Aryl radical cyclizations of N-(2-halobenzoyl)-cyclic ketene-N,S-acetals

Article abstract of DOI:10.1016/j.tetlet.2005.03.205

2-Ethylthiazolines react with 2-halobenzoyl chlorides to form N-(2-halobenzoyl)-cyclic ketene-N,S-acetals, which undergo stereo-controlled radical cyclizations to afford (R,S,S)-3-alkyl-10-methyl-2,3,10,10a- tetrahydrothiazolo[3,2-b]isoquinolin-5-one and (R,R,S)-3-alkyl-10-methyl-2,3,10, 10a-tetrahydrothiazolo[3,2-b]isoquinolin-5-one.

Full text of DOI:10.1016/j.tetlet.2005.03.205

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3801–3805
Aryl radical cyclizations of N-(2-halobenzoyl)-cyclic
ketene-N,S-acetals
Aihua Zhou* and Charles U. Pittman, Jr.*
Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA
Received 1 March 2005; accepted 30 March 2005
Available online 14 April 2005
Abstract—2-Ethylthiazolines react with 2-halobenzoyl chlorides to form N-(2-halobenzoyl)-cyclic ketene-N,S-acetals, which
undergo stereo-controlled radical cyclizations to afford (R,S,S)-3-alkyl-10-methyl-2,3,10,10a-tetrahydrothiazolo[3,2-b]isoquinolin-
5-one and (R,R,S)-3-alkyl-10-methyl-2,3,10,10a-tetrahydrothiazolo[3,2-b]isoquinolin-5-one.
Ó 2005 Elsevier Ltd. All rights reserved.
In recent years, there has been considerable interest in
the cyclization of radicals onto heterocyclic com-
pounds.1,2 Important synthetic routes to prepare various
heterocycles and many new methodologies have been
developed. Normally, radical cyclizations generate a
mixture of five- and six-membered ring compounds.3,4
The product ratio obtained depends on the structure
of the initiator and reactants as well as the reaction con-
ditions.5–7
R
X = Br, I
X
CH3
S
CH3
S
X
N
R
Benzene, Et3N
RT
N
+
Cl
O
O
R1
R1
2
1
Scheme 1. Reaction of 2-ethylthiazolines
chlorides
1 with 2-halobenzoyl
Cyclic ketene-N,S-acetal chemistry has been actively
investigated in our laboratory,8 but radical cyclizations
onto cyclic ketene-N,S-acetals as a route to heterocyclic
structures remains unreported. Radical cyclizations
onto electron-rich enamines are known.9 Cyclic ketene-
N,S-acetals are more electron-rich agents than enam-
ines. They simultaneously combine both enamine and
vinyl thioether functions, which enhance the p-electron
density at the double bond and also provide two hetero-
atoms when converted to a cyclization product.10 Many
classes of ketene acetals are extremely reactive and diffi-
cult to handle, which probably accounts for their less
frequent application in organic synthesis. While im-
proved handling and storage methods have been devel-
oped,8 the generation of cyclic ketene-N,S-acetals as
intermediates and their subsequent use in nucleophilic
cyclization reactions10 suggests they may be more
broadly applicable in synthesis.
We now find that 2-ethylthiazolines 1 readily react with
2-halobenzoyl chlorides to afford N-(2-halobenzoyl)-
cyclic ketene-N,S-acetals 2 in excellent yields (Scheme
1) in benzene at room temperature. Furthermore, these
N-(2-halobenzoyl)-cyclic ketene-N,S-acetals serve as
Table 1. The synthesis of 2-ethyloxazolines
CH3
(1) CH3CH2COCl
Et3N, CH2Cl2
H2N
R1
OH
O
H2N
R1
OH
NaBH4, I2
THF
N
S
(2) P2S5, Mineral oil
4
R1
3
4
1
Keywords: Radical cyclization; Cyclic ketene-N,S-acetals; 2-Alkyl-
thiazolines; Stereoselective cyclization; Tetrahydrothiazolo[3,2-b]iso-
quinolin-5-one.
Entry
R1 in 3
Product 1
Yielda (%)
1
2
–CH(CH3)2
–CH2CH(CH3)2
1a
1b
60
63
*
Corresponding authors. Tel.: +1 6623257616; fax: +1 6623257611;
e-mail: cpittman@ra.msstate.edu
a All are isolated yields based on 3.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.205

3802
A. Zhou, C. U. Pittman, Jr. / Tetrahedron Letters 46 (2005) 3801–3805
Table 2. Aryl radical cyclization of N-2-halobenzoyl cyclic ketene-N,S-acetalsa
R
R
R
CH3
X
H
H
CH3
H
CH3
H
R
S
R
R
AIBN, Bu3SnH
+
N
S
Benzene
O
O
N
N
O
S
S
S
R1
S
S
R1
R1
2
5
6
N-2-Halobenzoyl cyclic
ketene-N,S-acetal 2
Product 1
Product 2
Yieldb (5+6) (%)
H
H
CH3
S
Br
N
CH3
H
CH3
78
Ratio of
5a/6a = 1.4/1
H
S
2a
6a
N
S
N
O
5a
O
O
CH3
CH3
CH3
CH3
CH3
CH3
H
H
CH3
S
I
CH3
CH3
H
H
S
N
82
Ratio of
5a/6a = 1.5/1
6a
2b
N
S
O
5a
N
O
O
CH3
CH3
CH3
CH3
CH3
CH3
H
H
CH3
S
Br
N
CH3
CH3
H
H
2c
6b
5b
70
Ratio of
5b/6b = 1.1/1
N
S
N
S
O
O
O
CH3
CH3
CH3
CH3
CH3
CH3
H
H
CH3
S
I
CH3
H
CH3
H
S
N
6b
5b
2d
68
Ratio of
5b/6b = 1.3/1
N
N
S
O
O
O
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
CH3
Br
CH3
CH3
77
Ratio of
5c/6c = 1.5/1
H
S
H
S
6c
5c
2e
N
S
N
O
N
O
O
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
CH3
S
Br
N
H
CH3
CH3
H
H
67
Ratio of
5d/6d = 1.2/1
5d
2f
6d
N
S
O
N
S
O
O
CH3
CH3
CH3
CH3
CH3
CH3

A. Zhou, C. U. Pittman, Jr. / Tetrahedron Letters 46 (2005) 3801–3805
3803
Table 2 (continued)
N-2-Halobenzoyl cyclic
ketene-N,S-acetal 2
Product 1
Product 2
Yieldb (5+6) (%)
CH3O
CH3O
CH3
H
CH3O
Br
N
H
CH3
CH3
79
Ratio of
5e/6e = 1.4/1
H
S
H
S
S
2g
6e
5e
N
N
O
O
O
CH3
CH3
CH3
CH3
CH3
CH3
a The mole ratio of 2/Bu3SnH/AIBN used was 10/10/1. Reactions were refluxed in dry benzene under argon for 10 h.
b Isolated yields based on 1.
precursors for aryl radical cyclizations. The facile
formation of cyclic ketene-N,S-acetal double bonds
shown in Scheme 1, may be followed immediately by
an aryl radical cyclization with no need for further
purification of 2. In addition, by initially building a
stereogenic center at C-4 of these 2-ethylthiazolines 1,
the N-(2-halobenzoyl)-cyclic ketene-N,S-acetal formed
by N-benzoylation can then undergo stereocontrolled
radical cyclization.
cyclizations. These cyclizations occurred in good yields
in refluxing benzene (Table 2).
The suggested cyclization mechanism (Scheme 2) illus-
trates two pathways that appear possible. Initially
formed radical 7 would lead to either radical intermedi-
ate 8 or 10. Radical 8 would generate five-membered
ring compound 9 by hydrogen abstraction from
Bu3SnH, while radical 10 would produce six-membered
ring compound 5/6. Radical 7 was found to cyclize only
to the more stable tertiary radical 10 rather than the less
stable secondary radical 8. Therefore, this afforded the
less strained 6/5 ring products 5 and 6 upon hydrogen
abstraction from Bu3SnH. The more strained 5/5 ring
fusion product 9 could not be detected. Cyclization to
8 followed by rearrangement to 10 seems highly unli-
kely, because this would lead to the generation of both
R- and S-configurations of C-10 in product 5 and 6.
Only the R-configuration was formed.
The synthesis of 2-ethylthiazolines with a stereogenic
center at C-4 proceeds as shown in Table 1. Amino acids
3 (S-configuration) were reduced by NaBH4–I2 in THF
to give amino alcohols 4.11 These were treated with acid
chlorides to afford the corresponding hydroxyamides,
which were converted to 2-ethylthiazolines 1 with
P2S5.12
We recently reported that 2-alkylthiazolines react with
acid chlorides to afford N-acyl cyclic ketene acetals.13
N-(2-Halobenzoyl)-cyclic
ketene-N,S-acetals
were
1H, 13CNMR, GC–MS, DEPT135, HETCOR, and
NOESY verified the structures of 5/6. This cyclization
reaction could have given a mixture of four different dia-
stereomers. The aryl radical could possibly have
attacked the exocyclic double bond in 2 either cis or
trans to the C-4 isopropyl group. Then, hydrogen
abstraction by radical 10 could have occurred either
formed analogously in excellent yields using 2-halo-
benzoyl chlorides where the halogen is bromide or
iodide (Scheme 1). After the removal of triethylamine
and benzene from the product mixture by rotary evapo-
ration, these crude N-(2-halobenzoyl)-cyclic ketene-N,S-
acetals 2 were used without further workup in radical
R
X = Br, I
R
R
CH3
X
CH3
Bu3Sn
CH CH3
S
Bu3SnH (2 equiv)
AIBN, PhH
N
S
N
N
S
O
O
rearrangement
O
R1
R1
R1
8
2
7
10
CH3
S
Bu3SnH
R
R
R
N
O
10
10
CH3
CH3
S
R1
Bu3SnH
CH2 CH3
H
11
N
S
N
N
S
O
O
O
R1
R1
R1
9
10
5/6
Scheme 2. Possible aryl radical cyclizations of N-2-halobenzoyl cyclic ketene-N,S-acetals.

3804
A. Zhou, C. U. Pittman, Jr. / Tetrahedron Letters 46 (2005) 3801–3805
Acknowledgements
H
Partial support of this work by the National Science
Foundation, Grant No. EPS 012618 and by Mississippi
State University is acknowledged. Dr. E. A. Alley is
thanked for obtaining the mass spectra in the Supple-
mentary data.
H3C
H
H
10
CH3
10
S
H
H
S
H
N
H
H
3
N
3
C3H7
O
H
C3H7
H
O
Supplementary data
5a
6a
Scheme 3. Selected NOESY correlations for compounds 5a and 6a.
The detailed synthetic and isolation procedures and the
full spectral identification of all compounds are pro-
vided in Supplementary data. Supplementary data asso-
ciated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2005.03.205.
cis or trans to the C-4 isopropyl function. HPLC and
NMR data demonstrated that only two cyclization
products 5 and 6 were formed, and these were the major
products. These are given in Table 2. NOESY experi-
ments definitively determined the stereochemistry of 5
and 6. The methyl group on the central ring was trans
to the isopropyl group of the oxazolidine ring in
each case, confirming that aryl radical attack occurred
trans to the isopropyl group as 2 was converted to 10.
Radical 10 abstracted hydrogen from Bu3SnH both
trans and cis to the isopropyl group to generate 5/6a–e
(Scheme 3).
References and notes
1. (a) Giese, B. Radicals in Organic Synthesis: Formation of
Carbon–Carbon Bonds; Pergamon: Oxford, 1986; (b)
Curran, D. P. In Comprehensive Organic Synthesis; Trost,
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Radical Chain Reactions in Organic Synthesis; Academic:
London, 1992; (d) Giese, B. et al. Org. React. 1996, 48,
301.
2. (a) Leffler, J. E. An Introduction to Free Radicals; Wiley-
Interscience: New York, 1995; (b) Fossey, J.; Lefort, D.;
Sorba, J. Free Radicals in Organic Chemistry; Wiley: New
York, 1995; (c) Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions; VCH: Weinheim,
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3. (a) Beckwith, A. L. J.; OÕShea, D. M. Tetrahedron Lett.
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Chem. 1987, 52, 4072; (b) Snieckus, V.; Cuevas, J. C.;
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Polym. Sci. 1998, 2, 467; (b) Zhu, P. C.; Pittman, C. U., Jr.
J. Polym. Sci., Part A: Polym. Chem. 1996, 34, 169; (c)
Liu, Y.; Pittman, C. U., Jr. J. Polym. Sci., Part A: Polym.
Chem. 1997, 35, 3655; (d) Zhu, P. C.; Lin, J.; Pittman, C.
U., Jr. J. Org. Chem. 1995, 60, 5729; (e) Wu, Z.; Stanley,
R. R.; Pittman, C. U., Jr. J. Org. Chem. 1999, 64, 8386; (f)
Cao, L. Ph.D. Dissertation, Mississippi State University,
1999; (g) Li, H. MS, Thesis, Mississippi State University,
2005.
The selectivity of the hydrogen abstraction step by radi-
cal 10 is reduced by presence of the methyl group at the
10-position. The 3-isopropyl group hinders cis hydrogen
abstraction from Bu3SnH by 10. However, the 10-methyl
group hinders trans hydrogen abstraction, but it still re-
mains the dominant abstraction path. Studies of the
selectivity in the hydrogen abstraction step are underway
with (4S)-4-isopropyl-2-methylthiazoline, which will
generate an intermediate radical analogous to 10 with-
out the 10-methyl group. Furthermore, we have extended
analogous aryl radical cyclizations to cyclic ketene-
N,S-acetals generated from 2-alkylthiazines and
cyclic
ketene-N,O-acetals
formed
from
2-
alkyloxazolines.14
In conclusion, this is the first report where the electron-
rich double bond of a cyclic ketene-N,S-acetal was used
for radical cyclization. This very nucleophilic double
bond was produced by reacting 2-halobenzoyl chlorides
with 2-ethylthiazolines in presence of Et3N, and used in
the next cyclization step without isolation or purification
of the resulting ketene-N,S-acetal. The reactive (N-2-
halobenzoyl)-cyclic ketene-N,S-acetals are readily pre-
pared by the direct reaction of the corresponding benzoyl
chlorides and 2-ethylthiazolines. The stereogenic centers
in the starting materials control diastereoselectivity of
cyclization products. Studies of the selectivity in the
hydrogen abstraction step are underway with (4S)-4-iso-
propyl-2-methylthiazoline. The broad synthetic poten-
tial is evident from the ability to use both six- and
five-membered ring cyclic ketene-N,X-acetals (X =
S,O)14 and in analogy with stereoselective radical-medi-
ated cyclizations of norphedrine-derived a-iodoamides
to generate enantiopure pyrrolidines.15 A general experi-
mental procedure is provided.16
9. (a) Zhang, W.; Pugh, G. Tetrahedron 2003, 59, 3009; (b)
Jabin, I.; Netchitailo, P. Tetrahedron Lett. 2001, 42, 7823.
10. Zhou, A. H.; Pittman, C. U., Jr. Tetrahedron Lett. 2005,
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3805
11. Mckennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58,
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12. Richard, H. G.; Atkinson, E. R.; Granchelli, F. E.; Bruni,
R. J. J. Med. Chem. 1965, 8, 762.
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45, 8899.
14. (a) Zhou, A. H.; Njogu, M.; Pittman, C.U., Jr., unpub-
lished work; (b) Njogu, M. MS Thesis, Mississippi State
University, 2005.
15. (a) Belvisi, L.; Gennari, C.; Poli, G. Tetrahedron 1992, 48,
3945; (b) Belvisi, L.; Gennari, C.; Poli, G. Tetrahedron:
Asymmetry 1993, 4, 273.
16. General procedure of radical cyclization of cyclic ketene-
N,S-acetals: Bromobenzoyl chloride (220 mg, 1.00 mmol)
was added dropwise to a stirred solution of 2-ethylthia-
zolines 1a (157 mg, 1 mmol) and triethylamine (130 mg,
1.20 mmol) in benzene 40 mL at room temperature. Then
this solution was stirred for 3 h. The product mixture was
filtered and the solvent was removed by rotary evapora-
tion. Dry benzene (60 mL) was added to the crude residue.
Then Bu3SnH (0.36 mL, 1 mmol) and AIBN (17 mg,
0.1 mmol) were also added. The mixture was refluxed for
10 h and then the solvent was removed under reduced
pressure. The crude product was subjected to flash
chromatography on silica gel. 3-Isopropyl-10-methyl-
2,3,10,10a-tetrahydrooxazolo[3,2-b]isoquinolin-5-one was
obtained (191 mg, 78% (5+6)). The same procedure for
other aryl radical cyclization reactions.