Catalytic Enantioselective Synthesis of α-(Benzylamino)cyclobutanones

Article abstract of DOI:10.1002/ejoc.201500460

An organocatalytic enantioselective synthesis of α-(benzylamino)cyclobutanones has been achieved by employing a tandem condensation/intramolecular rearrangement/proton transfer reaction and starting from racemic α-hydroxycyclobutanone and a selection of benzylamines. This reaction sequence afforded the products in good to high yields with moderate to high enantioselectivities. An organocatalytic enantioselective synthesis of α-(benzylamino)cyclobutanones has been achieved by employing a tandem condensation/intramolecular rearrangement/proton transfer reaction. The reaction sequence began from readily available racemic α-hydroxycyclobutanone and a variety of benzylamines to afford the products in good to high yields and with moderate to high stereoselectivities.

Full text of DOI:10.1002/ejoc.201500460

FULL PAPER
DOI: 10.1002/ejoc.201500460
Catalytic Enantioselective Synthesis of α-(Benzylamino)cyclobutanones
[a]
[a]
[b]
[c]
[a]
Nicola Melis, Lorenza Ghisu, Régis Guillot, Pierluigi Caboni, Francesco Secci,
[b]
[a]
David J. Aitken, and Angelo Frongia*
Keywords: Synthetic methods / Organocatalysis / Enantioselectivity / Amines / Carbocycles / Tautomerism
An organocatalytic enantioselective synthesis of α-(benz- butanone and a selection of benzylamines. This reaction se-
ylamino)cyclobutanones has been achieved by employing a
tandem condensation/intramolecular rearrangement/proton
transfer reaction and starting from racemic α-hydroxycyclo-
quence afforded the products in good to high yields with
moderate to high enantioselectivities.
Introduction
new tandem condensation/intramolecular rearrangement/
[
11]
enantioselective proton transfer procedure, resulting in a
useful route for the preparation of optically active α-amino-
cyclobutanones that are beyond the reach of established
Chiral α-aminocyclobutanes[1] are useful intermediates in
organic synthesis because of their inherent ring strain and
rigidity and have been used for the preparation of a large
variety of chemically and biologically interesting synthetic
amination strategies (Scheme 1). To further develop our re-
[6,9]
cent discoveries,
we sought to apply the synthetic meth-
[
2]
compounds. In addition, the α-aminocyclobutane moiety
odology to the enantioselective construction of fully ali-
phatic α-(benzylamino)cyclobutanones. With regard to
enantioselective control, benzylamines are challenging part-
ners because of their high reactivity. In contrast with our
previous work in which weakly nucleophilic anilines were
[
3]
is found in a number of natural product structures. It is
the prevalence of α-aminocyclobutane derivatives that
makes the search and design of efficient methods for their
preparation of considerable interest. Despite this, only few
methods exist that allow for their direct asymmetric synthe-
[6]
employed, the enhanced nucleophilicity of the benzyl-
sis.[4,5]
amines makes the noncatalyzed (and thus racemic) reaction
a competitive pathway. If this reaction is as fast as the cata-
lyzed one, the asymmetric induction will be compromised.
In this context, we recently developed a new approach
for the asymmetric assembly of α-(arylamino)cyclobutan-
[
6]
ones based on the organocatalytic condensation reaction
between racemic 2-hydroxycyclobutanone and arylamines
by using commercially available cinchona alkaloids as the
[
7,8]
catalysts.
It was found that this method could be success-
fully applied to the stereoselective synthesis of cyclobutan-
one α-amino acid ester derivatives.[ An important aspect
of this approach is the unconventional manner in which the
nitrogen-containing group is stereoselectively introduced to
the carbocyclic ring, which is complementary to an alterna-
tive approach based on the asymmetric “electrophilic α-
amination” of carbonyl compounds.[ Our synthetic pro-
cedure was achieved by an unprecedented and conceptually
9]
10]
[
a] Dipartimento di Scienze Chimiche e Geologiche, Università
degli studi di Cagliari,
Complesso Universitario di Monserrato,
S.S. 554, Bivio per Sestu, 09042 Monserrato, Cagliari, Italy
E-mail: afrongia@unica.it
http://people.unica.it/angelofrongia/
[
[
b] CP3A Organic Synthesis Group & Services Communs,
ICMMO-CNRS UMR 8182, Université Paris-Sud,
1
5 rue Georges Clemenceau, 91405 Orsay cedex, France
c] Dipartimento di Scienze della vita e dell’ambiente, Università
degli studi di Cagliari
Scheme 1. Key steps in the organocatalytic enantioselective tandem
condensation/keto–enol tautomerization for the synthesis of op-
tically active α-aminocyclobutanones.
Via Ospedale 72, 09124 Cagliari, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500460.
4358
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4358–4366

Catalytic Enantioselective Synthesis of α-(Benzylamino)cyclobutanones
Results and Discussion
Having established the appropriate reaction conditions,
we next conducted experiments to evaluate the scope of this
transformation by varying the ring substituents on the di-
benzylamine substrate (Scheme 2). Good enantioselectivit-
ies were obtained by a series of dibenzylamines with elec-
tron-withdrawing groups on the aromatic ring. Dibenzyl-
amines 2b–2h, which contain one electron-withdrawing sub-
stituent at the para position, gave rise to the desired α-
We first examined the model reaction between α-
hydroxycyclobutanone (1) and dibenzylamine (2a) under
different conditions to give adduct 3a (Table 1). In the early
stages of this study, as we had suspected, the reaction pro-
ceeded with moderate conversion without a catalyst in 1,4-
dioxane at room temperature for 3 h (Table 1, Entry 1).
Table 1. Optimization of reaction conditions.[a]
Entry
Catalyst
–
Solvent
Yield 3a [%][b]
e.r.(3a)[c]
1
2
3
4
5
6
7
8
9
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
47
81
78
66
70
54
68
71
54
85
77
80
–
[
d]
(DHQD)
(DHQ) PYR
(DHQD)
(DHQ)
2
PYR
71:29
32:68
54:46
48:52
64:36
44:56
46:54
59:41
49:51
69:31
50:50
[
d]
2
[d]
2
PHAL
[d]
2
PHAL
[
d]
(DHQD)
(DHQ) AQN
quinidine
2
AQN
[
d]
2
(DHQD)
(DHQD)
(DHQD)
2
2
2
PYR
PYR
PYR
1
1
0
1
CHCl
CH COOEt
toluene
3
3
[
e]
12
2
(DHQD) PHAL
[
a] Reagents and conditions: 1 (669 μmol), 2 (224 μmol), catalyst
44.8 μmol), solvent (0.5 mL). [b] Isolated yield after chromatog-
raphy. [c] Enantiomeric ratio (e.r.) was determined by HPLC analy-
sis using a chiral stationary phase column. [d] (DHQD) PYR =
hydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether, (DHQ)
PYR hydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether,
PHAL = hydroquinidine 1,4-phthalazinediyl diether,
PHAL hydroquinine 1,4-phthalazinediyl diether,
DHQD) AQN = hydroquinidine (anthraquinone-1,4-diyl) diether,
DHQ) AQN = hydroquinine (anthraquinone-1,4-diyl) diether.
e] Reagents and conditions: (DHQD) PHAL (30 mol-%), toluene
0.5 mL), molecular sieves (4 Å; 0.6 g), 0 °C.
(
2
2
-
=
(
(
(
(
DHQD)
2
DHQ)
2
=
2
2
[
2
(
Under the same conditions, we used (DHQD) PYR as
2
the catalyst and were able isolate the desired product 3a
from the reaction mixture in 81% yield with encouraging
enantioselectivity (71:29 e.r.; Table 1, Entry 2). Moreover,
when the pseudoenantiomeric catalyst (DHQ) PYR was
2
employed, the reaction afforded the product enriched in the
opposite enantiomer with a slightly lower selectivity
(Table 1, Entry 3). In an effort to improve the enantio-
selectivity, several other catalysts were evaluated (Table 1,
Entries 4–8), but they were less rewarding with regard to
yield and selectivity than (DHQD) PYR and (DHQ) PYR.
2
2
By screening different solvents (Table 1, Entries 9–11), we
discovered that the initial use of 1,4-dioxane had been for-
tuitous, although the use of ethyl acetate gave almost Scheme 2. Substrate scope regarding aromatic ring substituents.
Reagents and conditions:
1 (669 μmol), 2 (224 μmol), and
equally favorable results. Notably, the reaction conditions
that had provided good to high enantioselectivity in our
previous study with anilines[ had no effect on the enantio-
control of this model reaction (Table 1, Entry 12).
(
DHQD) PYR (44.8 μmol) in 1,4-dioxane (0.5 mL). Yields are
2
given for isolated materials after column chromatography. The e.r.
values were determined by HPLC analysis using a chiral stationary
phase column.
6]
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4359

A. Frongia et al.
FULL PAPER
aminocyclobutanones 3b–3h in high yields (up to 94%) with guide to possible future developments, we found that N-
enantioselectivities up to 87:13 e.r. A representative meta- benzylglycine ester 4g was a more successful partner than
substituted dibenzylamine (i.e., 2i) performed almost its homologue 4f and afforded the desired product 5g in
equally well (77% yield, 78:22 e.r.), whereas ortho-substi- high yield (93%) with improved enantioselectivity (78:22
tuted dibenzylamine 2j furnished the desired product 3j in e.r.). Substrates 4h–4k, which have an electron-withdrawing
a diminished 48% yield and with an enantiomeric ratio of group (NO ) at the para position of the aromatic ring, per-
2
only 56:44. Dibenzylamines 2k–2m, which have one elec- formed perceptibly better than the nonsubstituted series
tron-donating substituent at the para position, also pro- 4a–4f and gave products 5h–5k with enantiomeric ratios
vided good yields of the corresponding adducts 3k–3m un- that ranged from 62:38 to 78:22. These results suggest that
der the designated reaction conditions. These products, steric factors and the electronic character of the N-alkyl
however, were obtained with lower enantioselectivities group of the benzylamine have a dramatic influence on the
(from 69:31 to 75:25 e.r.).
stereoselectivity of the reaction and that the presence of an
Of particular note, bis(para-substituted) dibenzylamines electron-withdrawing group at the para position of the aro-
that contain electron-withdrawing groups were tolerated matic ring is required to effect some enantioselectivity.[13]
and gave good to high chemical yields with high enantio-
selectivities. Indeed, by using dibenzylamines 2o–2t as sub-
strates, we obtained the corresponding α-(dibenzylamino)-
cyclobutanones 3o–3t in yields of 59–85% with up to 91:9
e.r. Importantly, by using a dibenzylamine that has an elec-
tron-donating substituent on one aryl group and an elec-
tron-withdrawing group on the other, compound 2n pro-
vided comparable results in terms of efficiency and stereo-
selectivity.
The absolute configuration of compound 3o was unam-
biguously determined to be (R) by single-crystal X-ray dif-
fraction analysis (Figure 1), and the configurations of the
other products 3a–3t were assumed to be (R) by analogy to
[12]
3o.
Scheme 3. Substrate scope regarding N-alkyl substituents. Reagents
and conditions: 1 (669 μmol), 4 (0.224 μmol), and (DHQD) PYR
44.8 μmol) in 1,4-dioxane (0.5 mL). Yields are given for isolated
2
(
materials after column chromatography. The e.r. values were deter-
mined by HPLC analysis using a chiral stationary phase column.
Figure 1. X-ray crystallographic structure of compound 3o.
We also examined N-alkylbenzylamines 4a–4g under the
Returning our focus to dibenzylamine substrates, we ex-
standard conditions (Scheme 3). Various N-alkyl groups amined the influence of a pre-existing stereogenic center on
such as methyl (i.e., 4a), ethyl (i.e., 4b), phenethyl (i.e., 4d), the stereochemical outcome of the tandem asymmetric re-
(
ethoxycarbonyl)ethyl (i.e., 4f) as well as the sterically more action by considering the chirality of both the secondary
[
14]
congested isopropyl group (i.e., 4c) provided products in amine and the catalyst.
As revealed in Scheme 4, with
good to high yields (79–93%). Only N-allyl substrate 4e af- homochiral benzylamines 6a and ent-6a, a moderate match/
forded a disappointing yield, even after a prolonged reac- mismatch effect between the amine and the catalyst was ob-
tion time (48% yield after 46 h). Furthermore, products 5a– served in both cases, without any significant improvement
5f were obtained with low selectivity, and this aspect of the to the stereoselectivity obtained by the catalyzed reaction
reactivity remains a challenge to control. However, as a of dibenzylamine 2a (Table 1, Entry 2). However, as ex-
4360
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Eur. J. Org. Chem. 2015, 4358–4366

Catalytic Enantioselective Synthesis of α-(Benzylamino)cyclobutanones
Conclusions
We have presented a simple and practical method for the
synthesis of highly functionalized and optically active α-
benzylamino)cyclobutanones by using a tandem condensa-
tion/intramolecular rearrangement/proton transfer reac-
tion. The reaction sequence began from readily available
racemic α-hydroxycyclobutanone and benzylamines and
was catalyzed by cinchona alkaloid derivatives to afford the
products in good to high yields and with moderate to high
stereoselectivities.
(
Experimental Section
General Procedure for α-Benzylamination of α-Hydroxycyclobutan-
ones: To a solution of freshly distilled α-hydroxycyclobutanone
(
2
0.058 g, 0.669 mmol) and (DHQD) PYR (0.0395 g, 0.0448 mmol)
in dry 1,4-dioxane (0.5 mL) at room temperature was added the
benzylamine (0.224 mmol) dropwise, and the resulting mixture was
stirred for 0.5–18 h. The crude reaction mixture was directly loaded
onto a silica gel column without aqueous workup, and the pure
products were obtained by flash column chromatography (silica gel;
hexane/ether, 5:1 Ǟ 1:1). The racemates were synthesized by using
-(dimethylamino)pyridine (DMAP) as a catalyst.
4
3
2
1
a: Yellow oil (48 mg, 81% yield). IR (neat): ν˜ = 3087, 3058, 3028,
930, 2844, 2812, 1778, 1653, 1495, 1453, 1400, 1374, 1069,
–
1
29
1
026 cm . [α]
): δ = 7.37 (d, J = 7.5 Hz, 4 H), 7.31 (t, J = 7.5 Hz, 4 H),
.24 (d, J = 7.0 Hz, 1 H), 4.28 (t, J = 9.3 Hz, 1 H), 3.76 (d, J =
D 3
= +19.2 (c = 2.18, CHCl ). H NMR (500 MHz,
CDCl
3
7
1
1
3.6 Hz, 2 H), 3.63 (d, J = 13.6 Hz, 2 H), 2.70 (dt, J = 19.5, 9.8 Hz,
H), 2.59 (ddd, J = 14.9, 7.3, 4.6 Hz, 1 H), 2.09–1.95 (m, 2
1
3
H) ppm. C NMR (126 MHz, CDCl
3
): δ = 209.97, 138.91, 129.00,
1
28.44, 127.31, 76.66, 55.14, 40.71, 14.94 ppm. HRMS (ESI): calcd.
for C18
H
19NO [M + 1]+ 266.1559; found 266.1558. The enantio-
meric ratio (71:29) was determined by HPLC (Chiracel OJ column;
–
1
R
hexane/iPrOH, 90:10; flow rate: 1.0 mLmin ; λ = 254 nm): t =
17.74 min (major), t
R
= 21.83 min (minor).
3
b: Yellow oil (61 mg, 82% yield). IR (neat): ν˜ = 3031, 2831, 1778,
–
1
1617, 1492, 1449, 1420, 1325, 1164, 1124, 1105, 1062, 1019 cm .
2
7
1
D 3 3
[α] = +20.1 (c = 3.07, CHCl ). H NMR (500 MHz, CDCl ): δ =
7
4
.56 (d, J = 8.2 Hz, 2 H), 7.49 (d, J = 8.1 Hz, 2 H), 7.37–7.28 (m,
H), 7.25 (dd, J = 9.6, 4.3 Hz, 1 H), 4.32–4.21 (m, 1 H), 3.81 (d,
J = 14.1 Hz, 1 H), 3.73 (dd, J = 28.1, 13.8 Hz, 2 H), 3.63 (d, J =
3.6 Hz, 1 H), 2.81–2.68 (m, 1 H), 2.67–2.57 (m, 1 H), 2.16–1.94
1
Scheme 4. Diastereoselective approach to α-(dibenzylamino)cyclo-
butanones.
13
(
3
m, 2 H) ppm. C NMR (126 MHz, CDCl ): δ = 209.40, 143.30,
138.41, 129.09, 128.98, 128.54, 127.52, 125.39 (q, J = 3.8 Hz),
7
C
6.65, 55.37, 54.71, 40.80, 15.09 ppm. HRMS (ESI): calcd. for
NO [M + 1]+ 334.1413; found 334.1426. The enantio-
19
H
18
F
3
pected, the introduction of an electron-withdrawing group
meric ratio (86:14) was determined by HPLC (Phenomenex Lux
(
CF ) at the para position of the aromatic ring (i.e., 6b and
3
–
1
Cellulose-1 column; hexane/iPrOH, 98:2; flow rate: 1.0 mLmin ;
λ = 254 nm): t = 11.43 min (major), t = 12.32 min (minor).
ent-6b) led to a considerable improvement in the stereose-
lectivity and afforded the desired α-(benzylamino)cyclobut-
anones 7b/7Јb in 81:19 diastereomeric ratio (d.r.) and ent-
R
R
3
c: Yellow oil (64 mg, 92% yield). IR (neat): ν˜ = 3022, 2841, 1774,
–
1
29
1
604, 1518, 1495, 1456, 1348, 1262, 1105, 1069 cm . [α]
D
= +10.9
): δ = 8.16 (d, J =
.7 Hz, 2 H), 7.55 (d, J = 8.8 Hz, 2 H), 7.35–7.23 (m, 5 H), 4.27
7b/ent-7Јb in 91:9 d.r., respectively, by using 30 mol-% of
1
(
3 3
c = 5.46, CHCl ). H NMR (500 MHz, CDCl
(
DHQD) PYR or (DHQ) PYR. Unfortunately, we could
2
2
8
not distinguish the diastereomers by TLC and failed to
separate them by silica gel column chromatography. It
should be noted that the reaction of either dibenzylamine
(
dd, J = 10.0, 8.4 Hz, 1 H), 3.85 (d, J = 14.5 Hz, 1 H), 3.74 (t, J =
1
2
8.5 Hz, 2 H), 3.64 (d, J = 13.6 Hz, 1 H), 2.83–2.70 (m, 1 H), 2.70–
.57 (m, 1 H), 2.12 (qd, J = 10.7, 4.5 Hz, 1 H), 2.07–1.96 (m, 1
6a or ent-6b without a catalyst proceeded with almost no
13
H) ppm. C NMR (126 MHz, CDCl
3
): δ = 209.03, 147.04, 138.03,
intrinsic stereochemical preference, which clearly suggests a 129.43, 128.96, 128.59, 127.65, 123.69, 76.68, 55.63, 54.56, 40.85,
+
catalyst-based control of the stereoselectivity.
15.22 ppm. HRMS (ESI): calcd. for C18
H
18
N
2
O
3
[M + 1] 311.139;
4361
Eur. J. Org. Chem. 2015, 4358–4366
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A. Frongia et al.
FULL PAPER
found 311.1394. The enantiomeric ratio (87:13) was determined by
(dt, J = 17.8, 7.5 Hz, 7 H), 6.99 (t, J = 8.7 Hz, 2 H), 4.26 (t, J =
9.2 Hz, 1 H), 3.72 (m, 2 H), 3.60 (dd, J = 13.6, 5.6 Hz, 2 H), 2.71
HPLC (Chiracel OJ column; hexane/iPrOH, 90:10; flow rate:
–1
1
.0 mLmin ; λ = 254 nm): t
R
= 41.52 min (major), t
R
= 36.36 min (ddd, J = 19.5, 10.8, 2.0 Hz, 1 H), 2.65–2.55 (m, 1 H), 2.11–1.93
1
3
(minor).
(m, 2 H) ppm. C NMR (126 MHz, CDCl
61.24, 138.72, 134.58 (d, J = 3.2 Hz), 130.49, 130.43, 128.96,
128.47, 127.38, 115.32, 115.15, 76.57, 55.10, 54.37, 40.75,
3
): δ = 209.77, 163.19,
1
3
1
5
8
4
2
1
d: Yellow oil (58 mg, 90% yield). IR (neat): ν˜ = 3031, 2831, 2231,
–1
27
774, 1610, 1499, 1456, 1371, 1075, 1023 cm . [α]
3 3
.49, CHCl ). H NMR (500 MHz, CDCl ): δ = 7.59 (d, J =
D
= +12.3 (c =
+
1
14.96 ppm. HRMS (ESI): calcd. for C18
84.1445; found 284.1452. The enantiomeric ratio (76:24) was de-
termined by HPLC (Phenomenex Lux Cellulose-1 column; hexane/
H18FNO [M + 1]
2
.0 Hz, 2 H), 7.49 (d, J = 8.0 Hz, 2 H), 7.31 (d, J = 4.3 Hz, 5 H),
.26 (t, J = 9.2 Hz, 1 H), 3.80 (d, J = 14.4 Hz, 1 H), 3.77–3.67 (m,
H), 3.63 (d, J = 13.5 Hz, 1 H), 2.80–2.70 (m, 1 H), 2.68–2.58 (m,
–
1
iPrOH, 99:1; flow rate: 1.0 mLmin ; λ = 254 nm): t
R
= 10.36 min
1
3
(major), t = 10.96 min (minor).
R
H), 2.10 (qd, J = 10.5, 4.5 Hz, 1 H), 2.06–1.96 (m, 1 H) ppm.
C
NMR (126 MHz, CDCl
3
): δ = 209.12, 144.90, 138.10, 132.26, 3i: Yellow oil (53 mg, 77% yield). IR (neat): ν˜ = 3071, 3025, 2838,
–
1
25
1
4
2
29.40, 128.93, 128.55, 127.58, 118.99, 111.12, 76.64, 55.53, 54.79, 1778, 1528, 1449, 1351, 1075, 1023 cm . [α] = +8.4 (c = 4.98,
0.81, 15.15 ppm. HRMS (ESI): calcd. for C19
91.1492; found 291.1497. The enantiomeric ratio (86:14) was de-
D
O [M + 1]+
1
H
18
N
2
3 3
CHCl ). H NMR (500 MHz, CDCl ): δ = 8.22 (s, 1 H), 8.09 (d, J
= 8.2 Hz, 1 H), 7.73 (d, J = 7.7 Hz, 1 H), 7.49 (d, J = 7.9 Hz, 1
H), 7.33 (t, J = 6.3 Hz, 5 H), 4.28 (t, J = 9.2 Hz, 1 H), 3.85 (d, J
= 14.2 Hz, 1 H), 3.76 (d, J = 14.5 Hz, 2 H), 3.65 (d, J = 13.6 Hz,
1 H), 2.82–2.71 (m, 1 H), 2.70–2.60 (m, 1 H), 2.13 (qd, J = 10.7,
termined by HPLC (Chiralpak AD-H column; hexane/iPrOH,
–1
R
95:5; flow rate: 1.0 mLmin ; λ = 254 nm): t = 22.76 min (major),
t
R
= 26.78 min (minor).
1
3
4
.6 Hz, 1 H), 2.08–1.98 (m, 1 H) ppm. C NMR (126 MHz,
CDCl ): δ = 209.02, 148.49, 141.46, 138.06, 134.95, 129.38, 129.00,
128.61, 127.62, 123.57, 122.46, 76.68, 55.56, 54.47, 40.87,
3
1
1
e: Yellow oil (50 mg, 69% yield). IR (neat): ν˜ = 3031, 2956, 2890,
774, 1722, 1614, 1574, 1492, 1436, 1387, 1282, 1190, 1170, 1111,
3
–1
20
1
075, 1023 cm . [α]
D 3
= +17.1 (c = 4.90, CHCl ). H NMR
+
18 2 3
15.30 ppm. HRMS (ESI): calcd. for C18H N O [M + 1] 311.139;
(400 MHz, CDCl
3
): δ = 7.99 (d, J = 8.2 Hz, 2 H), 7.45 (d, J =
found 311.1399. The enantiomeric ratio (78:22) was determined by
8
1
1
1
.2 Hz, 2 H), 7.30 (ddd, J = 18.4, 8.7, 5.9 Hz, 5 H), 4.31–4.23 (m,
H), 3.90 (s, 3 H), 3.80 (d, J = 14.1 Hz, 1 H), 3.72 (dd, J = 22.9,
3.8 Hz, 2 H), 3.62 (d, J = 13.6 Hz, 1 H), 2.72 (ddd, J = 19.5, 10.7,
HPLC (Phenomenex Lux Cellulose-1 column; hexane/iPrOH, 95:5;
–
1
R R
flow rate: 1.0 mLmin ; λ = 254 nm): t = 16.11 min (major), t =
1
3
17.18 min (minor).
.9 Hz, 1 H), 2.66–2.55 (m, 1 H), 2.13–1.94 (m, 2 H) ppm.
): δ = 209.50, 167.09, 144.49, 138.43,
29.75, 129.24, 128.96, 128.80, 128.48, 127.44, 76.61, 55.32, 54.85,
2.14, 40.74, 15.03 ppm. HRMS (ESI): calcd. for C20 [M
1] 324.1594; found 324.1602. The enantiomeric ratio (80:20) was
determined by HPLC (Chiralpak AS-H column; hexane/iPrOH,
C
NMR (101 MHz, CDCl
1
5
3
3
1
2
8
1
1
j: Yellow oil (33 mg, 48% yield). IR (neat): ν˜ = 3064, 3025, 1778,
–1
27
528, 1495, 1456, 1354, 1200, 1179, 1065 cm . [α]
3 3
.28, CHCl ). H NMR (500 MHz, CDCl ): δ = 7.81 (d, J =
D
= –13.1 (c =
H21NO
3
1
+
+
.2 Hz, 2 H), 7.55 (dd, J = 11.9, 4.3 Hz, 1 H), 7.37 (t, J = 7.7 Hz,
H), 7.30–7.26 (m, 5 H), 4.27–4.20 (m, 1 H), 4.15 (d, J = 15.3 Hz,
H), 3.97 (d, J = 15.3 Hz, 1 H), 3.77 (d, J = 13.5 Hz, 1 H), 3.64
–1
R
99:1; flow rate: 1.0 mLmin ; λ = 254 nm): t = 25.70 min (major),
t
R
= 32.21 min (minor).
(
(
d, J = 13.5 Hz,1H), 2.76–2.66 (m, 1 H), 2.65–2.56 (m, 1 H), 2.06
1
3
ddd, J = 18.4, 13.1, 7.1 Hz, 2 H) ppm. C NMR (126 MHz,
): δ = 209.33, 149.80, 138.09, 134.46, 132.84, 131.24, 128.97,
128.52, 128.08, 127.52, 124.45, 76.74, 56.34, 51.83, 40.73,
3
1
1
f: Pale yellow oil (73 mg, 94% yield). IR (neat): ν˜ = 3025, 2844,
778, 1653, 1591, 1489, 1449, 1403, 1374, 1249, 1164, 1072,
CDCl
3
–1
27
1
010 cm . [α]
): δ = 7.45–7.40 (m, 2 H), 7.35–7.28 (m, 5 H), 7.24 (d, J =
.5 Hz, 2 H), 4.25 (t, J = 9.2 Hz, 1 H), 3.76–3.67 (m, 2 H), 3.59 (t,
J = 12.8 Hz, 2 H), 2.71 (ddd, J = 18.3, 10.5, 9.3 Hz, 1 H), 2.65–2.55
D 3
= +16.5 (c = 6.29, CHCl ). H NMR (500 MHz,
+
1
18 2 3
5.03 ppm. HRMS (ESI): calcd. for C18H N O [M + 1] 311.139;
CDCl
7
3
found 311.1396. The enantiomeric ratio (56:44) was determined by
HPLC (Chiralpak AD-H column; hexane/iPrOH, 98:2; flow rate:
1.0 mLmin ; λ = 254 nm): t = 22.66 min (major), tR = 26.86 min
R
–
1
13
(
=
1
m, 1 H), 2.10–1.94 (m, 1 H) ppm. C NMR (126 MHz, CDCl
209.59, 138.55, 138.01, 131.53, 130.62, 128.94, 128.48, 127.42,
21.08, 76.55, 55.16, 54.46, 40.75, 15.01 ppm. HRMS (ESI): calcd.
3
): δ
(
minor).
3
2
1
k: Yellow oil (51 mg, 79% yield). IR (neat): ν˜ = 3028, 2982, 2926,
+
for C18
H18BrNO [M + 1] 344.0644; found 344.0651. The enantio-
812, 1778, 1515, 1492, 1449, 1371, 1253, 1200, 1170, 1115, 1075,
meric ratio (80:20) was determined by HPLC (Phenomenex Lux
–1
24
1
026 cm . [α]
): δ = 7.36 (d, J = 7.0 Hz, 2 H), 7.30 (t, J = 7.4 Hz, 2 H),
.24 (dd, J = 8.1, 4.7 Hz, 3 H), 7.11 (d, J = 7.8 Hz, 2 H), 4.27 (ddd,
D 3
= +17.7 (c = 5.31, CHCl ). H NMR (500 MHz,
–
1
Cellulose-1 column; hexane/iPrOH, 98:2; flow rate: 1.0 mLmin ;
λ = 254 nm): t = 20.28 min (major), t = 21.62 min (minor).
CDCl
7
3
R
R
3
2
1
g: Pale yellow oil (59 mg, 89% yield). IR (neat): ν˜ = 3025, 2838, J = 9.4, 4.5, 2.2 Hz, 1 H), 3.73 (t, J = 14.0 Hz, 2 H), 3.65–3.55 (m,
812, 1774, 1597, 1492, 1449, 1400, 1371, 1259, 1164, 1095, 1075,
2 H), 2.73–2.63 (m, 1 H), 2.58 (dddd, J = 9.2, 7.9, 5.4, 2.4 Hz, 1
–1
27
1
13
016 cm . [α]
D
= +19.4 (c = 5.46, CHCl
3
). H NMR (400 MHz):
H), 2.32 (s, 3 H), 2.05–1.98 (m, 2 H) ppm. C NMR (126 MHz,
δ = 7.36–7.22 (m, 9 H), 4.30–4.21 (m, 1 H), 3.73 (dd, J = 13.7,
6
2
CDCl
.8 Hz, 2 H), 3.60 (dd, J = 13.7, 3.6 Hz, 2 H), 2.78–2.66 (m, 1 H), 128.40, 127.24, 110.11, 76.61, 55.00, 54.82, 40.68, 21.23, 14.90 ppm.
.66–2.55 (m, 1 H), 2.11–1.94 (m, 2 H) ppm. 13C NMR (101 MHz, HRMS (ESI): calcd. for C19 21NO [M + 1]+ 280.1696; found
): δ = 209.67, 138.59, 137.49, 133.00, 130.27, 128.96, 128.59, 280.1697. The enantiomeric ratio (75:25) was determined by HPLC
28.49, 127.42, 76.55, 55.15, 54.41, 40.75, 14.98 ppm. HRMS
(Phenomenex Lux Cellulose-1 column; hexane/iPrOH, 98:2; flow
3
): δ = 210.04, 138.99, 136.87, 135.74, 129.11, 128.97, 128.96,
H
CDCl
3
1
(
+
–1
ESI): calcd. for C18
H
18ClNO [M + 1] 300.115; found 300.115.
R R
rate: 1.0 mLmin ; λ = 254 nm): t = 9.84 min (major), t =
The enantiomeric ratio (79:21) was determined by HPLC (Phe-
10.69 min (minor).
nomenex Lux Cellulose-1 column; hexane/iPrOH, 99:1; flow rate:
3
l: Yellow oil (62 mg, 91% yield). IR (neat): ν˜ = 3058, 3015, 2959,
–1
1
.0 mLmin ; λ = 254 nm): t
R
= 8.99 min (major), t
R
= 9.45 min
–1
27
1781, 1650, 1518, 1495, 1456, 1371, 1216, 1072 cm . [α]
D
= +14.5
): δ = 7.37 (d, J =
h: Pale yellow oil (58 mg, 92% yield). IR (neat): ν˜ = 3064, 2841, 7.1 Hz, 2 H), 7.29 (dd, J = 14.3, 7.6 Hz, 4 H), 7.25–7.20 (m, 1 H),
(minor).
1
(
3 3
c = 5.90, CHCl ). H NMR (500 MHz, CDCl
3
–1
24
1778, 1604, 1509, 1449, 1374, 1220, 1157, 1092, 1072 cm . [α]
D
=
7.16 (d, J = 8.0 Hz, 2 H), 4.33–4.26 (m, 1 H), 3.75 (t, J = 14.1 Hz,
2 H), 3.67–3.56 (m, 2 H), 2.88 (dt, J = 13.8, 6.9 Hz, 1 H), 2.74–
1
+
14.7 (c = 5.16, CHCl
3 3
). H NMR (500 MHz, CDCl ): δ = 7.32
4362
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4358–4366

Catalytic Enantioselective Synthesis of α-(Benzylamino)cyclobutanones
+
2
1
.64 (m, 1 H), 2.58 (dddd, J = 17.3, 9.2, 5.4, 2.5 Hz, 1 H), 2.09– [M + 1] 379.1264; found 379.1276. The enantiomeric ratio (88:12)
.96 (m, 2 H), 1.23 (d, J = 6.9 Hz, 6 H) ppm. 1 C NMR (126 MHz,
): δ = 210.08, 147.93, 139.04, 136.14, 128.97, 128.90, 128.40, hexane/iPrOH, 98:2; flow rate: 1.0 mLmin ; λ = 254 nm): t
27.24, 126.45, 76.64, 55.05, 54.81, 40.68, 33.91, 24.15, 14.87 ppm. 28.71 min (major), t = 26.67 min (minor).
3
was determined by HPLC (Phenomenex Lux Cellulose-1 column;
–
1
CDCl
1
3
R
=
R
+
HRMS (ESI): calcd. for C21H25NO [M + 1] 308.2009; found
3
2
1
q: Colorless oil (47 mg, 59% yield). IR (neat): ν˜ = 2966, 2844,
308.2004. The enantiomeric ratio (70:30) was determined by HPLC
227, 1778, 1620, 1610, 1420, 1325, 1164, 1121, 1102, 1069,
(Phenomenex Lux Cellulose-1 column; hexane/iPrOH, 99:1; flow
–1
22
1
019 cm . [α]
): δ = 7.61 (d, J = 8.2 Hz, 2 H), 7.58 (d, J = 8.1 Hz, 2 H),
.50–7.44 (m, 4 H), 4.29–4.20 (m, 1 H), 3.81 (d, J = 14.5 Hz, 2 H),
D 3
= +3.8 (c = 1.03, CHCl ). H NMR (500 MHz,
–1
rate: 0.8 mLmin ; λ = 254 nm): t
8
R R
= 8.52 min (major), t =
CDCl
3
.86 min (minor).
7
3
2
1
m: Pale yellow oil (59 mg, 89% yield). IR (neat): ν˜ = 2956, 2933,
3.71 (dd, J = 14.2, 3.1 Hz, 2 H), 2.79 (ddd, J = 19.6, 10.8, 1.9 Hz,
838, 1778, 1614, 1512, 1456, 1374, 1302, 1246, 1177, 1108, 1069,
1 H), 2.72–2.61 (m, 1 H), 2.14 (qd, J = 10.6, 4.4 Hz, 1 H), 2.09–
–1
28
1
13
033 cm . [α]
D
= +14.6 (c = 5.19, CHCl
3
). H NMR (500 MHz,
3
1.97 (m, 1 H) ppm. C NMR (126 MHz, CDCl ): δ = 208.65,
CDCl
J = 8.7 Hz, 2 H), 4.36–4.16 (m, 1 H), 3.78 (s, 3 H), 3.77–3.67 (m,
H), 3.59 (dd, J = 23.4, 13.5 Hz, 1 H), 2.75–2.64 (m, 1 H), 2.59
dddd, J = 17.3, 9.2, 5.3, 2.4 Hz, 1 H), 2.07–1.97 (m, 2 H) ppm.
3
): δ = 7.36 (d, J = 7.0 Hz, 2 H), 7.33–7.20 (m, 5 H), 6.85 (d, 144.35, 142.48, 142.47, 132.36, 129.39, 129.06, 125.52 (q, J =
3.8 Hz), 118.86, 111.39, 76.59, 55.08, 55.02, 40.89, 15.25 ppm.
HRMS (ESI): calcd. for C20
O [M + 1]+ 359.1366; found
1
17 3 2
H F N
(
359.1361. The enantiomeric ratio (90:10) was determined by HPLC
1
3
C NMR (126 MHz, CDCl
30.82 (s), 130.16 (s), 128.97 (s), 128.41 (s), 127.25 (s), 113.83 (s),
3
): δ = 210.10 (s), 158.96 (s), 139.02 (s),
(Phenomenex Lux Cellulose-1 column; hexane/iPrOH, 98:2; flow
rate: 1.0 mLmin ; λ = 254 nm): t = 29.10 min (major), t =
R R
–
1
1
7
6.57 (s), 55.37 (s), 54.95 (s), 54.48 (s), 40.70 (s), 14.90 (s) ppm.
26.39 min (minor).
+
HRMS (ESI): calcd. for C19
H
21NO
2
[M + 1] 296.1645; found
3
1
1
r: Colorless oil (68 mg, 85% yield). IR (neat): ν˜ = 2930, 2838,
778, 1623, 1492, 1417, 1371, 1325, 1161, 1121, 1105, 1065,
2
(
1
(
96.1649. The enantiomeric ratio (69:31) was determined by HPLC
Chiracel OJ column; hexane/iPrOH, 90:10; flow rate:
–1
22
1
016 cm . [α]
): δ = 7.57 (d, J = 8.1 Hz, 2 H), 7.46 (d, J = 8.0 Hz, 2 H),
.28 (s, 4 H), 4.28–4.20 (m, 1 H), 3.82–3.56 (m, 4 H), 2.80–2.70 (m,
H), 2.68–2.59 (m, 1 H), 2.14–2.04 (m, 1 H), 2.00 (dd, J = 19.7,
D 3
= +13.4 (c = 6.82, CHCl ). H NMR (500 MHz,
–1
R R
.0 mLmin ; λ = 254 nm): t = 17.75 min (major), t = 19.74 min
CDCl
3
minor).
7
1
9
3
1
1
n: Pale yellow oil (73 mg, 90% yield). IR (neat): ν˜ = 3008, 2844,
1
3
3
.6 Hz, 1 H) ppm. C NMR (126 MHz, CDCl ): δ = 209.12,
778, 1617, 1591, 1522, 1325, 1249, 1164, 1121, 1108, 1065, 1039,
–1
27
1
142.98, 136.97, 133.26, 130.25, 129.06, 128.70, 125.45 (q, J =
.8 Hz), 76.54, 54.74, 54.67, 40.84, 15.14 ppm. HRMS (ESI): calcd.
for C19 17ClF
NO [M + 1]+ 368.1023; found 368.1031. The enan-
tiomeric ratio (91:9) was determined by HPLC (Phenomenex Lux
019 cm . [α]
): δ = 7.57 (d, J = 8.1 Hz, 2 H), 7.50 (d, J = 8.0 Hz, 2 H),
.25 (d, J = 8.5 Hz, 2 H), 6.86 (d, J = 8.5 Hz, 2 H), 4.27 (t, J =
D 3
= +15.0 (c = 6.11, CHCl ). H NMR (500 MHz,
3
CDCl
3
H
3
7
9
3
2
1
1
.2 Hz, 1 H), 3.84–3.77 (m, 4 H), 3.70 (dd, J = 13.7, 5.5 Hz, 2 H),
.58 (d, J = 13.4 Hz, 1 H), 2.80–2.69 (m, 1 H), 2.68–2.58 (m, 1 H),
–
1
Cellulose-1 column; hexane/iPrOH, 99:1; flow rate: 1.0 mLmin ;
λ = 254 nm): tR = 11.61 min (major), tR = 11.09 min (minor).
.14–1.96 (m, 2 H) ppm. 13C NMR (126 MHz, CDCl
3
): δ = 209.55,
59.12, 143.44, 130.31, 130.17, 129.06, 125.36 (q, J = 3.8 Hz),
3
1
1
s: Colorless oil (64 mg, 82% yield). IR (neat): ν˜ = 2831, 1778,
620, 1604, 1509, 1420, 1325, 1226, 1161, 1124, 1105, 1069,
13.93, 76.57, 55.39, 54.74, 54.54, 40.80, 15.08 ppm. HRMS (ESI):
+
calcd. for C20
H
20
F
3
NO
2
[M + 1] 364.1519; found 364.1515. The
–1
22
1
016 cm . [α]
): δ = 7.57 (d, J = 8.1 Hz, 2 H), 7.47 (d, J = 8.0 Hz, 2 H),
.30 (dd, J = 8.4, 5.6 Hz, 2 H), 7.00 (t, J = 8.7 Hz, 2 H), 4.29–4.20
m, 1 H), 3.70 (ddd, J = 53.5, 38.2, 13.8 Hz, 4 H), 2.80–2.70 (m, 1
D 3
= +16.1 (c = 6.43, CHCl ). H NMR (500 MHz,
enantiomeric ratio (86:14) was determined by HPLC (Phenomenex
CDCl
7
(
3
Lux Cellulose-1 column; hexane/iPrOH, 97:3; flow rate:
–1
1
(
.0 mLmin ; λ = 254 nm): t
R R
= 13.79 min (major), t = 15.33 min
minor).
13
H), 2.68–2.58 (m, 1 H), 2.14–1.96 (m, 2 H) ppm. C NMR
126 MHz, CDCl ): δ = 209.24, 163.29, 161.34, 143.11, 134.09 (d,
(
3
3
=
1
CDCl
4
o: White solid (71 mg, 80% yield); m.p. 95–98 °C. IR (Nujol): ν˜
J = 3.1 Hz), 130.51, 130.44, 129.06, 125.43 (q, J = 3.7 Hz), 115.46,
115.29, 76.54, 54.68, 54.61, 40.84, 15.10 ppm. HRMS (ESI): calcd.
for C19
meric ratio (90:10) was determined by HPLC (Phenomenex Lux
Cellulose-1 column; hexane/iPrOH, 98:2; flow rate: 1.0 mLmin ;
2975, 2838, 1784, 1621, 1419, 1325, 1162, 1120, 1104, 1068,
–1
21
1
019 cm . [α]
D
= +12.2 (c = 7.65, CHCl
3
). H NMR (500 MHz,
17 4
H F
NO [M + 1]+ 352.1319; found 352.1346. The enantio-
3
): δ = 7.57 (d, J = 8.1 Hz, 4 H), 7.47 (d, J = 8.0 Hz, 4 H),
.29–4.23 (m, 1 H), 3.81 (d, J = 14.1 Hz, 2 H), 3.70 (d, J = 14.0
–
1
Hz, 2H), 2.83–2.71 (m, 1 H), 2.70–2.60 (m, 1 H), 2.12 (qd, J =
0.7, 4.5 Hz, 1 H), 2.08–1.98 (m, 1 H) ppm. 13C NMR (126 MHz,
λ = 254 nm): tR = 8.08 min (major), tR = 7.54 min (minor).
1
CDCl
3
): δ = 208.90, 142.76, 129.97, 129.71, 129.08, 125.48 (q, J = 3t: Yellow oil (75 mg, 85% yield). IR (neat): ν˜ = 2953, 2835, 1778,
–
1
3.8 Hz), 76.64, 54.97, 40.87, 15.20 ppm. HRMS (ESI): calcd. for
1722, 1617, 1440, 1417, 1321, 1282, 1164, 1105, 1069, 1019 cm .
+
20
1
C
20
H
17
F
6
NO [M + 1] 402.1287; found 402.1317. The enantio-
D 3 3
[α] = +10.4 (c = 7.49, CHCl ). H NMR (400 MHz, CDCl ): δ =
meric ratio (91:9) was determined by HPLC (Phenomenex Lux
7.99 (d, J = 8.0 Hz, 2 H), 7.57 (d, J = 8.1 Hz, 2 H), 7.45 (dd, J =
18.5, 8.0 Hz, 4 H), 4.25 (t, J = 9.2 Hz, 1 H), 3.91 (s, 3 H), 3.81 (d,
J = 14.0 Hz, 2 H), 3.70 (d, J = 14.0 Hz, 2H), 2.76 (ddd, J = 19.3,
–
1
Cellulose-1 column; hexane/iPrOH, 99:1; flow rate: 1.0 mLmin ;
λ = 254 nm): t = 8.48 min (major), t = 8.12 min (minor).
R
R
1
0.6, 1.5 Hz, 1 H), 2.69–2.58 (m, 1 H), 2.17–1.96 (m, 2 H) ppm.
3
p: Yellow oil (53 mg, 63% yield). IR (neat): ν˜ = 2976, 2844, 1774,
1
3
–
1
C NMR (101 MHz, CDCl
129.85, 129.47, 129.07, 128.81, 125.45 (d, J = 3.1 Hz), 76.61, 55.09,
4.89, 52.18, 40.83, 15.16 ppm. HRMS (ESI): calcd. for
NO
[M + 1]+ 392.1468; found 392.1489. The enantio-
meric ratio (90:10) was determined by HPLC (Phenomenex Lux
3
): δ = 209.01, 167.01, 143.92, 142.83,
1620, 1604, 1525, 1348, 1325, 1157, 1118, 1105, 1062, 1019 cm .
21
1
D 3 3
[α] = +4.0 (c = 4.43, CHCl ). H NMR (500 MHz, CDCl ): δ =
5
C
8.17 (d, J = 8.7 Hz, 2 H), 7.58 (d, J = 8.1 Hz, 2 H), 7.54 (d, J =
8.7 Hz, 2 H), 7.46 (d, J = 8.0 Hz, 2 H), 4.25 (dd, J = 10.0, 8.4 Hz,
1 H), 3.79 (tt, J = 16.2, 8.3 Hz, 4 H), 2.85–2.74 (m, 1 H), 2.72–2.63
21
H
20
F
3
3
–
1
Cellulose-1 column; hexane/iPrOH, 98:2; flow rate: 1.0 mLmin ;
λ = 254 nm): t = 21.30 min (major), t = 19.73 min (minor).
(
m, 1 H), 2.15 (qd, J = 10.7, 4.4 Hz, 1 H), 2.09–1.98 (m, 1 H) ppm.
1
3
R
R
C NMR (126 MHz, CDCl
42.39, 129.44, 129.08, 125.57 (q, J = 3.8 Hz), 123.79, 76.63, 55.17,
4.79, 40.93, 15.33 ppm. HRMS (ESI): calcd. for C19
3
): δ = 208.53, 147.53, 146.44, 142.40,
1
5
5a: Yellow oil (39 mg, 93% yield). IR (neat): ν˜ = 3028, 2982, 2792,
1778, 1643, 1495, 1453, 1403, 1075, 1059 cm . [α]
–
1
26
H
17
F
3
N
2
O
3
D
= +6.5 (c =
Eur. J. Org. Chem. 2015, 4358–4366
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4363

A. Frongia et al.
FULL PAPER
3
4
.36, CHCl
3
). 1H NMR (500 MHz, CDCl
3
): δ = 7.32 (d, J = 1]+ 216.1383; found 216.1387. The enantiomeric ratio (51:49) was
.2 Hz, 4 H), 7.26 (dd, J = 7.6, 3.8 Hz, 1 H), 4.11 (t, J = 9.0 Hz, 1 determined by HPLC (Phenomenex Lux Cellulose-1 column; hex-
–
1
H), 3.66 (s, 2 H), 2.86–2.75 (m, 1 H), 2.74–2.65 (m, 1 H), 2.29 (s, ane/iPrOH, 98:2; flow rate: 0.5 mLmin ; λ = 254 nm): t
H), 2.07 (ddd, J = 19.1, 12.6, 7.1 Hz, 2 H) ppm. 13C NMR
12.58 min (major), t = 12.08 min (minor).
126 MHz, CDCl ): δ = 208.63, 138.12, 129.24, 128.44, 127.39,
f: Colorless oil (47 mg, 77% yield). IR (neat): ν˜ = 2979, 1781,
R
=
3
(
R
3
5
78.91, 59.65, 41.07, 38.57, 14.79 ppm. HRMS (ESI): calcd. for
–
1
15NO [M + 1]+ 190.1226; found 190.1214. The enantiomeric
1728, 1646, 1495, 1449, 1397, 1374, 1253, 1187, 1075, 1029 cm .
12
C H
2
9
1
α]
7.35–7.16 (m, 5 H), 4.31–4.20 (m, 1 H), 4.32–4.21 (m, 2 H), 4.10
q, J = 7.2 Hz, 2 H), 3.76 (d, J = 13.9 Hz, 1 H), 3.70 (d, J =
3.9 Hz, 1 H), 2.93 (t, J = 7.2 Hz, 2 H), 2.77–2.65 (m, 1 H), 2.60
D 3 3
[ = +7.1 (c = 4.45, CHCl ). H NMR (500 MHz, CDCl ): δ =
ratio (55:45) was determined by HPLC (Phenomenex Lux Cellu-
lose-1 column; hexane/iPrOH, 98:2; flow rate: 1.0 mLmin ; λ =
2
–
1
(
1
54 nm): t
R R
= 8.87 min (major), t = 10.50 min (minor).
5
b: Yellow oil (38 mg, 84% yield). IR (neat): ν˜ = 2969, 1778, 1640,
(
dddd, J = 17.3, 10.0, 4.6, 2.5 Hz, 1 H), 2.54–2.41 (m, 2 H), 2.09
–1
27
1
499, 1453, 1394, 1377, 1065, 1026 cm . [α]
D
= +6.8 (c = 2.94,
): δ = 7.36–7.32 (m, 2 H), 7.31
dd, J = 10.0, 4.8 Hz, 2 H), 7.26–7.22 (m, 1 H), 4.27 (tt, J = 10.8,
(
qd, J = 10.8, 4.6 Hz, 1 H), 2.05–1.95 (m, 1 H), 1.23 (t, J = 7.1 Hz,
1
CHCl
(
3
). H NMR (500 MHz, CDCl
3
13
3
1
3
3
H) ppm. C NMR (126 MHz, CDCl ): δ = 209.54, 172.46,
38.69, 128.86, 128.43, 127.35, 77.51, 60.51, 55.10, 47.09, 40.51,
3.32, 15.75, 14.29 ppm. HRMS (ESI): calcd. for C16 [M
1] 276.1594; found 276.1593. The enantiomeric ratio (61:39) was
determined by HPLC (Phenomenex Lux Cellulose-1 column; hex-
2
2
4
7
1
1
.4 Hz, 1 H), 3.76 (d, J = 13.7 Hz, 1 H), 3.66 (d, J = 13.7 Hz,1H),
.80–2.69 (m, 1 H), 2.69–2.57 (m, 3 H), 2.09 (ddd, J = 20.7, 10.7,
.5 Hz, 1 H), 2.01 (ddd, J = 10.8, 9.9, 9.1 Hz, 1 H), 1.07 (t, J =
H
21NO
3
+
+
.1 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl
): δ = 209.88,
39.12, 128.99, 128.38, 127.19, 77.50, 54.44, 45.19, 40.66, 15.55,
2.61 ppm. HRMS (ESI): calcd. for C13H17NO [M + 1] 204.1382;
–1
3
ane/iPrOH, 98:2; flow rate: 1.0 mLmin ; λ = 254 nm): t
R
=
1
3.34 min (major), t = 14.42 min (minor).
R
+
found 204.1406. The enantiomeric ratio (54:46) was determined by
5g: Colorless oil (54 mg, 93% yield). IR (neat): ν˜ = 2982, 1778,
1732, 1659, 1499, 1456, 1377, 1197, 1161, 1079, 1029, 1000 cm .
–
1
HPLC (Phenomenex Lux Cellulose-1 column; hexane/iPrOH, 98:2;
–1
27
1
flow rate: 1.0 mLmin ; λ = 254 nm): t
R
= 9.26 min (major), t
R
=
[α]
7.35 (d, J = 7.0 Hz, 2 H), 7.31 (dd, J = 10.0, 4.6 Hz, 2 H), 7.28–
.23 (m, 1 H), 4.49–4.40 (m, 1 H), 4.15 (q, J = 7.1 Hz, 2 H), 3.92
d, J = 13.5 Hz, 1 H), 3.84 (d, J = 13.4 Hz, 1 H), 3.46 (d, J =
D 3 3
= +29.8 (c = 4.95, CHCl ). H NMR (500 MHz, CDCl ): δ =
10.52 min (minor).
7
(
5
c: Colorless oil (36 mg, 75% yield). IR (neat): ν˜ = 2969, 2926,
–
1
1781, 1633, 1499, 1459, 1394, 1371, 1279, 1174, 1128, 1059 cm .
1
2
9
7.3 Hz, 1 H), 3.35 (d, J = 17.2 Hz, 1 H), 2.87–2.73 (m, 1 H), 2.72–
.57 (m, 1 H), 2.20 (qd, J = 10.7, 4.3 Hz, 1 H), 2.02 (dt, J = 19.4,
32
1
[α]
D
= +6.8 (c = 3.48, CHCl
3 3
). H NMR (500 MHz, CDCl ): δ =
7.36 (dd, J = 7.6, 0.6 Hz, 2 H), 7.29 (t, J = 7.4 Hz, 2 H), 7.22 (t, J
1
3
.6 Hz, 1 H), 1.26 (t, J = 7.2 Hz, 3 H) ppm. C NMR (126 MHz,
): δ = 207.85, 171.38, 137.98, 129.20, 128.46, 127.50, 77.09,
0.56, 55.30, 51.86, 40.71, 17.14, 14.33 ppm. HRMS (ESI): calcd.
for C15
[M + 1]+ 262.1438; found 262.1442. The enantio-
meric ratio (78:22) was determined by HPLC (Phenomenex Lux
=
2
7.3 Hz, 1 H), 4.41 (td, J = 8.6, 2.1 Hz, 1 H), 3.69 (q, J = 14.4 Hz,
H), 2.88 (dt, J = 13.2, 6.6 Hz, 1 H), 2.78–2.66 (m, 1 H), 2.59–
CDCl
6
3
2
=
.50 (m, 1 H), 2.18–2.05 (m, 1 H), 2.03–1.92 (m, 1 H), 1.05 (d, J
H19NO
3
13
6.6 Hz, 3 H), 1.02 (d, J = 6.6 Hz, 3 H) ppm. C NMR
): δ = 211.13, 140.55, 128.48, 128.30, 126.95,
4.33, 51.18, 49.67, 40.52, 20.08, 19.83, 17.42 ppm. HRMS (ESI):
(126 MHz, CDCl
3
–
1
Cellulose-1 column; hexane/iPrOH, 99:1; flow rate: 0.9 mLmin ;
λ = 254 nm): t = 15.25 min (major), t = 15.96 min (minor).
7
+
R
R
calcd. for C14
H19NO [M + 1] 218.1539; found 218.1532. The enan-
tiomeric ratio (56:44) was determined by HPLC (Phenomenex Lux
5
h: Yellow oil (42 mg, 72% yield). IR (neat): 2972, 1778, 1600,
–
1
Cellulose-1 column; hexane/iPrOH, 98:2; flow rate: 1.0 mLmin ;
λ = 254 nm): t = 6.64 min (major), t = 7.34 min (minor).
–1
1518, 1456, 1394, 1341, 1216, 1190, 1128, 1111, 1062, 1010 cm .
22
1
R
R
[α]
= +16.7 (c = 3.59, CHCl
3 3
). H NMR (400 MHz, CDCl ): δ =
D
8
.24–8.06 (m, 2 H), 7.56 (d, J = 8.9 Hz, 2 H), 4.56–4.40 (m, 1 H),
5
d: Yellow oil (65 mg, 88% yield). IR (neat): ν˜ = 3031, 2976, 1778,
–1
29
3.88–3.65 (m, 2 H), 2.90–2.68 (m, 2 H), 2.67–2.48 (m, 1 H), 2.18
(qd, J = 10.8, 4.3 Hz, 1 H), 2.06–1.87 (m, 1 H), 1.06 (d, J = 6.8 Hz,
1
649, 1607, 1495, 1459, 1157, 1072 cm . [α]
D
= +6.0 (c = 3.62,
): δ = 7.36–7.28 (m, 4 H),
.28–7.23 (m, 3 H), 7.21–7.15 (m, 1 H), 7.15–7.10 (m, 2 H), 4.31
1
3 3
CHCl ). H NMR (500 MHz, CDCl
7
1
3
3
H), 1.04 (d, J = 6.7 Hz, 3 H) ppm. C NMR (101 MHz, CDCl
δ = 210.13, 148.90, 147.19, 128.89, 123.60, 74.21, 50.81, 50.50,
0.74, 20.16, 19.66, 17.63 ppm. HRMS (ESI): calcd. for
[M + 1]+ 263.139; found 263.1377. The enantiomeric
ratio (66:34) was determined by HPLC (Chiralpak AS-H column;
3
):
(
(
ddt, J = 10.7, 8.6, 2.3 Hz, 1 H), 3.84 (d, J = 13.7 Hz, 1 H), 3.75
d, J = 13.7 Hz, 1 H), 2.90–2.69 (m, 5 H), 2.60 (dddd, J = 17.3,
4
14 18 2 3
C H N O
10.0, 4.5, 2.5 Hz, 1 H), 2.09 (ddd, J = 20.8, 10.8, 4.5 Hz, 1 H), 1.97
13
(
ddd, J = 10.8, 9.9, 9.0 Hz, 1 H) ppm. C NMR (126 MHz,
CDCl ): δ = 209.67, 140.19, 138.93, 128.98, 128.87, 128.46, 128.45,
27.31, 126.13, 77.80, 55.21, 53.32, 40.60, 34.41, 15.74 ppm.
–
1
hexane/iPrOH, 95:5; flow rate: 1.0 mLmin ; λ = 254 nm): t
R
=
3
10.69 min (major), t
R
= 12.96 min (minor).
1
+
HRMS (ESI): calcd. for C19
80.1701. enantiomeric ratio (56:44) was determined by HPLC
Chiracel OJ column; hexane/iPrOH, 90:10; flow rate:
H21NO [M + 1] 280.1696; found
5
1
i: Yellow oil (54 mg, 93% yield). IR (neat): ν˜ = 3077, 2976, 1778,
2
(
–
1
23
600, 1515, 1341, 1203, 1174, 1111, 1069, 1016 cm . [α]
D
= +18.6
1
(
c = 5.03, CHCl
3
). H NMR (500 MHz, CDCl
3
): δ = 8.17 (d, J =
–1
1.0 mLmin ; λ = 254 nm): t
R
= 10.50 min (major), t
R
= 12.14 min
8
6
.8 Hz, 2 H), 7.53 (d, J = 8.8 Hz, 2 H), 5.83 (ddt, J = 16.8, 10.2,
.5 Hz, 1 H), 5.19 (ddd, J = 9.6, 8.5, 3.0 Hz, 2 H), 4.40–4.25 (m, 1
(minor).
5
e: Colorless oil (23 mg, 48% yield). IR (neat): ν˜ = 2979, 1778,
H), 3.81 (q, J = 14.6 Hz, 2 H), 3.23 (dd, J = 14.2, 6.3 Hz, 1 H),
3.15 (dd, J = 14.2, 6.7 Hz, 1 H), 2.87–2.73 (m, 1 H), 2.73–2.58 (m,
–
1
1
1
640, 1499, 1453, 1420, 1354, 1220, 1170, 1069, 1026 cm .
): δ = 7.29–7.14 (m, 5 H), 5.79 (ddt, J =
6.7, 10.1, 6.5 Hz, 1 H), 5.22–4.99 (m, 2 H), 4.35–4.14 (m, 1 H), NMR (126 MHz, CDCl
.68 (d, J = 13.6 Hz, 1 H), 3.58 (d, J = 13.6 Hz, 1 H), 3.30–2.95 123.68, 118.67, 54.69, 54.13, 40.78, 15.73 ppm. HRMS (ESI): calcd.
[M + 1]+ 261.1234; found 261.1239. The enantio-
): δ = meric ratio (78:22) was determined by HPLC (Phenomenex Lux
H
1
3
NMR (400 MHz, CDCl
3
1 H), 2.16 (qd, J = 10.8, 4.4 Hz, 1 H), 2.09–1.92 (m, 1 H) ppm.
C
1
3
3
): δ = 208.92, 147.13, 134.89, 129.40,
(
16 2 3
m, 2 H), 2.73–2.60 (m, 1 H), 2.53 (dddd, J = 17.3, 9.8, 4.7, 2.5 Hz, for C14H N O
1
2
5
H), 2.06–1.88 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl
09.85, 138.83, 135.68, 129.06, 128.43, 127.29, 118.10, 77.05, 54.88, Cellulose-1 column; hexane/iPrOH, 99:1; flow rate: 1.0 mLmin ;
4.27, 40.66, 15.36 ppm. HRMS (ESI): calcd. for C14 17NO [M + λ = 254 nm): t = 78.49 min (major), t = 21.51 min (minor).
3
–
1
H
R
R
4364
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4358–4366

Catalytic Enantioselective Synthesis of α-(Benzylamino)cyclobutanones
5
2
1
j: Pale yellow oil (43 mg, 63% yield). IR (neat): ν˜ = 2963, 2930,
Acknowledgments
861, 1778, 1640, 1604, 1522, 1469, 1348, 1177, 1115, 1072,
–1
20
1
013 cm . [α]
): δ = 8.17 (d, J = 8.4 Hz, 2 H), 7.53 (d, J = 8.4 Hz, 2 H),
.28 (t, J = 9.2 Hz, 1 H), 3.83 (d, J = 14.8 Hz, 1 H), 3.76 (d, J =
D 3
= +5.9 (c = 5.03, CHCl ). H NMR (500 MHz,
Financial support from the Ministero dell’Università e della
Ricerca (MIUR), Rome and by the University of Cagliari and Sar-
dinia Regional Government (POR Sardegna FSE Operational Pro-
gramme of the Autonomous Region of Sardinia, European Social
Fund 2007-2013-Axis IV Human Resources, Objective l.3, Line of
Activity l.3.1) is acknowledged. Similarly, we are grateful to the
Université Paris-Sud, the CHARM3AT LabEx, and the Ile-de-
France Region (SESAME program 2012 N°12018501).
CDCl
3
4
1
2
4.8 Hz, 1 H), 2.87–2.42 (m, 4 H), 2.15 (qd, J = 10.6, 4.4 Hz, 1 H),
.05–1.81 (m, 1 H), 1.54–1.17 (m, 6 H), 0.86 (t, J = 6.9 Hz, 3
13
H) ppm. C NMR (126 MHz, CDCl
3
): δ = 209.26, 147.64, 129.29,
23.64, 112.71, 77.68, 54.73, 51.93, 40.70, 29.42, 27.20, 22.61,
5.65, 14.12 ppm. HRMS (ESI): calcd. for
1
1
16 22 2 3
C H N O
+
[
M + 1] 291.1703; found 291.1693. The enantiomeric ratio (67:33)
was determined by HPLC (Phenomenex Lux Cellulose-1 column;
[
1] a) J. C. Namsylo, D. E. Kaufmann, Chem. Rev. 2003, 103,
–1
hexane/iPrOH, 99:1; flow rate: 1.0 mLmin ; λ = 254 nm): t
R
=
1
485–1537; b) E. Lee-Ruff, G. Mladenova, Chem. Rev. 2003,
R
13.94 min (major), t = 13.17 min (minor).
103, 1449–1484; c) N.-Y. Fu, S.-H. Chan, H. N. C. Wong in The
Chemistry of Cyclobutanes (Eds.: Z. Rappoport, J. F. Liebman),
John Wiley & Sons, Ltd., Chichester, 2005, pp. 357–440; d) E.
Lee-Ruff in The Chemistry of Cyclobutanes (Eds.: Z. Rappo-
port, J. F. Liebman), John Wiley & Sons, Ltd., Chichester,
5
1
1
k: Yellow oil (29 mg, 36% yield). IR (neat): ν˜ = 2933, 2858, 1778,
604, 1522, 1449, 1394, 1341, 1266, 1203, 1174, 1128, 1108, 1069,
–1
22
1
013 cm . [α]
): δ = 8.16 (d, J = 8.7 Hz, 2 H), 7.56 (d, J = 8.8 Hz, 2 H),
.58–4.41 (m, 1 H), 3.91–3.76 (m, 2 H), 2.88–2.69 (m, 1 H), 2.65–
D 3
= +14.5 (c = 2.47, CHCl ). H NMR (500 MHz,
2005, pp. 281–355; e) J. Salaün, Sci. Synth. 2004, 26, 557; f) F.
CDCl
3
Secci, A. Frongia, P. P. Piras, Molecules 2013, 18, 15541–15572.
2] For recent illustrations, see: a) T. Araki, T. Ozawa, H. Yokoe,
M. Kanematsu, M. Yoshida, K. Shishido, Org. Lett. 2013, 15,
4
2
4
1
[
.48 (m, 1 H), 2.33 (tt, J = 11.4, 3.4 Hz, 1 H), 2.18 (qd, J = 10.8,
.3 Hz, 1 H), 2.18 (qd, J = 10.8, 4.3 Hz, 1 H), 2.01–1.88 (m, 1 H),
.87–1.70 (m, 4 H), 1.58 (d, J = 12.6 Hz, 1 H), 1.28–0.96 (m, 5
2
00–203; b) T. Araki, Y. Manabe, K. Fujioka, H. Yokoe, M.
Kanematsu, M. Yoshida, K. Shishido, Tetrahedron Lett. 2013,
4, 1012–1014; c) T. Ozawa, M. Kanematsu, H. Yokoe, M.
13
H) ppm. C NMR (126 MHz, CDCl
3
): δ = 210.33, 149.23, 147.18,
28.75, 123.60, 75.25, 59.92, 50.89, 40.49, 31.10, 30.75, 26.16,
7.85 ppm. HRMS (ESI): calcd. for C17
[M + 1]+
03.1703; found 303.1700. The enantiomeric ratio (62:38) was de-
5
1
1
3
Yoshida, K. Shishido, Heterocycles 2012, 85, 2927–2932; d) T.
Ozawa, M. Kanematsu, H. Yokoe, M. Yoshida, K. Shishido, J.
Org. Chem. 2012, 77, 9240–9249; e) E. V. Filippova, L. A. Wes-
ton, M. L. Kuhn, B. Geissler, A. M. Gehring, N. Armoush,
C. T. Adkins, G. Minasov, I. Dubrovska, L. Shuvalova, J. R.
Wisnor, L. D. Lavis, K. J. F. Satchell, D. P. Becker, W. F. An-
derson, R. J. Johnson, J. Biol. Chem. 2013, 288, 10522–10535;
f) T. Meiresonne, S. Mangelinckx, N. De Kimpe, Org. Biomol.
Chem. 2011, 9, 7085–7091; g) E. Mayans, A. Gargallo, Á. Álva-
rez-Larena, O. Illa, R. M. Ortuño, Eur. J. Org. Chem. 2013,
22 2 3
H N O
termined by HPLC (Chiralpak AS-H column; hexane/iPrOH, 98:2;
flow rate: 1.0 mLmin ; λ = 254 nm): t
–
1
R R
= 15.01 min (major), t =
19.67 min (minor).
ent-7a/ent-7Јa: Colorless oil (50 mg, 81% yield, inseparable 71:29
mixture of diastereomers). IR (neat): ν˜ = 3028, 2972, 1778, 1597,
–
1
1
495, 1449, 1400, 1377, 1207, 1177, 1128, 1092, 1059, 1029 cm .
1
425–1433; h) V. Declerck, D. J. Aitken, Amino Acids 2011, 41,
1
H NMR (500 MHz, CDCl
3
): δ = 7.57–7.10 (m, 20 H), 4.36–4.17
587–595; i) H. Awada, S. Robin, R. Guillot, O. Yazbeck, D.
Naoufal, N. Jaber, A. Hachem, D. J. Aitken, Eur. J. Org. Chem.
2014, 7148–7155; j) W. Mansawat, C. Vilaivan, Á. Balázs, D. J.
Aitken, T. Vilaivan, Org. Lett. 2012, 14, 1440–1443.
(m, 2 H), 3.96–3.71 (m, 6 H), 2.71–2.58 (m, 2 H), 2.58–2.43 (m, 2
H), 2.10 (dd, J = 19.4, 9.6 Hz, 1 H), 2.01 (qd, J = 10.6, 4.4 Hz, 1
H), 1.91 (qd, J = 10.7, 4.5 Hz, 1 H), 1.82 (quint, J = 9.4 Hz, 1 H),
.43 (d, J = 6.8 Hz, 3 H), 1.38 (d, J = 6.8 Hz, 3 H) ppm. 1 C NMR
3
[3] a) V. M. Dembitsky, J. Nat. Med. 2008, 62, 1–33; b) Q. Zhou,
B. B. Snider, Org. Lett. 2011, 13, 526–529; c) J. E. Baldwin,
R. M. Adlington, M. F. Parisi, H. H. Ting, Tetrahedron 1986,
1
3
(126 MHz, CDCl ): δ = 211.31, 210.11, 140.08, 139.99, 139.91,
1
1
4
29.01, 128.78, 128.45, 128.37, 128.29, 127.74, 127.73, 127.23,
27.20, 127.00, 126.97, 74.86, 74.33, 56.67, 56.35, 51.93, 51.90,
1.23, 39.99, 17.40, 16.55, 16.16, 15.09 ppm. HRMS (ESI): calcd.
4
2, 2575–2586; d) R. M. Adlington, J. E. Baldwin, R. H. Jones,
J. A. Murphy, M. F. Parisi, J. Chem. Soc., Chem. Commun.
983, 24, 1479–1481; e) D. Bellus, B. Ernest, Angew. Chem. Int.
Ed. Engl. 1988, 27, 797–827.
1
+
for C19
H
21NO [M + 1] 280.1696; found 280.169.
ˇ
[
4] a) P. Kotrusz, S. Alemayehu, S. Toma, H.-G. Schmalz, A. Ad-
ler, Eur. J. Org. Chem. 2005, 4904–4911; b) L. Ghosez, G. Yang,
J. R. Cagnon, F. Le Bideau, J. Marchand-Brynaert, Tetrahe-
dron 2004, 60, 7591–7606; c) F. Mahuteau-Betzer, L. Ghosez,
Tetrahedron 2002, 58, 6991–7000; d) L. Ghosez, F. Mahuteau-
Betzer, C. Genicot, A. Vallribera, J.-F. Cordier, Chem. Eur. J.
ent-7b/ent-7Јb: Yellow oil (62 mg. 81% yield, inseparable 91:9 mix-
ture of diastereomers). IR (neat): ν˜ = 2976, 1781, 1620, 1495, 1449,
–
1
26
1
–
7
D
420, 1381, 1321, 1203, 1164, 1124, 1111, 1065, 1019 cm . [α] =
21.6 (c = 3.05, CHCl
1
3 3
). H NMR (500 MHz, CDCl ): δ = 7.61–
.54 (m, 10 H), 7.38 (d, J = 7.6 Hz, 4 H), 7.35–7.27 (m, 3 H), 7.23
2
002, 8, 3411–3422 and for further details, see ref. 10 in the
(
(
dd, J = 13.1, 5.7 Hz, 1 H), 4.32 (dd, J = 10.3, 8.7 Hz, 1 H), 4.27
t, J = 9.3 Hz, 1 H), 3.88 (dd, J = 13.3, 6.4 Hz, 2 H), 3.80 (q, J =
following paper: P. Bisel, E. Breitling, A. W. Frahm, Eur. J. Org.
Chem. 1998, 729–733.
1
=
9
4.3 Hz, 4 H), 2.75–2.63 (m, 2 H), 2.62–2.49 (m, 2 H), 2.05 (dd, J
16.7, 9.6 Hz, 4 H), 1.95 (dd, J = 10.7, 4.4 Hz, 1 H), 1.80 (t, J =
.9 Hz, 1 H), 1.43 (d, J = 6.8 Hz, 3 H), 1.39 (d, J = 6.8 Hz, 3
[
5] For organocatalytic asymmetric transformations of cyclobut-
anones reported by our group, see: a) F. Capitta, A. Frongia,
J. Ollivier, D. J. Aitken, F. Secci, P. P. Piras, R. Guillot, Synlett
2015, 26, 123–126; b) F. Secci, A. Frongia, M. G. Rubanu,
M. L. Sechi, G. Sarais, M. Arca, P. P. Piras, Eur. J. Org. Chem.
13
H) ppm. C NMR (126 MHz, CDCl
3
): δ = 210.59, 209.59, 144.57,
1
1
3
1
44.47, 144.41, 143.04, 142.85, 129.10, 128.85, 128.45, 128.42,
27.66, 127.25, 127.20, 125.40 (q, J = 3.8 Hz), 125.33 (q, J =
.8 Hz), 74.86, 74.40, 57.34, 56.96, 51.66, 51.57, 41.27, 40.17, 17.57,
20 3
6.66, 16.60, 15.35 ppm. HRMS (ESI): calcd. for C20H F NO [M
2014, 6659–6675; c) D. J. Aitken, A. M. Bernard, F. Capitta,
A. Frongia, R. Guillot, J. Ollivier, P. P. Piras, F. Secci, M.
Spiga, Org. Biomol. Chem. 2012, 10, 5045–5048; d) D. J.
Aitken, F. Capitta, A. Frongia, J. Ollivier, P. P. Piras, F. Secci,
Synlett 2012, 23, 727–730; e) D. J. Aitken, F. Capitta, A. Fron-
gia, D. Gori, R. Guillot, J. Ollivier, P. P. Piras, F. Secci, M.
Spiga, Synlett 2011, 712–716; f) F. Capitta, A. Frongia, J. Olliv-
ier, P. P. Piras, F. Secci, Synlett 2011, 89–93.
+
+
1] 348.157; found 348.1583.
Supporting Information (see footnote on the first page of this arti-
cle): General methods and characterization data.
Eur. J. Org. Chem. 2015, 4358–4366
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4365

A. Frongia et al.
FULL PAPER
[
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We thank a reviewer for the useful comments in this regard.
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Published Online: June 2, 2015
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