Radical cyanation of alkyl iodides with diethylphosphoryl cyanide

Article abstract of DOI:10.1055/s-0028-1087385

The β-elimination of an organophosphoryl group from an iminyl radical is observed for the first time. On the basis of this finding, radical cyanation of alkyl iodides is achieved by using diethylphosphoryl cyanide. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087385

LETTER
81
Radical Cyanation of Alkyl Iodides with Diethylphosphoryl Cyanide
Radical
C
yanatio
h
n Using Die
a
n
r
yl Cyanideg Ho Cho, Jin Young Lee, Sunggak Kim*
Department of Chemistry, School of Molecular Science (BK-21), Korea Advanced Institute of Science and Technology (KAIST),
Daejeon 305-701, Korea
Fax +82(42)3502810; E-mail: skim@kaist.ac.kr
Received 9 September 2008
O
O
O
Abstract: The b-elimination of an organophosphoryl group from
an iminyl radical is observed for the first time. On the basis of this
finding, radical cyanation of alkyl iodides is achieved by using di-
ethylphosphoryl cyanide.
PPh2
PPh2
PPh2
O
O
S
O
Bu3SnH, AIBN
(4)
(5)
O
O
•
R
R
N
SMe
R
R
Me
Key words: radical, cyanide, elimination, alkyl halides
SnBu3
SnBu3
N3
•
N
HN
Bu3SnH, AIBN
R
PO(OEt)2
R
PO(OEt)2
PO(OEt)2
The b-eliminations of an organophosphoryl and an organo-
phosphinoyl group in radical reactions have not been well
studied. Since the b-elimination of the phosphinoyl group
during a rearomatization process was observed,1 several
reports have appeared in recent years. The b-elimination
of a diphenylphosphinoyl group has been utilized in radi-
cal allylation (Scheme 1, equation 1)2 and in tandem rad-
ical cyclization (Scheme 1, equation 2).3
Scheme 2
formed and the strength of the s-bond broken. As shown
in Scheme 2, equations 4 and 5, the b-elimination of the
diethylphosphoryl group from a carbon-centered radical
and from a nitrogen-centered radical did not occur due to
the strong phosphorous–oxygen bond and the relatively
weak p-bond strength of the C=N bond, respectively.
We demonstrated the facile b-elimination of a dieth-
ylphosphoryl group from an alkoxy radical and its appli-
cation to intramolecular acylation approach, in which
acylphosphates were highly efficient carbonyl radical
acceptors4 and more reactive than previously known acyl
sulfides5 and acyl germanes (Scheme 1, equation 3).6 Ac-
cording to our previous studies on the relative b-elimina-
tion rates of the leaving groups,7 the success of the b-
elimination of the phosphoryl and the phosphinoyl groups
would depend very much on the nature of the p-bond
In connection with our continued interest on the radical
reactions of the organophosphoryl groups, we have inves-
tigated the possibility of the b-elimination of the phospho-
ryl and the phosphinoyl groups. Initially, we have
investigated the possibility of radical azidation using di-
ethylphosphoryl azide8 to study the cleavage of N–P
bond. The similar approach was previously employed in
the tin-free radical azidation using ethanesulfonyl azide.9
O
O
O
DLP
(1)
+
PPh2
PhCl, reflux
Cl
S
OEt
Cl
S
Ts
N
O
Ts
N
Cp2TiCl2, Mn
(2)
(3)
R1
THF
R1
Ph2P
O
HO
R2
R2
O
EtO2C
CO2Et
EtO2C
CO2Et
EtO2C
I
CO2Et
–
•
(Me3Sn)2
P(OEt)2
benzene
hv
C-PO(OEt)2
O•
P(OEt)2
O
O
O
Scheme 1
SYNLETT 2009, No. 1, pp 0081–0084
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087385; Art ID: U09508ST
© Georg Thieme Verlag Stuttgart · New York

82
C. H. Cho et al.
LETTER
Table 1 Radical Cyanation of 4-Phenoxybutyl Iodide
3
5
6
7
8
X
R = OEt, X = O
R = OPh, X = O
R = Ph, X = O
R = OEt, X = S
R = Ph, X = –
R2P CN
1.5 equiv
3.0 equiv
57 (24)a
80
40
67
53
70
41 (17a, 11b)
66
0 (61a, 14b)
0 (67a, 17b)
a Yield of the recovered starting material.
b Yield of the reduction product.
When a benzene solution of 4-phenoxybutyl iodide (2) conditions using dilauroyl peroxide initiator. Apparently,
and diethylphosphoryl azide was irradiated at 300 nm for the b-elimination of the diethylphosphoryl group did not
6 hours, the reaction did not occur and the starting iodide take place unlike that of the alkyl- and arylsulfonyl
was recovered unchanged in 78% yield (Scheme 3, equa- group.9,10
tion 6). Similarly, the reaction did not occur under tin-free
Table 2 Radical Cyanation of Alkyl Iodides Using Diethylphosphoryl Cyanide17
Entry
1
Conditionsa,b
Yield (%)
R
CN
R
I
A
B
80
CN
I
50 (20)c
PhO
Ph
PhO
Ph
O
O
A
B
85
2
51 (46)c
I
CN
4
O
O
4
3
4
A
A
87
86
I
CN
TBDPSO
TBDPSO
I
CN
9
9
O
O
I
CN
5
A
72
N
N
3
3
O
O
A
B
69
47
6
7
8
9
Ph
CN
Ph
I
A
A
A
68
71
76
I
I
CN
CN
4
4
Ts
N
I
Ts
N
CN
CN
I
10
11
A
A
0 (90)d
Br
Br
O2
S
O2
S
CN
0 (48c, 35e)
I
EtO2C
CO2Et
EtO2C
I
CO2Et
12
A
73
CN
a Photo conditions A: (Me3Sn)2 (1.2 equiv), benzene, hn (300 nm), 12 h.
b Thermal conditions B: DLP (0.7 equiv), chlorobenzene, 110 °C, 24 h.
c The yield of recovered starting material.
d The yield of dimerized product.
e The yield of reduction product, methyl phenyl sulfone.
Synlett 2009, No. 1, 81–84 © Thieme Stuttgart · New York

LETTER
Radical Cyanation Using Diethylphosphoryl Cyanide
83
O
cyclization and cyanation also works well, yielding the
desired cyclized cyanide in 73% yield (entry 12).
O
I
+
+
+
R
R
(EtO)2P N3
R
N3
O
P(OEt)
•
(6)
(7)
2
300 nm
hν
The synthetic importance of tin-free radical reactions has
been recognized in recent years due to the high toxicity of
organotin compounds.15 Thus, we studied the feasibility
of radical cyanation under tin-free conditions.
O
(EtO)2P
(Me3Sn)2
•
R
CN
I
(EtO)2P CN
C
N
benzene
300 nm
R
4
2
3
Since dialkyl and diaryl phosphoryl radicals can abstract
halogen atoms from alkyl halides,16 it should be feasible
to perform the present reaction under tin-free conditions.
When 2 was treated with 3 in the presence of lauroyl per-
oxide (DLP) initiator in chlorobenzene at 110 °C for 24
hours (conditions B), 4-phenoxybutyl cyanide was isolat-
ed in 50% yield along with recovery of the starting mate-
rial (20%). The use of diphenylphosphoryl cyanide was
much less satisfactory, providing 4 in 10% yield. To find
the optimum conditions, we investigated the effect of tem-
perature and initiator as shown in Table 3.
57%
R = PhO(CH2)4
Scheme 3
Our next attention was given to radical cyanation using
organophosphorus-related cyanides. The radical cyana-
tion using alkylsulfonyl and arylsulfonyl cyanides have
been extensively studied and proved to be synthetically
useful.11 Irradiation of a benzene solution of 2, diethyl-
phosphoryl cyanide (3, 1.5 equiv), and hexamethylditin at
300 nm for 6 hours afforded the desired cyanide in 57%
yield along with recovery of the starting material (24%,
Scheme 3, equation 7). To improve the reaction, we pre-
pared several similar types of reagents (Table 1). Com-
pound 3 and diphenylphosphoryl cyanide (5) were pre-
pared by treatment of triethyl phosphite and diphenyl
ethyl phosphite with cyanogen bromide in dichloro-
methane.12 Compound 3 and diphenylphosphinoyl cya-
nide (6) could also be conveniently prepared from diethyl
and diphenyphosphinoyl chloride with sodium cyanide
and phase-transfer catalysts.13 Diphenylcyanophosphine
(8) was prepared in a similar manner but it was unstable
and decomposed upon heating. Thus, 8 was used directly
without further purification.14
Table 3 Radical Cyanation under Thermal Conditions
Entry
Initiator
DLP
Temp (°C)
110
Yield (%)
50 (20)a
51
1
2
3
4
5
6
7
DLP
140
DLP
140
51 (30)a,b
61c
DLP
110
DLP
110
77d
benzoyl peroxide
benzoyl peroxide
110
51
140
50
Radical cyanations using several cyanophosphonates (1.5
equiv and 3.0 equiv) in the presence of hexamethylditin
were performed under photochemically initiated condi-
tions. Irradiation of a benzene solution of 2, 3 (3.0 equiv),
and hexamethylditin (1.2 equiv) at 300 nm for 12 hours
gave 4 in 80% yield. The experimental results are summa-
rized in Table 1, and several features are noteworthy.
First, 3 turned out to be most effective among cyanophos-
phonates tested in this study. Second, the use of an excess
amount (3.0 equiv) of the reagent provided better yields of
the cyanation product. Third, diphenyl cyanophosphine
(8) was totally ineffective, and a small amount of the re-
duction product was isolated. Thus, remaining reactions
were carried out with 3.0 equivalents of diethylphosphor-
yl cyanide (conditions A). Experimental results are listed
in Table 2 and illustrate the efficiency and scope of the
method. Primary and secondary alkyl iodides work rea-
sonably well, yielding the corresponding cyanides in high
yield. A sterically hindered adamantyl iodide underwent
the radical cyanation in 76% yield (entry 9). However, the
present method reaches a limit with relatively stable and
less reactive radicals. For instance, a stable benzylic radi-
cal did not react with 3 under the present conditions, and
the dimerized product was isolated in 90% yield (entry
10). Furthermore, a similar result was observed with a sta-
ble electrophilic radical derived from iodomethyl phenyl
sulfone (entry 11). A sequential radical reaction involving
a The numbers in parentheses indicate the yield of the recovered start-
ing iodide.
b The reaction was carried out under 80 atm of Ar atmosphere.
c Using 5.0 equiv of diethylphosphoryl cyanide.
d Using 1.5 equiv of (Me3Sn)2 for 5 h.
Although the yield was not improved by raising the reac-
tion temperature to 140 °C, the use of an excess amount of
the reagent (5 equiv) increased the yield to some extent
(entry 4). Two additional experimental results are listed in
Table 2. It is assumed that n-undecanyl radical from ther-
mal decomposition of DLP would react with diethylphos-
phoryl cyanide to generate diethyl phosphoryl radical to
propagate the chain reaction and the low yields might be
due to inefficient iodine atom transfer process. When the
reaction was carried out in the presence of hexamethyl-
ditin (1.5 equiv) under the similar conditions, the yield
was increased to 77% yield (entry 5). Furthermore, using
benzoyl peroxide initiator, the similar results were also
obtained (entries 6 and 7).
In conclusion, on the basis of the smooth b-elimination of
the diethylphosphoryl group from the iminyl radical, we
have developed a new radical cyanation method using di-
ethylphosphoryl cyanide.
Synlett 2009, No. 1, 81–84 © Thieme Stuttgart · New York

84
C. H. Cho et al.
LETTER
(12) Saunders, B. C.; Stacey, G. T.; Wild, F.; Wiling, I. G. E.
Acknowledgment
J. Chem. Soc. 1948, 699.
We are grateful to the Korea Science and Engineering Foundation
(KOSEF) (R01-2007-000-21315-0) and BK 21 program for finan-
cial support.
(13) (a) Shi, E.; Pei, C. Synth. Commun. 2005, 35, 669. (b) Shi,
E.; Pei, C. Synthesis 2004, 2995. (c) Shi, E.; Pei, C. Synth.
Commun. 2004, 34, 1285. (d) Shi, E.; Pei, C. Phosphorus,
Sulfur Silicon Relat. Elem. 2003, 178, 1093.
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Synthesis 2002, 835. (c) Quiclet-Sire, B.; Zard, S. Z. Chem.
Eur. J. 2006, 12, 6002.
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(17) Typical Procedure for Radical Cyanation
Photochemical Conditions A
A dry benzene solution (2 mL) of 4-phenoxybutyl iodide (2,
55 mg, 0.2 mmol), diethylphosphoryl cyanide (3, 90 mL, 0.6
mmol), and hexamethylditin (79 mg, 0.24 mmol) in a quartz
tube was degassed with nitrogen for 10 min and then
irradiated at 300 nm in Rayonet photochemical reactor for 12
h. The solvent was evaporated under reduced pressure, and
the residue was separated by a silica gel column
chromatography using EtOAc and n-hexane (1:5) as eluant
to give 4-phenoxybutyl cyanide (28 mg, 80%).11d MW
(C11H13NO): 175.23. 1H NMR (400 MHz, CDCl3): d = 1.85–
1.95 (m, 4 H), 2.41–2.45 (t, J = 6.7 Hz, 2 H), 3.98–4.00 (t,
J = 5.7 Hz, 2 H), 6.85–6.92 (d, J = 5.6 Hz, 2 H), 6.93–6.95
(t, J = 7.3 Hz, 1 H), 7.23–7.28 (m, 2 H). 13C NMR (100
MHz, CDCl3): d = 16.6, 22.0, 27.8, 66.0, 113.9, 119.0,
120.4, 129.0, 158.2. IR (polymer): 2927, 1601, 1586, 1497,
1474, 1247, 757, 693 cm–1. HRMS: m/z calcd for C11H13NO
[M+]: 175.0997; found: 175.0998.
Thermal Conditions B
A solution of 2 (110 mg, 0.4 mmol), 3 (180 mL, 1.2 mmol),
and DLP (31 mg, 0.08 mmol) in chlorobenzene (4 mL) was
degassed with nitrogen for 10 min, and then the solution was
heated at 110 °C under nitrogen for 24 h. The solvent was
evaporated under reduced pressure, and the residue was
separated by a silica gel column chromatography using
EtOAc and n-hexane (1:5) as eluant to give 4-phenoxybutyl
cyanide (35 mg, 50%) with recovery of 2 (22 mg, 20%).
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