Aza-Baylis-Hillman reactions of N-(arylmethylene) diphenylphosphinamides with activated olefins in the presence of various Lewis bases

Article abstract of DOI:10.1002/adsc.200404081

The aza-Baylis-Hillman reactions of N-(arylmethylene)diphenylphosphinamides with methyl vinyl ketone (MVK), methyl acrylate, acrylonitrile, ethyl vinyl ketone (EVK), phenyl vinyl ketone (PVK), phenyl acrylate, 2-cyclopenten-1-one, 2-cyclohexen-1-one have

Full text of DOI:10.1002/adsc.200404081

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Aza-Baylis–Hillman Reactions of N-(Arylmethylene)
diphenylphosphinamides with Activated Olefins in the Presence
of Various Lewis Bases
Min Shi,* Gui-Ling Zhao
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. China
Fax: (þ86)-21-64166128, mshi@pub.sioc.ac.cn
Received: March 12, 2004; Accepted: June 25, 2004
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de or from the author.
Abstract: The aza-Baylis–Hillman reactions of N-(ar- some cases exclusively) and their further transforma-
ylmethylene)diphenylphosphinamides with methyl vi- tions including catalytic, asymmetric version in the
nyl ketone (MVK), methyl acrylate, acrylonitrile, eth- presence of chiral nitrogen and phosphine Lewis bas-
yl vinyl ketone (EVK), phenyl vinyl ketone (PVK), es have been disclosed in this paper.
phenyl acrylate, 2-cyclopenten-1-one, 2-cyclohexen-
1-one have been systemically investigated in the pres-
ence of various Lewis bases. The Lewis base and sol- Keywords:
N-(arylmethylene)diphenylphosphin-
vent effects in these reactions have been discussed. A amide; aza-Baylis–Hillman reactions; DABCO, Lewis
new class of double aza-Baylis–Hillman reactions (in bases; organic catalysis; phosphanes
Introduction
acrylate, acrylonitrile, ethyl vinyl ketone (EVK), phenyl
vinyl ketone (PVK), phenyl acrylate, 2-cyclopenten-1-
Great progress has been made in the execution of Bay- one, and 2-cyclohexen-1-one in the presence of various
lis–Hillman reaction,[1] for which several catalytic, asym- Lewis base promoters. The Lewis base and solvent ef-
metric versions have been published,[2] since Baylis and fects in these aza-Baylis–Hillman reactions have been
Hillman first reported the reactions of acetaldehyde investigated. Some unprecedented reaction patterns de-
with ethyl acrylate and acrylonitrile in the presence of rived from double aza-Baylis–Hillman reactions are dis-
catalytic amounts of strong Lewis base such as 1,4-diaza- closed in this paper. In addition, the catalytic, asymmet-
bicyclo[2.2.2]octane (DABCO) in 1972.[3] Besides the ric version in the presence of chiral nitrogen and phos-
traditional Baylis–Hillman reactions,[4] recently, the phine Lewis bases has been investigated.
scope and limitations of aza-Baylis–Hillman reactions
have been extensively investigated.[5] Some unprece-
dented reaction patterns and a catalytic, asymmetric Results and Discussion
version of the aza-Baylis–Hillman reaction using N-sul-
fonated imines as the substrates have been disclosed by
Aza-Baylis–Hillman Reactions of 1 with MVK
our group.[6] N-(Arylmethylene)diphenylphosphina-
mides 1 are another well-known class of electron-defi-
cient imines.[7] Therefore, it will be of interest to investi- The Lewis base promoters and solvents for the aza-Bay-
gate their aza-Baylis–Hillman reactions with various ac- lis–Hillman reactions of N-(benzylidene)diphenylphos-
tivated olefins in the presence of Lewis base promoter. phinamide 1a with MVK were first systematically exam-
Previously, we reported the aza-Baylis–Hillman reac- ined (Scheme 1). The results are summarized in Table 1.
tions of 1 with methyl vinyl ketone, methyl acrylate, We found that the Lewis base and solvent played very
and acrylonitrile catalyzed by various Lewis bases to important roles for this reaction. For example, using
give the adducts in good yields in a short communica- 10 mol% of PPh3 as the Lewis base in DMF or MeCN,
tion.[6d,8] Herein, we wish to report the comprehensive the reaction proceeded very well to give the correspond-
aza-Baylis–Hillman reaction patterns of N-(arylmethy- ing normal aza-Baylis–Hillman adduct 2a in 81% and
lene)diphenylphosphinamides 1 with various activated 99% yields, respectively (Table 1, entries 2 and 4). Using
olefins including methyl vinyl ketone (MVK), methyl PPh2Me as the Lewis base, 2a was produced in a relative-
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ly low yield (76%) under the same conditions (Table 1, phenyl ring, the corresponding aza-Baylis–Hillman ad-
entry 5). Using PBu3 or PPhMe2 as the Lewis base, ducts 2d – h were produced in high yields (Table 2, en-
traces of 2a were produced along with many unidenti- tries 3–7, 12–15). In some cases, the reactions proceed-
fied products (Table 1, entries 6 and 7). The well estab- ed smoothly to furnish adduct 2 quantitatively.
lished strong nitrogen Lewis base, DABCO, gave a low-
er yield of 2a in manysolvents under the same conditions
as those catalyzed by PPh3 (Table 1, entries 8–11). In di- Aza-Baylis–Hillman Reactions of 1 with Methyl
chloromethane, 2a was obtained in moderate yield Acrylate
(66%) (Table 1, entry 11). On use of DMAP as a nitro-
gen Lewis base in DMF, 2a was produced in 72% within We next examined the aza-Baylis–Hillman reactions of
96 h (Table 1, entry 12). In all these cases, the normal N-(arylmethylene)diphenylphosphinamides
1
with
aza-Baylis–Hillman adduct 2a was formed exclusively. methyl acrylate in the presence of various Lewis bases
For aza-Baylis–Hillman reactions of other N-(arylme- (Scheme 3). Using PPh3 or DABCO as the Lewis base,
thylene)diphenylphosphinamides 1 with MVK using the reaction was sluggish (Table 3, entries 1–7). By
PPh3 as Lewis base under the optimized reaction condi- use of the nitrogen Lewis base DMAP, 3a was produced
tions, the adducts 2 were obtained in good to excellent in traces (Table 3, entry 14). Most of starting materials
yields (Scheme 2). The results are summarized in Ta- were recovered and no other product was detected.
ble 2. For N-(arylmethylene)diphenylphosphinamides But, we were pleased to find that on using PPh2Me as
1 having an electron-donating group on the phenyl the Lewis base in dichloromethane, the corresponding
ring, the corresponding aza-Baylis–Hillman adducts 2b aza-Baylis–Hillman adduct 3a was obtained in 71%
and 2c were obtained in low yields in DMF (Table 2, en- yield (Table 3, entry 10). In fact, N-(arylmethylene)di-
tries 1 and 2), but in MeCN or THF, 2b and 2c were phenylphosphinamides 1 are more soluble in dichloro-
formed in 77 and 80% yields (Table 2, entries 8 and methane than in other solvents such as THF or DMF.
10) or 90% and 70% yield (Table 2, entries 9 and 11), re- In addition, dichloromethane contains less free oxygen,
spectively. For N-(arylmethylene)diphenylphosphin-
amides 1 having an electron-withdrawing group on the
Scheme 2.
Scheme 1.
Table 2. Aza-Baylis–Hillman reactions of N-(arylmethyle-
ne)diphenylphosphinamides
(1.2 equivs.) in the presence of PPh3 (10 mol %) in DMF,
THF or MeCN.
1
(1.0 equiv.) with MVK
Table 1. Aza-Baylis–Hillman reactions of N-(benzylidene)-
diphenylphosphinamide (1a; 1.0 equiv.) with MVK (1.2
equivs.) in the presence of a Lewis base (10 mol %) at
room temperature in various solvents.
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which can oxidize a phosphine Lewis base during the re- or PBu3 as a Lewis base in THF, the abnormal aza-Bay-
action, than other solvents such as THFor DMF. There- lis–Hillman adduct 4a can be obtained as the major
fore, dichloromethane is the solvent of choice for this re- product along with minor normal aza-Baylis–Hillman
action. It should be emphasized here that when using product 3a (Table S1 in Supporting Information, entries
PBu3 or PPhMe2 as the Lewis base, 3a was obtained 4, 8). Using PMe3 as a Lewis base, the reaction became
only in 38% or 31% yields (Table 3, entries 8 and 9). sluggish, but also can produce the abnormal aza-Bay-
Upon further careful investigations such as HPLC sepa- lis–Hillman adduct 4a in 32% yield along with a 37%
ration and X-ray diffraction, we found that when using
PBu3 or PPhMe2 as the Lewis base promoter, the major
Table 3. Aza-Baylis–Hillman reactions of N-benzylidenedi-
product was a double aza-Baylis–Hillman adduct 4 as
phenylphosphinamide (1a; 1.0 equiv.) with methyl acrylate
mixtures of syn- and anti-isomers along with the normal
Baylis–Hillman adduct 3 (Scheme 4). Therefore, we
(1.2 equivs.) in the presence of a Lewis base (10 mol %) at
room temperature in various solvents.
found out different reaction conditions for the produc-
tion of either the normal or the abnormal aza-Baylis–
Hillman adduct by change of the employed Lewis base
under mild reaction conditions.
For the aza-Baylis–Hillman reactions of other N-(ar-
ylmethylene)diphenylphosphinamides 1 with methyl
acrylate using PPh2Me as a Lewis base under the opti-
mized reaction conditions, the normal adducts 3 were
obtained in moderate to good yields (Scheme 5). The re-
sults are summarized in Table 4. The aliphatic aza-Bay-
lis–Hillman adduct 3 h was formed in moderate yield
(Table 4, entry 7).
In fact, the formation of 4, the abnormal aza-Baylis–
Hillman adduct derived from a double aza-Baylis–Hill-
man reaction, has never been disclosed before in such a
reaction using methyl acrylate as a Michael acceptor.[9]
Using N-benzylidenediphenylphosphinamide 1a (no
substituent on the phenyl ring) as the substrate, we care-
fully examined the reaction conditions for this reaction
including Lewis bases and solvents (see Scheme S1 in
Supporting Information). The results are summarized
in Supporting Information as Table S1. Using PPhMe2
Scheme 3.
Scheme 5.
Scheme 4.
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Table 4. Aza-Baylis–Hillman reactions of N-(arylmethyene)-
diphenylphosphinamides 1 (1.0 equiv.) with methyl acrylate
(1.2 equivs.) in the presence of Ph2PMe (10 mol %) in di-
chloromethane.
4b was obtained along with the normal aza-Baylis–Hill-
man adduct 3b in THF (Table 6, entry 7). It should be
emphasized here that using the strongest nucleophilic
Lewis base PMe3, 4 was obtained in moderate yield
along with product 3 in moderate yield as well (Table 6,
entries 6 and 8). The ratio of 3:4 is variable with the em-
ployed different Lewis bases, solvents and reaction time
(see Table S2 in Supporting Information and Table S3in
Supporting Information, entry 5). Using PMe3 as a
Lewis base, the total yields of 3 and 4 were higher than
others. Thus we carried out the Baylis–Hillman reac-
tions of other N-(arylmethylene)diphenylphosphina-
mides 1 with methyl acrylate in the presence of PMe3
(see Scheme S3in Supporting Information). The results
are summarized in Supporting Information as Table S3.
However, using MVK or acrylonitrile as a Michael ac-
ceptor, no double Baylis–Hillman adduct was formed
at all. The relative configuration of abnormal aza-Bay-
yield of 3a in THF (see Table S1 in Supporting Informa- lis–Hillman adduct 4 was determined by X-ray crystal
tion, entry 9). These results suggest that with Lewis bas- diffraction. An ORTEP drawing of anti-4f is shown in
es having stronger nucleophilicity, the abnormal adduct Figure 1.[10] The ratios of syn and anti were determined
1
4 can be produced. However, during further investiga- by H NMR spectroscopic data (see Supporting Infor-
tions, we found that the substituents on the phenyl ring mation: Scheme S1, Table S1, Scheme S2, Table S2,
of 1 and the employed solvents can significantly affect Scheme S3, Table S3).
the formation of 4a. For example, with N-(p-chloroben-
Concerning the route of formation of 4, we confirmed
zylidene)diphenylphosphinamide 1e having an elec- that the abnormal aza-Baylis–Hillman adduct 4 was
tron-withdrawing group on the phenyl ring, the corre- formed from the reaction of 3 with methyl acrylate in
sponding normal aza-Baylis–Hillman adduct 3e was ob- the presence of PBu3 Lewis base by means of the control
tained as the sole product using PPhMe2 and PBu3 as experiments shown in Scheme 8. The plausible reaction
Lewis bases in MeCN and THF, respectively (see mechanism for the double aza-Baylis–Hillman reaction
Scheme S2 in Supporting Information, Table S2 in Sup-
porting Information, entries 2, 8). But, in dichlorome-
thane, 4e can be formed in moderate yields along with
the corresponding normal adduct 3e (see Table S2 in
Supporting Information, entries 1, 5). PPhMe2 gave
higher yields of 3e and 4e under the same conditions
Scheme 6.
(see Table S2 in Supporting Information, entries 1, 5).
Thus, for starting materials 1 having electron-withdraw-
ing groups on the phenyl ring, we used PPhMe2 as a
Lewis base and carried out these reactions in dichloro-
methane (Scheme 6). The double aza-Baylis–Hillman
adducts 4 were produced as the major products in
good yields (Table 5, entries 1–4). In some cases, ad-
ducts 4 were produced exclusively (Table 5, entries 1
and 3). On the other hand, for starting material N-(p-
methoxybenzylidene)diphenylphosphinamide 1c hav-
ing a strongly electron-donating methoxy group on the
phenyl ring, using PPhMe2 as a Lewis base in dichloro-
methane, the reaction became sluggish (Scheme 7, Ta-
ble 6, entry 1). Using PBu3 as a Lewis base in acetoni-
trile, DMF or CH2Cl2, the corresponding abnormal
aza-Baylis–Hillman adduct 4c was obtained as the major
product (Table 6, entries 3–5). However, a prolonged
time was required for this reaction. In THF, the corre-
sponding normal aza-Baylis–Hillman adduct 3c was ob-
tained in 70% yield exclusively (Table 6, entry 2). From
N-(p-methylbenzylidene)diphenylphosphinamide 1b,
Scheme 7.
Table 5. Aza-Baylis–Hillman reactions of N-(arylmethyl-
ene)diphenylphosphinamides 1 (1.0 equiv.) with methyl acry-
late (2.5 equivs.) in the presence of PPhMe2 (10 mol %) in di-
chloromethane.
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Table 6. Aza-Baylis–Hillman reactions of N-(arylmethylene)diphenylphosphinamides 1 (1.0 equiv.) having an electron-donat-
ing group with methyl acrylate (2.5 equivs) in the presence of Lewis base (10 mol %) in various solvents.
Figure 1. The X-ray crystal structure of anti-4f.
Scheme 8. The plausible reaction mechanism for the double
is described in Scheme 8. The first step is an aldol con-
Baylis–Hillman reaction
densation to form the normal Baylis–Hillman adduct
via intermediates A and B and the second step is a Mi-
chael addition of a Lewis base-generated enolate A examined many Lewis bases in a similar manner as de-
from methyl acrylate.[9a] The Michael addition reaction scribed above in DMF at room temperature, but we
(1,4-addition) takes place preferentially to give the dou- found that DABCO can effectively catalyze this reac-
ble aza-Baylis–Hillman adduct 4 because the enolate A tion to give the corresponding aza-Baylis–Hillman ad-
is a hindered nucleophile (Scheme 8). The nucleophilic- duct 5a in high yield (see Scheme S4 in Supporting Infor-
ity of the nitrogen Lewis base is too weak to promote mation, Table S4 in Supporting Information, entry 2).
such a double Baylis–Hillman reaction. With methyl vi- Using PPh3, PPhMe2, PBu3 or PPh2Me as the Lewis
nyl ketone as a Michael acceptor in the presence of base, the reaction mixture immediately became dark
stronger Lewis bases, this reaction produced a compli- and the reaction gave 5a in traces or relatively low to
cated mixture of unidentified products.
moderate yields (24–60%) along with many unidenti-
fied products (see Table S4 in Supporting Information,
entries 1, 3–5). With another nitrogen Lewis base,
Aza-Baylis–Hillman Reactions of 1 with Acrylonitrile DMAP, no reaction occurred (see Table S4 in Support-
ing Information, entry 6). The solvent effects have
For the aza-Baylis–Hillman reactions of N-(arylmethy- been also examined using DABCO as Lewis base. The
lene)diphenylphosphinamides 1 with acrylonitrile, we results are shown in Supporting Information as Table
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beginning, this version of the reaction was examined
with various Lewis bases. Using PPh3, DABCO,
PPhMe2, PPh2Me PMe3, or DBU as a Lewis base in
this reaction, the corresponding aza-Baylis–Hillman ad-
duct 6a was obtained in trace to moderate yields (56%)
(Table 8, entries 1–6). Using DABCO as the nitrogen
Lewis base in this reaction, we found that the adduct
6a was obtained in 17% along with the double aza-Bay-
lis–Hillman adduct 7a as a mixture of syn and anti-iso-
mers in 25% (Table 8, entry 2). By means of HPLC anal-
ysis and X-ray crystal structure diffraction (Figure 2),[11]
we found that when using PBu3 as a Lewis base, 6a was
formed in traces andthe reaction gave thedouble adduct
7a as amixture of syn and anti-isomers and the unexpect-
ed cyclized product 8a similarly as a mixture of syn- and
anti-isomers at the same time (Scheme 10, Table 8, en-
try 10). Next we carefully examined the unusual reac-
tion pattern in the reaction of 1a with phenyl acrylate us-
ing PBu3 as Lewis base. In order to improve the yields of
7a and 8a, the solvent effects were examined. The best
solvents were THF, Et2O, DME, and 1,4-dioxane (Ta-
ble 8, entries 10, 13, 15 and 16). Increasing the reaction
temperature did not improve the yields of 7a and 8a (Ta-
ble 8, entries 11, 12, 14 and 17).
Scheme 9.
Table 7. Aza-Baylis–Hillman reactions of N-(arylmethyle-
ne)diphenylphosphinamides 1 (1.0 equiv.) with acrylonitrile
(1.2 equivs.) in the presence of DABCO (10 mol %).
PPh3 and DBU are the best promoters for the forma-
S5. In MeCN, the aza-Baylis–Hillman adduct 5a was tion of the normal aza-Baylis–Hillman adduct 6a (Ta-
produced in 86% yield (see Table S5 in Supporting In- ble 8, entries 1 and 6). The solvent effect was also clari-
formation, entry 2).
fied by use of PPh3 as a Lewis base (see Scheme S5 in
Under the optimized reaction conditions, we next ex- Supporting Information, Table S6 in Supporting Infor-
amined the aza-Baylis–Hillman reactions of other N- mation, entries 1–4). The best result was obtained in
(arylmethylene)diphenylphosphinamides 1 with acrylo- MeCN using PPh3 as a Lewis base (see Table S6 in Sup-
nitrile (Scheme 9). The results are summarized in Ta- porting Information, entry 2). Under the optimized re-
ble 7. The normal aza-Baylis–Hillman adducts 5 were action conditions, we next examined the aza-Baylis–
obtained in moderate to good yields in most cases (Ta- Hillman reactions of other N-(arylmethylene)diphenyl-
ble 7).
phosphinamides 1 with phenyl acrylate (Scheme 11).
The results are summarized in Table 9. For N-(arylme-
thylene)diphenylphosphinamides 1 derived from aryl
aldehydes, the normal aza-Baylis–Hillman adducts 6
were obtained in moderate yields (Table 9, entries 1–
6). For N-(arylmethylene)diphenylphosphinamide 1 h
Aza-Baylis–Hillman Reactions of 1 with Phenyl
Acrylate
The interesting finding in this paper is in the aza-Baylis– derived from an aliphatic aldehyde, the corresponding
Hillman reactions of N-(arylmethylene)diphenylphos- adduct 6 h was obtained in low yield (19%) (Table 9, en-
phinamides 1 with phenyl acrylate (Scheme 10). At the try 7).
Scheme 10.
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Table 8. Aza-Baylis–Hillman reactions of N-benzylidenedi-
phenylphosphinamide (1a; 1.0 equiv.) with phenyl acrylate
(2.5 equivs.) in the presence of Lewis base PBu3
(10 mol %) in THF.
Under the optimized conditions, namely in THF at
room temperature, we carried out the reactions of vari-
ous N-(arylmethylenediphenylphosphinamides) 1 with
phenyl acrylate using PBu3 as a Lewis base (Scheme 12).
The results are listed in Table 10. In all cases, the double
aza-Baylis–Hillman adduct 7 as mixtures of syn- and
anti-isomers, except for 7 h, and the cyclized abnormal
aza-Baylis–Hillman product 8 also as mixtures of syn-
and anti-isomers, except for 8f and 8 h, were obtained
at the same time (Table 10, entries 1–7). The syn and
anti ratios of 7 were determined by 1H NMR spectrosco-
py. The configuration of the cyclized abnormal aza-Bay-
lis–Hillman product anti-8a was confirmed by X-ray
crystal diffraction (Figure 2). In order to confirm the
route of formation of 8, the control experiments shown
in Table 11 were carried out in the presence of various
bases or solid acids. In the presence of organic bases
such as DBU, PBu3, BSA [bis(trimethylsilyl)acetamide]
or solid acids such as montmorillonite KSF clay, no reac-
tions occurred with 7a (Table 11, entries 1, 2, 4, 5). The
stronger base NaOMe caused the decomposition of 7a
(Table 11, entry 6). Only in the presence of PBu3 and
phenyl acrylate was 8a formed in moderate yield (Ta-
ble 11, entry 3). This result suggests that the intermedi-
ate enolate D, derived from nucleophilic attack of
PBu3 tophenylacrylate (the Baylis–Hillman reaction in-
termediate) during the reaction, plays a very important
role in the formation of 8. The proton of the NH group is
abstracted by enolate D[12] to give the intermediate E
which produces 8 via an intramolecular nucleophilic at-
tack of NÀ to the carboxylate (Scheme 13). The syn- and
1
anti-isomeric ratios of 8 were determined by H NMR
spectroscopy data (see Supporting Information). We be-
lieve that the different syn/anti ratios between 7 and 8
are due to the different transformation rates of syn-
Table 9. Aza-Baylis–Hillman reactions of N-(arylmethyl-
ene)diphenylphosphinamides 1 (1.0 equiv.) with phenyl acry- and anti-isomers 7 to 8. In most cases the anti-7 is
late (2.5 equivs.) in the presence of PPh3 (10 mol %) at room
temperature in MeCN.
more easily converted to anti-8. At the present stage,
we cannot explain these different transformation rates.
Aza-Baylis–Hillman Reactions of 1 with Ethyl Vinyl
Ketone
In the aza-Baylis–Hillman reactions of 1a with ethyl vi-
nyl ketone (EVK), we found that only in the presence of
PPh3 did the reaction proceed smoothly and the corre-
sponding normal aza-Baylis-Hillman adduct 9a was ob-
tained as sole product (see Scheme S6 in Supporting In-
formation). On using stronger Lewis bases such as PBu3
or PPh2Me, this reaction gave many unidentified prod-
ucts as well as the double aza-Baylis–Hillman adduct.
Wehavenot yetbeen able topurifyor isolate these prod-
ucts by a column chromatography. Using DABCO,
DMAP, or DBU as a Lewis base, this reaction is sluggish.
The solvent effects were examined using PPh3 as a Lewis
base. The results are summarized in Supporting Infor-
mation as Table S7. The best result is obtained in THF
Scheme 11.
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Scheme 12.
Table 10. Baylis–Hillman reactions of N-(arylmethylene)di-
phenylphosphinamides 1 (1.0 equiv.) with phenyl acrylate
(2.5 equivs.) in the presence of PBu3 (10 mol %) in THF.
Figure 2. The X-ray crystal structure of anti-8a.
(see Table S7 in Supporting Information, entry 4). Un-
der the optimized conditions, we carried out the aza-
Baylis–Hillman reactions of various imines 1 with
EVK (Scheme 14). The results are shown in Table 12.
The corresponding normal aza-Baylis–Hillman adducts
9 were formed in moderate yields (Table 12, entries 1–
5).
Table 11. Synthesis of lactam 8.
Aza-Baylis–Hillman Reactions of 1 with Phenyl Vinyl
Ketone
On the other hand, for the aza-Baylis–Hillman reactions
of 1a with phenyl vinyl ketone (PVK) (see Scheme S7 in
Supporting Information), we found that only when using
PPh2Me as a Lewis base in THF was the corresponding
normal aza-Baylis–Hillman adduct 10a obtained in 23%
along with the double aza-Baylis–Hillman adduct 11a in
28% (see Table S8 in Supporting Information, entry 5).
Using DABCO or PPhMe2 as a Lewis base in this reac-
tion, adduct 11a was formed exclusively in 13% and 10%
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Scheme 13. A plausible mechanism for the formation of 8.
Scheme 14.
Table 12. The aza-Baylis–Hillman reaction of 1 (1 equiv.)
with EVK (1.2 equivs.) in the presence of PPh3 (10 mol %)
at room temperature in THF.
Figure 3. The X-ray crystal structure of anti-12a.
Scheme 15.
yield in THF, respectively (see Table S8 in Supporting
Information, entries 1, 6). In CH2Cl2, MeCN, and
DMF using PPh2Me as a Lewis base in this reaction,
In Scheme 15 and Table 13, we show that the double
the adducts 11a were formed in low yields (see Table aza-Baylis–Hillman adducts 11 could be exclusively
S8 in Supporting Information, entries 2–4). The best re- formed in the presence of PBu3 in moderate yields with-
sult was obtained in THF using PBu3 as a Lewis base (see in 3days from various imines 1. In Scheme 16 and Ta-
Table S8 in Supporting Information, entry 7). In all these ble 14, we indicate that with a prolonged reaction
cases the double adduct 11a was formed in the anti-con- time, the cyclized abnormal aza-Baylis–Hillman adducts
figuration.[13] In other solvents, this reaction became 12 were produced from various imines 1 along with dou-
sluggish using PBu3 as a Lewis base (see Table S8 in Sup- ble aza-Baylis–Hillman adducts 11. In general, the reac-
porting Information, entries 9–12). The interesting find- tion rates in this type of aza-Baylis–Hillman reaction are
ing in this reaction is that when the reaction time is pro- slow and the yields of 11 and 12 are moderate. The anti-
1
longed to 120 h, a cyclized abnormal aza-Baylis–Hill- configuration of 11 was determined by H NMR spec-
man adduct 12a was formed as the anti-conformer (see troscopy (see Supporting Information).
Scheme S7 in Supporting Information, Table S8 in Sup-
The formation route for the cyclized abnormal aza-
porting Information, entry 8 and 12). Its configuration Baylis–Hillman adducts 12 was determined by the con-
was confirmed by X-ray crystal diffraction (Figure 3).[14] trol experiments shown in Table 14. In the presence of
PBu3, the double adduct 11 can be transformed into
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Scheme 16.
Table 13. The double aza-Baylis–Hillman reaction of 1 (1
equiv.) with PVK (2.5 equivs.) catalyzed by PBu3
(10 mol %) in THF.
Table 14. The aza-Baylis–Hillman reaction of 1 (1 equiv.)
with PVK (2.5 equivs.) in the presence of PBu3 (10 mol %)
for a longer reaction time in THF.
Scheme 17. A plausible reaction mechanism for the forma-
tion of 12.
the cyclized abnormal adducts 12 after a prolonged reac-
tion period. Other bases or solid acids did not promote
this transformation (Table 15, entries 2 and 3). A possi-
ble mechanism for the formation of 12 is shown in
Scheme 17. The formed phosphonium enolate F derived
from the phenyl vinyl ketone moiety in 12 with PBu3 is in
an equilibrium with the zwitterionic intermediate G[15]
which produces the cyclized zwitterionic intermediate
H via an intramolecular nucleophilic addition. Proton
transfer and elimination of PBu3 then furnish the cy-
clized product 12 (Scheme 17).
Table 15. Mechanistic rationale for the formation of 12.
Aza-Baylis–Hillman Reactions of 1 with 2-
Cyclopenten-1-one and 2-Cyclohexen-1-one
For cyclic enones, we examined the aza-Baylis–Hillman
reactions of 1 with 2-cyclopenten-1-one or 2-cyclohex-
en-1-one in the presence of various Lewis bases in di-
chloromethane (see Scheme S8 in Supporting Informa-
tion). For 2-cyclopenten-1-one, the Lewis bases DAB-
CO and PPh3 showed no catalytic activity in this reaction
(see Table S9 in Supporting Information, entries 1 and
2). The Lewis bases PBu3 and PPh2Me gave good results
in dichloromethane (see Table S9 in Supporting Infor-
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Aza-Baylis–Hillman Reactions of N-(Arylmethylene)diphenylphosphinamides
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Scheme 18.
Scheme 19.
Table 16. Aza-Baylis–Hillman reactions of N-(arylmethyl-
ene)diphenylphosphinamides 1 (1.0 equiv.) with 2-cyclopen-
ten-1-one (1.2 equivs.) in the presence of PBu3 (10 mol %)
at room temperature in THF.
Table 17. Aza-Baylis–Hillman reactions of N-(arylmethyl-
ene)diphenylphosphinamides 1 (1.0 equivs.) with 2-cyclohex-
en-1-one (1.2 equivs.) in the presence of PPhMe2 (10 mol %)
at room temperature in THF.
mation, entries 3and 6). The corresponding normal aza-
Baylis–Hillman adduct 13a was obtained in 92% yield
Catalytic, Asymmetric Aza-Baylis–Hillman Reactions
using PBu3 as Lewis base promoter (see Scheme S8 in Furthermore, we have examined the catalytic, asymmet-
Supporting Information, Table S9 in Supporting Infor- ric aza-Baylis–Hillman reactions of N-(arylmethylene)-
mation, entry 6). After examination of the solvent ef- diphenylphosphinamides 1 with MVK in the presence of
fects, we found that when this reaction was carried out the chiral nitrogen Lewis base 4-(3-ethyl-4-oxa-1-azatri-
in THF, the yield of 13a can be improved to 97% at cyclo[4.4.0.03,8]dec-5-yl)-quinolin-6-ol (TQO)[2a, c,14] and
room temperature (see Table S10 in Supporting Infor- the phosphine Lewis base (R)-2’-diphenylphosphanyl-
mation entry 4). For other N-diphenylphosphorylimines [1,1’]binaphthalenyl-2-ol (Scheme 20).[6f] The results
1 under the optimized reaction conditions, the corre- are summarized in Table 18. We first used TQO[16]
sponding adducts 13 were obtained in good to excellent (10 mol %) as the chiral Lewis base in this aza-Baylis–
yields (Scheme 18). The results are summarized in Ta- Hillman reaction in various solvents. The reaction is
ble 16.
sluggish in DMF and acetonitrile at room temperature.
However, for 2-cyclohexen-1-one, the stronger Lewis The corresponding adduct 2a was obtained in low yields
bases PPhMe2 or PMe3 gave the best result in dichloro- and low enantioselectivities (23% ee and 12% ee), re-
methane and the corresponding normal aza-Baylis– spectively (Table 18, entries 1 and 3). Lowering the re-
Hillman adduct 14a was formed in 49% and 48% yields, action temperature to À208C did not improve the enan-
respectively (see Scheme S9 in Supporting Information, tioselectivity (Table 18, entry 4). In dichloromethane,
Table S11 in Supporting Information, entries 4 and 5). the adduct 2a was obtained in 73% yield, but still in
The Lewis bases DABCO, PPh3 and PPh2Me did not cat- only 28% ee (Table 18, entry 2). At À208C, a trace of
alyze this reaction (see Table S11 in Supporting Infor- 2a was obtained (Table 18, entry 5). When the chiral
mation, entries 1–3). Upon examination of the solvent phosphine Lewis base (10 mol %) was used as the cata-
effect, it was found that THF is also the best solvent lyst in dichloromethane (Scheme 20), the reaction pro-
for this reaction because 14a was isolated in 81% (see ceeded smoothly to give 2a in 82% yield with 47% ee, al-
Table S12 in Supporting Information, entry 4). For the though in DMF or THF this reaction was sluggish and
reaction of 2-cyclohexen-1-one with various N-(arylme- the achieved ee was low under the same conditions (Ta-
thylene)diphenylphosphinamides 1 under the opti- ble 18, entries 6, 7 and 10).[17] At À208C, this catalytic,
mized reaction conditions, the aza-Baylis–Hillman ad- asymmetric reaction was sluggish in dichloromethane
ducts 14 were obtained in moderate to good yields and DMF (Table 18, entries 8 and 9). The chiral HPLC
(Scheme 19, Table 17, entries 1–7).
charts are shown in Supporting Information.
In all cases, only the corresponding normal aza-Baylis-
Hillman adducts 13 and 14 were formed, respectively.
The catalytic, asymmetric aza-Baylis–Hillman reac-
tions of N-(arylmethylene)diphenylphosphinamides 1
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Table 18. Catalytic, asymmetric aza-Baylis–Hillman reac-
tions of N-benzylidenediphenylphosphinamide (1a; 1.0
equiv.) with MVK (1.2 equiv.) in the presence of chiral phos-
phine and nitrogen catalysts (10 mol %).
Scheme 20.
with acrylonitrile was carried out in the presence of the
chiral nitrogen Lewis base TQO with MeCN as the sol-
vent to give the adduct in 31% yield with 8% ee
(Scheme 21). This reaction is sluggish using the phos-
phine Lewis base (R)-2’-diphenylphosphanyl-[1,1’]bi-
naphthalenyl-2-ol. We also carried out the reaction of
N-(arylmethylene)diphenylphosphinamides 1 with phe-
nyl acrylate in the presence of the chiral phosphine
Lewis base (R)-2’-diphenylphosphanyl-[1,1’]binaphtha-
lenyl-2-ol in dichloromethane (Scheme 21) (this reac-
tion is sluggish using TQO as chiral Lewis base). The ad- phosphine Lewis base in dichloromethane at room tem-
duct was obtained in 51% yield with 23% ee. All of the perature. For other simple Michael acceptors, these re-
adducts were obtained in low ee and yields. Thus, reac- actions are sluggish in the presence of sterically bulky
tions under other conditions were not further examined. chiral Lewis base promoters.
In summary, moderate ee has been achieved in this
catalytic, asymmetric aza-Baylis–Hillman reactions us-
ing MVK as Michael acceptor in the presence of a chiral
Scheme 21.
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Aza-Baylis–Hillman Reactions of N-(Arylmethylene)diphenylphosphinamides
FULL PAPERS
Conclusion
Experimental Section
We have comprehensively examined the aza-Baylis–
Hillman reactions of N-(arylmethylene)diphenylphos-
phinamides 1 with various activated olefins. The Lewis
bases and solvents can significantly affect the reaction
products. We found that, when using stronger Lewis bas-
es such as PPhMe2 or PBu3 as promoters in the of 1 with
methyl acrylate, phenyl acrylate or PVK, the double
aza-Baylis–Hillman adducts 4, 7, and 11 and the abnor-
mal aza-Baylis–Hillman adducts 8 or 12, derived from
the further reactions of the double adducts, can be ob-
tained either as the major products or as the sole prod-
ucts depending on the reaction conditions. This is first
report to disclose the formation of abnormal aza-Bay-
lis–Hillman adducts 8 and 12 in aza-Baylis–Hillman re-
actions under mild conditions. In addition, the catalytic,
asymmetric version of this reaction using simple Mi-
chael acceptors such as MVK, acrylonitrile or phenyl
acrylate has been investigated. Moderate ee in the aza-
Baylis–Hillman reaction of N-benzylidenediphenyl-
phosphinamide (1a) with MVK has been achieved. On
the basis of our previous results of the aza-Baylis–Hill-
General Remarks
Unlessotherwise stated, all reactions were carriedout under an
argon atmosphere. All solvents were purified by distillation.
Methyl vinyl ketone and tributylphosphine were obtained
from Tokyo Chemical Industry (Tokyo Kasei Co. Ltd.) and
used without purification. All N-tosyl imines were prepared ac-
cording to the literature. Infrared spectra were measured on a
Perkin-Elmer 983spectrometer. 1H-NMR spectra were re-
corded on a 300 MHz spectrometer in CDCl3 using tetrame-
thylsilane as the internal standard. Mass spectra were recorded
with an HP-5989 instrument and HRMS were measured on a
Finnigan MAþmass spectrometer. Satisfactory CHN micro-
analyses were obtained with a Carlo-Erba 1106 analyzer. Melt-
ing points were obtained by means of a micromelting point ap-
paratus and are uncorrected.
Typical Reaction Procedure for Triphenylphosphine-
Catalyzed Baylis–Hillman Reaction of N-
Benzylidenediphenylphosphinamide (1a) with Methyl
Vinyl Ketone
¼
man reactions using N-sulfonated imines (ArCH NTs
Toa Schlenk tube containing 1a (76 mg, 0.25 mmol) and triphe-
nylphosphine (7 mg, 0.03mmol) in DMF (0.5 mL) was added
methyl vinylketone(MVK) (21 mg, 24.4 mL, 0.30 mmol) under
an argon atmosphere and the reaction mixture was stirred for
48 h at room temperature (208C). The mixture was then wash-
ed with water (3ꢀ10 mL) and extracted with dichloromethane
(2ꢀ10 mL). The organic layer was dried over anhydrous
Na2SO4, the solvent removed under reduced pressure and the
residue purified by silica gel column chromatography (eluent:
¼
or ArCH NMs) as the electrophiles, it is clear that the
reaction rate of this reaction is slow for many Michael
acceptors under the same conditions. The significant ad-
vantage in this type of aza-Baylis–Hillman reaction is
the ease of removal of the diphenylphosphinyl group
from the corresponding adduct because the sulfonyl
group (Ts or Ms) in the adducts derived from N-sulfo-
¼
¼
nated imines (ArCH NTs or ArCH NMs) is usually
very difficult to remove. A typical procedure is as fol-
lows: upon heating in 10–20% aqueous HCl solution
for several hours, the diphenylphosphinyl group can be
removed perfectly to give the corresponding b-amino-
carbonyl products (Scheme 22).[2d] Efforts are underway
to elucidate the mechanistic details of this reaction and
the key factors of the Lewis base for different substrates
of the Baylis-Hillman reaction. Work along this line is
currently in progress.
¼
EtOAc/petroleum 1/4) to give 2a as a colorless solid; yield:
72 mg (81%).
Acknowledgements
We thank the State Key Project of Basic Research (Project 973)
(No. G2000048007), Chinese Academy of Sciences (KGCX2-
210-01), Shanghai Municipal Committee of Science and Tech-
nology, and the National Natural Science Foundation of China
for financial support (203900502, 20025206 and 20272069).
References and Notes
[1] a) E. Ciganek, Org. React. 1997, 51, 201–350; b) D. Basa-
vaiah, P. D. Rao, R. S. Hyma, Tetrahedron 1996, 52,
8001–8062; c) S. E. Drewes, G. H. P. Roos, Tetrahedron
1988, 44, 4653–4670; d) L. J. Brzezinski, S. Rafel, J. M.
Leahy, J. Am. Chem. Soc. 1997, 119, 4317–4318; e) T.
Miyakoshi, S. Saito, Nippon Kagaku Kaishi 1983,
1623–1628; Chem. Abstr. 1984, 100, 156191 g; f) I. E.
Marko, P. G. Giles, N. J. Hindley, Tetrahedron 1997, 53,
1015–1024; g) H. Richter, G. Jung, Tetrahedron Lett.
1998, 39, 2729–2730; h) E. P. Kundig, L. H. Xu, P. Roma-
nens, G. Bernardinelli, Tetrahedron Lett. 1993, 34, 7049–
Scheme 22.
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7052; i) V. K. Aggarwal, A. Mereu, G. J. Tarver, R.
MaCague, J. Org. Chem. 1998, 63, 7183–7189; j) D. Basa-
vaiah, A. J. Rao, T. Satyanarayana, Chem. Rev. 2003, 103,
811–892.
833–834 (double Baylis–Hillman adduct in the reaction
of aryl aldehyde with excess of MVK in the presence
of the nitrogen Lewis base DABCO); b) M. Shi, C.-Q.
Li, J.-K. Jiang, Helve. Chem. Acta 2002, 85, 1051–1057
(double Baylis-Hillman adduct in the reaction of aryl al-
dehyde with excess of PVK in the presence of the nitro-
gen Lewis base DABCO); c) M. Shi, Y.-M. Xu, J. Org.
Chem. 2003, 68, 4784–4790 (double aza-Baylis–Hillman
adduct in the reaction of N-tosyl imine with excess of
phenyl vinyl ketone (PVK) in the presence of the nitro-
gen Lewis base DABCO).
[2] a) Y. Iwabuchi, M. Nakatani, N. Yokoyama, S. Hatakeya-
ma, J. Am. Chem. Soc. 1999, 121, 10219–10220;
b) A. G. M. Barrett, A. S. Cook, A. Kamimura, Chem.
Commun. 1998, 2533–2534; c) P. Langer, Angew.
Chem. Int. Ed. 2000, 39, 3049–3052; d) S. Kawahara,
A. Nakano, T. Esumi, Y. Iwabuchi, S. Hatakeyama,
Org. Lett. 2003, 5, 3103–3105; e) J. E. Imbriglio, M. M.
Vasbinder, S. J. Miller, Org. Lett. 2003, 5, 3741–3743;
f) N. T. McDougal, S. E. Schaus, J. Am. Chem. Soc.
2003, 125, 10219; g) K.-S. Yang, W.-D. Lee, J.-F. Pan,
K.-M. Chen, J. Org. Chem. 2003, 68, 915.
[3] a) A. B. Baylis, M. E. D. Hillman, Ger. Offen. 2,155,113,
1972; Chem. Abstr. 1972, 77, 34174q; M. E. D. Hillman,
A. B. Baylis, U. S. Patent 3,743,669, 1973; b) K. Morita,
Z. Suzuki, H. Hirose, Bull. Chem. Soc. Jpn. 1968, 41,
2815–2816.
[4] a) M. Shi, J.-K. Jiang, Y.-S. Feng, Org. Lett. 2000, 2, 23 9
7–2400; b) M. Shi, Y.-S. Feng, J. Org. Chem., 2001, 66,
406–411; c) M. Shi, J.-K. Jiang, S.-C. Cui, Y.-S. Feng, J.
Chem. Soc. Perkin Trans. 1 2001, 390–393; d) M. Shi,
J.-K. Jiang, Tetrahedron 2000, 56, 4793–4797; e) M. Shi,
C.-Q. Li, J.-K. Jiang, Chem. Commun. 2001, 833–834.
[5] Baylis–Hillman reactions using sulfonated imines or
phosphorylated imines as the substrate can be named
as aza-Baylis–Hillman reactions. For previous reports re-
lated with the Baylis–Hillman reactions of methyl acryl-
ate with imines, please see: a) P. Perlmutter, C. C. Teo,
Tetrahedron Lett. 1984, 25, 5951–5952; b) M. Takagi, K.
Yamamoto, Tetrahedron 1991, 47, 8869–8882; For previ-
ous reports related with the Baylis–Hillman reactions of
MVK with imines generated in situ, please see: c) S. Ber-
tenshow, M. Kahn, Tetrahedron Lett. 1989, 30, 2731–
2732; d) D. Balan, H. Adolfsson, J. Org. Chem. 2002,
67, 2329–2334 and references cited therein.
[6] a) M. Shi, Y.-M. Xu, Chem. Commun. 2001, 1876–1877;
b) M. Shi, Y.-M. Xu, Eur. J. Org. Chem. 2002, 696–701;
c) M. Shi, Y.-M. Xu, G.-L. Zhao, X.-F. Wu, Eur. J. Org.
Chem. 2002, 3666–3679; d) M. Shi, G.-L. Zhao, Tetrahe-
dron Lett. 2002, 43, 4499–4502; e) M. Shi, Y.-M. Xu, An-
gew. Chem. Int. Ed. 2002, 41, 4507–4510; f) M. Shi, L.-H.
Chen, Chem. Commun. 2003, 1310–1311; g) Y.-L. Shi,
Y.-M. Xu, M. Shi, Adv. Synth. Catal. 2004, 346, 1220–
1230.
[10] The crystal data of anti-4f have been deposited under
CCDC 191599. Empirical Formula: C27H27NO5PBr, for-
mula weight: 556.38, crystal color/habit: colorless/pris-
matic, crystal dimensions: 0.20ꢀ0.20ꢀ0.30 mm, crystal
System: monoclinic, lattice type: primitive, lattice param-
eters: a¼5.4081(6) ꢁ, b¼20.733(2) ꢁ, c¼23.224(3) ꢁ,
a¼908, b¼95.707(2)8, g¼908, V¼2591.1(5) ꢁ3, space
3
¼
group: Cc, Z¼4, Dcalc 1.426 g/cm , F000 ¼1144; diffrac-
tometer: Rigaku AFC7R, residuals: R, Rw: 0.0596,
0.1531.
[11] The crystal data of 8a have been deposited under CCDC
198221. Empirical formula: C31H26NO4P, formula weight:
507.50, crystal color/habit: colorless/prismatic, crystal di-
mensions: 0.626ꢀ0.153ꢀ0.062 mm, crystal system: or-
thorhombic, lattice type: primitive, lattice parameters:
a¼19.439(2) ꢁ, b¼14.4410(17) ꢁ, c¼9.3305(10) ꢁ,
a¼908, b¼908, g¼908, V¼2619.2(5) ꢁ3, space group:
3
¼
Pna2(1), Z¼4, Dcalc 1.287 g/cm , F000 ¼1064, diffractom-
eter: Rigaku AFC7R, residuals: R, Rw: 0.0552, 0.1087.
[12] For the reactions employing an enolate as a general base,
please see: a) D. A. White, M. M. Baizer, Tetrahedron
Lett. 1973, 3597; b) I. C. Stewart, R. G. Bergman, F. D.
Toste, J. Am. Chem. Soc. 2003, 125, 8696; c) J. Inanaga,
Y. Baba, T. Hanamoto, Chemistry Lett. 1993, 241; d) I.
Yavari, R. Hekmat-Shoar, A. Zonouzi, Tetrahedron
Lett. 1998, 39, 2391; e) R. B. Grossman, D. S. Pendhar-
kar, B. O. Patrick, J. Org. Chem. 1999, 64, 7178; f) R. B.
Grossman, S. Comesse, R. M. Rasne, K. Hattori, M. N.
Delong, J. Org. Chem. 2003, 68, 871.
[13] In the double aza-Baylis–Hillman reactions of N-tosyl
¼
imines (ArCH NTs) with PVK, we have reported that
the double aza-Baylis–Hillman adduct was formed as a
sole product in an anti-configuration.[9c]
[14] The crystal data of 12a has been deposited under CCDC
195448. Empirical formula: C37H34NO4P, formula weight:
587.62, crystal color/habit: colorless/prismatic, crystal di-
mensions: 0.368ꢀ0.288ꢀ0.151 mm, crystal system: tri-
clinic, lattice type: primitive, lattice parameters: a¼
11.6753(18) ꢁ, b¼11.9784(18) ꢁ, c¼12.1491(18) ꢁ,
[7] N-(Arylmethylene)diphenylphosphinamides 1 were pre-
pared according to the literature: a) W. B. Jennings,
C. J. Lovely, Tetrahedron 1991, 47, 5561–5568; b) K. Ya-
mada, S. J. Harwood, H. Groger, M. Shibasaki, Angew.
Chem. Int. Ed. 1999, 38, 3504–3506.
[8] A one-pot “three-component” aza-Baylis-Hillman reac-
tions of arylaldehydes and diphenylphosphinamide with
methyl vinyl ketone in the presence of TiCl4, PPh3, Et3
N has been disclosed: M. Shi, G.-L. Zhao, Tetrahedron
Lett. 2002, 43, 9171–9174.
a¼107.856(3)8, b¼91.723(3)8, g¼97.974(4)8, V¼
3
1596.8(4) ꢁ3, space group: P-1; Z¼2, Dcalc 1.222 g/cm ,
¼
F000 ¼620; diffractometer: Rigaku AFC7R, residuals: R,
Rw: 0.0695, 0.1730.
[15] For references related to the proposed mechanism for
the formation of 12, invoking a 1,2-prototropic shift,
please see a) B. M. Trost, U. Kazmaier, J. Am. Chem.
Soc. 1992, 114, 7933; b) X. Lu, C. Zhang, Z. Xu, Acc.
Chem. Res. 2001, 34, 535; c) B. M. Trost, C.-J. Li, J. Am.
[9] For the double Baylis–Hillman reactions, please see:
a) M. Shi, C.-Q. Li, J.-K. Jiang, Chem. Commun. 2001,
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Chem. Soc. 1994, 116, 3167; d) B. M. Trost, G. R. Dake, J.
Am. Chem. Soc. 1997, 119, 7595; e) C. Zhang, X. Lu, J.
Org. Chem. 1995, 60, 2906.
[17] Hatakayama has reported the catalytic, asymmetric Bay-
lis–Hillman reactions of aromatic imines with 1,1,1,3,3,3-
hexafluoroisopropyl acrylate (HFIPA) in the presence of
b-isocupreidine (b-ICD) (TQO): S. Kawahara, A. Naka-
no, T. Esumi, Y. Iwabuchi, S. Hatakayama, Org. Lett.
2003, 5, 3103–3105.
[16] The catalyst TQO was first prepared by Prof. Hoffman:
C. von Riesen, H. M. R. Hoffmann, Chem. Eur. J. 1996,
2, 680–684.
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