Copper-catalyzed arylation of alkenyl aziridines via three-component coupling reaction involving alkynes and benzyne

Article abstract of DOI:10.1055/s-0031-1290467

Alkenyl aziridines can be successfully arylated in a three-component coupling triggered by in situ generated benzyne with a simple copper catalyst (CuI-PPh, without the need of any palladium salts. The corresponding allylic amines can be obtained with good to high regioselectivity in mild reaction conditions with a variety of cyclic and acyclic alkenyl aziridines. A new domino reaction with ethyl propiolate to give tetrahydrophenanthridine was also found.

Full text of DOI:10.1055/s-0031-1290467

LETTER
▌2463
lCettoerpper-Catalyzed Arylation of Alkenyl Aziridines via Three-Component
Coupling Reaction involving Alkynes and Benzyne
Copper-Catalyzed Arylation of Alkenyl Aziridines
Francesco Berti, Paolo Crotti, Giulio Cassano, Mauro Pineschi*
Dipartimento di Scienze Farmaceutiche, Sede di Chimica Bioorganica e Biofarmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy
Fax +39(050)2219660; E-mail: pineschi@farm.unipi.it
Received: 19.07.2012; Accepted after revision: 27.08.2012
of i-Pr2NEt (5.0 equiv) in CH2Cl2,8a gave an unseparable
Abstract: Alkenyl aziridines can be successfully arylated in a
mixture of alkynylated adducts with very low conversions
(Scheme 1, Equation a). A recently reported cooperative
copper- and palladium-catalyzed three-component cou-
three-component coupling triggered by in situ generated benzyne
with a simple copper catalyst (CuI–PPh3), without the need of any
palladium salts. The corresponding allylic amines can be obtained
with good to high regioselectivity in mild reaction conditions with pling of benzynes, acyclic allylic epoxides, and terminal
alkynes,9 prompted us to explore the introduction of the
a variety of cyclic and acyclic alkenyl aziridines. A new domino re-
action with ethyl propiolate to give tetrahydrophenanthridine was
also found.
low-lying LUMO orbital triple bond of benzyne as a reac-
tion component.
Key words: arylation, copper catalysis, aziridine, terminal alkyne,
benzyne
O
O
N
N
N
Aziridines are versatile intermediates for the synthesis of
many nitrogen-containing biologically important com-
pounds.1 The C-arylative ring-opening reaction of aryl
aziridines with arene and heteroarenes as π-components in
accordance with a Friedel–Crafts-type process has been
described in several reports.2 Very recently, a mild nickel-
catalyzed arylative regioselective ring-opening process of
styrenyl aziridines making use of organozinc reagents has
also been described.3 On the other hand, the C-arylative
ring opening of alkenyl aziridines, otherwise called allylic
or vinyl aziridines, has received only scant attention. The
Friedel–Crafts arylation of allyl aziridines linked to an es-
ter group was shown to occur exclusively at the allylic po-
sition (SN2 addition).4 Interestingly, a complete reversal
of the regioselectivity (SN2′ addition) was obtained by the
use of arylboronic acids in combination with palladium
pincer complexes.5 In the last decade, the use of benzyne
as a carbon–carbon π-component for the construction of
two different carbon–carbon bonds ortho to each other has
gained considerable attention.6 In our ongoing interest for
stereoselective alkynylation of small ring heterocycles,7
we explored the function of some simple copper catalysts,
originally developed for the asymmetric alkynylation of
pyridinium ions,8 for the ring opening of alkenyl aziri-
dines. Herein, we report that simple copper complexes
catalyze novel regio- and stereoselective arylative ring-
opening reactions of alkenyl aziridines via a three-compo-
nent coupling making use of benzyne and terminal al-
kynes.
L1 (10 mol%)
NTs
inseparable
mixture of
alkynylated
products
CuI (10 mol%)
R
+
(a)
(b)
i-Pr2NEt (5 equiv)
CH2Cl2, r.t., 3 d
R = Ph, 2a
R = C6H13, 2b
1a
R
CuI (10 mol%)
L1 (10 mol%)
OTf
+ 1a +
TMS
R
i-Pr2NEt (5 equiv)
CsF (3.0 equiv)
toluene–MeCN,
55 °C, 18 h
3aa, 3ab
NHTs
Scheme 1 Preliminary results
In the presence of benzyne, generated with CsF in tolu-
ene–MeCN mixture at 55 °C, the direct ring-opening al-
kynylation process was completely suppressed, and only
trans-γ-adducts 3aa and 3ab were isolated in 85% and
55% yield, respectively, after chromatographic purifica-
tion (Scheme 1, Equation b). To our surprise, a three-com-
ponent coupling was possible also without a palladium
catalyst. In the absence of palladium complexes, only the
hydroalkynylation product was obtained in a related
three-component coupling involving acyclic allylic epox-
ides.9 Interestingly, the use of a stoichiometric amount of
an inorganic base, such as K2CO3, to suppress the two-
component coupling product obtained from alkynes and
arynes with a related copper catalyst, was also unneces-
sary.10 After these preliminary results, different fluoride
sources in a range of solvents for benzyne generation were
investigated for the model three-component reaction of
benzyne, phenylacetylene and aziridine 1a (Table 1). We
found that the use of i-Pr2NEt in the reaction mixture was
not essential for the reaction (entry 1). Aiming at an opti-
mization of the three-component coupling without any is-
At the outset of this study, the addition of phenylacetylene
(2a) and 1-octyne (2b) to aziridine 1a using CuI (10
mol%), (S,S)-PyBox ligand L1 (10 mol%) in the presence
SYNLETT 2012, 23, 2463–2468
Advanced online publication: 21.09.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290467; Art ID: ST-2012-B0606-L
© Georg Thieme Verlag Stuttgart · New York

2464
F. Berti et al.
LETTER
sues related to kinetic resolution process of the starting sponding E-allylic amines were obtained with high yields
aziridine, the chiral PyBox ligand was simplified to the (entries 3–5). As regards to cyclic alkenyl aziridines 1a
basic 2-oxazoline framework. Unfortunately, the use of and 1e, the three-component coupling was successful also
2-ethyl oxazoline (L2) as a ligand for copper revealed to with enyne 2c and propargylic acetate 2d (entries 6–8).
be less effective (entry 2). Better results were obtained However, the five-membered alkenyl aziridine 1e proved
with phosphorus-based ligands, such as Ph3P and diphe- to be less reactive than 1a, and a lower regioselectivity
nylphosphinopropane (dppp) (entries 3 and 4).
was observed (entry 8). The trans stereochemistry of ad-
duct 3ec was demonstrated by 1H NMR analysis and com-
parison with related 1,4-substituted cyclopentene
derivatives.7b
In particular, copper complexes with Ph3P allowed a com-
plete conversion of the starting aziridine (entry 3). The use
of an ethereal solvent such as DME gave an improved sol-
ubility of all reaction components, but at the expense of It should be noted that the application of the reaction con-
the reaction efficiency (entries 5 and 6). The generation of ditions developed by Cheng et al. for 1,3-butadiene mono-
benzyne with KF in the presence of 18-crown-6 at room epoxide (catalytic CuI–[Pd(dba)2/dppp] in toluene–
temperature, as usually reported for these reaction condi- MeCN) to acyclic aziridine 1b,9 caused mainly decompo-
tions, afforded compound 3aa with a low conversion (en- sition of the starting aziridine. Curiously, the use of only
try 7). The best results were obtained with the reaction MeCN in the same reaction afforded the corresponding
carried out in MeCN. Despite the heterogeneous nature of three-component SN2′ adduct 3ba with a lower yield
the reaction, a clean reaction mixture with a complete con- (55%) and regioselectivity (SN2′/SN2 = 82:18), albeit with
version of starting aziridine 1a was obtained in five hours an increase in diastereoselectivity (E/Z = ca. 88:12) with
at 55 °C using Ph3P as the ligand (entry 8). Interestingly, respect to the reaction carried out under exclusive copper
in these reaction conditions the hydroalkynylation prod- catalysis (see entry 1, Table 2). However, the use of palla-
uct was formed in a low amount (<10%) and it was never dium is not justified at all when dealing with the bench-
isolated, unlike the palladium–copper co-catalyzed reac- mark cyclic alkenyl aziridine 1a. With this substrate, only
tion of allylic epoxides carried out in MeCN as the only a complex mixture of products was obtained using the
reaction solvent.9
combination of palladium and copper catalysts.
To explore the scope of the present reaction, the optimized It is plausible that CsF efficiently promoted both the for-
reaction conditions were examined with a variety of alke- mation of benzyne and copper acetylide (species A,
nyl aziridines and terminal alkynes (Table 2). The reac- Scheme 2), that after the addition to the benzyne nucleus
tion was also highly SN2′ regioselective with acyclic give the key reactive aryl cuprous species B. At this point,
alkenyl aziridines (entries 1–5). With 1,3-butadiene- unlike allylic epoxides, the key oxidative addition step oc-
derived aziridine 1b mixtures of diastereoisomeric E/Z al- curs also without the aid of palladium salts. Attack of B at
lylic amines 3ba and 3bc were obtained (entries 1 and 2). the γ-position of the double bond (SN2′-addition) followed
On the other hand, it was interesting to find that when a by a fast reductive elimination, with only marginal isom-
cis/trans mixture of alkenyl aziridines 1c (cis/trans = erization to the corresponding α-adduct (SN2-addition),11
36:64), 1d (cis/trans = 31:69) was used, only the corre- gives the corresponding arylated allylic amines in a highly
Table 1 Results of the Screening of Different Reaction Conditionsa
NTs
CuI (6 mol%)
ligand (x mol%)
OTf
+
Ph
3aa
+
fluoride source (3.0 equiv)
solvent, time, T
TMS
2a
1a
Entry
Fluoride source
Solvent
Ligand (mol%)
Time (h), temp (°C)
16 h, 55
Conv. (%)b
L1 (6)
1
2
3
4
5
6
7
8
CsF
toluene–MeCN (1:1)
toluene–MeCN (1:1)
toluene–MeCN (1:1)
toluene–MeCN (1:1)
DME
80
44
L2 (12)
CsF
16 h, 55
CsF
Ph3P (12)
dppp (6)
Ph3P (12)
dppp (6)
Ph3P (12)
Ph3P (12)
16 h, 55
100
52
CsF
16 h, 55
CsF
16 h, 55
59
CsF
DME
16 h, 55
55
KF/18-crown-6
CsF
THF
16 h, r.t.
30
MeCN
5 h, 55
100
a General reaction conditions: benzyne precursor (1.1 equiv), phenylacetylene (1.0 equiv), aziridine 1a (0.9 equiv), fluoride salt (3.0 equiv), CuI
(0.06 equiv), ligand (x equiv). L2 = 2-ethyl oxazoline.
b Conversion of the starting aziridine 1a was determined by 1H NMR of the crude mixture.
Synlett 2012, 23, 2463–2468
© Georg Thieme Verlag Stuttgart · New York

LETTER
Copper-Catalyzed Arylation of Alkenyl Aziridines
2465
SN2' adducts 3
CsF
Cu(I)
+
R
HF
Cu
R
A
TMS
CsF
Cu
NTs
OTf
R
B
Scheme 2 Plausible mechanism for copper-catalyzed arylation
regioselective fashion. The results obtained indicate the phosphine complexes with respect to the corresponding
increased susceptibility of allylic aziridines to undergo allylic epoxides, in which the palladium catalysis is man-
ring opening via SN2′ displacement catalyzed by copper– datory.9
Table 2 Examination of the Scope of the Three-Component Reactiona
Entry
Aziridine
Alkyne
Time
Conversion SN2′/SN2b
Main product
Yield (%)c
Ph
1d
16 h
92
91:9
70e
NHTs
2a
1b
1b
NHTs
NHTs
NHTs
3ba E/Z = 60:40e
3bc E/Z = 63:37e
3ca
2
3
16 h
>95
>95
76:24
75e
2c
2a
Ph
Ph
5 h
>95:<5
82
NHTs
1c
1c
C6H13
Ph
4
5
2b
16 h
16 h
72
66
>95:<5
90:10
45
60
NHTs
NHTs
3cb
3dd
OAc
Ar
Ar
OAc
NHTs
2d
2c
1d Ar = 4-MeOC6H4
6
1a
16 h
95
>95:<5
74
NHTs
3ac
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2463–2468

2466
F. Berti et al.
LETTER
Table 2 Examination of the Scope of the Three-Component Reactiona (continued)
Entry
Aziridine
Alkyne
Time
16 h
Conversion SN2′/SN2b
Main product
Yield (%)c
OAc
7
1a
2d
100
92:8
84
NHTs
3ad
Ts
N
8
2c
16 h
85
88:12
57
NHTs
1e
3ec
a Unless stated otherwise, all reactions were carried out with benzyne precursor (1.1 equiv), terminal alkyne (1.0 equiv), aziridine (0.9 equiv),
CsF (3.0 equiv), CuI (0.06 equiv), Ph3P (0.12 equiv) in MeCN at 55 °C.
b Determined by 1H NMR of the crude mixture.
c Isolated yield after chromatographic purification.
d Reaction was carried out at 65 °C with CuI (0.1 equiv) and Ph3P (0.2 equiv).
e An unseparable diastereoisomeric mixture was obtained.
Interestingly, a particular result was obtained when ethyl alized allylic amines with good to high levels of regio- and
propiolate was used as the alkyne component. The initial stereoselectivity. Unlike related allylic epoxides, the use
formation of consistent amount (ca. 37% of the crude mix- of a cooperative palladium catalysis is not necessary, and
ture) of the SN2 adduct allowed a novel domino intramo- in most cases it was detrimental to the reaction efficiency.
lecular amination of the conjugated triple bond of ethyl
propiolate to give tetrahydrophenanthridine 4, which was
isolated with 30% yield after chromatographic purifica-
Acknowledgment
This work was supported by the Ministero dell’Università e della
Ricerca (PRIN 2008) and by the University of Pisa.
tion (Scheme 3).
COOEt
References
(1) For a recent review, see: Lu, P. Tetrahedron 2010, 66, 2549.
(2) For a comprehensive review, see: Krake, S.; Bergmeier, S.
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(3) Huang, C.-Y.; Doyle, A. G. J. Am. Chem. Soc. 2012, 134,
9541.
(4) Takada, H.; Yasui, E.; Sahara, Y.; Chinen, Y.; Tanaka, H.;
Morita, Y.; Kobiki, C.; Narisawa, D.; Mizukami, M.;
Miyashita, M.; Nagumo, S. Heterocycles 2011, 83, 555.
(5) Kjellgren, J.; Aydin, J.; Wallner, O. A.; Saltanova, I. V.;
Szabó, K. J. Chem.–Eur. J. 2005, 11, 5260.
(6) For recent reviews, see: (a) Worlikar, S. A.; Larock, R. C.
Curr. Org. Chem. 2011, 15, 3214. (b) Yoshida, H.; Takaki,
K. Heterocycles 2012, 85, 1333. (c) Okuma, K.
NHTs
CuI (6 mol%)
Ph3P (12 mol%)
OTf
3ae (54%)
+
+ EtOOC
1a
+
CsF (3.0 equiv)
MeCN, 55 °C, 20 h
EtOOC
TMS
2e
Ts
H
N
H
4 (30%)
Heterocycles 2012, 85, 515. (d) Bhunia, A.; Reddy Yetra, S.;
Biju, A. T. Chem. Soc. Rev. 2012, 41, 3140. (e) Tadross, P.
M.; Stoltz, B. M. Chem. Rev. 2012, 122, 3550. (f) Gampe, C.
M.; Carreira, E. M. Angew. Chem. Int. Ed. 2012, 51, 3766.
(7) (a) Crotti, S.; Bertolini, F.; Macchia, F.; Pineschi, M. Chem.
Commun. 2008, 3127. (b) Bertolini, F.; Woodward, S.;
Crotti, S.; Pineschi, M. Tetrahedron Lett. 2009, 50, 4515;
and references therein.
(8) (a) Sun, Z.; Yu, S.; Ding, Z.; Ma, D. J. Am. Chem. Soc. 2007,
129, 9300. (b) Black, D. A.; Beveridge, R. E.; Arndtsen,
B. A. J. Org. Chem. 2008, 73, 1906.
(9) Jeganmohan, M.; Bhuvaneswari, S.; Cheng, C.-H. Angew.
Chem. Int. Ed. 2009, 48, 391.
Scheme 3 New domino reaction pathway with ethyl propiolate
In conclusion, a novel regioselective and anti-stereoselec-
tive arylation of alkenyl aziridines by means of a three-
component reaction involving benzyne and alkynes cata-
lyzed by simple copper complexes has been developed.12
The use of a conjugated alkyne allows the consecutive
one-pot formation of two carbon–carbon bonds followed
by an intramolecular carbon–nitrogen bond formation.
The reaction occurs in mild conditions to afford function-
Synlett 2012, 23, 2463–2468
© Georg Thieme Verlag Stuttgart · New York

LETTER
Copper-Catalyzed Arylation of Alkenyl Aziridines
2467
(10) (a) Xie, C.; Liu, L.; Zhang, Y.; Xu, P. Org. Lett. 2008, 10,
2393. (b) See also: Bhuvaneswari, S.; Jeganmohan, M.;
Cheng, C.-H. Chem. Commun. 2008, 5013.
(11) For a review, see: Yoshikai, N.; Nakamura, E. Chem. Rev.
2012, 112, 2339.
(12) The following reagents were purchased from Aldrich and
used as received: CuI (99.999%); 2-(trimethylsilyl)phenyl
trifluoromethanesulfonate (97%); CsF (99.9%); Ph3P
(≥99%); phenylacetylene (98%); propargyl acetate (98%);
1-octyne (97%); ethyl propiolate (99%).
(m, 2 H), 3.75 (s, 3 H), 4.80–4.90 (m, 3 H), 5.18 (d, 1 H, J =
7.1 Hz), 5.49–5.56 (m, 2 H), 6.67–6.87 (m, 2 H), 6.97–7.43
(m, 8 H), 7.57 (d, 2 H, J = 8.3 Hz). 13C NMR (62.5 MHz,
CDCl3): δ = 20.7, 21.4, 37.1, 52.8, 55.2, 58.7, 84.8, 86.9,
113.7, 121.6, 127.1, 128.2, 128.9, 129.0, 129.2, 130.5,
130.7, 132.2, 132.6, 137.7, 141.8, 142.8, 158.9, 170.7. MS
(ESI): m/z = 530 [M + Na]+. Anal. Calcd for C29H29NO5S: C,
69.16; H, 5.80; N, 2.78. Found: C, 70.04; H, 5.76; N, 2.65.
Compound 3ac (Table 2, Entry 6): Following the typical
procedure the chromatographic purification was performed
with hexanes–EtOAc (9:1) containing 4% of Et3N (Rf 0.12)
to afford compound 3ac (43 mg, 74%) as a yellow oil. 1H
NMR (250 MHz, CDCl3): δ = 1.46–1.75 (m, 7 H), 2.09–2.25
(m, 5 H), 2.43 (s, 3 H), 3.91–4.03 (m, 2 H), 4.68 (br, 1 H,
NHTs), 5.57 (dt, 1 H, J = 10.1, 2.3 Hz), 5.76 (dt, 1 H, J =
10.1, 0.8 Hz), 6.13–6.20 (m, 1 H), 7.03–7.38 (m, 6 H), 7.80
(d, 2 H, J = 8.5 Hz). 13C NMR (62.5 MHz, CDCl3): δ = 21.4,
21.5, 22.2, 25.7, 28.7, 29.1, 29.7, 39.0, 49.6, 84.4, 95.5,
120.7, 122.8, 126.1, 126.8, 127.0, 127.9, 128.8, 129.7,
132.1, 133.8, 135.0, 138.2, 143.3, 145.8. MS (ESI): m/z =
454 [M + Na]+. Anal. Calcd for C27H29NO5S: C, 75.14; H,
6.77; N, 3.25. Found: C, 75.25; H, 6.60; N, 3.20.
Compound 3ad (Table 2, Entry 7): Following the typical
procedure, the title compound was purified by semipreparative
TLC plates eluting with toluene–hexanes–Et2O (4:2:1, 2
runs; Rf 0.18), to afford 3ad (48 mg, 84%) as a yellow oil. 1H
NMR (250 MHz, CDCl3): δ = 1.39–1.99 (m, 3 H), 2.01–2.19
(m, 4 H), 2.44 (s, 3 H), 3.79–3.89 (m, 1 H), 3.90–4.04 (m, 1
H), 4.50 (d, 1 H, J = 8.9 Hz, NHTs), 4.89 (s, 2 H), 5.58 (dt,
1 H, J = 10.1, 2.4 Hz), 5.73 (dt, 1 H, J = 10.1, 0.8 Hz), 7.06–
7.45 (m, 7 H), 7.80 (d, 2 H, J = 6.7 Hz). 13C NMR (62.5
MHz, CDCl3): δ = 20.8, 21.5, 29.0, 29.8, 39.0, 49.7, 52.8,
84.6, 87.0, 121.2, 126.2, 126.9, 127.0, 129.0, 129.1, 129.7,
132.7, 133.4, 138.3, 143.3, 146.7, 170.3. MS (ESI): m/z =
446 [M + Na]+. Anal. Calcd for C24H25NO4S: C, 68.06; H,
5.95; N, 3.31. Found: C, 68.60; H, 5.70; N, 3.30.
Typical Procedure for the Three-Component Coupling
with Alkenyl Aziridines (Table 1, Entry 8): In a dried
Schlenk tube flushed with argon, CuI (1.5 mg, 8.1 μmol),
and Ph3P (4.2 mg, 16.2 μmol) were placed in anhyd MeCN
(1.2 mL). The solution was stirred for 10 min at r.t. and then
CsF (68.4 mg, 0.45 mmol), o-trimethylsilylphenyl triflate
(41.3 μL, 0.17 mmol), phenylacetylene (16.5 μL, 0.15
mmol) and aziridine 1a (0.135 mmol) were sequentially
added. After stirring at 55 °C for 5 h, the suspension was
filtered on Celite through a glass sintered Buchner funnel
washing with CH2Cl2. The crude residue was purified by
flash chromatography eluting with hexanes–EtOAc (8:2;
Rf 0.10) to afford 46 mg (80%) of (1R*,4R*)-4-{[2-
(phenylethynyl)phenyl]cyclohex-2-enyl}benzenesulfon-
amide (3aa), as an oil. 1H NMR (250 MHz, CDCl3): δ =
1.60–2.22 (m, 4 H), 2.43 (s, 3 H), 4.00 (br, 2 H), 4.78 (br, 1
H, NHTs), 5.62 (d, 1 H, J = 10.1 Hz), 5.81 (d, 1 H, J = 10.1
Hz), 7.08–7.52 (m, 11 H), 7.81 (d, 2 H, J = 8.5 Hz). 13C NMR
(62.5 MHz, CDCl3): δ = 21.53, 28.9, 29.8, 39.2, 49.7, 87.5,
93.6, 122.3, 123.2, 126.3, 127.0, 128.4 (2 × C), 128.6, 129.0,
129.8, 131.4, 132.4, 133.7, 138.3, 143.4, 146.2. MS (ESI):
m/z = 450 [M + Na]+. Anal. Calcd for C27H25NO2S: C, 75.85;
H, 5.89; N, 3.28. Found: C, 76.04; H, 5.68; N, 3.13.
Compound 3ca (Table 2, Entry 3): Following the typical
procedure, the crude residue was purified by flash
chromatography eluting with hexanes–EtOAc (8:2; Rf 0.27),
to afford compound 3ca (53 mg, 82%) as an oil. 1H NMR
(250 MHz, CDCl3): δ = 2.34 (s, 3 H), 3.50 (d, 2 H, J = 6.1
Hz), 4.73 (d, 1 H, J = 7.1 Hz, NHTs), 4.92 (t, 1 H, J = 6.2
Hz), 5.52 (dd, 1 H, J = 15.3, 6.1 Hz), 5.60–5.77 (m, 1 H),
7.05–7.28 (m, 10 H), 7.30–7.39 (m, 3 H), 7.41–7.53 (m, 3
H), 7.57 (d, 2 H, J = 7.9 Hz). 13C NMR (62.5 MHz, CDCl3):
δ = 21.4, 37.1, 59.3, 87.8, 93.4, 122.7, 123.2, 126.2, 127.0,
127.1, 127.5, 128.3, 128.4 (2 × C), 128.5, 128.8, 129.3,
130.5, 131.2, 131.4, 132.2, 137.6, 139.9, 141.3, 143.0. MS
(ESI): m/z = 500 [M + Na]+. Anal. Calcd for C31H27NO2S: C,
77.96; H, 5.70; N, 3.28. Found: C, 78.02; H, 5.68; N, 3.14.
Compound 3cb (Table 2, Entry 4): Following the typical
procedure, the title compound was purified by semipreparative
TLC plates eluting with hexanes–EtOAc (9:1; Rf 0.16, two
runs), to afford compound 3cb (29 mg, 45%) as a yellowish
oil. 1H NMR (250 MHz, CDCl3): δ = 0.89 (t, 3 H, J = 6.0
Hz), 1.25–1.72 (m, 10 H), 2.37 (s, 3 H), 3.41 (d, 2 H, J = 6.3
Hz), 4.67 (d, 1 H, J = 6.5 Hz, NHTs), 4.92 (app. t, 1 H, J =
6.5 Hz), 5.49 (dd, 1 H, J = 6.3, 15.5 Hz), 5.59–5.71 (m, 1 H),
6.95–7.42 (m, 11 H), 7.58 (d, 2 H, J = 7.8 Hz). 13C NMR
(62.5 MHz, CDCl3): δ = 14.0, 19.5, 21.5, 22.5, 28.6, 28.8,
31.3, 37.0, 59.3, 79.1, 94.6, 123.6, 126.1, 127.0, 127.2,
127.6, 127.6, 128.5, 129.3, 130.3, 131.6, 132.2, 137.7,
140.0, 141.1, 143.1. MS (ESI): m/z = 508 [M + Na]+. Anal.
Calcd for C31H35NO2S: C, 76.66; H, 7.26; N, 2.88. Found: C,
76.85; H, 7.13; N, 2.80.
Compound 3ec (Table 2, Entry 8): Following the typical
procedure, the crude residue was purified by flash
chromatography eluting with hexanes–EtOAc (9:1)
containing 4% Et3N (Rf 0.07) to afford compound 3ec (32
mg, 57%) as a yellow oil. 1H NMR (250 MHz, CDCl3): δ =
1.57–1.75 (m, 4 H), 1.94–2.24 (m, 6 H), 2.42 (s, 3 H), 4.41–
4.65 (m, 3 H), 5.65–5.71 (m, 1 H), 5.90–5.96 (m, 1 H), 6.13–
6.20 (m, 1 H), 6.94–7.21 (m, 3 H), 7.25–7.40 (m, 3 H), 7.77
(d, 2 H, J = 8.3 Hz). 13C NMR (62.5 MHz, CDCl3): δ = 21.4,
21.5, 22.3, 25.7, 40.5, 46.0, 47.4, 59.7, 85.0, 97.2, 120.1,
123.0, 125.4, 126.3, 127.0, 128.1, 129.7, 131.9, 132.1,
135.1, 138.1, 143.1, 145.0, 145.5. MS (ESI): m/z = 440 [M
+ Na]+. Anal. Calcd for C26H27NO2S: C, 74.79; H, 6.52; N,
3.35. Found: C, 75.10; H, 6.45; N, 3.32.
Compound 3ae: Purified by flash chromatography eluting
with hexanes–EtOAc (8:2; Rf 0.12); yellowish oil. 1H NMR
(250 MHz, CDCl3): δ = 1.35 (t, 3 H, J = 7.0 Hz), 1.45–1.65
(m, 2 H), 1.85–2.00 (m, 1 H), 2.05–2.20 (m, 1 H), 2.43 (s, 3
H), 3.83–3.94 (m, 1 H), 3.93–4.05 (m, 1 H), 4.28 (q, 2 H, J
= 7.0 Hz), 4.71 (d, 1 H, J = 9.0 Hz, NHTs), 5.60–5.67 (m, 2
H), 7.10–7.41 (m, 5 H), 7.53 (d, 1 H, J = 7.8 Hz), 7.80 (d, 2
H, J = 8.3 Hz). 13C NMR (62.5 MHz, CDCl3): δ = 14.1, 21.5,
29.4, 29.8, 39.2, 49.6, 62.1, 84.3, 84.7, 118.7, 126.5, 127.0,
127.3, 129.6, 129.8, 130.9, 132.8, 133.9, 138.3, 143.4,
148.4, 174.9. MS (ESI): m/z = 446 [M + Na]+. Anal. Calcd
for C24H25NO4S: C, 68.06; H, 5.95; N, 3.31. Found: C,
68.22; H, 5.88; N, 3.24.
Compound 3dd (Table 2, Entry 5): Following the typical
procedure, the crude residue was purified by flash chroma-
tography eluting with hexanes–EtOAc (8:2; Rf 0.05) to
afford compound 3dd (41 mg, 60%) as a brown oil. 1H NMR
(250 MHz, CDCl3): δ = 2.11 (s, 3 H), 2.37 (s, 3 H), 3.30–3.50
Compound 4: Purified by flash chromatography eluting
with hexanes–EtOAc (8:2; Rf 0.28); yellowish oil. 1H NMR
(250 MHz, CDCl3): δ = 1.24 (t, 3 H, J = 7.0 Hz), 1.30–1.42
(m, 1 H), 1.82–2.02 (m, 1 H), 2.32 (s, 3 H), 2.28–2.38 (m, 1
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2463–2468

2468
F. Berti et al.
LETTER
H), 2.86 (br dd, 1 H, J = 2.8, 12.3 Hz), 3.14–3.32 (m, 2 H),
4.16 (q, 2 H, J = 7.0 Hz), 5.88–6.00 (m, 1 H), 6.11 (br d, 1
H, J = 11.5 Hz), 6.49 (s, 1 H), 6.81–7.42 (m, 8 H). 13C NMR
(62.5 MHz, CDCl3): δ = 14.3, 21.6, 25.7, 31.6, 40.6, 60.5,
60.6, 120.3, 121.2, 123.0, 124.9, 128.0, 128.7, 129.3, 129.6,
130.0, 132.7, 134.9, 137.6, 143.9, 147.0, 165.3. MS (ESI):
m/z = 446 [M + Na]+. Anal. Calcd for C24H25NO4S: C, 68.06;
H, 5.95; N, 3.31. Found: C, 68.45; H, 5.78; N, 3.28.
Synlett 2012, 23, 2463–2468
© Georg Thieme Verlag Stuttgart · New York

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