by Grubbs’ group when they investigated
the silylation of terminal alkynes at basic conditions [4]. Tsurugi and Mashima’s
group discovered that terminal alkynes could be converted into allenes and
further to internal alkynes catalyzed by organomagnesium complexes under mild
conditions [5].
Under strong basic condition in THF, the terminal alkyne-H can be deprotonated
to form propynylpotassium A. Then a 1,3-H shift occurs to give allenylpotassium B.
At this stage, species B could be protonated by t-BuOH to afford allene C. While, a
second 1,3-H shift would lead to the prop-2-yn-1-ylpotassium D, which is a much
stronger base than t-BuOH, and should be readily protonated by t-BuOH to provide
the product 3. I believe all the transformations are reversible and the distribution of
2, 3, and C depends greatly on the reaction conditions.
Problem 2: Dimerization of Terminal Aziridines to (E)-but-2-ene-1,4-diamines
In 2006, D. M. Hodgson’s group reported a dimerization of terminal aziridines
to give N-protected but-2-ene-1,4-diamines with complete E-olefin selectivity
when starting with enantiopure substrates [6]. The stereochemistry of the double
bond and the two chiral centers was proven unambiguously by X-ray crystallo-
graphic analysis of diamine (S,S)-2. The reaction was applied to the synthesis
of Cobicistat, a drug for the treatment of human immunodeficiency virus type 1
(HIV-1) infection [7]. The mechanism was discussed in Hodgson’s paper.
N
S N N OH
O
O
AMG-3969
N NHBn
O
O
1
LAH, THF
0 °C - reflux
N NH
Bn
2
t-BuOK
THF, rt
N NH
Bn
3
67%
2 steps
3 steps
CF
3
CF
3
H
2
N
4.1 Formation of Noncyclic Compounds 73
Please provide your own mechanism for the reaction.
N NHBn
2
H
H
H
N NHBn
C C
–
H
N NHBn
C C
–
H
H
A
N NHBn
H
H
N NHBn
3
H
t-BuOH
t-BuOK
1,3-H
shift
1,3-H shift
cat. by
t-BuOK
B
Cat. by
t-BuOK
N NHBn
C
H
H
H
C
D
t-BuOK
t-BuOK
t-BuOH
t-BuO
–
t-BuO
–
K
+
K
+
t-BuO
–
t-BuOH
t-BuOH
t-BuOK
K
+
N
Cy
SO O
Bus
LiTMP (3 eq.)
THF-hexane, –78 – 0 °C
80 min
97%
Cy
Cy
NHBus
NHBus
S
−1
S,S-2
N
Ph
SO O
LiTMP (3 eq.)
THF-hexane (1:3)
–10 °C
72%
Ph
Ph
HN
HN
S,S-4
S
S
O
O
O
O
Steps
N N
H
H
N
N
H
O
N
S
O
O
O
N
S
N
O
Ph
Ph
Cobicistat
S
−3
Experimental Procedure (from J. Org. Chem., 2007, 72, 10009)
General Procedure D: Synthesis of 2-ene-1,4-diamines from N-Bus
aziridines. n-BuLi (1.6 M in hexanes, 1.88 mL, 3.0 mmol) was added dropwise
to a stirred solution of 2,2,6,6-tetramethylpiperidine (0.51 mL, 3.0 mmol) in THF
(0.4 mL) at 78 °C. The mixture was warmed to 0 °C over 15 min, then re-cooled to
78 °C before dropwise addition of the aziridine (1.0 mmol) in THF (0.8 mL). The
mixture was stirred at 78 °C for 20 min, then at 0 °C for 1 h, before the addition of
4 Mechanism Problems from Reactions Give Expected Products74
MeOH (0.8 mL), sat. aq. NH
4
Cl (8 mL) and Et
2
O (16 mL). The layers were separated,
and the aqueous phase was extracted with Et
2
O (16 mL). The combined organic
phase was dried (MgSO
4
) and concentrated. Purification of the residue by column
chromatography (petroleum ether/Et
2
O, SiO
2
) gave the 2-ene-1,4-diamine.
Following General Procedure D, aziridine (S)-1 (31 mg, 0.13 mmol) gave
2-ene1,4-diamine (S,S)-2 as a white solid (30 mg, 97%).
[
α
]
25
D
= −3.5 (c 1.0, CHCl
3
);
(mp = 208 °C); R
f
0.18 (petroleum ether/Et
2
O 3:7); IR (film) 3270br.s, 2986 s, 2926 s,
2850 s, 1479 m, 1447 s, 1323 s, 1312 s, 1304 s, 1284 s and 1130 s cm
1
;
1
HNMR
(500 MHz, CDCl
3
) δ 5.57–5.54 (2H, m), 4.01 (2H, d, J 10), 3.81–3.73 (2H, m), 1.81–1.62
(10H, m), 1.51–1.37 (20H, m), 1.26–1.02 (10H, m);
13
CNMR (125 MHz, CDCl
3
) δ
131.4 (2 × CH), 61.4 (2 × CH), 59.8 (2 × C), 43.9 (2 × CH), 29.3 (2 × CH
2
), 28.9
(2 × CH
2
), 26.2 (2 × CH
2
), 26.2 (2 × CH
2
), 26.0 (2 × CH
2
), 24.3 (6 × CH
3
); MS CI m/z
(rel. int.) 508
(
M + NH
4
+
, 100
)
, 491 (M + H
+
, 5), 371 (10), 354 (35), 287 (20), 232 (40),
150 (25); HRMS m/z calcd for C
24
H
50
N
3
O
4
S
2
requires 508.3243, found 508.3242;
Anal found C 58.66, H 9.55, N 5.80, C
24
H
46
N
2
O
4
S
2
requires C 58.74, H 9.45, N 5.71.
The Mechanism
The preferential formation of the E-alkene isomer from enantiopure substrates can
be explained by a mechanism involving an initial diastereoselective trans-lithiation,
followed by the nucleophilic attack of one R-lithiated aziridine on another, which
acts as an electrophile. This step may proceed through a 1,2-metallate shift. The
subsequent syn elimination, driven by the steric constraints imposed by the aziri-
dine substituents and the N-Bus groups, results in the observed E-alkene products.
Problem 3: Thiourea-Mediated Conversion of Alcohols to Alkylhalides
Benzyl halides are an important class of organic compounds and have numerous
industrial and synthetic uses. Some halides are key building blocks for prep-
aration of several pharmaceuticals [8–11]. For example, 2-(bromomethyl)
benzonitriles (1a, 1b) are starting materials for synthesizing alogliptin (2) [8]
and fotagliptin (3) [9]. Therefore, conversion of relatively easier obtained benzyl
N
R
Bus
H
H
N
Li
LTMP
HTMP
N
Bus
H
Li
N
Ph
Bus
H
H
N
Bus
H
R
N
Bus
Li
Li
N
R
Bus
H
R
N
Bus
Li
Syn
elimination
R
R
NHBus
NHBus
E,R,R-2
R
HN
Bus
Li
N
R
Bus
H
Anti
elimination
NH HN
R
R
Bus
Bus
Z, R,R-2
not observed
N
Li
LTMP
Li
HTMP
4.1 Formation of Noncyclic Compounds 75
alcohols to benzyl halides is an important reaction. Recently, a group of Israel
chemists reported a straightforward methodology for the direct transformation
of a wide scope of alcohols to alkyl bromides and chlorides using thioureas and
N-halosuccinimides (NXS), in a single step under mild conditions [12].
A representative reaction is shown below. Please propose a mechanism for this
reaction.
Experimental Procedure (from J. Org. Chem., 2007, 85, 12901)
General Procedure for Bromination of Alcohols. Alcohols 7 (0.9–1.1 mmol,
1 eq.) and N,N′-dimethylthiourea (DMTU) (0.45 eq.) in dry dichlorometh-
ane (DCM) (4 mL) were stirred at room temperature until the starting mate-
rials were completely dissolved. The reaction mixture was vigorously stirred and
N-bromosuccinimide (NBS) (1.5 eq.) was added in a single portion. After comple-
tion of reaction, the mixture was diluted with DCM (5 mL) and an aliquot (1 μL)
injected to the gas chromatography-mass spectrometry (GC-MS). Then, the organic
layer was concentrated over rotary evaporator to produce crude product, which was
purified by silica gel flash chromatography over n-hexane (100%) as mobile phase
to afford the corresponding bromides, 8 (vide infra). The yields of known bromides
8a,c,f-h,k,n,t,w,x, 8zc and 8zd were determined by GC-MS (see Supporting
Information Figures S43–S82).
CN
R
Br
CN
CN
N
N
N
O
N
F
3 (Fotagliptin)
9
1a, R
=
H
1b, R
=
F
N N
O
N
2 (Alogliptin)
8
CO
2
–
O
F
4
Br
N
N
N
F
F
N
N
HN
O
O
5 (Vericiguat)
10
Cl
N
N
Br
N
N
N
N O
CN
O
N
6
7 (Tepotinib)
11
CO
2
–
N
+
H
3
N
+
H
3
NH
2
H
2
N
OH
NBS (1.5 eq.)
DMTU (0.45 eq.)
DCM, rt, 2 h
72%
Br
7d
8d
N
H
N
H
S
DMTU
(1,3-dimethylthiourea)
O
2
N
O
2
N
4 Mechanism Problems from Reactions Give Expected Products76
1-(bromomethyl)-4-nitrobenzene ( 8d). Reaction time: 2 h; obtained as pale yellow
solid (162 mg, 72%).
1
H NMR (400 MHz, CD
2
Cl
2
) δ 4.53 (s, 2H), 7.56 (d, J = 8 Hz, 2H),
8.17 (d, J = 8 Hz, 2H);
13
C NMR (100 MHz, CD
2
Cl
2
) δ 147.7, 145.0, 130.1, 129.8, 124.0,
123.8, 31.2; GC-MS (ESI) m/z calcd for C
7
H
6
BrNO
2
[M] 214.9, found: 214.9.
The Mechanism
The mechanism was studied by the Israel group and it was concluded that the reac-
tion was a free radical process [12]. As you can see below, one equivalent of DMTU
could generate a maximum of three equivalents of alkyl radical (R
•
) and three
equivalents of bromine radical (Br
•
); thus, substoichiometric amounts (0.45 eq) of
DMTU is enough.
Problem 4: Oxidative Decarboxylation of N-Aroylglycines with Lead(IV)
Acetate
In 1986, Threadgill’s group reported an oxidative decarboxylation of N-aroylglycines
to N-(acetoxymethy1)benzamides with lead (IV) acetate [13]. In the case of
(4-nitrobenzoyl)glycine 1d, the yield of product 2d was 72%. The yield from other
substrates was relatively low (2.5–39%). When catalytic amount of Cu(OAc)
2
was
added, the reaction yield was improved to 40–90% [14]. The scope of the reaction
was expanded to aliphatic analogs [15] and applied to the synthesis of the mar-
keted drug deruxtecan (5) [16]. Deruxtecan is a derivative of exatecan that acts as
topoisomerase I inhibitor. It is available as an antibody drug conjugate, linked to a
specific monoclonal antibody—such as trastuzumab deruxtecan, which is used to
treat breast cancer, as well as gastric or gastroesophageal adenocarcinoma.
Please propose a mechanism for this reaction.
N Br
O
O
NBS
S
NHMe
NHMe
DMTU
N
O
O
S
NHMe
NHMe
Br
+
B
A
R OH
ROH
HBr
S
NHMe
NHMe
O
R
S
NHMe
NHMe
O
+
R
.
C
S
NHMe
NHMe
O
C
NBS ROH
HBr
S
NHMe
NHMeO
+
D
O
ROH
HBr
S
NHMe
NHMe
O
+
R
.
E
O
O
N
O
O
A
H Br
NH
O
O
+ Br
R Br
product
A
NBS
A
R
.
R
.
O
2
N
N
H
O
OH
O
1d
Pb(OAc)
4
, Ac
2
O
AcOH, 60 °C, 10 min
72%
N
H
O
O
2d
O
O
2
N
4.1 Formation of Noncyclic Compounds 77
Experimental Procedure (from J. Org. Chem., 1986, 51, 3196)
N-(acetoxymethyl)-4-nitrobenzamide(2d). N-(4-nitrobenzyl) glycine (la)
(5.60 g, 25 mmol) was treated with Pb(OAc)
4
(22.15 g, 50 mmol) as for the prepa-
ration of 2b above except that chromatography was replaced by recrystallization
from ethyl acetate/light petroleum (bp 60–80 °C). The acetoxymethylbenzamide
2d (4.28 g, 72%) was obtained as a very pale greenish yellow solid: mp 94 °C
(lit. mp 120 °C); IR 3370, 1760, 1670 cm
1
; NMR (CDCl
3
) δ 2.10 (3H, s, COCH
3
),
5.45 (2H, d, J = 7 Hz, NCH
2
O), 7.90 (1H, ca. t, J = 7 Hz, NH), 8.05 (2H, d, J = 8 Hz)
and 8.35 (2H, d, J = 8 Hz) [Ar H].
(From WO 2019044947 A1)
({N-[(9H-fluoren-9-ylmethoxy) carbonyl] glycyl} amino) methyl acetate (4). THF
(9.75 L) and acetic acid (1.95 L) were added to N-[(9H-fluoren-ylmethoxy) carbonyl]
glycylglycine (3, 650.0 g, 1.834 mol), and dissolved by heating to 40 °C. Lead tet-
raacetate (1301.3 g, 2.935 mol) was added and refluxed for about 1.5 h. The mixture
was cooled to room temperature, the insolubles were filtered off, and the filtered
off insolubles were washed with ethyl acetate (3.25 L) and matched with the fil-
trate. To the resulting solution was added a 20 (w/v)% aqueous solution of trisodium
citrate dihydrate (3.25 L), and the mixture was stirred, separated, and the aqueous
layer was removed. The obtained organic layer was washed twice with 20 (w/v)%
aqueous trisodium citrate dihydrate (3.25 L), and then the organic layer was con-
centrated to 6.5 L under reduced pressure. Water (1.95 L) was added followed by
Fmoc
H
N
N
H
OH
O
O
Pb(OAc)
4
AcOH, THF
91%
Fmoc
H
N
N
H
O
O O
Steps
N
N
H
H
N
N
H
H
N
N
H
O
O
O
O
O
O
O
O
NH
O
N
N
O
O
O
HO
F
Deruxtecan (5)
N
N
H
H
N
N
H
H
N
N
H
O
O
O
O
O
O
O
O
NH
O
N
N
O
O
O
HO
F
S
Trastuzumab
Trastuzumab deruxtecan
sold under the brand name Enhertu
Antibody–drug conjugate
3
4
H
3
C
H
3
C