Cu(OTf) 2 -Catalyzed Beckmann Rearrangement of Ketones Using Hydroxylamine- O -sulfonic Acid (HOSA)

Article abstract of DOI:10.1055/s-0039-1690005

The Beckmann rearrangement (BKR) of ketones to secondary amides often requires harsh reaction conditions that limit its practicality and scope. Herein, the Cu(OTf) ₂ -catalyzed BKR of ketones under mild reaction conditions using hydroxylamine- O -sulfonic acid (HOSA), a commercial water soluble aminating agent, is described. This method is compatible with most functional groups and directly provides the desired amides in good to excellent yields.

Full text of DOI:10.1055/s-0039-1690005

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–F
paper
A
de
S. Munnuri et al.
Paper
Synthesis
Cu(OTf)2-Catalyzed Beckmann Rearrangement of Ketones Using
Hydroxylamine-O-sulfonic Acid (HOSA)
Sailu Munnuria
O
Saumya Vermab
Dinesh Chandrab
Raghunath Reddy Anugua
John R. Falcka
O
O
Cu(OTf)2, CsOH·H2O
R1
O
H2N
+
S
R2
R2
N
H
R1
O
TFE/DCM (1:4)
rt to 70 °C
OH
22 examples
up to 89% yield
R1,R2 = Aromatic or Aliphatic
Jawahar L. Jat*b
One pot, operationally simple
Water-soluble by-product
Open flask
Secondary amide directly from ketone
Wide functional group tolerance
a Division of Chemistry, Department of Biochemistry, UT Southwestern
Medical Center, Dallas, TX 75390, USA
b Department of Chemistry, Babasaheb Bhimrao Ambedkar University
(A Central University), Lucknow, India
Excellent yields, broad scope
jawaharlj@bbau.ac.in
jatjawahar@gmail.com
Received: 04.06.2019
Accepted after revision: 27.06.2019
Published online: 16.07.2019
O
H
MeO
N
O
N
Me
N
H
DOI: 10.1055/s-0039-1690005; Art ID: ss-2019-t0314-op
Me
O
Me
HO
OMe
Abstract The Beckmann rearrangement (BKR) of ketones to second-
ary amides often requires harsh reaction conditions that limit its practi-
cality and scope. Herein, the Cu(OTf)2-catalyzed BKR of ketones under
mild reaction conditions using hydroxylamine-O-sulfonic acid (HOSA), a
commercial water soluble aminating agent, is described. This method is
compatible with most functional groups and directly provides the de-
sired amides in good to excellent yields.
Paracetamol
Trimethobenzamide
Me
O
O
Me
Me
N
NH
N
N
H
MeO
Cl
Xylocaine
Moclobemide
Key words hydroxylamine-O-sulfonic acid (HOSA), ketone, Beckmann
rearrangement, Cu(OTf)2, secondary amide
O
OH
N
HN
N
N
N
O
Me
N
O
Me
H
Me
Me
O
The Beckmann rearrangement (BKR) is a popular meth-
od for the formation of amides from ketones and aldehydes
via an oxime intermediate.1 The conversion of an oxime
into an amide was done first by the German chemist Ernst
Otto Beckmann in 1886.2 Notably, the BKR enjoys a promi-
nent industrial role including the manufacture of monomer
for polymerization into nylon-6 and nylon-12.3 Also, amides
are common components in drugs, natural products, agro-
chemicals, and functional materials (Figure 1).4,5
The traditional BKR requires harsh conditions such as
high reaction temperatures and strongly acidic media, thus
restricting the variety of suitable substrates; often, the pro-
cess requires isolation of the oxime intermediate, which can
be labile and involves a cumbersome purification process
(Scheme 1a,b).6 More recent modifications have addressed
these limitations via catalysis with transition metals,7 calci-
um complexes,8 organocatalysts,9–13 inorganic Lewis ac-
ids,14 and boronic acids.15 Nevertheless, the need for a mild,
inexpensive, and environmentally friendly procedure, espe-
cially for the direct conversion from ketones,16 still persists.
N
H
Me
Valsartan
Melatonin
Figure 1 Amide bonds in drug molecules
Hydroxylamine-O-sulfonic acid (HOSA) attracted our at-
tention for the BKR because it is commercial, inexpensive,
water soluble, and readily handled.17 Indeed, it has found
sporadic utility in the BKR,18 but primarily with aliphatic
ketones. With aromatic ketones or hindered systems, strong
acid and/or high temperatures are still required.19 Fortu-
itously, we had observed early transition metal salts, espe-
cially Cu(OTf)2, accelerated the condensation and rearrange-
ment of aromatic ketones with HOSA.
To actualize our aim, an introductory study was done
using 2-methoxyacetophenone (1a) as a representative
substrate along with HOSA and Cu(OTf)2 at room tempera-
ture (Table 1). Our investigation to optimize the reaction
parameters to obtain amide 2a from 1a showed that a base
was needed to commence the reaction. With lithium hy-
droxide (LiOH), 95% of the starting material 1a was con-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. Munnuri et al.
Paper
Synthesis
(a) Traditional approach
O
O
NOH
strong acid
reflux
R2
R1
(Two-step process)
R1
R2
R2
R1
N
H
OSO2Ph
(b) Recent developments in amide synthesis
N
EtO
Me, TsOH·H2O
HgCl2, MeCN, 80 °C
ref. 7a
H2O, MeCN, rt, 24 h
ref. 16a
10 mol% Ca(NTf)2
NOH
O
R2
O
10 mol% nBu4NPF6
NH2OH·HCl, FeCl3·6H2O
130 °C, 0.45 h
R1
R2
N
R1
4:1 DCE/DME, 80 °C
ref. 8
H
R2
R1
ref. 16b
Boronic acid (5 mol%)
perfluoropinacol (5 mol%)
NH2OH·HCl, Fe2O3@SiO2
solvent, reflux
MeNO2/HFIP, rt, 24 h
ref. 15
ref. 6b
(ii) From ketone
(i) From oxime
O
NH2OH
R1
H
ref. 7c
(iii) From aldehyde
(c) This work
O
O
H2N-O-SO3H, Cu(OTf)2
R1
R2
R1
R2
N
CsOH·H2O, TFE/DCM (1:4)
rt to 70 °C
H
Scheme 1 Beckmann rearrangement of ketones and recent variations
Table 1 Optimization of Reaction Conditionsa
sumed and the expected amide was obtained in 85% yield
along with 10% of oxime 3a (Table 1, entry 1). The most sat-
isfactory result was achieved with cesium hydroxide mono-
hydrate (CsOH·H2O) in which the desired amide 2a was ob-
tained in 88% yield (entry 7) whereas other mild bases were
not very effective (entries 2–5) or in the case of K2CO3
proved ineffective (entry 6).
OH
Me
Me
O
N
O
Cu(OTf)2
H2NOSO3H
NH
OMe
2a
Me
OMe
+
base, solvent
rt, 14 h
OMe
3a
1a
Finally, a variety of solvents were screened including
hexafluoroisopropanol (HFIP), 2,2,2-trifluoroethanol (TFE),
methanol, ethyl alcohol, tetrahydrofuran (THF), acetonitrile,
dichloromethane, and a mixture of TFE/CH2Cl2 (1:4) (Table
1). While HFIP and TFE delivered amide 2a in comparable
yields (83% and 84%, respectively; Table 1, entries 8 and 9), a
mixture of TFE/CH2Cl2 was best for both the yield of amide
2a (88%, entry 7) and for solubilization of ketones. Only ace-
tonitrile, despite its frequent use in amidation reactions,
failed to support the BKRs (entry 14).
Having established the optimum reaction conditions,
the scope of the methodology was evaluated with a range of
representative ketones (Scheme 2). Generally, acetophe-
nones with strong aryl electron-donating groups reacted
smoothly at room temperature to deliver the derived N-
phenylacetamides in very good yields, for example, phenol
2b, 4-methoxy 2c, 3,4-dimethoxy 2d, and 4-allyloxy 2e. The
latter is notable for its chemoselectivity, that is, no allylic20
or CH amination21 or aziridination17c under the reaction
conditions. In contrast, 4-tolyl 2f, phenyl 2g, and naphthyl
2h required heating for a reasonable reaction rate, although
room temperature reactivity was restored in the homolo-
gous 2i, j. The halogenated ketones 2l–n were well behaved
Entry Base
Solvent
Yield (%)
2a 3a
1ab
1
LiOH
TFE/CH2Cl2 (1:4)
85
10
0
5
2c
3d
4d
5d
6
Na2CO3
TFE/CH2Cl2 (1:4)
TFE/CH2Cl2 (1:4)
TFE/CH2Cl2 (1:4)
TFE/CH2Cl2 (1:4)
TFE/CH2Cl2 (1:4)
10
60
60
40
NR
88
83
84
10
0
90
0
Et3N
40
40
60
pyridine
DMAP
0
0
K2CO3
100
0
7d
8d
9d
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
TFE/CH2Cl2 (1:4)
HFIP
0
0
0
TFE
0
0
10
MeOH
EtOH
90
50
30
90
0
11h
12i
13
50
70
0
THF
0
CH2Cl2
10
14
MeCN
NR
100
a Reaction conditions: Cu(OTf)2 (0.1equiv), HOSA (2 equiv), CsOH·H2O (2
equiv), TFE/CH2Cl2 (1:4), rt, 14 h. TFE = 2,2,2-trifluoroethanol. NR: No reac-
tion.
b Recovered 1a; 0% recovered = 100% consumed.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–F

C
S. Munnuri et al.
Paper
Synthesis
Cu(OTf)2 (10 mol%)
H2N-O-SO3H (2 equiv)
O
O
R1
R1
R2
N
R2
CsOH·H2O (2 equiv)
TFE/CH2Cl2 (1:4)
H
1
2
H
H
H
H
N
Me
N
Me
MeO
MeO
N
Me
N
Me
O
O
O
O
HO
MeO
O
2b: rt, 18 h, 80%
2c: rt, 16 h, 86%
2d: rt, 18 h, 80%
2e: rt, 16 h, 86%
H
H
H
H
N
N
Me
N
Me
N
Me
Me
O
O
O
O
Me
2f: 70 °C, 16 h, 85%
2g: 70 °C, 16 h, 80%
2h: 70 °C, 20 h, 70%
2i: rt, 16 h, 85%
Me
H
Cl
H
H
H
Me
N
Me
N
N
Me
N
Br
Me
O
O
O
O
Cl
2n: 70 °C, 20 h, 70%
R
2k: R = F, 70 °C, 24 h, 25%
2l: R = Br, 70 °C, 20 h, 60%
2j: rt, 24 h, 81%
2m: 70 °C, 8 h, 70%
Me
H
O
O
N
HN
O
N
H
N
O
H
N
Ts
2q: rt, 17 h, 80%
2r: rt, 32 h, 75%
2o: 70 °C, 20 h, 50%
2p: 70 °C,16 h, 50%
O
Me
H
Me
Me
N
O
HN
H
H
Me
Me
N
Me
O
H
H
HN
O
MeO
2v: 70 °C, 6 h, 50%
2s: rt, 17 h, 89%
2t: rt, 14 h, 85%
2u: rt, 22 h, 85%
Scheme 2 One-pot synthesis of secondary amides from ketones
and provided good yields of amide, except for 4′-fluoroace-
tophenone which was less reactive, as it delivered the cor-
responding amide 2k in 25% yield only at 70 °C in 24 hours.
The BKR of benzophenone and 3-acetyindole furnished 2o
and 2p, respectively, albeit in modest yields. Lactams 2q–t
were readily obtained from the corresponding cyclic ke-
tones in high yields. Following upon well-established mi-
gratory priorities, estrone 3-methyl ether and hex-2-one
led to 2u and 2v, respectively.
We propose the Cu(OTf)2 has a dual role in catalyzing
the BKR (Scheme 3). First, as a mild Lewis acid, it assists in
the formation of the transient ketoxime intermediate A that
could be observed in some cases. Second, by way of the
five-membered transition state B, the copper catalyzes the
migration of the R1 group to the nitrogen from which the
Beckmann product is finally obtained.
In conclusion, we have developed an operationally sim-
ple, one-pot BKR route to secondary amides directly from
ketones using inexpensive, easily handled HOSA as aminat-
ing agent via Cu(II)-catalysis.
Reactions, unless otherwise stated, were carried out with magnetic
stirring open to the atmosphere in oven-dried glassware. Reagents
were used as received, unless otherwise noted. For TLC precoated
plates (Merck silica gel 60, F254) were used and visualized with UV
light and/or charring after dipping in PMA or KMnO4 solution. The
compounds were purified by triturating the crude reaction mixture
under hexane or by flash column chromatography using silica gel
(100–200 mesh) with EtOAc/hexane as eluent. 1H and 13C NMR spec-
tra were recorded at 400 and 100 MHz, respectively, in CDCl3 or
DMSO-d6 as solvent. Chemical shifts  are reported in parts per mil-
lion (ppm) relative to residual undeuterated solvent as an internal ref-
erence (1H  = 7.26 and 13C  = 77.0 for CDCl3,  = 2.50 and 39.52 for
DMSO-d6, respectively). Standard abbreviations are used to indicate
NMR peak multiplicities.
O
O
S
O
O
O
O S
Cu(OTf)2
H2NOSO3H
O
O
O
(TfO)2Cu
O
H2O
N
N
R1
Amides from Ketones; General Procedure
R1
R2
R2
N
CsOH·H2O
TFE/DCM
H
R1
R2
R1
R2
To a stirred solution of Cu(OTf)2 (0.05 mmol, 10 mol%) in TFE/CH2Cl2
(1:4, 2–3 mL) were added ketone (0.5 mmol, 1.0 equiv), HOSA (2.0
equiv), and CsOH·H2O (2.0 equiv) at rt. The reaction mixture was
maintained at the temperature and for the time indicated in Scheme
2. After completion, the mixture was diluted with CH2Cl2 (10 mL) and
washed with sat. aq Na2CO3 (3 × 5 mL). The combined organic layers
Beckmann product
A
B
Scheme 3 Proposed mechanism for Cu(OTf)2 catalyzed Beckmann re-
arrangement
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–F

D
S. Munnuri et al.
Paper
Synthesis
were washed with brine (5 mL) and dried (anhyd Na2SO4). The crude
product obtained after removal of all volatiles in vacuo was purified
by SiO2 (100–200 mesh) chromatography using EtOAc/hexane as elu-
ent.
1H NMR (400 MHz, CDCl3):  = 7.53 (d, J = 8.0 Hz, 2 H), 7.31 (t, J = 7.8
Hz, 2 H), 7.09 (t, J = 7.3 Hz, 1 H), 2.51 (sept, J = 6.8 Hz, 1 H), 1.25 (d,
J = 6.8 Hz, 6 H).
N-(4-Fluorophenyl)acetamide (2k)28
N-(2-Methoxyphenyl)acetamide (2a)22
Yield: 19 mg (25%); white solid; mp 153–154.6 °C.
Yield: 73 mg (88%); white solid; mp 72–74 °C.
1H NMR (400 MHz, CDCl3):  = 7.45 (dd, J = 8.8, 4.8 Hz, 2 H), 7.31 (br s,
1 H), 7.00 (t, J = 8.6 Hz, 2 H), 2.16 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 8.35 (dd, J = 7.9, 1.7 Hz, 1 H), 7.77 (s, 1
H), 7.03 (td, J = 7.8, 1.7 Hz, 1 H), 6.95 (td, J = 7.8, 1.5 Hz, 1 H), 6.87 (dd,
J = 8.1, 1.5 Hz, 1 H), 3.88 (s, 3 H), 2.20 (s, 3 H).
N-(4-Bromophenyl)acetamide (2l)28
Yield: 65 mg (60%); white solid; mp 167–169 °C.
1H NMR (400 MHz, CDCl3):  = 7.47–7.36 (m, 4 H), 7.23 (br s, 1 H),
2.17 (s, 3 H).
N-(4-Hydroxyphenyl)acetamide (2b)23
Yield: 60 mg (80%); brown solid; mp 170–171 °C.
1H NMR (400 MHz, DMSO-d6):  = 9.64 (s, 1 H), 9.13 (s, 1 H), 7.33 (d,
J = 8.9 Hz, 2 H), 6.67 (d, J = 8.9 Hz, 2 H), 1.98 (s, 3 H).
N-(3-Bromophenyl)acetamide (2m)29
Yield: 75 mg (70%); white solid; mp 81–83 °C.
N-(4-Methoxyphenyl)acetamide (2c)15
1H NMR (400 MHz, CDCl3):  = 7.81 (s, 1 H), 7.69 (s, 1 H), 7.45 (d,
J = 7.8 Hz, 1 H), 7.29 (dd, J = 16.1, 4.4 Hz, 1 H), 7.20 (t, J = 7.9 Hz, 1 H),
2.22 (s, 3 H).
Yield: 82 mg (86%); white solid; mp 129–130 C.
1H NMR (400 MHz, CDCl3):  = 7.41–7.35 (m, 2 H), 6.87–6.81 (m, 2 H),
3.78 (s, 3 H), 2.14 (s, 3 H).
N-(2,4-Dichlorophenyl)acetamide (2n)30
N-(3,4-Dimethoxyphenyl)acetamide (2d)24
Yield: 38 mg (70%); brown solid; mp 142–144 °C.
Yield: 78 mg (80%); white solid; mp 126–127.7 °C.
1H NMR (400 MHz, CDCl3):  = 7.30 (d, J = 2.3 Hz, 1 H), 6.87–6.70 (m, 2
1H NMR (400 MHz, CDCl3):  = 8.34 (d, J = 8.7 Hz, 1 H), 7.55 (s, 1 H),
7.38 (d, J = 1.7 Hz, 1 H), 7.28–7.22 (m, 1 H), 2.24 (s, 3 H).
H), 3.86 (s, 3 H), 3.85 (s, 3 H), 2.15 (s, 3 H).
N-Phenylbenzamide (2o)13
N-[4-(Allyloxy)phenyl]acetamide (2e)25
Yield: 49 mg (50%); white solid; mp 164–165 °C.
Yield: 82 mg (86%); white solid; mp 94–95 °C.
1H NMR (400 MHz, CDCl3):  = 7.87 (d, J = 7.8 Hz, 2 H), 7.80 (s, 1 H),
7.64 (d, J = 8.1 Hz, 2 H), 7.56 (t, J = 7.0 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 2 H),
7.38 (t, J = 7.8 Hz, 2 H), 7.16 (t, J = 7.2 Hz, 1 H).
1H NMR (400 MHz, CDCl3):  = 7.37 (d, J = 8.7 Hz, 2 H), 7.14 (s, 1 H),
6.87 (d, J = 8.8 Hz, 2 H), 6.04 (ddd, J = 21.8, 10.4, 5.2 Hz, 1 H), 5.40 (d,
J = 17.3 Hz, 1 H), 5.28 (d, J = 10.5 Hz, 1 H), 4.51 (d, J = 5.1 Hz, 2 H), 2.15
(s, 3 H).
N-(1-Tosyl-1H-indol-3-yl)acetamide (2p)15
Yield: 82 mg (50%); white solid; mp 193–194 °C.
N-(p-Tolyl)acetamide (2f)23
1H NMR (400 MHz, CDCl3):  = 8.20 (s, 1 H), 8.07 (d, J = 8.3 Hz, 1 H),
7.76 (d, J = 8.4 Hz, 2 H), 7.41–7.32 (m, 2 H), 7.28–7.26 (m, 1 H), 7.25–
7.22 (m, 1 H), 7.18 (d, J = 8.0 Hz, 2 H), 2.31 (s, 3 H), 2.24 (s, 3 H).
Yield: 63 mg (85%); white solid; mp 151–152 °C.
1H NMR (400 MHz, CDCl3):  = 7.37 (d, J = 8.3 Hz, 2 H), 7.25 (br s, 1 H),
7.11 (d, J = 8.1 Hz, 2 H), 2.31 (s, 3 H), 2.15 (s, 3 H).
7-Phenylazepan-2-one (2q)31
N-Phenylacetamide (2g)26
Yield: 76 mg (80%); white solid; mp 134–136 °C.
Yield: 54 mg (80%); white solid; mp 114–115 °C.
1H NMR (400 MHz, CDCl3):  = 7.49 (d, J = 7.7 Hz, 2 H), 7.31 (t, J = 7.9
Hz, 2 H), 7.10 (t, J = 7.4 Hz, 1 H), 2.17 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.41–7.21 (m, 5 H), 6.18 (br s, 1 H),
4.46 (d, J = 9.3 Hz, 1 H), 2.66–2.49 (m, 2 H), 2.11–1.83 (m, 4 H), 1.76–
1.57 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 177.93, 141.92, 129.18, 128.22,
126.24, 58.85, 36.91, 36.79, 29.78, 22.91.
N-(Naphthalen-2-yl)acetamide(2h)27
Yield: 65 mg (70%); off-white solid; mp133–135 °C.
1H NMR (400 MHz, CDCl3):  = 8.18 (br s, 1 H), 7.80–7.77 (m, 3 H),
1,3,4,5-Tetrahydro-2H-benzo[b]azepin-2-one (2r)27
7.48–7.37 (m, 4 H), 2.24 (s, 3 H).
Yield: 61 mg (75%); white solid; mp 137–139 °C.
1H NMR (400 MHz, CDCl3):  = 7.56 (br s, 1 H), 7.25–7.20 (m, 2 H),
7.16–7.10 (m, 1 H), 6.96 (d, J = 7.6 Hz, 1 H), 2.80 (t, J = 7.2 Hz, 2 H),
2.36 (t, J = 7.3 Hz, 2 H), 2.27–2.21 (m, 2 H).
N-Phenylpropionamide (2i)13
Yield: 63 mg (85%); white solid; mp 107–108 °C.
1H NMR (400 MHz, CDCl3):  = 7.52 (d, J = 8.0 Hz, 2 H), 7.30 (t, J = 8.0
Hz, 2 H), 7.26 (br, 1 H), 7.10 (t, J = 7.4 Hz, 1 H), 2.38 (q, J = 7.6 Hz, 2 H),
1.24 (t, J = 7.6 Hz, 3 H).
Azacyclotetradecan-2-one (2s)32
Yield: 96 mg (89%); white solid; mp 155–157 °C.
1H NMR (400 MHz, CDCl3):  = 5.57 (br s, 1 H), 3.36–3.26 (m, 2 H),
2.25–2.15 (m, 2 H), 1.76–1.61 (m, 2 H), 1.54–1.44 (m, 2 H), 1.43–1.20
(m, 16 H).
N-Phenylisobutyramide (2j)9
Yield: 88 mg (81%); white solid; mp 109–111 °C.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–F

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S. Munnuri et al.
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Synthesis
13C NMR (101 MHz, CDCl3):  = 173.10, 38.46, 36.27, 28.31, 26.49,
25.79, 25.71, 25.63, 25.41, 25.26, 23.95, 23.70, 23.13.
rangements in Organic Synthesis; Rojas, C. M., Ed.; Wiley: New
York, 2015, 111–150. (h) Zhang, W.; Yang, S.; Lin, Q.; Cheng, H.;
Liu, J. J. Org. Chem. 2019, 84, 851.
5-(tert-Butyl)azepan-2-one (2t)33
(2) (a) Beckmann, E. Ber. Dtsch. Chem. Ges. 1886, 19, 988. (b) Blatt,
A. H. Chem. Rev. 1933, 12, 215.
Yield: 73 mg (85%); semi-solid.
(3) (a) Luedeke, V. D. In Encyclopedia of Chemical Processing and
Design, Vol. 6; Mcketta, J. J., Ed.; Marcel Dekker: New York, 1978,
72–95. (b) Rademacher, H. In Ullmann’s Encyclopedia of Indus-
trial Chemistry, 5th ed., Vol. A8; Gerhartz, W., Ed.; Wiley: New
York, 1987, 201. (c) Weber, J. N. In Kirk-Othmer Encyclopedia of
Chemical Technology, 4th ed., Vol. 19; Kroschwitz, J. I., Ed.; Wiley:
New York, 1990, 500. (d) Palmer, R. J. Encyclopedia of Polymer
Science and Technology, 4th ed; Wiley: New York, 2001.
(e) Wessermel, K.; Arpe, H.-J. Industrial Organic Chemistry, 4th
ed; Wiley-VCH: Weinheim, 2003, 239. (f) Owston, N. A.; Parker,
A. J.; Williams, J. M. J. Org. Lett. 2007, 9, 3599. (g) You, K.; Mao,
L.; Yin, D.; Liu, P.; Luo, H. Catal. Commun. 2008, 9, 1521.
(4) (a) The Chemistry of Amides; Zabicky, J., Ed.; Wiley-Interscience:
New York, 1970. (b) The Amide Linkage: Structural Significance
in Chemistry, Biochemistry, and Materials Science; Greenberg, A.;
Breneman, C. M.; Liebman, J. F., Ed.; Wiley: New York, 2000.
(c) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
Biomol. Chem. 2006, 4, 2337. (d) Cupido, T.; Tulla-Puche, J.;
Spengler, J.; Albericio, F. Curr. Opin. Drug Discovery Dev. 2007,
10, 768. (e) Pathare, S. P.; Jain, A. K. H.; Akamanchi, K. G. RSC
Adv. 2013, 3, 7697. (f) Rao, S. N.; Mohana, D. C.; Adimurthy, S.
RSC Adv. 2015, 5, 95313.
1H NMR (400 MHz, CD3OD):  = 3.33–3.25 (m, 2 H), 2.58–2.48 (m, 1
H), 2.16 (td, J = 13.4, 4.9 Hz, 1 H), 2.07–1.94 (m, 2 H), 1.84 (td, J = 13.9,
5.4 Hz, 1 H), 1.37–1.14 (m, 3 H), 0.90 (s, 9 H).
13C NMR (101 MHz, CD3OD):  = 167.50, 48.46, 33.23, 32.60, 28.76,
27.91, 27.64, 26.76.
(4aS,4bR,10bS,12aS)-8-Methoxy-12a-methyl-
3,4,4a,4b,5,6,10b,11,12,12a-decahydronaphtho[2,1-f]quinolin-
2(1H)-one (2u)34
Yield: 126 mg (85%); white solid; mp 220–222 °C.
1H NMR (400 MHz, CDCl3):  = 7.18 (d, J = 8.6 Hz, 1 H), 6.76–6.46 (m, 3
H), 3.77 (s, 3 H), 2.93–2.79 (m, 2 H), 2.56–2.34 (m, 4 H), 2.15–1.99 (m,
2 H), 1.89–1.81 (m, 1 H), 1.77–1.66 (m, 1 H), 1.58–1.25 (m, 5 H), 1.19
(s, 3 H).
13C NMR (101 MHz, CDCl3):  = 171.96, 157.65, 137.57, 131.79,
126.17, 113.52, 111.69, 55.21, 54.49, 46.49, 43.28, 39.85, 39.34, 30.65,
29.88, 26.67, 26.21, 22.19, 19.83.
N-Butylacetamide (2v)35
Yield: 82 mg (50%); clear oil.
1H NMR (400 MHz, CDCl3):  = 5.66 (s, 1 H), 3.26–3.18 (m, 2 H), 1.95
(s, 3 H), 1.52–1.41 (m, 2 H), 1.38–1.28 (m, 2 H), 0.90 (t, J = 7.3 Hz, 3 H).
(5) (a) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243. (b) Larock, R. C. Comprehensive Organic Transformatins,
2nd ed; Wiley-VCH: Weinheim, 1999, 1234. (c) Bode, J. W. Curr.
Opin. Drug Discovery Dev. 2006, 9, 765. (d) Selvamurugan, S.;
Ramachandran, R.; Prakash, G.; Viswanathamurthi, P.; Malecki,
J. G.; Endo, A. J. Organomet. Chem. 2016, 803, 119.
Funding Information
(6) (a) Kalia, J.; Raines, R. T. Angew. Chem. Int. Ed. 2008, 47, 7523.
(b) Jain, P. U.; Samant, S. D. ChemistrySelect 2018, 3, 1967.
(c) See also refs. 7–15, 17–19.
(7) (a) Ramalingan, C.; Park, Y.-T. J. Org. Chem. 2007, 72, 4536.
(b) Crochet, P.; Cadierno, V. Chem. Commun. 2015, 51, 2495.
(c) Martinez-Asencio, A.; Yus, M.; Ramon, D. J. Tetrahedron
2012, 68, 3948.
(8) Kiely-Collins, H. J.; Sechi, I.; Brennan, P. E.; McLaughlin, M. G.
Chem. Commun. 2018, 54, 654.
(9) Furuya, Y.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2005,
127, 11240.
J.L.J. thanks DST-SERB (YSS/2015/000838), UGC, New Delhi for UGC-
BSR Grant (No.F.30-382/2017) and BBAU, Lucknow for infrastructure.
J. R. F. received financial support from the Robert A. Welch Foundation
(I-0011) and USPHS NIH (HL139793).
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Acknowledgment
S. V. expresses her thanks to CSIR, New Delhi, India for the research
fellowship.
(10) Betti, C.; Landini, D.; Maia, A.; Pasi, M. Synlett 2008, 908.
(11) Hashimoto, M.; Obora, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem.
2008, 73, 2894.
Supporting Information
(12) Zhu, M.; Cha, C.; Deng, W.-P.; Shi, X.-X. Tetrahedron Lett. 2006,
47, 4861.
(13) Pi, H.-J.; Dong, J.-D.; An, N.; Du, W.; Deng, W.-P. Tetrahedron
2009, 65, 7790.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690005.
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(14) Zicmanis, A.; Katkevica, S.; Mekss, P. Catal. Commun. 2009, 10,
614.
References
(1) (a) Vinnik, M. I.; Zarakhani, N. G. Russ. Chem. Soc. 1967, 36, 51.
(b) Krow, G. R. Tetrahedron 1981, 37, 1283. (c) Gawley, R. E. Org.
React. 1988, 35, 1. (d) Katritzky, A. R.; Monteux, D. A.;
Tymoshenko, D. O. Org. Lett. 1999, 1, 577. (e) Smith, M. B.;
March, J. Advance Organic Chemistry, 5th ed; Wiley: New York,
2001, 1415; and references cited therei. (f) Chandrasekhar, S. In
Comprehensive Organic Synthesis II, Vol. 7; Knochel, P.;
Molander, G. A., Ed.; Elsevier: Amsterdam, 2014, 770. (g) Holth,
T. A. D.; Hutt, O. E.; Georg, G. I.; Rojas, C. M. In Molecular Rear-
(15) Mo, X.; Morgan, T. D. R.; Ang, H. T.; Hall, D. G. J. Am. Chem. Soc.
2018, 140, 5264.
(16) (a) Hyodo, K.; Hasegawa, G.; Oishi, N.; Kuroda, K.; Uchida, K.
J. Org. Chem. 2018, 83, 13080. (b) Mahajan, S.; Sharma, B.;
Kapoor, K. K. Tetrahedron Lett. 2015, 56, 1915.
(17) (a) Wallace, R. G. Aldrichimica Acta 1980, 13, 3. (b) Erdik, E.;
Saczewski, J. Hydroxylamine-O-sulfonic AcideEROS Encyclopedia
of Reagents for Organic Synthesis; Wiley: Hoboken, 2013, 1.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–F

F
S. Munnuri et al.
Paper
Synthesis
(c) Ma, Z.; Zhou, Z.; Kürti, L. Angew. Chem. Int. Ed. 2017, 56,
9886. (d) Sabir, S.; Kumar, G.; Jat, J. L. Org. Biomol. Chem. 2018,
16, 3314.
(27) Luca, L. D.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67,
6272.
(28) Mahajan, P. S.; Humne, V. T.; Tanpure, S. D.; Mhaske, S. B. Org.
Lett. 2016, 18, 3450.
(29) Pialat, A.; Liegault, B.; Taillefer, M. Org. Lett. 2013, 15, 1764.
(30) Singh, H.; Sen, C.; Sahoo, T.; Ghosh, S. C. Eur. J. Org. Chem. 2018,
4748.
(18) Olah, G. A.; Fung, A. P. Synthesis 1979, 537.
(19) (a) Sanford, J. K.; Blair, F. T.; Arroya, J.; Sherk, K. W. J. Am. Chem.
Soc. 1945, 67, 1941. (b) Freeman, J. P. J. Org. Chem. 1961, 26,
3507.
(20) Du Bois, J. Org. Process Res. Dev. 2011, 15, 758.
(21) Munnuri, S.; Anugu, R. R.; Falck, J. R. Org. Lett. 2019, 21, 1926.
(22) Srivastava, V. P.; Patel, R.; Garima, ; Yadav, L. D. S. Chem.
Commun. 2010, 46, 5808.
(31) Tokuyama, H.; Itabashi, S.; Shimomura, M.; Sato, M.; Azuma, H.;
Okano, K.; Sakata, J.; Hidetoshi, T. Synlett 2018, 29, 1786.
(32) Mudiyanselage, A. Y.; Viamajala, S.; Varanasi, S.; Yamamoto, K.
ACS Sustainable Chem. Eng. 2014, 2, 2831.
(23) Gao, Y.; Liu, J.; Li, Z.; Guo, T.; Xu, S.; Zhu, H.; Wei, F.; Chen, S.;
Gebru, H.; Guo, K. J. Org. Chem. 2018, 83, 2040.
(33) Aube, J.; Wang, Y.; Hammond, M.; Tanol, M.; Takusagawa, F.;
Velde, D. V. J. Am. Chem. Soc. 1990, 112, 4879.
(24) Schulz, L.; Enders, M.; Elsler, B.; Schollmeyer, D.; Dyballa, K. M.;
Franke, R.; Waldvogel, S. R. Angew. Chem. Int. Ed. 2017, 56, 4877.
(25) Schmidt, B.; Wolf, F. J. Org. Chem. 2017, 82, 4386.
(26) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J.
Am. Chem. Soc. 2008, 130, 16474.
(34) Liu, Z.-J.; Lu, X.; Wang, G.; Li, L.; Jiang, W.-T.; Wang, Y.-D.; Xiao,
B.; Fu, Y. J. Am. Chem. Soc. 2016, 138, 9714.
(35) Steffel, L. R.; Cashman, T. J.; Reutershan, M. H.; Linton, B. R. J. Am.
Chem. Soc. 2007, 129, 12956.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–F