Stereoselective olefination of N-sulfonyl imines with stabilized phosphonium ylides for the synthesis of electron-deficient alkenes

Article abstract of DOI:10.1002/ejoc.201001379

An unprecedented protocol has been developed for thestereoselective synthesis of structurally diverse electron-deficient alkenes in moderate to excellent yields from readily accessible N-sulfonyl imines and stabilized phosphonium ylides. Significantly, the olefination reaction of N-sulfonylimines with nitrile-stabilized phosphonium ylides affords an array of α,β-unsaturated nitriles with high Z selectivity, and the reactions with ester-, amide-, and ketone-stabilized phosphonium ylides afford α,β-unsaturated esters, amides, and ketones with high E selectivity, respectively. Spectroscopic analysis of the reaction mixtures and trapping of the intermediates allow plausible mechanisms to be proposed. Initialimine/ylide addition leads to the formation of betaines that cyclize to form 1,2-azaphosphetanes that subsequently eliminate iminophosphoranes to yield alkenes. For the synthesis of electron-deficient 1,2-disubstituted alkenes, the presence of an electron-withdrawing group in the betaine allows rapid interconversion between its two diastereomers through proton transfer. The Z/E selectivity for alkene synthesis is determined by the different rates at which the two betaine diastereomers form the corresponding 1,2-azaphosphetane diastereomers. In contrast, the Z/E selectivity for the synthesis of electron-deficient trisubstituted alkenes originates from the diastereoselective addition of stabilized phosphonium ylides to N-sulfonyl imines.

Full text of DOI:10.1002/ejoc.201001379

FULL PAPER
DOI: 10.1002/ejoc.201001379
Stereoselective Olefination of N-Sulfonyl Imines with Stabilized Phosphonium
Ylides for the Synthesis of Electron-Deficient Alkenes
Fan Fang,[a] Yuan Li,[a] and Shi-Kai Tian*[a]
Keywords: Alkenes / Olefination / Imines / Ylides / Reaction mechanisms
An unprecedented protocol has been developed for the
stereoselective synthesis of structurally diverse electron-
deficient alkenes in moderate to excellent yields from readily
accessible N-sulfonyl imines and stabilized phosphonium
ylides. Significantly, the olefination reaction of N-sulfonyl
imines with nitrile-stabilized phosphonium ylides affords an
array of α,β-unsaturated nitriles with high Z selectivity, and
the reactions with ester-, amide-, and ketone-stabilized phos-
phonium ylides afford α,β-unsaturated esters, amides, and
ketones with high E selectivity, respectively. Spectroscopic
analysis of the reaction mixtures and trapping of the interme-
diates allow plausible mechanisms to be proposed. Initial
imine/ylide addition leads to the formation of betaines that
cyclize to form 1,2-azaphosphetanes that subsequently elimi-
nate iminophosphoranes to yield alkenes. For the synthesis
of electron-deficient 1,2-disubstituted alkenes, the presence
of an electron-withdrawing group in the betaine allows rapid
interconversion between its two diastereomers through pro-
ton transfer. The Z/E selectivity for alkene synthesis is deter-
mined by the different rates at which the two betaine dia-
stereomers form the corresponding 1,2-azaphosphetane dia-
stereomers. In contrast, the Z/E selectivity for the synthesis of
electron-deficient trisubstituted alkenes originates from the
diastereoselective addition of stabilized phosphonium ylides
to N-sulfonyl imines.
sitional selectivity, and generally high levels of geometrical
control.[4] Stabilized triphenylphosphonium ylides have
been employed most frequently because they are readily ac-
cessible by the reaction of triphenylphosphane, which is an
inexpensive and air-stable phosphane, with α-halo carbonyl
compounds or nitriles, followed by treatment of the re-
sulting phosphonium salts with appropriate bases. In gene-
ral, the Wittig reaction yields electron-deficient (E)-alkenes
with high stereoselectivity for ester-, ketone-, and amide-
stabilized triphenylphosphonium ylides,[4,5] but with low
stereoselectivity for nitrile-stabilized triphenylphosphonium
ylides.[6] Efforts to improve the stereoselective synthesis of
electron-deficient alkenes have focused on replacing the sta-
bilized triphenylphosphonium ylides in the Wittig reaction
with other phosphorus-,[7] sulfur-,[8] silicon-,[9] arsenic-,[10]
or tellurium-stabilized[11] carbon nucleophiles.[3] However,
only limited successes have been achieved and many of the
modified olefination reactions suffer from inconvenient ac-
cess to heteroatom-stabilized carbon nucleophiles, narrow
substrate scope, and inconvenient operations.
In sharp contrast, little attention has been paid to the
replacement of aldehydes with other carbon electrophiles in
the Wittig reaction of stabilized phosphonium ylides. In
2004, Abdou and co-workers developed the reaction of N-
aryl imines with stabilized phosphonium ylides in chloro-
form heated under reflux to afford α,β-unsaturated nitriles,
esters, and ketones with exclusive E selectivity, albeit in only
about 20% yield; see Equation (1).[12] Four years later, Chen
and co-workers reported that an N-tert-butoxycarbonyl
Introduction
Electron-deficient alkenes are not only present in many
natural products of biological significance,[1] but also serve
as useful electrophilic species in a broad range of chemical
transformations, such as Michael addition, cycloaddition,
and cross-coupling reactions.[2] In this context, a plethora
of chemical methods have been developed for the synthesis
of electron-deficient alkenes that mainly focus on the issue
of stereoselectivity. Carbonyl olefination, alkyne addition,
alkenylation, and elimination are all effective methods that
are widely employed in the stereoselective synthesis of elec-
tron-deficient alkenes.[3] Particularly noteworthy is the ole-
fination reaction of aldehydes with carbon nucleophiles that
are stabilized by heteroatoms such as phosphorus (the Wit-
tig and Horner–Wadsworth–Emmons reactions), silicon
(the Peterson reaction), and sulfur (the Julia olefination).
In each case, the aldehyde/carbon nucleophile addition step
is followed by an elimination to form a carbon–carbon
double bond.
The Wittig reaction of stabilized phosphonium ylides
with aldehydes has enjoyed widespread prominence and re-
cognition owing to its simplicity, convenience, complete po-
[a] Department of Chemistry, University of Science and
Technology of China
Hefei, Anhui 230026, P. R. of China
Fax: +86-0551-3601592
E-mail: tiansk@ustc.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001379.
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Synthesis of Electron-Deficient Alkenes
(Boc) imine reacted with a stabilized phosphonium ylide in unsaturated nitriles with low stereoselectivity.[6] To improve
toluene in the presence of molecular sieves (MS) at 0 °C to or switch the stereoselectivity for the synthesis of α,β-unsat-
yield the corresponding imine/ylide adduct; see Equa- urated nitriles, we replaced the aldehydes in the Wittig reac-
tion (2).[13] Although these reactions are not useful for the tion with N-sulfonyl imines, which are reasonably stable in
stereoselective synthesis of electron-deficient alkenes, they air at room temperature and are easily prepared through
prompted us to hypothesize that the employment of more the condensation reaction of aldehydes with primary sul-
reactive imines might enhance the yields for the formation fonamides.[17] To our delight, the model reaction of (cyano-
of electron-deficient alkenes. In addition, switching the elec- methylene)triphenylphosphorane with N-benzylidene-p-tol-
tronic and steric properties of the group on the imine nitro- uenesulfonamide proceeded smoothly in a number of com-
gen might improve or switch the stereoselectivity for alkene mon organic solvents at room temperature to afford α,β-
synthesis when compared to the corresponding Wittig reac- unsaturated nitrile 1a in moderate to excellent yields and
tion with aldehydes.
with modest to excellent Z selectivity (Table 1, entries 1–8).
Acetonitrile was identified as the solvent of choice; under
these conditions the reaction afforded α,β-unsaturated ni-
trile 1a in 95% yield and with a Z/E selectivity of 95:5
(Table 1, entry 5). For comparison, we carried out the Wit-
tig reaction of benzaldehyde with (cyanomethylene)tri-
phenylphosphorane under the same reaction conditions and
obtained α,β-unsaturated nitrile 1a with a Z/E selectivity of
23:77.[18] Whereas elevated temperature enhanced the yield,
it decreased the stereoselectivity significantly (Table 1, entry
9). We further examined many other N-benzylidene sulfon-
amides in acetonitrile at room temperature and found that
the N-sulfonyl group significantly affected the yield and
stereoselectivity of the formation of α,β-unsaturated nitrile
1a (Table 1, entries 10–18).[19] However, the stereoselectivity
was not enhanced or switched by employing N-sulfonyl
groups that possess distinct electronic and steric properties.
(1)
(2)
In the course of applying carbon–nitrogen bond cleavage
to selective organic synthesis,[14] together with our interest
in stereoselective alkene synthesis,[15] we recently discovered
a highly tunable, stereoselective olefination of N-sulfonyl
imines with semistabilized phosphonium ylides.[16] To ex-
tent this chemistry to the stereoselective synthesis of elec-
tron-deficient alkenes, we investigated the reaction of N-sul-
fonyl imines with a wide variety of stabilized phosphonium
ylides, and synthesized structurally diverse electron-de-
ficient alkenes in moderate to excellent yields. Importantly,
these unprecedented reactions provided α,β-unsaturated ni-
triles with high Z selectivity, and α,β-unsaturated esters,
amides, and ketones with high E selectivity (Scheme 1).
Furthermore, spectroscopic analysis of the reaction mix-
tures and trapping of the intermediates allowed us to pro-
pose plausible mechanisms to account for the stereoselec-
tive formation of electron-deficient alkenes.
Table 1. Optimization of reaction conditions.[a]
Scheme 1. Stereoselective olefination of N-sulfonyl imines with sta-
bilized phosphonium ylides.
Results and Discussion
Stereoselective Olefination of N-Sulfonyl Imines with
Nitrile-Stabilized Phosphonium Ylides
[a] Reaction conditions: N-sulfonyl imine (0.25 mmol), phospho-
nium ylide (0.30 mmol), solvent (0.50 mL), 25 or 60 °C, 24 h. [b]
1
Isolated yield. [c] Determined by H NMR spectroscopic analysis.
The Wittig reaction of nitrile-stabilized phosphonium
Tetrahydrofuran (THF), N,N-dimethylformamide (DMF), di-
ylides with aldehydes has been reported to yield (E)-α,β- methyl sulfoxide (DMSO).
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A broad range of N-(p-tolylsulfonyl) aromatic and het-
eroaromatic imines smoothly underwent olefination reac-
tions with (cyanomethylene)triphenylphosphorane to afford
structurally diverse (Z)-α,β-unsaturated nitriles in good to
excellent yields and with excellent stereoselectivity (Table 2,
entries 1–11). It is noteworthy that both electron-with-
drawing and electron-donating groups could be introduced
into the (Z)-α,β-unsaturated nitrile by employing a suitable
imine bearing such a group on the aromatic ring. This Z
selective olefination reaction was successfully extended to
a range of N-(p-tolylsulfonyl) α,β-unsaturated imines, and
various α,β,γ,δ-unsaturated nitriles were synthesized with
excellent stereoselectivity (Table 2, entries 12–15). The geo-
metric configuration of the carbon–carbon double bond in
the N-sulfonyl imine was completely preserved in the ole-
fination reaction. By contrast, the reaction with an N-(p-
tolylsulfonyl) aliphatic imine proceeded slowly to afford the
corresponding electron-deficient alkene with good Z selec-
tivity (Table 2, entry 16).
(3)
Stereoselective Olefination of N-Sulfonyl Imines with Ester-
Stabilized Phosphonium Ylides
In contrast to (cyanomethylene)triphenylphosphorane,
the olefination reaction of (ethoxycarbonylmethylene)tri-
phenylphosphorane with N-benzylidene-p-toluenesulfon-
amide proceeded very slowly in a number of common or-
ganic solvents at room temperature and exhibited moderate
to very good E selectivity (Table 3, entries 1–5). Replace-
ment of the p-tolylsulfonyl group on the imine nitrogen with
another sulfonyl group did not enhance the yield or stereo-
selectivity (Table 3, entries 6–9). We further examined the
olefination reaction in p-xylene at an elevated temperature
(Table 3, entries 10–12), and, to our delight, α,β-unsatu-
rated ester 2a was obtained in 74% yield with an E/Z selec-
tivity of 98:2 when a methylsulfonyl group was employed to
activate the imine (Table 3, entry 12).
Table 2. Stereoselective olefination of N-sulfonyl imines with ni-
trile-stabilized phosphonium ylides.[a]
Table 3. Optimization of reaction conditions.[a]
[a] Reaction conditions: N-sulfonyl imine (0.25 mmol), phospho-
nium ylide (0.30 mmol), solvent (0.25 mL), 25 or 140 °C, 12 h. [b]
1
Isolated yield. [c] Determined by H NMR spectroscopic analysis.
[a] Reaction conditions: N-(p-tolylsulfonyl) imine (0.25 mmol),
phosphonium ylide (0.30 mmol), acetonitrile (1.0 mL), room temp.,
24 h. [b] Isolated yield. [c] Determined by H NMR spectroscopic
analysis. [d] The reaction was run for 48 h. Ts = p-tolylsulfonyl.
1
Under the optimized reaction conditions, (ethoxycarbon-
ylmethylene)triphenylphosphorane reacted with various N-
methylsulfonyl aromatic or heteroaromatic imines to afford
Poor reactivity and low stereoselectivity were observed in the corresponding (E)-α,β-unsaturated esters in good yields
the olefination reaction with a nitrile-stabilized phospho- and with excellent stereoselectivity (Table 4, entries 1–6). In
nium ylide with greater steric demand. For example, the contrast, very sluggish reactions were observed with N-
olefination reaction of (α-cyanoethylidene)triphenylphos- methylsulfonyl α,β-unsaturated or aliphatic imines. To our
phorane with N-benzylidene-p-toluenesulfonamide pro- delight, the olefination reaction worked well with a few
ceeded at room temperature for 48 h to afford trisubstituted other ester-stabilized phosphonium ylides having greater
α,β-unsaturated nitrile 1q in only 32% yield; see Equa- steric demands, and a range of trisubstituted α,β-unsatu-
tion (3). Moreover, this reaction exhibited moderate E selec- rated esters were synthesized in good yields and with excel-
tivity (30:70 Z/E), which is contrary to the stereoselectivity lent E selectivity from the corresponding N-methylsulfonyl
trend for the synthesis of α,β-disubstituted α,β-unsaturated imines and (α-alkoxycarbonylalkylidene)triphenylphos-
nitriles shown in Table 2.
phoranes (Table 4, entries 7–11).
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Synthesis of Electron-Deficient Alkenes
Table 4. Stereoselective olefination of N-sulfonyl imines with ester- entry 3). Replacement of the p-tolylsulfonyl group on the
stabilized phosphonium ylides.[a]
imine nitrogen with other sulfonyl groups did not switch
the stereoselectivity (Table 5, entries 5–9).
Various N-(p-tolylsulfonyl) aromatic and heteroaromatic
imines underwent olefination reactions with (1-piperidinyl-
carbonylmethylene)triphenylphosphorane to afford the cor-
responding (E)-α,β-unsaturated amides in good to excellent
yields and with excellent stereoselectivity (Table 6, entries
1–5). In contrast, a moderate yield was obtained from the
relatively slow reaction with an N-(p-tolylsulfonyl) aliphatic
imine (Table 6, entry 6). To our delight, the olefination reac-
tion worked well with a range of other amide-stabilized
phosphonium ylides bearing structurally diverse substitu-
ents on the amide nitrogen atoms, and various di- and tri-
substituted α,β-unsaturated amides were synthesized in
good to excellent yields and with excellent E selectivity
(Table 6, entries 7–12).
Table 6. Stereoselective olefination of N-sulfonyl imines with
amide-stabilized phosphonium ylides.[a]
[a] Reaction conditions: N-methylsulfonyl imine (0.25 mmol), phos-
phonium ylide (0.30 mmol), p-xylene (0.25 mL), 140 °C, 12 h. [b]
1
Isolated yield. [c] Determined by H NMR spectroscopic analysis,
Ms = methylsulfonyl.
Stereoselective Olefination of N-Sulfonyl Imines with
Amide-Stabilized Phosphonium Ylides
Elevated temperature was also needed to accelerate the
olefination reaction of N-sulfonyl imines with amide-stabi-
lized phosphonium ylides. A number of solvents were as-
sessed in the model reaction of (1-piperidinylcarbonylmeth-
ylene)triphenylphosphorane with N-benzylidene-p-toluene-
sulfonamide at 100 °C (Table 5, entries 1–4), and it was
found that dimethyl sulfoxide was the solvent of choice; un-
der these conditions α,β-unsaturated amide 3a was pro-
duced in 91% yield with an E/Z selectivity of 98:2 (Table 5,
[a] Reaction conditions: N-(p-tolylsulfonyl) imine (0.25 mmol),
phosphonium ylide (0.30 mmol), DMSO (0.25 mL), 100 °C, 12 h.
Table 5. Optimization of reaction conditions.[a]
[b] Isolated yield. [c] Determined by 1H NMR spectroscopic analy-
sis. [d] The reaction was run for 72 h.
Stereoselective Olefination of N-Sulfonyl Imines with
Ketone-Stabilized Phosphonium Ylides
A similar strategy was employed to optimize the reaction
conditions for ketone-stabilized phosphonium ylides, and
dimethyl sulfoxide was identified as the solvent of choice
(Table 7, entries 1–4). The model reaction of (benzoylmeth-
ylene)triphenylphosphorane with N-benzylidene-p-toluene-
sulfonamide proceeded in dimethyl sulfoxide at 100 °C to
afford α,β-unsaturated ketone 4a in 98% yield, with an E/Z
selectivity of 99:1 (Table 7, entry 3). Further investigations
revealed that the sulfonyl group on the imine nitrogen atom
only marginally affected the stereoselectivity in the alkene
synthesis (Table 7, entries 5–9).
[a] Reaction conditions: N-sulfonyl imine (0.25 mmol), phospho-
nium ylide (0.30 mmol), solvent (0.25 mL), 100 °C, 12 h. [b] Iso-
1
lated yield. [c] Determined by H NMR spectroscopic analysis.
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Table 7. Optimization of reaction conditions.[a]
nitriles with high Z selectivity, and α,β-unsaturated esters,
amides, and ketones with high E selectivity. Whereas the
stereoselectivity is highly tunable in the olefination reaction
of N-sulfonyl imines with semistabilized phosphonium
ylides,[16] it is difficult to tune the stereoselectivity for the
corresponding reaction with stabilized phosphonium ylides
simply by switching the electronic and steric properties of
the sulfonyl groups on the imine nitrogen atoms. To gain
insights into the reaction mechanism, we carried out spec-
troscopic analyses of the reaction mixtures and attempted
to trap the possible intermediates.
In contrast to semistabilized phosphonium ylides, which
are prepared in situ, stabilized phosphonium ylides are suf-
ficiently stable to be purified before use. Importantly, em-
ploying pure stabilized phosphonium ylides and N-sulfonyl
imines in the reaction greatly facilitated the spectroscopic
analyses of the reaction mixtures. A nitrile-stabilized and an
ester-stabilized phosphonium ylide were submitted to the
olefination reaction with two representative N-methylsulf-
onyl imines in deuterated chloroform at room temperature,
and, after 24 hours, each of the reaction mixtures was sub-
[a] Reaction conditions: N-sulfonyl imine (0.25 mmol), phospho-
nium ylide (0.30 mmol), solvent (0.25 mL), 100 °C, 12 h. [b] Iso-
1
lated yield. [c] Determined by H NMR spectroscopic analysis.
A broad range of N-(p-tolylsulfonyl) aromatic, α,β-unsat-
urated, and aliphatic imines served as suitable carbon elec-
trophiles; these underwent olefination reactions with a wide
variety of ketone-stabilized phosphonium ylides (Table 8).
Significantly, an array of di- and trisubstituted α,β-unsatu-
rated ketones were synthesized in moderate to excellent
yields and with excellent E selectivity.
1
jected to H NMR spectroscopic analysis. As summarized
in Table 9, significant amounts of imine/ylide adducts 5a–d
and vinylphosphonium salts 6a and 6b were identified as
intermediates, the generation of which was substantially
supported by 31P NMR spectroscopic analysis of the reac-
tion mixtures.[20] Moreover, vinylphosphonium salts 6a–d
were unambiguously detected in these reaction mixtures by
ESI-HRMS (electron spray ionization high-resolution mass
spectrometry) analysis. It is clear that only trace amounts
of intermediates 6c and 6d were generated in the reactions
with an ester-stabilized phosphonium ylide (Table 9, entries
3 and 4).
Table 8. Stereoselective olefination of N-sulfonyl imines with
ketone-stabilized phosphonium ylides.[a]
Table 9. Spectroscopic analysis of the reaction mixtures.[a]
[a] Reaction conditions: N-(p-tolylsulfonyl) imine (0.25 mmol),
phosphonium ylide (0.30 mmol), DMSO (0.25 mL), 100 °C, 12 h.
[b] Isolated yield. [c] Determined by 1H NMR spectroscopic analy-
sis. [d] The reaction was run for 24 h.
Mechanistic Studies
[a] Reaction conditions: N-methylsulfonyl imine (0.125 mmol),
phosphonium ylide (0.125 mmol), deuterated chloroform
(0.50 mL), room temp., 24 h. [b] Determined by 1H NMR spectro-
As demonstrated by the results summarized in Tables 2,
4, 6, and 8, the olefination reaction of N-sulfonyl imines
with stabilized phosphonium ylides affords α,β-unsaturated scopic analysis. [c] For electron-deficient alkenes.
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Synthesis of Electron-Deficient Alkenes
It is noteworthy that imine/ylide adduct 5d was isolated imines and stabilized phosphonium ylides (Scheme 3). The
with 95% purity (contaminated by the corresponding N- diastereoselective addition of a stabilized phosphonium
sulfonyl imine) by filtration after the reaction mixture was ylide to an N-sulfonyl imine results in the formation of be-
treated with petroleum ether and ethyl acetate (3:1) at room taine B (as a mixture of anti-isomer B1 and syn-isomer B2),
temperature. However, such a purification procedure did which cyclizes to form 1,2-azaphosphetane C (as a mixture
not allow the isolation of imine/ylide adducts 5a–c and vin- of cis-isomer C1 and trans-isomer C2) and subsequently
ylphosphonium salts 6a–d owing to their decomposition at eliminates an iminophosphorane to yield an alkene.[22]
room temperature to yield the corresponding electron-de- Owing to the presence of the electron-withdrawing group,
ficient alkenes.
proton transfer occurs readily to result in isomerization be-
Interestingly, treatment of the reaction mixture with for- tween B1 and B2 via ylide D,[23] which reversibly loses a
malin resulted in the trapping of vinylphosphonium salts 6 sulfonamide group to yield vinylphosphonium salt E. The
rather than imine/ylide adducts 5. For example, when for- large abundance of ylide D (and in some cases vinylphos-
malin was added after 1 h to the reaction of (cyanomethyl- phonium salt E) in the reaction mixture, as revealed by the
ene)triphenylphosphorane with N-(3,4,5-trimethoxy)benz- examples shown in Table 9, suggests that the conversion of
ylidenemethanesulfonamide in tetrahydrofuran at room betaine B into 1,2-azaphosphetane C is much slower than
temperature, allylic alcohol 7, 1,4-diene 8, and alkene Z1h the interconversion between betaine diastereomers B1 and
(88:12 Z/E) were obtained (Scheme 2). In contrast, allylic B2. Thus, it is reasonable to conclude that the Z/E selectiv-
amine derivative 9 was not obtained at all through the ity for alkene synthesis does not parallel the diastereoselec-
methylenation of intermediate 5a, probably due to its rapid tivity for the initial addition of a stabilized phosphonium
decomposition to yield alkene Z1h and/or intermediate 6a ylide to an N-sulfonyl imine. Instead, the Z/E selectivity for
under the reaction conditions. Tentatively, allylic alcohol 7 alkene synthesis is determined by the different rates for the
and 1,4-diene 8 are thought to be generated via intermedi- transformations of B1 and B2 into C1 and C2, respectively.
ate 6a, which was identified by the aforementioned NMR When the total interactions of the N-sulfonyl group, the R1
spectroscopic analysis (Table 9). The Michael addition of group, the P-phenyl group, and the EWG group that de-
water to intermediate 6a results in the formation of ylide velop in the formation of C2 are greater than that in the
10, which undergoes methylenation with formaldehyde to formation of C1, the olefination reaction prefers to afford
afford allylic alcohol 7. Alternatively, the Michael addition a (Z)-alkene (EWG = CN), otherwise, an (E)-alkene is pro-
of (cyanomethylene)triphenylphosphorane to intermediate duced predominantly (EWG = CO2R, CONRRЈ, COR).
6a followed by deprotonation leads to the formation of 1,3-
diylide 12, which undergoes double methylenation with
formaldehyde to afford 1,4-diene 8.
Scheme 3. Proposed mechanism for the stereoselective synthesis of
electron-deficient 1,2-disubstituted alkenes from N-sulfonyl imines
and stabilized phosphonium ylides.
For the synthesis of an electron-deficient trisubstituted
Scheme 2. Treatment of the reaction mixture with formalin.
alkene, no intermediate was observed by 1H NMR, 31P
On the basis of our results and on previous studies re- NMR, or ESI-MS analysis of the reaction mixture. Of
ported in literature,[12,13,21] we propose the following mecha- course, it is unlikely that the reaction would generate inter-
nism to account for the stereoselectivity for the synthesis of mediates analogous to D and E when the α-hydrogen in a
electron-deficient 1,2-disubstituted alkenes from N-sulfonyl stabilized phosphonium ylide is replaced with an alkyl (R2)
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group (Scheme 4). Thus, we propose that the diastereoselec- nates from the diastereoselective addition of a stabilized
tive addition of a stabilized phosphonium ylide to an N- phosphonium ylide to an N-sulfonyl imine.
sulfonyl imine preferentially results in the formation of be-
taine B3, which cyclizes to form 1,2-azaphosphetane C3
and subsequently eliminates an iminophosphorane to yield
an electron-deficient (E)-trisubstituted alkene. The stereose-
lectivity for alkene synthesis is determined by the total in-
teractions of the N-sulfonyl group, the R1 group, the Ph3P
group, the EWG group, and the R2 group that develop as
the ylide and imine approach one another, and the favorable
formation of betaine B3 accounts for the E selectivity ex-
hibited in the synthesis of an electron-deficient trisubsti-
tuted alkene.
Experimental Section
General Procedure for the Stereoselective Olefination of N-Sulfonyl
Imines with Nitrile-Stabilized Phosphonium Ylides: (Table 2): To a
solution of N-(p-tolylsulfonyl) imine (0.25 mmol) in acetonitrile
(1.0 mL) under nitrogen at room temperature was added the corre-
sponding nitrile-stabilized phosphonium ylide (0.30 mmol). The
mixture was stirred at room temperature for 24 h, and purified by
flash column chromatography on silica gel or by preparative thin
layer chromatography (TLC), eluting or developing with petroleum
ether/ethyl acetate (10:1 to 3:1), to give α,β-unsaturated nitrile Z1.
General Procedure for the Stereoselective Olefination of N-Sulfonyl
Imines with Ester-Stabilized Phosphonium Ylides: (Table 4): To a
solution of N-(methylsulfonyl) imine (0.25 mmol) in p-xylene
(0.25 mL) under nitrogen was added the corresponding ester-stabi-
lized phosphonium ylides (0.30 mmol). The mixture was stirred at
140 °C for 12 h, purified by flash column chromatography on silica
gel or by preparative TLC, eluting or developing with petroleum
ether/ethyl acetate (10:1 to 3:1), to give α,β-unsaturated ester E2.
General Procedure for the Stereoselective Olefination of N-Sulfonyl
Imines with Amide- or Ketone-Stabilized Phosphonium Ylides:
(Tables 6 and 8): To a solution of N-(p-tolylsulfonyl) imine
(0.25 mmol) in dimethyl sulfoxide (0.25 mL) under nitrogen was
added the corresponding amide- or ketone-stabilized phosphonium
ylide (0.30 mmol). The mixture was stirred at 100 °C for 12 h, and
purified by flash column chromatography on silica gel or by prepar-
ative TLC, eluting or developing with petroleum ether/ethyl acetate
(10:1 to 3:1), to give α,β-unsaturated amide E3 or α,β-unsaturated
ketone E4.
Scheme 4. Proposed mechanism for the stereoselective synthesis of
electron-deficient trisubstituted alkenes from N-sulfonyl imines and
stabilized phosphonium ylides.
Conclusions
In conclusion, we have developed an unprecedented pro-
tocol for the stereoselective synthesis of structurally diverse
electron-deficient alkenes in moderate to excellent yields
from readily accessible N-sulfonyl imines and stabilized
phosphonium ylides. Significantly, the olefination reaction
of N-sulfonyl imines with nitrile-stabilized phosphonium
ylides affords an array of α,β-unsaturated nitriles with high
Z selectivity, and the reactions with ester-, amide-, and
ketone-stabilized phosphonium ylides afford α,β-unsatu-
rated esters, amides, and ketones with high E selectivity,
respectively.
Supporting Information (see footnote on the first page of this arti-
cle): General information, experimental procedures, characteriza-
1
tion data, and copies of H and 13C NMR spectra for products.
Acknowledgments
We are grateful for the financial support from the National Natural
Science Foundation of China (20972147 and 20732006), the
National Basic Research Program of China (973 Program
2010CB833300), and the Chinese Academy of Sciences.
On the basis of spectroscopic analyses of reaction mix-
tures and the trapping of intermediates, plausible mecha-
nisms have been proposed that account for the stereoselecti-
vity of alkene synthesis. The diastereoselective addition of
a stabilized phosphonium ylide to an N-sulfonyl imine re-
sults in the formation of a betaine, which cyclizes to form
a 1,2-azaphosphetane and subsequently eliminates an imi-
nophosphorane to yield an alkene. For the synthesis of an
electron-deficient 1,2-disubstituted alkene, the presence of
an electron-withdrawing group in the betaine allows rapid
interconversion between its two diastereomers through pro-
ton transfer, and the Z/E selectivity for alkene synthesis is
determined by the different rates at which the two betaine
diastereomers form the corresponding 1,2-azaphosphetane
diastereomers. In contrast, the Z/E selectivity for the syn-
thesis of an electron-deficient trisubstituted alkene origi-
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Received: October 7, 2010
Published Online: January 12, 2011
Eur. J. Org. Chem. 2011, 1084–1091
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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