Selenocyclizations: Control by Coordination and by the Counterion

Article abstract of DOI:10.1002/anie.200352884

Selective cyclizations of selenium electrophiles lead to either tetrahydrofurans or lactones (see scheme), depending on the counterions and additives. Modification of the selenium electrophiles allow selective cyclizations, irrespective of the reaction conditions applied.

Full text of DOI:10.1002/anie.200352884

Angewandte
Chemie
Cyclizations
obtained as mixtures of cis (2a, 3a) and trans isomers (2b,
3b). Only an X-ray crystallographic analysis of 3a (E = I)
allowed an unambiguous assignment.[10] The radical deiodin-
ation led to the same compound 3a (E = H) as the radical
deselenation of 3a with E = SePh. The ratios 2a/2b and 3a/3b
in all experiments described herein were determined by
Selenocyclizations: Control by Coordination and
by the Counterion**
Shaista S. Khokhar and Thomas Wirth*
1
integration of characteristic H NMR signals.
We observed that small amounts of additives can influ-
ence the course of selenenylation reactions.[11] The results of
selenocyclizations with phenylselenenyl triflate as electro-
phile in different solvents and with different additives are
shown in Table 1. Two main interactions influence the
Electrophilic selenenylation reactions of alkenes have been
used successfully to functionalize inactivated carbon–carbon
double bonds.[1] Stereoselective variants of this reaction with
chiral selenium electrophiles have been performed by numer-
ous research groups.[2,3] These reagents can also be employed
in cyclization reactions for the stereoselective synthesis of
different heterocyclic compounds.[4] This reaction continues
to draw attention, both from a methodological and synthetic
perspective, for the elaboration of highly functionalized
heterocyclic compounds. Different electrophilic selenium
reagents and a variety of reaction conditions have been
employed and recent reviews have highlighted the scope of
this general process.[3,5]
Table 1: Cyclizations of 1 with phenylselenenyl triflate (E=PhSe) and
additives.
Entry
Solvent
Additive
(10 equiv)
2a/2b
3a/3b
2/3[a]
Yield
[%]
1
2
3
4
5
6
7
8
9
Et2O
Et2O
Et2O
Et2O
CH2Cl2
MeCN
Et2O
Et2O
CH2Cl2
MeCN
–
49:51
13:87
27:73
0:100
33:67
46:54
53:47
47:53
41:59
49:51
72:28
81:19
64:36
77:23
73:28
50:50
100:0
–
75:25
63:37
89:11
27:73
43:57
84:16
88:12
100:0
75:25
63:37
83
67
76
58[c]
85
90
69
90
92
88
MeOH
BnOH[b]
H2O
MeOH
MeOH
PhCO2H
AcOH
AcOH
AcOH
The effect of counterions in selenenylations[2c,6] and the
interactions of selenium electrophiles with nearby hetero-
atoms have been reported previously,[7] but these observa-
tions do not yet allow for a conclusive picture. We recently
observed interesting effects of external nucleophiles on the
course of selenenylation reactions.[8] In order to probe in
which way different nucleophiles, solvents, and counterions
affect selenocyclizations, we synthesized alkene 1, which
contains two competing nucleophiles, an alcohol group, and a
carboxylic acid function.[9] We describe herein how the
interactions of nucleophiles, solvents, and counterions with
selenium electrophiles affect the direction of cyclization and
how selective cyclizations can be achieved.
76:24
65:35
10
[a] Tetrahydrofuran/lactone ratio. [b] Bn=benzyl. [c] This reaction was
very slow and (PhSe)2 was isolated in 25% yield.
cyclization. First, the selenium electrophile can interact with
the internal nucleophile of the unsaturated substrate, with the
alcohol group, or with the acid function. Second, there are
interactions between the electrophile and the external
nucleophile/additive or the solvent. Both interactions are
additionally influenced by the counterion.
Electrophilic 5-exo-cyclization of 1 can lead to either
tetrahydrofurans 2 or to lactones 3, depending on the
attacking nucleophile (Scheme 1). Unfortunately, NOE
experiments could not clarify the relative stereochemistry
because of overlapping signals in 2 and 3, which are both
An alcohol has a higher nucleophilicity than a carboxylic
acid, and the selenium electrophile coordinates to the
hydroxy group rather than to the carboxylic acid moiety of
the substrate. This interaction can, however, be dramatically
influenced by additives, as shown in Table 1 and is partially
overridden in cyclizations involving the triflate counterion. In
these latter cyclizations, the formation of the tetrahydrofur-
ans 2 is favored over the formation of the lactones 3. Only if
the electrophile–hydroxy group interaction is disturbed by the
addition of water, is 3 formed preferentially (Table 1,
entry 4). On the other hand, acetic acid, as a weakly
coordinating additive, tunes the reactivity of the electrophile
and the tetrahydrofurans 2 are formed highly selectively
(Table 1, entry 8). This seems to be a quite unique combina-
tion, as benzoic acid (Table 1, entry 7) or other additional
solvents (Table 1, entries 9 and 10) lead to the formation of a
considerable amount of lactones 3. In these examples, there
seems to be almost no coordination of the electrophile to the
carboxylic acid moiety of the substrate, because the cis and
trans isomers of the tetrahydrofuran 2 are formed in similar
amounts. A coordination to the carboxylic acid moiety should
have led to a preferred formation of the cis isomer 2a.[12]
Scheme 1. Electrophilic cyclization of 1 to tetrahydrofurans 2 and
lactones 3.
[*] S. S. Khokhar, Prof. Dr. T. Wirth
Department of Chemistry, Cardiff University
PO Box 912, Cardiff, CF10 3TB (UK)
Fax: (+44)29-2087-6968
E-mail: wirth@cf.ac.uk
[**] This work was supported by the EPSRC.
Angew. Chem. Int. Ed. 2004, 43, 631 –633
DOI: 10.1002/anie.200352884
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631

Communications
The outcome of the competitive selenocyclizations is
Forcing the additive to coordinate to the selenium
electrophile can be achieved in an intramolecular fashion,
which we already investigated theoretically.[7b] The selenium
electrophiles 6–10, generated from the corresponding disele-
nides,[14] were employed in the cyclization of 1 with and
without additional additives (Table 3). Using these modified
reagents, the additive now seems to have almost no influence
on the course of the cyclization, undoubtedly because of the
different when other counterions are involved. Whereas the
phenylselenenyl bromide and triflate yield mixtures of
tetrahydrofurans 2 and lactones 3 (Table 2, entries 1–3), the
Table 2: Selenocyclizations with the phenylselenenyl electrophile in
diethyl ether with different counterions.
Entry Reagent
Additive
(10 equiv)
2a/2b 3a/3b 2/3[a]
Yield
[%]
1
2
3
4
5
6
7
8
PhSeBr
–
–
20:80
49:51
13:87
0:100
–
0:100
42:58
–
63:37 54:46
72:28 75:25
81:19 63:37
84:16 14:86
74
83
67
70
PhSeOTf
PhSeOTf
PhSeBF4
PhSePF6
PhSePF6[b]
PhSePF6
(PhSe)2SO4
MeOH
MeOH
MeOH
MeOH
AcOH
MeOH
78:22
0:100 50
73:27 30:70
85
11
100:0
67:33
92:8
0:100 42
[c]
[a] Tetrahydrofuran/lactone ratio. [b] Reaction time 5.5 h instead of 2.5 h.
[c] This reaction was slow owing to the insolubility of Ag2SO4, and
starting material 1 (40%) was recovered. Tf=trifluoromethanesulfonyl.
Table 3: Selenocyclizations with different selenium electrophiles.
Entry Electrophile Additive
(10 equiv)
2a/2b
3a/3b
2/3[a]
Yield
[%]
corresponding hexafluorophosphate (Table 2, entry 5) or
sulfate (Table 2, entry 8) can be used to synthesize exclusively
the lactone 3 under the standard reaction conditions. Pro-
longed reaction times with phenylselenenyl hexafluorophos-
phate lead to the formation of small amounts of tetrahydro-
furan 2b (Table 2, entry 6). The addition of methanol
(10 equiv) in these reactions is important as its replacement
with acetic acid (10 equiv) leads to the formation of a mixture
of 2 and 3 in very low yield (Table 2, entry 7). As already
mentioned, the coordination of the selenium electrophile to
the hydroxy group of the substrate is stronger than to the
carboxylic acid moiety. Irrespective of the additive used, this
behavior is reflected in the cis/trans ratio (3a/3b) as
coordination to the alcohol moiety of 1 leads to the cis
lactone 3a as the major isomer.
We have developed conditions for highly selective cycli-
zations with the phenylselenenyl electrophile. The exclusive
formation of the tetrahydrofuran 2 can be achieved with the
triflate counterion with additional acetic acid (Table 1,
entry 8), whereas the cyclization can be also directed towards
complete formation of lactone 3 with the hexafluorophos-
phate or sulfate counterion with additional methanol
(Table 2, entries 5 and 8).
1
2
3
6
6
6
–
–
–
–
80:20
80:20
80:20
82:18
84:16
83:17
82:18
81:19
0:100 51[b]
0:100 40[b]
0:100 45[b]
MeOH
AcOH
–
4
7
32:68
33:67
52:48
50:50
25:75
24:76
–
46:54
52:48
49:51
41:59
44:56
50:50
89
99
45
74
79
91
5
6
7
7
7
8
MeOH
AcOH
–
8
9
10
12
11
8
8
9
10
11
MeOH
AcOH
MeOH
MeOH
MeOH
84:16
79[c]:21[d]
82[e]:18[f]
0:100 40[b]
0:100 68
–
30[g]:70[g] 85[h]:15[i] 50:50
77
[a] Tetrahydrofuran/lactone ratio. [b] This reaction was slow and a
considerable amount (24–27%) of diselenide was formed. [c] 69:31 d.r.
[d] 78:22 d.r. [e] 79:21 d.r. [f] 88:22 d.r. [g] d.r. not determined. [h] 88:12
d.r. [i] 89:11 d.r.
efficient coordination of the internal oxygen atoms in 6–8 to
the selenium electrophile. The cis/trans ratio (3a/3b) is
consistent in these reactions (Table 3, entries 1–9), indicating
again some interaction with the hydroxy group of 1. Electro-
philes 6 and 9 have very strong internal selenium–oxygen
coordination, which allows an exclusive synthesis of the
corresponding lactones 3, even with the triflate counterion
and irrespective of any additive (Table 3, entries 1–3, 10).
The coordination of the acid and ester moieties in 7 and 8,
respectively, is weaker, and mixtures of 2 and 3 are formed.
Chiral selenium electrophiles can also be used. With the
sterically less-hindered electrophile 9, exclusively lactone
formation was observed (Table 3, entry 10). The additional
methoxy group in 11 leads, as established earlier, to slightly
higher stereoselectivities, but also to a mixture of 2 and 3
owing to steric interactions.[15] There is a distinct difference in
the diastereoselectivities of the cis and trans isomers, which
was determined by radical cleavage of the selenium moiety
and subsequent analysis by HPLC. This further proves that
The cyclization of substrate 4[13] with phenylselenenyl
triflate in the presence of methanol (10 equiv) generates the
diastereomers 5a and 5b (60:40) albeit in lower yield (36%).
A preference for the cis isomer 5a is again observed
(Scheme 2).
Scheme 2. Cyclization of the alkene 4 to cis and trans tetrahydrofurans
5a and 5b.
632
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k) T. G. Back, Z. Moussa, M. Parvez, J. Org. Chem. 2002, 67,
the differential coordination of the alcohol or acid moiety of
the substrate 1 to the electrophile influences the face
selectivity of the reaction with the double bond.
499 – 509; l) M. Tiecco, L. Testaferri, C. Santi, C. Tomassini, F.
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Ed. 2000, 39, 3742– 3749.
Attempts to synthesize compound 12a failed because of
decomposition during selective reduction of 12b;[16] only a
[4] G. Fragale, T. Wirth, Eur. J. Org. Chem. 1998, 1361 – 1369.
[5] a) P. L. Beaulieu, R. DØziel in Organoselenium Chemistry (Ed.:
T. G. Back), Oxford University, Oxford, 1999, pp. 35 – 66; b) N.
Petragnani, H. A. Stefani, C. J. Valduga, Tetrahedron 2001, 57,
1411 – 1448.
[6] M. Gruttadauria, C. Aprile, R. Noto, Tetrahedron Lett. 2002, 43,
1669 – 1672.
complete reduction to 12c was successful. Various electro-
philes (I+, PhSe+, 9) led to cyclization products of 12c in yields
between 45 and 79% with cis/trans rations of about 10:90.
In conclusion, we were able to develop conditions for
nucleophile-selective electrophilic cyclizations. We have
shown that the cyclization can be dramatically influenced
and directed by the counterion and additives to the phenyl-
selenenyl electrophile, or by internal coordination with
hydroxy moieties.
[7] a) H. Komatsu, M. Iwaoka, S. Tomoda, Chem. Commun. 1999,
205 – 206; b) M. Spichty, G. Fragale, T. Wirth, J. Am. Chem. Soc.
2000, 122, 10914 – 10916; c) C. Aprile, M. Gruttadauria, M. E.
Amato, F. D'Anna, P. Lo Meo, S. Riela, R. Noto, Tetrahedron
2003, 59, 2241 – 2251.
[8] L. Uehlin, G. Fragale, T. Wirth, Chem. Eur. J. 2002, 8, 1125 –
1133.
[9] Alkene 1 was synthesized by reaction of 3-bromo-2-phenyl-
propene with the enolate of methyl 3-hydroxypropionate and
subsequent hydrolysis of the ester.
[10] CCDC-214760 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
[11] G. Fragale, T. Wirth, Chem. Eur. J. 1997, 3, 1894 – 1902.
[12] The energies of the tetrahydrofurans 2a and 2b and of the
lactones 3a and 3b are almost identical, as shown by ab initio
calculations at different levels (6-31G*, 6-311G*).
Experimental Section
Cyclization with selenium electrophiles:[4] In an inert atmosphere, the
diselenide (0.085 mmol) was dissolved in diethyl ether (3.5 mL),
cooled to À788C, and treated with bromine (0.085 mmol, 0.085 mL of
a 1m solution in CCl4). After 10 min, a solution of silver triflate
(0.24 mmol, 61 mg) in methanol (2 mmol, 80 mL) (or the correspond-
ing amount of a silver salt dissolved in 10 equiv of the additive used)
was added at À788C and stirred for 10 min. The mixture was treated
with the substrate (0.17 mmol) and stirred at À788C for 3 h followed
by 1 h at room temperature. The mixture was treated with sym-
collidine (0.13 mmol, 17 mL) and then with water (20 mL). After
extraction with tert-butyl methyl ether, the organic extracts were
combined, dried with MgSO4, and the solvent was evaporated to
produce a crude product, which was purified by flash column
chromatography on silica gel (tert-butyl methyl ether/petroleum
ether eluent).
[13] Alkene 4 was synthesized by reduction of 1 with lithium
aluminum hydride in 85% yield.
[14] a) 2,2’-diselenobisbenzyl alcohol: M. Iwaoka, S. Tomoda, Phos-
phorus Sulfur Relat. Elem. 1992, 67, 125 – 130; b) 2,2’-diseleno-
bisbenzoic acid: H. Rosenmund, Ber. Dtsch. Chem. Ges. 1920,
53, 2238; c) methyl 2,2’-diselenobisbenzoate: T. Onami, M.
Ikeda, S. S. Woodard, Bull. Chem. Soc. Jpn. 1996, 69, 3601 –
3605; d) (S,S)-bis[2-(1-hydroxypropyl)-phenyl] diselenides;[11]
e) (S,S)-bis-2-(1-methoxymethoxypropyl)phenyl] diselenide;[8]
f) (S,S)-bis[2-(1-hydroxyethyl)-6-methoxyphenyl] diselenides.[8]
[15] Although not yet determined, we assume, in analogy to earlier
experiments, that the structures shown in Scheme 1 represent
the absolute configurations of the major diastereomers.
[16] Compound 12b was synthesized by addition of carbon dioxide to
the enolate of methyl 5-phenyl-4-pentenoate.
Received: September 16, 2003 [Z52884]
Keywords: alkenes · electrophiles · heterocycles · selenium ·
.
stereoselective synthesis
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