Synthesis of β-halo-pyrrolidinones through a tandem sequence of 5-endo halolactamization and C-H oxidative functionalization

Article abstract of DOI:10.1021/ol400208f

A tandem sequence of 5-endo halolactamization and direct C-H oxidative functionalization is described. A range of β-halo-pyrrolidinones can be efficiently synthesized using this method, making it an excellent approach for constructing natural products containing pyrrolidinones.

Full text of DOI:10.1021/ol400208f

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1382–1385
Synthesis of β‑Halo-pyrrolidinones
through a Tandem Sequence of 5‑Endo
Halolactamization and CꢀH Oxidative
Functionalization
Yu Tang,* Mingcan Lv, Xiaofan Liu, Hejing Feng, and Liwei Liu
Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, School of
Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P. R. China
tangyu114@gmail.com
Received February 6, 2013
ABSTRACT
A tandem sequence of 5-endo halolactamization and direct CꢀH oxidative functionalization is described. A range of β-halo-pyrrolidinones can be
efficiently synthesized using this method, making it an excellent approach for constructing natural products containing pyrrolidinones.
Halocyclization of unsaturated compounds, an impor-
tant type of organic reaction, has been extensively investi-
gated as a way to synthesize heterocyclic compounds,
especially those that are biologically active.1 In most cases,
the cyclizations follow Baldwin’s rules. Thus, closure of
3- to 7-membered rings often favors exo-trig and 6- to 7-endo
processes, but not 3- to 5-endo processes. In addition, the
regioselectivity of the reaction can be influenced by structural
modifications; for example, substituents on the double bond
can exert electronic effects that alter selectivity.
Numerous studies have examined 5-exo halocyclization,
especially 5-exo iodolactonization of unsaturated car-
boxylic acids and amides.2,3 In contrast, 5-endo halocycli-
zation of these compounds is poorly understood because it
is relatively uncommon. In particular, few studies have
examined lactam formation through 5-endo halocycliza-
tion ofunsaturated amides.4 Li and co-workers described a
5-endo amidyl radical cyclization for the formation of
unsaturated lactams; the reaction was promoted by vinylic
(3) (a) Hu, T.; Liu, K.; Shen, M.; Yuan, X.; Tang, Y.; Li, C. J. Org.
Chem. 2007, 72, 8555. (b) Kundig, E. P.; Laxmisha, M. S.; Cannas, R.;
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Chem. Soc. 2003, 125, 5642. (d) Lee, C.-W.; Gil, J. M.; Oh, D. Y.
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J. Chem. Soc., Perkin Trans. 1 1990, 627. (f) Takano, S.; Sato, S.; Goto,
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104, 3233. (c) Corey, E. J.; Fleet, G. W.; Kato, M. Tetrahedron Lett.
1973, 14, 3963. (d) Rajendra, G.; Miller, M. J. Tetrahedron Lett. 1987,
28, 6257. (e) Nagaka, W.; Takeda, K. J. Pharm. Soc. Jpn. 1952, 72, 1566.
(f) Tilley, J. W.; Clader, J. W.; Wirkus, M.; Blount, J. F. J. Org. Chem.
1985, 50, 2220. (g) Yamawaki, Y.; Wantanaki, M.; Yamamura, S.; Saito,
T. J. Pharm. Soc. Jpn. 1977, 97, 127. (h) Hino, T.; Uehara, H.;
Takashima, M.; Kawate, T.; Seki, H.; Hara, R.; Kuramochi, T.;
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(1) For recent reviews on halocyclizations, see: (a) Robin, S.;
Rousseau, G. Tetrahedron 1998, 54, 13681. (b) Robin, S.; Rousseau,
G. Eur. J. Org. Chem. 2002, 3099. (c) Harding, K. E.; Tiner, T. H. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: New
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46, 3321. (e) Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev. 2011,
111, 2937.
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A. X.; Wang, F.; Zhang, S. B. J. Org. Chem. 2004, 69, 2874. (c) Shen, M.;
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r
10.1021/ol400208f
Published on Web 03/05/2013
2013 American Chemical Society

iodine substitution.5 The same researchers found tBuOCl/
I2 to be an efficient iodinating reagent for the synthesis of
iminolactones.6
Table 1. Optimization of Reaction Conditions
iodinating reagent
time
(h)
yield
(%)
entry
(equiv)
solvent
a
1
I2/Na2CO3 (3)
ICl (3)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
H2O
96
1
ꢀ
2
21b
trace
38
3
BPIT (3)
96
72
15
20
10
72
15
3
4
NIS (2)
5
tBuOCl/I2 (3/2)
NIS (4)
58
6
65
7
NIS (6)
63
8
tBuOCl/I2 (1/1)
tBuOCl/I2 (3/3)
tBuOCl/I2 (3/3)
tBuOCl/I2 (3/3)
tBuOCl/I2 (3/3)
tBuOCl/I2 (3/3)
tBuOCl/I2 (3/3)
NIS (4)
19
Figure 1. Examples of pyrrolidinone-containing natural products.
9
67
a
10
11
12
13
14
15
ꢀ
THF
3
16
31
13
83
19
Our interest in novel approaches to natural product
synthesis led us to wonder whether 5-endo amidyl cyclization
could be combined with the oxidative functionalization7 of
CꢀH bonds. Many studies have examined the functionaliza-
tion of such bonds adjacent to electron-rich tertiary amines or
electron-poor amides; these reactions are catalyzed by Ru,8
Fe,9 Cu,10 Rh,11 Ir,12 Pd,13 and photoredox catalysts.14 In
addition, some studies have explored the oxidative function-
alization of CꢀH bonds using nonmetal oxidants.15
CH2Cl2
3
acetone
3
CH3CN
3
CH3CN
96
a No product was identified by TLC. b The Cl-substituted product
was formed in 34% yield.
transformed into highly reactive N-acyliminium ions.
These ions have historically been generated in situ by Lewis
acid or Brønsted acid promoted elimination.17 They have
been used widely in the synthesis of alkaloid natural
products (Figure 1).18 Here we describe sequential 5-endo
halolactamization and CꢀH oxidative functionalization
for the synthesis of β-halo-pyrrolidinones. In our case, the
reactions underwent halocyclization precesses rather than
radical cyclization which has been reported previously in
Li’s pyrrolidinone synthesis.
Pyrrolidinone (1)16 and its derivatives exhibit a wide
range of potent biological activities, and that can easily be
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In initial screening experiments, we selected 2a and
CH3CN/H2O as the reactant/solvent combination in order
to determine optimal reaction conditions. First, we
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Org. Lett., Vol. 15, No. 6, 2013
1383

screened a series of iodinating reagents that included
t
I2/Na2CO3, ICl, IPyBF4 (BPIT), NIS, and BuOCl/I2
sequence. Under the optimized conditions, the N-phenyl,
benzyl, and n-butyl substrates 2aꢀ2k gave iodo-pyrrolidi-
nones 3aꢀ3k in moderate-to-excellent yields using both
methods (Table 2). Intriguingly, substrates containing
either an electron-donating or -withdrawing group at the
para position gave low yields of iodo-pyrrolidinones. The
molecular structure of 3e was determined by X-ray crystal-
lography (Figure 2).
(Table 1, entries 1ꢀ5). While most showed no or poor activity,
NIS and tBuOCl/I2 were moderately active. Then we exam-
ined the loading of NIS and tBuOCl/I2. Use of 4 equiv of NIS
gave our desired pyrrolidinone 3a in 65% yield (entry 6). No
desired product was formed when water was employed as
solvent (entry 10). Low yields of 3a were obtained when
CH2Cl2 and THF were used as solvents (entries 11, 12). In the
t
presence of BuOCl/I2 and commercial acetonitrile, 3a was
obtained in 83% yield (entry 14). NIS, however, gave only a
19% yield under similar conditions (entry 15).
Table 2. Formation of Iodo-pyrrolidinones 3a
entry
R1
Me
R2
R3
yield (%)b
Figure 2. X-ray structure of 3e.
1
H
H
H
H
H
H
H
H
H
H
Me
Ph (a)
Bn (b)
83 (65)
65 (80)
70 (76)
45 (58)c
60 (40)
83 (82)
81 (94)
65
2
Me
Our success in transforming vinyl iodide 2 into iodo-
pyrrolidinones through sequential 5-endo halolactamiza-
tion and CꢀH oxidative functionalization prompted us to
further investigate the use of vinyl bromide 4 as the
substrate (Table 3). The bromo-pyrrolidinones 5 were ob-
tained in moderate-to-good yields when the reaction tem-
perature was increased to 50 °C. When N-phenyl amides
were used as substrates, the products could be further
3
Me
n-Bu (c)
p-OMeC6H4 (d)
p-NO2C6H4 (e)
Ph (f)
4
Me
5
Me
6
C4H9
C4H9
C4H9
C6H13
C6H13
C4H9
7
Bn (g)
8
n-Bu (h)
Ph (i)
9
78
10
11
Bn (j)
77
Ph (k)
51
a Method A: Substrate (1 equiv) was mixed with BuOCl (3 equiv)
and I2 (3 equiv) at room temperature for 4 h in CH3CN. Method B:
Substrate (1 equiv) was mixed with NIS (4 equiv) at room temperature
for 20 h in CH3CN/H2O (1:1). b Numbers in parentheses are the yields of
3 using method B. c The reaction was run for ca. 48 h.
t
Scheme 1. Miscellaneous Alkenyl Amide Reactions
Table 3. Formation of Bromo-pyrrolidinones 5a
entry
R1
R2
yield (%)
1
2
3
4
C4H9
Me
Ph (a)
Ph (b)
Bn (c)
n-Bu (d)
40b
36b,c
58
Me
Me
63
a Substrate (1 equiv) was mixed with NBS (4 equiv) at 50 °C for 10 h n
CH3CN/H2O (1:1). b The derivative with a bromo substitution at the para
position of the phenyl group was obtained. c 20% of the starting material
was recovered.
We next studied the scope and limitation of the halo-
lactamization/CꢀH oxidative functionalization reaction
1384
Org. Lett., Vol. 15, No. 6, 2013

Scheme 2. Application of Vinyl Iodo Amides
Scheme 3. Proposed Mechanism for Formation of 3
function as intermediates, 3a was subjected to standard
Suzuki coupling conditions,19 and the corresponding cou-
pling product 9 was obtained in good yield. Applying the
PictetꢀSpengler condensation reaction to 10 allowed the
construction of a second ring in one step and afforded
compound 11, which contains the core structure of the
alkaloid crispine A.20
We propose the mechanism for the formation of 3 in
Scheme 3. First, electrophilic attack by Iþ on the olefin gives
iodonium species 12. Then, closure through the amide nitro-
gen gives the lactam 13. Elimination of hydrogen iodide
generates enamide 14, which undergoes allylic oxidative
functionalization to yield intermediate 15. Quenching the
functionalization with water affords iodo-pyrrolidinone 3.
In summary, we have developed a practical, efficient,
and rapid process for the synthesis of halo-pyrrolidinones.
These products readily undergo cross-coupling reactions
or PictetꢀSpengler condensation to afford useful synthetic
intermediates.
converted to the para-bromo-substituted derivatives 5a and
5b in moderate yields. Running the reactions at room
temperature gave only trace amounts of the desired products.
Using vinyl bromide 4a as a substrate gave the unsepa-
rated products 3fand bromo-pyrrolidinone 5a0 in 36% and
6% yield. For comparison, we repeated the above reaction
conditions using compounds 6 and 7 as the substrates
(Scheme 1). These gave rise to messy reactions with
tBuOCl/I2, and no identifiable products could be isolated.
Our results indicate that the halogen atom in 2 does not act
simply as a substituent but plays a crucial role in the
reaction. When trans-2a or 2f was employed as the substrate
in the reaction with tBuOCl/I2, the reaction was sluggish and
the substrate decomposed after prolonged stirring. Using
the N-hydrogen substituted substrate 2l gave the corre-
sponding compound 3l in moderate yield. When the sub-
strate was an N-tert-butyl-substituted amide, the product 8
was obtained in good yield. Using a substrate with a more
crowded structure led to the cyclic intermediate 3m.
Acknowledgment. This project was supported by the
National Natural Science Foundation of China (21172169).
We thank Professors Chaozhong Li (SIOC), Jianhui Huang
(TJU), and Richard P. Hsung (UW-Madion) for invaluable
discussions.
The halo-pyrrolidinones can be used as synthetic inter-
mediates as illustrated in Scheme 2. The presence of the
vinylic halogen makes possible numerous cross-coupling
reactions catalyzed by transition metals. To demonstrate
that the compounds prepared with our method can
Supporting Information Available. Detailed experimen-
1
tal procedures, characterization data, copies of H and
13C NMR spectra for all products, and X-ray crystal-
lographic data for 3e. This material is available free of
charge via the Internet at http://pubs.acs.org.
(19) Zhou, X. B.; Zhang, H. M.; Xie, X.; Li, Y. Z. J. Org. Chem. 2008,
73, 3958.
(20) Chiou, W. H.; Lin, G. H.; Hsu, C. C.; Chaterpaul, S. J.; Ojima, I.
Org. Lett. 2009, 11, 2659.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
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