Tandem metal and organocatalysis in sequential hydroformylation and enantioselective mannich reactions

Article abstract of DOI:10.1002/adsc.200800720

Metal-catalysed hydroformylation is successfully combined with an organocatalysed stereoselective Mannich reaction in a tandem reaction sequence. This novel type of "tandem catalysis" allows access to complex molecular systems with high levels of enantioselectivity, using simple starting materials and an amino acid as the chiral catalyst.

Full text of DOI:10.1002/adsc.200800720

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DOI: 10.1002/adsc.200800720
Tandem Metal and Organocatalysis in Sequential
Hydroformylation and Enantioselective Mannich Reactions
Serghei Chercheja,a Thomas Rothenbꢀcher,a and Peter Eilbrachta,*
a
Fachbereich Chemie, Organische Chemie I, Technische Universitꢁt Dortmund, Otto-Hahn-Str. 6, 44227 Dortmund,
Germany
Fax : (+49)-231-755-5363; e-mail: peter.eilbracht@udo.edu
Received: November 19, 2008; Published online: February 6, 2009
Abstract: Metal-catalysed hydroformylation is suc-
cessfully combined with an organocatalysed stereo-
selective Mannich reaction in a tandem reaction se-
quence. This novel type of “tandem catalysis”
allows access to complex molecular systems with
high levels of enantioselectivity, using simple start-
ing materials and an amino acid as the chiral cata-
lyst.
use of this methodology in sequential hydroformyla-
tion and asymmetric Mannich reactions.
The proposed sequential transformation involves
hydroformylation of an alkene mediated by a triphen-
yl phosphite-modified Rh catalyst and l-proline-cata-
lysed enantioselective Mannich reaction of the alde-
hyde formed in situ, an aromatic amine and a ketone
(Scheme 1). Like the related tandem hydroformyla-
tion/enantioselective aldol reactions,[4d,e] this process
leads to the generation of up to four new adjacent ste-
reogenic centres in the product, and clearly, when
high levels of control are observed, these approaches
are of considerable importance.
Keywords: hydroformylation; Mannich reaction; or-
ganocatalysis; tandem reactions
The synthetic plan relied on finding optimal condi-
tions for both hydroformylation and enantioselective
Recent syntheses of natural and drug-like compounds Mannich reactions and then combining these reac-
have clearly revealed the advantages of combining tions into a tandem sequence.
several reactions into a tandem reaction sequence to
provide complex molecules in a clean and efficient using the previously reported protocol.[4d] The catalyst
manner.[1] We and others have demonstrated that was readily prepared in situ from [Rh
(acac)(CO)2]
The hydroformylation reactions were performed
AHCTUNGTRENNUNG
tandem reactions under hydroformylation conditions and an excess of triphenyl phosphite. Cyclic olefins
are a useful strategy for the synthesis of complex mo- were used as substrates in order to avoid the regiose-
lecular systems.[2] More recent attention has been fo- lectivity problems of hydroformylation reactions. The
cused on “tandem catalysis”[3] where a metal catalyst hydroformylation experiments were performed in ace-
works together with a chiral organocatalyst affording tone, since in subsequent Mannich reactions acetone
highly functionalised molecules with excellent levels will serve both as the enamine component and as sol-
of enantioselectivity.[4] Here we now report the first vent (Table 1). As shown in Table 1, excellent conver-
Scheme 1. Hydroformylation/enantioselective Mannich reactions.
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339

Serghei Chercheja et al.
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Table 1. Rh-catalysed hydroformylation of cyclic olefins.
Chlorinated co-solvents and acetone gave moderate
yields (50–55%) of the desired product 3 (Table 2, en-
tries 1, 5 and 6). However, good enantioselectivity
(65–72% ee) was obtained only in dichloromethane
(DCM) and acetone. Changing the solvent to dime-
thylformamide (DMF) or dimethyl sulfoxide
(DMSO) led to decreases in both enantioselectivity
and yield of the Mannich product. The stereochemical
outcome of the reaction was assigned by analogy with
the known b-amino ketone obtained from the l-pro-
line-catalysed reaction of cyclohexanecarbaldehyde,
4-methoxyaniline and acetone.[6] In order to enforce
the equilibrium favouring the Mannich product a 30-
fold excess of acetone is normally required, therefore
the aldehyde concentration was kept at 0.1M
(Table 2).[5g,7]
Entry Substrate
T
t
Conversion Aldehyde
[8C] [h] [%][b]
yield [%][b]
1
2
3
4
cyclopentene 25
cyclopentene 40
cycloheptene 25
cycloheptene 40
72 94
94
72 >99
120 >99
72 >99
>99
>99
>99
[a]
Conditions: 20/20 bar CO/H2, 0.5 mol% [Rh
ACHTUNGTRNE(NUNG acac)-
A
ACHTUNGTRENNUNG
[b]
Determined by GC using dodecane as an internal stan-
dard.
We next investigated sequential hydroformylation
and Mannich reactions under optimised conditions
sions were obtained. As was expected, at 258C the hy- (Table 3). In contrast to the hydroformylation experi-
droformylation rate was lower than at 408C. In order ments from Table 1, in the sequential reaction we had
to have full cycloheptene conversion at room temper- to use a more dilute solution in order to keep a 30-
ature, the reaction time was increased to 120 h fold excess of acetone. According to the GC analysis,
(Table 1, entry 3). According to GC and 1H NMR at this low Rh catalyst concentration the hydroformy-
analyses of the crude mixtures, only aldehydes are lation did not proceed at room temperature (Table 3,
formed during the hydroformylation reaction.
entry 1). At 408C, however, cyclopentene was fully
After conditions for the hydroformylation of cyclic converted within 72 h (entries 2, 3 and 4). Using ace-
olefins in acetone were optimised, we focused our at- tone as the reaction solvent, the product was generat-
tention on the enantioselective organocatalysed Man- ed in moderate yield; however, the stereoselectivity
nich reaction. l-Proline was selected as the first candi- was very low. Chloroform/acetone led to an almost
date as it is usually a highly stereoselective organoca- complete loss of the enantioselectivity (Table 3,
talyst in the direct catalytic Mannich reaction.[5] The entry 3). Efforts to improve the enantioselectivity by
l-proline-catalysed reaction of cyclopentanecarbalde- using DCM as co-solvent with acetone led to a con-
hyde, p-chloroaniline and acetone was chosen as a siderable improvement, affording the Mannich prod-
representative example (Table 2).
uct in 52% yield and 71% ee (Table 3, entry 4). Based
on these results, we judged DCM/acetone to be the
most promising solvent system for further investiga-
tions.
Hayashiꢃs group has previously reported that high
pressure (2000 bar) accelerates the l-proline-catalysed
Mannich reaction of various aldehydes, p-anisidine
and acetone, giving both better yields and better
enantioselectivities.[6]
Table 2. l-Proline-catalysed enantioselective Mannich reac-
tion.
We wondered if the pressure used for the hydrofor-
mylation (20–80 bar) would have some effect on the
reaction yields and stereoselectivities. Various CO
and H2 partial pressures were studied to ascertain the
effects of pressure on tandem hydroformylation and
enantioselective Mannich reactions.
Entry
Solvent
Isolated yield
3 [%]
ee 3
[%][b]
The reaction between cyclopentene, p-chloroaniline
and acetone was performed at 10/10, 20/20, 30/30 and
40/40 bar pressures of CO/H2 (Table 4).
The total pressure was found to have an impact not
only on the product yield, but also on the enantiose-
lectivity. Reaction at 10/10 bar pressure generated the
desired product in reasonable yield and reasonable ee
(Table 4, entry 1). Increasing the pressure to 20/20 or
30/30 bar provided the product in similar yields, but
1
2
3
4
5
6
CHCl3/acetone 4:1
toluene/acetone 4:1
DMSO/acetone 4:1
DMF/acetone 4:1
CH2Cl2/acetone 4:1
acetone
50
25
8
9
52
55
16
45
13
17
72
65
[a]
Conditions: 30 mol% l-proline, room temperature, 72 h,
solvent (0.1M aldehyde).
Determined by chiral HPLC.
[b]
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Sequential Hydroformylation and Enantioselective Mannich Reactions
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Table 3. Sequential hydroformylation/enantioselective Mannich reactions.
Entry
Solvent
T [8C]
Alkene conversion [%][b]
Isolated yield 3 [%]
ee 3 [%][c]
1
2
3
4
CH2Cl2/acetone 4:1
acetone
CHCl3/acetone 4:1
CH2Cl2/acetone 4:1
25
40
40
40
<5
–
–
19
1
>99
>99
>99
53
49
52
71
[a]
Conditions: 20/20 bar CO/H2, 0.5 mol% [RhACHTNUGRTENNUG(acac)(CO)2], 2 mol% PACHTUGNTREN(NUGN OPh)3, 30 mol% l-proline, 408C, 72 h, solvent
(0.1M alkene).
Determined by GC using dodecane as an internal standard.
Determined by chiral HPLC.
[b]
[c]
Table 4. Influence of CO and H2 partial pressures on se-
quential hydroformylation/Mannich reaction.
Cl) on the phenyl ring gave better enantioselectivities
although in some cases yields were lower (Table 5, en-
tries 3–6).
In conclusion, for the first time, we could success-
fully combine metal-catalysed hydroformylation with
the organocatalysed, stereoselective Mannich reaction
in a tandem reaction sequence. This is a powerful ap-
proach for the generation of optically active nitrogen-
containing molecules. The yields and enantioselectivi-
ties of the process were found to be highly dependent
on the substrates and conditions used. We are cur-
rently investigating the tandem reaction of more com-
plex starting materials, including prochiral olefins and
prochiral ketones using proline and other organocata-
lysts.
Entry PCO
PH
Cyclopentene con- Isolated
ee 3
2
[bar] [bar] version [%][b]
yield 3 [%] [%][c]
1
2
3
4
10
20
30
40
10
20
30
40
>99
>99
>99
>99
51
52
48
23
54
71
74
77
[a]
Conditions: 0.5 mol% [Rh(acac)(CO)2],
2
mol%
PACHTUNGTRENNUNG(OPh)3, 30 mol% l-proline, 408C, 72 h, CH2Cl2/acetone
4:1 (0.1M alkene).
Determined by GC using dodecane as an internal stan-
Experimental Section
[b]
[c]
dard.
General Remarks
Determined by chiral HPLC.
Hydroformylation experiments were carried out in a Ber-
ghof HR-200 high pressure reactor with magnetic stirring
and electrical heating. The inside part of the cover was
made from Teflonꢄ to protect the solution from direct con-
tact with the stainless steel. All reactions were carried out in
freshly distilled solvents. Dichloromethane was distilled
higher enantioselectivities (entries 2 and 3). Further
increasing the pressure to 40/40 bar resulted in im-
proved enantioselectivity, but diminished yield
(entry 4). Thus, the original pressure choice (20/20 bar from calcium hydride. Acetone was stirred over boric anhy-
dride for 24 h and then distilled. Commercial reagents were
used as received. Column chromatography was carried out
using MN Kieselgel 60 (0.063–0.2 mm/70–230 mesh). TLC
was performed on Merck Silica gel 60 F254 plates. Visualisa-
tion of the developed chromatograms was performed by ul-
traviolet irradiation (254 nm) or by anisaldehyde stain. For
gas chromatographic analyses, a Carlo Erba HRGC Mega2
Series MFC 800 chromatograph with a Carlo Erba EL 580
flame ionisation detector (FID) was used. Separations were
performed on the column CHROMPACK DB-1701 (25 mꢅ
CO/H2) was found to be optimal.
Next, tandem reactions of cyclic olefins with aro-
matic amines and acetone were examined (Table 5).
Again, excellent alkene conversions were obtained
using the triphenyl phosphite-modified Rh catalyst.
The tandem reaction with an amine bearing an elec-
tron-donating substituent (OMe) on the phenyl ring
provided products in modest yields and poor enantio-
selectivities (Table 5, entries 1 and 2). In contrast, an
amine bearing an electron-withdrawing substituent (F, 0.32 mmꢅ1.0 mm). 1H NMR spectra were recorded on a
Adv. Synth. Catal. 2009, 351, 339 – 344
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341

Serghei Chercheja et al.
COMMUNICATIONS
Table 5. Investigation of different alkenes and aromatic amines.
Entry
1
Alkene
R
Alkene conversion [%][b]
Product
Isolated yield [%]
ee [%][c]
OCH3
>99
53
50
32
2
3
OCH3
>99
>99
42
71
Cl
52
4
5
Cl
F
>99
>99
>99
25
44
21
74
72
51
6
F
[a]
Conditions: 20/20 bar CO/H2, 0.5 mol% [RhACTHNUGTRENN(UG acac)(CO)2], 2 mol% PAHCUTNGTREN(NGUN OPh)3, 30 mol% l-proline, 408C, 72 h, CH2Cl2/ace-
tone 4:1 (0.1M alkene).
Determined by GC using dodecane as an internal standard.
Determined by chiral HPLC.
[b]
[c]
Bruker 400 spectrometer, with residual proton signal of the
deuterated solvent as the internal reference (dH =7.26 ppm
for CDCl3). 13C NMR spectra were recorded on the same
spectrometer and referenced to solvent signals (dc =77 ppm
for CDCl3). Chemical shifts (d) are given in parts per mil-
lion (ppm) and coupling constants (J) are given in Hertz
(Hz). The proton spectra are reported as follows d/ppm
(multiplicity, number of protons, coupling constant J in Hz).
Semipreparative HPLC was performed using a SUPELCO-
SILTM LC-SI 5 mm (25 cmꢅ21.2 mm) column. Analytical
HPLC was performed on a Hewlett–Packard 1050 Series
chromatographs using
a
CHIRALCEL OJ-H (250ꢅ
4.6 mm), CHIRALPAK AD (250ꢅ4.6 mm) and CHIRAL-
CEL OD-H (250ꢅ4.6 mm) columns as noted.
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Sequential Hydroformylation and Enantioselective Mannich Reactions
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1.1 equiv.) and l-proline (35 mg, 0.3 mmol, 0.3 equiv.). The
vial was transferred to the autoclave, pressurised with CO
and H2 and heated. After the reaction was completed, the
autoclave was cooled down to room temperature, depressur-
ised, flushed with argon and opened to obtain a sample for
GC analysis. Then the reaction mixture was filtered through
a column filled with silica gel. Additionally the column was
washed with 50 mL of diethyl ether. The filtrate was concen-
trated under vacuum and the crude product was purified by
column chromatography.
(S)-4-Cyclopentyl-4-(4-methoxyphenylamino)butan-2-one
(4): Purified using column chromatography (EtOAc/cyclo-
hexane 1:5, Rf =0.50) to afford the title compound as a
brown oil; yield: 138 mg (53%). 1H NMR (400 MHz,
CDCl3): d=6.75–6.72 (m, 2H, J=8.7 Hz), 6.58–6.55 (m, 2H,
J=8.7 Hz), 3.72 (s, 3H), 3.65–3.60 (m, 1H), 3.44 (br. s, 1H),
2.66–2.56 (m, 2H), 2.10 (s, 3H), 2.07–2.03 (m, 1H), 1.80–
1.53 (m, 6H), 1.26–1.23 (m, 2H); 13C NMR (100 MHz,
CDCl3): d=25.2, 29.6, 30.9, 35.4, 45.1, 46.9, 55.3, 55.6, 114.8,
141.7, 151.9, 208.5; ESI-MS: m/z=262.18002, calcd. for
[M+H]+ (C16H24NO2: 262.18070; elemental analysis (%),
calcd. for C16H23NO2: C 73.53, H 8.87; found: C 73.14, H
8.98; IR (film/NaCl): nmax =3381, 2949, 2831, 2359, 1715,
1618, 1512 cmÀ1; [a]D20: +6.2 (c 0.50, n-heptane); HPLC:
CHIRALCEL OJ-H, n-heptane/i-PrOH, 90:10, 1.0 mLꢅ
minÀ1, 254 nm, ee=32%: tR (major)=16.4 min; tR (minor)=
14.6 min.
General Procedure for Rh-Catalysed
Hydroformylation of Cyclic Olefins (Table 1)
To a solution of [Rh
ACHTUNGTRENNUNG
equiv.) in 5 mL of acetone in a vial, was added PACHTUNGTRENNUNG
(24 mg, 0.078 mmol, 0.02 equiv.). The solution was stirred
with a magnetic stirrer for 5 min and then charged with
olefin (3.9 mmol, 1 equiv.) and dodecane (199 mg,
1.17 mmol, 0.3 equiv.). The vial was transferred to the auto-
clave, pressurised to 20/20 bar CO/H2 and heated to given
temperature. After the reaction was completed, the auto-
clave was cooled down to room temperature, depressurised,
flushed with argon and opened to obtain a sample for GC
analysis. The carrier gas was 40 kPa He, temperature pro-
gramme of 308C for 10 min, then 158C/min to 2608C; reten-
tion times: 4.57 min for cyclopentene, 14.20 min for cyclo-
heptene, 17.60 min for cyclopentanecarbaldehyde, 21.23 min
for dodecane, 22.39 min for cycloheptanecarbaldehyde.
l-Proline-Catalysed Mannich Reaction under
Atmospheric Pressure (Table 2)
To a stirred suspension of l-proline (35 mg, 0.3 mmol,
0.3 equiv.) in 10 mL of solvent were added 4-chloroaniline
(140 mg, 1.1 mmol, 1.1 equiv.) and cyclopentanecarbalde-
hyde (98 mg, 1 mmol, 1 equiv.). The resulting mixture was
stirred at room temperature for 72 h. Two different work-up
procedures were used: a) when DMSO and DMF were used
as solvents (Table 2, entries 3 and 4) the reaction mixture
was quenched with 5 mL 0.5M phosphate buffer (pH 7) and
extracted with diethyl ether. The combined organic layers
were dried over MgSO4 and concentrated under vacuum to
give the crude product; b) when chloroform, toluene, DCM
or acetone (Table 2, entries 1, 2, 5 and 6) were used, the re-
action mixture was filtered through a column filled with
silica gel. Additionally the column was washed with 50 mL
of diethyl ether. The filtrate was concentrated under
vacuum to give the crude product. In both cases the crude
product was purified by column chromatography (EtOAc/
(S)-4-Cycloheptyl-4-(4-methoxyphenylamino)butan-2-one
(5): Purified using column chromatography (EtOAc/cyclo-
hexane 1:5, Rf =0.30) to afford the title compound as a
brown oil; yield: 145 mg (50%). 1H NMR (400 MHz,
CDCl3): d=6.75–6.73 (m, 2H, J=8.7 Hz), 6.56–6.54 (m, 2H,
J=8.7 Hz), 3.72 (s, 3H), 3.70–3.67 (m, 1H), 3.41 (br. s, 1H),
2.60–2.46 (m, 2H), 2.13 (s, 3H), 1.71–1.20 (m, 13H);
13C NMR (100 MHz, CDCl3): d=26.9, 27.0, 28.2, 30.1, 30.5,
42.1, 45.3, 55.7, 56.3, 114.9, 141.4, 152.0, 208.5; ESI-MS:
m/z=290.21151,
calcd.
for
[M+H]+ (C18H28NO2):
290.21200; elemental analysis (%), calcd. for C18H27NO2: C
74.70, H 9.40; found: C 74.29, H 10.03; IR (film/NaCl):
nmax =3369, 2919, 2853, 2359, 1704, 1590, 1505 cmÀ1; [a]D20:
+5.9 (c 0.50, n-heptane); HPLC: CHIRALCEL OJ-H, n-
heptane/i-PrOH, 90:10, 1.0 mLꢅminÀ1, 254 nm, ee=42%: tR
(major)=19.9 min; tR (minor)=17.6 min.
cyclohexane 1:4, Rf =0.40) to afford (S)-4-(4-chlorophenyl-
1
A
(400 MHz, CDCl3): d=7.08–7.06 (m, 2H), 6.53–6.51 (m,
2H), 3.76 (br. s., 1H), 3.70–3.64 (m, 1H), 2.67 (dd, 1H, J=
16.7, 5.1 Hz), 2.61 (dd, 1H, J=16.7, 5.4 Hz), 2.12 (s, 3H),
2.11–2.02 (m, 1H), 1.82–1.48 (m, 6H), 1.28–1.16 (m, 2H);
13C NMR (100 MHz, CDCl3): d=25.2, 29.6, 31.0, 35.7, 45.2,
46.8, 54.3, 114.2, 121.6, 129.1, 146.2, 208.1; ESI-MS: m/z
266.13064, calcd. for [M+H]+ (C15H21ClNO): 266.13117, ele-
mental analysis (%), calcd. for C15H20ClNO: C 67.79, H
7.58; found: C 67.48, H 7.86; IR (film): nmax =3386, 2952,
2866, 1708, 1598, 1500 cmÀ1; [a]2D0: +25.8 (c 0.51, n-heptane).
HPLC: CHIRALCEL OD-H, n-heptane/i-PrOH, 90:10,
1.0 mLꢅ minÀ1, 254 nm, ee=72%: tR (major)=6.6 min; tR
(minor)=5.4 min.
(S)-4-(4-Chlorophenylamino)-4-cycloheptylbutan-2-one
(6): Purified using column chromatography (EtOAc/cyclo-
hexane 1:5, Rf =0.29) to afford the title compound as a light
1
yellow oil; yield: 76 mg (26%). H NMR (400 MHz, CDCl3):
d=7.09–7.06 (m, 2H, J=8.7 Hz), 6.51–6.49 (m, 2H, J=
8.7 Hz), 3.71 (br. s., 2H), 2.63–2.48 (m, 2H), 2.13 (s, 3H),
1.74–1.24 (m, 13H); 13C NMR (100 MHz, CDCl3): d=26.9,
27.8, 28.2, 30.3, 36.3, 42.3, 45.2, 55.2, 114.3, 129.1, 145.9,
208.1; ESI-MS: m/z 294.16205, calcd. for [M+H]+
(C17H25ClNO): 294.16247; elemental analysis (%), calcd. for
C17H24ClNO: C 69.49, H 8.23; found: C 69.09, H 8.50; IR
(film/NaCl): nmax =3367, 2923, 2852, 1712, 1598, 1489 cmÀ1
;
Sequential Hydroformylation and Enantioselective
Mannich Reactions (Table 3, entry 4)
[a]2D0: +26.2 (c 0.50, n-heptane); HPLC: CHIRALCEL OD-
H, n-heptane/i-PrOH, 90:10, 1.0 mLꢅminÀ1, 254 nm, ee=
74%: tR (major)=6.4 min; tR (minor)=8.0 min.
To a solution of [RhACHTNUTRGNE(NUG acac)(CO)2] (1.3 mg, 0.005 mmol, 0.005
(S)-4-Cyclopentyl-4-(4-fluorophenylamino)butan-2-one
(7): Purified using column chromatography (EtOAc/cyclo-
hexane 1:5) to afford the title compound as a yellow oil;
equiv.) in 10 mL of solvent in a vial, was added triphenyl
phosphite (6.2 mg, 0.02 mmol, 0.02 equiv.). The solution was
stirred with a magnetic stirrer for 5 min and then charged
with alkene (1.0 mmol, 1 equiv.), aromatic amine (1.1 mmol,
1
yield: 111 mg (44%). H NMR (400 MHz, CDCl3): d=6.85–
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Serghei Chercheja et al.
COMMUNICATIONS
6.80 (m, 2H), 6.52–6.50 (m, 2H), 3.63–3.60 (m, 2H), 2.62-
2.60 (m, 2H), 2.10 (s, 3H), 2.06–2.02 (m, 1H), 1.62–1.59 (m,
7H), 1.25–1.21 (m, 2H); 13C NMR (100 MHz, CDCl3): d=
25.3, 29.7, 31.0, 36.3, 45.2, 46.8, 55.0, 114.3, 115.5, 115.7,
120.1, 125.5, 129.8, 143.9, 156.8, 208.3; ESI-MS: m/z=
250.16017, calcd. for [M+H]+ (C15H21FNO): 250.16072; ele-
mental analysis (%), calcd. for C15H21FNO: C 71.97, H 8.46;
found: C 71.83, H 8.59; IR (film/NaCl): nmax =3389, 2952,
2867, 2365, 1712, 1612, 1514 cmÀ1; [a]D20: +26.8 (c 0.48, n-
heptane); HPLC: CHIRALCEL OD-H, n-heptane/i-PrOH,
90:10, 1.0 mLꢅminÀ1, 254 nm, ee=72%: tR (major)=
10.8 min; tR (minor)=10.0 min.
Schmidt, Chem. Rev. 1999, 99, 3329; for selected exam-
ples, see: c) B. Breit, W. Seiche, Synthesis 2001, 1–36;
d) B. Breit, S. K. Zahn, Tetrahedron 2005, 61, 6171–
6179; e) B. Breit, S. K. Zahn, Angew. Chem. 2001, 113,
1964–1967; Angew. Chem. Int. Ed. 2001, 40, 1910–1913;
f) G. Guazzelli, R. Lazzaroni, R. Settambolo, Beilstein J.
Org. Chem. 2008, 4, 2; g) B. P. Bondzic, P. Eilbracht,
Org. Biomol. Chem. 2008, 6, 4059; h) B. P. Bondzic, A.
Farwick, J. Liebich, P. Eilbracht, Org. Biomol. Chem.
2008, 6, 3723; i) B. P. Bondzic, P. Eilbracht, Org. Lett.
2008, 10, 3433; j) P. Linnepe (nꢆe Kohling), A. M.
Schmidt, P. Eilbracht, Org. Biomol. Chem. 2006, 4, 302.
[3] a) J. C. Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan,
Chem. Rev. 2005, 105, 1001; b) J. M. Lee, Y. Na, H. Han,
Chem. Soc. Rev. 2004, 33, 302; c) D. E. Fogg, E. N.
Santos, Coord. Chem. Rev. 2004, 248, 2365.
[4] a) K. Sorimachi, M. Terada, J. Am. Chem. Soc. 2008,
130, 14452; b) W. Hu, X. Xu, J. Zhou, W.-J Liu, H.
Huang, J. Hu, L. Yang, L.-Z. Gong, J. Am. Chem. Soc.
2008, 130, 7782; c) T. Yang, A. Ferrali, L. Campbell,
D. J. Dixon, Chem. Commun. 2008, 2923; d) S. Cherche-
ja, P. Eilbracht, Adv. Synth. Catal. 2007, 349, 1897; e) O.
Abillard, B. Breit, Adv. Synth. Catal. 2007, 349, 1891;
f) S. Mukherjee, B. List, J. Am. Chem. Soc. 2007, 129,
11336; g) I. Ibrahem, A. Cꢇrdova, Angew. Chem. 2006,
118, 1986; Angew. Chem. Int. Ed. 2006, 45, 1952; h) V.
Komanduri, M. J. Krische, J. Am. Chem. Soc. 2006, 128,
16448.
(S)-4-Cycloheptyl-4-(4-fluorophenylamino)butan-2-one
(8): Purified using column chromatography (EtOAc/cyclo-
hexane 1:5, Rf =0.29) to afford the title compound as a
1
yellow oil; yield: 60 mg (21%). H NMR (400 MHz, CDCl3):
d=6.87–6.82 (m, 2H), 6.53–6.50 (m, 2H), 3.72–3.68 (m,
1H), 2.61–2.47 (m, 2H), 2.13 (s, 3H), 1.74–1.36 (m, 13H);
13C NMR (100 MHz, CDCl3): d=27.1, 27.9, 28.3, 30.3, 30.5,
30.6, 42.3, 45.3, 56.0, 114.4, 115.7, 143.8, 154.6, 154.9, 208.4;
ESI-MS: m/z=278.19147, calcd. for [M+H]+ (C17H25FNO):
278.19202; elemental analysis (%), calcd. for C15H24FNO: C
73.61, H 8.72; found: C 73.28, H 8.90; IR (film/NaCl): nmax
=
3389, 2928, 2854, 2365, 1711, 1612, 1513 cmÀ1; [a]D20: +21.9 (c
0.50, n-heptane); HPLC: CHIRALCEL OD-H, n-heptane/i-
PrOH, 90:10, 1.0 mLꢅminÀ1, 254 nm, ee=72%: tR (major)=
6.4 min; tR (minor)=5.1 min.
[5] For reviews on organocatalysed Mannich reaction, see:
a) J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M.
Quaedflieg, F. P. J. T. Rutjes, Chem. Soc. Rev. 2008, 37,
29; b) S. Mukherjee, J. W. Yang, S. Hoffman, B. List,
Chem. Rev. 2007, 107, 5471; c) A. Cꢇrdova, Acc. Chem.
Res. 2004, 37, 102; for selected examples, see: d) D.
Enders, M. Vrettou, Synthesis 2006, 2155; e) A. Cordo-
va, Chem. Eur. J. 2004, 10, 1987; f) Y. Hayashi, W.
Tsuboi, I. Ashimine, T. Urushima, M. Shoji, K. Sakai,
Angew. Chem. 2003, 115, 3805; Angew. Chem. Int. Ed.
2003, 42, 3677; g) W. Notz, K. Sakthivel, T. Bui, G.
Zhong, C. F. Barbas III, Tetrahedron Lett. 2001, 42, 199;
h) B. List, J. Am. Chem. Soc. 2000, 122, 9336.
References
[1] For recent reviews, see: a) M. M. Hussain, P. J. Walsh,
Acc. Chem. Res. 2008, 41, 883–893; b) C. J. Chapman,
C. G. Frost, Synthesis 2007, 1; c) V. Dragutan, I. Dragu-
tan, J. Organomet. Chem. 2006, 691, 5129; d) K. C. Nico-
laou, D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006,
118, 7292; Angew. Chem. Int. Ed. 2006, 45, 7134; e) L. F.
Tietze, G. Brasche, K. Gericke, Domino Reactions in Or-
ganic Synthesis Wiley-VCH, Weinheim, 2006; for select-
ed example, see: f) L. G. Arini, P. Szeto, D. L. Hughesc,
R. A. Stockman, Tetrahedron Lett. 2004, 45, 8371–8374.
[2] For reviews, see: a) P. Eilbracht, A. M. Schmidt, Transi-
tion Metals for Organic Synthesis, (Ed.: M. Beller, C.
Bolm), Wiley-VCH, Weinheim, 2004; b) P. Eilbracht, L.
Barfacker, C. Buss, C. Hollman, B. E. Kitsos-Rzychon,
C. L. Kranemann, T. Rische, R. Roggenbuck, A.
[6] Y. Hayashi, W. Tsuboi, M. Shoji, N. Suzuki, J. Am.
Chem. Soc. 2003, 125, 11208.
[7] K. Sakthivel, W. Notz, T. Bui, C. F. Barbas III, J. Am.
Chem. Soc. 2001, 123, 5261.
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Adv. Synth. Catal. 2009, 351, 339 – 344