Direct access to cumbersome aminated quaternary centers by hyperbaric aza-Michael additions

Article abstract of DOI:10.1002/ejoc.201000984

The aza-Michael addition of secondary amines to α, β or ββdisubstituted α, βunsaturated esters was efficiently achieved under high pressure (10-16 kbar) in protic solvents in the absence of any catalyst. The expected cumbersome β-aminoesters bearing a tertiary amine directly connected to a quaternary carbon atom could be isolated in fair to good yields. By using αβδγ-unsaturated esters (alkyl sorbate), the addition took place regioselectively in a 1,6 manner and afforded the β,γ -unsaturated δ-aminoesters. Copyright

Full text of DOI:10.1002/ejoc.201000984

FULL PAPER
DOI: 10.1002/ejoc.201000984
Direct Access to Cumbersome Aminated Quaternary Centers by Hyperbaric
Aza-Michael Additions
Alexander Yu. Rulev,[a] Saleha Azad,[b] Hiyoshizo Kotsuki,[b] and Jacques Maddaluno*[c]
Keywords: Michael addition / High-pressure chemistry / Chirality / Amines
The aza-Michael addition of secondary amines to α,β- or β,β-
disubstituted α,β-unsaturated esters was efficiently achieved
nary carbon atom could be isolated in fair to good yields. By
using α,β,δ,γ-unsaturated esters (alkyl sorbate), the addition
under high pressure (10–16 kbar) in protic solvents in the ab- took place regioselectively in a 1,6 manner and afforded the
sence of any catalyst. The expected cumbersome β-aminoes-
β,γ-unsaturated δ-aminoesters.
ters bearing a tertiary amine directly connected to a quater-
bulkiness of the partners; the amenability of C–N bond for-
mation is inversely proportional to the steric bulk of the
reactants.[9] The application of high pressure (HP, Ն8–
10 kbar) brings a solution to this problem, as HP is known
to overcome severe steric impairments. More precisely, it
has been established that sterically congested reactions are
accelerated by pressure to a greater extent than that pre-
dicted by comparison with similar reactions free of steric
hindrance, at least for reactions with late transition
states.[10] Accordingly, we[11] and others[12] have shown pre-
viously that HP facilitates to a large extent the aza-Michael
addition to the conjugated double bonds of α,β-unsaturated
esters. In this paper, we show that the hyperbaric aza-
Michael addition of amines is a good way to assemble qua-
ternary centers substituted with tertiary amines.
Introduction
Coordinating the substitution of quaternary carbon cen-
ters remains a thorny issue in organic synthesis, particularly
when bulky appendages are to be borne by the new center.
In most cases, no general solution is available and the fine-
tuning of particular reaction conditions is necessary to
achieve the target in acceptable yields and selectivities.[1]
Aminated quaternary carbon centers are no exception to
this rule, even if they are found in many natural products
such as important alkaloids, including, FR901483[2] and
(+)-lepadiformine C,[3] and the proteosome inhibitors sali-
nosporamide A, omuralide, and lactacystin.[4] The design of
efficient routes to these compounds is far from trivial, and
significant difficulties lie in the assembling of the aminated
quaternary center. Carbon–nitrogen bond formation by
conjugate addition of nitrogen nucleophiles to olefins acti-
vated by electron-withdrawing groups, better known as the
aza-Michael reaction,[5] offers an efficient route to tertiary
centers, exemplified particularly well by the lithium
Results and Discussion
Our previous studies had shown that protic solvents such
amides.[6] Steric hindrance often restricts the application of as alcohols are particularly favorable for aza-Michael ad-
the aza-Michael, and thus far, such reactions have not been ditions.[11b,13] We first considered the case of β-monosubsti-
readily applicable to the creation of quaternary centers. In tuted unsaturated esters that are known to react under ther-
these cases, the yields of 1,4 adducts become disappoint- mal or catalytic control, albeit sometimes requiring very
ingly low,[7] unless appropriate catalysts are used.[8] In ad- harsh conditions. We thus added morpholine to methyl cro-
dition, the reversibility of this reaction is enhanced by the tonates and cinnamates, taken as model Michael acceptors,
and compared the resulting yields of the reactions run by
using thermal (uncatalyzed) conditions to those obtained
[a] A. E. Favorski Institute of Chemistry,
Siberian Division of the Russian Academy of Sciences,
Irkutsk 664033, Russia
by using HP conditions (Table 1). Even for such simple
cases, the application of pressure proved beneficial (Table 1,
Entries 1–4), in particular in the case of methyl cinnamate.
However, when the substrate bears two substituents in
both the α and β positions to the ester (Table 1, Entry 5),
the addition takes place with low diastereoselectivity to af-
ford 2c as a 3:1 mixture.[14] The origin of this poor ste-
reocontrol is probably related to the N–O–C proton trans-
fer mechanism. First, intramolecular O-protonation of the
View this journal online at
[b] Laboratory of Natural Products Chemistry,
Faculty of Science, Kochi University,
Akebono-cho, Kochi 780-8520, Japan
[c] CNRS UMR 6014 & FR 3038,
Université de Rouen et INSA de Rouen,
76821 Mont Saint-Aignan Cedex, France
Fax: +33-235-522-971
E-mail: jmaddalu@crihan.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000984.
wileyonlinelibrary.com
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A. Yu. Rulev, S. Azad, H. Kotsuki, J. Maddaluno
FULL PAPER
Table 1. Access to amine-substituted tertiary centers by aza- philes that the controlled addition to electron-deficient
dienes can be unpredictable.[16]
Michael addition to methyl crotonates and cinnamates.
In our hands, δ-aminoester 4a was obtained regioselec-
tively in good yields after 24 h in EtOH (Table 2, Entries 1
and 2). Because the solvent likely plays a key role in dictat-
ing the regioselectivity of the protonation, we repeated the
reaction in THF. Interestingly, aminoesters 4a and 4b (con-
taminated with minute amounts of esters 5a and 5b) were
obtained, suggesting that the source of the proton is, as
noted above, the intermediate allylic ammonium species
(Table 2). However, proton transfer in this case likely pro-
ceeds through an eight-membered transition state that is
probably less favored than an intermolecular process. It is
interesting to note that (i) no product of 1,2- or 1,4-addition
could be observed in these cases and (ii) esters 4a and 4b
were always obtained selectively as their (E) isomers.
[a] Isolated yield. [b] After 6 h. [c] Starting ester 1b was recovered
in 27%. [d] Obtained as a mixture (3:1) of two diastereomers.
Table 2. Aza-Michael addition of morpholine to alkyl sorbates.
intermediate enolate by the ammonium is expected. One
can thus expect the following enol isomerization to control
the stereochemical outcome of the reaction. If a lasting in-
tramolecular interaction between the nitrogen atom and the
proton occurs, a semi-rigid six-membered arrangement is
likely that can be depicted as two threshold half-chair con-
figurations (Scheme 1). The difference between these two
half-chairs lies in the pseudoequatorial or pseudoaxial posi-
tion of the R group. The more likely equatorial situation
would trigger syn hydroamination of the double bond. The
anti diastereomer could then arise either from the pseu-
doaxial arrangement of R or from an intermolecular pro-
tonation (by the solvent) guided by the nitrogen lone pair,
pointing syn to the R group. Note that the importance of
[a] Isolated yield. [b] The corresponding (E)-α,β-unsaturated δ-
the methanol–amine interaction during the process of the
aminoesters were also isolated (Entry 3: 5a 2%; Entry 4: 5b 8%).
aza-Michael addition has been highlighted in a fine theoret-
ical study by Giessner-Prettre, Dumas, and co-workers.[15]
We further pursued this study by using β,β-disubstituted
α,β-unsaturated esters as Michael acceptors and decided to
use secondary amines to evaluate if the addition could af-
ford highly crowded systems consisting of a quaternary car-
bon center next to a tertiary amine. The possibility of a
retro-Michael addition of the amino group upon release of
the pressure posed a serious threat to this strategy. This
reversibility is known to limit the utility of hyperbaric oxa-
Michael additions, even though its intramolecular version
makes feasible a number of interesting synthetic routes.[17]
Initial experiments were run under classical thermal con-
ditions by using senecioic esters 6a and 6b (3,3-dimethyl-
acrylate, Table 3) in alcoholic solvent.[18] The data show
that even nucleophilic cyclic amines such as morpholine did
not react in refluxing MeOH (Table 3, Entry 1). In contrast,
substituted acrylates.
Scheme 1. Proton transfers during the aza-Michael addition on
these amines added smoothly under pressure (Table 3, En-
We next tested the reaction of alkyl sorbates with morph- tries 2 and 3). The more sluggish acyclic dialkylamines re-
oline to evaluate the regioselectivity of reactions involving quired an increase in pressure and/or reaction time (Table 3,
polyunsaturated systems. It is known for carbon nucleo- Entries 4 and 5). At 16 kbar both oxa- and aza-Michael
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Access to Aminated Quaternary Centers by Hyperbaric Aza-Michael Additions
additions were observed (Table 3, Entry 6) as MeOH be- Table 4. Synthesis of amino-substituted quaternary centers by hy-
perbaric aza-Michael addition on alkyl cycloalkylidene esters.
haved under these conditions as a competing nucleophile.
At the same pressure, the use of EtOH as solvent (and
working with ethyl ester 6b to avoid transesterification) af-
forded β-aminoesters 7c and 7d in moderate yields (Table 3,
Entry 5). Interestingly, the use of N,N,NЈ-trimethylethylene-
diamine as nucleophile led to satisfying yields even at
10 kbar (Table 3, Entry 7). In contrast, hexamethyldisilaz-
ane (HMDS) did not react at all with 6 under the same
conditions (Table 3, Entry 8). The use of ethyl β-methyl-
cinnamate [i.e. (E)-ethyl 3-phenylbut-2-enoate] instead of
senecioates was also attempted. However, the only reaction
observed was the conversion of the ester into the corre-
sponding unsaturated amide, as a result of 1,2-addition of
morpholine, in 26% yield (together with 68% starting mate-
rial).
Table 3. Synthesis of amine-substituted quaternary centers by
hyperbaric aza-Michael addition on alkyl senecioates.
[a] Isolated yield unless otherwise specified. [b] Yield based on inte-
gration of the NMR spectroscopy signals. [c] Large amounts of
starting material 8 were also recovered.
[a] Isolated yield. [b] In refluxing MeOH. [c] Dimethylamine gener-
ated in situ by neutralization of its hydrochloride salt with triethyl-
amine. [d] After 48 h. [e] The oxa-Michael adduct (3-methoxy-3-
methyl butanoate) was isolated in 46% yield.
More positive results were obtained with cyclic substrates
such as cycloalkylidenic esters 8 (Table 4).[11b–11e] Hyper-
baric addition was found to be superior to thermal addition
Figure 1. X-ray crystal structure of 9a.
(Table 4, Entry 1 vs. 2). However, migration of the double
bond of 8 to afford the deconjugated esters 9c and 10b or
amide 10c interfered with the desired aza-Michael addition
(Table 4, Entries 3–6). Nevertheless, highly nucleophilic
Table 5. Hyperbaric aza-Michael addition of morpholine and
piperidine on various activated olefins (isolated yields).
amines such as morpholine reacted remarkably well: bicy-
clic β-aminoester 9a was obtained in almost quantitative
yield and as a single diastereomer. Interestingly, the ad-
dition took place in a selective equatorial manner, as evi-
denced by the X-ray crystal structure of 9a (Figure 1). Note
that such β-aminoesters can be regarded as convenient pre-
cursors to spiro β-lactams.[19]
We next tried to extend this protocol to other Michael
acceptors such as ketone 11, sulfone 12, and nitroalkene
13.[20] Mesityloxide 11 is commercially available, whereas
the two latter substrates were easily prepared (see the Sup-
porting Information). These substrates were treated with
the same cyclic secondary amines as above, and the results
are presented in Table 5.
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A. Yu. Rulev, S. Azad, H. Kotsuki, J. Maddaluno
FULL PAPER
Ketone 11 did not provide any aza-Michael adduct al-
though it is known to react readily with ammonia at atmo-
spheric pressure.[21] A competing, but reversible, 1,2-ad-
dition leading to a hemiaminal or iminium intermediate[22]
is probably responsible for this failure. Only a small amount
of 15a, resulting from the conjugate addition of MeOH,
was recovered under 10 kbar (Table 5, Entries 1 and 2).[23]
In contrast, the same amines added easily onto sulfone 12,
leading to β-aminosulfones 14a and 14b in good yields
(Table 5, Entries 3 and 4), even at lower pressures. Finally,
nitroolefin 13 gave only a complex mixture of products un-
der the same reaction conditions (Table 5, Entries 5 and 6),
possibly because of uncontrolled polymerization.
These data suggest that unsaturated esters and sulfones
might be the most appropriate substrates for these hyper-
baric reactions. For reactive substrates (such as unsaturated
ketones or nitroolefins), catalytic,[24] neat,[25] or photochem-
ical[26] conditions at atmospheric pressure are perhaps more
amenable to aza-Michael additions. Alternatively, an aque-
ous medium has also been shown to facilitate the addition
of amines on nitroolefins.[27]
Conclusions
The results presented here suggest that the hyperbaric
aza-Michael reaction constitutes a direct method to as-
semble aminated quaternary centers in an atom economical
way and without requiring additive. The reaction is per-
formed under mild chemical conditions (room temperature,
no catalyst), and depending on the substrate, good yields
and selectivities can be achieved. The irreversible character
of the addition under HP suggests that the observed selec-
tivities favor the kinetic isomer. Overall, the results pre-
sented here indicate that the hyperbaric aza-Michael ad-
dition offers attractive solutions to problems in organic
methodology that are, otherwise, often tedious to solve.
Consequently, the hyperbaric aza-Michael reaction makes
available unusual shortcuts for the synthesis of complex
molecules bearing cumbersome aminated quaternary cen-
ters.
Experimental Section
We finally considered bis-nucleophiles or bis-electro-
philes as possible substrates for double additions
(Scheme 2). We first evaluated the reaction of diamines and
methyl senecioate by using the conditions of Table 1. De-
pending on the flexibility of the diamine, the simultaneous
creation of two quaternary centers or the addition–lactam-
ization occurred. Thus, by using piperazine as the nucleo-
phile, bis(β-aminoester) 16 was recovered in good isolated
yield, whereas N,NЈ-dimethylethylenediamine gave ef-
ficiently seven-membered aminolactam 17 (Scheme 2). Un-
der comparable conditions, two molecules of the latter di-
amine reacted with diester 18 to furnish dispirocyclic bis-
(lactam) 19, albeit in poor yield. The same diester reacted
with morpholine to afford cyclic diamino diester 20 in
slightly better yield.
General: 1H and 13C NMR spectra were recorded with a Bruker
Avance 300 MHz spectrometer (300 and 75 MHz, respectively) or
a JEOL LA-400 spectrometer (400 and 100 MHz, respectively) for
solution in CDCl3. Chemical shifts (δ) in ppm are reported by using
residual chloroform (7.25 ppm for 1H and 77.20 ppm for 13C) as
internal reference. IR spectra were measured with a Perkin–Elmer
16 PC FTIR instrument. Mass spectra were recorded with an ATI-
Unicam Automass spectrometer (EI, 70 eV), and ammoniac was
used for chemical ionization (CI). High-pressure reactions were
performed in a Psika piston-cylinder type apparatus, designed for
pressures up to 20 kbar. The silica gel used for flash chromatog-
raphy was 230–400 mesh. All reagents were of reagent grade and
were used as such or distilled prior to use. All the solvents were
dried according to standard procedures and freshly distilled prior
to use.
β,β-Disubstituted α,β-Unsaturated Sulfone 12: To a solution of
methyl phenyl sulfone (5.2 g, 0.04 mol) in THF (175 mL), cooled
to –78 °C, was added nBuLi (1.59  hexane, 25 mL, 0.04 mol). The
mixture was stirred at –78 °C for 30 min before acetone (3 mL,
0.04 mol) was added. The resulting light solution was stirred at
–78 °C for 90 min and then treated with aqueous saturated NH4Cl.
The organic layer was separated, and the aqueous layer was ex-
tracted with EtOAc (3ϫ20 mL). The combined organic layers were
dried (MgSO4), filtered, and concentrated. The crude resulting
alcohol and DMAP (0.5 g, 0.004 mol) were dissolved in CH2Cl2.
The mixture was cooled to 0 °C before Et3N (11.2 mL, 0.08 mol)
and TFAA (6.7 mL, 0.05 mol) were successively added. The reac-
tion mixture was stirred at 0 °C for 30 min, allowed to reach room
temperature, and stirred at room temperature for 3 h. After hydrol-
ysis with aqueous saturated NH4Cl, the organic layer was sepa-
rated, and the aqueous layer was extracted with CH2Cl2. The com-
bined organic layers were dried (MgSO4), filtered, and concen-
trated. The residue was purified by flash chromatography (hexane/
EtOAc, 2:1) to afford 2-methyl-1-phenylsulfonyl-1-propene (12) as
a light yellowish mica crystal (yield 72%). 1H NMR (400 MHz,
CDCl3): δ = 1.89 (d, J = 1.2 Hz, 3 H), 2.15 (d, J = 1.0 Hz, 3 H),
6.2 (q, 1 H), 7.49–7.68 (m, 3 H), 7.87–7.95 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 19.10, 26.99, 126.06, 126.91 (2 C),129.02 (2
C), 132.91, 142.19, 154.31 ppm.
Scheme 2. Double hyperbaric aza-Michael additions (r.t., 12–
16 kbar, 24 h, MeOH).
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Access to Aminated Quaternary Centers by Hyperbaric Aza-Michael Additions
Typical Procedure for the Aza-Michael Reaction of Sulfone 12 with
Amines: A mixture of amine (1.2 mmol), and 12 (1.0 mmol) in
MeOH (1.5 mL) was placed in a Teflon reaction vessel, and the
mixture was pressurized to 8 kbar at room temperature for 48 h.
After the pressure was released, the mixture was concentrated in
vacuo. The crude product was purified by column chromatography
(silica gel, hexane/EtOAc).
4 H), 2.84 (quint., J = 6.7 Hz, 1 H), 3.02 (d, J = 6.8 Hz, 2 H),
3.55–3.65 (m, 4 H), 3.59 (s, 3 H), 5.40 (dd, J = 7.8, 15.4 Hz, 1 H),
1
5.56 (dt, J = 6.8, 15.4 Hz, 1 H) ppm. H NMR (300 MHz, CDCl3,
minor isomer): δ = 1.04 (d, J = 6.7 Hz, 3 H), 2.35–2.50 (m, 4 H),
2.84 (quint., J = 6.7 Hz, 1 H), 3.02 (d, J = 6.8 Hz, 2 H), 3.55–3.65
(m, 4 H), 3.59 (s, 3 H), 5.40 (dd, J = 7.8, 15.4 Hz, 1 H), 5.56 (dt,
J = 6.8, 15.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3, major
isomer): δ = 17.43 (CH3CH), 37.55 (CH2CO), 50.48 (NCH2), 51.90
(OMe), 62.39 (CHCH3), 67.14 (OCH2), 123.64 (CH=), 136.12
(CH=), 172.17 (C=O) ppm. 13C NMR (75 MHz, CDCl3, minor
isomer): δ = 18.09 (CH3CH), 33.10 (CH2CO), 50.85 (NCH2), 51.84
(OMe), 57.34 (CHCH3), 67.21 (OCH2), 122.39 (CH=), 135.34
Typical Procedure for the Treatment of Ester 1 with Amines: A solu-
tion of the ester (1 mmol) and amine (1 mmol) in THF (1–1.5 mL)
was allowed to stand under 10–16 kbar of pressure at room tem-
perature. After reversion to atmospheric pressure, the solvent was
evaporated. The residue was purified by chromatography (silica gel;
CH2Cl2/MeOH, 9:1; Et2O/pentane, 1:3) to yield the corresponding
products. The following compounds were prepared according to
this procedure.
(CH=), 171.89 (C=O) ppm. IR: ν = 1653 (C=C), 1741 (C=O) cm–1.
˜
MS (IE): m/z (%) = 213 (13) [M]+, 198 (100). C11H19NO3 (213.28):
calcd. C 61.95, H 8.98, N 6.57; found C 61.68, H 9.11, N 6.65.
Methyl 5-Morpholin-4-ylhex-2-enoate (5b): 1H NMR (300 MHz,
CDCl3): δ = 0.96 (d, J = 6.6 Hz, 3 H), 2.12 (ddt, J = 1.4, 8.0,
14.3 Hz, 1 H), 2.35–2.50 (m, 5 H), 2.63 (quint., J = 6.6 Hz, 1 H),
3.55–3.65 (m, 4 H), 3.67 (s, 3 H), 5.79 (dt, J = 1.4, 14.3 Hz, 1 H),
6.91 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.93 (CH3),
36.05 (CH2), 49.02 (NCH2), 51.60 (OMe), 58.89 (CH), 67.44
Methyl 3-Morpholin-4-ylbutanoate (2a): 1H NMR (300 MHz,
CDCl3): δ = 1.00 (d, J = 6.6 Hz, 3 H), 2.19 (dd, J = 7.9, 14.3 Hz,
1 H), 2.40–2.55 (m, 5 H), 3.00–3.10 (m, 1 H), 3.55–3.65 (m, 7 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 14.69 (CH3CH), 38.12
(CH2), 48.61 (NCH2), 51.48 (OCH3), 56.62 (C-N), 67.27 (OCH2),
172.83 (C=O) ppm. IR: ν = 1738 (C=O) cm–1. MS (IE): m/z (%) =
˜
187 (8) [M]+, 172 (11), 114 (100). C9H17NO3 (187.24): calcd. C
57.73, H 9.15, N 7.48; found C 57.32, H 9.23, N 7.76.
2
(OCH ), 122.33 (CH=), 147.56 (CH=), 167.06 (C=O) ppm. IR: ν
˜
= 1656 (C=C), 1723 (C=O) cm–1. MS (IE): m/z (%) = 213 (2)
[M]+, 185 (4), 140 (25), 114 (100). C11H19NO3 (213.28): calcd. C
61.95, H 8.98, N 6.57; found C 61.72, H 9.09, N 6.61.
Methyl 3-Morpholin-4-ylphenylpropanoate (2b): 1H NMR
(300 MHz, CDCl3): δ = 2.35–2.45 (m, 4 H), 2.67 (dd, J = 7.4,
14.9 Hz, 1 H), 3.01 (m, 1 H), 3.60 (s, 3 H), 3.65–3.75 (m, 4 H), 3.92
(t, J = 7.5 Hz, 1 H), 7.25–7.35 (m, 5 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 38.05 (CH2), 50.39 (NCH2), 51.60 (OCH3), 66.25
(CHN), 67.18 (OCH2), 127.63, 128.23, 128.29, 138.56 (Ph), 172.12
Methyl 3-Methyl-3-morpholin-4-ylbutanoate (7a): 1H NMR
(300 MHz, CDCl3): δ = 1.12 (s, 6 H), 2.37 (s, 2 H), 2.45–2.60 (m,
4 H), 3.55–3.70 (m, 7 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
24.11 (CH3), 43.32 (CH2), 46.25 (NCH2), 51.37 (OCH3), 56.21 (C-
(C=O) ppm. IR: ν = 1738 (C=O) cm–1. MS (IE): m/z (%) = 249
˜
N), 67.81 (OCH ), 172.37 (C=O) ppm. IR: ν = 1734 (C=O) cm–1.
˜
2
(7) [M]+, 176 (100). C14H19NO3 (249.31): calcd. C 67.45, H 7.68,
N 5.62; found C 67.45, H 7.66, N 5.60.
MS (IE): m/z (%) = 201 (3) [M]+, 186 (20), 128 (100). C10H19NO3
(201.27): calcd. C 59.68, H 9.52, N 6.96; found C 59.32, H 9.62, N
7.04.
Methyl 2-Methyl-3-morpholin-4-ylpentanoate (2c): 1H NMR
(300 MHz, CDCl3, major diastereomer): δ = 0.89 (t, J = 7.4 Hz, 3
H), 1.15 (d, J = 6.8 Hz, 3 H), 1.20–1.35 (m, 1 H), 1.50–1.60 (m, 1
Methyl 3-Methyl-3-piperidin-4-ylbutanoate (7b): 1H NMR
(300 MHz, CDCl3): δ = 1.08 (s, 6 H), 1.25–1.35 (m, 2 H), 1.35–
1.50 5 (m, 4 H), 2.32 (s, 2 H), 2.35–2.50 (m, 4 H), 3.55 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 24.78 (CH3), 24.85, 26.90
(CH2 piperidine), 42.70 (CH2), 46.80 (NCH2), 51.27 (OCH3), 56.54
1
H), 2.55–2.65 (m, 6 H), 3.55–3.60 (m, 4 H), 3.63 (s, 3 H) ppm. H
NMR (300 MHz, CDCl3, minor diastereomer): δ = 0.88 (t, J =
7.4 Hz, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 1.15–1.25 (m, 1 H), 1.30–
1.60 (m, 1 H), 2.40–2.65 (m, 6 H), 3.45–3.50 (m, 4 H), 3.56 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3, major diastereomer): δ =
12.86 (CH3CH2), 15.32 (CH3CH), 21.72 (CH2CH3), 42.89
(CHCH3), 49.85 (NCH2), 51.64 (OCH3), 67.91 (OCH2), 68.25
(CHN), 176.83 (C=O) ppm. 13C NMR (75 MHz, CDCl3, minor
(C-N), 172.93 (C=O) ppm. IR: ν = 1738 (C=O) cm–1. MS (IE):
˜
m/z (%) = 199 (8) [M]+, 184 (60), 126 (100). C11H21NO2 (199.29):
calcd. C 66.29, H 10.62, N 7.03; found C 66.65, H 10.87, N 7.10.
Ethyl 3-(Dimethylamino)-3-methylbutanoate (7c): 1H NMR
(300 MHz, CDCl3): δ = 1.13 (s, 6 H), 1.20 (t, J = 7.1 Hz, 3 H),
2.20 (s, 6 H), 2.32 (s, 2 H), 4.06 (q, J = 7.1 Hz, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.35 (CH3CH2), 24.41 (CH3C),
38.63 (CH3N), 41.69 (CH2), 56.14 (C-N), 60.22 (OCH2), 172.48
diastereomer):
δ = 13.15 (CH3CH2), 14.80 (CH3CH), 20.67
(CH2CH3), 43.50 (CHCH3), 49.52 (NCH2), 51.25 (OCH3), 67.90
(OCH ), 68.95 (CHN), 176.59 (C=O) ppm. IR: ν = 1737 (C=O)
˜
2
cm–1. MS (IE): m/z (%) = 215 (1) [M]+, 186 (8), 128 (100).
C11H21NO3 (215.29): calcd. C 61.37, H 9.83, N 6.51; found C
61.23, H 10.14, N 6.28.
(C=O) ppm. IR: ν = 1732 (C=O) cm–1. MS (IE): m/z (%) = 173
˜
(5) [M]+, 158 (14), 86 (100). C9H19NO2 (173.25): calcd. C 62.39, H
11.05, N 8.08; found C 62.13, H 11.14, N 8.14.
Ethyl 5-Morpholin-4-ylhex-3-enoate (4a): 1H NMR (300 MHz,
CDCl3): δ = 1.12 (d, J = 6.7 Hz, 3 H), 1.22 (t, J = 7.2 Hz, 3 H),
2.35–2.55 (m, 4 H), 2.84 (quint., J = 6.7 Hz, 1 H), 3.02 (d, J =
6.8 Hz, 2 H), 3.60–3.75 (m, 4 H), 4.10 (q, J = 7.2 Hz, 2 H), 5.45
(dd, J = 7.8, 15.4 Hz, 1 H), 5.62 (dt, J = 6.8, 15.4 Hz, 1 H) ppm.
Ethyl 3-(Diethylamino)-3-methylbutanoate (7d): 1H NMR
(300 MHz, CDCl3): δ = 1.01 (t, J = 7.1 Hz, 6 H), 1.20 (s, 6 H),
1.25 (t, J = 7.2 Hz, 3 H), 2.39 (s, 2 H), 2.54 (q, J = 7.1 Hz, 4 H),
4.10 (q, J = 7.2 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
14.42 (CH3CH2O), 16.84 (CH3CH2N), 26.30 (CH3), 43.76 (CH2),
43.19 (NCH2), 57.63 (C-N), 60.16 (OCH2), 172.64 (C=O) ppm. IR:
13C NMR (75 MHz, CDCl3):
δ = 14.35 (CH3CH2), 17.61
(CH3CH), 37.97 (CH2CO), 50.62 (NCH2), 60.83 (CH2CH3), 62.60
(CHCH3), 67.33 (OCH2), 124.04 (CH=), 136.07 (CH=), 171.95
ν = 1731 (C=O) cm–1. MS (IE): m/z (%) = 201 (4) [M]+, 186 (20),
˜
(C=O) ppm. IR: ν = 1651 (C=C), 1735 (C=O) cm–1. MS (IE): m/z
114 (100). C11H23NO2 (201.31): calcd. C 65.63, H 11.52, N 6.96;
found C 65.78, H 11.56, N 7.18.
˜
(%) = 227 (17) [M]+, 212 (50), 114 (100). C10H19NO3 (201.27):
calcd. C 63.41, H 9.31, N 6.16; found C 63.16, H 9.26, N 6.04.
Methyl
3-{[2-(Dimethylamino)ethyl](methyl)amino}-3-methylbut-
Methyl 5-Morpholin-4-ylhex-3-enoate (4b): 1H NMR (300 MHz,
CDCl3, major isomer): δ = 1.06 (d, J = 6.7 Hz, 3 H), 2.35–2.50 (m,
anoate (7f): 1H NMR (300 MHz, CDCl3): δ = 1.15 (s, 6 H), 2.20
(s, 3 H), 2.23 (s, 6 H), 2.35–2.55 (m, 6 H), 3.62 (s, 3 H) ppm. 13C
Eur. J. Org. Chem. 2010, 6423–6429
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6427

A. Yu. Rulev, S. Azad, H. Kotsuki, J. Maddaluno
FULL PAPER
NMR (75 MHz, CDCl3): δ = 24.72 (CH3C), 35.49 (CH3N), 42.34
(2 C), 57.11, 61.81, 127.74 (2 C), 129.04 (2 C), 133.18, 141.87 ppm.
(CH2), 45.82 (CH3N), 48.91 (NCH2), 51.31 (OCH3), 56.81 (C-N), C15H23NO2S (281.41): calcd. C 64.02, H 8.24, N 4.98; found C
59.27 (NCH ), 172.61 (C=O) ppm. IR: ν = 1736 (C=O) cm–1. MS
64.25, H 8.49, N 4.75.
˜
2
(IE): m/z (%) = 216 (4) [M]+, 158 (100). C11H24N2O2 (216.32):
4-Methoxy-4-methylpentan-2-one (15a): 1H NMR (400 MHz,
CDCl3): δ = 1.26 (s, 6 H), 2.22 (s, 3 H), 2.57 (s, 2 H), 3.29 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 24.83 (3 C), 49.16, 54.10,
74.39, 208.51 ppm.
calcd. C 61.07, H 11.18, N 12.95; found C 61.05, H 11.22, N 12.89.
Methyl 3-Methoxy-3-methylbutanoate: 1H NMR (300 MHz,
CDCl3): δ = 1.24 (s, 6 H), 2.46 (s, 2 H), 3.19 (s, 3 H), 3.63 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 25.23 (CH3), 44.78 (CH2),
49.60 (OCH3), 51.54 (COOCH3), 73.88 (COCH3), 171.46 (C=O)
[(2-Methoxy-2-methylpropyl)sulfonyl]benzene (15b): 1H NMR
(400 MHz, CDCl3): δ = 1.42 (s, 6 H), 3.03 (s, 3 H), 3.40 (s, 2 H),
7.54–7.65 (m, 3 H), 7.90–7.95 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 25.30 (2 C), 49.24, 64.40, 73.99, 127.96 (2 C), 128.97
(2 C), 133.36, 141.43 ppm.
ppm. IR: ν = 1740 (C=O) cm–1. MS (IC, isobutane): m/z (%) = 147
˜
(50) [M + 1]+, 115 (82), 85 (82), 71 (100). C7H14O3 (146.19): calcd.
C 57.51, H 9.65; found C 57.39, H 9.62.
Methyl (4-tert-Butyl-1-morpholinocyclohexyl)acetate (9a): 1H NMR
(300 MHz, CDCl3): δ = 0.84 (s, 9 H), 0.95–1.05 (m, 1 H), 1.05–
1.20 (m, 2 H), 1.30–1.45 (m, 2 H), 1.65–1.80 (m, 2 H), 1.85–2.00
(m, 2 H), 2.51 (s, 2 H), 2.57–2.70 (m, 4 H), 3.57–3.70 (m, 4 H),
3.64 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.74 (C-3,5),
27.69 [(CH3)3C], 32.44 (CMe3), 32.55 (C-2,6), 36.98 (CH2O), 45.96
(NCH2), 47.80 (C-4), 51.39 (OCH3), 58.81 (C-1), 62.28 (OCH2),
Dimethyl 3,3Ј-(Piperazine-1,4-diyl)bis(3-methylbutanoate) (16): 1H
NMR (300 MHz, CDCl3): δ = 1.08 (s, 12 H), 2.32 (s, 4 H), 2.45–
2.55 (m, 8 H), 3.56 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 24.33 (CH3), 42.80 (CH2), 46.17 (NCH2), 51.25 (OCH3), 55.88
[C(CH ) ], 172.59 (C=O) ppm. IR: ν = 1731 (C=O) cm–1. MS (EI):
˜
3 2
m/z (%) = 314 (12) [M]+, 241 (100). C16H30N2O4·H2O: calcd. C
57.81, H 9.70, N 8.43; found C 58.12, H 9.76, N 8.83.
172.89 (C=O) ppm. IR: ν = 1731 (C=O) cm–1. MS (EI): m/z (%) =
˜
1,4,7,7-Tetramethyl-1,4-diazepan-5-one (17): 1H NMR (300 MHz,
CDCl3): δ = 0.86 (s, 6 H), 2.05 (s, 3 H), 2.40 (s, 2 H), 2.50–2.55
(m, 2 H), 2.72 (s, 3 H), 3.15–3.25 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 35.21 [C(CH3)2], 38.54 (NCH3), 50.26
(CH2CO), 50.55, 52.45 (NCH2), 53.21 [C(CH3)2], 172.77 (C=O)
297 (3) [M]+, 265 (2), 240 (4), 224 (100), 198 (33), 87 (9).
C17H31NO3 (297.44): calcd. C 68.65, H 10.51, N 4.71; found C
68.58, H 10.45, N 4.74.
Methyl (4-tert-Butyl-1-piperidinocyclohexyl)acetate (9b): 1H NMR
(300 MHz, CDCl3): δ = 0.84 (s, 9 H), 0.95–1.20 (m, 3 H), 1.35–
1.75 (m, 10 H), 1.97–2.10 (m, 2 H), 2.51 (s, 2 H), 2.55–2.70 (m, 4
H), 3.65 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.90 (C-
3,5), 25.11, 27.07 (CH2 piperidine), 27.66 [(CH3)3C], 32.39 (CMe3),
33.35 (C-2,6), 36.35 (CH2O), 46.59 (NCH2), 47.48 (C-4), 51.44
ppm. IR: ν = 1635 (C=O) cm–1. MS (EI): m/z = 171 [M + H]+.
˜
C9H18N2O (170.25): calcd. C 63.49, H 10.66, N 16.45; found C
63.53, H 10.76, N 16.39.
Bis-1,4-Dimethyl-1,4-diazepan-5-one (19): 1H NMR (300 MHz,
CDCl3): δ = 1.40–1.80 (m, 8 H), 2.30 (s, 6 H), 2.33 (s, 4 H), 2.50–
2.70 (br. m, 2 H), 2.90 (s, 6 H), 2.90–3.05 (br. m., 4 H), 3.15–3.45
(br. m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 30.18 (CH2
cyclohex.), 35.09, 36.02 (NCH3), 42.35 (CH2CO), 46.14, 50.38,
(OCH ), 59.02 (C-1), 173.18 (C=O) ppm. IR: ν = 1738 (C=O) cm–1.
˜
3
MS (EI): m/z (%) = 295 (4) [M]+, 222 (100), 196 (27), 84 (22).
C18H33NO2 (295.46): calcd. C 73.17, H 11.26, N 4.74; found C
73.19, H 11.26, N 4.76.
53.82 (NCH ), 50.63 (C-1), 172.91, 173.31 (C=O) ppm. IR: ν =
˜
2
Ethyl (1-Pyrrolidin-1-ylcyclopentyl)acetate (10a): 1H NMR
(300 MHz, CDCl3): δ = 1.25 (t, J = 7.2 Hz, 3 H), 1.55–1.90 (m, 12
H), 2.51 (s, 2 H), 2.65–2.75 (m, 4 H), 4.11 (q, J = 7.2 Hz, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 14.24 (CH3), 24.12, 24.46
(C-2–5), 32.28 (CH2 pyrrolidine), 39.71 (CH2CO), 46.76 (NCH2),
1628 (C=O) cm–1. MS (EI): m/z (%) = 366 (68) [M]+, 169 (100).
C18H32N4O2 (336.48): calcd. C 64.25, H 9.59, N 16.46; found C
64.42, H 9.45, N 16.46.
Dimethyl 2,2Ј-(1,4-Dimorpholinocyclohexane-1,4-diyl)diacetate (20):
1H NMR (300 MHz, CDCl3, minor diastereomer): δ = 1.55–1.85
60.18 (OCH ), 67.29 (C-1), 172.64 (C=O) ppm. IR: ν = 1731 (C=O)
˜
2
cm–1. MS (EI): m/z (%) = 225 (2) [M]+, 196 (23), 138 (100). (m, 8 H), 2.28 (s, 4 H), 2.40–2.50 (m, 8 H), 3.60–3.70 (m, 8 H), 3.67
1
C13H23NO2 (225.33): calcd. C 69.29, H 10.29, N 6.22; found C
69.44, H 10.32, N 6.27.
(s, 6 H) ppm. H NMR (300 MHz, CDCl3, major diastereomer): δ
= 1.45–1.90 (m, 8 H), 2.41 (s, 4 H), 2.50–2.60 (m, 8 H), 3.63 (s, 6
H), 3.60–3.70 (m, 8 H) ppm. 13C NMR (75 MHz, CDCl3, minor
diastereomer): δ = 27.00 (CH2 cyclohex), 38.89 (CH2O), 44.81
(NCH2), 51.73 (COOCH3), 57.29 (C-1), 68.12 (OCH2), 173.13
(C=O) ppm. 13C NMR (75 MHz, CDCl3, major diastereomer): δ
= 26.96 (C-3,5), 37.90 (CH2O), 45.27 (NCH2), 51.53 (COOCH3),
1-(Cyclopent-1-en-1-ylacetyl)pyrrolidine (10c): 1H NMR (300 MHz,
CDCl3): δ = 1.75–1.95 (m, 6 H), 2.25–2.40 (m, 4 H), 3.05 (s, 2 H),
3.35–3.50 (m, 4 H), 5.41 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 23.39, 24.49, 26.24 (C-3,4,5), 32.53, 35.38 (CH2 pyrrolidine),
38.39 (CH2CO), 45.74, 46.89 (NCH2), 126.98 (C-2), 137.61 (C-1),
57.75 (C-1), 68.05 (OCH ), 172.75 (C=O) ppm. IR: ν = 1731 (C=O)
˜
169.56 (C=O) ppm. IR: ν = 1636, (br. s, C=C, C=O) cm–1. MS
2
˜
cm–1. MS (EI): m/z (%) = 398 (1) [M]+, 240 (100). C20H34N2O6
(398.50): calcd. C 60.28, H 8.60, N 7.03; found C 60.02, H 8.62, N
6.79.
(EI): m/z (%) = 179 (33) [M]+, 98 (100). C11H17NO·H2O: calcd. C
66.97, H 9.71; found C 66.81, H 9.85.
1
4-[1,1-Dimethyl-2-(phenylsulfonyl)ethyl]morpholine (14a): H NMR
Supporting Information (see footnote on the first page of this arti-
(400 MHz, CDCl3): δ = 1.35 (s, 6 H), 2.48 (t, J = 4.5 Hz, 4 H),
3.21 (s, 2 H), 3.50 (t, J = 4.5 Hz, 4 H), 7.53–7.67 (m, 3 H), 7.89–
7.98 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.49 (2 C),
45.88 (2 C), 56.92, 62.03, 67.12 (2 C), 127.81 (2 C), 129.10 (2 C),
133.35, 141.74 ppm. C14H21NO3S (283.38): calcd. C 59.34, H 7.47,
N 4.94; found C 59.40, H 7.66, N 5.08.
1
cle): H and 13C spectra for all β-aminoesters.
Acknowledgments
A. R. thanks the Centre National de la Recherche Scientifique
(CNRS) for two research associate grants (2008 and 2009). The
4-[1,1-Dimethyl-2-(phenylsulfonyl)ethyl]piperidine (14b): 1H NMR
(400 MHz, CDCl3): δ = 1.22–1.46 (m, 12 H), 2.42–2.44 (m, 4 H), collaboration between the Rouen and Kochi laboratories was made
3.22 (s, 2 H), 7.53–7.67 (m, 3 H), 7.92–7.97 (m, 2 H) ppm. 13C
possible thanks to the Japan Society for the Promotion of Science
NMR (100 MHz, CDCl3): δ = 24.52, 25.37 (2 C), 26.42 (2 C), 46.44 (JSPS)-CNRS Sakura program (2008-2009). We are grateful to
6428
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6423–6429

Access to Aminated Quaternary Centers by Hyperbaric Aza-Michael Additions
M. I. Uddin, K. Nakano, Y. Ichikawa, H. Kotsuki, Synlett
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Prof. Hassan Oulyadi (Rouen) for his help with the NMR spectra.
The Région Haute-Normandie is acknowledged for its support of
our HP activities through the Centre de Recherche Universitaire
Normand de Chimie (CRUNCh) inter-regional cooperation pro-
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Received: July 12, 2010
Published Online: October 12, 2010
Eur. J. Org. Chem. 2010, 6423–6429
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6429