General, stereoselective synthesis of (Z)-β,γ-unsaturated nitriles promoted by samarium diiodide

Article abstract of DOI:10.1021/ol801752m

(Chemical Equation Presented) A method to obtain (Z)-β,γ- unsaturated nitriles in high or good yields and with moderate or high stereoselectivity is described. The products were achieved through the photoinduced metalation of 3-acetoxy-4-chloronitriles with Sml₂. The starting compounds were readily prepared, and a mechanism is proposed to explain this stereoselective β-elimination reaction.

Full text of DOI:10.1021/ol801752m

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4549-4552
General, Stereoselective Synthesis of
(Z)-ꢀ,γ-Unsaturated Nitriles Promoted by
Samarium Diiodide
Jose´ M. Concello´n,*,† Humberto Rodríguez-Solla,† Carmen Simal,†
David Santos,† and Nieves R. Paz‡
Departamento de Química Orga´nica e Inorga´nica, UniVersidad de OViedo,
Julia´n ClaVería 8, 33071 OViedo, Spain, and Instituto de Productos Naturales y
Agrobiología del C.S.I.C., Carretera de La Esperanza 3,
38206 La Laguna, Tenerife, Spain
jmcg@unioVi.es
Received July 30, 2008
ABSTRACT
A method to obtain (Z)-ꢀ,γ-unsaturated nitriles in high or good yields and with moderate or high stereoselectivity is described. The products
were achieved through the photoinduced metalation of 3-acetoxy-4-chloronitriles with SmI2. The starting compounds were readily prepared,
and a mechanism is proposed to explain this stereoselective ꢀ-elimination reaction.
Nitriles are important compounds in organic synthesis since
they have been widely employed for the introduction of a
variety of functional groups.1 It has been shown that ꢀ,γ-
unsaturated nitriles are useful substrates,2 and several
methods have been reported regarding their synthesis. In
particular, the synthesis of (E)-ꢀ,γ-unsaturated nitriles is
generally achieved from the cyanation process of different
starting materials such as allylic alcohols,3 halides,3b ac-
etates,4 carbonates,4 ethers,2a,b phosphates,2c carbonyl com-
pounds,5 or the hydrocyanation of butadiene.6 Other methods
employ isomerization processes,7 a carbenoid insertion into
alkenylzirconocenes,8 Ru-catalyzed cross-metathesis reac-
tions,9 or classical methods such as the Wittig reaction.10
However, most of these methods require toxic reagents2-6
or expensive catalysts.9 Other methods are limited by their
poor generality,2a,3a,7,8 low yields,2a,7,8,10 or the low stereo-
selectivity during the generation of the CdC bond.4b,8-10
Finally, in other cases, the utilization of unsaturated com-
pounds (with the appropriate relative configuration) as
starting materials constitutes a drawback.2-7 Taking into
account that, in general, Z-unsaturated compounds are more
difficult to access than the corresponding E-isomers, it was
† University of Oviedo.
‡ Instituto de Productos Naturales y Agrobiología del C.S.I.C.
(1) Rappoport, Z. The Chemistry of the Cyano Group; Wiley-Inter-
science: New York, 1970.
(2) (a) Murakami, M.; Kato, T.; Mukaiyama, T. Chem. Lett. 1987, 1167–
1170. (b) Hayashi, Y.; Mukaiyama, T. Chem. Lett. 1987, 1811, 1814. (c)
Araki, S.; Minami, K.; Butsugan, Y. Bull. Chem. Soc. Jpn. 1981, 54, 629–
630.
(5) Yoneda, R.; Harusawa, S.; Kurihara, T. J. Org. Chem. 1991, 56,
1827–1832.
(6) Bini, L.; Müller, C.; Wilting, J.; von Chrzanowski, S. A. L.; Vogt,
D. J. Am. Chem. Soc. 2007, 129, 12622–12623.
(7) Acosta-Ramírez, A.; Mun˜oz-Herna´ndez, M.; Jones, W. D.; García,
J. J. Organometallics 2007, 26, 5766–5769.
(3) (a) Rad, M. N. S.; Khalafi-Nezhad, A.; Behrouz, S.; Faghihi, M. A.
Tetrahedron Lett. 2007, 48, 6779–6784. (b) Kanai, T.; Kanagawa, Y.; Ishii,
Y. J. Org. Chem. 1990, 55, 3274–3277.
(8) Kasatkin, A. N.; Whitby, R. J. Tetrahedron Lett. 2000, 41, 6211–
6216.
(4) (a) Tsuji, Y.; Kusui, T.; Kojima, T.; Sugiura, Y.; Yamada, N.;
Tanaka, S.; Ebihara, M.; Kawamura, T. Organometallics 1998, 17, 4835–
4841. (b) Tsuji, Y.; Yamada, N.; Tanaka, S. J. Org. Chem. 1993, 58, 16–
17.
(9) Hoveyda, H. R.; Ve´zina, M. Org. Lett. 2005, 7, 2113–2116.
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1653–1657.
10.1021/ol801752m CCC: $40.75
Published on Web 09/23/2008
2008 American Chemical Society

not surprising to find in the literature only one example
described. In this case, the (Z)-ꢀ,γ-unsaturated nitrile was
prepared from (Z)-1-iodohex-2-ene, and to the best of our
knowledge, no general method for the preparation of (Z)-
ꢀ,γ-unsaturated nitriles through an elimination reaction has
been reported to date. Therefore, an efficient method to
synthesize (Z)-ꢀ,γ-unsaturated nitriles with high stereose-
lectivity, in which nontoxic starting materials are employed,
would be desirable.
the starting compounds 2 could be readily modified by using
the appropriate (linear, branched, or unsaturated) aldehyde
or/and nitrile (Scheme 1).
Scheme 1. Synthesis of Starting Materials 2
Samarium diiodide has been widely employed to promote
ꢀ-elimination reactions with high or total stereoselectivity.11
In this field, we have previously reported the SmI2-promoted
stereoselective synthesis of (E)-R,ꢀ-unsaturated esters,12
amides,13 or ketones,14 (Z)-vinyl halides,15 and (Z)-vinyl and
allylsilanes.16 In all these cases, the 1,2-elimination reaction
was initiated by the metalation of an activated C-halogen
bond.
Initially, the ꢀ-elimination reaction of compounds 2 was
carried out on 3-acetoxy-4-chlorodecanenitrile 2a (R1 )
n-C6H13; R2 ) H) at room temperature and in the absence
of visible light. No reaction took place, and the starting
material was recovered unchanged (Table 1).
However, samarium diiodide has been scarcely utilized
to promote elimination reactions through the metalation of
nonactivated C-Cl bonds due to the lack of reactivity of
these bonds. Several methods have been described to
overcome this drawback, the photoinduced metalation of
nonactivated C-Hal bonds being the most effective. Thus,
some synthetic applications based on the photoinduced
metalation of nonactivated C-Hal bonds with SmI2 have
been reported.17 In this field, we have recently reported the
photoinduced SmI2-promoted metalation of nonactivated
C-Cl bonds of O-acetyl chlorohydrins toward the synthesis
of nonfunctionalized alkenes with total or high (Z)-selectiv-
ity.18
Table 1. Synthesis of 2a under Various Reaction Conditions
entry
400 W lamp
temp
time (h)
Z/Ea
yield (%)b
1
2
3
4
no
no
yes
yes
rt
reflux
rt
10
10
6.5
6.5
-
-
80/20
78/22
80/20
22
85
87
reflux
a Z/E ratio was determined by GC-MS and/or 300 MHz 1H NMR
analysis of the crude product 3a. b Isolated yield after column chromatog-
raphy based on compound 2a.
In this paper, we wish to report a new and easy route to
(Z)-ꢀ,γ-unsaturated nitriles by treatment of 3-acetoxy-4-
chloronitriles, with SmI2 in the presence of visible light (400
W). A mechanism to explain the Z-stereoselectivity of this
process is also proposed.
After testing the reaction conditions shown in Table 1,
the best results were obtained by treatment of 3-acetoxy-4-
chlorodecanenitrile 2a (0.4 mmol, 1 equiv) with SmI220 (3.0
equiv) at reflux, in the presence of visible light (400 W lamp).
ꢀ,γ-Unsaturated nitrile 3a was then obtained with good (Z)-
stereoselectivity and high yield (Table 1, entry 4).
To study the generality of this method, the ꢀ-elimination
reaction was performed on various 3-acetoxy-4-chloronitriles
2. As shown in Table 2, the reaction seems to be general,
and linear or branched aliphatic or unsaturated nitriles could
be efficiently obtained with good Z-stereoselectivity and high
yield.
When compounds 2g and 2l (derived from 2-chlorophe-
nylacetaldehyde) were utilized as starting materials, a change
of the stereoselectivity was observed, affording the corre-
sponding (E)-ꢀ,γ-unsaturated nitriles 3g and 3l with good
stereoselectivity (Table 2, entries 7 and 12). An explanation
of the different E- or Z-stereoselectivity observed on products
3 depending on the aldehyde used will be discussed below.
The starting materials 2 were readily prepared in good
overall yields (63-85%) after the successive treatment of
R-chloroaldehydes 119 with the lithium enolate of the
corresponding nitrile and acetic anhydride. The structure of
(11) To see a review about ꢀ-elimination reactions promoted by SmI2,
see: Concello´n, J. M.; Rodríguez-Solla, H. Chem. Soc. ReV. 2004, 33, 599–
609.
(12) Concello´n, J. M.; Pe´rez-Andre´s, J. A.; Rodríguez-Solla, H. Angew.
Chem., Int. Ed. 2000, 39, 2773–2775.
(13) Concello´n, J. M.; Pe´rez-Andre´s, J. A.; Rodríguez-Solla, H.
Chem.-Eur. J. 2001, 7, 3062–3068.
(14) Concello´n, J. M.; Huerta, M. Tetrahedron Lett. 2003, 44, 1931–
1934.
(15) Concello´n, J. M.; Bernad, P. L.; Pe´rez-Andre´s, J. A. Angew. Chem.,
Int. Ed. 1999, 38, 2384–2386.
(16) (a) Concello´n, J. M.; Bernad, P. L.; Bardales, E. Org. Lett. 2001,
3, 937–939. (b) Concello´n, J. M.; Rodríguez-Solla, H.; Simal, C.; Go´mez,
C. Synlett 2007, 75–78.
(17) (a) Tomisaka, Y.; Harato, N.; Sato, M.; Nomoto, A.; Ogawa, A.
Bull. Chem. Soc. Jpn. 2006, 79, 1444–1446. (b) Prasad, E.; Knettle, B. W.;
Flowers, R. A., II Chem.-Eur. J. 2005, 11, 3105–3112. (c) Sumino, Y.;
Harato, N.; Tomisaka, Y.; Ogawa, A. Tetrahedron 2003, 59, 10499–10508.
(d) Molander, G. A.; Alonso-Alija, C. J. Org. Chem. 1998, 63, 4366–4373.
(e) Molander, G. A.; Wolfe, C. N. J. Org. Chem. 1998, 63, 9031–9036. (f)
Ogawa, A.; Sumino, Y.; Nanke, T.; Ohya, S.; Sonoda, N.; Hirao, T. J. Am.
Chem. Soc. 1997, 119, 2745–2746. (g) Skene, W. G.; Scaiano, J. C.; Cozens,
F. L. J. Org. Chem. 1996, 61, 7918–7921.
(19) (a) R-Chloroaldehydes can be easily obtained, see: Halland, N.;
Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A. J. Am. Chem.
Soc. 2004, 126, 4790–4791. (b) Chlorination of R-alkylated aldehydes was
carried out using sulfuryl chloride: Stevens, C. L.; Farkas, E.; Gillis, B.
J. Am. Chem. Soc. 1954, 76, 2695-2698.
(20) The solution of SmI2 in THF was rapidly obtained by reaction of
diiodomethane with samarium powder in the presence of sonic waves:
Concello´n, J. M.; Rodríguez-Solla, H.; Bardales, E.; Huerta, M. Eur. J.
Org. Chem. 2003, 177 5-1778.
(18) Concello´n, J. M.; Rodríguez-Solla, H.; Simal, C.; Huerta, M. Org.
Lett. 2005, 7, 5833–5835.
4550
Org. Lett., Vol. 10, No. 20, 2008

Table 2. Synthesis of (Z)-ꢀ,γ-Unsaturated Nitriles 3
Scheme 2
.
Mechanistic Proposal for the Conversion of 2a-f
and 2h-k into 3a-f and 3h-k
entry
3
R1
R2
Z/Ea
yield (%)b
1
2
3
4
5
6
7
8
3a n-C6H13
3b n-C10H21
3c CH2dCH(CH2)7
3d (Z)-EtCHdCH(CH2)4
3e PhCH2
H
H
H
H
H
H
H
Me
Me
Me
81/19
84/16
75/25
80/20
75/25
75/25
15/85
87/13c
85/15c
93/7
87
85
80
77
92
71
95
84
81
76
74
86
3f
PhCH(Me)
3g Ph
3h n-C6H13
We could surmise that the stereochemistry of this ꢀ-e-
limination reaction is governed by the chelation of the
oxophilic samarium(III) center23 to the carbonyl oxygen atom
of the acetoxy group to generate species 5. Thus, the
elimination reaction could take place through transition state
I, depicted in Scheme 2.15,16b,8 It is noteworthy that the acetyl
group plays two key roles: on one hand, it facilitates the
elimination reaction (acetoxy group is a better leaving group
than OH), and on the other hand, the coordination with the
SmIII center controls the stereochemical course of the
elimination reaction. Thus, the elimination reaction (under
the same reaction conditions) from nonacetylated compounds
2 afforded a complex mixture of unidentified products.
In the proposed transition state I, the CHR2CN group
adopts an equatorial orientation to avoid 1,3-diaxial interac-
tions with the samarium coordination sphere. R1 adopts an
axial orientation since no 1,3-diaxial interactions are present
and would avoid interactions with the samarium coordination
sphere. A ꢀ-elimination reaction from I as that shown in 5
affords (Z)-ꢀ,γ-unsaturated nitriles 3.
9
3i
3j
CH2dCH(CH2)7
PhCH2
10
11
12
3k n-C10H21
3l Ph
n-Pr 93/7c
n-Pr 10/90c
a Z/E ratio was determined by GC-MS and/or 300 MHz 1H NMR
analysis of the crude products 3. b Isolated yield after column chromatog-
raphy based on compound 2. c The major diastereoisomer was obtained
pure after flash chromatography.
When compounds 2, in which the chlorine atom is attached
to a tertiary carbon atom, were used, the corresponding
nitriles were obtained as a 1/1 Z/E mixture.
Starting from nitriles 2 in which (R2 * H), ꢀ,γ-unsaturated
nitriles were obtained with higher stereoselectivity (Table
1, entries 8-11).
The Z/E ratio was determined on the crude reaction
1
products by GC-MS and/or H NMR (300 MHz) spectros-
copy. Unsaturated nitriles 2h, i, k, and l could be purified
by flash chromatography and were isolated as a pure
diastereoisomer (Table 2).
The higher stereoselectivities observed from chloronitriles
2 in which R2 * H could be explained by taking into account
that when the size of R2 (H, Me, and n-Pr) is increased the
equatorial orientation of the CHR2CN group is even more
favored than the axial orientation.
The (Z)-stereochemistry of the C-C double bond in ꢀ,γ-
unsaturated nitriles 3a-f and 3h-k was assigned on the basis
of the value of the 1H NMR coupling constants between the
olefinic protons.21 In the particular case of (E)-ꢀ,γ-unsatur-
ated nitriles 3g and 3l, the stereochemistry was assigned by
This model also explains the absence of selectivity
observed from compounds 2, in which the chlorine atom is
attached to a tertiary carbon atom. In this case, the alkyl
group would occupy the equatorial orientation that, in the
case of compounds 2a-f, h-k, is occupied by the hydrogen
atom bonded to C-4 atom. Thus, since the steric hindrance
of the alkyl group is higher than that shown by an H atom,
this alkyl group competes with R1 to occupy the axial
1
the value of the H NMR coupling constant between the
olefinic protons (15.9 and 15.8 Hz, respectively) and
comparison with the NMR data previously reported in the
literature for compound 3g.9
It is noteworthy that in all cases the starting materials were
used as a nearly equimolecular mixture of two (2a-g) or
four (2h-l) diastereoisomers.
The synthesis of compounds 3 takes place by an initial
reaction of the C-Cl bond in compounds 2, with 1 equiv of
SmI2 mediated by irradiation with visible light (400 W lamp),
to generate a radical 4 (Scheme 2). Reduction of 4 with a
second equivalent of SmI2 would afford the organosamarium
species 5 which, after 1,2-elimination, yields alkenes 3.22
(22) The treatment of a mixture of diastereoisomers of the starting
compounds 2 with SmI2 could allow to the corresponding organosamarium
intermediate, as a mixture of diastereoisomers. The diastereoisomer with
the adequate stereochemistry to generate the proposed cyclic transition state
I could eliminate affording the corresponding unsaturated nitrile 3. The
other diastereoisomer, in which the coordination of the samarium with the
oxygen carbonyl group would not be favored, could experiment an
isomerization affording the other diastereoisomer, which could afford 3
through the transition state I. This elimination mechanism has been used
to explain an important number of 1,2-elimination reactions promoted by
SmI2 (see refs 12-16).
(21) The coupling constants between the olefinic protons of compounds
3a-f and 3h-k ranging between J ) 10.2 and 10.8 Hz were in accordance
with the average literature values: Silverstein, R. M.; Bassler, G. C.; Morrill,
T. C. Spectrometric Identification of Organic Compound; John Wiley and
Sons: New York, 1991; Chapter 4, Appendix F, p 221.
(23) (a) Molander, G. A. Org. React. 1995, 46, 211–368. (b) Keck, G. E.;
Truong, A. P. Org. Lett. 2002, 4, 3131–3134.
Org. Lett., Vol. 10, No. 20, 2008
4551

orientation, and the elimination process takes place without
stereoselectivity.
with other previously described ꢀ-elimination processes
promoted by samarium diiodide in which a benzylic radical
or anion is generated.16b,18,24
In conclusion, we have described a ꢀ-elimination reaction
promoted by samarium diiodide utilized in the stereoselective
synthesis of (Z)-ꢀ,γ-unsaturated nitriles. This process has
been carried out by the photoinduced metalation of nonac-
tivated C-Cl bonds on readily available 3-acetoxy-4-
chloronitriles.
The E-selectivity observed in the reaction of aromatic
chlorohydrins 2g and 2l, which is in opposition to the
Z-selectivity shown by the other compounds, could be
explained by taking into account the fact that the metalation
with 2 equiv of SmI2 affords a benzylic anion 6g,l which is
stabilized by the phenyl group. This delocalization by
resonance would impede the elimination taking place via the
cyclic transition state. Thus, the 1,2-elimination reaction
occurs from the anion 6g,l affording the thermodynamically
favored E-alkene (Scheme 3). This result is in accordance
Acknowledgment. We acknowledge the Ministerio de
Educacio´n y Cultura (CTQ2007-61132) for financial support.
J.M.C. thanks his wife Carmen Ferna´ndez-Flo´rez for her
time. H.R.S. and C.S. thank M.E.C. for a Ramo´n y Cajal
Contract (Fondo Social Europeo) and for a predoctoral
fellowship, respectively. N.R.P. thanks CSIC for a I3P
contract. Our thanks to Euan C. Goddard (CRL, University
of Oxford) for his revision of the English.
Scheme 3
.
Mechanistic Proposal for the Conversion of 2g,l into
3g,l
Supporting Information Available: General procedures
1
for the synthesis of compounds 2 and 3 and copies of H
and 13C NMR spectra for compounds 3. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL801752M
(24) (a) Davies, S. G.; Rodríguez-Solla, H.; Tamayo, J. A.; Cowley,
A. R.; Concello´n, C.; Garner, A. C.; Parkes, A. L.; Smith, A. D. Org. Biomol.
Chem. 2005, 3, 1435–1447. (b) Davies, S. G.; Rodríguez-Solla, H.; Tamayo,
J. A.; Garner, A. C.; Smith, A. D. Chem. Commun. 2004, 2502–2503
.
4552
Org. Lett., Vol. 10, No. 20, 2008