Generation and intermodular additions of pyridylmethyl radicals

2996

FEATURE ARTICLE

Generation and Intermolecular Additions of Pyridylmethyl Radicals

G

eneration and

o

Intermolecul

r

a

r

Addit

a

ions of Pyr

n

idylmethyl

R

a

dicals Ferjancic, Béatrice Quiclet-Sire, Samir Z. Zard*

Laboratoire de Synthèse Organique associé, CNRS Ecole Polytechnique, 91128 Palaiseau, France

Fax +33(1)69335972; E-mail: zard@poly.polytechnique.fr

Received 29 March 2008

This paper is dedicated with respect to the memory of Professor Albert I. Meyers.

necessary in this case. Thus, a moderate, but useful, yield

Abstract: 2-, 3-, or 4-Pyridylmethyl radicals can be made to add to

nonactivated alkenes to give a variety of otherwise inaccessible py-

ridine derivatives. Bicyclic structures can be obtained by combining

the radical addition with ionic ring-closure steps.

of adduct 3 was observed with the more reactive vinyl piv-

alate, whereas addition to the strongly electrophilic N-

methylmaleimide proceeded with high efficiency to give

trans-addition product 4 in 80% yield.

Key words: radical additions, heterocycles, pyridines, alkenes,

cyclization

We hoped, nevertheless, to expand the scope and utility of

the xanthate transfer process by switching to the pyridine

series. By increasing the electrophilic character of the rad-

ical, it appeared possible to enhance the rate of addition

and overcome the kinetic barrier. If successful, a new

route to valuable pyridine derivatives would become

available. Pyridine motifs are ubiquitous in biologically

active substances and in ligands for transition metals in

organometallic chemistry.^3,4

We have developed over the past few years a powerful

radical process based on the chemistry of xanthates and

related derivatives.¹This technology provides one of the

most general solutions to the problem of the intermolecu-

lar creation of C–C bonds starting with nonactivated alk-

enes. The success of this approach hinges on providing the

intermediate radicals with a relatively long lifetime under

concentrated conditions, thereby enabling bimolecular

additions even to poorly reactive radical traps.¹

To test this approach, we prepared xanthate 5 by the reac-

tion of potassium O-ethyl xanthate with commercially

available 2-chloro-5-(chloromethyl)pyridine (Scheme 2).

The inclusion of the chlorine group in position 2 serves

two purposes. On the one hand, it sterically and electron-

ically diminishes the nucleophilicity of the pyridine nitro-

gen and, thus, eliminates the formation of potential

inhibitors by slow ionic decomposition of the xanthate

group.⁵On the other, the presence of the chlorine at this

particular position provides a very useful handle for fur-

ther modifications through direct or transition-metal-cata-

lyzed substitutions.^3,4

S

OEt

OAc

MeO

OAc

S

peroxide

MeO

S

OEt

2

OMe

OPiv

peroxide

1

MeO

In the event, we were gratified to find that addition of lau-

royl peroxide (DLP) to a concentrated solution of 5 and al-

lyl acetate in refluxing 1,2-dichloroethane led to the

formation of the expected adduct 7 in 49% yield (or 61%

based on recovered starting materials), through the addi-

tion of the intermediate radical 6.

MeO

S

OPiv

O

N

O

MeO

S

OEt

3, 48%

Ph

O

S

peroxide

OMe

EtO

N

Ph

OMe

Addition to various other alkenes was accomplished in the

same manner, as shown by the examples pictured in

Scheme 2. In some of the reactions, 1,2-dichloroethane

was replaced by methyl ethyl ketone or ethyl acetate. In

fact, the process tolerates a broad variety of solvents. The

desired transformation appeared to be fairly general, and

the yields, albeit somewhat variable, were reasonable

(yields in parentheses are based on recovered starting ma-

terial throughout the article). The main side product was

1,2-bis(6-chloro-3-pyridyl)ethane, arising from the sym-

metrical coupling of two 6-chloro-3-pyridylmethyl radi-

cals. Even though pyridylmethyl radicals proved more

reactive than their benzyl counterpart, this reactivity re-

mains comparatively modest. Their concentration thus

builds up in the medium to a point where unwanted radical

O

4, 80%

Scheme 1

In contrast to various radicals we have so far examined,

benzyl radicals proved too unreactive towards simple alk-

enes. For instance, reaction of S-3,4,5-trimethoxybenzyl

xanthate 1 with allyl acetate did not lead to the expected

adduct 2 in any significant yield under the usual condi-

tions (Scheme 1).²Some activation of the alkene appeared

SYNTHESIS 2008, No. 18, pp 2996–3008

x

x.

x

.

2

0

8

Advanced online publication: 24.07.2008

DOI: 10.1055/s-2008-1067198; Art ID: M01708SS

FEATURE ARTICLE

Generation and Intermolecular Additions of Pyridylmethyl Radicals

2997

S

OEt

OAc

Cl

N

S

peroxide

Cl

N

5

S

OEt

7, 49% (61%)

Cl

N

6

PO(OEt)₂

Cl

N

S

SiMe₃

Cl

N

S

8, 67%

S

OEt

S

OEt

9, 62%

SiMe₃

Cl

N

S

Cl

N

S

OPiv

10, 55% (63%)

S

OEt

S

OEt 11, 45%

CO₂Et

NHBoc

O

Cl

N

S

Cl

N

S

OEt

S

OEt

12, 36%

13, 47% (56%)

O

H

O

N

Ph

Cl

N

S

O

Cl

N

S

OEt

O

S

OEt

14, 57%

15, 46%

OMe

Cl

N

S

OAc

16, 55%

S

OEt

Scheme 2

couplings become competitive.⁶It is worth stressing, fi-

nally, that many functional groups are compatible with the

reaction conditions and that the process allows the expe-

dient modification of the side chain of the pyridine ring.

Access to most of the structures in Scheme 2 would have

been tedious at best with conventional approaches.

17, R = CO₂Me

18, R = CH₂CH₂N(Me)Boc

R

CO₂Me

19, 56% (65%)

20, 51% (60%)

Cl

N

S

OEt

Boc

The successful addition to the long-chain methyl undec-

10-enoate (17) and homologous carbamate 18, displayed

in Scheme 3, opens the possibility of a simple access to a

number of pyridine alkaloids⁷such as the antileukemic

theonalledins C (21) and D (22),^7a–7dor the antimicrobial

xestamines D (23) and E (24).^7e,f

N

Me

R

N

H

theonelladin C (21), R = H

theonelladin D (22), R = Me

N

Radical 6 derived from xanthate 5 is in the meta position

with respect to the nitrogen atom and therefore only expe-

riences indirectly its electronegativity. It was therefore

important to explore and compare the behavior of the

ortho and para isomeric xanthates 25 and 26. These were

prepared from the corresponding chloropicolines by a

Wohl–Ziegler bromination with N-bromosuccinimide⁷

and displacement of the bromine with potassium O-ethyl

OMe

N

xestamine D (23), n = 2

xestamine E (24), n = 3

Me

n

Scheme 3

Synthesis 2008, No. 18, 2996–3008 © Thieme Stuttgart · New York

2998

Z. Ferjancic et al.

FEATURE ARTICLE

xanthate (Scheme 4). The modest overall yield is due to xanthate 25 to N-allyl-4-chlorobenzenesulfonamide and

the somewhat inefficient bromination step.

of xanthate 26 to diethyl allylphosphonate were per-

formed to give the respectively compounds 31 and 36 in

an identical yield of 66%.

Addition to allyl acetate, allyltrimethylsilane, trimeth-

yl(vinyl)silane, and methyl undec-10-enoate gave adducts

27–30 from xanthate 25 and the corresponding adduct 32– Even though a similar broad compatibility with the alkene

35 from xanthate 26. Two further successful additions of partner was observed, the yields in most cases were no-

ticeably higher than for additions of xanthate 5. This is

S

OEt

presumably due to the increased electrophilic character of

the corresponding ortho and para radicals 37 and 38 be-

cause of better delocalization towards the more electrone-

gative nitrogen atom of the pyridine ring, as compared

with the isomeric meta radical 6 (Scheme 5).

1) NBS

25, 40%

S

2) KSCSOEt

acetone

Cl

N

Cl

N

S

OEt

1) NBS

S

The enhanced reactivity of xanthate 26 over xanthate 5

was ascertained by a competition experiment towards al-

lyltrimethylsilane. Examination of the crude mixture in

the early stages of the reaction by NMR spectroscopy in-

dicated a 3:1 preference in favor of adduct 34 over 10

(Scheme 5).

2) KSCSOEt

acetone

26, 24%

N

Cl

N

S

OEt

S

OEt

SiMe₃

S

OEt

SiMe₃

S

OAc

Cl

The synthetic utility of the chlorine atom on the pyridine

ring can be gauged by the sequences displayed in

Scheme 6. The radical addition products (e.g., 40–42) de-

rived from the 2-chloro-substituted xanthate 39 may be

easily transformed into interesting bicyclic pyridine struc-

tures by intramolecular substitution of the chlorine atom.

Thus, saponification of the xanthate in adduct 40 with so-

dium hydroxide and heating the resulting thiol in N,N-

dimethylformamide in the presence of sodium borohy-

dride gave rise to the rare 2H-thiopyrano[2,3-b]pyridine

structure 43 in 50% overall yield.⁸The role of the borohy-

dride is to reverse any aerial oxidation of the thiol into the

disulfide, which is difficult to avoid on a small scale. Al-

ternatively, the xanthate group in the addition product 42

N

Cl

N

Cl

N

29, 68%

28, 68%

27, 57%

S

OEt

S

OEt

O

S

CO₂Me

S

N

7

H

Cl

N

Cl

N

Cl

31, 66%

30, 61%

SiMe₃

S

SiMe₃

S

OAc

S

OEt

34, 84%

OEt

Cl

N

Cl

N

Cl

N

33, 70%

32, 47% (56%)

S

CO₂Me

PO(OEt)₂

S

CH₃

7

1) NBs, Bz₂O_2,CCl₄

2) KSCSOEt, acetone

S

OEt

S

35, 74%

36, 66%

N

Cl

N

Cl

OEt

Cl

N

39, 43%

Cl

N

R

(lauroyl peroxide)

R

Scheme 4

1) KOH, MeOH, r.t.

2) NaBH₄, DMF,

S

N

S

100 °C

N

Cl

S

OEt

NHBoc

43, 50% (from 40)

40, R = NHBoc, 54%

41, R = SiMe₃, 58% (65%)

42, R = CN, 47% (55%)

Cl

N

Cl

N

Cl

N

DBU

6

38

37

CN

OEt

BnNH₂

100 °C

SiMe₃

S

Cl

N

S

C

Cl

NH

N

Cl

45, 78%

44, 82% (from 42)

S

OEt

Ph

SiMe₃

10

5

xylene

reflux

Cl

N

lauroyl peroxide

S

SiMe₃

CN

S

OEt

N

OEt

S

Ph

Cl

N

34

26

46, 84%

Cl

N

Scheme 5

Scheme 6

Synthesis 2008, No. 18, 2996–3008 © Thieme Stuttgart · New York

FEATURE ARTICLE

Generation and Intermolecular Additions of Pyridylmethyl Radicals

2999

to allyl cyanide could be easily eliminated with base, since smoothly. The radical addition to allyl acetate and cyanide

it is located in the b-position with respect to the nitrile gave respectively the expected adducts 50 and 51 in syn-

group. In turn, the unsaturated nitrile 44 thus produced thetically useful yields. Also interesting is the behavior of

can undergo Michael addition with benzylamine to fur- bis-xanthate 52 derived from the same starting diol. Rea-

nish adduct 45, which is then converted into tetrahy- sonable selectivity in the radical monoaddition could be

droazaquinoline 46 in good overall yield by heating in accomplished leading to 54, with only minor amounts of

refluxing xylene. Tetrahydroazaquinolines represent a symmetrical adduct 53 being formed. The former sub-

class of valuable compounds for medicinal chemistry^9,10stance underwent a second radical addition to vinyl ace-

and a library of such structures could in principle be built tate to furnish unsymmetrical addition product 55 in 64%

by simply replacing the benzylamine with various other yield as a 1:1 mixture of diastereomers. Only the xanthate

primary amines.

in the ‘benzylic’ position in 54 participates actively in the

radical chain process since it much easier to cleave than

the other, purely aliphatic xanthate. By altering the alkene

partners, it should be possible to access numerous unsym-

metrically substituted pyridines.

OOCPh

OCOPh

48, 22%

OH

BzCl

N

HO

N

OH

pyridine

In summary, we have described a simple and direct, yet

effective and versatile, route to various pyridine deriva-

tives. The process is convergent, atom-economical, and

compatible with a variety of useful functional groups. It

complements our earlier and different route to pyridine

structures^5aand, more generally, highlights the broad util-

ity of radical-based approaches, which have been largely

neglected in this area of heterocyclic chemistry.

1) PPh₃, CBr₄

CH₂Cl₂

2) KSCSOEt

acetone

47, 50%

1) PPh₃, CBr₄

CH₂Cl₂

2) KSCSOEt

acetone

EtO

S

OEt

S

OEt

S

N

OOCPh

N

Solvents were used as received. Merck Geduran SI 60 Å silica gel

(35–70 mm) was used for column chromatography. IR spectra were

recorded on a Perkin-Elmer 1420 spectrophotometer. ¹H NMR and

¹³C NMR spectra were recorded using 400 MHz ARX 400 Bruker

spectrometers; spectra are referenced to the residual proton reso-

nances of the solvents. Petroleum ether = PE.

52, 64%

49, 78%

CN

R

(lauroyl

peroxide)

(lauroyl

peroxide)

S

OEt

CN

S

OEt

S

OEt

S

CN

R

S

Xanthate Adducts; General Procedure

OOCPh

A soln of xanthate (1 mmol) and the desired alkene (4 mmol) in

DCE, MEK, PhCl, or EtOAc (1 mL) was refluxed for 10 min under

N₂. DLP (5 mol%) or dicumyl peroxide was then added to the re-

fluxing soln, followed by additional portions (5 mol%) every 1.5 h

until the starting xanthate was completely consumed. The mixture

was then cooled to r.t., concentrated under reduced pressure, and

purified by flash chromatography (silica gel).

N

+

N

53, 8% (11%)

50, R = OAc, 52%

51, R = CN, 34% (50%)

S

OEt

CN

EtO

S

OEt

OAc

S

OEt

N

CN

OAc

54, 36% (54%)

S-6-Chloro-3-pyridylmethyl O-Ethyl Dithiocarbonate (5)

To a soln of the commercially available 2-chloro-5-(chlorometh-

yl)pyridine (1 g, 6.17 mmol) in acetone (12 mL) was added under

N₂and portionwise potassium O-ethyl xanthate (1.09 g, 1.1 equiv).

After addition of H₂O, evaporation of the acetone, and extraction

with Et₂O, the combined organic layers were dried (MgSO₄), fil-

tered, and evaporated under reduced pressure to give the pure 5

(94% yield) as pale yellow crystals; mp 60–61 °C (EtOAc–PE).

S

(lauroyl

peroxide)

55, 64%

N

Scheme 7

Finally, it is important to stress that the main requirement

for a successful xanthate transfer addition is to block the

nefarious nucleophilic activity of the pyridine nucleus.

The chlorine atom, even though highly useful, may be re-

placed by various other functional groups that are able to

shield the pyridine nitrogen. Some possibilities are col-

lected in Scheme 7.

IR (Nujol): 1582, 1561 (C=N), 1229, 1053 cm^–1(C–O, CS).

¹H NMR (400 MHz, CDCl₃): d = 8.39 (d, J = 2.3 Hz, 1 H, CH_Ar),

7.67 (dd, J = 2.3 Hz, J = 8.2 Hz, 1 H, CH_Ar), 7.29 (d, J = 8.2 Hz, 1

H, CH_Ar), 4.65 (q, J = 7.2 Hz, 2 H, OCH₂CH₃), 4.33 (s, 2 H, CH₂S),

1.43 (t, J = 7.2 Hz, 3 H, OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 212.7 (C=S), 150.5 (C_Ar), 149.9

(CH_Ar), 139.3 (CH_Ar), 131.4 (C_Ar), 124.2 (CH_Ar), 70.6 (OCH₂CH₃),

36.5 (CH₂S), 13.8 (OCH₂CH₃).

For example, reaction of 2,6-pyridinedimethanol with one

equivalent of benzoyl chloride gave monobenzoate 47 in

addition to lesser amounts of dibenzoate 48. Conversion

of the free alcohol into the corresponding bromide then

into xanthate 49 using standard conditions proceeded

MS (CI, NH₃): m/z = 248, 250 [M + H]⁺.

HRMS (EI): m/z [M]⁺calcd for C₉H₁₀ClNOS₂: 246.9892; found:

246.9888.

Synthesis 2008, No. 18, 2996–3008 © Thieme Stuttgart · New York

3000

Z. Ferjancic et al.

FEATURE ARTICLE

S-1-(Acetoxymethyl)-3-(6-chloro-3-pyridyl)propyl O-Ethyl

Dithiocarbonate (7)

J = 14.4 Hz, 1 H, CH₂Ar), 2.71 (ddd, J = 7.1 Hz, J = 9.5 Hz,

J = 14.1 Hz, 1 H, CH₂Ar), 2.40 (m, 2 H, CH₂CH₂Ar, CH₂P), 2.16

(ddd, J = 9.9 Hz, J = 15.4 Hz, J = 16.9 Hz, 1 H, CH₂P), 2.03 (m, 1

H, CH₂CH₂Ar), 1.42 (t, J = 7.1 Hz, 3 H, 2 OCH₂CH₃), 1.31 (td,

J = 7.1 Hz, 6 H, 2 CH₃CH₂OP).

¹³C NMR (100 MHz, CDCl₃): d = 212.5 (C=S), 149.6 (CH_Ar), 149.2

(C_Ar), 138.9 (CH_Ar), 135.2 (C_Ar), 123.9 (CH_Ar), 70.1 (OCH₂CH₃),

61.9 (t, J = 6.7 Hz, 2 CH₃CH₂OP), 44.8 (CHS), 34.4 (d, J = 3.1 Hz,

CH₂CHS), 31.5 (d, J = 136.2 Hz, CH₂P), 29.2 (CH₂Ar), 16.4 (d,

J = 6.1 Hz, 2 CH₃CH₂OP), 13.7 (OCH₂CH₃).

Following the general procedure using xanthate (0.8 mmol, 1 equiv)

and allyl acetate (4 equiv) in DCE (0.8 mL). After the addition of

DLP (2 × 5 mol%), further allyl acetate (4 equiv) and DLP (2 × 5

mol%) were added. Column chromatography (silica gel, toluene–

Et₂O, 95:5) furnished 7 (49% yield, 61% based on recovered start-

ing material) as a pale yellow oil.

IR (CCl₄): 1748 (OCOMe), 1584, 1560 (C=N), 1224, 1054 cm^–1

(C–O, CS).

¹H NMR (400 MHz, CDCl₃): d = 8.23 (d, J = 2.4 Hz, 1 H, CH_Ar),

7.48 (dd, J = 2.5 Hz, J = 8.1 Hz, 1 H, CH_Ar), 7.26 (d, J = 8.5 Hz, 1

H, CH_Ar), 4.65 (q, J = 7.1 Hz, 2 H, OCH₂CH₃), 4.31 (dd, J = 5.0 Hz,

J = 11.4 Hz, 1 H, CH₂OCO), 4.26 (dd, J = 6.0 Hz, J = 11.4 Hz, 1 H,

CH₂OCO), 3.95 (m, 1 H, CHS), 2.84 (m, 1 H, CH₂Ar), 2.73 (m, 1

H, CH₂Ar), 2.07 (ms, 4 H, CH₃CO, CH₂CHS), 1.94 (m, 1 H,

CH₂CHS), 1.42 (t, J = 7.1 Hz, 3 H, OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 212.6 (C=S), 170.6 (OCOCH₃),

149.6 (CH_Ar), 149.4 (C_Ar), 138.9 (CH_Ar), 135.1 (C_Ar), 124.1 (CH_Ar),

70.5 (OCH₂CH₃), 65.4 (CH₂OAc), 48.8 (CHS), 32.1, 29.4 (2 CH₂),

20.8 (COCH₃), 13.8 (OCH₂CH₃).

MS (CI, NH₃): m/z = 426, 428 [M + H]⁺.

HRMS (EI): m/z [M]⁺calcd for C₁₆H₂₅ClNO₄PS₂: 425.0651; found:

425.0657.

S-3-(6-Chloro-3-pyridyl)-1-[(trimethylsilyl)methyl]propyl

O-Ethyl Dithiocarbonate (10)

Following the general procedure using xanthate 5 (100 mg, 0.40

mmol) and allyltrimethylsilane (185 mg, 1.61 mmol, 4 equiv) in

MEK (0.4 mL) and requiring DLP (40 mol%) to go to completion.

Further allyltrimethylsilane (93 mg, 0.80 mmol, 2 equiv) was as

added to the mixture after 6 h. Flash chromatography (silica gel,

PE–Et₂O, 25:2) afforded 10 (80 mg, 55%) as a light yellow oil, to-

gether with recovered starting xanthate (13 mg). The yield based on

recovered starting xanthate was 63%.

MS (CI, NH₃): m/z = 348, 350 [M + H]⁺.

HRMS (EI): m/z [M]⁺calcd for C₁₄H₁₈ClNO₃S₂: 347.0417; found:

347.0417.

IR (CCl₄): 2953, 1584, 1561, 1458, 1383, 1250, 1215, 1110, 1054

cm^–1.

S-3-(6-Chloro-3-pyridyl)-1-(trimethylsilyl)propyl O-Ethyl

Dithiocarbonate (8)

¹H NMR (400 MHz, CDCl₃): d = 8.18 (d, J = 2.8 Hz, 1 H, CH_Ar),

7.44 (dd, J₁= 2.4 Hz, J₂= 8.4 Hz, 1 H, CH_Ar), 7.21 (d, J = 8.4 Hz,

1 H, CH_Ar), 4.62 (q, J = 7.2 Hz, 2 H, OCH₂CH₃), 3.88–3.81 (m, 1

H, CHS), 2.74–2.68 (m, 2 H, CH₂Ar), 1.99–1.92 (m, 2 H,

CH₂CHS), 1.39 (t, J = 7.2 Hz, 3 H, OCH₂CH₃), 1.13 (dd, J₁= 7.2

Hz, J₂= 14.8 Hz, 1 H, CH₂Si), 1.04 (dd, J₁= 8.0 Hz, J₂= 15.2 Hz,

1 H, CH₂Si), 0.03 [s, 9 H, Si(CH₃)₃].

¹³C NMR (100 MHz, CDCl₃): d = 214.0 (C=S), 149.4 (CH_Ar), 149.1

(C), 138.7 (CH_Ar), 135.6 (C), 123.8 (CH_Ar), 69.6 (OCH₂CH₃), 47.9

(CHS), 38.4 (CH₂CHS), 29.3 (CH₂Ar), 22.9 (CH₂Si), 13.7

(OCH₂CH₃), –0.8 [Si(CH₃)₃].

Following the general procedure using xanthate 5 (100 mg, 0.40

mmol) and trimethyl(vinyl)silane (243 mg, 2.42 mmol, 6 equiv) in

MEK (0.4 mL) and requiring DLP (40 mol%) to go to completion.

Further trimethyl(vinyl)silane (121 mg, 1.21 mmol, 3 equiv) was

added to the mixture after 6 h. Flash chromatography (silica gel,

PE–EtOAc, 95:5) afforded 8 (94 mg, 67%) as crystals; mp 48–49

°C.

IR (CCl₄): 2956, 1561, 1458, 1382, 1218, 1109, 1051 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 8.13 (d, J = 2.4 Hz, 1 H, CH_Ar),

7.40 (dd, J₁= 2.4 Hz, J₂= 8.0 Hz, 1 H, CH_Ar), 7.15 (d, J = 8.4 Hz,

1 H, CH_Ar), 4.59 (q, J = 7.2 Hz, 2 H, OCH₂CH₃), 3.13 (dd, J₁= 4.0

Hz, J₂= 10.0 Hz, 1 H, SiCHS), 2.79–2.72 (m, 1 H, CH₂Ar), 2.66–

2.59 (m, 1 H, CH₂Ar), 2.05–1.96 (m, 1 H, CH₂CHS), 1.77–1.67 (m,

1 H, CH₂CHS), 1.35 (t, J = 7.2 Hz, 3 H, OCH₂CH₃), 0.05 [s, 9 H,

Si(CH₃)₃].

¹³C NMR (100 MHz, CDCl₃): d = 215.7 (C=S), 149.3 (CH_Ar), 148.8

(C), 138.6 (CH_Ar), 135.8 (C), 123.6 (CH_Ar), 70.2 (OCH₂CH₃), 36.2

(SiCHS), 32.4 (CH₂CHS), 30.6 (CH₂Ar), 13.6 (OCH₂CH₃), –2.7

[Si(CH₃)₃].

MS (CI, NH₃): m/z = 362 [M + H]⁺(100%).

HRMS (EI): m/z [M]⁺calcd for C₁₅H₂₄ClNOS₂Si: 361.0757; found:

361.0758.

S-3-(6-Chloro-3-pyridyl)-1-(2,2-dimethylpropanoyl)propyl

O-Ethyl Dithiocarbonate (11)

Following the general procedure using xanthate (1 mmol, 1 equiv)

and vinyl pivalate (2 equiv) in DCE (1 mL). After the addition of

DLP (2 × 5 mol%), further alkene (2 equiv) and DLP (2 × 5 mol%)

were added. Column chromatography (silica gel, gradient toluene–

EtOAc, 10:0 to 98:2) afforded 11 (45% yield) as a colorless oil.

MS (CI, NH₃): m/z = 348 [M + H]⁺(100%);

HRMS (EI): m/z [M]⁺calcd for C₁₄H₂₂ClNOS₂Si: 347.060

1; found: 347.0588.

IR (CCl₄): 1739 (OCO), 1228, 1052 cm^–1(C–O, CS).

¹H NMR (400 MHz, CDCl₃): d = 8.22 (d, J = 2.0 Hz, 1 H, CH_Ar),

7.49 (dd, J = 2.6 Hz, J = 8.2 Hz, 1 H, CH_Ar), 7.26 (d, J = 8.1 Hz, 1

H, CH_Ar), 6.61 (t, J = 6.5 Hz, 1 H, CHS), 4.63 (m, 2 H, OCH₂CH₃),

2.74 (t, J = 7.9 Hz, 2 H, CH₂), 2.24 (m, 2 H, CH₂), 1.40 (t, J = 7.2

Hz, 3 H, OCH₂CH₃), 1.20 [s, 9 H, C(CH₃)₃].

¹³C NMR (100 MHz, CDCl₃): d = 209.9 (C=S), 176.8 (C=O), 149.6

(CH_Ar), 138.8 (CH_Ar), 124.1 (CH_Ar), 80.1 (CHS), 70.3 (OCH₂CH₃),

38.9 [C(O)Me₃], 35.4, 28.2 (2 CH₂), 27.0 [C(CH₃)₃], 13.7

(OCH₂CH₃).

S-3-(6-Chloro-3-pyridyl)-1-[(diethoxyphosphoryl)methyl]pro-

pyl O-Ethyl Dithiocarbonate (9)

Following the general procedure using xanthate (0.8 mmol, 1 equiv)

and diethyl allylphosphonate (4 equiv) in DCE (0.2 mL) and DLP

(32.5 mol%). Column chromatography (silica gel, gradient toluene–

EtOAc, 10:0 to 6:4) furnished 9 (62% yield) as a yellow oil.

IR (CCl₄): 1583, 1560 (C=N), 1221, 1050 cm^–1(C–O, CS).

¹H NMR (400 MHz, CDCl₃): d = 8.22 (d, J = 2.4 Hz, 1 H, CH_Ar),

7.52 (dd, J = 2.5 Hz, J = 8.2 Hz, 1 H, CH_Ar), 7.25 (d, J = 8.1 Hz, 1

H, CH_Ar), 4.65 (q, J = 7.1 Hz, 2 H, OCH₂CH₃), 4.09 (m, 4 H, 2

CH₃CH₂OP), 3.97 (m, 1 H, CHS), 2.84 (ddd, J = 4.9 Hz, J = 9.8 Hz,

MS (CI, NH₃): m/z = 376, 378 [M + H]⁺.

HRMS (EI): m/z [M – SCSOCH₂CH₃]⁺calcd for C₁₃H₁₇ClNO₂:

254.0948; found: 254.0952.

Synthesis 2008, No. 18, 2996–3008 © Thieme Stuttgart · New York

FEATURE ARTICLE

Generation and Intermolecular Additions of Pyridylmethyl Radicals

3001

S-1-{2-[(tert-Butoxycarbonyl)amino]-2,2-bis(ethoxycarbon-

yl)ethyl}-3-(6-chloro-3-pyridyl)propyl O-Ethyl Dithiocarbon-

ate (12)

Following the general procedure using xanthate (0.8 mmol, 1 equiv)

and alkene (4 equiv) in PhCl (0.2 mL) and DLP (27.5 mol%) in an

oil bath at 100 °C. Column chromatography (gradient PE–EtOAc,

10:0 to 8:2) gave 12 (36% yield) as a colorless oil.

H, CH_Ar), 7.42 (t, J = 7.4 Hz, 1 H, CH_Ar), 7.32 (d, J = 8.2 Hz, 1 H,

CH_Ar), 7.26 (d, J = 7.2 Hz, 2 H, CH_Ar), 4.66 (m, 2 H, OCH₂CH₃),

4.22 (d, J = 6.8 Hz, 1 H, CHS), 3.67 (dd, J = 6.1 Hz, J = 12.7 Hz, 1

H, CHCH₂), 3.32 (apparent d, J = 5.9 Hz, 2 H, CH₂CH), 1.43 (t,

J = 7.1 Hz, 3 H, OCH₂CH₃).

¹³C NMR (100 MHz, DMSO-d₆): d = 210.6 (C=S), 175.1 (C=O),

172 (C=O), 150.3 (CH_Ar), 148.6 (C_Ar), 140.4 (CH_Ar), 132.8, 132.1

(2 C_Ar), 128.9, 128.4, 126.6, 123.7 (6 CH_Ar), 71.0 (OCH₂CH₃), 50.0,

49.9 (CHS, CH), 30.9 (CH₂Ar), 13.3 (OCH₂CH₃).

IR (CCl₄): 3419 (NH), 1741, 1720 (C=O), 1217, 1052 cm^–1(C–O,

CS).

¹H NMR (400 MHz, CDCl₃): d = 8.20 (d, J = 2.3 Hz, 1 H, CH_Ar),

7.46 (dd, J = 2.5 Hz, J = 8.2 Hz, 1 H, CH_Ar), 7.23 (d, J = 8.1 Hz, 1

H,, CH_Ar), 6.04 (s, 1 H, NH), 4.63 (qd, J = 7.1 Hz, 2 H, OCH₂CH₃),

4.28 (m, 2 H, CO₂CH₂CH₃), 4.18 (m, 2 H, CO₂CH₂CH₃), 3.71 (m,

1 H, CHS), 2.91 (dd, J = 2.7 Hz, J = 15.5 Hz, 1 H, CH₂), 2.69 (m, 3

H, CH₂, CH₂), 1.99 (m, 2 H, CH₂), 1.43 [s + t, 12 H, OC(CH₃)₃,

OCH₂CH₃], 1.27 (t, J = 7.1 Hz, 3 H, CO₂CH₂CH₃), 1.24 (t, J = 7.1

Hz, 3 H, CO₂CH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 212.9 (C=S), 167.8 (OCOCMe₃),

154.1 (CONH), 149.7 (CH_Ar), 149.3 (C_Ar), 138.8 (CH_Ar), 135.5

(C_Ar), 124.0 (CH_Ar), 80.7 (CMe₃), 70.1 (OCH₂CH₃), 65.3 (C_q), 63.2,

62.6 (2 CO₂CH₂CH₃), 45.4 (CHS), 37.8, 36.1, 29.4 (3 CH₂), 28.3

[C(CH₃)₃], 14.1, 13.9 (2 CO₂CH₂CH₃), 13.8 (OCH₂CH₃).

HRMS (EI): m/z [M – SCSOEt]⁺calcd for C₁₆H₁₂ClN₂O₂S:

299.0587; found: 299.0586.

S-3-(6-Chloro-3-pyridyl)-1-[(4-methoxyphenylsulfonylami-

no)methyl]propyl O-Ethyl Dithiocarbonate (15)

Following the general procedure as the solvent using xanthate (0.8

mmol, 1 equiv) and alkene (4 equiv) in PhCl (0.2 mL) and DLP

(4 × 5 mol%) in an oil bath at 100 °C. Column chromatography

(gradient PE–EtOAc, 10:0 to 8:2) gave 15 (46% yield) as a colorless

oil.

IR (CCl₄): 3270 (NH), 1593 (C=C, C=N), 1333, 1155 (NSO₂),

1222, 1053 cm^–1(C–O, CS).

¹H NMR (400 MHz, CDCl₃): d = 8.18 (d, J = 2.5 Hz, 1 H, CH_Ar),

7.77 (d, J = 9.0 Hz, 2 H, CH_Ar), 7.47 (dd, J = 2.5 Hz, J = 8.2 Hz, 1

H, CH_Ar), 7.25 (d, J = 8.2 Hz, 1 H, CH_Ar), 6.97 (d, J = 8.9 Hz, 2 H,

CH_Ar), 4.86 (br t, J = 5.8 Hz, 1 H, NH), 4.61 (qd, 2 H, OCH₂CH₃),

3.87 (m, 1 H, CHS), 3.73 (s, 3 H, OCH₃), 3.24 (m, 2 H, CH₂N), 2.79

(m, 1 H, CH₂CHS), 2.69 (m, 1 H, CH₂CHS), 2.07 (m, 1 H,

CH₂CH₂CHS), 1.90 (m, 1 H, CH₂CH₂CHS), 1.41 (t, J = 7.1 Hz, 3

H, OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 212.5 (C=S), 163.0 (C_Ar), 149.6

(CH_Ar), 149.3 (C_Ar), 139.0 (CH_Ar), 135.1, 131.4 (2 C_q), 129.2

(CH_Ar), 124.1 (CH_Ar), 114.4 (CH_Ar), 70.6 (OCH₂CH₃), 55.7

(OCH₃), 49.9 (CHS), 46.2 (CH₂N), 32.01, 29.3 (2 CH₂), 13.8

(OCH₂CH₃).

MS (CI, NH₃): m/z = 563, 565 [M + H]⁺.

HRMS (EI): m/z [M]⁺calcd for C₂₄H₃₅ClN₂O₇S₂: 562.1574; found:

562.1572.

S-1-[2-(6-Chloro-3-pyridyl)ethyl]-3-(5,5-dimethyl-1,3-dioxan-

2-yl)-3-methylbutyl O-Ethyl Dithiocarbonate (13)

Following the general procedure using xanthate (0.8 mmol, 1 equiv)

and alkene (4 equiv) in PhCl (0.2 mL) and DLP (35 mol%) in an oil

bath at 100 °C. Column chromatography (silica gel, gradient PE–

Et₂O, 10:0 to 9:1) furnished 13 (47% yield, 56% based on recovered

starting material) as a solid. Recrystallization (PE) afforded white

crystals; mp 65–66 °C.

IR (CCl₄): 1214, 1054 (C–O, CS), 1110 cm^–1(C–O–C).

MS (CI, NH₃): m/z = 475, 477 [M + H]⁺.

¹H NMR (400 MHz, CDCl₃): d = 8.21 (d, J = 2.1 Hz, 1 H, CH_Ar),

7.47 (dd, J = 2.5 Hz, J = 8.2 Hz, 1 H, CH_Ar), 7.22 (d, J = 8.1 Hz, 1

H, CH_Ar), 4.63 (q, J = 7.1 Hz, 2 H, OCH₂CH₃), 4.08 [s, 1 H,

CH(CH₂O)₂], 3.86 (m, 1 H, CHS), 3.57 (d, J = 10.9 Hz, 2 H, CH₂O),

3.35 (d, J = 10.8 Hz, 2 H, CH₂O), 2.71 (m, 2 H, CH₂Ar), 1.97 (dd,

J = 7.2 Hz, J = 15.4 Hz, 2 H, CH₂CH₂Ar), 1.75 (d, J = 5.6 Hz, 2 H,

CH₂CHS), 1.40 (t, J = 7.1 Hz, 3 H, OCH₂CH₃), 1.13 (s, 3 H, CH₃),

0.98 (s, 3 H, CH₃), 0.97 (s, 3 H, CH₃), 0.69 (s, 3 H, CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 214.4 (C=S), 149.6 (CH_Ar), 149.1

(C_Ar), 138.9 (CH_Ar), 136.0 (C_Ar), 123.9 (CH_Ar), 106.6 (CH), 77.34,

77.27 (2 CH₂O), 69.8 (OCH₂CH₃), 46.6 (CHS), 40.6, 39.2 (2 CH₂),

38.2, 30.2 (OC_qMe₂, C_qMe₂), 29.4 (CH₂), 23.0, 22.9, 22.5, 21.8 (4

CH₃), 13.9 (OCH₂CH₃).

HRMS (EI): m/z [M – SCSOCH₂CH₃]⁺calcd for C₁₆H₁₈ClN₂O₃S:

353.0727; found: 353.0724.

S-1-(2-Acetoxyethyl)-3-(6-chloro-3-pyridyl)propyl O-Ethyl

Dithiocarbonate (16)

Following the general procedure using xanthate (0.8 mmol, 1 equiv)

and alkene (4 equiv) in heptane (0.2 mL) and dicumyl peroxide

(2 × 25 mol%) as the initiator. Column chromatography (silica gel,

gradient PE–EtOAc, 95:5 to 8:2) afforded 16 (55% yield) as a col-

orless oil.

IR (CCl₄): 1743 (OCOMe), 1583, 1560 (C=N), 1226, 1053 cm^–1

(C–O, CS).

¹H NMR (400 MHz, CDCl₃): d = 8.19 (s, 1 H, CH_Ar), 7.46 (dd,

J = 1.8 Hz, J = 8.2 Hz, 1 H, CH_Ar), 7.23 (dd, J = 1.1 Hz, J = 8.2 Hz,

1 H), 4.61 (qd, J = 7.1 Hz, 2 H, OCH₂CH₃), 4.16 (m, 2 H, CH₂OAc),

3.82 (m, 1 H, CHS), 2.74 (m, 2 H, CH₂), 2.01 (m, 7 H, 2 CH₂,

COCH₃), 1.39 (t, J = 7.1 Hz, 3 H, OCH₂CH_3.).

MS (CI, NH₃): m/z = 446, 448 [M + H]⁺.

HRMS (EI): m/z [M]⁺calcd for C₂₁H₃₂ClNO₃S₂: 445.1512; found:

445.1509.

S-4-[(6-Chloro-3-pyridyl)methyl]-2,5-dioxo-1-phenylpyrroli-

din-3-yl O-Ethyl Dithiocarbonate (14)

¹³C NMR (100 MHz, CDCl₃): d = 213.4 (C=S), 170.9 (OCOCH₃),

149.6 (CH_Ar), 149.3 (C_Ar), 138.8 (CH_Ar), 135.4 (C_Ar), 124.0 (CH_Ar),

70.2 (OCH₂CH₃), 61.6 (CH₂OAc), 47.5 (CHS), 35.7, 33.3, 29.4 (3

CH₂), 20.9 (COCH₃), 13.8 (OCH₂CH₃).

HRMS (EI): m/z [M]⁺calcd for C₁₅H₂₀ClNO₃S₂: 361.0573; found:

361.0568.

Following the general procedure using N-phenylmaleimide (0.58

mmol, 1 equiv) and xanthate (2 equiv) in PhCl (0.5 mL) and DLP

(5 mol%) in an oil bath at 100 °C. The addition product crystallized

from the mixture and the obtained crystals were triturated (Et₂O–

MeOH) to yield the pure 14 (57% yield) as pink crystals; mp 164–

165 °C.

IR (Nujol): 1782, 1711 (C=O), 1235, 1042 cm^–1(C–O, CS).

¹H NMR (400 MHz, CDCl₃): d = 8.34 (d, J = 2.2 Hz, 1 H, CH_Ar),

7.61 (dd, J = 2.5 Hz, J = 8.2 Hz, 1 H, CH_Ar), 7.49 (t, J = 7.4 Hz, 2

N-(tert-Butoxycarbonyl)-N-methyldodec-11-enamine (18)

To a stirred soln of dodec-11-enal (1.45 g, 7.96 mmol) in MeOH

(26.0 mL) was added 10% MeNH₂in MeOH (3.7 mL, 11.9 mmol)

and the mixture was stirred at r.t. for 1 h. The mixture was treated

Synthesis 2008, No. 18, 2996–3008 © Thieme Stuttgart · New York

3002

Z. Ferjancic et al.

FEATURE ARTICLE

with NaBH₄(435 mg, 11.7 mmol) and stirred for an additional 1 h.

The MeOH was evaporated under reduced pressure and the residue

was taken up in CH₂Cl₂and H₂O. The organic layer was separated,

dried (anhyd MgSO₄), filtered, and evaporated under reduced pres-

sure. The crude N-methyldodec-11-enamine (1.3 g) was used in the

next step without further purification.

H, CHS), 3.14 (t, J = 6.8 Hz, 2 H, NCH₂), 2.79 (s, 3 H, NCH₃),

2.74–2.67 (m, 2 H, CH₂Ar), 2.00–1.85 (m, 2 H, CH₂CHS), 1.69–

1.62 (m, 2 H, CH₂CHS), 1.47–1.18 (m, 16 H), 1.41 [s, 9 H,

C(CH₃)₃], 1.38 (t, J = 7.2 Hz, 3 H, OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 214.2 (C=S), 155.7 (C=O), 149.4

(CH_Ar), 149.1 (C), 138.7 (CH_Ar), 135.6 (C), 123.8 (CH_Ar), 78.9 (C),

69.8 (OCH₂CH₃), 50.6 (CHS), 48.7 (CH₂N), 35.6 (CH₂CHS), 34.1

(CH₂CHS), 33.9 (NCH₃), 29.6, 29.5, 29.4 (7 CH₂), 28.5

[COC(CH₃)₃], 26.8 (CH₂), 26.7 (CH₂), 13.8 (OCH₂CH₃).

To a stirred soln of N-methyldodec-11-enamine (1.3 g, 6.63 mmol)

in CH₂Cl₂(40 mL) at 0 °C under N₂, was added dropwise Boc₂O

(1.4 g, 6.63 mmol), and the soln was stirred at r.t. for 24 h. CH₂Cl₂

and H₂O were added and the organic layer was separated, dried (an-

hyd MgSO₄), filtered, and evaporated under reduced pressure. The

residue was purified by flash chromatography (silica gel, PE–

EtOAc, 95:5) to yield 18 (1.62 g, 68%, two steps) as a light yellow

oil.

MS (CI, NH₃): m/z = 545 [M + H]⁺(100%).

HRMS (EI): m/z [M]⁺calcd for C₂₇H₄₅ClN₂O₃S₂: 544.2560; found:

544.2559.

S-(6-Chloro-2-pyridyl)methyl O-Ethyl Dithiocarbonate (25)

2-Chloro-6-methylpyridine (710 mg, 5.56 mmol), NBS (990 mg,

5.56 mmol), and Bz₂O₂(130 mg) in CCl₄(17 mL) were refluxed for

3 h under N₂. The succinimide was removed by filtration and to the

filtrate was added CH₂Cl₂. The organic layer was washed with 5%

aq NaOH and H₂O, dried (anhyd MgSO₄), filtered, and evaporated

under reduced pressure. The residue was purified by flash chroma-

tography (silica gel, PE–Et₂O, 25:2) to yield 2-(bromomethyl)-6-

chloropyridine (648 mg, 56%) as an inseparable mixture with the

starting compound (52 mg); this sample was used in the next step

without further purification.

IR: 2974, 2927, 2856, 1695, 1459, 1394, 1307, 1164 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 5.78–5.68 (m, 1 H, CH₂=CH),

4.94–4.84 (m, 2 H, CH=CH₂), 3.12 (t, J = 6.0 Hz, 2 H, CH₂N), 2.76

(s, 3 H, NCH₃), 1.99–1.94 (m, 2 H, CH₂=CHCH₂), 1.46–1.17 (m, 16

H), 1.39 [s, 9 H, C(CH₃)₃].

¹³C NMR (100 MHz, CDCl₃): d = 155.6 (C=O), 138.9 (CH₂=CH),

114.0 (CH₂=CH), 78.8 (C), 48.6 (CH₂N), 33.8 (NCH₃), 33.7 (CH₂),

29.4 (2 CH₂), 29.3 (CH₂), 29.2 (CH₂), 29.0 (CH₂), 28.8 (CH₂), 28.3

[COC(CH₃)₃], 27.7 (CH₂), 26.5 (CH₂).

MS (CI, NH₃): m/z = 298 [M + H]⁺(10%).

To a soln of 2-(bromomethyl)-6-chloropyridine (648 mg, 3.14

mmol) in acetone (10 mL) was added portionwise potassium O-eth-

yl xanthate (553 mg, 2.46 mmol) at 0 °C under N₂. The mixture was

stirred at r.t. until complete consumption of the starting material.

Acetone was evaporated under reduced pressure and the residue

was taken up in CH₂Cl₂, washed with sat. aq NH₄Cl and H₂O, dried

(anhyd MgSO₄), filtered, and evaporated under reduced pressure.

The residue was purified by flash chromatography (silica gel, PE–

Et₂O, 25:2) to yield 25 (560 mg, 72%) as a yellow oil.

HRMS (EI): m/z [M]⁺calcd for C₁₈H₃₅NO₂: 297.2668; found:

297.2673.

Methyl 12-(6-Chloro-3-pyridyl)-10-(ethoxythiocarbonylsulfa-

nyl)dodecanoate (19)

Following the general procedure using xanthate (2.01 mmol, 1

equiv) and methyl undec-10-enoate (4 equiv) in DCE (0.2 mL) and

DLP (32.5 mol%). Column chromatography (silica gel, PE–EtOAc,

95:5) furnished 19 (56% yield, 65% based on recovered starting ma-

terial) as a yellow oil.

IR: 2987, 1577, 1562, 1434, 1220, 1137, 1113, 1054 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 7.56 (t, J = 8.0 Hz, 1 H, CH_Ar),

7.31 (d, J = 7.6 Hz, 1 H, CH_Ar), 7.16 (d, J = 8.0 Hz, 1 H, CH_Ar), 4.58

(q, J = 7.2 Hz, 2 H, OCH₂CH₃), 4.41 (s, 2 H, CH₂S), 1.34 (t, J = 7.2

Hz, 3 H, OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 212.9 (C=S), 157.0 (C), 150.6

(C), 139.1 (CH_Ar), 122.8 (CH_Ar), 121.5 (CH_Ar), 70.2 (OCH₂CH₃),

41.0 (CH₂Ar), 13.6 (OCH₂CH₃).

IR (CCl₄): 1740 (CO₂Me), 1583, 1561 (C=N), 1216, 1054 cm^–1

(C–O, CS).

¹H NMR (400 MHz, CDCl₃): d = 8.22 (d, J = 2.4 Hz, 1 H, CH_Ar),

7.48 (dd, J = 2.4 Hz, J = 8.2 Hz, 1 H, CH_Ar), 7.25 (d, J = 8.2 Hz, 1

H, CH_Ar), 4.65 (q, J = 7.1 Hz, 2 H, OCH₂CH₃), 3.74 (m, 1 H, CHS),

3.67 (s, 3 H, OCH₃), 2.74 (m, 2 H, CH₂), 2.30 (t, 2 H, CH₂), 1.96 (m,

2 H, CH₂), 1.65 (m, 4 H, 2 CH₂), 1.42 (t, J = 7.1 Hz, 3 H,

OCH₂CH₃), 1.28 (m, 10 H, 5 CH₂).

MS (CI, NH₃): m/z = 248 [M + H]⁺(100%).

¹³C NMR (100 MHz, CDCl₃): d = 214.4 (C=S), 174.3 (C=O), 149.6

(CH_Ar), 149.2 (C_Ar), 138.9 (CH_Ar), 135.8 (C_Ar), 124.0 (CH_Ar), 69.9

(OCH₂CH₃), 51.5, 50.8 (CHS, OCH₃), 35.8, 34.3, 34.1, 29.6, 29.4,

29.3, 29.2, 29.1, 26.8, 24.9 (CH₂), 13.9 (OCH₂CH₃).

MS (CI, NH₃): m/z = 446, 448 [M + H]⁺.

HRMS (EI): m/z [M]⁺calcd for C₂₁H₃₂ClNO₃S₂: 445.1512; found:

HRMS (EI): m/z [M]⁺calcd for C₉H₁₀ClNOS₂: 246.9892; found:

246.9900.

S-2-Chloro-4-pyridyl)methyl O-Ethyl Dithiocarbonate (26)

2-Chloro-4-methylpyridine (1.0 g, 7.83 mmol), NBS (1.4 g, 7.83

mmol), and Bz₂O₂(180 mg) in CCl₄(23 mL) were refluxed for 3 h

under N₂. The succinimide was removed by filtration and CH₂Cl₂

was added to the filtrate. The organic layer was washed with 5% aq

NaOH and H₂O, dried (anhyd MgSO₄), filtered, and evaporated un-

der reduced pressure. The residue was purified by flash chromatog-

raphy (silica gel, PE–EtOAc, 25:2) to yield 4-(bromomethyl)-2-

chloropyridine (480 mg, 29%) as a yellow oil.

445.1510.

S-11-[(tert-Butoxycarbonyl)(methyl)amino]-1-[2-(6-chloro-3-

pyridyl)ethyl]undecyl O-Ethyl Dithiocarbonate (20)

Following the general procedure using xanthate 5 (70 mg, 0.28

mmol) and 18 (334 mg, 1.13 mmol, 4 equiv) in MEK (0.3 mL) and

requiring DLP (35 mol%) to go to completion. Flash chromatogra-

phy (silica gel, PE–Et₂O, 6:1) afforded 20 (86 mg, 51%) as a yellow

oil, together with recovered starting xanthate (12 mg). The yield

based on recovered starting xanthate was 60%.

To a soln of 4-(bromomethyl)-2-chloropyridine (430 mg, 2.08

mmol) in acetone (10 mL) was added portionwise potassium O-eth-

yl xanthate (366 mg, 2.28 mmol) at 0 °C under N₂. The mixture was

stirred at r.t. until complete consumption of the starting material.

Acetone was evaporated under reduced pressure and the residue

was taken up in CH₂Cl₂, washed with sat. aq NH₄Cl and H₂O, dried

(anhyd MgSO₄), filtered, and evaporated under reduced pressure.

The residue was purified by flash chromatography (silica gel, PE–

Et₂O, 25:2) to yield 26 (450 mg, 84%) as a yellow oil.

IR: 2929, 2856, 1695, 1459, 1392, 1216, 1163, 1110, 1054 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 8.18 (d, J = 2.0 Hz, 1 H, CH_Ar),

7.44 (dd, J₁= 2.4 Hz, J₂= 8.0 Hz, 1 H, CH_Ar), 7.21 (d, J = 8.0 Hz,

1 H, CH_Ar), 4.60 (q, J = 7.2 Hz, 2 H, OCH₂CH₃), 3.73–3.66 (m, 1

Synthesis 2008, No. 18, 2996–3008 © Thieme Stuttgart · New York

FEATURE ARTICLE

Generation and Intermolecular Additions of Pyridylmethyl Radicals

3003

IR: 2987, 1588, 1380, 1229, 1113, 1052 cm^–1.

S-3-(6-Chloro-2-pyridyl)-1-(trimethylsilyl)propyl O-Ethyl

Dithiocarbonate (29)

¹H NMR (400 MHz, CDCl₃): d = 8.23 (d, J = 5.2 Hz, 1 H, CH_Ar),

7.26 (s, 1 H, CH_Ar), 7.15 (dd, J₁= 1.2 Hz, J₂= 5.2 Hz, 1 H, CH_Ar),

4.56 (q, J = 7.2 Hz, 2 H, OCH₂CH₃), 4.24 (s, 2 H, CH₂S), 1.33 (t,

J = 7.2 Hz, 3 H, OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 211.9 (C=S), 151.40 (C), 149.4

(CH_Ar), 148.7 (C), 124.0 (CH_Ar), 122.4 (CH_Ar), 70.5 (OCH₂CH₃),

38.0 (CH₂S), 13.5 (OCH₂CH₃).

Following the general procedure using xanthate 25 (100 mg, 0.40

mmol) and trimethyl(vinyl)silane (245 mg, 2.42 mmol, 6 equiv) in

MEK (0.4 mL) and requiring DLP (25 mol%) to go to completion.

Flash chromatography (silica gel, PE–Et₂O, 25:1) afforded 29 (95

mg, 68%) as a light yellow oil.

IR: 2956, 1582, 1558, 1437, 1216, 1111, 1050 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 7.52 (t, J = 7.6 Hz, 1 H, CH_Ar),

7.12 (d, J = 7.6 Hz, 1 H, CH_Ar), 7.04 (d, J = 7.6 Hz, 1 H, CH_Ar), 4.63

(q, J = 7.2 Hz, 2 H, OCH₂CH₃), 3.20 (dd, J₁= 3.6 Hz, J₂= 10.4 Hz,

1 H, SiCHS), 3.01–2.93 (m, 1 H, CH₂Ar), 2.84 (ddd, J₁= 6.0 Hz,

J₂= 10.4 Hz, J₃= 16.4 Hz, 1 H, CH₂Ar), 2.29–2.21 (m, 1 H,

CH₂CHS), 1.89–1.79 (m, 1 H, CH₂CHS), 1.40 (t, J = 7.2 Hz, 3 H,

OCH₂CH₃), 0.10 [s, 9 H, Si(CH₃)₃].

¹³C NMR (100 MHz, CDCl₃): d = 216.2 (C=S), 162.6 (C), 150.7

(C), 138.8 (CH_Ar), 121.5 (CH_Ar), 121.3 (CH_Ar), 70.2 (OCH₂CH₃),

36.7 (CHS), 36.4 (CH₂Ar), 30.7 (CH₂CHS), 13.8 (OCH₂CH₃), –2.6

[Si(CH₃)₃].

MS (CI, NH₃): m/z = 248 [M + H]⁺(100%).

HRMS (EI): m/z [M]⁺calcd for C₉H₁₀ClNOS₂: 246.9892; found:

246.9885.

S-1-(Acetoxymethyl)-3-(6-chloro-2-pyridyl)propyl O-Ethyl

Dithiocarbonate (27)

Following the general procedure using xanthate 25 (100 mg, 0.40

mmol) and allyl acetate (162 mg, 1.61 mmol, 4 equiv) in MEK (0.4

mL) and requiring DLP (20 mol%) to go to completion. Flash chro-

matography (silica gel, PE–EtOAc, 9:1) afforded 27 (80 mg, 57%)

as a light yellow oil.

MS (CI, NH₃): m/z = 348 [M + H]⁺(100%).

HRMS (EI): m/z [M]⁺calcd for C₁₄H₂₂ClNOS₂Si: 347.0601; found:

IR: 2956, 1582, 1558, 1437, 1216, 1111, 1050 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 7.53 (t, J = 7.6 Hz, 1 H, CH_Ar),

7.14 (d, J = 8.0 Hz, 1 H, CH_Ar), 7.05 (d, J = 7.6 Hz, 1 H, CH_Ar), 4.61

(dq, J₁= 2.0 Hz, J₂= 7.2 Hz, 2 H, OCH₂CH₃), 4.30–4.21 (m, 2 H,

CH₂OAc), 3.99–3.93 (m, 1 H, CHS), 2.99–2.92 (m, 1 H, CH₂Ar),

2.89–2.82 (m, 1 H, CH₂Ar), 2.29–2.20 (m, 1 H, CH₂CHS), 2.06–

1.96 (m, 1 H, CH₂CHS), 2.04 (s, 3 H, OCCH₃), 1.38 (dt, J₁= 1.6 Hz,

J₂= 7.2 Hz, 3 H, OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 212.8 (C=S), 170.5 (C=O), 161.5

(C), 150.8 (C), 138.9 (CH_Ar), 121.8 (CH_Ar), 121.4 (CH_Ar), 70.1

(OCH₂CH₃), 65.4 (CH₂OAc), 48.8 (CHS), 34.8 (CH₂Ar), 30.2

(CH₂CHS), 20.7 (OCCH₃), 13.6 (OCH₂CH₃).

347.0602.

Methyl 12-(6-Chloro-2-pyridyl)-10-(ethoxythiocarbonylsulfa-

nyl)dodecanoate (30)

Following the general procedure using xanthate 25 (100 mg, 0.40

mmol) and methyl undec-10-enoate (320 mg, 1.61 mmol, 4 equiv)

in DCE (0.4 mL) and requiring DLP (20 mol%) to go to completion.

Flash chromatography (silica gel, PE–Et₂O, 25:2) afforded 30 (110

mg, 61%) as a light yellow oil.

IR: 2930, 2856, 1741, 1582, 1559, 1438, 1214, 1111, 1055 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 7.51 (t, J = 7.6 Hz, 1 H, CH_Ar),

7.11 (d, J = 7.6 Hz, 1 H, CH_Ar), 7.03 (d, J = 7.2 Hz, 1 H, CH_Ar), 4.59

(q, J = 7.2 Hz, 2 H, OCH₂CH₃), 3.75–3.70 (m, 1 H, CHS), 3.62 (s,

3 H, OCH₃), 2.92–2.79 (m, 2 H, CH₂Ar), 2.25 (t, J = 7.6 Hz, 2 H,

OCCH₂), 2.17–2.08 (m, 1 H, CH₂CHS), 2.02–1.93 (m, 1 H,

CH₂CHS), 1.69–1.61 (m, 2 H, CHSCH₂), 1.59–1.53 (m, 2 H), 1.40–

1.34 (m, 2 H), 1.36 (t, J = 7.2 Hz, 3 H, OCH₂CH₃), 1.23 (m, 8 H).

¹³C NMR (100 MHz, CDCl₃): d = 214.4 (C=S), 174.1 (C=O), 162.2

(C), 150.6 (C), 138.8 (CH_Ar), 121.5 (CH_Ar), 121.2 (CH_Ar), 69.6

(OCH₂CH₃), 51.3 (OCH₃), 50.8 (CHS), 35.0 (CH₂Ar), 34.1

(CHSCH₂), 33.9 (OCCH₂), 33.8 (CH₂CHS), 29.2 (CH₂), 29.1

(CH₂), 29.0 (CH₂), 28.9 (CH₂), 26.6 (CH₂), 24.8 (CH₂), 13.7

(OCH₂CH₃).

MS (CI, NH₃): m/z = 348 [M + H]⁺(100%).

HRMS (EI): m/z [M]⁺calcd for C₁₄H₁₈ClNO₃S₂: 347.0417; found:

347.0416.

S-3-(6-Chloro-2-pyridyl)-1-[(trimethylsilyl)methyl]propyl

O-Ethyl Dithiocarbonate (28)

Following the general procedure using xanthate 25 (100 mg, 0.40

mmol) and allyltrimethylsilane (185 mg, 1.61 mmol, 4 equiv) in

MEK (0.4 mL) and requiring DLP (20 mol%) to go to completion.

Further allyltrimethylsilane (93 mg, 0.80 mmol, 2 equiv) were add-

ed to the mixture after 4.5 h. Flash chromatography (silica gel, PE–

Et₂O, 25:2) afforded 28 (100 mg, 68%) as a light yellow oil.

IR: 2955, 1582, 1558, 1438, 1214, 1111, 1054 cm^–1.

MS (CI, NH₃): m/z = 446 [M + H]⁺(100%).

HRMS (EI): m/z [M]⁺calcd for C₂₁H₃₂ClNO₃S₂: 445.1512; found:

¹H NMR (400 MHz, CDCl₃): d = 7.52 (t, J = 8.0 Hz, 1 H, CH_Ar),

7.12 (d, J = 8.0 Hz, 1 H, CH_Ar), 7.04 (d, J = 7.6 Hz, 1 H, CH_Ar), 4.60

(dq, J₁= 1.6 Hz, J₂= 7.2 Hz, 2 H, OCH₂CH₃), 3.87–3.80 (m, 1 H,

CHS), 2.90–2.85 (m, 2 H, CH₂Ar), 2.23–2.14 (m, 1 H, CH₂CHS),

2.06–1.97 (m, 1 H, CH₂CHS), 1.38 (t, J = 7.2 Hz, 3 H, OCH₂CH₃),

1.12 (dd, J₁= 7.2 Hz, J₂= 14.8 Hz, 1 H, CH₂Si), 1.06 (dd, J₁= 8.0

Hz, J₂= 14.8 Hz, 1 H, CH₂Si), 0.03 [s, 9 H, Si(CH₃)₃].

¹³C NMR (100 MHz, CDCl₃): d = 214.2 (C=S), 162.2 (C), 150.7

(C), 138.8 (CH_Ar), 121.6 (CH_Ar), 121.4 (CH_Ar), 69.4 (OCH₂CH₃),

48.0 (CHS), 36.5 (CH₂CHS), 34.9 (CH₂Ar), 23.2 (CH₂Si), 13.7

(OCH₂CH₃), –0.8 [Si(CH₃)₃].

445.1505.

S-1-[(4-Chlorophenylsulfonylamino)methyl]-3-(6-chloro-2-py-

ridyl)propyl O-Ethyl Dithiocarbonate (31)

Following the general procedure using xanthate 25 (100 mg, 0.40

mmol) and N-allyl-4-chlorobenzenesulfonamide (372 mg, 1.61

mmol, 4 equiv) in DCE (0.4 mL) and requiring DLP (20 mol%) to

go to completion. Flash chromatography (silica gel, PE–EtOAc,

8:2) afforded 31 (128 mg, 66%) as a light yellow oil.

IR: 2956, 1582, 1558, 1437, 1216, 1111, 1050 cm^–1.

MS (CI, NH₃): m/z = 362 (M + H]⁺(100%).

HRMS (EI): m/z [M]⁺calcd for C₁₅H₂₄ClNOS₂Si: 361.0757; found:

¹H NMR (400 MHz, CDCl₃): d = 7.78 (d, J = 8.8 Hz, 2 H, CH_Ar),

7.53 (t, J = 8.0 Hz, 1 H, CH_Ar), 7.44 (d, J = 8.8 Hz, 2 H, CH_Ar), 7.13

(d, J = 8.0 Hz, 1 H, CH_Ar), 7.03 (d, J = 7.6 Hz, 1 H, CH_Ar), 5.62 (t,

J = 6.4 Hz, 1 H, NH), 4.56 (q, J = 7.2 Hz, 2 H, OCH₂CH₃), 3.79

(ddd, J₁= 6.0 Hz, J₂= 8.8 Hz, J₃= 14.8 Hz, 1 H, CHS), 3.27 (t,

J = 6.0 Hz, 2 H, CH₂N), 2.93–2.86 (m, 1 H, CH₂Ar), 2.84–2.77 (m,

361.0741.

Synthesis 2008, No. 18, 2996–3008 © Thieme Stuttgart · New York

3004

Z. Ferjancic et al.

FEATURE ARTICLE

1 H, CH₂Ar), 2.22–2.14 (m, 1 H, CH₂CHS), 2.02–1.92 (m, 1 H,

CH₂CHS), 1.36 (t, J = 7.2 Hz, 3 H, OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 212.5 (C=S), 161.3 (C), 150.7

(C), 139.1 (CH_Ar), 139.0 (C), 138.4 (C), 129.3 (2 CH_Ar), 128.4 (2

CH_Ar), 121.9 (CH_Ar), 121.5 (CH_Ar), 70.3 (OCH₂CH₃), 49.9 (CHS),

46.0 (CH₂N), 34.3 (CH₂Ar), 30.2 (CH₂CHS), 13.6 (OCH₂CH₃).

MS (CI, NH₃): m/z = 479 [M + H]⁺(100%).

HRMS (EI): m/z [M]⁺calcd for C₁₈H₂₀Cl₂N₂O₃S₃: 478.0013; found:

MEK (0.4 mL) and requiring DLP (15 mol%) to go to completion.

Flash chromatography (silica gel, PE–Et₂O, 25:3) afforded 34 (131

mg, 84%) as a light yellow oil.

IR: 2954, 1590, 1385, 1216, 1112, 1053 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 8.23 (d, J = 5.2 Hz, 1 H, CH_Ar),

7.11 (s, 1 H, CH_Ar), 7.00 (dd, J₁= 1.2 Hz, J₂= 5.2 Hz, 1 H, CH_Ar),

4.61 (dq, J₁= 1.2 Hz, J₂= 7.2 Hz, 2 H, OCH₂CH₃), 3.85–3.81 (m, 1

H, CHS), 2.73–2.68 (m, 2 H, CH₂Ar), 2.00–1.93 (m, 2 H,

CH₂CHS), 1.38 (t, J = 7.2 Hz, 3 H, OCH₂CH₃), 1.10 (dd, J₁= 7.6

Hz, J₂= 15.2 Hz, 1 H, CH₂Si), 1.02 (dd, J₁= 8.0 Hz, J₂= 15.2 Hz,

1 H, CH₂Si), 0.03 [s, 9 H, Si(CH₃)₃].

¹³C NMR (100 MHz, CDCl₃): d = 213.8 (C=S), 153.8 (C), 151.5

(C), 149.4 (CH_Ar), 124.0 (CH_Ar), 122.6 (CH_Ar), 69.6 (OCH₂CH₃),

47.8 (CHS), 37.5 (CH₂CHS), 31.9 (CH₂Ar), 22.8 (CH₂Si), 13.7

(OCH₂CH₃), –0.8 [Si(CH₃)₃].

477.9991.

S-1-(Acetoxymethyl)-3-(2-chloro-4-pyridyl)propyl O-Ethyl

Dithiocarbonate (32)

Following the general procedure using xanthate 26 (100 mg, 0.40

mmol) and allyl acetate (162 mg, 1.61 mmol, 4 equiv) in MEK (0.4

mL) and requiring DLP (15 mol%) to go to completion. Flash chro-

matography (silica gel, PE–EtOAc, 9:1) afforded 32 (66 mg, 47%)

as a light yellow oil, together with recovered starting xanthate (24

mg). The yield based on recovered starting xanthate was 56%.

MS (CI, NH₃): m/z = 362 [M + H]⁺(100%).

HRMS (EI): m/z [M]⁺calcd for C₁₅H₂₄ClNOS₂Si: 361.0757; found:

361.0745.

IR: 2940, 1749, 1590, 1384, 1225, 1112, 1054 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 8.26 (d, J = 5.2 Hz, 1 H, CH_Ar),

7.15 (br s, 1 H, CH_Ar), 7.03 (dd, J₁= 1.2 Hz, J₂= 4.8 Hz, 1 H, CH_Ar),

4.63 (q, J = 7.2 Hz, 2 H, OCH₂CH₃), 4.30 (dd, J₁= 4.8 Hz, J₂= 11.6

Hz, 1 H, CH₂OAc), 4.23 (dd, J₁= 6.4 Hz, J₂= 11.6 Hz, 1 H,

CH₂OAc), 3.95–3.91 (m, 1 H, CHS), 2.86–2.79 (m, 1 H, CH₂Ar),

2.76–2.68 (m, 1 H, CH₂Ar), 2.12–2.03 (m, 1 H, CH₂CHS), 2.06 (s,

3 H, O=CCH₃), 2.01–1.88 (m, 1 H, CH₂CHS), 1.40 (t, J = 7.2 Hz, 3

H, OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 212.4 (C=S), 170.5 (C=O), 153.1

(C), 151.7 (C), 149.6 (CH_Ar), 124.1 (CH_Ar), 122.5 (CH_Ar), 70.4

(OCH₂CH₃), 65.2 (CH₂OAc), 48.7 (CHS), 32.0 (CH₂Ar), 31.1

(CH₂CHS), 20.7 (Ac), 13.7 (OCH₂CH₃).

Methyl 12-(2-Chloro-4-pyridyl)-10-(ethoxythiocarbonylsulfa-

nyl)dodecanoate (35)

Following the general procedure using xanthate 26 (100 mg, 0.40

mmol) and methyl undec-10-enoate (320 mg, 1.61 mmol, 4 equiv)

in DCE (0.4 mL) and requiring DLP (20 mol%) to go to completion.

Flash chromatography (silica gel, PE–EtOAc, 9:1) afforded 35 (134

mg, 74%) as a light yellow oil.

IR: 2931, 2857, 1741, 1590, 1548, 1461, 1384, 1216, 1113, 1054

cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 8.20 (d, J = 5.2 Hz, 1 H, CH_Ar),

7.10 (s, 1 H, CH_Ar), 6.99 (dd, J₁= 1.2 Hz, J₂= 5.2 Hz, 1 H, CH_Ar),

4.58 (q, J = 7.2 Hz, 2 H, OCH₂CH₃), 3.71–3.64 (m, 1 H, CHS), 3.59

(s, 3 H, OCH₃), 2.74–2.62 (m, 2 H, CH₂Ar), 2.23 (t, J = 7.2 Hz, 2 H,

O=CCH₂), 1.98–1.87 (m, 2 H, CH₂CHS), 1.66–1.60 (m, 2 H,

CH₂CHS), 1.59–1.51 (m, 2 H), 1.37–1.33 (m, 2 H), 1.35 (t, J = 7.2

Hz, 3 H, OCH₂CH₃), 1.22 (m, 8 H).

MS (CI, NH₃): m/z = 348 [M + H]⁺(100%).

HRMS (EI): m/z [M]⁺calcd for C₁₄H₁₈ClNO₃S₂: 347.0417; found:

347.0419.

S-3-(2-Chloro-4-pyridyl)-1-(trimethylsilyl)propyl O-Ethyl

Dithiocarbonate (33)

Following the general procedure using xanthate 26 (100 mg, 0.40

mmol) and trimethyl(vinyl)silane (245 mg, 2.42 mmol, 6 equiv) in

MEK (0.4 mL) and requiring DLP (20 mol%) to go to completion.

Flash chromatography (silica gel, PE–Et₂O, 25:3) afforded 33 (98

mg, 70%) as a light yellow oil.

¹³C NMR (100 MHz, CDCl₃): d = 214.0 (C=S), 174.0 (C=O), 153.8

(C), 151.4 (C), 149.3 (CH_Ar), 124.0 (CH_Ar), 122.5 (CH_Ar), 69.7

(OCH₂CH₃), 51.2 (OCH₃), 50.5 (CHS), 34.6 (CH₂CHS), 34.0

(CH₂CHS), 33.8 (O=CCH₂), 32.0 (CH₂Ar), 29.1 (CH₂), 29.0 (CH₂),

28.9 (CH₂), 28.8 (CH₂), 26.5 (CH₂), 24.7 (CH₂), 13.6 (OCH₂CH₃).

MS (CI, NH₃): m/z = 446 [M + H]⁺(100%).

HRMS (EI): m/z [M]⁺calcd for C₂₁H₃₂ClNO₃S₂: 445.1512; found:

IR: 2956, 1589, 1548, 1385, 1219, 1111, 1050 cm^–1.

445.1498.

¹H NMR (400 MHz, CDCl₃): d = 8.22 (d, J = 4.8 Hz, 1 H, CH_Ar),

7.12 (br s, 1 H, CH_Ar), 7.00 (dd, J₁= 1.6 Hz, J₂= 4.8 Hz, 1 H, CH_Ar),

4.63 (dq, J₁= 1.2 Hz, J₂= 7.2 Hz, 2 H, OCH₂CH₃), 3.17 (dd,

J₁= 4.0 Hz, J₂= 10.0 Hz, 1 H, SiCHS), 2.84–2.76 (m, 1 H, CH₂Ar),

2.66 (ddd, J₁= 6.0 Hz, J₂= 11.2 Hz, J₃= 16.8 Hz, 1 H, CH₂Ar),

2.11–2.02 (m, 1 H, CH₂CHS), 1.81–1.71 (m, 1 H, CH₂CHS), 1.40

(t, J = 7.2 Hz, 3 H, OCH₂CH₃), 0.10 [s, 9 H, Si(CH₃)₃].

¹³C NMR (100 MHz, CDCl₃): d = 215.9 (C=S), 154.2 (C), 151.5

(C), 149.4 (CH_Ar), 124.1 (CH_Ar), 122.6 (CH_Ar), 70.4 (OCH₂CH₃),

36.5 (CHS), 33.5 (CH₂Ar), 31.7 (CH₂CHS), 13.8 (OCH₂CH₃), –2.6

[Si(CH₃)₃].

S-3-(2-Chloro-4-pyridyl)-1-[(diethoxyphosphoryl)methyl]pro-

pyl O-Ethyl Dithiocarbonate (36)

Following the general procedure using xanthate 26 (100 mg, 0.40

mmol) and allyl diethylphosphonate (287 mg, 1.61 mmol, 4 equiv)

in DCE (0.4 mL) and requiring DLP (20 mol%) to go to completion.

Evaporation of the excess of alkene followed by flash chromatogra-

phy (silica gel, EtOAc–toluene, 3:2) afforded 36 (112 mg, 66%) as

a light yellow oil.

IR: 2984, 1590, 1584, 1388, 1222, 1111, 1051 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 8.20 (d, J = 5.2 Hz, 1 H, CH_Ar),

7.13 (s, 1 H), 7.02 (dd, J₁= 1.2 Hz, J₂= 5.2 Hz, 1 H, CH_Ar), 4.59 (q,

J = 7.2 Hz, 2 H, OCH₂CH₃), 4.08–4.00 (m, 4 H, 2 CH₂OP), 3.95–

3.85 (m, 1 H, CHS), 2.79 (ddd, J₁= 4.8 Hz, J₂= 9.6 Hz, J₃= 14.4

Hz, 1 H, CH₂Ar), 2.66 (ddd, J₁= 7.2 Hz, J₂= 9.2 Hz, J₃= 14.0 Hz,

1 H, CH₂Ar), 2.41–2.29 (m, 2 H, CH₂P, CH₂CHS), 2.15–2.05 (m, 1

H, CH₂P), 2.03–1.93 (m, 1 H, CH₂CHS), 1.36 (t, J = 7.2 Hz, 3 H,

OCH₂CH₃), 1.25 (t, J = 7.2 Hz, 6 H, 2 CH₃CH₂OP).

MS (CI, NH₃): m/z = 348 [M + H]⁺(100%).

HRMS (EI): m/z [M]⁺calcd for C₁₄H₂₂ClNOS₂Si: 347.0601; found:

347.0604.

S-3-(2-Chloro-4-pyridyl)-1-[(trimethylsilyl)methyl]propyl

O-Ethyl Dithiocarbonate (34)

Following the general procedure using xanthate 26 (100 mg, 0.40

mmol) and allyltrimethylsilane (185 mg, 1.61 mmol, 4 equiv) in

FEATURE ARTICLE

Generation and Intermolecular Additions of Pyridylmethyl Radicals

3005

¹³C NMR (100 MHz, CDCl₃): d = 212.2 (C=S), 153.2 (C), 151.5

(C), 149.4 (CH_Ar), 124.1 (CH_Ar), 122.6 (CH_Ar), 70.0 (OCH₂CH₃),

61.8 (t, J = 6.3 Hz, CH₂OP), 44.7 (CHS), 33.4 (d, J = 3.0 Hz,

CH₂CHS), 31.7 (CH₂Ar), 31.5 (d, J = 135.5 Hz, CH₂P), 16.3 (d,

J = 6.0 Hz, 2 CH₃CH₂OP), 13.6 (OCH₂CH₃).

HRMS (EI): m/z [M]⁺calcd for C₁₇H₂₅ClN₂O₃S₂: 404.0995; found:

404.1007.

S-3-(2-Chloro-3-pyridyl)-1-[(trimethylsilyl)methyl]propyl

O-Ethyl Dithiocarbonate (41)

Following the general procedure using xanthate 39 (200 mg, 0.81

mmol) and allyltrimethylsilane (369 mg, 3.23 mmol, 4 equiv) in

DCE (0.8 mL), and requiring DLP (40 mol%) to go to completion.

Flash chromatography (silica gel, PE–Et₂O, 25:3) afforded 41 (171

mg, 58%) as a yellow oil, together with recovered starting xanthate

(21 mg). The yield based on recovered starting xanthate was 65%.

MS (CI, NH₃): m/z = 426 [M + H]⁺(100%).

HRMS (EI): m/z [M]⁺calcd for C₁₆H₂₅ClNO₄PS₂: 425.0651; found:

425.0642.

S-(2-Chloro-3-pyridyl)methyl O-Ethyl Dithiocarbonate (39)

2-Chloro-3-methylpyridine (1.0 g, 7.83 mmol), NBS (1.4 g, 7.83

mmol), and Bz₂O₂(180 mg) in CCl₄(23 mL) were refluxed for 3 h

under N₂. The succinimide was removed by filtration and to the fil-

trate was added CH₂Cl₂. The organic layer was washed with 5% aq

NaOH and H₂O, dried (anhyd MgSO₄), filtered, and evaporated un-

der reduced pressure. The residue was purified by flash chromatog-

raphy (silica gel, PE–Et₂O, 25:3) to yield 3-(bromomethyl)-2-

chloropyridine (800 mg, 49%) as a yellow oil.

IR: 2954, 2901, 1560, 1447, 1409, 1250, 1214, 1112, 1055 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 8.22 (dd, J₁= 2.0 Hz, J₂= 4.8 Hz,

1 H, CH_Ar), 7.51 (d, J₁= 2.0 Hz, J₂= 7.6 Hz, 1 H, CH_Ar), 7.14 (dd,

J₁= 4.8 Hz, J₂= 7.2 Hz, 1 H, CH_Ar), 4.61 (q, J = 7.2 Hz, 2 H,

OCH₂CH₃), 3.83 (ddd, J₁= 4.8 Hz, J₂= 8.0 Hz, J₃= 14.8 Hz, 1 H,

CHS), 2.88–2.78 (m, 2 H, CH₂Ar), 2.09–2.00 (m, 1 H, CH₂CHS),

1.96–1.87 (m, 1 H, CH₂CHS), 1.39 (t, J = 7.2 Hz, 3 H, OCH₂CH₃),

1.15 (dd, J₁= 6.8 Hz, J₂= 14.8 Hz, 1 H, CH₂Si), 1.06 (dd, J₁= 8.0

Hz, J₂= 14.8 Hz, 1 H, CH₂Si), 0.03 [s, 9 H, Si(CH₃)₃].

¹³C NMR (100 MHz, CDCl₃): d = 214.1 (C=S), 151.1 (C), 147.3

(CH_Ar), 138.9 (CH_Ar), 135.5 (C), 122.5 (CH_Ar), 69.5 (OCH₂CH₃),

48.1 (CHS), 36.1 (CH₂CHS), 30.5 (CH₂Ar), 23.0 (CH₂Si), 13.7

(OCH₂CH₃), –0.8 [Si(CH₃)₃].

To a soln of 3-(bromomethyl)-2-chloropyridine (800 mg, 3.87

mmol) in acetone (11 mL) was added portionwise potassium O-eth-

yl xanthate (681 mg, 4.26 mmol) at 0 °C under N₂. The mixture was

stirred at r.t. until complete consumption of the starting material.

Acetone was evaporated under reduced pressure and the residue

was taken up in CH₂Cl₂, washed with sat. aq NH₄Cl and H₂O, dried

(anhyd MgSO₄), filtered, and evaporated under reduced pressure.

The residue was purified by flash chromatography (silica gel, PE–

Et₂O, 6:1) to yield 39 (850 mg, 88%) as a yellow oil.

MS (CI, NH₃): m/z = 362 [M + H]⁺(100%);

HRMS (EI): m/z [M]⁺calcd for C₁₅H₂₄ClNOS₂Si: 361.0757; found:

361.0754.

IR: 2987, 1561, 1409, 1220, 1112, 1051 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 8.26 (dd, J₁= 2.0 Hz, J₂= 4.8 Hz,

1 H, CH_Ar), 7.81 (dd, J₁= 2.0 Hz, J₂= 7.6 Hz, 1 H, CH_Ar), 7.17 (dd,

J₁= 4.4 Hz, J₂= 7.2 Hz, 1 H, CH_Ar), 4.60 (q, J = 7.2 Hz, 2 H,

OCH₂CH₃), 4.41 (s, 2 H, CH₂S), 1.36 (t, J = 7.2 Hz, 3 H,

OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 212.8 (C=S), 152.0 (C), 148.4

(CH_Ar), 139.2 (CH_Ar), 130.9 (C), 122.4 (CH_Ar), 70.4 (OCH₂CH₃),

37.1 (CH₂S), 13.6 (OCH₂CH₃).

S-3-(2-Chloro-3-pyridyl)-1-(cyanomethyl)propyl O-Ethyl

Dithiocarbonate (42)

Following the general procedure using xanthate 39 (200 mg, 0.81

mmol) and allyl cyanide (216 mg, 3.23 mmol, 4 equiv) in DCE (0.8

mL) and requiring DLP (45 mol%) to go to completion. Flash chro-

matography (silica gel, PE–EtOAc, 8:2) afforded 42 (120 mg, 47%)

as a yellow oil, together with recovered starting xanthate (30 mg).

The yield based on recovered starting xanthate was 55%.

IR: 2985, 2928, 1561, 1411, 1226, 1112, 1054 cm^–1.

MS (CI, NH₃): m/z = 248 [M + H]⁺(100%).

¹H NMR (400 MHz, CDCl₃): d = 8.24 (dd, J₁= 2.0 Hz, J₂= 4.8 Hz,

1 H, CH_Ar), 7.53 (d, J₁= 2.0 Hz, J₂= 7.6 Hz, 1 H, CH_Ar), 7.16 (dd,

J₁= 4.8 Hz, J₂= 7.6 Hz, 1 H, CH_Ar), 4.63 (q, J = 7.2 Hz, 2 H,

OCH₂CH₃), 3.89–3.82 (m, 1 H, CHS), 2.99–2.92 (m, 1 H, CH₂Ar),

2.91–2.89 (m, 2 H, NCCH₂), 2.81 (ddd, J₁= 6.0 Hz, J₂= 9.6 Hz,

J₃= 16.0 Hz, 1 H, CH₂Ar), 2.22–2.13 (m, 1 H, CH₂CHS), 2.08 (ddd,

J₁= 5.2 Hz, J₂= 10.0 Hz, J₃= 19.6 Hz, 1 H, CH₂CHS), 1.40 (t,

J = 7.2 Hz, 3 H, OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 211.7 (C=S), 151.0 (C), 147.8

(CH_Ar), 138.8 (CH_Ar), 134.1 (C), 122.7 (CH_Ar), 116.8 (CN), 70.5

(OCH₂CH₃), 45.8 (CHS), 31.5 (CH₂CHS), 30.4 (CH₂Ar), 23.8

(CH₂CN), 13.6 (OCH₂CH₃).

HRMS (EI): m/z [M]⁺calcd for C₉H₁₀ClNOS₂: 246.9892; found:

246.9888.

S-1-[(tert-Butoxycarbonylamino)methyl]-3-(2-chloro-3-pyri-

dyl)propyl O-Ethyl Dithiocarbonate (40)

Following the general procedure using xanthate 39 (200 mg, 0.81

mmol) and N-(tert-butoxycarbonyl)allylamine (507 mg, 3.23

mmol, 4 equiv) in DCE (0.8 mL) and requiring DLP (35 mol%) to

go to completion. Flash chromatography (silica gel, PE–EtOAc,

8:2) afforded 40 (176 mg, 54%) as a yellow oil.

IR: 3455, 2978, 2931, 1720, 1503, 1410, 1222, 1168, 1111, 1055

cm^–1.

MS (CI, NH₃): m/z = 315 [M + H]⁺(100%).

HRMS (EI): m/z [M]⁺calcd for C₁₃H₁₅ClN₂OS₂: 314.0314; found:

¹H NMR (400 MHz, CDCl₃): d = 8.20 (dd, J₁= 1.6 Hz, J₂= 4.8 Hz,

1 H, CH_Ar), 7.53 (d, J = 7.2 Hz, 1 H, CH_Ar), 7.12 (dd, J₁= 4.8 Hz,

J₂= 7.6 Hz, 1 H, CH_Ar), 4.95–4.93 (m, 1 H, NH), 4.60 (q, J = 7.2

Hz, 2 H, OCH₂CH₃), 3.82–3.76 (m, 1 H, CHS), 3.55–3.49 (m, 1 H,

NCH₂), 3.40–3.33 (m, 1 H, NCH₂), 2.94–2.79 (m, 2 H, CH₂Ar),

2.07–1.99 (m, 1 H, CH₂CHS), 1.92–1.83 (m, 1 H, CH₂CHS), 1.38

[s, 9 H, C(CH₃)₃], 1.37 (t, J = 7.2 Hz, 3 H, OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 213.0 (C=S), 155.8 (C=O), 151.0

(C), 147.4 (CH_Ar), 139.0 (CH_Ar), 135.1 (C), 122.5 (CH_Ar), 79.4 (C),

70.1 (OCH₂CH₃), 51.2 (CHS), 43.3 (CH₂N), 30.6 (CH₂CHS), 30.5

(CH₂Ar), 28.2 (3 CH₃), 13.6 (OCH₂CH₃).

314.0314.

2-[(tert-Butoxycarbonylamino)methyl]-3,4-dihydro-2H-thio-

pyrano[2,3-b]pyridine (43)

To a soln of xanthate 40 (110 mg, 0.27 mmol) in MeOH (1.5 mL)

was added KOH (61 mg, 1.10 mmol) at r.t. under N₂. The mixture

was stirred at r.t. for 1 h and MeOH was evaporated under reduced

pressure. The residue was dissolved in DMF (1.2 mL), NaBH₄(10

mg, 0.27 mmol) was added and the mixture was stirred at 100 °C for

1 h under N₂. CH₂Cl₂and H₂O were added and the organic layer was

separated, washed with H₂O, dried (anhyd MgSO₄), filtered, and

evaporated under reduced pressure. The residue was purified by

MS (CI, NH₃): m/z (%) = 405 [M + H]⁺(80), 349 [M + NH₄– t-Bu]⁺

(100).

3006

Z. Ferjancic et al.

FEATURE ARTICLE

flash chromatography (silica gel, PE–EtOAc, 7:3) to yield 43 (38

mg, 50%) as a white powder; mp 131–132 °C.

HRMS (EI): m/z [M]⁺calcd for C₁₇H₁₇N₃: 263.1422; found:

263.1419.

IR: 3458, 2975, 2928, 1720, 1502, 1407, 1367, 1248, 1168, 1087

cm^–1.

6-(Benzoyloxy)pyridine-2-methanol (47)

To a soln of 2,6-pyridinedimethanol (1 g, 7.19 mmol) in anhyd

pyridine (1 mL) was added BzCl (0.84 mL, 7.19 mmol) at 0 °C. Af-

ter extraction with CH₂Cl₂, washing with sat. NaHCO₃and H₂O, the

residue was column chromatographed (silica gel) to afford

monobenzoate 47 (50% yield) as a white solid, which was used

without further purification, and dibenzoate 48 (22% yield).

¹H NMR (400 MHz, CDCl₃): d = 8.12 (dd, J = 1.2 Hz, J = 8.4 Hz,

2 H, CH_Ar), 7.72 (t, J = 7.7 Hz, 1 H, CH_Ar), 7.60 (t, J = 7.4 Hz, 1 H,

CH_Ar), 7.47 (t, J = 7.7 Hz, 2 H, CH_Ar), 7.36 (d, J = 7.7 Hz, 1 H,

CH_Ar), 7.20 (d, J = 7.7 Hz, 1 H, CH_Ar), 5.49 (s, 2 H, CH₂OCOAr),

4.78 (s, 2 H, CH₂OH), 3.87 (s, 1 H, OH).

¹H NMR (400 MHz, CDCl₃): d = 8.24 (dd, J₁= 1.2 Hz, J₂= 4.4 Hz,

1 H, CH_Ar), 7.26 (d, J = 6.8 Hz, 1 H, CH_Ar), 6.90 (dd, J₁= 4.8 Hz,

J₂= 7.6 Hz, 1 H, CH_Ar), 5.00–4.98 (m, 1 H, NH), 3.62–3.58 (m, 1

H, CHS), 3.53–3.46 (m, 1 H, NCH₂), 3.35–3.28 (m, 1 H, NCH₂),

2.91–2.85 (m, 1 H, CH₂Ar), 2.83–2.76 (m, 1 H, CH₂Ar), 2.24–2.18

(m, 1 H, CH₂CHS), 1.84 (ddd, J₁= 4.0 Hz, J₂= 9.2 Hz, J₃= 18.0

Hz, 1 H, CH₂CHS), 1.43 [s, 9 H, C(CH₃)₃].

¹³C NMR (100 MHz, CDCl₃): d = 156.2 (C), 155.9 (C=O), 147.7

(CH_Ar), 136.6 (CH_Ar), 129.9 (C), 119.2 (CH_Ar), 79.6 (C), 45.1

(CH₂N), 43.1 (CHS), 28.3 (3 CH₃), 27.8 (CH₂Ar), 25.8 (CH₂CHS).

MS (CI, NH₃): m/z = 281 [M + H]⁺(100%).

HRMS (EI): m/z [M]⁺calcd for C₁₄H₂₀N₂O₂S: 280.1246; found:

S-{6-[(Benzoyloxy)methyl]-2-pyridyl}methyl O-Ethyl Dithio-

carbonate (49)

To a mixture of monobenzoate 47 (0.8 g, 3.28 mmol) and PPh₃(1.1

equiv, 0.95g), dissolved in anhyd CH₂Cl₂(15 mL), was added at 0

°C, under N₂and portionwise, CBr₄(1.31 g, 1.2 equiv). The mixture

was then filtered through a column (silica gel, gradient PE–EtOAc)

to afford the bromo derivative (95% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃): d = 8.12 (dd, J = 1.0 Hz, J = 8.1 Hz,

2 H, CH_Ar), 7.73 (t, J = 7.8 Hz, 1 H, CH_Ar), 7.59 (t, J = 7.4 Hz, 1 H,

CH_Ar), 7.47 (t, J = 7.7 Hz, 2 H, CH_Ar), 7.40 (d, J = 7.7 Hz, 1 H,

CH_Ar), 7.37 (d, J = 7.8 Hz, 1 H, CH_Ar), 5.48 (s, 2 H, CH₂OCOAr),

4.56 (s, 2 H, CH₂Br).

¹³C NMR (100 MHz, CDCl₃): d = 166.2 (C=O), 156.7, 156.1 (C_Ar),

137.9, 133.3 (CH_Ar), 129.9 (CH_Ar, C_Ar), 128.5 (CH_Ar), 122.7, 120.8

(CH_Ar), 67.0 (CH₂OCOAr), 33.7 (CH₂Br).

280.1256.

3-(Benzylamino)-5-(2-chloro-3-pyridyl)pentanenitrile (45)

To a stirred soln of xanthate 42 (0.15 g, 0.477 mmol) in CDCl₃(5

mL) was added DBU (0.214 mL, 1.43 mmol) at r.t. The mixture was

stirred at r.t. for 5 h and then diluted with CH₂Cl₂, washed with sat.

NaHCO₃and H₂O. The organic layer was dried (anhyd MgSO₄), fil-

tered, and evaporated under reduced pressure. The residue was pu-

rified by flash chromatography (silica gel, PE–EtOAc, 6:4) to yield

44 (75 mg, 82%) as a mixture of Z/E isomers in a ratio 1:1. A soln

of the latter (0.185 g, 0.96 mmol) and BnNH₂(1.05 mL, 10 equiv)

was heated at 100 °C until consumption of the starting material. Af-

ter evaporation of the excess of BnNH₂under a N₂flow, the residue

was purified by flash chromatography (silica gel, PE–EtOAc, 6:4)

to yield 45 (224 mg, 78%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃): d = 8.30 (dd, J = 1.9 Hz, J = 4.7 Hz,

1 H, CH_Ar), 7.53 (dd, J = 1.9 Hz, J = 7.5 Hz, 1 H, CH_Ar), 7.36 (m, 5

H, CH_Ar), 7.20 (dd, J = 4.8 Hz, J = 7.5 Hz, 1 H, CH_Ar), 3.96 (d,

J = 13.1 Hz, 1 H, NCH₂Ph), 3.81 (d, J = 13.1 Hz, 1 H, NCH₂Ph),

2.97 (m, 2 H, CH, CH₂Ar), 2.82 (m, 1 H, CH₂Ar), 2.69 (dd, J = 5.7

Hz, J = 16.8 Hz, 1 H, CH₂CN), 2.56 (dd, J = 4.7 Hz, J = 16.8 Hz, 1

H, CH₂CN), 1.94 (m, 2 H, CH₂), 1.51 (br s, 1 H, NH).

MS (CI, NH₃): m/z = 306, 308 [M + H]⁺.

To a soln of the bromide derivative (1 g, 3.26 mmol) in acetone (7.5

mL) was added under N₂and portionwise potassium O-ethyl xan-

thate (0.661 g, 1.1 equiv). After addition of H₂O, evaporation of ac-

etone and extraction with CH₂Cl₂, the organic layers were dried

(MgSO₄), filtered, and evaporated under reduced pressure to give a

residue, which was purified by column chromatography (silica gel,

gradient PE–EtOAc, 9:1 to 8:2) to give pure 49 (82% yield). Re-

crystallization (Et₂O–PE) afforded off-white crystals; mp 40–41 °C

(PE–Et₂O).

¹³C NMR (100 MHz, CDCl₃): d = 151.0 (C_q), 147.5 (CH_Ar), 139.4

(C_q), 138.8, 128.5, 128.0, 127.3, 122.6 (CH_Ar), 117.6 (CN), 52.7

(CH), 50.6 (CH₂Ph), 33.8, 29.4, 22.8 (3 CH₂).

IR (CCl₄): 1727 (OCOAr), 1588 (C=N), 1219, 1055 cm^–1(C–O,

CS).

MS (CI, NH₃): m/z = 300 [M + H]⁺.

¹H NMR (400 MHz, CDCl₃): d = 8.12 (d, J = 8.4 Hz, 2 H, CH_Ar),

7.67 (t, J = 7.8 Hz, 1 H, CH_Ar), 7.59 (t, J = 7.4 Hz, 1 H, CH_Ar), 7.47

(t, J = 7.6 Hz, 2 H, CH_Ar), 7.37 (d, J = 7.8 Hz, 1 H, CH_Ar), 7.34 (d,

J = 7.7 Hz, 1 H, CH_Ar), 5.47 (s, 2 H, CH₂OCOAr), 4.64 (qd, J = 7.1

Hz, 2 H, OCH₂CH₃), 4.53 (s, 2 H, CH₂S), 1.40 (td, J = 7.1 Hz, 3 H,

OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 213.8 (C=S), 166.2 (C=O),

156.04, 156.03 (2 C_Ar), 137.5, 133.3 (2 CH_Ar), 129.9 (C_qAr, 2

CH_Ar), 129.8 (2 CH_Ar), 122.4, 120.2 (2 CH_Ar), 70.3 (OCH₂CH₃),

67.1 (CH₂OCOAr), 41.9 (CH₂S), 13.8 (OCH₂CH₃).

(1-Benzyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)acetoni-

trile (46)

A soln of 45 (0.224 g, 0.75 mmol) in xylene (1 mL) was refluxed

for 6 h under N₂. After evaporation of the solvent under an N₂flow,

the residue was purified by flash chromatography (silica gel, PE–

EtOAc, 7:3) to yield 46 (165 mg, 84%) as a yellow oil.

IR (CCl₄): 2249 (CN), 1593, 1570 cm^–1(C=N).

¹H NMR (400 MHz, CDCl₃): d = 8.09 (d, J = 3.5 Hz, 1 H, CH_Ar),

7.33 (m, 6 H, CH_Ar), 6.64 (dd, J = 4.9 Hz, J = 7.2 Hz, 1 H, CH_Ar),

5.56 (d, J = 15.8 Hz, 1 H, NCH₂Ph), 4.53 (d, J = 15.8 Hz, 1 H,

NCH₂Ph), 3.91 (m, 1 H, CH), 2.88 (m, 2 H, CH₂Ar), 2.64 (dd,

J = 4.8 Hz, J = 16.8 Hz, 1 H, CH₂CN), 2.47 (dd, J = 9.4 Hz,

J = 16.9 Hz, 1 H, CH₂CN), 2.20 (m, 1 H, CHCH₂), 1.97 (m, 1 H,

CHCH₂).

¹³C NMR (100 MHz, CDCl₃): d = 153.9 (C_Ar), 146.4 (CH_Ar), 138.7

(C_Ar), 136.4 (CH_Ar), 128.7 (2 CH_Ar), 127.4 (2 CH_Ar), 127.2 (CH_Ar),

117.6, 115.4 (C_q, CN), 113.1 (CH_Ar), 52.2 (CH), 49.5 (NCH₂Ph),

29.9, 22.7, 20.6 (3 CH₂).

MS (CI, NH₃): m/z = 348 [M + H]⁺.

S-1-(Acetoxymethyl)-3-{6-[(benzoyloxy)methyl]-2-pyridyl}pro-

pyl O-Ethyl Dithiocarbonate (50)

Following the general procedure using xanthate (0.5 mmol, 1 equiv)

and allyl acetate (4 equiv) in DCE (0.5 mL). After the addition of

DLP (2 × 5 mol%), further alkene (2 equiv) and DLP (5 mol%)

were added. Column chromatography (silica gel, gradient PE–

EtOAc, 10:0 to 8:2) afforded 50 (52% yield) as a colorless oil.

MS (CI, NH₃): m/z = 264 [M + H]⁺.

IR (CCl₄): 1731 (C=O), 1588 (C=N), 1225, 1055 cm^–1(C–O, CS).

FEATURE ARTICLE

Generation and Intermolecular Additions of Pyridylmethyl Radicals

3007

¹H NMR (400 MHz, CDCl₃): d = 8.15 (d, J = 7.3 Hz, 2 H, CH_Ar),

7.66 (t, J = 7.7 Hz, 1 H, CH_Ar), 7.61 (t, J = 7.1 Hz, 1 H, CH_Ar), 7.49

(t, J = 7.8 Hz, 2 H, CH_Ar), 7.31 (d, J = 7.7 Hz, 1 H, CH_Ar), 7.13 (d,

J = 7.7 Hz, 1 H, CH_Ar), 5.49 (s, 2 H, CH₂OCOAr), 4.66 (q, J = 7.1

Hz, 2 H, OCH₂CH₃), 4.36 (dd, J = 5.1 Hz, J = 11.5 Hz, 1 H), 4.31

(dd, J = 5.9 Hz, J = 11.5 Hz, 1 H, CH₂OAc), 4.06 (m, 1 H, CHS),

3.06 (m, 1 H, CH₂Ar), 2.96 (m, 1 H, CH₂Ar), 2.31 (m, 1 H,

CHCHS), 2.09 H, (s + m, 4 H, CHCHS, CH₃CO), 1.43 (t, J = 7.1

Hz, 3 H, OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 213.1 (C=S), 170.7 (OCOCH₃),

166.2 (OCOAr), 160.3, 155.6 (2 C_qAr), 137.3, 133.2 (2 CH_Ar),

129.9 (C_qAr), 129.8, 128.5 (4 CH_Ar), 122.1, 119.1 (2 CH_Ar), 70.2

(OCH₂CH₃), 67.2 (CH₂OCOAr), 65.6 (CH₂OCOCH₃), 49.0 (CHS),

35.2 (CH₂Ar), 30.5 (CH₂CHS), 20.8 (CH₃CO), 13.8 (OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 213.7 (C=S), 156.0 (C_Ar), 137.3

(CH_Ar), 121.8 (CH_Ar), 70.3 (OCH₂CH₃), 41.9 (CH₂S), 13.8

(OCH₂CH₃).

MS (CI, NH₃): m/z = 348 [M + H]⁺.

HRMS (EI): m/z [M]⁺calcd for C₁₃H₁₇NO₂S₂: 347.0142; found:

347.0144.

S-1-(Cyanomethyl)-3-{6-[(ethoxythiocarbonylsulfanyl)methyl]-

2-pyridyl}propyl O-Ethyl Dithiocarbonate (54) and Diaddition

Product 53

Following the general procedure using xanthate (0.57 mmol, 1

equiv) and allyl cyanide (6 equiv) in EtOAc (0.3 mL). After the ad-

dition of DLP (3 × 5 mol%), further alkene (6 equiv) and DLP

(3 × 5 mol%) were added. Chromatography (gradient PE–Et₂O,

10:0 to 8:2) furnished the monoaddition product 54 (36% yield,

54% based on recovered starting material) as a colorless oil and the

diaddition product 53 (8% yield, 11% based on recovered starting

material) as an oil.

MS (CI, NH₃): m/z = 448 [M + H]⁺.

HRMS (EI): m/z [M]⁺calcd for C₂₂H₂₅NO₅S₂: 447.1174; found:

447.1173.

S-3-{6-[(Benzoyloxy)methyl]-2-pyridyl}-1-(cyanomethyl)pro-

pyl O-Ethyl Dithiocarbonate (51)

Monoaddition Product 54

IR (CCl₄): 2251 (CN), 1584 (C=N), 1220, 1051 cm^–1(C–O, CS).

Following the general procedure using xanthate (0.5 mmol, 1 equiv)

and allyl cyanide (3 equiv) in MEK (0.5 mL). After the addition of

DLP (3 × 5 mol%), further alkene (3 equiv) and DLP (3 × 5 mol%)

were added. Column chromatography (silica gel, PE–EtOAc, 10:0

to 7:3) afforded 51 (34% yield, 50% based on recovered starting

material) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): d = 7.56 (t, J = 7.7 Hz, 1 H, CH_Ar),

7.25 (d, J = 7.7 Hz, 1 H, CH_Ar), 7.04 (d, J = 7.7 Hz, 1 H), 4.64 (m,

4 H, 2 OCH₂CH₃), 4.49 (s, 2 H, CH₂S), 3.94 (m, 1 H, CHS), 2.95

(m, 4 H, CH₂CN, CH₂Ar), 2.33 (m, 1 H, CH₂CHS), 2.19 (m, 1 H,

CH₂CHS), 1.41 (2 td, J = 7.1 Hz, 6 H, 2 OCH₂CH₃).

IR (CCl₄): 2250 (CN), 1726 (COAr), 1589 (C=N), 1223, 1054 cm^–1

(C–O, CS).

¹³C NMR (100 MHz, CDCl₃): d = 213.8, 212.2 (2 C=S), 159.6,

155.6 (2 C_Ar), 137.2 (CH_Ar), 121.6, 120.9 (2 CH_Ar), 117.2 (CN),

70.4, 70.2 (OCH₂CH₃), 45.8 (CHS), 42.0 (CH₂S), 34.7, 31.7

(CH₂Ar, CH₂CN), 23.9 (CH₂CHS), 13.8, 13.7 (OCH₂CH₃).

HRMS (EI): m/z [M]⁺calcd for C₁₇H₂₂N₂O₂S₄: 414.0564; found:

414.0567

¹H NMR (400 MHz, CDCl₃): d = 8.13 (dd, J = 1.3 Hz, J = 8.3 Hz,

2 H, CH_Ar), 7.64 (t, J = 7.7 Hz, 1 H, CH_Ar), 7.59 (br t, J = 7.4 Hz, 1

H, CH_Ar), 7.47 (t, J = 7.7 Hz, 2 H, CH_Ar), 7.29 (d, J = 7.7 Hz, 1 H,

CH_Ar), 7.11 (d, J = 7.7 Hz, 1 H, CH_Ar), 5.46 (s, 2 H, CH₂OCOAr),

4.64 (q, J = 7.1 Hz, 2 H, OCH₂CH), 3.95 (m, 1 H, CHS), 2.97 (m +

t, 4 H, CH₂Ar, CH₂CN), 2.36 (m, 1 H, CH₂CHS), 2.21 (m, 1 H,

CH₂CHS), 1.42 (t, J = 7.1 Hz, 3 H, OCH₂CH₃).

Diaddition Product 53

IR (CCl₄): 2249 (C≡N), 1583 (C=N), 1220, 1052 cm^–1(C–O, CS).

¹³C NMR (100 MHz, CDCl₃): d = 212.3 (C=S), 166.2 (OCOAr),

159.5, 155.7 (2 C_Ar), 137.3, 133.2 (2 CH_Ar), 129.9 (C_Ar), 129.8,

128.5 (4 CH_Ar), 122.1, 119.3 (2 CH_Ar), 117.1 (CN), 70.4

(OCH₂CH₃), 67.2 (CH₂OCOAr), 45.9 (CHS), 34.8, 31.8 (CH₂Ar,

CH₂CN), 23.9 (CH₂CHS), 13.8 (OCH₂CH₃).

¹H NMR (400 MHz, CDCl₃): d = 7.52 (t, J = 7.7 Hz, 1 H, CH_Ar),

6.99 (d, J = 7.7 Hz, 2 H, 2 CH_Ar), 4.65 (q, J = 7.1 Hz, 4 H, 2

OCH₂CH₃), 3.95 (m, 2 H, CHS), 2.96 (m, 8 H, 4 CH₂), 2.36 (m, 2

H, 2 CH₂CHS), 2.20 (m, 2 H, 2 CH₂CHS), 1.43 (t, J = 7.1 Hz, 6 H,

2 OCH₂CH₃).

HRMS (EI): m/z [M]⁺calcd for C₂₁H₂₂N₂O₃S₂: 414.1072; found:

414.1068.

¹³C NMR (100 MHz, CDCl₃): d = 212.6, 212.5 (C=S), 159.5 (2 C_Ar),

137.2 (2 CH_Ar), 120.9 (2 CH_Ar), 117.3 (2 C≡N), 70.1 (2 OCH₂CH₃),

46.1, 46.0 (2 CHS), 35.0, 34.9 (2 CH₂), 31.8 (2 CH₂), 23.9 (2 CH₂),

13.9 (2 OCH₂CH₃).

HRMS (EI): m/z [M – CSOCH₂CH₃]⁺calcd for C₁₈H₂₂N₃OS₃:

392.0925; found: 392.0926.

O,O¢-Diethyl S,S¢-(Pyridine-2,6-diyldimethanediyl) Bis(dithio-

carbonate) (52)

To a mixture of 2,6-pyridinedimethanol (0.25 g, 1.79 mmol) and

PPh₃(1.13 g, 2.4 equiv) in anhyd CH₂Cl₂(15 mL) was added at 0

°C, under N₂and portionwise, CBr₄(1.43 g, 2.4 equiv). The mixture

was then filtered through a column (silica gel, gradient PE–EtOAc)

to afford the known 2,6-bis(bromomethyl)pyridine (70% yield) as a

white solid.

5-{6-[2-Acetoxy-2-(ethoxythiocarbonylsulfanyl)propyl]-2-pyri-

dyl}-2-(ethoxythiocarbonylsulfanyl)pentanenitrile (55)

Following the general procedure as the solvent using xanthate 54

(0.17 mmol, 1 equiv), vinyl acetate (6 equiv) in EtOAc (0.1 mL) and

DLP (2 × 5 mol%). Chromatography (gradient PE–EtOAc, 10:0 to

8:2) furnished the addition product 55 (64% yield) as a yellow oil as

a mixture of 2 diastereomers.

To a soln of 2,6-bis(bromomethyl)pyridine (1.26 mmol) in acetone

(2.5 mL) was added under N₂and portionwise potassium O-ethyl

xanthate (0.44 g, 2.2 equiv). The mixture was stirred at r.t. until con-

sumption of the starting material. H₂O was then added and the ace-

tone evaporated to give the pure 52 (91% yield) as a pale yellow oil.

IR (CCl₄): 2250 (C≡N), 1583 (C=N), 1223, 1054 cm^–1(C–O, CS).

¹H NMR (400 MHz, CDCl₃): d = 7.51 (t, J = 7.7 Hz, 1 H, CH_Ar),

6.98 (dd, J = 4.0 Hz, J = 7.6 Hz, 2 H, CH_Ar), 6.70 (2 t, overlapping,

J = 6.6 Hz, J = 8.7 Hz, 1 H, CHS), 4.62 (m, 4 H, 2 OCH₂CH₃), 3.93

(m, 1 H, CHS), 2.92 (m, 6 H, 3 CH₂), 2.37 (m, 3 H, CH₂, CH₂), 2.18

(m, 1 H, CH₂), 2.07 (s, 1.5 H, CH₃CO), 2.06 (s, 1.5 H, CH₃CO),

1.42, 1.39 (2 t, overlapping, J = 7.1 Hz, 6 H, 2 OCH₂CH₃).

IR (CCl₄): 1574 (C=N), 1217, 1054 cm^–1(C–O, CS).

¹H NMR (400 MHz, CDCl₃): d = 7.58 (t, J = 7.8 Hz, 1 H, CH_Ar),

7.31 (d, J = 7.7 Hz, 2 H, 2 CH_Ar), 4.65 (qd, J = 7.1 Hz, 4 H, 2

OCH₂CH₃), 4.50 (s, 4 H, 2 CH₂S), 1.41 (td, J = 7.1 Hz, 6 H, 2

OCH₂CH₃).

¹³C NMR (100 MHz, CDCl₃): d = 212.5, 210.4 (C=S), 169.43,

169.42 (C=O), 159.6, 159.37, 159.36 (2 C_Ar), 137.0 (CH_Ar), 120.7,

3008

Z. Ferjancic et al.

FEATURE ARTICLE

120.6 (CH_Ar), 117.3 (CN), 80.51, 80.49 (CHS), 70.5, 70.2

(OCH₂CH₃), 46.0, 45.9 (CHS), 34.95, 34.93, 33.9, 33.7, 31.84,

31.81 (5 CH₂), 23.90, 23.89 (CH₃CO), 13.8, 13.7 (OCH₂CH₃).

MS (CI, NH₃): m/z = 501 [M + H]⁺.

HRMS (EI): m/z [M]⁺calcd for C₂₁H₂₈N₂O₄S₄: 500.09321; found:

500.09310.

(9) (a) Taylor, E. C.; Macor, J. E. J. Org. Chem. 1987, 52, 4280.

(b) Haenel, F.; Rainer, J.; Seitz, G. Arch. Pharm. (Weinheim,

Ger.) 1992, 325, 349. (c) Ming, Y.-F.; Horlemann, N.;

Warmhoff, H. Chem. Ber. 1987, 120, 1427. (d) Da Settimo,

A.; Marini, A.-M.; Primofiore, G.; Da Settimo, F.; Salerno,

S.; La Motta, C.; Pardi, G.; Ferrarini, P.-L.; Mori, C.

J. Heterocycl. Chem. 2000, 37, 379. (e) Primofiore, G.;

Marini, A.-M.; Da Settimo, F.; Salerno, S.; Bertini, D.;

Via Dalla, L.; Magno, S. M. J. Heterocycl. Chem. 2003, 40,

783. (f) Primofiore, G.; Da Settimo, F.; Marini, A.-M.;

Simorini, F.; La Motta, C.; Taliani, S.; Laneri, S.;

Acknowledgment

We thank L’Oréal for generous financial support to one of us (Z.F.).

Trincavelli, L.; Martini, C. Arch. Pharm. (Weinheim, Ger.)

1992, 338, 126.

(10) For some recent studies see: (a) Boys, M. L.; Lori, A.;

Schretzman, L. A.; Nizal, S.; Chandrakumar, N. S.;

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Article Doi

Generation and intermodular additions of pyridylmethyl radicals

DOI: 10.1055/s-2008-1067198

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Article abstract of DOI:10.1055/s-2008-1067198

Full text of DOI:10.1055/s-2008-1067198

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