Synthesis of enantiomerically pure β-azidoselenides starting from natural terpenes

Article abstract of DOI:10.1016/j.tet.2007.09.047

Several unsaturated natural terpenes have been easily converted, in good yields, into the corresponding enantiomerically pure β-azidoselenides by addition of the electrophilic selenium reagent PhSeOTf in the presence of sodium azide. These reactions are stereospecific anti additions, which occur with a Markovnikov orientation. Examples of the synthetic importance of these β-azidoselenides are also reported.

Full text of DOI:10.1016/j.tet.2007.09.047

Tetrahedron 63 (2007) 12373–12378
Synthesis of enantiomerically pure b-azidoselenides starting
from natural terpenes
*
*
Marcello Tiecco, Lorenzo Testaferri, Claudio Santi, Cristina Tomassini,
Stefano Santoro, Francesca Marini, Luana Bagnoli and Andrea Temperini
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Universitaꢀ di Perugia, Perugia I-06123, Italy
Received 25 July 2007; revised 5 September 2007; accepted 20 September 2007
Available online 26 September 2007
Abstract—Several unsaturated natural terpenes have been easily converted, in good yields, into the corresponding enantiomerically pure
b-azidoselenides by addition of the electrophilic selenium reagent PhSeOTf in the presence of sodium azide. These reactions are stereospecific
anti additions, which occur with a Markovnikov orientation. Examples of the synthetic importance of these b-azidoselenides are also reported.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
in good yields and with a very high level of facial selectivity.
This process was made possible by the use of chiral nonra-
cemic selenium reagents in the presence of sodium azide.8
Electrophilic reagents produced from enantiomerically
pure diselenides were previously employed also to effect
asymmetric hydroxy9 and methoxy selenenylations10 as
well as cyclofunctionalization reactions11 with very high
facial selectivity under very mild experimental conditions.
Organic azides are valuable synthetic intermediates.1 They
can be used in cycloaddition reactions, in the synthesis of
amine derivatives, and as precursors of nitrogen-containing
heterocycles and of nitrenes.2 The preparation of azido de-
rivatives has been considerably improved by the use of orga-
noselenium reagents to produce b-azidoselenides. These
products have a greater synthetic importance since they
combine the well known reactivity of the azido group with
that of the selenium containing group.3 b-Azidoselenides
can be conveniently prepared from alkenes by reaction
with an electrophilic organoselenium reagent, such as phe-
nylselenenyl halide or triflate, in the presence of sodium
azide. This addition reaction is regioselective (Markovni-
kov) and stereospecific (anti).4 Radical azidoselenenylation
of alkenes can also be effected. In this case the reactions are
initiated by the azido radicals, produced by oxidation of azi-
do anions with iodobenzene diacetate; the final products are
then formed by trapping the so-formed carbon radical with
diphenyl diselenide.5 Obviously, in this case the reaction is
not stereospecific and produces the anti-Markovnikov re-
gioisomers. Asymmetric synthesis of azido derivatives is
very rarely reported in the literature. They can involve dia-
stereoselective reaction of a preformed chiral center,6 or a de-
symmetrization reaction of meso-epoxides promoted by
chiral auxiliaries.7
2. Results and discussion
A different approach for the synthesis of enantiomerically
pure b-azidoselenides is now proposed starting from unsat-
urated natural terpenes. According to the ‘chiral pool ap-
proach’, terpenes can be considered as convenient starting
materials in asymmetric synthesis because they are commer-
cially available, not expensive, and generally easily accessi-
ble in both enantiomeric forms. Azidoselenenylation of
unsaturated terpenes can be obtained by treatment with
PhSeOTf 1 and NaN3 in dry MeCN at 0 ꢀC. In a typical ex-
periment, silver triflate (1.1 mmol) was added to a solution
of PhSeBr (1.0 mmol) in MeCN (2.5 mL) at 0 ꢀC and after
15 min NaN3 (1.0 mmol) was added. The reaction mixture
was stirred for 30 min and then 1.0 mmol of terpenes 2a–f
were added. The mixture was allowed to gradually reach
room temperature. The progress of the reaction was moni-
tored by TLC and GC–MS. The final mixture was filtered
through anhydrous K2CO3 and the filtrate was evaporated
under vacuum. b-Azidoselenides were then purified by flash
column chromatography. Reaction times, chemical yields,
and diastereomeric ratios are reported in Table 1.
Very recently, we reported the first example of an asymmet-
ric electrophilic azidoselenenylation of olefins, which occurs
* Corresponding authors. Tel.: +39 075 5855100; fax: +39 075 5855116
(M.T.); tel.: +39 075 5855112; fax: +39 075 5855116 (C.S.); e-mail
addresses: tiecco@unipg.it; santi@unipg.it
These results clearly indicate that the azidoselenenylation
reaction is a stereospecific trans addition, which occurs
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.047

12374
M. Tiecco et al. / Tetrahedron 63 (2007) 12373–12378
Table 1. b-Azidoselenides from the reaction of terpenes with PhSeOTf and
NaN3 in CH3CN at 0 ꢀC
was observed and two isomers 3c and 4c were obtained in
a ratio of 77:23.
Entry
Terpene
b-Azidoselenide
Time Yield
(h)
(%)
AgOTf
PhSeOTf + AgBr
1
PhSeBr
CH3CN
N3
SePh
1
24
60
-OTf
Ph
R'
R"
PhSe
*R
+
Se
3a
2a
R'
*R
H
H
N3
NaN3
1
N3
R''
3
*R
H
R'
SePh
CH3CN
R''
CH3CN
*R
R'
H
R''
*R
2
N3
H
2
24
65
Se
+
R'
R"
-OTf
PhSe
Ph
4
2b
3b
Scheme 1. The azidoselenenylation reaction.
SePh
N3
SePh
N3
H
H
H
H
Starting from the linear (À)-citronellal 2d (entry 4) an equi-
molar mixture of b-azidoselenides 3d and 4d has been
observed. This is not surprising if one considers that in 2d
the olefinic double bond to be attacked by the electrophile
is very far from the chiral center.
54 (3c)
16 (4c)
3
4
5
30
30
24
H
H
2c
4c
3c
The reaction with 2d was also performed using the enantio-
merically pure sulfur-containing reagent 6, generated in situ
by treatment of Ar*SeCl 5 with silver triflate (Scheme 2).
CHO
CHO
SePh
30 (3d)
30 (4d)
N3
2d
3d/4d
SMe
SeCl
SMe
AgOTf
CH3CN
+ AgCl
SeOTf
O
O
∗
6 = Ar SeOTf
5
45 (3e)
45 (4e)
SePh
CHO
CHO
N3
6
d.r 4:1
yield 60%
∗
2e
SeAr
3e/4e
NaN3
CH3CN
∗
N3
N3
SePh
SePh
SePh
N3
7d, 8d
2d
41 (3f)
41 (4f)
6
26
Scheme 2. Azidoselenenylation reaction promoted by Ar*SeOTf 6.
SePh
N3
3f
N3
4f
2f
From this reaction a mixture of compounds 7d and 8d was
obtained in 60% yield and in a 4:1 diastereoisomeric ratio.
In both cases the two diastereoisomers (3d, 4d and 7d, 8d)
could not be separated and the diastereomeric ratios were de-
termined from the proton NMR spectra of the crude reaction
mixtures and then confirmed after purification by column
chromatography.
regioselectively with Markovnikov orientation. As indicated
in Scheme 1, the reaction of terpenes 2 with phenyselenenyl
triflate 1 proceeds through the formation of a seleniranium
ion intermediate, which is then trapped by the azide anion
to afford addition products 3 and 4. With cyclohexene deriv-
atives 2a and 2b, as well as with 2f (entries 1, 2, and 6) the
ring opening of the seleniranium ion intermediate occurs to
give a trans diaxial addition product, a phenomenon, which
has been named Furst–Plattner rule.12 Thus, starting from
(+)-3-carene 2a (entry 1) and (+)-p-menth-1-ene 2b (entry
2) the azidoselenenylation reaction leads to the stereospe-
cific formation of compounds 3a and 3b, respectively, de-
rived from the attack of the electrophilic selenium reagent
from the less hindered face of the double bond. When the
addition occurs in an exocyclic olefin, as in the case of
(+)-aromadendrene (entry 3), a lower diastereoselectivity
In order to investigate the competition between two carbon–
carbon double bonds present in the molecule, azidoselene-
nylation reactions were then carried out on (R)-(À)-carvone
2e and (R)-(+)-limonene 2f. In the first case, as a conse-
quence of the conjugation of the endocyclic double bond
with the carbonyl group, the electrophilic reagent reacted
only with the terminal double bond affording the two diaste-
reoisomers 3e and 4e in a 1:1 ratio and in 90% yield.
The reaction of 2e with NaBH4 in MeOH proceeded
stereospecifically and afforded allylic alcohol 9.13 Under
the experimental conditions described above, the

M. Tiecco et al. / Tetrahedron 63 (2007) 12373–12378
12375
NHCOR
SePh
NH2
SePh
azidoselenenylation reaction did not afford the azidoselene-
nylation product but afforded the two diastereoisomeric
cyclic ethers 10 arising from an intramolecular cyclofunc-
tionalization reaction (Scheme 3).
N3
SePh
Ph3P, H2O
Ph3P, H2O
RCOCl
11
2a
12 R = Me
13 R = Ph
OH
O
PhSeOTf
NaN3
NaBH4
MeOH
O
Scheme 5. Examples of the elaboration of the azido group.
SePh
as good starting materials for the synthesis of enantiomeri-
cally pure oxazolines, thiazolines, and aziridines.8 Further
elaborations can be effected on the phenylseleno group.3
2e
Scheme 3. The cyclization of allylic alcohol 9.
9
10
Finally, in the case of (R)-(+)-limonene 2f, the reaction of
0.5 mmol of 1 with 0.5 mmol of terpene in the presence of
NaN3 produced a mixture of the mono- and the bis-addition
derivatives in a ratio of 4:1 indicating that the attack of the
electrophile on the two different double bonds proceeds
with a similar rate. The reaction was therefore repeated using
double the amount of selenenylating reagent. From this
experiment the two diastereoisomers 3f and 4f were obtained
in good yield and in a 1:1 ratio. As observed in the case of (+)-
3-carene (entry 1) and (+)-p-menth-1-ene (entry 2) the azido-
selenenylation of the endocyclic double bond is stereospecific
and the isomers 3f and 4f are the results of a regiospecific but
not stereospecific addition to the second double bond.
3. Conclusion
In conclusion, the results reported in this paper illustrate a con-
venient approach for the synthesis of enantiomerically pure
b-azidoselenides, using as chiral substrates some natural
olefins, which are easily accessible and which are able to pro-
duce a good stereocontrol on the addition of the electrophilic
selenium reagents to the carbon–carbon double bond.
4. Experimental section
4.1. General
The absolute configurations of the chiral centers generated
during the azidoselenenylation and reported in Table 1
were assigned by proton NMR spectroscopy on the basis
of the values of the coupling constants, and were then con-
firmed by some NOE correlations. These are summarized
in Scheme 4.
All new compounds were fully characterized by 1H and 13
C
NMR, mass, and IR spectroscopies. 1H and 13C NMR spec-
tra were recorded at 400 and 100.62 MHz, respectively, on
a Bruker Avance-DRX 400 instrument. Unless otherwise
specified, CDCl3 was used as the solvent and TMS as inter-
nal standard. GC–MS analyses were carried out with an
HP-6890 gas chromatograph (dimethyl silicone column,
12.5 m) equipped with an HP-5973 mass-selective detector.
IR spectra were recorded on a JASCO FT/IR-410 spectro-
photometer using a multiple reflection horizontal ATR
(HATR) accessory. Optical rotations were measured with
a JASCO DIP-1000 digital polarimeter.
Examples of the possible synthetic uses of b-azidoselenides
described above are illustrated in Scheme 5. Using classical
procedures, compound 2a was transformed into enantio-
merically pure b-aminoselenide 11, and into b-amidosele-
nides 12 and 13. As previously reported for similar
b-amidoselenide compounds, 12 and 13 can be employed
4.2. Azidoselenenylation: general procedure
N3
H
SePh
H
SePh
The azidoselenenylation experiments were carried out as
follows: AgOTf (258 mg, 1.1 mmol) was added to a solution
containing PhSeBr (236 mg, 1 mmol) in dry CH3CN
(2.5 mL) at 0 ꢀC. After 15 min, NaN3 (65 mg, 1 mmol)
was added and the reaction mixture was stirred at the same
temperature for additional 30 min observing the progressive
change of the mixture color from orange to pale yellow.
Then, alkenes 2a–f or 9 (1.0 mmol) was added and the
mixture was allowed to gradually reach room temperature.
The progress of the reaction was monitored by TLC and
GC–MS. The reaction mixture was filtered through an-
hydrous K2CO3 and the filtrate was concentrated under vac-
uum. The reaction products were isolated by flash column
chromatography on silica gel. The eluant employed and
the physical and spectral data of products 3a–f and 4c–f
are reported below.
Me
H
H
H
H3C
noe
N3
CH3
noe
3b
3a
PhSe
N3
noe
H
H
H
H
CH3
H3C
3c
PhSe
PhSe
H
H
H
CH3
H
CH3
N
H
N
3
3
H
CH3
CH2
SePh
N3
N3
noe
noe
CH3
PhSe
3f
4f
4.2.1. ((1S,3R,4R,6R)-4-Azido-4,7,7-trimethylbicy-
clo[4.1.0] heptan-3-yl)(phenyl)selane 3a. It was purified
Scheme 4. Nuclear Overhauser effects.

12376
M. Tiecco et al. / Tetrahedron 63 (2007) 12373–12378
by flash column chromatography (1% Et2O/petroleum ether)
to give the title compound 3a (200 mg, 60%) as colorless oil;
Rf (2% Et2O/petroleum ether) 0.64; [a]2D6.0 À12.2 (c 1.25,
CHCl3); n (N3) (HATAR) 2092.87 cmÀ1; dH (400 MHz,
CDCl3) 7.60–7.55 (2H, m, Ar–H), 7.30–7.20 (3H, m,
Ar–H), 3.20 (1H, dd, J 7.2, 12.1 Hz, CHSe), 2.25–2.18
(2H, m, CH2), 2.15–2.10 (1H, m, CHH), 1.45 (3H, s,
CH3), 1.45–1.40 (1H, m, CHH), 1.00 (3H, s, CH3), 0.95
(3H, s, CH3), 0.85 (1H, dt, J 4.7, 9.5 Hz, CHC), 0.65 (1H,
dd, J 8.0, 9.5 Hz, CHC); dC (100 MHz, CDCl3) 135.0,
130.0, 129.4, 127.9, 64.2, 51.9, 33.2, 29.0, 28.7, 20.7,
19.3, 19.2, 18.4, 15.7. Anal. Calcd for C16H21N3Se: C,
57.48; H, 6.33; N, 12.57. Found: C, 56.97; H, 6.29; N, 12.68.
40.8, 36.5, 36.3, 35.0, 30.1, 29.7, 29.0, 28.9, 28.8, 27.2,
21.6, 16.6, 16.5. Anal. Calcd for C21H29N3Se: C, 62.67; H,
7.26; N, 10.44. Found: C, 62.20; H, 7.23; N, 10.50.
4.2.5. (S)-7-Azido-3,7-dimethyl-6-(phenylselenenyl)octa-
nal (3d/4d). They were purified by flash column chromato-
graphy (10% Et2O/petroleum ether) to give a mixture of
compounds 3d and 4d (212 mg, 60%) as colorless oil; Rf
(20% Et2O/petroleum ether) 0.50 (3d) 0.49 (4d); some
spectral data were assigned from enriched fractions of 3d
and 4d.
Main signals for the enriched fraction of 3d: n (N3) (HATAR)
2093.35 cmÀ1; n (CHO) 1723.09 cmÀ1; dH (400 MHz,
CDCl3) 9.76 (1H, t, J 2.3 Hz, CHO), 7.60–7.50 (2H, m,
Ar–H), 7.30–7.20 (3H, m, Ar–H), 2.92 (1H, t, J 9.1 Hz,
CHSe), 2.45–2.40 (1H, m, CHH–CHO), 2.25–2.20 (1H, m,
CHH–CHO), 2.10–2.00 (1H, m, CH–CH3), 2.00–1.90 (1H,
m, CHH), 1.90–1.80 (1H, m, CHH), 1.65–1.40 (2H, m,
CH2), 1.45 (3H, s, CH3), 1.39 (3H, s, CH3), 0.98 (3H, d,
J 6.3 Hz, CH–CH3); dC (100 MHz, CDCl3) 203.0, 134.5,
131.6, 129.6, 127.9, 66.4, 59.3, 51.0, 36.4, 29.7, 28.5,
4.2.2. ((1S,2S,5R)-2-Azido-5-isopropyl-2-methylcyclo-
hexyl) (phenyl)selane (3b). It was purified by flash column
chromatography (1% Et2O/petroleum ether) to give the title
compound 3b (219 mg, 65%) as colorless oil; Rf (2% Et2O/
petroleum ether) 0.50; [a]2D0.3 +69.5 (c 063, CHCl3); n (N3)
(HATAR) 2099.14 cmÀ1; dH (400 MHz, CDCl3) 7.75–7.50
(2H, m, Ar–H), 7.50–7.30 (3H, m, Ar–H), 3.46 (1H, td, J
3.5, 2.5, 2.5 Hz, CHSe), 1.90–1.30 (8H, m, 3CH2 and
2CH), 1.5 (3H, s, CH3), 0.90 (3H, d, J 6.5 Hz, CH3CH),
0.86 (3H, d, J 6.5 Hz, CH3CH); dC (100 MHz, CDCl3)
134.8, 130.9, 129.4, 128.1, 65.9, 53.1, 38.9, 33.6, 32.9,
32.4, 26.7, 25.2, 20.3, 20.2, 20.1; GC–MS m/z (relative in-
ꢁ
26.1, 24.1, 20.7; MS m/z (relative intensity): 353 (5) [M+ ],
351 (2), 307 (3), 269 (3), 216 (7), 191 (37), 168 (100), 157
(53), 111 (32), 93 (50), 81 (26), 69 (41), 56 (68).
ꢁ
tensity): 337 (10) [M+ ], 309 (4), 266 (4), 228 (7), 157
Main signals for the enriched fraction of 4d: n (N3) (HATAR)
2093.77 cmÀ1; n (CHO) 1722.89 cmÀ1; dH (400 MHz,
CDCl3) 9.70 (1H, t, J 2.2 Hz, CHO), 7.60–7.50 (2H, m,
Ar–H), 7.30–7.20 (3H, m, Ar–H), 2.91 (1H, t, J 8.8 Hz,
CHSe), 2.40–2.25 (2H, m, CH2–CHO), 2.10–2.00 (1H, m,
CH–CH3), 1.80–1.70 (2H, m, CH2), 1.65–1.40 (2H, m,
CH2), 1.45 (3H, s, CH3), 1.40 (3H, s, CH3), 0.96 (3H, d,
J 6.3 Hz, CH–CH3); dC (100 MHz, CDCl3) 202.9, 134.5,
131.6, 129.4, 127.9, 66.4, 59.1, 51.6, 36.1, 29.5, 28.1,
26.1, 24.2, 19.7.
(18), 125 (25), 110 (40), 95 (18), 81 (26), 69 (100), 55 (64).
4.2.3. (((1aS,4R,4aR,7R,7aS,7bR)-4-Azido-1,1,7-tri-
methyldecahydro-1H-cyclopropa[e]azulen-4-yl)methyl)-
(phenyl)selane (3c). It was purified by flash column
chromatography (cyclohexane) to give the title com-
pound 3c (218 mg, 54%) as colorless oil; Rf (cyclohexane)
0.20; [a]2D6.0 À81.1 (c 2.40, CHCl3); n (N3) (HATAR)
2096.24 cmÀ1; dH (400 MHz, CDCl3) 7.60–7.55 (2H, m,
Ar–H), 7.25–7.20 (3H, m, Ar–H), 3.17 (1H, dd, J 1.9,
12.4 Hz, CHHSe), 3.08 (1H, dd, J 12.4 Hz, CHHSe), 2.44
(1H, dd, J 6.9, 13.6 Hz, CH), 2.31 (1H, ddd, J 6.9, 8.3,
9.3 Hz, CH), 2.05 (1H, ddt, J 6.9, 13.6, 15.5 Hz, CHH),
1.88 (1H, ddt, J 6.2, 8.3, 12.7 Hz, CHH), 1.70–1.65 (1H,
m, CHCH3), 1.75–1.30 (5H, m, 3CHH and CH2), 1.03
(3H, s, CH3CCH3), 0.96 (3H, d, J 7.1 Hz, CH3), 0.95 (3H,
s, CH3CCH3), 0.78 (1H, dt, J 11.2, 15.2 Hz, CHH), 065
(1H, dt, J 5.8, 9.1 Hz, CH), 0.59 (1H, dd, J 9.1, 10.5 Hz,
CH); dC (100 MHz, CDCl3) 147.0, 133.9, 129.5, 127.6,
69.3, 55.2, 39.8, 37.0, 36.9, 34.9, 32.2, 28.9, 28.7, 27.0,
26.9, 20.6, 19.9, 16.3, 16.2. Anal. Calcd for C21H29N3Se:
C, 62.67; H, 7.26; N, 10.44. Found: C, 63.17; H, 7.32; N,
10.38.
4.2.6. (R)-5-(2-Azido-1-(phenylselenenyl)propan-2-yl)-2-
methylcyclohex-2-enone (3e/4e). They were purified by
flash column chromatography (10% Et2O/petroleum ether)
to give a 1:1 mixture of compounds 3e and 4e (314 mg,
90%) as colorless oil; Rf (20% Et2O/petroleum ether) 0.36;
n (N3) (HATAR) 2096.73 cmÀ1; n (CO) 1820.00 cmÀ1; dH
7.70–7.60 (4H, m, Ar–H), 7.45–7.30 (6H, m, Ar–H), 6.80–
6.75 (2H, m, 2CH]), 3.70 (1H, d, J 12.3 Hz, CHHSe),
3.66 (1H, d, J 12.1 Hz, CHHSe), 3.42 (1H, d, J 12.3 Hz,
CHHSe), 3.41 (1H, d, J 12.1 Hz, CHHSe), 2.80–2.30
(10H, m), 1.78 (6H, s, 2CH3), 1.80 (3H, s, CH3), 1.30 (3H, s,
CH3); some 13C NMR signals were assigned from enriched
fraction of 3e and 4e: compound 3e dC 199.5, 144.8, 139.1,
135.8, 129.8, 129.6, 125.8, 59.7, 52.7, 41.8, 40.9, 28.9, 23.8,
16.0; compound 4e dC 199.4, 144.9, 139.1, 135.8, 129.8,
129.6, 125.8, 59.7, 52.7, 41.9, 40.6, 28.5, 23.4, 16.1. Anal.
Calcd for C16H19N3OSe: C, 55.17; H, 5.50; N, 12.06. Found:
C, 55.56; H, 5.48; N, 12.16.
4.2.4. (((1aS,4S,4aR,7R,7aS,7bR)-4-Azido-1,1,7-tri-
methyldecahydro-1H-cyclopropa[e]azulen-4-yl)methyl)-
(phenyl)selane (4c). It was purified by flash column chro-
matography (cyclohexane) to give the title compound 4c
(64 mg, 16%) as colorless oil; Rf (cyclohexane) 0.30 [a]D27.5
À18.8 (c 2.50, CHCl3); n (N3) (HATAR) 2090.30 cmÀ1; dH
(400 MHz, CDCl3) 7.60–7.50 (2H, m, Ar–H), 7.30–7.20
(3H, m, Ar–H), 3.94 (1H, d, J 12.0 Hz, CHHSe), 3.22 (1H,
d, J 12.0 Hz, CHHSe), 2.20–1.95 (3H, m, 3CH), 1.85–1.40
(8H, m, 4CH2), 1.14 (3H, s, CH3CCH3), 1.05 (3H, s,
CH3CCH3), 0.98 (3H, d, J 6.9 Hz, CH3CH), 0.75–0.65
(2H, m, 2CH); dC 139.2, 129.3, 129.2, 125.7, 62.7, 52.9,
4.2.7. (2-Azido-2-((1R,3S,4S)-4-azido-4-methyl-3-
(phenylselenenyl)cyclohexyl)propyl)(phenyl)selane
(3f/4f). They were purified by flash column chromatography
(5% Et2O/petroleum ether) to give a 5.5:4.5 mixture of
compounds 3f and 4f (438 mg, 82%) as colorless oil;
Rf (10% Et2O/petroleum ether) 0.48; n (N3) (HATAR)
2102.5 cmÀ1
.

M. Tiecco et al. / Tetrahedron 63 (2007) 12373–12378
12377
Some spectral data were assigned from enriched fraction of
3f and 4f.
213 (18), 152 (69), 138 (59), 124 (69), 110 (12), 107 (10),
91 (17), 70 (100).
Main signals for the enriched fraction of 3f: dH (400 MHz,
CDCl3) 7.60–7.50 (4H, m, Ar–H), 7.30–7.20 (6H, m,
Ar–H), 3.55 (1H, ddd, J 2.6, 5.9, 10.8 Hz, CHSe), 3.19
(1H, d, J 11.7 Hz, CHHSe), 3.15 (1H, d, J 11.7 Hz, CHHSe),
2.62 (1H, tdd, J 3.4, 11.0, 14.5 Hz, CHH), 2.25–2.05 (1H, m,
CHH), 1.90–1.88 (1H, m, CH), 1.83–1.60 (4H, m, 1CHH
and 3CHH), 1.36 (3H, s, CH3), 1.12 (3H, s, CH3); dC
(100 MHz, CDCl3) 133.9, 132.6, 131.0, 130.3, 129.0,
128.9, 127.2, 126.8, 76.5, 74.4, 45.3, 39.3, 33.7, 32.0,
27.9, 26.5, 26.3, 21.8.
4.4. Synthesis of amido derivatives 12 and 13
A solution of azide 3a (1.0 mmol) and Ph3P (1.1 mmol) in
THF (10 mL) was stirred at 40 ꢀC overnight. Then, H2O
(50.0 mmol) was added and stirring was maintained at
50 ꢀC for additional 5 h. After this time, the reaction mixture
was poured in C6H6 and the azeotropic mixture was com-
pletely evaporated under vacuum. The crude product was dis-
solved in THF (10 mL) and Et3N (2.0 mmol), and then
1.1 mmol of CH3COCl (for the synthesis of 12) or PhCOCl
(for the synthesis of 13) was added at 0 ꢀC stirring for 3 h.
After this time, the reaction mixture was poured in H2O and
extracted three times with CH2Cl2. The combined organic
layers were washed with brine, dried over Na2SO4, concen-
trated under vacuum, and purified by flash chromatography.
Physical and spectral data for 12 and 13 are reported below.
Main signals for the enriched fraction of 4f: dH (400 MHz,
CDCl3) 7.60–7.50 (4H, m, Ar–H), 7.30–7.20 (6H, m,
Ar–H), 3.48 (1H, ddd, J 2.5, 5.6, 10.8 Hz, CHSe), 3.14
(2H, s, CH2Se), 2.41 (1H, tdd, J 3.5, 11.1, 14.6 Hz, CHH),
2.25–2.05 (1H, m, CHH), 2.05–1.95 (1H, m, CHH), 1.90–
1.88 (H, m, CH), 1.70–1.50 (3H, m, 3CHH), 1.38 (3H, s,
CH3), 1.13 (3H, s, CH3); dC (100 MHz, CDCl3) 133.9,
132.7, 131.0, 130.2, 129.0, 128.9, 127.2, 126.9, 76.5, 74.5,
45.3, 39.7, 33.5, 31.9, 27.6, 26.5, 25.9, 22.1. Anal. Calcd
for C22H26N6Se2: C, 49.63; H, 4.92; N, 15.79. Found: C,
50.0; H, 4.89; N, 15.73.
4.4.1. N-((1R,3R,4R,6S)-3,7,7-Trimethyl-4-(phenylsele-
nenyl)bicyclo[4.1.0]heptan-3-yl)acetamide (12). It was
purified by flash column chromatography (40% Et2O/petro-
leum ether) to give the title compound 12 (225 mg, 64%)
as colorless oil; Rf (80% Et2O/petroleum ether) 0.59;
[a]D20.0 À46.5 (c 0.40, CHCl3); dH (400 MHz, CDCl3) 7.60–
7.50 (2H, m, Ar–H), 7.30–7.20 (3H, m, Ar–H), 5.50 (1H, s,
NH), 3.75 (1H, dd, J 7.2, 12.3 Hz, CHSe), 2.49 (1H, dd,
J 10.1, 14.6 Hz, CHH), 2.30 (1H, dd, J 7.2, 4.6 Hz, CHH),
2.19 (1H, ddd, J 7.8, 12.3, 14.6 Hz, CHH), 1.96 (1H, dd,
J 4.0, 14.6 Hz, CHH), 1.66 (3H, s, CH3CO), 1.27 (3H, s,
CH3), 1.06 (3H, s, CH3), 0.98 (3H, s, CH3), 0.78 (1H, ddd,
J 4.0, 9.0, 10.1 Hz, CH), 0.60 (1H, dd, J 7.8, 9.0 Hz, CH);
dC (100 MHz, CDCl3) 169.9, 134.7, 130.1, 129.6, 127.9,
56.8, 51.1, 30.7, 29.1, 28.3, 24.7, 20.8, 20.5, 19.4, 15.9;
4.2.8. (1S,5S)-4,7-Dimethyl-7-(phenylselenenylmethyl)-
6-oxabicyclo[3.2.1]oct-3-ene (10). They were purified by
flash column chromatography (15% Et2O/petroleum ether)
to give a 1:1 mixture of isomers 10 (154 mg, 50%) as color-
less oil; Rf (30% Et2O/petroleum ether) 0.68; GC–MS m/z
ꢁ
(relative intensity), first GC eluted isomer: 308 (30) [M+ ],
306 (15), 215 (79), 213 (42), 197 (25), 195 (13), 171 (19),
158 (27), 137 (43), 93 (100), 77 (40); second GC eluted
ꢁ
isomer: 308 (22) [M+ ], 306 (11), 171 (12), 157 (10), 137
(100), 119 (9), 107 (15), 93 (88), 77 (21).
ꢁ
GC–MS m/z (relative intensity): 351 (22) [M+ ], 349 (11),
292 (87), 290 (41), 270 (13), 194 (34), 135 (76), 119 (42),
107 (25), 73 (100), 70 (44).
4.3. Reduction of the azido group: synthesis of 11
A solution of azide 3a (1.0 mmol) and Ph3P (1.1 mmol) in
THF (10 mL) was stirred at 40 ꢀC overnight. Then, H2O
(50.0 mmol) was added and stirring was maintained at
50 ꢀC for additional 5 h. After this time, the reaction mixture
was poured in H2O and extracted three times with Et2O.
The organic layer was washed with brine, dried over
Na2SO4, concentrated under vacuum, and purified by flash
chromatography.
4.4.2. N-((1R,3R,4R,6S)-3,7,7-Trimethyl-4-(phenylsele-
nenyl)bicyclo[4.1.0]heptan-3-yl)benzamide (13). It was
purified by flash column chromatography (10% Et2O/petro-
leum ether) to give the title compound 13 (264 mg, 64%) as
colorless oil; Rf (20% Et2O/petroleum ether) 0.45; [a]D23.4
À17.5 (c 0.85, CHCl3); dH (400 MHz, CDCl3) 7.60–7.30
(10H, m, Ar–H), 6.40 (1H, s, N), 3.77 (1H, dd, J 7.3,
12.1 Hz, CHSe), 2.83 (1H, dd, J 10.1, 14.7 Hz, CHH),
2.38 (1H, ddd, J 1.0, 7.3, 15.1 Hz, CHH), 2.31 (1H, ddd,
J 7.6, 12.1, 15.1 Hz, CHH), 1.94 (1H, dd, J 4.8, 14.7 Hz,
CHH), 1.51 (3H, s, CH3), 1.10 (3H, s, CH3), 1.02 (3H, s,
CH3), 0.85 (1H, ddd, J 4.8, 9.3, 10.1 Hz, CH), 0.67 (1H,
ddd, J 1.0, 7.6, 9.3 Hz, CH); dC (100 MHz, CDCl3) 167.0,
136.0, 135.0, 134.5, 131.4, 129.7, 128.7, 127.9, 127.1,
57.1, 52.3, 30.9, 30.1, 29.1, 28.7, 21.0, 20.2, 19.4, 18.1,
16.0. Anal. Calcd for C23H27NOSe: C, 66.98; H, 6.60; N,
3.40. Found: C, 66.71; H, 6.65; N, 3.42.
4.3.1. (1R,3R,4R,6S)-3,7,7-Trimethyl-4-(phenylselene-
nyl)bicyclo[4.1.0]heptan-3-amine (11). It was purified by
flash column chromatography (1% CH2Cl2/MeOH) to give
the title compound 11 (186 mg, 60%) as colorless oil; Rf
(2% CH2Cl2/MeOH) 0.22; n (NH2) (HATAR) 3350.1 cmÀ1
;
[a]D21.2 À70.2 (c 0.80, CHCl3); dH (400 MHz, CDCl3)7.50–
7.40 (2H, m, Ar–H), 7.30–7.20 (3H, m, Ar–H), 2.96 (1H,
dd, J 7.2, 12.3 Hz, CHSe), 2.32 (1H, dd, J 7.2, 15.1 Hz,
CHH), 2.20 (1H, ddd, J 7.8, 12.3, 15.1 Hz, CHH), 2.07
(1H, dd, J 9.7, 14.2 Hz, CHH), 1.25 (1H, dd, J 4.9, 14.2 Hz,
CHH), 1.21 (3H, s, CH3), 0.98 (6H, s, 2CH3), 0.78 (1H,
ddd, J 4.9, 9.5, 9.7 Hz, CH), 0.62 (1H, dd, J 7.8, 9.5 Hz,
CH); dC (100 MHz, CDCl3) 134.4, 131.0, 129.5, 127.6,
58.2, 52.5, 35.5, 29.9, 29.1, 23.5, 21.2, 20.1 18.0, 15.8;
Acknowledgements
Financial support from MIUR, National Projects PRIN2005
and FIRB2001, Consorzio CINMPIS, Bari and University
of Perugia is gratefully acknowledged.
ꢁ
GC–MS m/z (relative intensity): 309 (22) [M+ ], 307 (7),

12378
M. Tiecco et al. / Tetrahedron 63 (2007) 12373–12378
D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996, 52,
References and notes
14361–14384; (c) Rondon, A. C.; Panek, J. S. Chemtracts
1997, 10, 1058–1061; (d) Gianneschi, N. C.; Bertin, P. A.;
Nguyen, S. T.; Mirkin, C. A.; Zakharov, L. N.; Rheingold,
A. L. J. Am. Chem. Soc. 2003, 125, 10508–10509.
1. (a) Sheradsky, T. The Chemistry of the Azido Group; Patai, S.,
Ed.; Wiley-Interscience: New York, NY, 1971; (b) Scriven,
E. F. V.; Turbull, K. Chem. Rev. 1988, 88, 297–368.
8. Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.; Marini, F.;
Bagnoli, L.; Temperini, A. Angew. Chem., Int. Ed. 2003, 42,
3131–3133.
9. Tiecco, M.; Testaferri, L.; Bagnoli, L.; Marini, F.; Temperini,
A.; Tomassini, C.; Santi, C. Tetrahedron Lett. 2000, 41,
3241–3245.
€
2. Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem., Int. Ed. 2005, 44, 5188–5240.
3. (a)Tiecco,M.;Testaferri, L.;Temperini, A.;Bagnoli, L.;Marini,
F.; Santi, C. Synth. Commun. 1998, 28, 2167–2179; (b) Riela, S.;
Aprile, C.; Gruttadauria, M.; Lo Melo, P.; Noto, R. Molecules
2005, 10, 383–393; (c) Ward, V. R.; Cooper, N. A.; Ward,
A. P. J. Chem. Soc., Perkin Trans. 1 2001, 944–945;
(d) Broggini, G.; Molteni, G.; Zucchi, G. Synthesis 1995, 647–
648.
4. (a) Denis, J. N.; Vicens, J.; Krief, A. Tetrahedron Lett. 1979, 20,
2697–2700; (b) Hasser, A.; Amarasekara, A. S. Tetrahedron
Lett. 1987, 28, 5185–5188; (c) Giuliano, R. M.; Duarte, F.
Synlett 1992, 419–421.
5. Tingoli, M.; Tiecco, M.; Chianelli, D.; Balducci, R.; Temperini,
A. J. Org. Chem. 1991, 56, 6809–6813.
6. (a) He, L.; Byun, H. S.; Bittman, R. J. Org. Chem. 2000, 65,
7627–7633; (b) Alvarez de Cienfuegos, L.; Rodriguez, C.;
Mota, A. J.; Robles, R. Org. Lett. 2003, 5, 2743–2745; (c)
Enders, D.; Klein, D. Synlett 1999, 719–720.
10. Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.; Marini, F.;
Bagnoli, L.; Temperini, A. Chem.—Eur. J. 2002, 8, 1118–1124.
11. (a) Tiecco, M.; Testaferri, L.; Marini, F.; Sternativo, S.;
Temperini, A.; Bagnoli, L.; Santi, C. Tetrahedron: Asymmetry
2001, 12, 1493–1502; (b) Tiecco, M.; Testaferri, L.; Bagnoli,
L.; Purgatorio, V.; Temperini, A.; Marini, F.; Santi, C.
Tetrahedron: Asymmetry 2001, 12, 3297–3304; (c) For recent
reviews on these asymmetric selenenylation reactions, see:
Browne, D. M. M.; Wirth, T. Curr. Org. Chem. 2006, 10,
1893–1903 and Tiecco, M.; Testaferri, L.; Bagnoli, L.;
Marini, F.; Santi, C.; Temperini, A.; Scarponi, C.; Sternativo,
S.; Terlizzi, R.; Tomassini, C. Arkivoc 2006, 186–206.
12. Furst, A.; Plattner, P. A. Helv. Chim. Acta 1949, 32, 275–281.
13. Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454–
5459.
7. (a) Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen,
E. N. J. Am. Chem. Soc. 1995, 117, 5897–5898; (b) Hodgson,