Organophotoredox/Copper Hybrid Catalysis for Regioselective Allylic Aminodecarboxylation of β,γ-Unsaturated Carboxylic Acids

Article abstract of DOI:10.1055/s-0036-1591983

A new cooperative organophotoredox/copper catalysis allowing for the conversion of β,γ-unsaturated carboxylic acids into allylic hydrazides via radical regioselective allylic decarboxylative amination is reported. The coexistence of the copper catalyst is essential for the high yield and regioselectivity.

Full text of DOI:10.1055/s-0036-1591983

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–L
special topic
A
en
A.-D. Manick et al.
Special Topic
Synthesis
Organophotoredox/Copper Hybrid Catalysis for Regioselective
Allylic Aminodecarboxylation of β,γ-Unsaturated Carboxylic Acids
Anne-Doriane Manick
Hirotaka Tanaka
R3 R3
CO2R4
R4O2C
NH
R3
R1
PC
Cu
CO2H
N
Kounosuke Oisaki*
R2
Motomu Kanai*
0
0
0
0
0-
0
0
3
1-
9
7
7
7-
6
4
8
R1
R3
+
R2
R4O2C
N
Graduate School of Pharmaceutical of Sciences, The University
of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
oisaki@mol.f.u-tokyo.ac.jp
CO2R4
N
15 examples
up to 78% yield
R1, R2, R3 = H, alkyl
4 = alkyl
controlled
regioselectivity
kanai@mol.f.u-tokyo.ac.jp
R
Published as part of the Special Topic Modern Radical Methods
and their Strategic Applications in Synthesis
Received: 27.02.2018
Accepted after revision: 14.03.2018
Published online: 24.04.2018
ramine salts via two-electron redox pathways (Scheme 1,
a).7 This protocol led to the generation of a mixture of
regioisomers. Decarboxylation of this type of acid using
hypervalent iodine has been reported, with uncontrolled
regioselectivity.8 Only one example of photocatalyzed ami-
nodecarboxylation of β,γ-unsaturated carboxylic acids has
been accomplished, by Tunge and co-workers (Scheme 1,
b).9 This reaction catalyzed by an organic photocatalyst was
limited to 1-cyclohexene-1-acetic acid with one type of
azodicarboxylate, leading to a mixture of regioisomers de-
spite high selectivity. As represented by these precedents,
controlling regioselectivity (α- vs γ-) in allylic aminodecar-
boxylation with broad substrate generality remains chal-
lenging.
DOI: 10.1055/s-0036-1591983; Art ID: ss-2018-c0125-st
Abstract A new cooperative organophotoredox/copper catalysis al-
lowing for the conversion of β,γ-unsaturated carboxylic acids into allylic
hydrazides via radical regioselective allylic decarboxylative amination is
reported. The coexistence of the copper catalyst is essential for the high
yield and regioselectivity.
Key words photoredox catalysis, copper, decarboxylation, β,γ-unsat-
urated carboxylic acids, allylic hydrazides, dual catalysis
Carboxylic acids are abundant and relatively inexpen-
sive, and thus widely used in organic synthesis in both lab-
oratory and industrial scale chemistry.1 The decarboxyl-
ative reaction of carboxylic acids represents in particular a
powerful tool to form carbon–carbon and carbon–heteroat-
om bonds.2 The difficulty of this method is based on the ex-
trusion of CO2 which generally requires harsh conditions or
preactivation of the carboxylic acid.3
a) Minakata et al. [ref. 7]
Me
cat. I2
Me
Ph
NHTs
Me
Me
Ph
γ
Chloramine-T
CO2H
+
α
NHTs
Ph
DMF, 50 °C, 12 h
Me Me
Me Me
Me
A decarboxylation process promoted by visible-light
photoredox catalysis has recently attracted much atten-
tion.4 This strategy involves radical precursors and pro-
ceeds under mild conditions compared with traditional
radical decarboxylations. The formation of C–C and C–X
bonds (X = heteroatom) via decarboxylative conjugate addi-
tion,5a,b alkynylation,5c,d alkenylation,5e,f arylation,5g,h alkyla-
tion,5i and allylation reactions5j has been investigated.
Among these approaches, the photoredox aminodecarbox-
ylation of carboxylic acids has emerged as a broadly appli-
cable method to synthesize alkyl amines,6 although it re-
mains largely unexplored by organic chemists. For allylic
aminodecarboxylation in particular, only a few examples
have been reported to date (Scheme 1). Minakata and co-
workers described the decarboxylative amidation of β,γ-
unsaturated carboxylic acids catalyzed by iodine with chlo-
50%, α/γ = 80:20
b) Tunge et al. [ref. 9]
CO2H
CO2iPr
α
H
NH
cat. Mes-Acr+-Ph
CO2iPr
iPrO2C
N
N
N
CO2iPr
iPrO2C
N N
+
CO2iPr
γ
MeCN, rt, blue LEDs
67%, α/γ = 16:1 (one example)
c) This work
R3
CO2R4
cat. Mes-Acr+-Me
cat. [Cu]
R4O2C
NH
R3
R3
N
R4O2C
N
N
CO2R4
single regioisomer
R1
CO2H
R1
R3
MeCN, 4 °C, blue LEDs
R2
R2
Scheme 1 Strategies for catalytic aminodecarboxylation of β,γ-unsat-
urated carboxylic acids
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

B
A.-D. Manick et al.
Special Topic
Synthesis
Inspired by these reported methodologies, we devel-
oped a new organophotoredox/copper hybrid catalysis for
the generation of allylic hydrazides via regioselective ami-
nodecarboxylation of β,γ-unsaturated carboxylic acids
(Scheme 1, c).
under irradiation with blue LED lamps. In the absence of a
metal source, a mixture of allylic hydrazides 2a and 3a in an
80:20 ratio was obtained in 57% yield (Table 1, entry 1). The
regioselectivity of the reaction was influenced by the pres-
ence of CuOAc and (R,R)-Me-DuPHOS ((–)-1,2-bis[(2R,5R)-
2,5-dimethylphospholano]benzene) as the ligand with the
formation of single regioisomer 2a in a very good yield
without prefunctionalization of the acid (78%, entry 2).
Bi(OAc)3 afforded the same regioselectivity with a slightly
lower yield (73%, entry 3). The use of indium, zinc, iron, and
nickel sources also produced the single regioisomer 2a, but
the yield was substantially decreased (53%, 51%, 53%, and
36%, respectively; entries 4–7). Silver and boron sources
gave similar results (entries 8 and 9), whereas Co(OAc)2 led
to a loss of regioselectivity (2a/3a = 90:10, entry 10). Ytter-
bium, titanium, and scandium sources usually promote the
carbonyl allylation reaction as redox-inert Lewis acid cata-
lysts.15 Use of these metals, however, led to a significant
Based on the rich literature on metallophotoredox-cata-
lyzed transformations,6e,f,10 and the background of copper-
catalyzed allylation reactions in our laboratory,11 we began
our investigation into regioselective aminodecarboxylation
of β,γ-unsaturated carboxylic acids by screening the metal
source (Table 1). (E)-2,2-Dimethylnon-3-enoic acid (1a) and
azodicarboxylate, respectively, were selected as the model
substrate and electrophilic radical-trapping agent to form
the C–N bond.12,13 The reaction was performed in the pres-
ence of 9-mesityl-10-methylacridinium perchlorate photo-
catalyst (Mes-Acr+-Me, 5 mol%),14 di-tert-butyl azodicar-
boxylate (DTBAD, 3 equiv), and 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU) as the base (25 mol%) in MeCN at 4 °C
Table 1 Optimization of the Metal Source for Allylic Aminodecarboxylation of 1aa
Mes-Acr+-Me (5 mol%)
[Metal] (10 mol%)
DTBAD (3 equiv)
DBU (25 mol%)
H
N
CO2tBu
Me Me
N
Me Me
CO2tBu
Me
N
tBuO2C
Me
OH
+
Me
Me
Me
NH
MeCN, 4 °C, 24 h
blue LEDs
tBuO2C
3a
O
2a
1a
Entry
[Metal]
Yield (%)b
Ratio 2a/3ac
1
2e
3
–
57
78
73
53
51
53
36
56
49
67
7
80:20d
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
90:10
–
CuOAc
Bi(OAc)3
In(OH)3
ZnEt2
4
5f
6
Fe(OAc)2
Ni(COD)2
AgOAc
7g
8
9
B(OH)3
10
11
12
13
14
15
16
Co(OAc)2
Yb(CF3SO3)3
Ti(OEt)4
ScCl3(H2O)6
NaH
6
–
0
–
0
–
LiH
0
–
nBu2Mg
0
–
a Reaction conditions: 1a (0.2 mmol), [metal] (0.02 mmol), Mes-Acr+-Me (0.01 mmol), DTBAD (0.6 mmol), DBU (0.05 mmol), MeCN (2 mL), 4 °C, blue LEDs, 24 h.
b Yields refer to isolated products.
c The product ratio was determined by 1H NMR analysis of the crude mixture.
d Mixture of inseparable regioisomers (see Supporting Information).
e Addition of (R,R)-Me-DuPHOS (0.02 mmol).
f Addition of (S,S)-(–)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline) (0.2 mmol), ZnEt2 (1 equiv), substrate (2 equiv).
g Addition of 2,2′-bis[(4S)-4-benzyl-2-oxazoline] (0.02 mmol).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

C
A.-D. Manick et al.
Special Topic
Synthesis
Table 2 Optimization of the Copper Source Using 1aa
Mes-Acr+-Me (5 mol%)
[Cu] (10 mol%)
(R,R)-Me-DuPHOS (10 mol%)
DTBAD (3 equiv)
Me Me
N
H
N
CO2tBu
Me Me
O
CO2tBu
Me
Me
N
DBU (25 mol%)
tBuO2C
OH
+
Me
NH
Me
Me
MeCN, 4 °C, 24 h
blue LEDs
tBuO2C
3a
2a
1a
Entry
[Cu]
Yield (%)b
Ratio 2a/3ac
1
2
Cu(I)OAc
78
77
61
52
0
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
Cu(I)PF6(CH3CN)4
Cu(I)Mes
3
4
Cu(I)CN
5
Cu(I)Cl
6
Cu(II)(CF3SO3)2
Cu(II)(OMe)2
Cu(II)(OH)2
Cu(II)(OAc)2
Cu(II)Br2
64
64
63
56
45
7
8
9
10
a Reaction conditions: 1a (0.2 mmol), [Cu] (0.02 mmol), (R,R)-Me-DuPHOS (0.02 mmol), Mes-Acr+-Me (0.01 mmol), DTBAD (0.6 mmol), DBU (0.05 mmol), MeCN
(2 mL), 4 °C, blue LEDs, 24 h.
b Yields refer to isolated products.
c The product ratio was determined by 1H NMR analysis of the crude mixture.
loss of the product yield (entries 11–13). Finally, the use of
alkali and alkaline earth metals completely inhibited the re-
action (entries 14–16).
Table 3 Optimization of Solvent and Base Using 1aa
This first set of experiments highlighted the potential of
Mes-Acr+-Me (5 mol%)
copper salts to promote the reaction in high yield and regi-
CuOAc (10 mol%)
oselectivity. A number of Cu(I) sources were therefore in-
(R,R)-Me-DuPHOS (10 mol%)
H
CO2tBu
N
Me Me
DTBAD (3 equiv)
base (25 mol%)
vestigated (Table 2, entries 1–5). The use of weakly coordi-
nating anions resulted in a similar yield as copper acetate
(entry 2 vs 1), while a copper source bearing mesitylene as
the ligand (CuMes), generating a copper carboxylate of the
substrate through an acid–base reaction, decreased the
yield (61%, entry 3). Replacing CuOAc with CuCN afforded
less satisfactory results (52%, entry 4), while CuCl inhibited
the reaction (entry 5). Cu(II) sources were also examined
and afforded 2a in a slightly lower yield compared with
Cu(I)OAc (entries 6–10). Interestingly, all the reactions us-
ing copper as a metal complex catalyst proceeded with ex-
cellent regioselectivity.
Keeping acid 1a as a model substrate (1 equiv), Mes-
Acr+-Me (5 mol%), CuOAc (10 mol%), (R,R)-Me-DuPHOS (10
mol%), and DBU (25 mol%), we next focused on the effects
of the solvent on the reaction outcome (Table 3). Replacing
MeCN with THF, CH2Cl2, or acetone drastically decreased
the yield (20%, 18%, and 15%, respectively, vs 78%; entries
1–3 vs 5). The use of DMF led to complete recovery of the
starting material (entry 4). The effect of the base was then
examined, keeping MeCN as solvent. Organic bases such as
N
Me
tBuO2C
OH
Me
Me
Me
solvent, 4 °C, 24 h
blue LEDs
O
2a
1a
Entry
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
DBU
DBU
DBU
DBU
DBU
DIPEA
Et3N
THF
20
18
15
0
CH2Cl2
acetone
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
78
54
19
12
66
pyridine
Cs2CO3
a Reaction conditions: 1a (0.2 mmol), CuOAc (0.02 mmol), (R,R)-Me-Du-
PHOS (0.02 mmol), Mes-Acr+-Me (0.01 mmol), DTBAD (0.6 mmol), base
(0.05 mmol), solvent (2 mL), 4 °C, blue LEDs, 24 h.
b Yields refer to isolated products. All entries produced single regioisomer
2a.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

D
A.-D. Manick et al.
Special Topic
Synthesis
N,N-diisopropylethylamine (DIPEA), triethylamine, or pyri-
dine (entries 6–8) and an inorganic base like Cs2CO3 (entry
9) gave less satisfactory results than DBU (entry 5).
Table 4 Effects of Reaction Parametersa
Mes-Acr+-Me (5 mol%)
CuOAc (10 mol%)
(R,R)-Me-DuPHOS (10 mol%)
DTBAD (3 equiv)
To elucidate the critical parameters in this transforma-
tion, various control experiments were conducted. In the
absence of light, no desired product was observed, reveal-
ing that visible light is essential for the reaction (Table 4,
entry 1 vs 2). Moreover, no reaction occurred in the absence
of the base, indicating that a catalytic amount of the base
also plays an important role in initiating the reaction (entry
3). In addition, both copper and ligand proved to be essen-
tial for the reaction to proceed smoothly, as the absence of
this combination led to decreased yield and regioselectivity
(entries 4 and 5). Unfortunately, chiral ligands did not affect
the enantioselectivity of the reaction (see Supporting Infor-
mation for details).
H
CO2tBu
N
Me Me
O
N
Me
tBuO2C
DBU (25 mol%)
OH
Me
Me
MeCN, 4 °C, 24 h
blue LEDs
Me
2a
1a
Entry
Variation from the ‘standard’ reaction conditions
Yield (%)b
1
2
3
4
5
none
78
0
absence of LED irradiation
absence of DBU
0
absence of DuPHOS ligand
absence of CuOAc
70c
36c
a Standard reaction conditions: 1a (0.2 mmol), CuOAc (0.02 mmol), (R,R)-
Me-DuPHOS (0.02 mmol), Mes-Acr+-Me (0.01 mmol), DTBAD (0.6 mmol),
DBU (0.05 mmol), MeCN (2 mL), 4 °C, blue LEDs, 24 h.
b Yields refer to isolated products.
With the optimized conditions in hand, the scope of
azodicarboxylates was examined using 1a as a partner
(Scheme 2). Allylic hydrazides 2a, 4a, and 5a from dialkyl
azodicarboxylates were produced in good yields with con-
trolled regioselectivity (78%, 68%, and 52% yield, respective-
ly). Ether functional groups were tolerated, leading to the
formation of the product 6a (60% yield). It is noteworthy
that dibenzyl azodicarboxylate completely inhibited the re-
action. Replacing CuOAc/DuPHOS ligand with Bi(OAc)3,
however, produced 7a in moderate yield (38%).
Next, the transformation of various β,γ-unsaturated car-
boxylic acids was envisioned with our optimized conditions
(Table 5). The reaction proved to easily tolerate acyclic and
cyclic (including heterocyclic) substituents at the α-posi-
tion. The desired products 2a, 2b, 2c, and 2d were isolated
in good to excellent yields (78%, 68%, 75%, and 76%, respec-
tively; entries 1–4). The substrates 1e, with no substituents
at the γ-position (terminal alkene), and 1f, bearing an aryl-
c Traces of regioisomer 3a.
alkyl substituent at the γ-position, were submitted to the
optimized conditions, leading to the isolation of regioiso-
mers 2e and 2f in moderate yields (44% and 58%, entries 5
and 6). Interestingly, the reaction proceeded with excellent
regioselectivity using acid 1e compared with the copper-
free conditions (85:15 ratio of inseparable regioisomers,
see Supporting Information). The use of an α-unsubstituted
substrate, (E)-non-3-enoic acid (1g), resulted in a lower
yield (29%, entry 7) and the γ-regioselectivity was surpris-
ingly observed. In this example, it is important to empha-
size that the absence of copper and ligand induced a better
yield of 2g. The regioselectivity, however, was drastically
decreased (49% yield, 7:3 ratio of regioisomers; see Sup-
Mes-Acr+-Me (5 mol%)
CuOAc (10 mol%)
(R,R)-Me-DuPHOS (10 mol%)
azodicarboxylate (3 equiv)
DBU (25 mol%)
H
R
N
Me Me
O
N
R
Me
OH
Me
Me
Me
Me
MeCN, 4 °C, 24 h
blue LEDs
2a–7a
1a
H
H
N
H
N
CO2tBu
CO2iPr
CO2Et
N
Me
N
N
N
tBuO2C
iPrO2C
EtO2C
Me
Me
Me
Me
Me
Me
Me
2a
78%
4a
68%
5a
52%
O
N
O
O
O
OMe
H
N
N
CO2Bn
Me
MeO
Me
NH
BnO2C
Me
Me
Me
Me
6a
60%
7a
38%a
Scheme 2 Scope of azodicarboxylates. a CuOAc-DuPHOS was replaced with Bi(OAc)3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

E
A.-D. Manick et al.
Special Topic
Synthesis
porting Information). Using 1,2-β,γ-disubstituted substrate
1-cyclohexene-1-acetic acid (1h), the reaction proceeded
smoothly to produce allylic hydrazide 2h in good yield and
high α-selectivity with the formation of stable cyclic alkene
(56%, entry 8). Notably, with the copper-free conditions de-
scribed by Tunge and co-workers,9 no desired product was
obtained. Substrates bearing alkyl substituents at the β- or
γ-position provided the α-selective compounds 2i and 2j
with moderate to good yields (60% and 51%, respectively;
entries 9 and 10). The α-selectivity was favored in these
cases with the formation of a more substituted double
bond. Finally, the reaction was extended to α-amino acid 1k
to give the desired product 2k in excellent yield (72%, entry
11). The α-selectivity was also observed by stabilizing the
carbon-centered radical with the carbamate group at the α-
position.
Table 5 Scope of β,γ-Unsaturated Carboxylic Acidsa
Mes-Acr+-Me (5 mol%)
CuOAc (10 mol%)
(R,R)-Me-DuPHOS (10 mol%)
H
N
CO2tBu
R3
R3 R3
R3 R3
DTBAD (3 equiv)
DBU (25 mol%)
N
tBuO2C
OH
CO2tBu
CO2tBu
R1
R1
N
R1
R3
or
R2
R2
O
HN
MeCN, 4 °C, 24 h
blue LEDs
R2
Entry
1
Acid
Product
Yield (%)b
78
H
N
CO2tBu
Me Me
CO2H
N
Me
tBuO2C
Me
Me
Me
1a
1b
2a
H
CO2tBu
Et Et
CO2H
N
N
Et
tBuO2C
tBuO2C
Me
Me
2
3
68
75
Me
Me
Et
2b
H
CO2tBu
N
N
CO2H
1c
1d
2c
O
H
CO2tBu
N
O
N
tBuO2C
4
76
Me
CO2H
Me
2d
H
N
CO2tBu
Me Me
CO2H
N
Me
tBuO2C
5
6
44
58
Me
1e
2e
H
CO2tBu
Me Me
CO2H
N
N
Me
tBuO2C
Ph
Ph
Me
1f
2f
H
CO2tBu
N
N
tBuO2C
Me
CO2H
7
29
Me
1g
2g
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

F
A.-D. Manick et al.
Special Topic
Synthesis
Table 5 (continued)
Entry
Acid
Product
Yield (%)b
56
CO2tBu
CO2tBu
CO2H
N
HN
8
9
1h
2h
CO2tBu
CO2H
N
Me
1i
Me HN
60
51
CO2tBu
2i
Me
Me
CO2tBu
CO2tBu
CO2H
N
HN
10
Me
Me
1j
2j
CO2tBu
NH
CO2H
N
N
N
11
72
CO2tBu
CO2tBu
CO2tBu
1k
2k
a Reaction conditions: β,γ-unsaturated carboxylic acid 1 (0.2 mmol), CuOAc (0.02 mmol), (R,R)-Me-DuPHOS (0.02 mmol), Mes-Acr+-Me (0.01 mmol), DTBAD (0.6
mmol), DBU (0.05 mmol), MeCN (2 mL), 4 °C, blue LEDs, 24 h.
b Yields refer to isolated products.
Postfunctionalizations of the hydrazide derivative 2a
were examined (Scheme 3). The N–N bond could be easily
cleaved using the Magnus protocol to give the correspond-
ing carbamate 8 in 42% yield in two steps.16 Derivative 8 un-
der ozonolysis conditions, followed by treatment with
NaBH4, led to the formation of the corresponding 1,2-amino
alcohol 9 as a potentially useful building block in 60% yield
in only two steps.17
action was completely inhibited in the presence of the radi-
cal scavenger TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl)
under the standard conditions. Only the radical-trapping
product 11 was formed and isolated in 58% yield. This result
demonstrated that the allylic radical X (and the resonance
form Y) was generated by the loss of CO2 via single-electron
oxidation by photoredox catalysis (Scheme 4, b).
On the basis of the above-described investigations and
previous reports, a presumable mechanism is proposed
(Scheme 5).9,14a,18 The reaction is initiated by oxidation of
carboxylate by photoexcited Mes-Acr+-Me*, resulting in the
allylic radical (C) after CO2 extrusion.19 The generated ter-
tiary radical may be intercepted directly by the azodicar-
boxylate, providing the minor regioisomer (3) due to the
steric hindrance of the radical. Otherwise, radical addition
of the resonance form (D), which is expected to be stabi-
lized by the substituted alkene, to DTBAD may occur to give
the nitrogen-centered radical intermediate (E). The allyla-
tion step could be accelerated in the presence of the copper
catalyst, possibly acting as a Lewis acid.10a,20 Moreover,
regioselectivity was improved in the presence of the copper
catalyst, likely due to the enhanced steric hindrance of
DTBAD by coordination to the copper complex. The cop-
per(I) catalyst might not trap the carbon-centered radical
(C) or (D), presumably because the electron-rich copper
complex would preferentially combine with more electron-
deficient radicals.21 As a result, no enantioinduction was
observed when using chiral ligands. The observations that
O
1)
Br
OMe
(2 equiv)
Cs2CO3 (2.5 equiv)
MeCN, 50 °C
CO2tBu
tBuO2C
tBuO2C
NH
Me
NH Me
N
2) Cs2CO3 (3 equiv)
MeCN, reflux
Me
Me
Me
Me
2a
8
42% over 2 steps
tBuO2C
1) ozonolysis
CH2Cl2, –78 °C;
NH
OH
Me
2) NaBH4 (3 equiv)
MeOH
9
60% over 2 steps
Scheme 3 Postfunctionalization of the product 2a
Next, to gain insight into the mechanism of decarboxyl-
ative allylation of β,γ-unsaturated carboxylic acids cata-
lyzed by the copper/organophotoredox system, a radical-
trapping experiment was carried out (Scheme 4, a). The re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

G
A.-D. Manick et al.
Special Topic
Synthesis
redox-innocent Bi(OAc)3 afforded comparable and im-
proved results to CuOAc for 1a (Table 1, entries 2 and 3) and
for formation of 7a (Scheme 2), respectively, would support
the hypothetical Lewis acid role of the catalytic CuOAc.22 Fi-
nally, regeneration of the photocatalyst Mes-Acr+-Me takes
place with formation of the amide anion (F), which could
deprotonate the acid substrate, leading to the carboxylate
(A) and the predominant regioisomer (2).
In summary, regioselective allylic aminodecarboxyl-
ation of β,γ-unsaturated carboxylic acids involving a dual
organophotoredox/copper catalysis was developed. The
mild and efficient reaction conditions provided access to
allylic hydrazides with total control of the regioselectivity
and high yields. Simple postfunctionalizations of the syn-
thesized allylic hydrazides could provide highly valuable
building units.
All reagents were purchased from chemical suppliers and used with-
out further purification. Reactions were performed using dried
MeCN, THF, CH2Cl2, DMF, and acetone purchased from chemical sup-
pliers. Allylic aminodecarboxylation reactions were carried out in
dried and degassed solvents under argon atmosphere. Analytical TLC
was performed on commercial silica gel 60F254 plates. Flash column
chromatography was performed on silica gel 60 (40–63 μm, pur-
chased from Kanto Chemical Co., Inc.) or by using a Biotage® Isolera™
One 3.0 system with a prepacked Biotage® SNAP Ultra column. NMR
spectra were recorded on JEOL ECX500 (500 MHz for 1H NMR, 125
1
MHz for 13C NMR) and JEOL ECS400 (400 MHz for H NMR, 100 MHz
CO2tBu
Me Me
tBuO2C
NH
N
Me
Me
Me Me
Me
O
N
"standard conditions"
OH
Me
Me
Me
Me
(a)
Me
Me
TEMPO (3 equiv)
O
2a
10
0%
0%
1a
Me
Me
N
Me
O
Me
Me
Me
Me
11
58%
Me
Me
(b)
Me
Me
Me
Me
Y
X
Scheme 4 Mechanistic study of the reaction
hυ
Mes-Acr+-Me*
Mes-Acr+-Me
CO2H
Me Me
CO2
A
1
CO2tBu
CO2tBu
Me Me
tBuO2C
N
Me
A
tBuO2C
N
Me
N
CO2
N
H
Me
Me
F
Mes-Acr-Me
Me
Me Me
B
regioisomer 2
–CO2
CO2tBu
major
tBuO2C
N
Me
N
Me Me
Me
Me
O
E
C
D
OtBu
N
N
tBuO2C
CO2tBu
[Cu(I)]L
[Cu(I)]L = Lewis acid
N
CO2tBu
N
H
Me Me
regioisomer 3
minor
Scheme 5 Proposed mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

H
A.-D. Manick et al.
Special Topic
Synthesis
for 13C NMR) spectrometers. Chemical shifts are reported in ppm on
the δ scale relative to residual CHCl3 (δ = 7.26 for H NMR, δ = 77.16
HRMS (ESI): m/z [M + Na]+ calcd for C22H42N2O4Na: 421.3042; found:
421.3021.
1
for 13C NMR) as an internal reference. Coupling constants (J) are re-
ported in hertz units (Hz); multiplicities are described using standard
abbreviations. ESI-mass spectra were measured on a Shimadzu
LCMS-2020 spectrometer (for LRMS) and a JEOL JMS-T100LC AccuTOF
spectrometer (for HRMS). IR spectra were recorded on a JASCO FT/IR
410 Fourier transform infrared spectrophotometer. The syntheses of
substrates 1a–1d, 1f, 1i, and 1j are described in the Supporting Infor-
mation.
Di-tert-butyl 1-(1-Cyclopentylideneheptan-2-yl)hydrazine-1,2-di-
carboxylate (2c)
Prepared from (E)-1-(hept-1-en-1-yl)cyclopentane-1-carboxylic acid
(1c) and di-tert-butyl azodicarboxylate.
Colorless foam; yield: 40 mg (75%).
Rf = 0.37 (pentane/EtOAc, 9:1).
IR (KBr): 3266, 2957, 1701, 1455, 1366, 1253, 1162, 1048, 1020, 864,
758 cm–1
.
Allylic Aminodecarboxylation of β,γ-Unsaturated Carboxylic Ac-
ids; General Procedure
1H NMR (500 MHz, CDCl3): δ = 6.08–5.93 (br s, 1 H, NH), 5.19 (d, J =
8.5 Hz, 1 H), 4.72–4.54 (br m, 1 H), 2.42–2.08 (br m, 4 H), 1.72–1.51
(m, 5 H), 1.45 (s, 18 H), 1.35–1.06 (br m, 7 H), 0.87 (t, J = 5.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 155.1, 130.6, 119.1, 80.8, 56.9, 33.8,
33.3, 31.9, 29.4, 28.5, 28.4, 26.5, 26.3, 25.9, 22.8, 14.1.
LRMS (ESI): m/z = 419 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H40N2O4Na: 419.2886; found:
A β,γ-unsaturated carboxylic acid 1 (1 equiv) in degassed MeCN
(concn = 0.1 M) was added into a 4-mL vial equipped with a Teflon-
coated magnetic stirring bar. The vial was sealed with a septum cap
and the internal atmosphere was exchanged with argon via three re-
peated cycles of vacuum–refill. Then, 9-mesityl-10-methylacridinium
perchlorate (5 mol%) was added, followed by CuOAc (10 mol%), (R,R)-
Me-DuPHOS (10 mol%), the azodicarboxylate (3 equiv), and DBU (25
mol%). The vial was irradiated with blue LEDs (Aldrich® micro photo-
chemical reactor, 100–240 V, 435–445 nm) under vigorous stirring at
4 °C (cold room). After 24 h, the solvent was removed under reduced
pressure. The crude mixture was purified by flash chromatography
on silica gel (pentane/EtOAc, 9:1 to 8:2) which provided the desired
product.
419.2898.
Di-tert-butyl 1-(1-(Tetrahydro-4H-pyran-4-ylidene)heptan-2-
yl)hydrazine-1,2-dicarboxylate (2d)
Prepared from (E)-4-(hept-1-en-1-yl)tetrahydro-2H-pyran-4-carbox-
ylic acid (1d) and di-tert-butyl azodicarboxylate.
White foam; yield: 47 mg (76%).
Di-tert-butyl 1-(2-Methylnon-2-en-4-yl)hydrazine-1,2-dicarboxyl-
Rf = 0.24 (pentane/EtOAc, 9:1).
ate (2a)
Prepared from (E)-2,2-dimethylnon-3-enoic acid (1a) and di-tert-bu-
tyl azodicarboxylate.
IR (KBr): 3313, 2977, 2857, 1801, 1746, 1456, 1367, 1251, 1049, 854,
759 cm–1
.
Colorless oil; yield: 61 mg (78%).
1H NMR (500 MHz, CDCl3): δ = 6.05–5.93 (br s, 1 H, NH), 5.15 (d, J =
8.5 Hz, 1 H), 4.85–4.74 (br m, 1 H), 3.89–3.57 (br m, 4 H), 2.48–2.26
(br m, 2 H), 2.25–2.15 (br m, 2 H), 1.56–1.48 (br m, 4 H), 1.47 (s, 9 H),
1.46 (s, 9 H), 1.33–1.23 (br m, 4 H), 0.88 (t, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 154.8, 122.3, 83.7, 81.1, 69.6, 68.9,
54.2, 37.1, 33.2, 31.8, 30.8, 28.4, 28.3, 28.1, 25.9, 22.7, 14.1.
Rf = 0.42 (pentane/EtOAc, 9:1).
IR (KBr): 3267, 2930, 1699, 1456, 1366, 1244, 1160, 1049, 865, 730
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.22–5.89 (br s, 1 H, NH), 5.06 (d, J =
8.5 Hz, 1 H), 4.89–4.60 (br m, 1 H), 1.76–1.58 (m, 6 H), 1.45 (s, 18 H),
1.39–1.14 (br m, 8 H), 0.87 (t, J = 5.6 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 154.9, 123.9, 80.7, 55.5, 33.3, 31.8,
28.4, 28.2, 25.7, 25.6, 22.6, 18.5, 14.0.
LRMS (ESI): m/z = 435 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H40N2O5Na: 435.2835; found:
435.2811.
LRMS (ESI): m/z = 393 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C20H38N2O4Na: 393.2729; found:
Di-tert-butyl 1-(3-Methylbut-2-en-1-yl)hydrazine-1,2-dicarboxyl-
ate (2e)
393.2728.
Prepared from 2,2-dimethylbut-3-enoic acid (1e) and di-tert-butyl
azodicarboxylate.
Di-tert-butyl 1-(3-Ethyldec-3-en-5-yl)hydrazine-1,2-dicarboxyl-
ate (2b)
White foam; yield: 35 mg (44%).
Rf = 0.41 (pentane/EtOAc, 9:1).
IR (KBr): 3319, 2977, 1705, 1455, 1366, 1254, 1157 cm–1
.
Prepared from (E)-2,2-diethylnon-3-enoic acid (1b) and di-tert-butyl
azodicarboxylate.
Colorless foam; yield: 72 mg (68%).
1H NMR (500 MHz, CDCl3, 50 °C): δ = 6.10–5.75 (br m, 1 H, NH), 4.97
(t, J = 7.0 Hz, 1 H), 3.79 (d, J = 6.0 Hz, 2 H), 1.47 (s, 3 H), 1.40 (s, 3 H),
1.21 (s, 9 H), 1.21 (s, 9 H).
13C NMR (100 MHz, CDCl3, 50 °C): δ = 155.5, 136.7, 119.4, 81.2, 47.4,
28.4, 25.8, 17.9.
LRMS (ESI): m/z = 323.0 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C15H28N2O4Na: 323.1947; found:
Rf = 0.38 (pentane/EtOAc, 9:1).
IR (KBr): 2966, 1702, 1366, 1162, 1022, 755 cm–1
1H NMR (500 MHz, CDCl3): δ = 6.07–5.69 (br s, 1 H, NH), 5.03 (d, J =
9.0 Hz, 1 H), 4.87–4.73 (br m, 1 H), 2.10 (q, J = 7.5 Hz, 2 H), 2.03 (q, J =
7.0 Hz, 2 H), 1.70–1.22 (m, 8 H), 1.46 (s, 18 H), 0.99 (t, J = 7.5 Hz, 3 H),
0.97 (t, J = 7.5 Hz, 3 H), 0.88 (t, J = 6.0 Hz, 3 H).
.
323.1938.
13C NMR (125 MHz, CDCl3): δ = 154.9, 121.7, 80.9, 54.8, 33.6, 31.9,
29.1, 28.5, 28.4, 25.9, 24.1, 22.7, 14.1, 13.4, 12.9.
Data are in accordance with the literature.23
LRMS (ESI): m/z = 421 [M + Na]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

I
A.-D. Manick et al.
Special Topic
Synthesis
Di-tert-butyl 1-(5-Methyl-1-phenylhex-4-en-3-yl)hydrazine-1,2-
IR (KBr): 3585, 2278, 1702, 1069, 667 cm–1
.
dicarboxylate (2f)
1H NMR (500 MHz, CDCl3): δ = 6.36–6.07 (br s, 1 H, NH), 4.87 (s, 1 H),
Prepared from (E)-2,2-dimethyl-6-phenylhex-3-enoic acid (1f) and
di-tert-butyl azodicarboxylate.
4.81 (s, 1 H), 4.07–3.87 (br m, 2 H), 1.73 (s, 3 H), 1.47 (s, 9 H), 1.47 (s, 9
H).
13C NMR (100 MHz, CDCl3): δ = 155.6, 140.9, 112.9, 81.4, 81.3, 53.5,
Pale foam; yield: 39 mg (58%).
29.9, 28.4, 20.3.
Rf = 0.40 (pentane/EtOAc, 9:1).
LRMS (ESI): m/z = 309 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C14H26N2O4Na: 309.1790; found:
IR (KBr): 3267, 2977, 2930, 1703, 1455, 1392, 1366, 1250, 1160, 699,
654 cm–1
.
1H NMR (500 MHz, CDCl3, 50 °C): δ = 7.32–7.23 (m, 2 H), 7.23–7.12
(m, 3 H), 6.05–5.80 (br m, 1 H), 5.13 (d, J = 9.0 Hz, 1 H), 4.89–4.69 (br
m, 1 H), 2.86–2.56 (br m, 2 H), 2.09–1.91 (br m, 1 H), 1.72 (s, 3 H), 1.64
(s, 3 H), 1.71–1.59 (br m, 1 H), 1.47 (s, 9 H), 1.46 (s, 9 H).
309.1799.
Di-tert-butyl 1-((E)-4-Methylpent-2-en-1-yl)hydrazine-1,2-dicar-
boxylate (2j)
13C NMR (125 MHz, CDCl3, 50 °C): δ = 155.9, 155.0, 142.5, 135.9,
Prepared from (E)-5-methylhex-3-enoic acid (1j) and di-tert-butyl
azodicarboxylate.
128.6, 128.4, 125.8, 123.5, 81.1, 55.4, 35.1, 32.6, 28.4, 28.4, 25.8, 18.7.
LRMS (ESI): m/z = 427.1 [M + Na]+.
Colorless foam; yield: 31 mg (51%).
HRMS (ESI): m/z [M + Na]+ calcd for C23H36N2O4Na: 427.2573; found:
Rf = 0.33 (pentane/EtOAc, 9:1).
IR (KBr): 3326, 2977, 1707, 1652, 1541, 1365, 1152 cm–1
.
427.2566.
1H NMR (500 MHz, CDCl3): δ = 6.39–6.11 (br s, 1 H, NH), 5.56 (dd, J =
6.5, 15.5 Hz, 1 H), 5.40 (dtd, J = 1.0, 6.5, 15.5 Hz, 1 H), 4.05–3.91 (br m,
2 H), 2.35–2.23 (m, 1 H), 1.47 (s, 9 H), 1.46 (s, 9 H), 0.98 (d, J = 7.0 Hz,
6 H).
Di-tert-butyl 1-(Oct-1-en-3-yl)hydrazine-1,2-dicarboxylate (2g)
Prepared from (E)-non-3-enoic acid (1g) and di-tert-butyl azodicar-
boxylate.
13C NMR (125 MHz, CDCl3): δ = 155.4, 141.9, 121.5, 81.2, 53.1, 51.5,
Colorless oil; yield: 19 mg (29%).
30.9, 28.3, 22.4.
Rf = 0.35 (pentane/EtOAc, 9:1).
LRMS (ESI): m/z = 337 [M + Na]+.
IR (KBr): 3303, 2929, 1705, 1456, 1392, 1157, 601 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C16H30N2O4Na: 337.2103; found:
337.2106.
1H NMR (500 MHz, CDCl3): δ = 6.10–5.88 (br s, 1 H, NH), 5.88–5.73 (m,
1 H), 5.19–5.08 (br m, 2 H), 4.59–4.44 (br m, 1 H), 1.74–1.59 (br m, 1
H), 1.46 (s, 18 H), 1.40–1.22 (br m, 7 H), 0.88 (br m, 3 H).
Di-tert-butyl 1-(1-(tert-Butoxycarbonyl)-2,5-dihydro-1H-pyrrol-
2-yl)hydrazine-1,2-dicarboxylate (2k)
13C NMR (125 MHz, CDCl3): δ = 155.1, 137.1, 116.4, 81.3, 60.4, 31.8,
31.5, 28.4, 28.4, 25.9, 22.7, 14.1.
Prepared from 1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-
carboxylic acid (1k) and di-tert-butyl azodicarboxylate.
LRMS (ESI): m/z = 365 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C18H34N2O4Na: 365.2416; found:
Yellow foam; yield: 76 mg (72%).
365.2419.
Rf = 0.35 (pentane/EtOAc, 8:2).
Di-tert-butyl 1-(Cyclohex-1-en-1-ylmethyl)hydrazine-1,2-dicar-
boxylate (2h)
IR (KBr): 3314, 2978, 1707, 1478, 1418, 1391, 1327, 1244, 1164, 896,
635 cm–1
.
1H NMR (500 MHz, CDCl3, 50 °C): δ = 6.73–6.53 (br m, 1 H), 6.21–5.89
(br m, 2 H), 5.84–5.59 (br m, 1 H), 4.21–3.95 (br m, 2 H), 1.47 (s, 18 H),
1.44 (s, 9 H).
13C NMR (125 MHz, CDCl3, 50 °C): δ = 155.9, 120.2, 111.9, 83.7, 81.6,
52.8, 28.4, 28.2.
LRMS (ESI): m/z = 422.1 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C19H33N3O6Na: 422.2267; found:
Prepared from 1-cyclohexene-1-acetic acid (1h) and di-tert-butyl
azodicarboxylate.
Colorless foam; yield: 23 mg (56%).
Rf = 0.34 (pentane/EtOAc, 9:1).
IR (KBr): 2930, 1699, 1366, 1156, 759 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 6.32–5.86 (br s, 1 H, NH), 5.60–5.45 (br
m, 1 H), 4.06–3.73 (br m, 2 H), 2.09–1.97 (br m, 2 H), 1.96–1.83 (br m,
2 H), 1.68–1.52 (br m, 4 H), 1.46 (s, 18 H).
422.2265.
13C NMR (100 MHz, CDCl3): δ = 155.7, 133.4, 125.1, 81.2, 56.2, 28.4,
26.6, 25.3, 22.8, 22.5.
LRMS (ESI): m/z = 349 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C17H30N2O4Na: 349.2103; found:
Diisopropyl 1-(2-Methylnon-2-en-4-yl)hydrazine-1,2-dicarboxyl-
ate (4a)
Prepared from (E)-2,2-dimethylnon-3-enoic acid (1a) and diisopropyl
azodicarboxylate.
349.2105.
Colorless foam; yield: 25 mg (68%).
Rf = 0.35 (pentane/EtOAc, 9:1).
IR (KBr): 2927, 2359, 1715, 1385, 1109, 762 cm–1
Di-tert-butyl 1-(2-Methylallyl)hydrazine-1,2-dicarboxylate (2i)
.
Prepared from 3-methylbut-3-enoic acid (1i) and di-tert-butyl azodi-
1H NMR (500 MHz, CDCl3): δ = 6.17–6.02 (br s, 1 H, NH), 5.06 (d, J =
8.0 Hz, 1 H), 5.01–4.88 (br m, 2 H), 4.87–4.69 (m, 1 H), 1.70 (s, 3 H),
1.67 (s, 3 H), 1.49–1.02 (m, 20 H), 0.87 (t, J = 6.5 Hz, 3 H).
carboxylate.
Colorless foam; yield: 37 mg (60%).
Rf = 0.31 (pentane/EtOAc, 9:1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

J
A.-D. Manick et al.
Special Topic
Synthesis
13C NMR (125 MHz, CDCl3): δ = 156.4, 155.6, 136.1, 123.4, 69.9, 69.5,
LRMS (ESI): m/z = 461 [M + Na]+.
55.6, 33.2, 31.8, 25.8, 22.8, 22.2, 22.2, 22.1, 18.7, 14.2.
LRMS (ESI): m/z = 365 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C26H34N2O4Na: 461.2416; found:
461.2433.
HRMS (ESI): m/z [M + Na]+ calcd for C18H34N2O4Na: 365.2416; found:
365.2438.
Di-tert-butyl (E)-1-(2-Methylnon-3-en-2-yl)hydrazine-1,2-dicar-
boxylate (3a)
Prepared from (E)-2,2-dimethylnon-3-enoic acid (1a) and di-tert-bu-
tyl azodicarboxylate under standard conditions, in the absence of
CuOAc and DuPHOS ligand.
Diethyl 1-(2-Methylnon-2-en-4-yl)hydrazine-1,2-dicarboxylate
(5a)
Prepared from (E)-2,2-dimethylnon-3-enoic acid (1a) and diethyl
azodicarboxylate.
Mixture of inseparable regioisomers 2a and 3a (ratio 2a/3a = 80:20).
Colorless foam; yield: 24 mg (52%).
1H NMR (400 MHz, CDCl3, 50 °C): δ = 6.28–5.89 (br m, 0.8 H, NH, 2a),
5.86–5.75 (br m, 0.2 H, NH, 3a), 5.66 (d, J = 14.8 Hz, 0.2 H, 3a), 5.43
(dt, J = 6.4, 16.0 Hz, 0.2 H, 3a), 5.06 (d, J = 8.8 Hz, 0.8 H, 2a), 4.94–4.57
(br m, 0.8 H, 2a), 2.00 (q, J = 7.2 Hz, 0.4 H, 3a), 1.79–1.58 (m, 6 H, 2a,
3a), 1.54–1.03 (m, 25.6 H, 2a, 3a), 0.93–0.80 (m, 3 H, 2a, 3a).
Rf = 0.31 (pentane/EtOAc, 9:1).
IR (KBr): 2932, 1708, 1412, 1222, 1061, 667 cm–1
1H NMR (500 MHz, CDCl3): δ = 6.26–6.00 (br s, 1 H, NH), 5.06 (d, J =
9.0 Hz, 1 H), 4.85–4.71 (br m, 1 H), 4.18 (q, J = 7.0 Hz, 4 H), 1.70 (s, 3
H), 1.68 (s, 3 H), 1.47–1.16 (m, 14 H), 0.87 (t, J = 6.5 Hz, 3 H).
.
Di-tert-butyl 1-(2-Methylbut-3-en-2-yl)hydrazine-1,2-dicarboxyl-
ate (3e)
13C NMR (125 MHz, CDCl3): δ = 156.8, 156.0, 136.2, 123.1, 62.4, 62.0,
55.9, 33.1, 31.8, 25.8, 22.7, 18.7, 14.6, 14.6, 14.2.
LRMS (ESI): m/z = 337 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C16H30N2O4Na: 337.2103; found:
Prepared from 2,2-dimethylbut-3-enoic acid (1e) and di-tert-butyl
azodicarboxylate under standard conditions, in the absence of CuOAc
and DuPHOS ligand.
Mixture of inseparable regioisomers 2e and 3e (ratio 2e/3e = 85:15).
337.2090.
1H NMR (500 MHz, CDCl3, 50 °C): δ = 6.49–6.08 (br m, 1.7 H, NH, 2e),
6.01–5.91 (br m, 0.3 H, NH, 3e), 5.21 (t, J = 7.0 Hz, 1.3 H, 2e), 5.11–5.00
(m, 0.4 H, 3e), 4.99–4.93 (m, 0.2 H, 3e), 1.73 (s, 3 H, 2e, 3e), 1.65 (s, 3
H, 2e, 3e), 1.46 (s, 18 H, 2e, 3e).
Bis(2-methoxyethyl) 1-(2-Methylnon-2-en-4-yl)hydrazine-1,2-di-
carboxylate (6a)
Prepared from (E)-2,2-dimethylnon-3-enoic acid (1a) and bis(2-me-
thoxyethyl) azodicarboxylate.
Di-tert-butyl (E)-1-(Oct-2-en-1-yl)hydrazine-1,2-dicarboxylate
(3g)
Colorless foam; yield: 21 mg (60%).
Rf = 0.28 (pentane/EtOAc, 1:1).
Prepared from (E)-non-3-enoic acid (1g) and di-tert-butyl azodicar-
boxylate under standard conditions, in the absence of CuOAc and Du-
PHOS ligand.
IR (KBr): 3284, 2927, 1757, 1714, 1519, 1455, 1245, 1128, 1067, 850,
759 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.59–6.29 (br s, 1 H, NH), 5.05 (d, J =
8.8 Hz, 1 H), 4.92–4.67 (br m, 1 H), 4.39–4.14 (br m, 4 H), 3.68–3.50
(br m, 4 H), 3.39 (s, 3 H), 3.36 (s, 3 H), 1.70 (s, 3 H), 1.68 (s, 3 H), 1.44–
1.17 (m, 8 H), 0.87 (t, J = 6.8 Hz, 3 H).
Mixture of separable regioisomers 2g and 3g (ratio 2g/3g = 7:3).
Colorless oil; yield: 29 mg (49%).
Rf = 0.35 (pentane/EtOAc, 9:1).
IR (KBr): 3321, 2925, 1716, 1456, 1393, 1367, 1254, 1155, 629 cm–1
.
13C NMR (125 MHz, CDCl3): δ = 156.5, 135.4, 122.9, 70.8, 65.4, 64.9,
1H NMR (400 MHz, CDCl3): δ = 6.36–5.93 (br s, 1 H, NH), 5.64–5.53 (br
m, 1 H), 5.49–5.37 (br m, 1 H), 4.11–3.86 (br m, 2 H), 2.02 (q, J = 7.2
Hz, 2 H), 1.46 (s, 18 H), 1.38–1.26 (br m, 6 H), 0.88 (t, J = 7.2 Hz, 3 H).
59.1, 59.0, 33.1, 31.8, 25.8, 25.7, 22.7, 14.2.
LRMS (ESI): m/z = 397 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C18H34N2O6Na: 397.2765; found:
397.2747.
13C NMR (125 MHz, CDCl3): δ = 155.4, 135.2, 124.5, 81.3, 61.5, 32.4,
31.5, 29.9, 29.0, 28.4, 22.6, 14.1.
Dibenzyl 1-(2-Methylnon-2-en-4-yl)hydrazine-1,2-dicarboxylate
(7a)
HRMS (ESI): m/z [M + Na]+ calcd for C18H34N2O4Na: 365.2416; found:
365.2407.
Prepared from (E)-2,2-dimethylnon-3-enoic acid (1a) and dibenzyl
azodicarboxylate; reaction conditions: Bi(OAc)3 utilized instead of
CuOAc/DuPHOS ligand.
tert-Butyl (2-Methylnon-2-en-4-yl)carbamate (8)
In a round-bottom flask were placed di-tert-butyl 1-(2-methylnon-2-
en-4-yl)hydrazine-1,2-dicarboxylate (2a, 1.0 equiv) and Cs2CO3 (2.5
equiv) in MeCN (concn = 0.175 M) under argon. At r.t., methyl bromo-
acetate (2.0 equiv) was added. The mixture was heated at 50 °C for 18
h. The reaction was quenched with aq NH4Cl and the resulting mix-
ture was extracted with EtOAc (3 ×). The combined organic phases
were dried over Na2SO4, filtered, and the solvent was removed under
reduced pressure. The crude was placed in a round-bottom flask in
MeCN (concn = 0.18 M). Then, Cs2CO3 (3 equiv) was added at r.t. The
mixture was heated at reflux for 16 h. The reaction was quenched
with aq NH4Cl and the resulting mixture was extracted with EtOAc
(3 ×). The combined organic phases were dried over Na2SO4, filtered,
Colorless foam; yield: 18 mg (38%).
Rf = 0.21 (pentane/EtOAc, 9:1).
IR (KBr): 2926, 2361, 1709, 1407, 1217, 1049, 600 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.48–7.17 (br m, 10 H), 6.48–6.25 (br s,
1 H, NH), 5.28–5.08 (br m, 4 H), 5.05 (d, J = 6.5 Hz, 1 H), 4.90–4.68 (br
m, 1 H), 1.74–1.01 (br m, 14 H), 0.92–0.73 (br m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 156.8, 136.2, 135.9, 128.7, 128.6,
128.5, 128.3, 128.3, 128.1, 122.9, 68.1, 67.8, 56.0, 33.2, 31.8, 25.8,
22.7, 18.7, 14.2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

K
A.-D. Manick et al.
Special Topic
Synthesis
and the solvent was removed under reduced pressure. The crude resi-
due was purified by silica gel flash chromatography (pentane/EtOAc,
98:2 to 95:5).
Funding Information
This work was supported by a JSPS postdoctoral fellowship (A.-D.M.),
JSPS KAKENHI Grant Number JP16H01007 in Precisely Designed Cata-
lysts with Customized Scaffolding (K.O.), and JSPS KAKENHI Grant
White foam; yield: 21 mg (42% over 2 steps).
Rf = 0.51 (pentane/EtOAc, 9:1).
Number JP17H06442 in Hybrid Catalysis (M.K.).
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IR (KBr): 3419, 2284, 1055, 782, 601 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.93 (d, J = 8.5 Hz, 1 H), 4.44–4.28 (br
m, 1 H), 4.28–4.15 (br m, 1 H), 1.69 (s, 3 H), 1.68 (s, 3 H), 1.43 (s, 9 H),
1.39–1.19 (br m, 8 H), 0.87 (t, J = 7.0 Hz, 3 H).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591983.
13C NMR (125 MHz, CDCl3): δ = 155.5, 134.6, 126.5, 79.1, 49.4, 36.7,
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31.9, 28.6, 25.7, 25.5, 22.8, 18.5, 14.1.
LRMS (ESI): m/z = 278 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C15H29NO2Na: 278.2096; found:
References
278.2077.
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tert-Butyl (1-Hydroxyheptan-2-yl)carbamate (9)
(2) For a recent review, see: . Patra, T.; Maiti, D. Chem. Eur. J. 2017,
23, 7382.
A solution of tert-butyl (2-methylnon-2-en-4-yl)carbamate (8; 20 mg,
0.08 mmol, 1 equiv) in CH2Cl2 (1 mL) was cooled to –78 °C, which was
followed by bubbling of ozone (converted from oxygen by an ozone
generator) for 5 min with stirring. After the reaction color changed to
blue, oxygen was bubbled through the solution to remove ozone.
MeOH (0.5 mL) and NaBH4 (3 equiv) were added to the mixture at –
78 °C. Then, the reaction mixture was allowed to warm to r.t. for 1 h.
The solvents were removed in vacuo and the residue was purified by
silica gel flash chromatography (pentane/EtOAc, 6:4).
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White foam; yield: 10 mg (60% over 2 steps).
Rf = 0.18 (pentane/EtOAc, 9:1).
IR (KBr): 3853, 3585, 3346, 2929, 2359, 1684, 1508, 1457, 1365, 1251,
1061, 670 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.62–4.42 (br s, 1 H, NH), 3.70–3.52 (br
m, 2 H), 3.57–3.51 (br m, 1 H), 2.15–1.89 (br m, 1 H), 1.46 (s, 9 H),
1.43–1.24 (br m, 8 H), 0.90 (t, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 156.7, 79.8, 66.3, 53.3, 31.9, 31.8, 28.6,
25.8, 22.7, 14.0.
LRMS (ESI): m/z = 232 [M + H]+, 254 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C12H25NO3Na: 254.1732; found:
254.1716.
2,2,6,6-Tetramethyl-1-((2-methylnon-2-en-4-yl)oxy)piperidine
(11)
Using the general procedure, prepared from (E)-2,2-dimethylnon-3-
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of TEMPO (3 equiv).
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Orange foam; yield: 22 mg (58%).
Rf = 0.63 (pentane/EtOAc, 95:5).
IR (KBr): 2871, 1774, 1459, 1375, 1248, 1154, 1048, 957, 865 cm–1
1H NMR (500 MHz, CDCl3): δ = 5.11–5.03 (m, 1 H), 4.33 (td, J = 4.0, 8.5
Hz, 1 H), 1.63 (s, 3 H), 1.62 (s, 3 H), 1.44–1.35 (m, 4 H), 1.35–1.17 (m,
10 H), 1.15 (s, 6 H), 1.08 (s, 6 H), 0.87 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 132.5, 129.1, 80.6, 60.3, 40.6, 39.5,
35.1, 32.3, 31.7, 27.9, 25.9, 25.2, 22.8, 20.7, 18.7, 17.6, 17.2, 14.1.
LRMS (ESI): m/z = 296 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H38NO: 296.2875; found:
.
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296.2890.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

L
A.-D. Manick et al.
Special Topic
Synthesis
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•
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L