Synthesis of quaternary α-benzyl- and α-allyl-α-methylamino cyclobutanones: Dedicated to Professor Achille Umani Ronchi for his 80th birthday

Article abstract of DOI:10.1016/j.tet.2016.10.024

A simple and practical protocol for the construction of synthetically important quaternary α-benzyl- and α-allyl-α-methylamino cyclobutanones in good to high yield, via a sequential one-pot methylation/sigmatropic rearrangement, has been accomplished for

Full text of DOI:10.1016/j.tet.2016.10.024

Accepted Manuscript
Synthesis of quaternary α-benzyl- and α-allyl-α-methylamino cyclobutanones
Lorenza Ghisu, Nicola Melis, Francesco Secci, Pierluigi Caboni, Angelo Frongia
PII:
S0040-4020(16)31046-8
10.1016/j.tet.2016.10.024
TET 28165
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 July 2016
Revised Date: 29 September 2016
Accepted Date: 10 October 2016
Please cite this article as: Ghisu L, Melis N, Secci F, Caboni P, Frongia A, Synthesis of quaternary α-
benzyl- and α-allyl-α-methylamino cyclobutanones, Tetrahedron (2016), doi: 10.1016/j.tet.2016.10.024.
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Synthesis of Quaternary α-Benzyl- and α-
Allyl-α-Methylamino Cyclobutanones
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Lorenza Ghisua, Nicola Melisa, Francesco Seccia, Pierluigi Cabonib and Angelo Frongiaa,*

1
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Tetrahedron
journal homepage: www.elsevier.com
Synthesis of Quaternary α-Benzyl- and α-Allyl-α-Methylamino Cyclobutanones
Lorenza Ghisua, Nicola Melisa, Francesco Seccia, Pierluigi Cabonib and Angelo Frongiaa,*
aDipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari, Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu, I-09042,
Monserrato, Cagliari, Italy
E-mail: afrongia@unica.it
bDipartimento di Scienze della Vita e dell’Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, 09124, Cagliari, Italy
Dedicated to Professor Achille Umani Ronchi for his 80th birthday
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and practical protocol for the construction of synthetically important quaternary α-
benzyl- and α-allyl-α-methylamino cyclobutanones in good to high yield, via a sequential one-
pot methylation/sigmatropic rearrangement, has been accomplished for the first time. The
quaternary α-alkyl-α-amino cyclobutanones could be further manipulated, affording
synthetically interesting scaffolds such as highly substituted tryptamines and cyclobuta-fused
indolines.
Available online
Keywords:
Amines
2009 Elsevier Ltd. All rights reserved
.
α-Aminoketones
Cyclobutanes
Rearrangements
Strained carbocyclic systems
1. Introduction
Our investigation began with the sequential one pot
methylation/[1,2]-rearrangement of the α-dibenzylamino
cyclobutanone 1a, selected as a model substrate.
Among
cyclobutane
derivatives,1
α-amino
cyclobutanes2 are especially useful as they are widely
encountered in a number of natural products and
pharmaceutically active compounds.3 They are also
important molecular building blocks which can be easily
transformed into more complex organic intermediates
owing to their inherent ring strain. Therefore, the
development of new methods for synthesizing highly
functionalized α-amino cyclobutanes from readily
available materials is highly desirable. In this regard, to
the best of our knowledge, the synthesis of quaternary α-
alkyl-α-amino cyclobutanones has not been explored
previously and thus remains a challenge.4
Scheme 1. Key steps in the synthesis of quaternary α-
alkyl-α-amino cyclobutanones involving a base-induced
sigmatropic rearrangement of an in situ generated
ammonium salt.
O
Alk/Aryl
N
O
N
Alk/Aryl
As a continuation of our previous work on the
synthesis5 and transformations6 of cyclobutanones, herein
we shall report our recent results on the synthesis of α-
benzyl- and α-allyl-α-methylamino cyclobutanones. This
Sigmatropic
CF3SO3Me
rearrangement
approach involves
a
K2CO3-induced sigmatropic
rearrangement7 of an in situ generated ammonium salt,
prepared by quaternization of nitrogen of the
O
O
corresponding
starting
α-amino
cyclobutanone
N
N
Alk/Aryl
Alk/Aryl
derivatives using CF3SO3Me as the alkylating reagent
(Scheme 1).
K2CO3
CF3SO3
CF3SO3
K
2. Results and discussion

2
Tetrahedron
ACCEPTED MANUSCRIPT
The representative results are summarized in Table 1. A
Dibenzylamino cyclobutanones 1g-i bearing one
2:1 molar ratio of methylating reagent to α-benzylamino
cyclobutanone 1a and 2.5 equivalents of base were used
in all the experiments (Table 1). In the experimental
procedure, the methylating reagent was added neat to 1a
at room temperature. After 3 h the solvent and the base
were subsequently introduced in one portion, and the
mixture heated under reflux for 16 h. The purification of
the adduct 2a was easily carried out by direct application
of the crude reaction mixture to the head of a
chromatographic column followed by elution with a
mixture of petroleum ether/ether. Among various
potential methylating reagents screened in acetonitrile as
the solvent, CF3SO3Me was identified as the optimal
alkylating agent for this reaction. The expected adduct 2a
can be obtained in 66% yield (Table 1, entry 3).
electron-withdrawing substituent in the aromatic ring also
gave good to high yields of the corresponding adducts 2g,
g'-i, i' but with higher regioisomeric ratios (between
1.5:1 and 4.5:1 r.r.) under the designated reaction
conditions.
Interestingly, although the
regioselectivity was generally low, in all cases, except for
α-dibenzylamino cyclobutanones 1b, c which gave a
1.0:1.0 regioisomeric mixture and 1d which exhibited a
slight preference for the “opposite” regioisomer, it was
the benzyl group with the substituent on the aromatic ring
(both electron-donating and electron-withdrawing
groups) that was favored during the migration process.
The preferential migration of the para-substituted benzyl
group in the dibenzylamine substrates might suggest a
radical character of the migrating group8 and support
homolytic cleavage of the carbon-nitrogen bond followed
by recombination to provide the products as illustrated in
previously reported [1,2]-Stevens-type rearrangements.9
By screening different bases (Table 1, entries 5-8) it
was revealed that the initial use of K2CO3 gave the best
results. Other bases such as Li2CO3, Cs2CO3, Na2CO3,
and t-BuOK gave significantly lower yields. A brief
Scheme 2. Substrate scope regarding aromatic ring
solvent screen (Table 1, entries 9-13) showed that THF
was ideal providing product 2a in 79% yield (Table 1,
entry 10). The latter conditions were chosen for further
investigation.
substituents.a
Table 1. Evaluation of reaction conditions.a
Entry
Methylating
reagent
Base
Solvent
Yield 2a (%)b
-
1
Me3O+BF4
K2CO3
K2CO3
K2CO3
K2CO3
Li2CO3
Cs2CO3
Na2CO3
t-BuOK
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3COOEt
THF
36
39
66
8
2
Me2SO4
3
CF3SO3Me
MeI
4
5
CF3SO3Me
CF3SO3Me
CF3SO3Me
CF3SO3Me
CF3SO3Me
CF3SO3Me
CF3SO3Me
CF3SO3Me
CF3SO3Me
11
45
26
38
48
79
57
0c
6
7
8
9
10
11
12
13
1,4-Dioxane
DMF
EtOH
0c
a Conditions: 1 (380 µmol), CF3SO3Me (760 µmol), K2CO3 (950 µmol), THF
(4 mL). Yields are given for isolated materials after column chromatography.
The r.r. values were based on relative 1HNMR integrations and the
assignment of the major regioisomer was based on chemical shifts of the
benzyl group protons. b The reaction was carried out at room temperature for
120 h; 8 mL of THF was used.
a
Conditions: 1a (380 µmol), methylating reagent (760 µmol), base (950
µmol), solvent (4 mL). b Isolated yield after chromatography.
c Decomposition products were obtained
A survey of the scope of the rearrangement with respect
to the presence of ring substituents on the dibenzylamine
substrate is presented in Scheme 2. Good to high
chemical yields of the Stevens rearrangement products
2b, b'-f, f' were obtained as an inseparable mixture of
regioisomers (between 1:1 and 1.6:1 r.r.) with a series of
α-dibenzylamino cyclobutanones 1b-f bearing different
electron-donating groups on the aromatic ring. α-
A representative bis-para-substituted α-dibenzylamino
cyclobutanone with electron-withdrawing groups such as
1j was tolerated and gave moderate chemical yield. The
scope of substrates was further explored as shown in
Scheme 3. The reactions of several
cyclobutanones 1k-r bearing different
N
N
-alkyl benzyl
-alkyl groups
such as methyl (1k), ethyl (1l), n-pentyl (1m) phenethyl

3
(
1p), carboethoxymethyl (1q), carboethoxyethyl (1r) as
performed in CH COOEt at room temperature for 3
3
ACCEPTED MANUSCRIPT
well as the more sterically congested isopropyl (1n) and
-hexyl (1o) groups, under the standard conditions, were
days (for the full optimization, see the supporting
Information).
c
found to afford the corresponding Stevens rearrangement
products 2k-r in moderate to good yields.
Scheme 4. Substrate scope regarding other cyclic and acyclic α-
amino ketones.a
In addition, the reactions of compounds 1s and 1t
bearing an aromatic ring on the nitrogen were also
successful although the desired products 2s and 2t were
obtained with lower chemical yield. On the other hand,
the reaction of 1u and 1v bearing an allyl substituent on
the nitrogen atom occurred preferentially via a [2,3]-
rearrangement affording, as the sole product, the
corresponding α-allyl-α-benzylamino cyclobutanones 2u
and 2v 10
.
Scheme 3. Substrate scope regarding N-alkyl substituents.a
a Conditions: 3 (380 µmol), CF3SO3Me (760 µmol), K2CO3 (950 µmol), THF
(4 mL). Yields are given for isolated materials after column chromatography.
Under the same reaction conditions, various α-
-arylamino cyclobutanones11 were subjected to the
analogous sequential one-pot methylation/[2,3]-
rearrangement.12
N-allyl-
N
Scheme 5. Substrate scope regarding α-N-allyl-N-arylamino
cyclobutanones.a
a Conditions: 1 (380 µmol), CF3SO3Me (760 µmol), K2CO3 (950 µmol), THF
(4 mL). Yields are given for isolated materials after column chromatography.
As a result, the applicability of the reaction protocol to
other cyclic (3a and 3b) as well as acyclic (3c) α-amino
ketones was then preliminary investigated (Scheme 4).
Gratifyingly,
(dibenzylamino)cyclopentanone
(dibenzylamino)cyclohexanone
the
reactions
of
2-
2-
3-
(3a),
(
3b
)
and
(dibenzylamino)butan-2-one (3c) proceeded with good to
high chemical yields in each case thus highlighting the
broad generality of this protocol.
Next, the substrate scope was extended to include the
synthesis of other structurally related derivatives such as
quaternary α-allyl-α-arylamino cyclobutanones (Scheme
5). To our delight, parent substrate 5a afforded the
product 6a in good yield when the reaction was

4
Tetrahedron
Scheme 6. Application in synthesis: preparation of 2-
ACCEPTED MANUSCRIPT
R
O
1) CF3SO3Me
neat, R.T., 5 h
R
allyl tryptamine
7 and cyclobuta-fused indolines 8a-f.
O
N
N
2) K2CO3
CH3COOEt, R.T, 3 d
6
5
O
O
O
N
N
O
N
N
6a
Y: 73%
6b
Y: 66%
6c
Y: 72%
6d
Y: 55%
Cl
Br
Ph
O
O
O
O
N
N
N
N
6f
Y: 65%
6g
Y: 76%
6h
Y: 66%
6e
Y: 59%
Ph
F
O
O
O
O
O
O
N
N
N
N
6i
Y: 61%
6j
Y: 68%
6k
Y: 63%
6l
Y: 0%
We then sought to demonstrate the potential of these
products as synthetic precursors of biologically important
derivatives (Scheme 6). Based on our previous work,6b
O
O
the reaction of 6a and
under the catalysis of PTSA. We were happy to find that
the corresponding 2-allyl tryptamine13
along with
isomeric derivative 7' could be obtained in 68% overall
yield (ratio 7' =86:14) through a solvent-free cascade
N-methyl aniline was investigated
O
O
O
O
N
N
N
N
7
6m
Y: 53%
6n
Y: 69%
6o
Y: 59%
6p
Y: 77%
7
:
reaction. The formation of 7' may be explained via an
acid-mediated isomerization of the terminal double bond
aConditions:
5 (380 µmol), CF3SO3Me (760 µmol), K2CO3 (950 µmol),
CH3COOEt (4 mL). Yields are given for isolated materials after column
chromatography.
of tryptamine
7
.
On the other hand, when we
carried out the reaction of 6a with primary anilines the
isolated compounds from the reaction were the
cyclobuta-2,3-fused indoline derivatives14 8a-f (44-90%
yields), and only a trace amount of the corresponding
tryptamines, coming from a subsequent acid catalyzed
“depart-and-return” process,6b were observed. The lower
basicity of the less substituted aniline is a potential
explanation for the observed difference in reaction
outcome.
With α-N-allyl-N-arylamino cyclobutanones bearing
different electron-donating groups on the para position of
the aromatic ring such as -Me (5b), -Et (5c), -OMe (5j), -
OPh (5k) and -Ph (5f), the reaction proceeds smoothly to
furnish the desired products in moderate to good yields.
Interestingly, even substrates with sterically demanding
-butyl (5d) and t-butyl groups (5e) on the aromatic ring
readily participated in the reaction sequence to generate
the corresponding α-allyl-α-arylamino cyclobutanones in
n
moderate to good yields. α-N-Allyl-N-arylamino
3. Conclusion
cyclobutanones such as 5g-i bearing one halogen as the
substituent in a para-position were also found to be good
substrates, affording the corresponding products 6g-i in
good yields.
In conclusion, we have developed a simple and
practical method for the synthesis of quaternary highly
functionalized α-benzyl- and α-allyl-α-methylamino
A
representative
meta-substituted
arylamino
cyclobutanones
using
a
sequential
one
pot
cyclobutanone 5m performed almost equally well in this
reaction (53% yield) whereas the ortho-substituted
arylamino cyclobutanone 5l failed to participate in this
reaction. Of particular note, disubstituted arylamino
cyclobutanones 5n-p with electron-donating groups were
tolerated and gave moderate to good chemical yields.
methylation/sigmatropic rearrangement starting from α-
amino cyclobutanones. The method presented in this
work provides the first general and efficient route to
assemble these important structural motifs. Furthermore,
one of the α-alkyl-α-amino cyclobutanones, 6a was used
to prepare a new highly substituted tryptamine derivative

5
and some valuable cyclobuta-2,3-fused indolines. The
extension and synthetic application of this reaction are
currently under investigation in our laboratories.
133.7, 130.2, 130.1, 129.1, 128.9, 128.8, 128.44,
ACCEPTED MANUSCRIPT
128.40, 128.2, 86.5, 56.1, 55.8, 41.9, 35.6, 35.5, 33.8,
33.4, 21.06, 21.00, 20.9. HRMS (ESI) Calcd. for
C20H24NO (M+H) m/z 294.1852, found 294.1864.
4. Experimental section
General Methods
(2c+2c’): Spectral data determined from the 1.0:1.0
inseparable mixture of two regioisomers: Yield 86%
(0.105 g); yellow oil; Rf (petroleum ether/ether, 5:1) 0.74.
IR (neat): 3030, 2963, 2870, 2795, 1772, 1515, 1493,
1458, 1387, 1365, 1059 cm-1. 1H NMR (400 MHz,
CDCl3) δ 7.32 – 7.10 (m, 18H), 3.92 – 3.80 (m, 2H), 3.59
1H NMR spectra were recorded on a Varian 500, or
Varian 400 MHz spectrometer at ambient temperature
with CDCl3 as solvent. Data are reported as follows:
chemical shifts (
δ
), multiplicity, coupling constants and
(dd,
– 2.78 (m, 6H), 2.29 (s, 3H), 2.28 (s, 3H), 2.19 – 1.96 (m,
6H), 1.24 (d,
= 6.9 Hz, 12H). 13C NMR (101 MHz,
CDCl3) δ 210.0, 209.8, 147.5, 146.9, 139.5, 136.9, 136.7,
134.0, 130.2, 130.1, 128.43, 128.40, 128.1, 126.8, 126.4,
126.3, 126.2, 86.5, 56.1, 55.8, 41.9, 35.6, 33.8, 33.7,
33.6, 33.5, 24.0, 23.9, 20.9. HRMS (ESI) Calcd. for
C22H28NO (M+H) m/z 322.2165, found 322.2172
J = 13.3, 8.4 Hz, 2H), 3.20 (t, J = 13.3 Hz, 2H), 2.93
integration. 13C NMR spectra were recorded operating
respectively at 126, or 101 MHz at 27 °C with CDCl3 as
solvent. Infrared spectra were recorded on a FT-IR
spectrophotometer. High resolution mass spectra
(HRMS) were recorded on a spectrometer using Positive
Electro Ionization (ESI) mode. Analytical thin layer
chromatography was performed using 0.25 mm silica gel
60-F plates. Flash chromatography was performed using
columns of 230-400 mesh silica gel 60 (0.040-0.063
mm). Yields refer to chromatographically pure materials.
J
(2d+2d’): Spectral data determined from the 1.0:1.1
inseparable mixture of two regioisomers: Yield 82%
(0.104 g); yellow oil; Rf (petroleum ether/ether, 5:1) 0.75.
IR (neat): 3034, 2959, 2866, 2791, 1777, 1511, 1493,
1453, 1387, 1360, 1272, 1068 cm-1. 1H NMR (400 MHz,
General Procedure for the synthesis of α-benzyl-α-
dialkylamino cyclobutanones 2a-f, 2k-v and α-benzyl-
α-dialkylaminoketones 4a-c.
CDCl3) δ 7.36 – 7.11 (m, 18H), 3.85 (t,
3.60 (dd, = 13.4, 6.8 Hz, 2H), 3.20 (t,
2.85 (ddd,
J
J
= 14.2 Hz, 2H),
= 13.8 Hz, 2H),
J
CF3SO3Me (760 µmol, 0.086 mL) was added neat to α-
J
= 12.8, 8.3, 3.7 Hz, 4H), 2.29 (s, 3H), 2.28
dibenzylamino ketone 1a-f
,
1k-s or 3a-c (380 µmol) at
(s, 3H), 2.16 – 1.97 (m, 6H), 1.31 (s, 9H), 1.30 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 210.1, 209.8, 149.7,
149.2, 139.5, 136.9, 136.3, 133.6, 130.2, 129.9, 128.4,
128.3, 128.19, 128.12, 126.8, 126.3, 125.2, 125.1, 86.5,
56.1, 55.7, 41.9, 35.6, 33.8, 33.4, 31.38, 31.34, 20.9.
HRMS (ESI) Calcd. for C23H30NO (M+H) m/z 336.2321,
found 336.2327.
room temperature. After 3 h (5 h for 3a-c), THF (4 mL)
and K2CO3 (950 µmol, 0.131 g) were subsequently
introduced in one portion, and the mixture heated under
reflux for 16 h. The crude reaction mixture was directly
loaded to a silica gel column without aqueous work-up
and pure products were obtained by flash column
chromatography (silica gel, mixture of petroleum
ether/ether, 10:1
→
1:1).
(2e+2e’): Spectral data determined from the 1.3:1.0
inseparable mixture of two regioisomers: Yield 61%
(0.071 g); yellow oil; Rf (petroleum ether/ether, 5:1) 0.43.
IR (neat): 2970, 2932, 2886, 1776, 1610, 1512, 1465,
1379, 1249, 1160, 1127 cm-1. 1H NMR (500 MHz,
CDCl3) δ 7.31 – 7.27 (m, 8H), 7.24 – 7.18 (m, 4H), 7.15
(2a): Yield 79% (0.084 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.68. IR (neat): 3087, 3063, 3030, 2959,
2923, 2847, 2795, 1773, 1604, 1495, 1454, 1063 cm-1. 1H
NMR (500 MHz, CDCl3) δ 7.32 – 7.27 (m, 6H), 7.26 –
7.19 (m, 4H), 3.88 (d,
J
= 15.0 Hz, 1H), 3.62 (d,
J
= 15.0
– 7.10 (m, 2H), 6.87 – 6.81 (m, 4H), 3.86 (d,
1H), 3.80 (d, = 13.3 Hz, 1H), 3.78 (s, 3H), 3.78 (s, 3H),
3.60 (d, = 13.4 Hz, 1H), 3.54 (d, = 13.2 Hz, 1H), 3.18
(dd, = 21.5, 13.4 Hz, 2H), 2.91 – 2.78 (m, 4H), 2.27 (s,
J = 13.4 Hz,
Hz, 1H), 3.22 (d, = 15.0 Hz, 1H), 2.93 – 2.82 (m, 2H),
J
J
2.29 (s, 3H), 2.20 – 2.09 (m, 1H), 2.09 – 1.97 (m, 2H).
13C NMR (126 MHz, CDCl3) δ 209.7, 139.4, 136.9,
130.2, 128.43, 128.40, 128.2, 126.8, 126.4, 86.5, 56.1,
41.9, 35.6, 33.9, 20.9. HRMS (ESI) Calcd. for C19H22NO
(M+H) m/z 280.1695, found 280.1699.
J
J
J
3H), 2.26 (s, 3H), 2.21 – 1.92 (m, 6H). 13C NMR (126
MHz, CDCl3) δ 210.2, 209.9, 158.5, 158.1, 139.4, 136.9,
131.1, 130.2, 129.5, 128.6, 128.4, 128.3, 128.1, 126.8,
126.3, 86.5, 86.4, 56.0, 55.4, 55.19, 55.14, 41.93, 41.90,
35.5, 35.3, 33.8, 33.0, 20.8, 20.7. HRMS (ESI) Calcd. for
C20H24NO2 (M+H) m/z 310.1801, found 310.1807.
(2b+2b’): Spectral data determined from the 1.0:1.0
inseparable mixture of two regioisomers: Yield 76%
(0.084 g); yellow oil; Rf (petroleum ether/ether, 5:1) 0.69.
IR (neat): 3025, 2999, 2954, 2919, 2844, 2791, 1772,
(2f+2f’): Spectral data determined from the 1.6:1.0
inseparable mixture of two regioisomers: Yield 52%
(0.064 g); yellow oil; Rf (petroleum ether/ether, 5:1) 0.50.
IR (neat): 2971, 2930, 2884, 1773, 1511, 1465, 1380,
1300, 1341, 1254, 1160, 1127, 1103, 1049 cm-1. 1H NMR
(500 MHz, CDCl3) δ 7.33 – 7.26 (m, 8H), 7.26 – 7.16 (m,
1520, 1493, 1458, 1259, 1064 cm-1. H NMR (400 MHz,
1
CDCl3) δ 7.23 – 7.02 (m, 18H), 3.78 (dd,
J
= 19.8, 13.4
J = 13.2 Hz,
Hz, 2H), 3.52 (t, = 13.2 Hz, 2H), 3.12 (t,
J
2H), 2.86 – 2.72 (m, 4H), 2.25 (s, 3H), 2.24 (s, 3H), 2.21
(s, 6H), 2.12 – 1.90 (m, 6H). 13C NMR (101 MHz,
CDCl3) δ 210.0, 209.8, 139.5, 136.9, 136.4, 136.3, 135.9,
4H), 7.11 (d,
J = 8.5 Hz, 2H), 6.83 (td, J = 7.0, 3.7 Hz,

6
Tetrahedron
1
4H), 4.01 (qd,
1H), 3.79 (d,
3.55 (d,
(d, = 13.5 Hz, 1H), 2.91 – 2.77 (m, 4H), 2.27 (s, 3H),
2.27 (s, 3H), 2.21 – 1.95 (m, 6H), 1.40 (td, = 7.0, 1.8
J
= 7.0, 2.5 Hz, 4H), 3.86 (d,
J
= 13.5 Hz,
1257, 1094 cm-1. H NMR (500 MHz, CDCl ) δ 7.29 –
ACCEPTED MANUSCRIPT
3
J
= 13.2 Hz, 1H), 3.60 (d,
= 13.2 Hz, 1H), 3.20 (d,
J
= 13.5 Hz, 1H),
= 13.3 Hz, 1H), 3.15
7.16 (m, 5H), 3.14 (d,
2H), 2.68 (ddd,
2.20 – 2.07 (m, 1H), 1.97 (dtd,
J
= 13.4 Hz, 1H), 2.90 – 2.80 (m,
J
J
J
= 16.8, 10.7, 5.2 Hz, 1H), 2.37 (s, 3H),
= 16.1, 10.7, 6.4 Hz,
J
J
J
2H), 1.83 – 1.71 (m, 2H), 1.67 – 1.61 (m, 3H), 1.50 –
1.36 (m, 2H), 1.35 – 1.21 (m, 2H), 1.14 – 0.97 (m, 1H).
13C NMR (126 MHz, CDCl3) δ 211.2, 137.0, 130.1,
128.2, 126.3, 87.0, 57.0, 41.8, 37.5, 31.7, 30.8, 29.9,
26.3, 26.2, 26.0, 20.9. HRMS (ESI) Calcd. for C18H26NO
(M+H) m/z 272.2008, found 272.2008.
Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 210.2, 209.9,
158.0, 157.5, 139.5, 137.0, 131.2, 130.2, 129.5, 128.6,
128.4, 128.3, 128.2, 126.8, 126.3, 114.4, 114.2, 86.6,
86.5, 63.4, 63.3, 56.1, 55.4, 41.98, 41.95, 35.6, 35.4,
33.9, 33.1, 20.9, 20.8, 14.86, 14.84. HRMS (ESI) Calcd.
for C21H26NO2 (M+H) m/z 324.1957, found 324.1963.
(2p): Yield 70% (0.078 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.28. IR (neat): 3090, 3063, 3027, 2959,
2923, 2850, 2798, 1779, 1604, 1498, 1451, 1063 cm-1. 1H
NMR (400 MHz, CDCl3) δ 7.32 – 7.12 (m, 10H), 3.09 (d,
(2k): Yield 66% (0.051 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.2. IR (neat): 2981, 2946, 2866, 2826,
2791, 1777, 1458, 1064 cm-1. 1H NMR (500 MHz,
CDCl3) δ 7.29 – 7.16 (m, 5H), 3.10 (d,
2.79 (d, = 13.3 Hz, 1H), 2.71 (ddd,
J
= 13.2 Hz, 1H),
J = 13.2 Hz, 1H), 3.00 – 2.86 (m, 1H), 2.77 – 2.65 (m,
J
J
= 15.6, 11.6, 5.8
5H), 2.49 (s, 3H), 2.06 – 1.78 (m, 3H). 13C NMR (101
MHz, CDCl3) δ 209.8, 140.3, 136.9, 130.2, 128.8, 128.3,
128.2, 126.3, 126.0, 86.5, 54.1, 41.8, 36.0, 35.2, 33.6,
20.8. HRMS (ESI) Calcd. for C20H24NO (M+H) m/z
294.1852, found 294.1864.
Hz, 1H), 2.40 (s, 6H), 2.10 – 1.97 (m, 2H), 1.95 – 1.85
(m, 1H). 13C NMR (101 MHz, CDCl3) δ 210.6, 136.8,
130.2, 128.4, 126.4, 86.2, 41.9, 39.3, 33.8, 19.2. HRMS
(ESI) Calcd. for C13H18NO (M+H) m/z 204.1382, found
204.1384.
(2q): Yield 75% (0.079 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.15. IR (neat): 2985, 1779, 1744, 1496,
1454, 1385, 1265, 1198, 1163, 1102, 1067, 1031 cm-1. 1H
NMR (500 MHz, CDCl3) δ 7.29 – 7.16 (m, 5H), 4.17 (q,
(2l): Yield 63% (0.052 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.25. IR (neat): 3030, 2972, 2928, 2853,
1
2791, 1777, 1502, 1453, 1383, 1068 cm-1. H NMR (500
MHz, CDCl3) δ 7.28 – 7.15 (m, 5H), 3.10 (d,
1H), 2.81 – 2.68 (m, 3H), 2.55 (dq, = 14.2, 7.1 Hz, 1H),
= 7.1 Hz,
J
= 13.2 Hz,
J
= 5.0 Hz, 2H), 3.66 (d,
15.0 Hz, 1H), 3.05 (d, = 15.0 Hz, 1H), 2.89 – 2.73 (m,
= 10.0
J = 15.0 Hz, 1H), 3.34 (d, J =
J
J
2.39 (s, 3H), 2.03 – 1.90 (m, 3H), 1.08 (t,
J
2H), 2.50 (s, 3H), 2.12 – 1.97 (m, 3H), 1.27 (t, J
3H). 13C NMR (126 MHz, CDCl3) δ 210.4, 137.0, 130.2,
128.3, 126.3, 86.7, 45.8, 41.8, 35.2, 33.8, 20.8, 13.7.
HRMS (ESI) Calcd. for C14H20NO (M+H) m/z 218.1539,
found 218.1547.
Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 209.5, 171.2,
136.3, 130.1, 128.3, 126.5, 85.1, 60.5, 53.6, 41.8, 37.0,
34.7, 21.0, 14.1. HRMS (ESI) Calcd. for C16H22NO3
(M+H) m/z 276.1593, found 276.1601.
(2m): Yield 43% (0.042 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.37. IR (neat): 2959, 2932, 1774, 1495,
1468, 1454, 1385, 1095 cm-1. 1H NMR (400 MHz,
(2r): Yield 49% (0.054 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.10. IR (neat): 2972, 2930, 2866, 1774,
1725, 1495, 1465, 1381, 1160, 1128, 1099, 1082, 1072
cm-1. 1H NMR (500 MHz, CDCl3) δ 7.27 – 7.14 (m, 5H),
CDCl3) δ 7.28 – 7.15 (m, 5H), 3.10 (d,
2.82 – 2.71 (m, 2H), 2.71 – 2.61 (m, 1H), 2.49 – 2.40 (m,
1H), 2.38 (s, 3H), 2.07 – 1.90 (m, 3H), 1.45 (dd, = 14.6,
= 7.0 Hz,
J = 13.2 Hz, 1H),
4.12 (q,
(dt, = 13.4, 6.8 Hz, 1H), 2.88 – 2.81 (m, 1H), 2.79 –
2.69 (m, 2H), 2.46 (td, = 7.2, 2.9 Hz, 2H), 2.41 (s, 3H),
2.07 – 1.87 (m, 3H), 1.25 (t,
= 7.1 Hz, 3H). 13C NMR
J = 7.1 Hz, 2H), 3.10 (d, J = 13.3 Hz, 1H), 2.93
J
J
7.4 Hz, 2H), 1.40 – 1.21 (m, 4H), 0.90 (t,
J
J
3H). 13C NMR (101 MHz, CDCl3) δ 210.2, 137.1, 130.2,
128.3, 126.2, 86.7, 51.9, 41.8, 35.8, 33.5, 29.4, 28.0,
22.6, 20.8, 14.0. HRMS (ESI) Calcd. for C17H26NO
(M+H) m/z 260.2008, found 260.2034.
J
(126 MHz, CDCl3) δ 209.4, 172.3, 136.8, 130.2, 128.3,
126.3, 86.4, 60.3, 47.6, 41.8, 35.8, 33.8, 33.4, 20.9, 14.1.
HRMS (ESI) Calcd. for C17H24NO3 (M+H) m/z
290.1750, found 290.1758.
(2n): Yield 70% (0.062 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.2. IR (neat): 3087, 3065, 3033, 2970,
2929, 2847, 2795, 1779, 1495, 1457, 1388, 1361, 1110,
1050 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.19 (m,
(2s): Yield 40% (0.045 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.46. IR (neat): 2971, 2933, 2884, 1777,
1
1510, 1422, 1380, 1265, 1075 cm-1. H NMR (500 MHz,
5H), 3.38 (dt,
1H), 2.88 (d,
J
J
= 13.2, 6.6 Hz, 1H), 3.14 (d,
= 13.4 Hz, 1H), 2.66 (ddd,
J
= 13.4 Hz,
CDCl3) δ 7.29 – 7.15 (m, 5H), 6.87-6.82 (m, 4H), 3.78 (s,
3H), 3.15 (d, J = 13.6 Hz, 1H), 2.98 (d, J = 13.6 Hz, 1H),
J
= 13.3, 10.7,
3.8 Hz, 1H), 2.31 (s, 3H), 2.22 – 2.10 (m, 1H), 2.07 –
1.81 (m, 2H), 1.13 – 0.94 (m, 6H). 13C NMR (101 MHz,
CDCl3) δ 211.4, 136.9, 130.1, 128.2, 126.3, 87.0, 47.6,
41.8, 37.4, 28.3, 20.9, 20.6, 19.6. HRMS (ESI) Calcd. for
C15H22NO (M+H) m/z 232.1695, found 232.1697.
2.95 (s, 3H), 2.77 – 2.66 (m, 1H), 2.36 – 2.04 (m, 3H).
13C NMR (126 MHz, CDCl3) δ 209.4, 154.1, 142.1,
136.4, 130.2, 128.3, 126.6, 121.6, 114.1, 84.7, 55.5, 42.3,
37.9, 37.3, 21.9. HRMS (ESI) Calcd. for C19H22NO2
(M+H) m/z 296.1644, found 296.1655.
(2o): Yield 64% (0.066 g); yellow oil; Rf (petroleum
(2t): Yield 29% (0.029 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.32. IR (neat): 2975, 2934, 1775, 1381,
ether/ether, 5:1) 0.65. IR (neat): 3206, 2915, 2822, 1776,

7
1
1597, 1497 cm-1. H NMR (500 MHz, CDCl ) δ 7.30 –
(ESI) Calcd. for C H NO (M+H) m/z 308.2008, found
308.2014.
ACCEPTED MANUSCRIPT
3
21 26
7.23 (m, 5H), 7.17 (d,
Hz, 1H), 6.77 (d,
1H), 3.10 (d,
J
= 7.2 Hz, 2H), 6.82 (t,
J
= 7.3
J
= 8.2 Hz, 2H), 3.23 (d,
J = 13.6 Hz,
J
= 13.6 Hz, 1H), 3.03 (s, 3H), 2.85 – 2.80
(4c): Yield 61% (0.065 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.43. IR (neat): 2973, 2933, 2889, 1708,
1457, 1379, 1255, 1160, 1128, 1095, 1074, 1029 cm-1. 1H
NMR (500 MHz, CDCl3) δ 7.36 – 7.18 (m, 10H), 3.60 (d,
(m, 1H), 2.39 – 2.30 (m, 3H). 13C NMR (126 MHz,
CDCl3) δ 207.5, 147.7, 136.4, 130.4, 128.9, 128.6, 126.8,
118.4, 116.5, 83.8, 42.7, 36.7, 36.4, 23.8. HRMS (ESI)
Calcd. for C18H20NO (M+H) m/z 266.1539, found
266.1541.
J
= 14.2 Hz, 1H), 3.51 (d,
J
= 14.2 Hz, 1H), 3.23 (d,
J =
13.4 Hz, 1H), 2.89 (d,
J
= 13.4 Hz, 1H), 2.30 (s, 3H),
2.20 (s, 3H), 1.18 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
211.9, 139.7, 137.6, 130.5, 128.3, 128.04, 127.9, 126.8,
126.3, 71.7, 55.9, 39.3, 35.2, 25.5, 16.4. HRMS (ESI)
Calcd. for C19H24NO (M+H) m/z 282.1852, found
282.1863.
(2u): Yield 50% (0.044 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.46. IR (neat): 2923, 2848, 1776, 905,
729 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.23 (m,
5H), 5.91 – 5.82 (m, 1H), 5.19 – 5.14 (m, 2H), 3.75 (d,
J
= 13.4 Hz, 1H), 3.55 (d, = 13.4 Hz, 1H), 2.99 – 2.97
J
(m, 1H), 2.85 – 2.83 (m, 1H), 2.62 – 2.60 (m, 1H), 2.48 –
2.46 (m, 1H), 2.20 (s, 3H), 2.18 – 2.14 (m, 1H), 2.00 –
1.93 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 210.3,
139.5, 133.5, 128.6, 128.3, 127.0, 118.6, 85.8, 56.1, 41.6,
35.8, 34.2, 20.4. HRMS (ESI) Calcd. for C15H20NO
(M+H) m/z 230.1539, found 230.1543.
General Procedure for the synthesis of α-benzyl-α-
dialkylamino cyclobutanones 2g-j.
CF3SO3Me (760 µmol, 0.086 mL) was added neat to α-
dibenzylamino cyclobutanone 1g-j (380 µmol) at room
temperature. After 3 h, THF (8 mL) and K2CO3 (950
µmol, 0.131 g) were subsequently introduced in one
portion, and the mixture stirred for 120 h at room
temperature.The crude reaction mixture was directly
loaded onto a silica gel column without aqueous work-up
and pure products were obtained by flash column
chromatography (silica gel, mixture of petroleum
(2v): Yield 52% (0.059 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.54. IR (neat): 2959, 2853, 1777, 1322,
905, 729 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.55 (d,
J =
8.1 Hz, 2H), 7.43 (d,
1H), 5.19 – 5.15 (m, 2H), 3.84 (d,
(d, = 13.9 Hz, 1H), 3.00 – 2.97 (m, 1H), 2.88-2.86 (m,
1H), 2.62 (dd, = 14.2, 7.0 Hz, 1H), 2.46 (dd, = 14.2,
J
= 8.0 Hz, 2H), 5.92 – 5.82 (m,
J
= 13.9 Hz, 1H), 3.59
J
ether/ether, 10:1→1:1).
J
J
7.5 Hz, 1H), 2.20 (s, 3H), 2.18 – 2.12 (m, 1H), 2.03 –
(2g+2g’): Column chromatography afforded pure
regioisomer fraction of 2g and 2g’. Combined yield 59%
(0.073 g); (2g): Yellow oil; Rf (petroleum ether/ether, 5:1)
0.24. IR (neat): 3083, 3065, 3030, 2954, 2848, 2800,
1.95 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 210.0,
143.8, 133.2, 128.7 (2 C), 125.3 (q,
J = 3.2 Hz), 118.8,
85.6, 55.8, 41.6, 35.9, 34.2, 20.5. HRMS (ESI) Calcd. for
C16H19F3NO (M+H) m/z 298.1413, found 298.1417.
1
1777, 1604, 1515, 1347, 1117, 860 cm-1. H NMR (500
MHz, CDCl3) δ 8.17 – 8.15 (m, 2H), 7.42 (d,
2H), 7.32 – 7.24 (m, 5H), 3.83 (d, = 15.0 Hz, 1H), 3.62
(d, = 15.0 Hz, 1H), 3.33 (d, = 15.0 Hz, 1H), 3.02 (dq,
J = 5.0 Hz,
(4a): Yield 65% (0.072 g); yellow oil; Rf (petroleum
J
ether/ether, 5:1) 0.4. IR (neat): 2972, 2932, 2885, 1733,
J
J
1
1492, 1464, 1381 cm-1. H NMR (500 MHz, CDCl3) δ
J = 12.5, 10.0 Hz, 2H), 2.43 – 2.36 (m, 1H), 2.27 (s, 3H),
7.36 – 7.08 (m, 10H), 3.90 (d,
J
= 14.0 Hz, 1H), 3.54 (d,
2.25 – 2.15 (m, 1H), 1.94 – 1.88 (m, 1H). 13C NMR (126
MHz, CDCl3) δ 208.3, 146.7, 145.0, 138.8, 131.1, 128.3
(2 C), 127.1, 123.5, 86.5, 56.0, 42.1, 35.5, 34.5, 20.6.
HRMS (ESI) Calcd. for C19H21N2O3 (M+H) m/z
J
= 14.0 Hz, 1H), 3.20 (d, = 13.3 Hz, 1H), 2.84 (d, J =
J
13.3 Hz, 1H), 2.53 – 2.40 (m, 1H), 2.19 (s, 3H), 2.17 –
2.09 (m, 1H), 2.01 – 1.87 (m, 2H), 1.69 – 1.58 (m, 1H),
1.53 – 1.44 (m, 1H). 13C NMR (126 MHz, CDCl3) δ
215.2, 140.3, 138.0, 130.5, 128.25, 128.21, 128.0, 126.7,
126.1, 70.1, 54.2, 36.6, 34.0, 33.0, 31.3, 17.5. HRMS
(ESI) Calcd. for C20H24NO (M+H) m/z 294.1852, found
294.1875.
325.1546, found 325.1551.
(2g’): Yellow oil; Rf
(petroleum ether/ether, 5:1) 0.23. IR (neat): 2981, 2853,
1
2795, 1777, 1515, 1347, 1112, 1064, 856 cm-1. H NMR
(400 MHz, CDCl3) δ 8.16 (d,
= 8.5 Hz, 2H), 7.31 – 7.20 (m, 5H), 4.07 (d,
1H), 3.68 (d, = 14.5 Hz, 1H), 3.21 (d, = 13.4 Hz, 1H),
J
= 8.6 Hz, 2H), 7.45 (d,
J
J
= 14.5 Hz,
J
J
(4b): Yield 74% (0.087 g); white solid; m. p. = 64-66°C;
Rf (petroleum ether/ether, 5:1) 0.56. IR (neat): 2970,
1710, 1494, 1453, 1422, 1379, 1264, 1159, 1125, 1080,
1029 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.33 – 7.16 (m,
3.07 – 2.74 (m, 2H), 2.29 (s, 3H), 2.27 – 2.16 (m, 1H),
2.09 – 2.04 (m, 2H). 13C NMR (126 MHz, CDCl3) δ
209.4, 147.5, 147.1, 136.4, 130.2, 128.8, 128.5, 126.6,
123.5, 86.2, 55.7, 42.0, 35.8, 34.2, 21.2. HRMS (ESI)
Calcd. for C19H21N2O3 (M+H) m/z 325.1546, found
325.1558.
10H), 3.70 (d,
J
= 14.2 Hz, 1H), 3.45 (d,
= 13.4 Hz, 1H), 3.17 (td, = 13.2, 6.4 Hz,
= 13.5 Hz, 1H), 2.26 – 2.18 (m, 1H), 2.15
J = 14.2 Hz,
1H), 3.41 (d,
1H), 2.65 (d,
J
J
J
(s, 3H), 2.14 – 2.11 (m, 1H), 2.09 – 1.94 (m, 2H), 1.52
(2h+2h’): Column chromatography afforded pure
regioisomer fraction of 2h and 2h’. Combined yield 64%
(0.084 g); (2h): Yellow oil; Rf (petroleum ether/ether,
5:1) 0.58. IR (neat): 3030, 2892, 2853, 2800, 1777, 1329,
(dt, J = 8.9, 7.8 Hz, 1H), 1.45 (d, J = 13.3 Hz, 1H), 1.23 –
1.09 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 213.6,
139.6, 138.8, 131.3, 128.3, 128.0, 127.8, 126.8, 125.7,
71.2, 54.3, 38.8, 35.3, 33.4, 32.2, 27.9, 19.9. HRMS
1
1166, 1126, 1068 cm-1. H NMR (500 MHz, CDCl3) δ

8
Tetrahedron
ACCEPTED MANUSCRIPT
7.56 (d,
7.24 (m, 5H), 3.85 (d,
Hz, 1H), 3.28 (d, = 13.5 Hz, 1H), 3.02 – 2.98 (m, 1H),
2.97 – 2.93 (m, 1H), 2.36 – 2.22 (m, 1H), 2.28 (s, 3H),
2.21 – 2.09 (m, 1H), 1.94 (td,
= 11.1, 6.4 Hz, 1H).13C
NMR (101 MHz, CDCl3) δ 208.9, 141.3, 139.1, 130.6,
128.3 (2 C), 128.2 (2 C), 127.0, 125.2 (q, = 3.43 Hz),
J
= 8.0 Hz, 2H), 7.35 (d,
J
= 8.0 Hz, 2H), 7.32 –
temperature.The crude reaction mixture was directly
J
= 13.4 Hz, 1H), 3.62 (d,
J
= 13.4
loaded onto a silica gel column without aqueous work-up
and pure products were obtained by flash column
chromatography (silica gel, mixture of petroleum
J
J
ether/ether, 10:1→1:1).
J
(6a): Yield 73% (0.060 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.36. IR (neat): 2969, 1782, 1510, 1229
cm-1. 1H NMR (400 MHz, CDCl3) δ 7.26 – 7.22 (m, 2H),
6.86 – 6.81 (m, 3H), 5.84 – 5.77 (m, 1H), 5.15 – 5.10 (m,
2H), 3.03 (s, 3H), 3.00 – 2.78 (m, 2H), 2.66 – 2.56 (m,
2H), 2.43 – 2.27 (m, 2H). 13C NMR (101 MHz, CDCl3) δ
207.9, 148.0, 132.8, 128.9, 119.3, 119.2, 117.9, 83.2,
42.4, 36.9, 35.7, 23.3. Calcd. for C14H18NO (M+H) m/z
216.1383, found 216.1381.
86.4, 56.0, 42.1, 35.6, 34.0, 20.7. HRMS (ESI) Calcd. for
C20H21F3NO (M+H) m/z 348.1569, found 348.1569.
(
2h’): Yellow oil; Rf (petroleum ether/ether, 5:1) 0.48. IR
(neat): 3087, 3063, 3030, 2962, 2923, 2852, 2798, 1779,
1323, 1162, 1123, 1066, 1020 cm-1. H NMR (500 MHz,
1
CDCl3) δ 7.55 (d,
2H), 7.30 (t, = 7.4 Hz, 2H), 7.28 – 7.19 (m, 3H), 3.99
(d, = 14.0 Hz, 1H), 3.65 (d, = 14.0 Hz, 1H), 3.21 (d,
= 13.3 Hz, 1H), 2.92 – 2.83 (m, 2H), 2.28 (s, 3H), 2.19
(dt, = 18.0, 8.0 Hz, 1H), 2.06 (dt, = 10.7, 6.4 Hz, 2H).
13C NMR (126 MHz, CDCl3) δ 209.5, 143.7, 136.6,
130.2, 128.53, 128.50, 126.5, 125.1 (q, = 3.78 Hz),
J = 8.0 Hz, 2H), 7.40 (d, J = 7.9 Hz,
J
J
J
J
J
J
(6b): Yield 66% (0.057 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.20. IR (neat): 2962, 1780, 1515 cm-1.
1H NMR (400 MHz, CDCl3) δ 7.06 – 7.04 (m, 2H), 6.80
– 6.78 (m, 2H), 5.85 – 5.75 (m, 1H), 5.14 – 5.07 (m, 2H),
2.97 (s, 3H), 2.91 – 2.79 (m, 2H), 2.63 – 2.51 (m, 2H),
2.42 – 2.34 (m, 1H), 2.27 (s, 3H), 2.26 – 2.18 (m, 1H).
13C NMR (101 MHz, CDC3) δ 208.8, 146.0, 132.9, 129.6,
129.5, 119.6, 119.1, 83.7, 42.3, 37.6, 36.0, 22.6, 20.6.
Calcd. for C15H20NO (M+H) m/z 230.1539, found
230.1539.
J
86.3, 55.8, 42.0, 35.7, 34.1, 21.1. HRMS (ESI) Calcd. for
C20H21F3NO (M+H) m/z 348.1569, found 348.1566.
(2i+2i’): Spectral data determined from the 2.1:1.0
inseparable mixture of two regioisomers: Yield 78%
(0.100 g); yellow oil; Rf (petroleum ether/ether, 5:1) 0.34.
IR (neat): 3034, 2954, 2853, 2800, 1772, 1719, 1458,
1436, 1281, 1108 cm-1. 1H NMR (400 MHz, CDCl3) δ
7.97 (d,
= 14.0 Hz, 1H), 3.91 (s, 3H), 3.91 (s, 3H), 3.86 (d,
13.5 Hz, 1H), 3.64 (t, = 13.6 Hz, 2H), 3.27 (d,
Hz, 1H), 3.21 (d, = 13.3 Hz, 1H), 3.01 – 2.82 (m, 4H),
J
= 8.1 Hz, 4H), 7.41 – 7.17 (m, 14H), 3.97 (d,
J
=
(6c): Yield 72% (0.066 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.33. IR (neat): 2963, 1779, 1513 cm-1.
1H NMR (400 MHz, CDCl3) δ 7.09 – 7.07 (m, 2H), 6.81
– 6.79 (m, 2H), 5.84 – 5.75 (m, 1H), 5.14 – 5.08 (m, 2H),
2.98 (s, 3H), 2.92 – 2.83 (m, 2H), 2.61 – 2.55 (m, 4H),
J
J
J = 13.3
J
2.28 (s, 6H), 2.26 – 1.89 (m, 6H).13C NMR (126 MHz,
CDCl3) δ 209.5, 208.9, 167.0, 166.9, 145.0, 142.6, 139.2,
136.7, 130.3, 130.2, 129.6, 129.5, 128.46, 128.44, 128.3,
128.26, 128.24, 126.9, 126.5, 86.48, 86.40, 56.0, 55.9,
52.0, 51.9, 42.0, 41.9, 35.7, 35.5, 34.0, 21.0, 20.9. HRMS
(ESI) Calcd. for C21H24NO3 (M+H) m/z 338.1750, found
338.1752.
2.40 – 2.37 (m, 1H), 2.27 – 2.23 (m, 1H), 1.21 (td,
J =
7.6, 2.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 208.6,
146.1, 135.9, 133.0, 128.2, 119.3, 119.1, 83.7, 42.3, 37.5,
35.9, 28.0, 22.7, 15.8. Calcd. for C16H22NO (M+H) m/z
244.1696, found 244.1698.
(6d): Yield 55% (0.057 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.22. IR (neat): 2961, 1780, 1515 cm-1.
1H NMR (400 MHz, CDCl3) δ 7.07 – 7.05 (m, 2H), 6.80
– 6.78 (m, 2H), 5.84 – 5.75 (m, 1H), 5.14 – 5.08 (m, 2H),
2.98 (s, 3H), 2.92 – 2.84 (m, 2H), 2.61 – 2.48 (m, 4H),
2.41 – 2.35 (m, 1H), 2.27 – 2.22 (m, 1H), 1.59 – 1.55 (m,
(2j): Yield 54% (0.085 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.45. IR (neat): 2981, 2888, 2852, 2798,
1
1779, 1325, 1162, 1123, 1068, 1020 cm-1. H NMR (500
MHz, CDCl3) δ 7.56 (t,
4H), 3.96 (d, = 15.0 Hz, 1H), 3.65 (d,
3.27 (d, = 15.0 Hz, 1H), 3.05 – 2.90 (m, 2H), 2.35 –
J
= 5.0 Hz, 4H), 7.38 – 7.26 (m,
J
J
= 15.0 Hz, 1H),
J
2H), 1.36 – 1.32 (m, 2H), 0.92 (t, J
= 7.3 Hz, 3H). 13C
2.29 (m, 1H), 2.27 (s, 3H), 2.16 – 2.00 (m, 1H), 2.03 –
NMR (101 MHz, CDCl3) δ 208.7, 146.1, 134.6, 133.0,
128.8, 119.2, 119.1, 83.7, 42.3, 37.5, 36.0, 34.8, 33.9,
22.7, 22.5, 14.1. Calcd. for C18H26NO (M+H) m/z
272.2009, found 272.2008.
1.93 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 208.6,
143.4, 141.0, 130.5, 128.4, 125.3 (q,
J = 3.78 Hz), 125.2
(q, = 3.78 Hz), 86.2, 55.7, 42.1, 35.6, 34.2, 20.8. HRMS
J
(ESI) Calcd. for C21H20F6NO (M+H) m/z 416.1443,
found 416.1449.
(6e): Yield 59% (0.061 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.36. IR (neat): 2962, 1780, 1515 cm-1.
1H NMR (500 MHz, CDCl3) δ 7.27 – 7.25 (m, 2H), 6.79
– 6.78 (m, 2H), 5.85 – 5.76 (m, 1H), 5.15 – 5.10 (m, 2H),
3.00 (s, 3H), 2.94 – 2.84 (m, 2H), 2.62 – 2.58 (m, 2H),
2.40 – 2.38 (m, 1H), 2.30 – 2.26 (m, 1H), 1.30 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 208.4, 145.7, 142.3,
133.0, 125.7, 119.2, 118.1, 83.5, 42.4, 37.2, 35.7, 34.1,
31.6, 22.9. Calcd. for C18H26NO (M+H) m/z 272.2009,
found 272.2011.
General procedure for the synthesis of α-allyl-α-
methylarylamino cyclobutanones 6a-p.
CF3SO3Me (760 µmol, 0.086 mL) was added neat to α-
allylamino cyclobutanone 5a-p (380 µmol) at room
temperature. After 5 h, CH3COOEt (8 mL) and K2CO3
(950 µmol, 0.131 g) were subsequently introduced in one
portion, and the mixture stirred for 72 h at room

9
(6f): Yield 65% (0.072 g); yellow oil; R (petroleum
ether/ether, 5:1) 0.30. IR (neat): 2959, 1779, 1516, 1201
121.4, 120.0, 119.2, 118.1, 83.9, 42.1, 38.0, 36.3, 22.4.
ACCEPTED MANUSCRIPT
f
Calcd. for C20H21NO3 (M+H) m/z 308.1645, found
308.1648.
cm-1. 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.38 (m, 6H),
7.42 – 7.25 (m, 1H), 6.87 – 6.85 (m, 2H), 5.86 – 5.78 (m,
1H), 5.18 – 5.13 (m, 2H), 3.09 (s, 3H), 3.03 – 2.85 (m,
2H), 2.70 – 2.61 (m, 2H), 2.47 – 2.35 (m, 2H). 13C NMR
(126 MHz, CDCl3) δ 207.4, 147.2, 141.0, 132.7, 131.6,
128.8, 127.5, 126.5, 126.5, 119.5, 117.5, 83.1, 42.5, 36.7,
35.7, 23.6. Calcd. for C20H22NO (M+H) m/z 292.1696,
found 292.1700.
(6l): Yield 0%.
(6m): Yield 53% (0.046 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.49. IR (neat): 2960, 1780, 1516, 1276
cm-1. 1H NMR (400 MHz, CDCl3) δ 7.14 – 7.10 (m, 1H),
6.68 – 6.62 (m, 3H), 5.84 – 5.76 (m, 1H), 5.16 – 5.10 (m,
2H), 3.02 (s, 3H), 2.99 – 2.81 (m, 2H), 2.64 – 2.56 (m,
2H), 2.43 – 2.33 (m, 1H), 2.32 (s, 3H), 2.30 – 2.26 (m,
1H) 13C NMR (101 MHz, CDCl3) δ 208.0, 148.1, 138.7,
132.9, 128.6, 120.2, 119.3, 118.8, 115.2, 83.3, 42.4, 37.0,
35.8, 23.3, 22.0. Calcd. for C15H20NO (M+H) m/z
230.1539, found 230.1536.
(6g): Yield 76% (0.072 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.64. IR (neat): 2962, 1780, 1503, 1233
cm-1. 1H NMR (400 MHz, CDCl3) δ 7.18 (d,
J
= 9.0 Hz,
2H), 6.73 (d,
J = 9.0 Hz, 2H), 5.81 – 5.73 (m, 1H), 5.16 –
5.09 (m, 2H), 3.01 (s, 3H), 2.99 – 2.88 (m, 2H), 2.65 –
2.53 (m, 2H), 2.36 – 2.25 (m, 2H). 13C NMR (126 MHz,
CDCl3) δ 207.3, 146.6, 132.5, 128.8, 124.2, 119.6, 118.8,
83.1, 42.3, 36.9, 35.8, 23.4. Calcd. for C14H1735ClNO
(M+H) m/z 250.0993, found 250.0995.
(6n): Yield 69% (0.063 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.50. IR (neat): 2966, 1776, 1587, 1277
cm-1. 1H NMR (400 MHz, CDCl3) δ 6.52 (s, 1H), 6.45 (s,
2H), 5.85 – 5.76 (m, 1H), 5.16 – 5.10 (m, 2H), 3.00 (s,
3H), 2.99 – 2.80 (m, 2H), 2.67 – 2.55 (m, 2H), 2.43 –
2.35 (m, 1H), 2.32 – 2.23 (m, 1H), 2.28 (s, 6H). 13C
NMR (126 MHz, CDCl3) δ 208.1, 148.2, 138.4, 133.0,
121.4, 119.2, 116.1, 83.4, 42.4, 37.1, 35.9, 23.3, 21.8.
Calcd. for C16H22NO (M+H) m/z 244.1696, found
244.1699.
(6h): Yield 66% (0.073 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.39. IR (neat): 2962, 1780, 1503, 1233
cm-1. 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.30 (m, 2H),
6.67 – 6.65 (m, 2H), 5.81 – 5.73 (m, 1H), 5.16 – 5.10 (m,
2H), 3.01 (s, 3H), 2.99 – 2.84 (m, 2H), 2.66 – 2.54 (m,
2H), 2.38 – 2.28 (m, 2H). 13C NMR (126 MHz, CDCl3) δ
207.0, 146.9, 132.4, 131.6, 119.6, 118.9, 111.2, 82.9,
42.4, 36.7, 35.7, 23.5. Calcd. for C14H1779BrNO (M+H)
m/z 294.0488, found 294.0490.
(6o): Yield 59% (0.062 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.15. IR (neat): 2961, 1780, 1497, 1233
1
cm-1. H NMR (500 MHz, CDCl3) δ 6.78 (d,
J
= 8.4 Hz,
(6i): Yield 61% (0.054 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.61. IR (neat): 2959, 1779, 1516, 1201
cm-1. 1H NMR (500 MHz, CDCl3) δ 6.96 – 6.88 (m, 4H),
5.81 – 5.76 (m, 1H), 5.13 – 5.05 (m, 2H), 2.92 (s, 3H),
2.88 – 2.84 (m, 2H), 2.59 – 2.48 (m, 2H), 2.38 – 2.32 (m,
1H), 2.20 – 2.14 (m, 1H). 13C NMR (126 MHz, CDCl3) δ
1H), 6.67 (s, 1H), 6.55 (d,
J
= 8.3 Hz, 1H), 5.84 – 5.77
(m, 1H), 5.13 – 5.05 (m, 2H), 3.854 (s, 3H), 3.845 (s,
3H), 2.89 (s, 3H), 2.84 – 2.80 (m, 2H), 2.54 – 2.49 (m,
2H), 2.44 – 2.38 (m, 1H), 2.12 – 2.07 (m, 1H). 13C NMR
(126 MHz, CDCl3) δ 210.3, 149.2, 144.9, 143.0, 133.0,
118.9, 114.3, 111.7, 108.0, 84.7, 56.3, 56.0, 41.7, 38.8,
37.1, 21.5. Calcd. for C16H22NO3 (M+H) m/z 276.1594,
found 276.1599.
208.8, 157.8 (d,
J
= 240.5 Hz), 144.8, 132.7, 122.0 (d,
J =
7.6 Hz), 119.1, 115.4 (d,
J
= 22.1 Hz), 83.9, 41.9, 38.1,
36.4, 22.2. Calcd. for C14H17FNO (M+H) m/z 234.1288,
found 234.1291.
(6p): Yield 77% (0.075 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.72. IR (neat): 2953, 1776, 1588, 1477
cm-1. 1H NMR (400 MHz, CDCl3) δ 7.09 – 6.89 (m, 3H),
5.80 – 5.70 (m, 1H), 5.04 – 4.89 (m, 2H), 2.92 – 2.76 (m,
6H), 2.74 (s, 3H), 2.58 – 2.39 (m, 3H), 2.07 – 1.98 (m,
3H). 13C NMR (101 MHz, CDCl3) δ 211.9, 146.1, 145.9,
141.5, 133.1, 126.6, 122.3, 120.6, 118.1, 85.0, 41.6, 38.7,
37.9, 33.5, 31.6, 25.3, 20.8. Calcd. for C17H22NO (M+H)
m/z 256.1696, found 256.1696.
(6j): Yield 68% (0.059 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.20. IR (neat): 2963, 1779, 1496 cm-1.
1H NMR (500 MHz, CDCl3) δ 6.98 – 6.96 (m, 2H), 6.83
– 6.81 (m, 2H), 5.83 – 5.77 (m, 1H), 5.12 – 5.04 (m, 2H),
3.78 (s, 3H), 2.87 (s, 3H), 2.85 – 2.80 (m, 2H), 2.53 –
2.34 (m, 3H), 2.11 – 2.05 (m, 1H). 13C NMR (101 MHz,
CDCl3) δ 210.4, 155.2, 142.5, 133.0, 124.2, 118.8, 114.2,
84.7, 55.6, 41.8, 38.9, 37.0, 21.4. Calcd. for C15H20NO2
(M+H) m/z 230.1539, found 230.1538.
Procedure for the synthesis of tryptamines 7 and 7’.
(6k): Yield 63% (0.074 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.18. IR (neat): 2963, 1778, 1597, 1233
cm-1. 1H NMR (500 MHz, CDCl3) δ 7.32 – 7.29 (m, 2H),
7.07 – 7.03 (m, 1H), 6.98 – 6.94 (m, 2H), 6.93 – 6.87 (m,
4H), 5.85 – 5.76 (m, 1H), 5.15 – 5.08 (m, 2H), 2.97 (s,
3H), 2.93 – 2.86 (m, 2H), 2.60 – 2.52 (m, 2H), 2.41 –
2.36 (m, 1H), 2.23 – 2.17 (m, 1H). 13C NMR (101 MHz,
CDCl3) δ 208.8, 158.3, 150.7, 144.5, 132.8, 129.7, 122.7,
A mixture of N-methyl aniline (0.465 mmol, 0.050 g), α-
allyl-α-amino cyclobutanone, 6a (0.465 mmol, 0.112 g),
and PTSA (0.186 mmol, 0.035 g) was stirred at 50°C for
4 days. The crude reaction mixture was directly loaded
onto a silica gel column without aqueous work-up and
pure products were obtained by flash column
chromatography (silica gel, mixture of petroleum
ether/ether, 10:1
→1:1).

10
Tetrahedron
(7+7’): Yield 68% (0.096 g); yellow oil; R (petroleum
1H), 6.56 (d,
J
= 7.9 Hz, 1H), 6.26 (d,
J
= 8.7 Hz, 2H),
6.06 – 5.98 (m, 1H), 5.15 – 5.06 (m, 2H), 4.25 (brs, 1H),
2.74 (s, 3H), 2.57 (d, = 7.3 Hz, 2H), 2.38 – 2.31 (m,
1H), 2.16 (dd, = 20.8, 10.7 Hz, 1H), 1.94 – 1.86 (m,
ACfCEPTED MANUSCRIPT
ether/ether, 5:1) 0.57. IR (neat): 3056, 1598, 1504, 1469,
745, 691 cm-1. Spectral data determined from the 86:14
J
1
inseparable mixture of two isomers; (
MHz, CDCl3) δ 7.57 (d,
3H), 7.21 – 7.16 (m, 1H), 7.14 – 7.09 (m, 1H), 6.77 (d,
= 8.0 Hz, 2H), 6.70 (t, = 7.2 Hz, 1H), 5.99 – 5.88 (m,
1H), 5.09 (dd, = 10.1, 1.6 Hz, 1H), 4.93 (dd, = 17.1,
1.7 Hz, 1H), 3.63 (s, 3H), 3.55 – 3.49 (m, 4H), 2.98 –
2.95 (m, 2H), 2.93 (s, 3H). 13C NMR (101 MHz, CDCl3)
δ 149.0, 137.0, 135.3, 134.5, 129.3, 127.7, 121.1, 119.0,
118.2, 116.4, 116.0, 112.2, 109.5, 108.9, 53.9, 38.5, 29.7,
28.8, 21.6. Calcd. for C21H25N2 (M+H) m/z 305.2012,
found 305.2015.
7
): H NMR (400
J
J
= 7.8 Hz, 1H), 7.30 – 7.23 (m,
1H), 1.80 – 1.74 (m, 1H). 13C NMR (101 MHz, CDCl3) δ
153.5, 144.7, 134.5, 132.0, 131.5, 129.4, 124.2, 118.7,
117.8, 116.2, 109.2, 108.5, 71.1, 65.1, 36.8, 33.0, 29.8,
21.7. Calcd. for C20H2279BrN2 (M+H) m/z 368.0888,
found 368.0892.
J
J
J
J
(8d): Yield 76% (0.115 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.73. IR (neat): 3077, 2976, 1600, 1492,
1311 cm-1. H NMR (400 MHz, CDCl3) δ 7.17 (td,
J
=
1
7.9, 1.3 Hz, 1H), 7.02 (dd,
J
= 7.3, 0.8 Hz, 1H), 6.92 –
6.88 (m, 2H), 6.65 (td, = 7.4, 0.8 Hz, 1H), 6.56 (d,
J
J
=
Procedure for the synthesis of cyclobuta-fused
indolines 8a-f.
7.9 Hz, 1H), 6.32 – 6.28 (m, 2H), 6.09-5.98 (m, 1H), 5.17
– 5.06 (m, 2H), 4.24 (brs, 1H), 2.74 (s, 3H), 2.58 (d,
7.3 Hz, 2H), 2.34 (ddd, = 11.3, 9.4, 3.0 Hz, 1H), 2.16
(dd, = 20.7, 10.8 Hz, 1H), 1.90 (dt, = 12.0, 9.5 Hz,
1H), 1.77 (ddd,
= 12.2, 10.7, 3.0 Hz, 1H). 13C NMR
(101 MHz, CDCl3) δ 153.5, 144.3, 134.5, 132.1, 129.3,
128.7, 124.2, 122.0, 118.7, 117.8, 115.7, 108.5, 71.1,
65.2, 36.8, 33.0, 29.8, 21.7. Calcd. for C20H2235ClN2
(M+H) m/z 324.1398, found 324.1398.
J
=
J
A mixture of aniline (0.93 mmol), α-allyl-α-amino
cyclobutanone, 6a (0.465 mmol, 0.112 g), and PTSA
(0.093 mmol, 0.018 g) was stirred at room temperature
for 4 days. The crude reaction mixture was directly
loaded onto a silica gel column without aqueous work-up
and pure products were obtained by flash column
chromatography (silica gel, mixture of petroleum
J
J
J
ether/ether, 5:1
→
1:1).
(8e): Yield 83% (0.121 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.10. IR (neat): 2981, 2869, 2214, 1604,
1518 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.23 – 7.19 (m,
(8a): Yield 44% (0.059 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.73. IR (neat): 3056, 2976, 1600, 1505,
3H), 7.02 (dd,
Hz, 1H), 6.59 (d,
J
= 7.3, 0.8 Hz, 1H), 6.67 (td, = 7.4, 0.8
J
1495 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.16 (t,
J
= 7.3
= 7.7 Hz,
= 8.7 Hz, 2H),
= 8.1 Hz, 2H), 6.10 – 6.03 (m, 1H), 5.16 – 5.06
(m, 2H), 4.20 (brs, 1H), 2.74 (s, 3H), 2.60 (d, = 7.2 Hz,
2H), 2.39 – 2.32 (m, 1H), 2.19 (dd, = 20.6, 10.3 Hz,
1H), 1.91 (dt,
J
= 7.9 Hz, 1H), 6.36 (d, J = 8.8 Hz,
Hz, 1H), 7.06 (d,
2H), 6.63 (t, = 7.2 Hz, 1H), 6.57 (t,
6.39 (d,
J
= 7.2 Hz, 1H), 6.97 (t,
J
2H), 6.03 – 5.97 (m, 1H), 5.13 – 5.06 (m, 2H), 4.74 (s,
1H), 2.75 (s, 3H), 2.56 (t, = 6.9 Hz, 2H), 2.38 (ddd,
11.4, 9.4, 2.9 Hz, 1H), 2.20 (dd, = 20.8, 10.8 Hz, 1H),
1.93 (dt, = 12.1, 9.5 Hz, 1H), 1.80 (ddd, = 12.3, 10.8,
J
J
J
J =
J
J
J
J
J
J
2.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 153.4, 149.3,
134.0, 133.3, 131.2, 129.7, 124.0, 120.5, 118.9, 118.2,
114.3, 108.8, 99.2, 71.2, 64.8, 36.7, 32.8, 29.7, 21.8.
Calcd. for C21H22N3 (M+H) m/z 316.1808, found
316.1807.
J
= 19.4, 9.6 Hz, 1H), 1.81 – 1.74 (m, 1H).
13C NMR (101 MHz, CDCl3) δ 153.5, 145.7, 134.8,
129.3, 129.1, 128.8, 124.2, 118.6, 117.7, 117.3, 114.5,
108.4, 71.1, 65.2, 36.8, 33.1, 29.8, 21.7. Calcd. for
C20H23N2 (M+H) m/z 291.1855, found 291.1854.
(8f): Yield 67% (0.105 g); yellow oil; Rf (petroleum
(8b): Yield 45% (0.063 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.75. IR (neat): 2923, 2857, 1608, 1516,
ether/ether, 5:1) 0.10. IR (neat): 3374, 2936, 1596, 1472,
1297 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.81 (d,
J
= 9.3
= 7.4 Hz,
= 8.0 Hz, 1H),
= 9.1 Hz, 2H), 5.95 – 5.90 (m, 1H), 5.06 – 4.93
(m, 2H), 4.93 (s, 1H), 2.69 (s, 3H), 2.55 – 2.45 (m, 2H),
1307 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.15 (t,
J
= 7.6
= 8.0 Hz,
= 7.9 Hz, 1H),
= 8.1 Hz, 2H), 6.10 – 6.03 (m, 1H), 5.16-5.06
(m, 2H), 4.11 (brs, 1H), 2.74 (s, 3H), 2.60 (d, = 7.2 Hz,
2H), 2.36 – 2.28 (m, 1H), 2.22 – 2.16 (m, 1H), 2.13 (s,
Hz, 2H), 7.13 (t,
1H), 6.61 (t, = 7.4 Hz, 1H), 6.53 (d,
6.28 (d,
J = 7.7 Hz, 1H), 6.96 (d, J
Hz, 1H), 7.04 (d,
2H), 6.63 (t, = 7.4 Hz, 1H), 6.55 (d,
6.31 (d,
J
= 7.3 Hz, 1H), 6.78 (d,
J
J
J
J
J
J
J
J
2.36 – 2.31 (m, 1H), 2.16 (q, J = 10.6 Hz, 1H), 1.91 –
1.84 (m, 1H), 1.77 – 1.72 (m, 1H). 13C NMR (126 MHz,
CDCl3) δ 153.4, 151.4, 138.5, 133.9, 131.0, 129.9, 125.9,
124.0, 119.0, 118.3, 113.3, 108.9, 71.3, 65.0, 36.7, 32.8,
29.7, 21.9. Calcd. for C20H22N3O2 (M+H) m/z 336.1706,
found 336.1708.
3H), 1.89 (dd,
J = 20.5, 10.6 Hz, 1H), 1.77 (td, J = 12.0,
2.7 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 153.5, 143.3,
134.9, 132.9, 129.4, 129.1, 126.4, 124.2, 118.6, 117.6,
114.6, 108.3, 71.1, 65.4, 36.9, 33.1, 29.8, 21.7, 20.4.
Calcd. for C21H25N2 (M+H) m/z 305.2012, found
305.2014.
Acknowledgments
Financial support from the MIUR, Rome, and by the
University of Cagliari and Fondazione Banco di Sardegna is
acknowledged.
(8c): Yield 90% (0.154 g); yellow oil; Rf (petroleum
ether/ether, 5:1) 0.73. IR (neat): 3336, 2973, 2923, 1637,
1596, 1489 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.17 (t,
J
= 7.7 Hz, 1H), 7.05 – 7.01 (m, 3H), 6.65 (t,
J = 7.4 Hz,

11
Secci, F.; Aitken, D. J.; Frongia, A. Eur. J. Org. Chem. 2015,
4358-4366.
References and notes
ACCEPTED MANUSCRIPT
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Ç
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11. The requisite starting material 5a-p was prepared by the
condensation reaction between α-hydroxy cyclobutanone and the
corresponding N-allyl aniline, in the presence of catalytic amount
of DMAP (20 mol%). Unfortunately, no reactivity was observed
for N-allyl anilines carrying an electron-withdrawing group such
as -NO2 or -CN in the para-position of the aromatic ring.
12. For recent examples on the application of [2,3]-rearrangement of
allylic ammonium ylides to the synthesis of α-amino acid
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and co-workers observed, unexpectedly, the formation of the
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mixture of two diastereomers from 2-benzyloxycyclobutanone and
(S)-or (R)-phenyl ethylamine using PTSA as a catalyst and xylene
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ACCEPTED MANUSCRIPT
O
Alk/Aryl
N
O
N
Alk/Aryl
Sigmatropic
rearrangement
CF3SO3Me
O
O
N
N
Alk/Aryl
Alk/Aryl
K2CO3
CF3SO3
CF3SO3
K
Scheme 1.
Entry
Methylating
reagent
Base
Solvent
Yield 2a (%)b
-
1
Me3O+BF4
K2CO3
K2CO3
K2CO3
K2CO3
Li2CO3
Cs2CO3
Na2CO3
t-BuOK
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3COOEt
THF
36
39
66
8
2
Me2SO4
3
CF3SO3Me
MeI
4
5
CF3SO3Me
CF3SO3Me
CF3SO3Me
CF3SO3Me
CF3SO3Me
CF3SO3Me
CF3SO3Me
CF3SO3Me
CF3SO3Me
11
45
26
38
48
79
57
0c
6
7
8
9
10
11
12
13
1,4-Dioxane
DMF
EtOH
0c
Table 1

ACCEPTED MANUSCRIPT
Scheme 2.
Scheme 3

ACCEPTED MANUSCRIPT
Scheme 4
R
O
1) CF3SO3Me
neat, R.T., 5 h
R
O
N
N
2) K2CO3
CH3COOEt, R.T, 3 d
6
5
O
O
O
N
N
O
N
N
6a
Y: 73%
6b
Y: 66%
6c
Y: 72%
6d
Y: 55%
Cl
Br
Ph
O
O
O
O
N
N
N
N
6f
Y: 65%
6g
Y: 76%
6h
Y: 66%
6e
Y: 59%
Ph
O
F
O
O
O
O
O
N
N
N
N
6i
Y: 61%
6j
Y: 68%
6k
Y: 63%
6l
Y: 0%
O
O
O
O
O
O
N
N
N
N
6m
Y: 53%
6n
Y: 69%
6o
Y: 59%
6p
Y: 77%
Scheme 5

ACCEPTED MANUSCRIPT
Scheme 6
Graphical Abstract