Regioselective alkylation of 3,4-dihydro-2H-pyran by xanthate-mediated free radical nonchain process

Article abstract of DOI:10.1016/j.tetlet.2005.09.049

An intermolecular xanthate-mediated free radical nonchain addition reaction is introduced for the regioselective alkylation of 3,4-dihydro-2H-pyran. Additionally, we observed that the free radical nonchain reaction depends on the nature of the radical precursor.

Full text of DOI:10.1016/j.tetlet.2005.09.049

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7691–7694
Regioselective alkylation of 3,4-dihydro-2H-pyran by
xanthate-mediated free radical nonchain process
Jaime Torres-Murro, Leticia Quintero* and Fernando Sartillo-Piscil*
Centro de Investigacio´n en Sı´ntesis Orga´nica, Beneme´rita Universidad Auto´noma de Puebla, 72570 Puebla, Mexico
Received 8 July 2005; revised 7 September 2005; accepted 8 September 2005
Available online 26 September 2005
Abstract—An intermolecular xanthate-mediated free radical nonchain addition reaction is introduced for the regioselective alkyl-
ation of 3,4-dihydro-2H-pyran. Additionally, we observed that the free radical nonchain reaction depends on the nature of the radi-
cal precursor.
Ó 2005 Elsevier Ltd. All rights reserved.
An ongoing project in our laboratory required the syn-
thesis of an optically pure acetamide 1 as the starting
material of a natural occurring compound. Accordingly,
as 1 is a derived compound from inexpensive commer-
cially available 3,4-dihydro-2H-pyran 2, we envisioned
the possibility of a regioselective coupling reaction
between compounds 2 and 3 (Scheme 1).
ing to the formation of isomeric unsaturated lactams
4–6 (Scheme 2).
In this presumably free radical nonchain reaction, the di-
lauroyl peroxide (DLP) was suggested to act as the radical
initiator and as oxidant. Therefore, the isomeric lactams
4–6 were obtained by an intramolecular 5-endo-trig radi-
cal addition followed by oxidation of radical B, which
after proton elimination afforded the isomeric lactams
4–6 (Scheme 2). If we take a look at the lactam 4, we
notice that it corresponds to a formal selective intra-
molecular alkylation at the alkenyl carbon of the enam-
ine. Based on this, we now considered the possibility
for obtaining the desired compound 1 by intermolecular
radical addition of radical E onto 2 followed by radical
oxidation and final proton elimination of the six-
membered ring oxocarbenium ion G (Scheme 3).
By inspection on Scheme 1, we can realize that, in
order to connect C5 and Ca in a direct way, a novel
coupling reaction needs to be developed. The well-
known Heck coupling reaction1 or similar coupling
reactions2 cannot be applied herein because there is
no halide atom present in the double bond of 2.
Apparently, a convenient way to accomplish the reac-
tion is through a free radical addition onto the olefinic
bond (e.g., halogen atom transfer) followed by a radi-
cal or ionic elimination reaction.3 Thus, we turned
our attention to a recent Zard and Miranda work,4
where a xanthate-mediated 5-endo radical cycliza-
tion occurred under free radical nonchain process lead-
Accordingly, nonchiral xanthate 9 was selected as a free
radical model of study. Thus, this compound was pre-
pared as depicted in Scheme 4. Bromoacetyl bromide
11 and benzylamine 12 were allowed to react in the pres-
ence of triethyl amine to give 14 quantitatively. Amide
14 was finally treated with potassium O-ethyl xanthate
to afford 9 (Scheme 4).5
X = suitable group
O
O
O
O
N
H
Ph
5
α
+
N
Ph
Xanthate 9 was submitted to different free radical reac-
tion conditions. Modest yields of the analogous
expected product 16 were observed with 10 equiv of
3,4-dihydro-2H-pyran 2, and 2 equiv of DLP in reflux-
ing 1,2-dichloroethane (Table 1, entry 3).6
H
X
1
2
3
Scheme 1.
Keywords: Radical nonchain reaction; Xanthates.
*
Additionally, a direct xanthate reduction product 17
was obtained in low yield (Table 1). When peroxides,
Corresponding authors. Tel.: +52 2222 295500x7387; fax: +52 2222
454293; e-mail: fsarpis@siu.buap.mx
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.049

7692
J. Torres-Murro et al. / Tetrahedron Letters 46 (2005) 7691–7694
+
+
Bn
N
Bn
N
DLP
OEt
Bn
N
S
Bn
N
O
O
6
O
5
O
4
S
7
DLP
[RC(O)O]2
[RC(O)O]2
5-endo
O
N
O
N
N
O
O
N
Bn
Bn
Bn
Bn
D
C
A
B
Scheme 2.
Following the same route depicted in Scheme 4, opti-
cally pure xanthate (S)-10 was synthesized and allowed
to react under the condition reactions described in Table
1 (entry 4) to afford the expected product 1 along with
the corresponding xanthate reduction product 187 in
60% and 17% yield, respectively.
O
O
O
O
-H
DLP
H
1
HN
O
O
2
Ph
HN
HN
F
E
G
Scheme 3.
O
O
O
2 eq. DLP
ClCH2CH2Cl
reflux
+
N
H
Ph
2
+
10
R
N
Ph
O
R
O
H
NEt3
CH2Cl2
Br
1
18
17%
Br
+
Ph
NH2
N
Ph
Br
60%
H
12: R = H
13: R = Me
11
14: R = H
15: R = Me
Scheme 5.
O
R
S
S
KSC(S)OEt
Acetone
N
Ph
H
OEt
OH
O
OH
O
9: R = H (72%) from 12
10: R = Me (74%) from 13
O
O
9
O
O
DLP
NHBn
NHBn
Scheme 4.
H
20
19
dicumyl peroxide (DCP), or dibenzyl peroxide (DBP)
were used, neither the coupling product 16 nor the
reduction product 17 was observed (entries 6–8).
Complex mixture
Scheme 6.
Table 1. Radical addition/proton eliminationa,b
O
O
O
O
O
S
S
Peroxide
Solvent
+
Ph
N
Ph
+
N
Ph
H
H
N
H
OEt
17
9
16
2
Entry
2 (equiv)
Peroxide (equiv)
Solvent
16 (Yield)
17 (Yield)
1
2
3
4
5
6
7
8
2
5
DLP (0.5)
DLP (1)
DLP (1)
DLP (2)
DLP (2)
DCP (2)
DCP (2)
DBP (2)
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
C6H6
ClCH2CH2Cl
C6H6
ClCH2CH2Cl
Trace
10
21
—
Trace
7
12
—
—
—
—
10
10
10
10
10
10
58
Trace
NR
NR
NR
NR = no reaction.
a All reactions were carried out in refluxing solvents.
b Dilauryl peroxide (DLP), dibenzyl peroxide (DBP), and dicumyl peroxide (DCP).

J. Torres-Murro et al. / Tetrahedron Letters 46 (2005) 7691–7694
7693
OEt
OEt
S
S
S
O
S
O
S
O
OMe
DLP
OMe
O
OMe
+
+
EtO
S
O
Benzene
72%
O
21
22b
22a
38
2
Benzene
or ClCH2CH2Cl
DLP
:
62
O
O
O
O
OMe
OMe
23
I
Scheme 7.
The formation of the reduction product 18 (and also 17)
might correspond to a disproportionation product, as it
would explain the formation of the olefinic double bond
of 16 and 1, however, the ratio of 16/17 or 1/18 should
be equimolar or close to that (Scheme 5).
Acknowledgements
We thank CONACyT, for financial support, Project No.
´
´
35102, and Benemerita Universidad Autonoma de Pue-
bla (BUAP), for partial support (F.S.-P.). Authors also
thank Dr. Alejandro Cordero (from ZardÕs laboratory),
for helpful discussion.
Thus, like Zard and Miranda, we propose that the reac-
tion mechanism may occur through direct oxidation by
the peroxide of the incipient radical F into oxocarbe-
nium ion G, which then by proton elimination, the dou-
ble bond is recovered (see Scheme 3).4,8 In this regard,
we attempted trapping the oxocarbenium ion by using
an internal nucleophile with the expectation that cycliza-
tion might be competitive with proton elimination
(Scheme 6).
References and notes
1. Heck, R. F. Palladium Reagents in Organic Syntheses;
Academic Press: New York, 1985, p 179.
2. Heck, R. F. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: New York, 1991;
Vol. 4, p 833.
Accordingly, 3,4-dihydro-2H-pyran-2-methanol 19 was
allowed to react with xanthate 9 and 2 equiv of DLP
in refluxing ClCH2CH2Cl, resulting in the formation
of a rather complex reaction mixture. Unfortunately,
we could not accomplish the ring closure onto oxocarbe-
nium ion (compound 20), which would be the unambig-
uous proof for the existence of oxocarbenium ion as
the intermediate of this reaction (as well as the forma-
tion of the lactams, see Scheme 2).9 On the other
hand, a xanthic acid elimination (which should result
from xanthate-mediated free radical chain reaction) is
not supported because of an additional experiment
between compound 2 and xanthate 21 under standard
conditions afforded an inseparable mixture of products
22a and 22b (in a ratio of 48/62, respectively)10 resulted
from a xanthate-mediated free radical chain reaction
(Scheme 7).11
3. For example, Halogen Atom Transfer (HAT) followed
by base-catalyzed E2-elimination. For application of
HAT reactions, see: Jasperse, C. P.; Curran, D.; Fevig,
T. L. Chem. Rev. 1991, 91, 1237–1286; A very interesting
example of radical addition–radical elimination in one
pot (vinylation reaction): Bertrant, F.; Quiclet-Sire, B.;
Zard, S. Z. Angew. Chem., Int. Ed. 1999, 38, 1943–
1946.
4. Miranda, L. D.; Zard, S. Z. Org. Lett. 2002, 4, 1135–
1138.
5. Synthesis of the free radical precursors: To a solution of
amine (1 equiv) and triethylamine (1.2 equiv) in dry THF
(approx 1 g/50 mL of THF) at 0 °C was added dropwise
bromoacetyl bromide (1.1 equiv) dissolved in dry THF
(approx 1 mL/20 mL). The reaction mixture was warmed
to room temperature and allowed to react for 2 h, and
then quenched with 50 mL of H2O. The reaction mixture
was extracted with ethyl acetate, washed with brine, dried
over NaSO4, and concentrated in vacuo to yield a colorless
oil. The crude mixture was dissolved in 40 mL of acetone
and cooled to 0 °C, and then potassium ethyl xanthate
(1.5 equiv) was added. The reaction mixture was allowed
to react for 4 h at room temperature and the solution was
concentrated under reduced pressure. The resulting vis-
cous oil was purified under chromatography with ethyl
acetate and hexane as the eluant.
Until now, we have not been able to find an explanation
about the difference in reactivity among these two types
of carbon-centered radicals a to a carbonyl group (from
amides and esters), so a number of interesting questions
are raised. Thus, more laboratory quality time as well as
theoretic studies on this regard is in progress.
S-(Benzylcarbamoyl)methyl O-ethyl carbonodithioate 9:
1
Mp = 94–95 °C; H NMR (400 MHz, CDCl3): d 1.38 (t,
In conclusion, a novel intermolecular free radical non-
chain addition reaction onto 3,4-dihydro-2H-pyran is
reported. Although this reaction was developed for the
synthesis of a specific compound, we anticipate very
similar behavior for those with few variants into the
framework.
3H, J = 7.2 Hz), 3.87 (s, 2H), 4.44 (d, 2H, J = 5.6 Hz),
4.62 (q, 2H, J = 7.2 Hz), 6.69 (br, 1H), 7.27 (m, 5H); 13C
NMR (75 MHz, CDCl3): d 13.6, 39.0, 43.8, 71.0, 127.5,
127.6, 128.6, 137.6, 166.8, 212.8; MS (EI): m/z = 148
(54%, M+ÀEtOCSS), 269 (12%, M+); (FAB-HRMS)
m/z = 270.0622 (calcd for C12H16NO2S2: 270.0616).

7694
J. Torres-Murro et al. / Tetrahedron Letters 46 (2005) 7691–7694
HRMS) m/z = 232.1330 [M+H+] (calcd for C14H17NO2:
S-[(S)-1-Phenylethylcarbamoyl]methyl O-ethyl carbono-
dithioate 10: Mp = 59–60 °C; 1H NMR (400 MHz,
CDCl3): d 1.38 (t, 3H, J = 7.2 Hz), 1.47 (d, 3H, J =
7.2 Hz), 3.79 (d, 1H, J = 15.9 Hz), 3.85 (d, 1H,
J = 15.9 Hz), 4.61 (m, 2H), 5.11 (sept, 1H, J = 6.8 Hz),
6.58 (br d, 1H, J = 6.2 Hz), 7.28 (m, 5H); 13C NMR
(75 MHz, CDCl3): d 13.6, 21.6, 39.1, 49.1, 71.0, 126.0,
127.4, 128.6, 142.6, 165.9, 212.9; MS (EI): m/z = 162
(45%, M+ÀEtOCSS), 283 (8%, M+); (FAB-HRMS)
m/z = 283.0700 (calcd for C13H17NO2S2: 283.0701).
232.1338).
(S)-2-(5,6-Dihydro-4H-pyran-3-yl)-N-(1-phenylethyl)acet-
amide 1: [a]D À27.5 (c 1, CHCl3); mp = 93–94 °C; 1H
NMR (400 MHz, CDCl3): d: 1.47 (d, 3H, J = 6.8 Hz), 1.85
(m, 2H), 1.95 (m, 2H), 2.77 (dd, 1H, J = 16.4, 3.2 Hz),
2.82 (dd, 1H, J = 16.2, 2.9 Hz), 3.92 (apparent t, 2H,
J = 5.6 Hz), 5.13 (sept, 1H, J = 6.8 Hz), 5.97 (d, 1H,
J = 6.8 Hz), 6.38 (s, 1H), 7.28 (m, 5H); 13C NMR
(75 MHz, CDCl3): d 21.8, 22.3, 23.3, 41.5, 48.5, 65.4,
107.5, 125.8, 127.2, 128.5, 142.6, 142.9, 169.9; MS (EI):
m/z = 245 (58%, M+); (FAB-HRMS) m/z = 246.1490
[M+H+] (calcd for C15H20NO2: 246.1494).
6. General procedure: 2 equiv of DLP dissolved in dichloro-
ethane (2 mL/100 mg) were added portionwise to
a
solution of xanthate and 10 equiv of 3,4-dihydro-2H-
pyran dissolved in dichloroethane (5 mL/100 mg of xan-
thate) at reflux over 4 h (0.5 equiv/1 h). The reaction
mixture was cooled to room temperature and solvent
removed under reduced pressure. The resulting viscous oil
was purified under chromatography with ethyl acetate and
hexanes as the eluant.
7. Top, S.; Jaouen, G. J. Org. Chem. 1981, 46, 78–82.
8. This radical oxidation has been observed even in the
presence of Bu3SnH. Guerrero, M. A.; Cruz-Almanza, R.;
Miranda, L. D. Tetrahedron 2003, 59, 4953–4958.
´
9. A similar strategy has been used by Suarez in the synthesis
of anhydrosugars: Francisco, C. G.; Herrera, A. J.;
´
N-Benzyl-2-(5,6-dihydro-4H-pyran-3-yl)acetamide
16:
Suarez, E. J. Org. Chem. 2002, 67, 7439–7445.
Mp = 96–97 °C; 1H NMR (400 MHz, CDCl3): d 1.85
(m, 2H,), 1.99 (m, 2H), 2.83 (s, 2H), 3.91 (apparent t, 2H,
J = 5.1 Hz), 4.43 (d, 2H, J = 5.7 Hz), 6.10 (br, 1H), 6.37
(s, 1H), 7.27 (m, 5H); 13C NMR (75 MHz, CDCl3): d 22.1,
23.3, 41.3, 43.5, 65.3, 107.4, 127.4, 127.5, 128.7, 138.3,
142.8, 171.0; MS (EI): m/z = 231 (64%, M+); (FAB-
10. The ratio of 22a/22b was calculated from the intensity of
the anomeric signals: Ha: 5.60 ppm (3JH–H = 6.0 Hz); Hb:
6.22 ppm (3JH–H = 3.9 Hz).
11. A recent review of xanthate-mediated radical chain
reactions. Zard, S. Z. Angew. Chem., Int. Ed. 1997, 36,
672–686.