Asymmetric aza-Morita-Baylis-Hillman reactions of alkyl vinyl ketones with N-protected imines or in situ generated N-protected imines

Article abstract of DOI:10.1002/ejoc.201000496

DABCO-catalyzed aza-MBH reactions of N-Boc imines with MVK and EVK have been thoroughly investigated in the paper. The asymmetric version of this aza-MBH reaction was also systematically investigated by using a chiral amine or a chiral phosphane catalyst. It was found that most of the JVprotected imines are suitable substrates under the mild reaction conditions and are able to give the corresponding adducts in moderate yields with high ee values. The TQO- or LB1-catalyzed aza-MBH reactions of N-protected a-amidoalkyl phenyl sulfones or a-amidoalkyl p-tolyl sulfones with MVK could be well conducted, which provides a facile and direct route to obtain highly enantioselective aza-MBH adducts. The Boc protecting group of the aza-MBH product could be easily removed under acidic conditions to give the corresponding α-methylene-α-amino ketone or α-methyleneβ-amino alcohol derivatives in good yields.

Full text of DOI:10.1002/ejoc.201000496

FULL PAPER
DOI: 10.1002/ejoc.201000496
Asymmetric Aza-Morita–Baylis–Hillman Reactions of Alkyl Vinyl Ketones
with N-Protected Imines or In Situ Generated N-Protected Imines
Xiao-Yang Guan,[a] Yin Wei,*[a] and Min Shi*[a]
Keywords: Nucleophilic addition / Enantioselectivity / Sulfur / Phosphanes / Lewis bases / Asymmetric synthesis
DABCO-catalyzed aza-MBH reactions of N-Boc imines with
MVK and EVK have been thoroughly investigated in the pa-
per. The asymmetric version of this aza-MBH reaction was
also systematically investigated by using a chiral amine or a
chiral phosphane catalyst. It was found that most of the N-
protected imines are suitable substrates under the mild reac-
tion conditions and are able to give the corresponding ad-
ducts in moderate yields with high ee values. The TQO- or
LB1-catalyzed aza-MBH reactions of N-protected α-amido-
alkyl phenyl sulfones or α-amidoalkyl p-tolyl sulfones with
MVK could be well conducted, which provides a facile and
direct route to obtain highly enantioselective aza-MBH ad-
ducts. The Boc protecting group of the aza-MBH product
could be easily removed under acidic conditions to give the
corresponding α-methylene-β-amino ketone or α-methylene-
β-amino alcohol derivatives in good yields.
moiety in the product can be readily deprotected through
acidic methanolysis in excellent yields, which provides a
convenient method for the synthesis of synthetically valu-
able α-methylene-β-amino ketone or acid derivatives. Aro-
matic N-carbamate-activated imines, especially Boc-pro-
tected ones, are seldom used in the aza-MBH reaction,[4]
despite their high reactivity and the easy removal of the
protecting group. Previously, Córdova[4b] reported that pro-
line/DABCO-catalyzed aza-MBH reactions between aryl
Boc imines and unmodified α,β-unsaturated aldehydes pro-
ceeded with high chemo- and enantioselectivity to furnish
α-amino aldehydes with an α-alkylidene group. Recently, we
reported the asymmetric aza-MBH reaction between tosyl-
imines and MVK catalyzed by axially chiral 1,1Ј-bi-
naphthalene-2,2Ј-diol (BINOL)-derived bifunctional phos-
phanes or 4-(3-ethyl-4-oxa-1-azatricyclo[4,4,0,03,8]dec-5-yl)-
quinolin-6-ol (TQO, Scheme 1).[5] Inspired by our previous
work and as a part of our continuing interest in nucleo-
philic phosphane and amine mediated or catalyzed reac-
tions, we turned our attention to Lewis base catalyzed aza-
MBH reactions between easily removable N-protected im-
ines and alkyl vinyl ketones and its asymmetric version.
Meanwhile, it is notable that the significantly simpler pro-
cedure involving the use of stable α-amido sulfones as imine
precursors has been applied recently in phase-transfer-cata-
lyzed aza-Henry-type reactions,[6] and cinchona alkaloid[7]
or thourea-cinchona alkaloid[8] catalyzed Mannich reac-
tions of malonates, DABCO-catalyzed aza-MBH reactions
of electron-deficient alkenes,[9,10] and proline-catalyzed aza-
MBH reactions of α,β-unsaturated aldehydes.[11] Thus, we
envisioned to develop a facile and direct route to enantiose-
lective aza-MBH adducts by the reaction of alkyl vinyl
ketones with α-amido sulfones.
Introduction
The aza-Morita–Baylis–Hillman (aza-MBH) reaction is
one of the most useful and interesting carbon–carbon
bond-forming reactions to give enantiomerically enriched
β,β-amino carbonyl compounds bearing an α-alkylidene
group with enormous potential synthetic utility under mild
reaction conditions.[1] Usually, the aza-MBH reaction oc-
curs between activated imines and electron-deficient alkenes
in the presence of a Lewis base, generally a tertiary amine
or phosphane. Many kinds of activated imines have been
involved in this reaction, such as tosylimines, nosylimines,
SES-imines, and phosphinoylimines.[1j] Ts-Imines are the
most commonly used electrophiles in aza-MBH reactions
because of their easy preparation and high electrophilicity.
However, removal of the Ts protecting group is difficult and
limits further development of aza-MBH adducts. Thus far,
some imines with easily removable protecting group have
also been used in the aza-MBH reaction. For example, we
have reported the aza-MBH reaction of N-arylmethylidene-
diphenylphosphinamides with activated olefins in the pres-
ence of various Lewis bases to afford the corresponding ad-
ducts in good yields.[2] Zhou et al. demonstrated that N-
thiophosphoryl or N-thiophosphinoyl imines exhibited
good reactivity with methyl vinyl ketone (MVK) or methyl
acrylate in the aza-MBH reaction.[3] The N-thiophosphoryl
[a] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Fax: +86-21-64166128
E-mail: mshi@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000496.
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Asymmetric Aza-MBH Reactions of Alkyl Vinyl Ketones
Table 1. Catalyst and solvent screening for the MBH reaction of
MVK and N-Boc imine 1a.
Scheme 1. Asymmetric aza-Morita–Baylis–Hillman reactions of N-
sulfonated imines with MVK in our previous reports.
[a] All reactions were carried out with 1a (0.2 mmol) and MVK
(0.4 mmol) in the presence of Lewis base in solvent (1.0 mL) at
room temperature. [b] Isolated yield.
Results and Discussion
We initiated our investigations by seeking the best cata-
lyst for the aza-MBH reaction between N-Boc imines 1 and
MVK. Several phosphorus-containing or nitrogen-contain-
ing achiral Lewis bases were tested in the reaction of N-Boc
imine 1a with MVK in THF. 1,4-Diazabicyclic[2,2,2]octane
(DABCO), which is one of the most popular catalysts used
in MBH reactions, was the most effective catalyst, as it gave
racemic aza-MBH product rac-2a in 75% yield. However,
another nitrogen-containing Lewis base 4-(N,N-dimethyl)-
aminopyridine (DMAP) could not catalyze this reaction
(Table 1, Entries 1 and 4). PPh3 is another commonly used
catalyst in MBH reactions. In this reaction, it was less effec-
tive than DABCO and gave rac-2a in 55% yield under iden-
tical conditions. Moreover, increasing the nucleophilicities
of the phosphanes compromised the yield of rac-2a. The
stronger nucleophilic phosphane methyldiphenylphosphane
(PPh2Me) gave rac-2a in only 24% yield (Table 1, Entries 2
and 3). Decreasing the amount of DABCO from 20 to
10 mol-% led to a decrease in the yield of rac-2a from 75 to
44% (Table 1, Entries 1 and 5). Solvent effects were sub-
sequently examined with the use of 10 mol-% of DABCO
as the catalyst. The more polar solvents dimethyl sulfoxide
(DMSO), N,N-dimethylformamide (DMF), and 1,4-di-
oxane were suitable for this reaction and gave rac-2a in 45–
55% yields (Table 1, Entries 6–8). Acetonitrile was the best
solvent and gave rac-2a in 80% yield (Table 1, Entry 9).
However, the moderately polar solvent toluene retarded the
reaction and led to 24% yield of rac-2a (Table 1, Entry 10).
Having identified the optimal reaction conditions, we
next set out to examine the scope and limitations of this
reaction by using various N-Boc imines 1 with different
substituents on the benzene rings, and the results are sum-
Entries 1–10). Unfortunately, this reaction was not suitable
for alkyl N-Boc imines. Ethyl vinyl ketone (EVK) was also
examined in this reaction to give the corresponding rac-2l
in 35% yield (Table 2, Entry 11).
Table 2. Aza-MBH reaction of other N-Boc imines with MVK or
EVK catalyzed by DABCO.
[a] All reactions were carried out with N-Boc imine 1 (0.2 mmol)
and MVK or EVK (0.4 mmol) in the presence of DABCO in
CH3CN (1.0 mL) at room temperature. [b] Isolated yield.
In view of our results on aza-MBH reactions of N-Boc
marized in Table 2. Electron-withdrawing and electron-do- imines 1 with alkyl vinyl ketones catalyzed effectively by
nating groups at the ortho, meta, or para position of the DABCO and PPh3, the next logical step was to investigate
benzene ring of N-Boc imines 1 or furfural N-(tert-butoxy- the asymmetric version of this reaction by using some chiral
carbonyl)imine 1k were employed; the reactions proceeded catalysts that we reported before. First, (R)-2Ј-diphenylphos-
smoothly to give rac-2 in moderate to good yields (Table 2, phanyl[1,1Ј]binaphthalenyl-2-ol (LB1) and TQO[12] were
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tested in this reaction. With the use of LB1 (10 mol-%) as Table 3. Solvent screening for the asymmetric aza-MBH reaction
of N-Boc imine 1a with MVK.
the catalyst, 2a was obtained in 30% yield with 55%ee in
dichloromethane (DCM); TQO was more effective and gave
2a in 49% yield and 88%ee under the same reaction condi-
tions. Some other cinchona alkaloid derivatives were also
examined in this reaction (Scheme 2). Catalysts LB2, LB3,
and LB4 could not catalyze this reaction, but LB5 gave 2a
in 56% yield and 89%ee.
[a] All reactions were carried out with N-Boc imine 1a (0.2 mmol)
and MVK (0.4 mmol) in the presence of TQO in solvent (1.0 mL).
[b] Isolated yield. [c] Determined by chiral HPLC. [d] 4 Å MS were
added. [e] 20 mol-% of TQO was used. [f] At –30 °C.
Scheme 2. Some chiral catalysts examined in the aza-MBH reaction
of N-Boc imine 1a and MVK.
Though LB5 could give slightly better results than TQO,
the synthetically easier accessed TQO was chosen as the Table 4, electron-withdrawing and electron-donating groups
catalyst to proceed with the following investigations. By at the meta or para position of the benzene ring of N-Boc
using TQO as the catalyst, solvents were optimized to im- imines 1 or furfural N-(tert-butoxycarbonyl)imine 1k were
prove the yield and enantioselectivity, and the results are employed, and the reactions proceeded smoothly to give 2
summarized in Table 3. Higher ee values were attained at in moderate yields with high ee values (Table 4, Entries 3–
room temperature in THF and dioxane, 91 and 94%, 8, 11, and 12). The absolute configuration of 2d was deter-
respectively (Table 3, Entries 2 and 6). However, the yields mined by X-ray crystallography to be S (Figure 1). In the
were not so high. Addition of 4 Å MS and increasing the reaction of N-Boc imines 1 bearing a substituent at the or-
amount of TQO did not improve the yields (Table 3, En- tho position of the benzene ring with MVK, o-methoxy-
tries 3, 7, and 8). In acetonitrile, 2a was obtained in the benzaldehyde N-Boc imine 1i gave aza-MBH adduct 2i in
best yield of 96% with 87%ee at room temperature (20 °C; 90%ee, but o-chlorobenzaldehyde N-Boc imine 1j gave 2j in
Table 3, Entry 4). At lower temperature (–30 °C), the ee only 60%ee (Table 4, Entries 9 and 10).
value could not be improved and the yield fell to 60%
It is well documented that N-Boc-protected α-amidoalkyl
(Table 3, Entry 8). Thus, the highest ee value was attained p-tolyl sulfones or α-amidoalkyl phenyl sulfones can be con-
at room temperature in dioxane, but the best chemical yield sidered as a stable, crystalline, and easy to handle equiva-
was achieved at room temperature in acetonitrile. To obtain lent of N-Boc imines. Recently, a number of papers have
aza-MBH adduct 2a in high ee and yield, we next investi- reported the nucleophilic addition to N-carbamate imines
gated the reaction in acetonitrile/dioxane. The best condi- in situ generated from the aforementioned α-amido sulfones
tions were acetonitrile/dioxane (1:2) to give 2a in 82% yield by base-induced elimination, which inspired us to envision
with 91%ee (Table 3, Entry 15).
the aza-MBH reaction of N-Boc α-amidoalkyl phenyl sul-
With these optimal reaction conditions, we next turned fone 3a with MVK in the presence of cesium carbonate by
our attention to examine the scope of these catalytic, asym- using TQO as the catalyst. Aza-MBH adduct 2a was ob-
metric aza-MBH reactions with respect to a variety of N- tained in 60% yield with rather low ee (2%ee; Scheme 3).
Boc imines. In the reaction of p-trifluoromethylbenzal- The result showed that TQO had catalytic activity for this
dehyde N-Boc imine 1b with MVK, similar yields were at- reaction; however, some loss of stereoselectivity was ob-
tained in acetonitrile (61%) or acetonitrile/dioxane (1:2, served. It should be mentioned here that this reaction could
60%). However, a higher ee value was obtained in acetoni- not occur without TQO. Byproduct 9 was isolated from the
trile/dioxane (1:2) than in acetonitrile (Table 4, Entries 1 reaction mixture, which implies that the intermediate gener-
and 2). Thus, examination of the reaction scope was only ated from 3a may directly react with MVK by a Michael-
conducted in acetonitrile/dioxane (1:2). As shown in type addition during the formation of the N-Boc imine.
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Asymmetric Aza-MBH Reactions of Alkyl Vinyl Ketones
Table 4. Aza-MBH reaction of N-Boc imines with MVK or EVK alyst TQO may easily be protonated in the catalytic cycle,
leading to poor enantioselectivity.[14] Thus, we added some
catalyzed by TQO.
auxiliary bases such as NEt3 and iPr2NH to avoid genera-
tion of a protonated chiral catalyst; however, the enantio-
selectivity did not improve (Table 5, Entries 1 and 2). Sur-
prisingly, it was found that the enantioselectivity was im-
proved with the use of water as an additive. By using tolu-
ene as the solvent and water (0.2 mL) as the additive, 2a
was obtained in 88%ee, though the yield was only 27%
(Table 5, Entry 3). Acetonitrile and dioxane, which are suit-
able solvents for the aza-MBH reactions of N-Boc imines
with MVK, gave poor results (Table 5, Entries 4 and 5).
Without cesium carbonate and water, 2a was obtained in
38% yield with 70%ee, which indicates the importance of
water in this reaction. Decreasing the amount of water from
0.2 mL to 0.05 mL did not reduce the enantioselectivity, but
a slightly higher yield was observed. Acetonitrile and diox-
ane were tested again under the same conditions, and the
enantioselectivities were rather low, even though 5.0 equiv.
of MVK was employed. Then, we examined the reaction
temperature and other bases instead of cesium carbonate,
which afforded unsatisfactory results (Table 5, Entries 13–
[a] All reactions were carried out with N-Boc imine 1 (0.2 mmol)
and MVK or EVK (0.4 mmol) in solvent (1.0 mL) at room tem-
16). The best enantioselectivity was obtained with 5.0 equiv.
of MVK in toluene as the solvent and without any additives
(Table 5, Entry 17); however, the yield was low under these
conditions.
perature. [b] Isolated yield. [c] In CH3CN. [d] Determined by chiral
HPLC. [e] Determined by the sign of the specific rotation.
Table 5. The aza-MBH reaction of N-Boc-amidoalkyl phenyl sul-
fone 3a with MVK by using TQO as the catalyst.
Figure 1. ORTEP drawing of compound 2d.[13]
Scheme 3. The reaction of N-Boc α-amidoalkyl phenyl sulfone 3a
with MVK in the presence of cesium carbonate by using TQO as
the catalyst.
[a] The reactions were carried out with N-Boc-amidoalkyl phenyl
sulfone 3a (0.2 mmol) and MVK (0.4 mmol) in solvent (1.0 mL).
[b] Isolated yield. [c] Determined by chiral HPLC. [d] 5.0 equiv. of
MVK was used. [e] At 50 °C. [f] At –20 °C. [g] 0.8 mL of solvent
Subsequently, solvent and additive effects were examined
to improve the yield and enantioselectivity, and the results
are summarized in Table 5. We hypothesized that chiral cat- was used.
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On the basis of the above experiments, we have identified Table 6. The aza-MBH reaction of N-Boc α-amidoalkyl phenyl sul-
fone 3a with MVK by using LB1 as the catalyst.
a facile and direct route to obtain aza-MBH adducts by a
one-pot approach, although we did not achieve it in high
yield and excellent ee by using a chiral amine catalyst,
which stimulated us to search other catalytically active and
enantioselective catalysts. Then, we again turned our atten-
tion to chiral phosphane catalysts. LB1 was first examined
in this reaction, leading to product 2a in 87% yield with
26%ee (Table 6, Entry 1). Such a high yield encouraged us
to examine other conditions to get higher enantioselectivity
(Table 6). Without cesium carbonate, 2a was obtained in a
higher yield of 95% along with 23%ee (Table 6, Entry 2).
Some other solvents, such as acetonitrile, dioxane, DCM,
and THF, were further examined (Table 6, Entries 3–6).
DCM gave the best reaction outcome: 98% yield and
50%ee. Using DCM as the solvent, catalysts LB6 and LB7
were examined, which led to higher enantioselectivities with
relatively lower yields (Table 6, Entries 7 and 8). The
enantioselectivity was found to be sensitive to the solvent,
so we tried other chlorinated solvents using LB1 as the cat-
alyst (Table 6, Entries 9–11). Chloroform gave 2a in higher
enantioselectivity: up to 65%ee (Table 6, Entry 9). In the
presence of chloroform, by decreasing the temperature to
–40 or –20 °C a similar enantioselectivity was achieved and
the yield was quantitative at –20 °C. It is notable that the
enantioselectivity dropped to 54%ee when water was not
added to the reaction mixture (Table 6, Entry 14). Decreas-
ing the amount of water from 0.05 to 0.0036 mL (1.0 equiv.
of water), the enantioselectivity did not change (Table 6,
Entries 13 and 15). The enantioselectivity increased slightly
[a] All reactions were carried out with N-Boc α-amidoalkyl phenyl
to 86%ee without cesium carbonate, which was the best
result we obtained (Table 6, Entry 16). Catalysts LB7, LB8,
and LB9 were also examined at –20 °C in chloroform, with
0.05 mL of water as the additive. Under these reaction con-
ditions, LB7 and LB8 could not catalyze this reaction, and
LB9 gave a slightly lower yield and enantioselectivity than
LB1 (Table 6, Entries 17–19).
sulfone 3a (0.2 mmol) and MVK (1.0 mmol). LB1, R = Ph; LB6,
R = Bu; LB7, R = Cy; LB8, R = 3,5-bis(trifluoromethyl)phenyl;
LB9, R = 3,5-dimethylphenyl. [b] Isolated yield. [c] Determined by
chiral HPLC. [d] Without Cs2CO3. [e] LB6 was used as the catalyst.
[f] LB7 was used as the catalyst. [g] LB8 was used as the catalyst.
[h] LB9 was used as the catalyst. [i] At –40 °C. [j] At –20 °C.
[k] Without water. [l] 0.0036 mL of water was used.
Subsequently, we used N-Boc-amidoalkyl p-tolyl sulfone
4a as the substrate to examine the effect of the phenylsulfin-
ate (Table 7). Under the same reaction conditions, the reac-
tions of 4a with MVK proceeded smoothly, leading to sim-
ilar results in terms of yields and enantioselectivities
(Table 7, Entries 1–3).
Table 7. The aza-MBH reaction of N-Boc α-amidoalkyl p-tolyl sul-
fone 4a with MVK using by LB1 or TQO as the catalyst.
With these optimal reaction conditions, the scope of the
aza-MBH reaction was further investigated with respect to
a series of N-Boc α-amidoalkyl phenyl sulfones 3 by using
LB1 as the catalyst (Table 8). Compared with the results in
Table 4, LB1 gave product 2 in much higher yields, espe-
cially for those substrates possessing substituent at the meta
or para position of the benzene ring, irrespective of their
electronic nature, though the enantioselectivity was slightly
[a] All reactions were carried out with N-Boc α-amidoalkyl p-tolyl
lower (Table 8, Entries 1–3). In the reaction of N-Boc α- sulfone 4a (0.2 mmol) and MVK (1.0 mmol) in solvent (1.0 mL).
[b] Isolated yield. [c] Determined by chiral HPLC. [d] At –20 °C.
amidoalkyl phenyl sulfones 3 bearing substitutes at the or-
tho position of the benzene ring with MVK, 3i gave aza-
MBH adduct 2i in 82%ee, but 3j gave 2j in only 60%ee
(Table 8, Entries 4 and 5). These differences in enantio- (Table 4, Entries 9 and 10). It should be noted that 2b and
selectivity were similar to the results in the TQO-catalyzed 2h could be obtained in 97 and Ͼ99%ee, respectively, after
aza-MBH reaction between N-Boc imines 1 and MVK being recrystallized once from petroleum ether and DCM.
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Asymmetric Aza-MBH Reactions of Alkyl Vinyl Ketones
Table 8. The aza-MBH reaction of N-Boc α-amidoalkyl phenyl sul-
fones 3 with MVK by using LB1 as the catalyst.
Table 10. The aza-MBH reaction of α-amidoalkyl phenyl sulfones
7 with MVK.
[a] All reactions were carried out with α-amidoalkyl phenyl sulfones
7 (0.2 mmol) and MVK (1.0 mmol) in solvent (1.0 mL). [b] Isolated
yield. [c] Determined by chiral HPLC. [d] At –20 °C.
[a] All reactions were carried out with N-Boc α-amidoalkyl phenyl
sulfones
3 (0.2 mmol) and MVK (1.0 mmol) in chloroform
(1.0 mL) and water (0.05 mL). [b] Isolated yield. [c] Determined by
chiral HPLC. [d] Determined by the sign of the specific rotation.
In our LB1-catalyzed aza-MBH reactions of N-protected
α-amidoalkyl phenyl sulfones with MVK, the in situ forma-
tion of imines may be rationalized by the mechanism shown
in Scheme 4. Catalyst LB1 as a nucleophile reacts with
MVK to produce zwitterionic intermediate C1, which sub-
sequently deprotonates the N-protected α-amidoalkyl
phenyl sulfones to generate C2 and C3. Anion C2 releases
phenylsulfinate to form the imine, and the phenylsulfinate
undergoes nucleophilic substitution of C3 to furnish prod-
uct 9 and regenerate the catalyst.
N-Bz or N-CO2Et imines 5 were tested in the aza-MBH
reaction with MVK (Table 9) to further investigate the
scope and limitations of this reaction. For N-Bz imine 5a,
dioxane was a better solvent than acetonitrile in both yield
and enantioselectivity to give the corresponding adduct 6a
in 75% yield with 86%ee (Table 9, Entry 3). Product 6b was
obtained in higher enantioselectivity than 6a (93% ee;
Table 9, Entry 6). According to these results, we conclude
that N-carbamate imines, such as N-Boc or N-CO2Et im-
ines, are superior in providing higher levels of enantio-
selectivity than N-Bz imines in the aza-MBH reaction with
MVK.
Generally, the Boc group could be easily removed by
using HCl in the presence of EtOAc. After 2a was stirred
in the EtOAc solution of HCl (a saturated solution with
HCl gas, ca. 4.0 ) at room temperature for 12 h, a white
Table 9. Catalyst and solvent screening for the aza-MBH reaction solid was acquired (Scheme 5). Surprisingly, obtained prod-
of imines 5 with MVK.
uct 8a was an adduct of HCl with the normal product α-
methylene-β-amino ketone 8b, and the structure of product
8a was assigned on the basis of spectroscopic analysis and
subsequently confirmed unequivocally by single-crystal X-
ray analysis (Figure 2). The Boc protecting group could also
be successfully removed by using a dilute HCl solution of
EtOAc (ca. 0.2 ) at room temperature, but a mixture of 8a
and the corresponding aza-MBH product 8b was obtained
in 80% yield (Scheme 5).
Reduction of the carbonyl group of rac-2a with NaBH4
and CeCl3 produced α-methylene-β-amino alcohol rac-9b
as a pair of diastereoisomers (1:1) in good yield, and the
Boc protecting group could also be easily removed with a
EtOAc solution of HCl (a saturated solution with HCl
gas) at room temperature for 12 h, affording product 10 in
90% yield (Scheme 6). Another more efficient method is
to use easily available solid p-toluenesulfonic acid (TsOH)
[a] All reactions were carried out with imines 5 (0.2 mmol) and
MVK (0.4 mmol) in solvent (1.0 mL). [b] Isolated yield. [c] Deter-
mined by chiral HPLC.
α-Amidoalkyl phenyl sulfones 7, precursors of N-Bz or to remove the Boc protecting group.[16] After a solution of
N-CO2Et imines 5 went smoothly in their aza-MBH reac- rac-2a and TsOH (4.0 equiv.) in DCM/THF (1:1) was
tions with MVK (Table 10). Chiral phosphane catalyst LB1 stirred at room temperature for 48 h, the TsOH salt of the
exhibited its good catalytic activity and selectivity, affording corresponding aza-MBH product α-methylene-β-amino
corresponding adducts 6a or 6b in higher yields and ketone 11 was obtained in 80% yield in pure form
enantioselectivities.
(Scheme 6).
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Scheme 4. Plausible mechanism for the in situ formation of imines in the LB1-catalyzed aza-MBH reaction of α-amidoalkyl phenyl
sulfones with MVK.
ric version of this aza-MBH reaction of N-protected imines
was systematically investigated by using chiral amine and
chiral phosphane catalysts. The reaction was found to be
general with respect to various N-protected imines under
mild reaction conditions, furnishing the corresponding ad-
duct in moderate yield with high ee value. Gratifyingly, we
have identified a facile and direct route to obtain highly
enantioselective aza-MBH adducts from N-protected α-
amidoalkyl phenyl sulfones with alkyl vinyl ketones cata-
lyzed by chiral phosphane catalyst LB1. This one-pot ap-
proach avoids handling of preformed imines, which are usu-
Scheme 5. Removal of the Boc protecting group from adduct rac-
ally unstable. Interestingly, an adduct of HCl with the cor-
responding aza-MBH product could be obtained during the
removal of the Boc group of 2a by using HCl in EtOAc,
and the normal aza-MBH product could be also produced
as a salt by treating 2a with TsOH under mild conditions.
Efforts are in progress to elucidate further mechanistic de-
tails of these reactions and to understand their scope and
limitations.
2a.
Experimental Section
General Remarks: 1H and 13C NMR spectra were recorded at 400
and 100 MHz, respectively. Low- and high-resolution mass spectra
were recorded by ESI method. The used organic solvents were
dried by standard methods if it was necessary. Satisfactory CHN
microanalyses were obtained with an analyzer. Commercially ob-
tained reagents were used without further purification. All these
reactions were monitored by TLC with silica-gel-coated plates.
Flash column chromatography was carried out by using silica gel
at increased pressure.
Figure 2. ORTEP drawing of compound 8a.[15]
General Procedure for the DABCO- or TQO-Catalyzed Aza-MBH
Reactions of N-Boc Imine 1 with MVK: N-Boc imine 1 (0.2 mmol),
MVK (0.4 mmol), DABCO or TQO (0.02 mmol), and acetonitrile
(1.0 mL) were added into a Schlenk tube. The reaction mixture was
stirred at room temperature for 48 h, the solvent was removed un-
der reduced pressure, and the residue was purified by flash column
chromatography.
rac-2a: White solid (44 mg, 80%), m.p. 76–78 °C. 1H NMR
(400 MHz, CDCl3, TMS): δ = 1.44 (s, 9 H, CH3), 2.30 (s, 3 H,
CH3), 5.53 (br. s, 1 H, NH), 5.65 (d, J = 8.4 Hz, 1 H, CH), 6.11
(s, 1 H, =CH), 6.22 (s, 1 H, =CH), 7.21–7.31 (m, 5 H, Ar) ppm.
13C NMR (100 MHz, CDCl3, TMS): δ = 26.5, 28.3, 56.0, 79.6,
126.4, 126.7, 127.3, 128.4, 140.1, 147.8, 154.9, 198.8 ppm. IR
Scheme 6. Removal of the Boc group from adduct rac-2a or 9b.
Conclusions
We have developed DABCO-catalyzed aza-MBH reac-
(CH Cl ): ν = 3443, 3350, 3088, 3062, 3030, 2980, 2931, 1723, 1494,
˜
2
2
tions of N-Boc imines with MVK and EVK. The asymmet- 1454, 1367, 1283, 1248, 1174, 1046, 1023, 975, 885, 754, 700 cm–1.
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Eur. J. Org. Chem. 2010, 4098–4105

Asymmetric Aza-MBH Reactions of Alkyl Vinyl Ketones
MS (ESI): m/z (%) = 298.1 (100) [M + Na]+. HRMS (ESI): calcd.
Kang, Z.-K. Hu, Y.-C. Chen, J. Am. Chem. Soc. 2008, 130,
2456–2457.
for C16H21N1Na1O3 [M + Na]+ 298.14136; found 298.14189.
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General Procedure for the Removal of the Boc Group: Compound
rac-2a (125 mg, 0.45 mmol) was stirred in an EtOAc (4.0 mL) solu-
tion of HCl (a saturated solution with HCl gas) at room tempera-
ture for 12 h, a white solid was formed, and the solvent was re-
moved under reduced pressure. The residue was washed with Et2O,
and pure product 8a (90 mg, 80% yield) was obtained as a white
solid.
CCDC-739399 (for 2d) and -743651 (for 8a) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic data of all new compounds, detailed descrip-
tions of the experimental procedures, X-ray data for compounds
2d and 8a.
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[13] Crystal data of 2d: Empirical formula: C16H20BrNO3; formula
weight: 354.24; crystal size: 0.369ϫ0.317ϫ0.112; crystal color,
habit: colorless, prismatic; crystal system: monoclinic; lattice
type: primitive; lattice parameters: a = 5.2878(8) Å, b =
20.966(3) Å, c = 15.487(2) Å, α = 90°, β = 97.8883(3)°, γ = 90°,
Acknowledgments
We thank the Shanghai Municipal Committee of Science and Tech-
nology (06XD14005, 08dj1400100-2), National Basic Research
Program of China (973)-2010CB833302, and the National Natural
Science Foundation of China (20872162, 20672127, 20821002,
20732008, and 20702059) for financial support and also thank Mr.
Sun Jie for performing the X-ray diffraction experiments.
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V
= 1700.8(4) Å3; space group: P21; Z = 4; Dcalcd.
=
1.383 gcm–3; F(000) = 728; R1 = 0.0544, wR2 = 0.1148. Dif-
fractometer: Rigaku AFC7R.
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[15] Crystal data of 8a: Empirical formula: C11H16Cl2NO1.50; for-
mula weight: 257.15; crystal size: 0.453ϫ0.330ϫ0.297; crystal
color, habit: colorless, prismatic; crystal system: monoclinic;
lattice type: primitive; lattice parameters: a = 27.807(3) Å, b =
5.8683(6) Å, c = 15.8859(16) Å, α = 90°, β = 103.310(2)°, γ
= 90°, V = 2522.6(4) Å3; space group: C2/c; Z = 8; Dcalcd.
=
1.354 gcm–3; F(000) = 1080; R1 = 0.0401, wR2 = 0.1055. Dif-
fractometer: Rigaku AFC7R.
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Received: April 12, 2010
Published Online: June 2, 2010
Eur. J. Org. Chem. 2010, 4098–4105
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4105