Copper-catalyzed intramolecular N-vinylation of sulfonamides: General and efficient synthesis of heterocyclic enamines and macrolactams

Article abstract of DOI:10.1021/jo8016617

(Chemical Equation Presented) With the catalysis of CuI/N,N′- dimethylethylenediamine, intramolecular C-N coupling between sulfonamides and vinyl halides was successfully implemented, leading to the efficient synthesis of 5-, 6-, 7-, and even 8-membered heterocyclic enamines in both exo and endo modes. The bicyclic enamines thus formed provided a convenient entry to the corresponding 9- to 12-membered lactams by oxidative C=C bond cleavage.

Full text of DOI:10.1021/jo8016617

The nondehydrative methods include the intramolecular addition
of vinyl radicals to azomethine nitrogens,4 the lanthanide-
catalyzed intramolecular hydroamination of alkynes,5 and the
copper-catalyzed 1,2-double amination of 1-halo-1-alkynes
recently reported by Urabe et al.6 It is therefore highly desirable
to develop efficient and general methods for the synthesis of
heterocyclic enamines. Herein we report that 5-, 6-, 7-, and even
8-membered heterocyclic enamines in either exo or endo type
can be conveniently and efficiently synthesized by copper-
catalyzed intramolecular C-N coupling between sulfonamides
and alkenyl halides.
Copper-Catalyzed Intramolecular N-Vinylation of
Sulfonamides: General and Efficient Synthesis of
Heterocyclic Enamines and Macrolactams
Hongjian Lu, Xinting Yuan, Shana Zhu, Changhui Sun, and
Chaozhong Li*
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Road,
Shanghai 200032, People’s Republic of China
clig@mail.sioc.ac.cn
The formation of aromatic C-N bonds via copper-catalyzed
Ullmann coupling between aryl halides and N-centered nucleo-
philes has received considerable attention in the past few years.7
The high stability and low costs of the copper catalysts enable
these transformations to be a useful complement to the more
extensively studied palladium-catalyzed processes.8 By the
appropriate choice of copper source, ligand, base, and solvent,
these reactions have been developed to include a wide range of
substrates under mild conditions. This methodology was suc-
cessfully extended to the vinylic C-N bond formation and found
important application in natural product synthesis.9 We recently
reported that, with the catalysis of CuI/N,N′-dimethylethylene-
diamine (DMEDA), N-(3-chloro-1-phenylbut-3-enyl)toluene-
sulfonamide 1 underwent efficient C-N coupling via a 4-exo
ring closure to afford 2-alkylideneazetidine 2, which could be
readily converted to the corresponding ꢀ-lactam 3 by oxidation
with O3 (Scheme 1).10 Our interest in Cu(I)-catalyzed intramo-
lecular vinylation10,11 urged us to extend this methodology to
the formation of heterocyclic enamines of various sizes.
ReceiVed July 27, 2008
With the catalysis of CuI/N,N′-dimethylethylenediamine,
intramolecular C-N coupling between sulfonamides and
vinyl halides was successfully implemented, leading to the
efficient synthesis of 5-, 6-, 7-, and even 8-membered
heterocyclic enamines in both exo and endo modes. The
bicyclic enamines thus formed provided a convenient entry
to the corresponding 9- to 12-membered lactams by oxidative
CdC bond cleavage.
(7) For reviews, see: (a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428.
(b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (c)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337. (d)
Deng, W.; Liu, L.; Guo, Q.-X. Chin. J. Org. Chem. 2004, 24, 150. (e) Dehli,
J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 973. (f) Chemler, S. R.; Fuller,
P. H. Chem. Soc. ReV. 2007, 36, 1153.
(8) For reviews, see: (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem.
2002, 219, 131. (b) Hartwig, J. F. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negichi, E.-i., Ed.; Wiley: New York, 2002; Vol. 1, p
1051. (c) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176. (d)
Prim, D.; Campagne, J. M.; Joseph, D.; rioletti, B. Tetrahedron 2002, 58, 2041.
(e) Yang, B. Y.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125. (f) Wolfe,
J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
805. (g) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. (h) Hartwig,
J. F. Acc. Chem. Res. 1998, 31, 852.
(9) For the latest examples of copper-catalyzed N-vinylation, see: (a) Jiang,
B.; Tian, H.; Huang, Z.-G.; Xu, M. Org. Lett. 2008, 10, 2737. (b) Fukudome,
Y.; Naito, H.; Hata, T.; Urabe, H. J. Am. Chem. Soc. 2008, 130, 1820. (c)
Bolshan, Y.; Batey, R. A. Angew. Chem., Int. Ed. 2008, 47, 2109. (d) Mao, J.;
Hua, Q.; Guo, J.; Shi, D.; Ji, S. Synlett 2008, 2011. (e) Martin, R.; Cuenca, A.;
Buchwald, S. L. Org. Lett. 2007, 9, 5521. (f) Cesati, R. R., III.; Dwyer, G.;
Jones, R. C.; Hayes, M. P.; Yalamanchili, P.; Casebier, D. S. Org. Lett. 2007,
9, 5617. (g) Martin, R.; Larsen, C. H.; Cuenca, A.; Buchwald, S. L. Org. Lett.
2007, 9, 3379. (h) He, G.; Wang, J.; Ma, D. Org. Lett. 2007, 9, 1367. (i) Yang,
L.; Deng, G.; Wang, D.-X.; Huang, Z.-T.; Zhu, J.-P.; Wang, M.-X. Org. Lett.
2007, 9, 1387. (j) Rivero, M. R.; Buchwald, S. L. Org. Lett. 2007, 9, 973. (k)
Toumi, M.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2007, 46, 572. (l)
Yuan, X.; Xu, X.; Zhou, X.; Yuan, J.; Mai, L.; Li, Y. J. Org. Chem. 2007, 72,
1510.
Enamines are important synthetic intermediates.1 Heterocyclic
enamines, in particular, are powerful and versatile intermediates
in the preparation of natural products and fused heterocyclic
compounds.2 The syntheses of heterocyclic enamines have been
studied mainly with the use of N-heterocycles as the starting
materials.2 Methods by constructing a N-heterocyclic ring moiety
are few3-6 and dominated by dehydrative condensations where
the selectivity has to be determined by thermodynamic factors.3
(1) (a) Whitesell, J. K. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, UK, 1991. (b) Enamines: Synthesis,
Structure and Reactions, 2nd ed.; Cook, A. G., Ed.; Dekker: New York, 1988.
(c) The Chemistry of Enamines, Part I; Rappoport, Z., Ed.; Wiley: New York,
1994.
(2) (a) Lue, P.; Greenhill, J. V. AdV. Heterocycl. Chem. 1997, 67, 209. (b)
Granik, V. G.; Makarov, V. A. AdV. Heterocycl. Chem. 1999, 72, 283.
(3) (a) Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833. (b) Lambert,
P. H.; Vaultier, M.; Carrie, R. J. Org. Chem. 1985, 50, 5352. (c) Michael, J. P.;
Hosken, G. D.; Howard, A. S. Tetrahedron 1988, 44, 3025. (d) Wang, M.-X.;
Liu, Y.; Gao, H.-Y.; Zhang, Y.; Yu, C.-Y.; Huang, Z.-T.; Fleet, G. W. J. J. Org.
Chem. 2003, 68, 3281. (e) Zhao, M.-X.; Wang, M.-X.; Yu, C.-Y.; Huang, Z.-
T.; Fleet, G. W. J. J. Org. Chem. 2004, 69, 997.
(4) (a) Prabhakaran, E. N.; Nugent, B. M.; Williams, A. L.; Nailor, K. E.;
Johnston, J. M. Org. Lett. 2002, 4, 4197. (b) Nugent, B. M.; Williams, A. L.;
Prabhakaran, E. N.; Johnston, J. N. Tetrahedron 2003, 59, 8877.
(5) (a) Stubbert, B. D.; Marks, T. J. J. Am. Chem. Soc. 2007, 129, 4253. (b)
Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673. (c) Li, Y.; Marks, T. J.
J. Am. Chem. Soc. 1998, 120, 1757.
(10) Lu, H.; Li, C. Org. Lett. 2006, 8, 5365.
(11) (a) Fang, Y.; Li, C. Chem. Commun. 2005, 3574. (b) Hu, T.; Li, C.
Org. Lett. 2005, 7, 2035. (c) Fang, Y.; Li, C. J. Org. Chem. 2006, 71, 6427. (d)
Pan, Y.; Lu, H.; Fang, Y.; Fang, X.; Chen, L.; Qian, J.; Wang, J.; Li, C. Synthesis
2007, 1242. (e) Fang, Y.; Li, C. J. Am. Chem. Soc. 2007, 129, 8092.
(6) Fukudome, Y.; Naito, H.; Hata, T.; Urabe, H. J. Am. Chem. Soc. 2008,
130, 1820.
10.1021/jo8016617 CCC: $40.75
Published on Web 10/07/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8665–8668 8665

TABLE 2. Intramolecular N-Vinylation via Endo Modes
SCHEME 1
TABLE 1. Intramolecular N-Vinylation via Exo Modes
a Conditions: 4 (0.3 mmol), CuI/DMEDA ) 1:2, solvent (10 mL),
reflux. b 68, 100 and 153 °C refer to the refluxing temperatures of THF,
dioxane, and DMF, respectively. c Isolated yield based on 6. d No
reaction.
formation of 5a and 5d-f implied that the 5-exo ring closure
is of comparable rate to the corresponding 4-exo ring closure,10
which will be further discussed later.
We then extended the strategy to the C-N bond formation
via a 6-exo or 7-exo mode of cyclization. The prolonged reaction
of 4g in refluxing dioxane gave the expected enamine 5g in
only 19% yield while a large portion of the substrate 4g was
recovered (entry 7, Table 1). However, the cyclization of the
bromo analogue 4h proceeded smoothly in refluxing THF
leading to the quantitative formation of 5g. Substrate 4i behaved
similarly to 4h. The 7-exo cyclization of 4j was also successful,
although a larger amount of the catalyst CuI was required and
the product yield was lower (entry 10, Table 1). In all cases
screened, the enamines 5 with an exocyclic double bond were
obtained without isomerization, indicating the mildness of the
copper-catalyzed method. The results in Table 1 also showed
that the rate of cyclization follows the order of 4-exo ≈ 5-exo
> 6-exo > 7-exo.
The above reactions dealt with the intramolecular C-N
coupling via exo modes of cyclization. We then applied this
methodology further to the cyclization via endo modes. To
facilitate the endo cyclization, the vinylic halogen atom and the
nitrogen-containing alkyl chain have to be in a (Z)-configuration.
To avoid the possible contamination of the (E)-isomers,
2-substituted 1-bromocyclohexenes 6a-f were chosen as the
model substrates. These compounds were easily prepared from
the readily available 1-bromo-2-bromomethylcyclohexene via
conventional methods. The results are presented in Table 2.
Sulfonamide 6a underwent smooth cyclization in refluxing THF
to afford the product 7a quantitatively (entry 1, Table 2). This
a Conditions: 4 (0.3 mmol), CuI/DMEDA ) 1:2, solvent (10 mL),
reflux. b 68, 100 and 153 °C refer to the refluxing temperatures of THF,
dioxane, and DMF, respectively. c Isolated yield based on 4.
N-(4-Chloropent-4-enyl)toluenesulfonamide (4a) was thus
synthesized.12 Our previous optimized conditions (20 mol %
CuI, 40 mol % DMEDA, 200 mol % cesium carbonate, dioxane,
reflux)10 were directly applied. We were delighted to find that
the starting material 4a was all consumed within 4 h and the
expected coupling product 5a via a 5-exo ring closure was
obtained in quantitative yield. Thus, a number of substrates of
typical structures, which were readily prepared according to the
literature procedures,12 were tested and the results are sum-
marized in Table 1. The iodide 4c had the highest reactivity
and its reaction took place even at room temperature (entry 3,
Table 1). The vinyl bromide 4b showed a higher reactivity than
its chloro analogue 4a (entry 2, Table 1). Methanesulfonamide
4d had a similar behavior as toluenesulfonamide 4a. With
methyl or gem-dimethyl substitution (4e and 4f), the expected
cyclization products were also obtained quantitatively. The easy
(12) Lu, H.; Chen, Q.; Li, C. J. Org. Chem. 2007, 72, 2564.
8666 J. Org. Chem. Vol. 73, No. 21, 2008

TABLE 3. Optimization of Conditions for the Oxidation of 7c
SCHEME 2
entry
conditions
yield (%)a
1
2
O3, -78 °C; then PPh3 (2.5 equiv), -78 °C to rt, 4 h
O3, -78 °C; then (NH2)2CS (1.3 equiv), NaHCO3 (1.0
equiv), -78 °C to rt, 4 h
0
0
3
4
NaIO4 (2.0 equiv), MeOH/H2O, rt, 5 h
RuO2 ·2H2O (3 mol %), NaIO4 (2.0 equiv), MeOH/
H2O, rt, 5 h
RuO2 ·2H2O (3 mol %), NaIO4 (2.0 equiv), CCl4/H2O,
rt, 5 h
NR
NR
suggests that the 5-endo cyclization is of comparable rate to
the 5-exo cyclization of 4b. The 6-endo cyclization of 6b was
also successful, although it had to be conducted at a higher
temperature (dioxane, reflux). The gem-dimethyl substitution
in 6c significantly facilitated the 6-endo cyclization (entries 2-4,
Table 2). The 7-endo cyclization also turned out to be an
efficient process as evidenced by the high yield generation of
7d and 7e (entries 6 and 7, Table 2). Furthermore, 8-endo
cyclization was also possible (entries 8 and 9, Table 2). While
the reaction of 6f was sluggish in refluxing dioxane, a good
yield of the 8-endo cyclization product 7f could be achieved
by simply raising the reaction temperature. The above results
also indicated that the relative rate of cyclization follows the
order of 5-exo ≈ 5-endo > 6-endo > 7-endo > 8-endo.
The results in Tables 1 and 2 clearly demonstrate that the
intramolecular N-vinylation of sulfonamides with vinyl halides
provides a convenient and general entry to heterocyclic enam-
ines. In addition, the smaller the ring size, the easier the
cyclization. We recently reported that the uncommon 4-exo ring
closure is in fact fundamentally preferred in the intramolecular
O-vinylation of alcohols.11e It is certainly of interest to see if
this is also the case in the above N-vinylation. Thus, dibromide
8 was synthesized and subjected to the above C-N coupling
5
6
37b
80
RuO2 ·2H2O (3 mol %), NaIO4 (4.0 equiv), CCl4/H2O,
rt, 5 h
a Isolated yield based on 7c. b 7c was recovered in 49% yield.
FIGURE 1. Synthesis of macrolactams 13 from cyclic enamines 7.
However, when the oxidation was performed in CCl4-H2O
mixture,16 the ring enlargement product 13c was obtained in
80% yield.
1
conditions (THF, reflux, 2 h). H NMR of the crude products
Thus, bicyclic enamines 7a-f were subjected to the optimized
conditions (entry 6, Table 3), respectively. We were glad to
find that the expected 9- to 12-membered keto-lactams 13a-f
were obtained in satisfactory yields (Figure 1). Therefore, the
copper-catalyzed C-N bond formation followed by subsequent
oxidation offers a facile route to the synthesis of macrocyclic
lactams. This methodology should find important application
in natural product synthesis. For example, by further reduction,
these keto-amides can be converted to macrocyclic amines,
whose skeletons are embedded in a number of natural products
such as protopine alkaloids17 and isohaliclorensin.18
In summary, the chemistry detailed above has clearly
demonstrated that the Cu(I)-catalyzed intramolecular C-N
coupling of sulfonamides with vinyl halides is a highly efficient
process, providing a convenient and general entry to heterocyclic
enamines of various sizes in both endo and exo modes. Our
investigations have also illustrated that the rate of cyclization
decreases when the size of the ring closure increases. This
finding allows the rational design of new synthetic strategies
based on the vinylic C-N bond formation. As an extension,
we have showed that, by oxidation with NaIO4 under the
catalysis of RuO2, the bicyclic enamines thus synthesized offer
indicated that the ratio of 9 (4-exo) to 10 (5-exo) was about 2:1
in favor of the 4-exo ring closure (Scheme 2). Since the
enamines 9 and 10 were not very stable and difficult to separate
by column chromatography on basic alumina, they were
converted to the corresponding ketones 11 and 12 via hydrolysis
in acidic conditions, which were then separated and character-
ized. The ratio of 11 to 12 (ca. 2:1) further confirmed our NMR
analysis. Although the selectivity is not high, the 4-exo
cyclization is still the most favored process. This phenomenon,
in combination with our previous finding in O-vinylation,11e
reveals the unique property of Cu(I) in cross-coupling reactions.
The bicyclic enamines 7 are unable to be produced by
hydroamination of alkynes. The easy preparations of 7 via
copper catalysis should expand the synthetic application of
heterocyclic enamines. For example, the oxidative CdC bond
cleavage of 7 could provide a facile entry to macrolactams,
which are an important class of compounds not easily accessed
by other methods. As an extension, the oxidation of 7 was also
investigated here (Table 3). Ozonolysis of 7c followed by
treatment of PPh3 failed to give any expected product.13
Changing PPh3 to thiourea14 did not help. We then tried the
oxidation with sodium periodate in aqueous methanol.15 No
reaction occurred even with the catalysis of ruthenium dioxide.
(16) (a) Mehta, G.; Murty, A. N. J. Org. Chem. 1990, 55, 3568. (b) Mehta,
G.; Murty, A. N. J. Org. Chem. 1987, 52, 2875.
(13) Hon, Y.; Lin, S.; Lu, L.; Chen, Y. Tetrahedron 1995, 51, 5019.
(14) Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe,
A. L.; Ueno, Y. J. Am. Chem. Soc. 1997, 119, 12976.
(17) Wada, Y.; Kaga, H.; Uchiito, S.; Kumazawa, E.; Tomiki, M.; Onozaki,
Y.; Kurono, N.; Tokuda, M.; Ohkuma, T.; Orito, K. J. Org. Chem. 2007, 72,
7301.
(15) Gatta, F.; Misiti, D. J. Heterocycl. Chem. 1989, 26, 537.
(18) Zheng, J.-F.; Jin, L.-R.; Huang, P.-Q. Org. Lett. 2004, 6, 1139.
J. Org. Chem. Vol. 73, No. 21, 2008 8667

136.6, 144.5, 174.6, 213.5; ESI-MS m/z 374 (M+ + Na). Anal.
Calcd for C18H25NO4S: C, 61.51; H, 7.17; N, 3.99. Found: C, 61.64;
H, 7.25; N, 3.75.
an efficient and easy entry to the corresponding macrocyclic
keto-lactams.
N-(7-Bromo-2-oxooct-7-en-4-yl)-4-methylbenzenesulfonamide (11)
and N-(2-Bromo-7-oxooct-1-en-4-yl)-4-methylbenzenesulfonamide
(12). The mixture of N-(2,7-dibromoocta-1,7-dien-4-yl)-4-methyl-
benzenesulfonamide (8, 219 mg, 0.50 mmol), CuI (10 mg, 0.05
mmol), N,N′-dimethylethylenediamine (11 µL, 0.10 mmol), and
Cs2CO3 (326 mg, 1.0 mmol) in THF (15 mL) was refluxed for 2 h
under nitrogen atmosphere. The resulting mixture was cooled to
room temperature and filtered. Aqueous hydrochloric acid (1 N, 2
mL) was added to the filtrate and the solution was stirred at rt for
1 h. Water (15 mL) was added and mixture was extracted with
ethyl acetate (3 × 20 mL). The combined organic phase was dried
(Na2SO4) and then concentrated in vacuo. The resulting crude
products were separated by column chromatography on silica gel
with hexane/EtOAc (3:1, v:v) as the eluent to give the pure 11
(112 mg, 60% yield) and 12 (56 mg, 30% yield). 11: colorless oil;
Experimental Section
Typical Procedure for the Cu(I)-Catalyzed Intramolecular
C-N Coupling. The mixture of N-(3-chloro-1-phenylbut-3-en-1-
yl)toluenesulfonamide (4a, 82 mg, 0.30 mmol), CuI (11 mg, 0.06
mmol), N,N′-dimethylethylenediamine (13 µL, 0.12 mmol), and
Cs2CO3 (196 mg, 0.60 mmol) in dioxane (10 mL) was refluxed for
2 h under nitrogen atmosphere. The resulting mixture was cooled
to room temperature and filtered. The filtrate was concentrated in
vacuo and the crude product 5a was essentially pure. It could be
further purified by flash chromatography on basic alumina with
hexane/EtOAc (4:1, v:v) as the eluent. Yield 70 mg (99%); colorless
oil; 1H NMR (300 MHz, CDCl3) δ 1.72-1.82 (2H, m), 2.33-2.40
(2H, m), 2.43 (3H, s), 3.66 (2H, t, J ) 6.6 Hz), 4.24 (lH, s), 5.06
(1H, s), 7.30 (2H, d, J ) 8.1 Hz), 7.76 (2H, d, J ) 8.1 Hz); 13C
NMR (75.4 MHz, CDCl3) δ 21.5, 22.0, 32.8, 51.5, 90.4, 127.4,
129.4, 134.9, 143.8, 144.5; EIMS m/z (rel intensity) 237 (M+, 18),
172 (46), 155 (10), 105 (59), 91 (100), 82 (63), 65 (49), 55 (44).
Anal. Calcd for C12H15NO2S: C, 60.73; H, 6.37; N, 5.90. Found:
C, 60.34; H, 6.35; N, 5.59.
1
IR (film) ν (cm-1) 3281, 1714, 1159, 1093; H NMR (300 MHz,
CDCl3) δ 1.60-1.80 (2H, m), 2.00 (3H, s), 2.25-2.45 (2H, m),
2.42 (3H, s), 2.47-2.61 (2H, m), 3.40-3.52 (1H, m), 5.33 (1H,
s), 5.42 (1H, d, J ) 9.3 Hz), 5.45 (1H, s), 7.29 (2H, d, J ) 7.8
Hz), 7.72 (2H, d, J ) 8.4 Hz); 13C NMR (75.4 MHz, CDCl3) δ
21.5, 30.7, 33.0, 37.9, 47.0, 49.5, 117.6, 127.0, 129.8, 132.9, 138.1,
143.5, 207.5; ESI-MS m/z 398/396 (M+ + Na); HRMS calcd for
C15H20BrNO3SNa (M+ + Na) 396.0245, found 396.0239. 12:
Typical Procedure for the Synthesis of Macrocyclic Lactams.
The mixture of N-(3-(2-bromocyclohex-1-enyl)-2,2-dimethyl)-4-
methylbenzenesulfonamide (6c, 400 mg, 1.0 mmol), CuI (19 mg,
0.10 mmol), N,N′-dimethylethylenediamine (22 µL, 0.20 mmol),
and Cs2CO3 (652 mg, 2.0 mmol) in THF (30 mL) was refluxed for
3 h under nitrogen atmosphere. The resulting mixture was cooled
to room temperature and filtered. The filtrate was concentrated in
vacuo and the crude product 7c (319 mg, ∼1.0 mmol), without
further purification, was dissolved in CCl4 (10 mL). The water (10
mL) solution of NaIO4 (857 mg, 4.0 mmol) was added. RuO2 ·2H2O
(5 mg, 0.03 mmol) was then added and the mixture was vigorously
stirred at rt for 10 h. Isopropanol (10 mL) was then added to quench
the reaction. The two layers were separated and the aqueous phase
was extracted with ethyl acetate (3 × 20 mL). The combined
organic phase was dried (Na2SO4) and then concentrated in vacuo.
The resulting crude product was purified by column chromatography
on silica gel with hexane/EtOAc (1:1, v:v) as the eluent to give
the pure 13c as a white solid. Yield 280 mg (80%); mp 162-164
1
colorless oil; IR (film) ν (cm-1) 3278, 2925, 1714; H NMR (300
MHz, CDCl3) δ 1.48-1.61 (1H, m), 1.79-1.83 (1H, m), 2.10 (3H,
s), 2.30-2.64 (7H, m), 3.44-3.56 (1H, m), 4.95 (1H, d, J ) 8.7
Hz), 5.34 (1H, s), 5.52 (1H, s), 7.29 (2H, d, J ) 7.8 Hz), 7.74 (2H,
d, J ) 8.4 Hz); 13C NMR (75.4 MHz, CDCl3) δ 21.5, 27.3, 30.0,
39.5, 47.3, 52.1, 120.2, 127.1, 129.0, 129.6, 137.8, 143.4, 208.6;
ESI-MS m/z 398/396 (M+ + Na); HRMS calcd for C15H20-
BrNO3SNa (M+ + Na) 396.0245, found 396.0239.
Acknowledgment. This project was supported by the Na-
tional NSF of China (Grant Nos. 20672136, 20702060, and
20832006) and by the Shanghai Municipal Committee of
Science and Technology (Grant No. 07XD14038).
Supporting Information Available: Characterizations of
4-13. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
°C; H NMR (300 MHz, CDCl3) δ 1.28 (6H, s), 1.83 (4H, br),
2.35-2.41 (6H, m), 2.41 (3H, s), 3.95 (2H, s), 7.28 (2H, d, J )
8.1 Hz), 7.73 (2H, d, J ) 8.1 Hz); 13C NMR (75.4 MHz, CDCl3)
δ 21.6, 23.7, 24.4, 27.8, 32.6, 36.6, 45.2, 47.1, 53.7, 128.3, 129.4,
JO8016617
8668 J. Org. Chem. Vol. 73, No. 21, 2008