Enantioselective one-pot conjugate addition of Grignard reagents to cyclic enones followed by amidomethylation

Article abstract of DOI:10.1021/jo202146f

Enantioselective conjugate addition of Grignard reagents to enones, catalyzed by Cu-Taniaphos or Josiphos complex, affords chiral enolates. Ensuing one-pot Mannich reaction with TiCl₄-generated imine leads to aminocarbonyl compounds with benzyloxycarbonyl-protected nitrogen. Both diastereomers of these compounds are isolated in moderate yields but high enantiomeric purities (up to er 97.5:2.5).

Full text of DOI:10.1021/jo202146f

Note
pubs.acs.org/joc
Enantioselective One-Pot Conjugate Addition of Grignard Reagents
to Cyclic Enones Followed by Amidomethylation
†
†
‡
,†
̌
Filip Bilcík, Michal Drusan, Jozef Marak, and Radovan Sebesta*
̌
́
†Department of Organic Chemistry and Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University,
‡
Mlynska dolina CH-2, SK-84215 Bratislava, Slovakia
S
* Supporting Information
ABSTRACT: Enantioselective conjugate addition of Grignard reagents
to enones, catalyzed by Cu-Taniaphos or Josiphos complex, affords
chiral enolates. Ensuing one-pot Mannich reaction with TiCl4-
generated imine leads to aminocarbonyl compounds with benzyl-
oxycarbonyl-protected nitrogen. Both diastereomers of these com-
pounds are isolated in moderate yields but high enantiomeric purities
(up to er 97.5:2.5).
here is a growing demand for synthesis of compounds
with multiple stereogennic centers and functional groups.
work of Evans38 and Seebach39,40 on diastereoselective synthesis
of β-amino acids. In this methodology, a titanium enolate, usually
obtained by a soft enolization of an acyl oxazolidone, reacted
with formaldehyde imine equivalent, formed in situ from
CbzNHCH2OR by the action of TiCl4. In this context, we
asked whether amidomethylation can be performed also with
enolates formed by enantioselective conjugate addition. This
report shows the results using cyclic and linear enones with
several Grignard reagents.
T
However, efficient and stereocontrolled construction of com-
plex molecules is still a considerable challenge. Stepwise processes,
in which each reaction step is followed by a purification op-
eration, are slow and laborious. Therefore, stereoselective domino
reactions or one-pot arrangements of reactions constitute a
significant improvement in terms of step economy.1 Performing
such transformations in a catalytic manner adds to the benefits.
Domino reactions require appropriate initiator reaction which
provides a reactive intermediate for the subsequent step. A con-
venient starting reaction is a metal-catalyzed conjugate addition
of organometallic reagents to α,β-unsaturated carbonyl com-
pounds.2−10 The 1,4-addition of organometallic nucleophiles
affords reactive metal enolates, which can be advantageously
reacted with a broad range of electrophilic reagents.11,12 Such
enolate trapping reactions work well with aldehydes,13−17 alkyl
halides,18,19 allylic bromides and acetates,20−23 nitroso com-
pounds.24 Metal enolates also open epoxides,25 take part in
cross-coupling,26 or cyclopropanation reactions.27 The concept
was also utilized in an intramolecular fashion with another un-
saturated carbonyl compound.28−30 Imines also acted as elec-
trophilic trapping reagents for zinc enolates formed by con-
jugate addition of dialkylzinc reagents.31−33 Zinc enolates are
most commonly used because of their easy formation and
appropriate reactivity. However, structural variability is difficult
to obtain because of limited availability of dialkylzinc reagents.
On the other hand, magnesium enolates can be formed by
conjugate addition with a broad range of Grignard reagents.
Nevertheless, magnesium enolates were used in trapping reac-
tions to much lesser extent.16,34,35 We have showed that Mg
enolates resulting from Cu-catalyzed addition of Grignard reagents
can be trapped with imines derived from aromatic aldehydes.36,37
Although seemingly simple, enolate trapping with form-
aldehyde-derived imines is unknown, because of instability of
such imines. Such methodology, however, would broaden the scope
of enolate trapping by opening a way to new β-aminocarbonyl
compounds in a catalytic manner. We were inspired by the
Conjugate additions of Grignard reagents to cyclic enones,41−44
and our own studies36 of enolate trapping with imines, served as
a starting point for our investigation. The conjugate addition of
ethylmagnesium bromide was catalyzed by a complex formed in
situ from CuCl and ferrocene ligand Taniaphos in an ethereal
solvent. Imine was generated by treating amidomethylation
reagent with TiCl4 in a separate flask. We quickly discovered
that the projected enolate trapping with formaldehyde imine
equivalent would not be compatible with oxygenated solvents,
such as Et2O or t-BuOMe, because of high oxophilicity of
titanium. It is, however, possible to perform the conjugate
addition in ethereal solvents such as t-BuOMe or Et2O and
then add a solution of amidomethylation reagent with TiCl4 in
CH2Cl2. In this way, the reaction of cyclohex-2-enone (1) with
EtMgBr catalyzed by Cu−Taniaphos complex afforded Cbz-
protected aminocarbonyl compound 2 (Scheme 1).
The conjugate addition of organometallic reagents can be
performed also in CH2Cl2 at low temperatures.45 Therefore, we
also tried conjugate addition of EtMgBr followed by amido-
methylation in CH2Cl2. This reaction set up led to the best
outcome of the enolate trapping. By this way, compound 2 was
isolated in overall 64% yield (sum of isolated trans- and cis-2).
Product 2 always formed as a mixture of trans- and cis-
diastereomers. It was, however, surprising that diastereoselec-
tivity was relatively low with typical ratio trans/cis 2:1. On the
Received: October 20, 2011
Published: November 27, 2011
© 2011 American Chemical Society
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The Journal of Organic Chemistry
Note
Scheme 1
cyclopentylmagnesium bromide, which afforded compound 6
in moderate enantiomeric purity (er 87:13). Arylmagnesium
halides were not used in the one-pot reaction because they
are unreactive in the conjugate addition catalyzed by Cu−
Taniaphos complex.36,41 We also verified conjugate addition
with methylmagnesium bromide in CH2Cl2 without subsequent
amidomethylation. GC analysis of the reaction mixture showed
98% conversion and 77% of the 1,4-addition product. Table 2
Table 2. One-Pot Reaction of Enone 1 with Various
a
Grignard Reagents
b
c
RMgX
yield (%) (trans/cis)
dr
er (trans/cis)
MeMgBr
MeMgI
47/19
20/7
2:1
96:4/97.5:2.5
92:8/94:6
2.7:1
2.1:1
2.4:1
2.2:1
n.d.
other hand, both diastereoisomers can be separated by column
chromatography. Enantiomeric purity of both trans- and cis-2
was high (up to e.r. of 97:3). The most reliable results were
obtained with CuCl as copper source. Table 1 summarizes the
results of screening for optimal solvent and copper source.
EtMgBr
37/21
33/30
21/13
10/6
96:4/95:5
n-PentMgBr
i-PentMgBr
CpMgBr
HexMgBr
96:4/80:20
96:4/80:20
87:13/87:13
96:4/96:4
26/15
1.8:1
a
All reaction were carried out with 375 μmol of enone, 563 μmol of
RMgBr, 18.8 μmol of CuCl (5 mol %), and 22.5 μmol of Taniaphos
Table 1. Screening for Conditions for the One-Pot Reaction
of Ketone 1 with EtMgBr
a
b
1
(6 mol %) in 3.75 mL of CH2Cl2. Determined by H NMR of the
c
crude reaction mixture. Determined by HPLC.
yield (%)
(trans/cis)
b
c
CuX
solvent
dr
er (trans/cis)
summarizes the results of the one-pot reaction of enone 1 with
several Grignard reagents.
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
t-BuOMe
Et2O
28/20
28/16
37/21
41/23
32/2
2.4:1
2:1
96:4/95:5
93:7/88:12
96:4/95:5
The scope of the reaction with respect to enone was evalu-
ated on several cyclic α,β-unsaturated ketones. 4,4,-Dimethyl-
cyclohex-2-enone afforded expected product 8 of the one-pot
reaction with MeMgBr. Yields and enantioselectivities were
slightly lower, probably because of higher steric crowding near
C-3 atom (Figure 1). This notion is also supported by the fact
d
CH2Cl2
CH2Cl2
2.1:1
1.6:1
2.3:1
3.2:1
2.5:1
2.3:1
2.3:1
2:1
e
96.5:3.5/97:3
79:21/60:40
f
mTHF
THF
21/23
36/18
34/16
22/15
32/19
52:48/60:40 (-)
95:5/92:8
CuBr.SMe2
CuTC
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
95:5/84:16
92:8/88:12
86:14/92:8
Cu(OTf)2
[Cu(MeCN)4]
PF6
CuI
CH2Cl2
CH2Cl2
23/17
20/12
2.2:1
2.3:1
94:6/91:9
CuF2
53.5:46.5/52:48
a
All reactions were carried out with 375 μmol of cyclohex-2-enone,
563 μmol of MeMgBr, 18.8 μmol of CuX (5 mol %), and 22.5 μmol of
b
Taniaphos (6 mol %) in 3.75 mL of solvent. Determined by 1H NMR
c
d
of the crude reaction mixture. Determined by HPLC. Average of two
Figure 1. Products of one-pot reactions with other cyclic enones.
e
f
parallel runs. Catalyst loading 10 mol %. mTHF stands for 2-
methyltetrahydrofuran.
that, the reaction with EtMgBr and HexMgBr did not proceed
with chiral Cu−Taniaphos catalyst. Corresponding products 9
and 10 were only isolated from racemic reactions carried out
with a stoichiometric amount of copper and PBu3 as ligand.
Using cyclopent-2-enone as substrate, we isolated only traces of
the desired product. All additions to 4,4-dimethylcyclohex-2-
enone were accompanied by a significant amount of 1,2-addi-
tion product, which is inactive in amidomethylation reaction.
On the other hand, with cyclohept-2-enone, a one-pot reaction
product 11 was isolated in 20% yield and with an er of 87:13
(trans). In this case, however, we were not able to isolate dia-
stereomers (Figure 1).
With proper experimental conditions, we tested a variety of
alkyl Grignard reagents in the reaction with cyclohex-2-enone
(1) (Scheme 2). Compounds 3−7 were also obtained as
Scheme 2
Relative configuration of both diastereomers of compound 9
was determined by 2D NMR techniques. Assignment of signals
was performed from gDQCOSY and gHSQCAD experiments,
and then the spatial relationship of relevant protons was
deduced from NOESY experiments. All other compounds were
assigned by comparison of H−H coupling constants between
COCH and CHNH. For trans-isomers JHH = 6.5−6.9 Hz and
for cis-isomers JHH = 9.0−10.0 Hz.
separable trans- and cis-isomers, with similarly modest
diastereomeric ratios, typically 2:1. Enantiomeric ratios were
usually high (up to er of 97.5:2.5) with the exception of
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The Journal of Organic Chemistry
Note
dissolved in CH2Cl2 (2.5 mL) at −40 °C. This solution was stirred for
2 h at −40 °C, and then it was added via canula to the solution of
conjugate addition at −60 °C. The temperature of the resulting mix-
ture was allowed to rise to rt overnight. The reaction was quenched
with aq NH4Cl and then extracted with CH2Cl2. Combined organic
extracts were concentrated. Column chromatography (SiO2, hexane/
EtOAc/CH2Cl2 83:14:3) of the crude product afforded pure dia-
stereomers of the product. The nantiomeric ratio was determined by
HPLC with chiral stationary phase and detected by UV at 211 nm.
(R,R)-Benzyl ((2-Ethyl-6-oxocyclohexyl)methyl)carbamate ((R,R)-2.).
Following general procedure for cyclic ketones with EtMgBr: colorless
oil: [α]D −8.2 (c 1.0, CHCl3, 92% ee); 1H NMR (300 MHz, CDCl3, δ)
7.40−7.27 (m, 5H), 5.39 (br, 1H), 5.15−4.98 (m, 2H), 3.55 (ddd,
J = 13.8, 6.7, 2.6 Hz, 1H), 3.28 (ddd, J = 13.9, 7.5, 6.4 Hz, 1H), 2.46−
2.20 (m, 3H), 2.14−1.98 (m, 1H), 1.98−1.84 (m, 1H), 1.80−1.32 (m,
5H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3, δ) 213.8
(CO), 156.4 (qC), 136.7 (qC), 128.5 (CH), 128.00 (CH), 127.98
(CH), 66.5 (CH2), 55.2 (CH), 42.3 (CH), 42.0 (CH2), 37.8 (CH2),
29.7 (CH2), 25.95 (CH2), 25.94 (CH2), 10.0 (CH3); HRMS (m/z)
[M + H]+ calcd for C17H24NO3 290.1751, found 290.1725; HPLC
(OD-H, hexane/i-PrOH = 85:15, 0.6 mL min−1) tR(major) 13.6 min,
tR(minor) 17.7 min; IR (ATR) νmax (cm−1) 3455, 3390 (m, N−H),
1699 (s, CO).
We also tested the one-pot reaction on linear enones
(Scheme 3). In contrast to the one-pot reaction with cyclic enones,
Scheme 3
conjugate addition on linear enones performed in CH2Cl2 was
less enantioselective. Therefore, we performed the reaction of
oct-2-enone (10) with methyl-, ethyl-, and hexylmagnesium
bromide in t-BuOMe, and only amidomethylating reagent was
added in CH2Cl2. In this case, we used Josiphos ligand because
it works well in the conjugate addition of Grignard reagents to
linear enones.46 Products 13−15 were isolated in slightly lower
yields and as diastereomeric mixtures. Enantioselectivities were,
however, high, up to 97.5:2.5.
The one-pot conjugate addition and amidomethylation, both
on cyclic and linear enones, affords products with diaster-
eoselectivity lower than expected. We proposed that it can be
the result of TiCl4-mediated epimerization of the product. Control
experiments proved this conjecture. Stirring pure diaster-
eomers, either (R,R)-2 or (R,S)-2, in the presence of TiCl4 at
−60 °C lead in both cases to diastereomeric mixtures trans/cis
2:1. Attempts at thermodynamic equilibration either in acidic
(pTsOH in refluxing toluene) or basic (DBU in CH2Cl2) con-
ditions also afforded similar results.
(S,R)-Benzyl ((2-Eethyl-6-oxocyclohexyl)methyl)carbamate ((S,R)-2.).
Following the general procedure for cyclic ketones with EtMgBr:
colorless oil; [α]D +2.8 (c 1.0, CHCl3, 92% ee); 1H NMR (600 MHz,
CDCl3, δ) 7.39−7.27 (m, 5H), 5.12 (br, 1H), 5.10−5.02 (m, 2H),
3.38 (ddd, J = 14.2, 9.9, 4.5 Hz, 1H), 3.27 (ddd, J = 13.4, 8.2, 4.0 Hz,
1H), 2.78−2.70 (m, 1H), 2.41−2.33 (m, 1H), 2.31−2.22 (m, 1H),
2.17−2.09 (m, 1H), 1.94−1.71 (m, 4H), 1.36−1.26 (m, 1H), 1.09−
0.98 (m, 1H), 0.85 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3, δ)
213.1 (CO), 156.4 (qC), 136.6 (qC), 128.5 (CH), 128.05 (CH),
128.02 (CH), 66.6 (CH2), 55.4 (CH), 42.0 (CH), 41.5 (CH2), 39.0
(CH2), 27.0 (CH2), 22.4 (CH2), 20.2 (CH2), 11.5 (CH3); HRMS (m/z)
[M + H]+ calcd for C17H24NO3 290.1751, found 290.1750; HPLC
(OJ-H, hexane/i-PrOH = 95:5, 0.6 mL min−1): tR(major) 36.8 min,
tR(minor) 40.6 min; IR (ATR) νmax (cm−1) 3342 (m, N−H), 1698
(s, CO).
(R,R)-Benzyl ((2-Methyl-6-oxocyclohexyl)methyl)carbamate
((R,R)-3). Following the general procedure for cyclic ketones with
We have also investigated the nature of amidomethylating
reagent by 1H NMR. Addition of TiCl4 led to downfield shift of
protons indicating only complexation of titanium to oxygen.
The corresponding imine was not detected.
1
MeMgBr: colorless oil; [α]D −1.5 (c 1.0, CHCl3, 92% ee); H NMR
(300 MHz, CDCl3, δ) 7.42−7.27 (m, 5H), 5.39 (br s, 1H), 5.07
(s, 2H), 3.56 (ddd, J = 13.7, 6.6, 2.7 Hz, 1H), 3.30 (td, J = 13.8, 6.9 Hz,
1H), 2.44−2.25 (m, 2H), 2.25−2.13 (m, 1H), 2.10−1.98 (m, 1H),
1.93−1.79 (m, 1H), 1.75−1.40 (m, 3H), 1.16 (d, J = 6.3 Hz, 3H); 13C
NMR (75 MHz, CDCl3, δ) 213.4 (CO), 156.4 (qC), 136.7 (qC),
128.5 (CH), 128.01 (CH), 127.99 (CH), 66.5 (CH2), 57.6 (CH), 41.9
(CH2), 37.9 (CH2), 36.7 (CH), 34.1 (CH2), 26.1 (CH2), 20.5 (CH3);
HRMS (m/z) [M + H]+ calcd for C16H22NO3, 276.1594, found
276.1622; HPLC (OD-H, hexane/i-PrOH 85:15; 0.7 mL.min−1)
tR(major) 14.0 min, tR(minor) 17.1 min; IR (ATR) νmax (cm−1) 3454,
3373 (m, NH), 1699 (s, CO).
In summary, we report here a catalytic one-pot conjugate
addition followed by amidomethylation. Magnesium enolates,
formed by enantioselective copper-catalyzed conjugate addition
of Grignard reagents to enones, can be trapped with TiCl4-
generated imine. In this way, Cbz-protected aminocarbonyl
compounds were prepared in moderate yields. Diastereoselecti-
vities were relatively low because of Ti-mediated epimerization
of the products, but diastereomers (from cyclic enones) were
separated by column chromatography. Enantiomeric purities
of obtained compounds were high (up to e.r. 97.5:2.5) in the
majority of examples.
(S,R)-Benzyl ((2-Methyl-6-oxocyclohexyl)methyl)carbamate
((S,R)-3). Following the general procedure for cyclic ketones with
MeMgBr: colorless crystalline solid; [α]D +4.6 (c 0.9, CHCl3, 92% ee);
1H NMR (300 MHz, CDCl3, δ) 7.40−7.27 (m, 5H), 5.17 (br s, 1H),
EXPERIMENTAL SECTION
5.12−5.00 (m, 2H), 3.38−3.17 (m, 2H), 2.78−2.66 (m, 1H), 2.52−
2.39 (m, 1H), 2.39−2.17 (m, 2H), 2.02−1.81 (m, 3H), 1.77−1.58
(m, 1H), 0.81 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3, δ)
213.2 (CO), 156.4 (qC), 136.6 (qC), 128.5 (CH), 128.1 (CH), 128.0
(CH), 66.6 (CH2), 54.9 (CH), 41.8 (CH2), 39.4 (CH2), 35.1 (CH),
32.0 (CH2), 22.5 (CH2), 14.1 (CH3); HPLC (OD-H, hexane/i-PrOH
95:5; 0.6 mL min−1) tR(major) 29.5 min, tR(minor) 32.6 min; IR
(ATR) νmax (cm−1) 3321 (s, NH), 1708, 1681 (s, CO). Anal. Calcd
for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.48; H, 7.65;
N, 5.04.
(R,R)-Benzyl ((2-Oxo-6-pentylcyclohexyl)methyl)carbamate
((R,R)-4). Following the general procedure for cyclic ketones with
nPentMgBr: colorless oil; [α]D −5.6 (c 1.0, CHCl3, 92% ee); 1H
NMR (600 MHz, CDCl3, δ) 7.40−7.32 (m, 4H), 7.32−7.27 (m, 1H),
■
General Considerations. All reactions were carried out under
nitrogen using standard Schlenk techniques. Commercially available
reagents were used without further purification. Solvents were dried
according to the standard procedures.
General Procedure for One-Pot Reaction on Cyclic
Ketones. Ligand Taniaphos (15.5 mg, 22.5 μmol) and CuCl (1.9 mg,
18.8 μmol) were dissolved in CH2Cl2 (3.75 mL), and the resulting
solution was stirred 1 h at rt. The reaction mixture was then cooled
at −60 °C, and ketone (375 μmol) was added via syringe. The result-
ing mixture was stirred for an additional 10 min at −60 °C. Into this
mixture, Grignard reagent (563 μmol) was added during 5 min and the
mixture was stirred for 2 h at −60 °C. In another flask, TiCl4 (35 μL,
330 μmol) was added into a solution of CbzNHCH2O-i-Pr (300 μmol)
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The Journal of Organic Chemistry
Note
5.42−5.32 (m, 1H), 5.14−5.02 (m, 2H), 3.57 (ddd, J = 13.7, 6.8,
2.6 Hz, 1H), 3.28 (ddd, J = 13.9, 7.6, 6.3 Hz, 1H), 2.41−2.34 (m, 1H),
2.33−2.24 (m, 2H), 2.10−2.02 (m, 1H), 1.99−1.91 (m, 1H), 1.70−
1.63 (m, 1H), 1.63−1.53 (m, 2H), 1.48−1.38 (m, 2H), 1.38−1.18
(m, 6H), 0.89 (t, J = 7,0 Hz, 3H); 13C NMR (75 MHz, CDCl3, δ)
213.8 (CO), 156.4 (qC), 136.7 (qC), 128.5 (CH), 128.01 (CH),
127.98 (CH), 66.5 (CH2), 55.8 (CH), 42.0 (CH2), 41.3 (CH), 38.0
(CH2), 33.4 (CH2), 32.0 (CH2), 30.3 (CH2), 26.0 (CH2), 25.7 (CH2),
22.6 (CH2), 14.1 (CH3); HRMS (m/z) [M + H]+ calcd for C20H30-
NO3 332.2220, found 332.2230; HPLC (OD-H, hexane/i-PrOH =
85:15, 0.6 mL min−1) tR(major) 11.4 min, tR(minor) 17.0 min; IR
(ATR) νmax (cm−1) 3457 (m, N−H), 1722, 1704 (s, CO).
tR(major) 29.9 min, tR(minor) 33.2 min; IR (ATR) νmax (cm−1) 3297
(m, N−H), 1723, 1694 (s, CO). Anal. Calcd for C20H27NO3: C,
72.92; H, 8.26; N, 4.25. Found: C, 72.61; H, 8.27; N, 4.03.
(R,S)-Benzyl ((6-Cyclopentyl-2-oxocyclohexyl)methyl)carbamate
((R,S)-6). Following the general procedure for cyclic ketones with
1
CpMgBr: colorless oil; [α]D −0.8 (c 0.8, CHCl3, 74% ee); H NMR
(600 MHz, CDCl3, δ) 7.38−7.27 (m, 5H), 5.35 (br, 1H), 5.09 (d, J =
12.3 Hz, 1H), 5.04 (d, J = 12.3 Hz, 1H), 3.59 (ddd, J = 13.6, 6.6, 3.3 Hz,
1H), 3.32 (ddd, J = 14.0, 8.0, 6.3 Hz, 1H), 2.45−2.35 (m, 2H), 2.28
(ddd, J = 12.8, 12.6, 6.1 Hz, 1H), 2.20−2.10 (m, 1H), 2.05 (dq,
J = 9.1, 4.6 Hz, 1H), 1.89−1.82 (m, 1H), 1.78−1.69 (m, 2H), 1.69−
1.45 (m, 7H), 1.32−1.23 (m, 2H); 13C NMR (150 MHz, CDCl3, δ)
214.0 (CO), 156.4 (qC), 136.6 (qC), 128.4 (CH), 127.98 (CH),
127.94 (CH), 66.5 (CH2), 55.4 (CH), 44.2 (CH), 41.5 (CH2), 40.5
(CH), 38.6 (CH2), 30.3 (CH2), 26.2 (CH2), 25.7 (CH2), 25.5 (CH2),
25.3 (CH2), 24.6 (CH2); HRMS (m/z) [M + H]+ calcd for C20H28-
NO3 330.2064, found 330.2030; HPLC (OD-H, hexane/i-PrOH =
85:15, 0.6 mL min−1) tR(major) 13.9 min, tR(minor) 17.9 min; IR (ATR)
νmax (cm−1) 3335 (m, N−H), 1705 (s, CO).
(S,R)-Benzyl ((2-Oxo-6-pentylcyclohexyl)methyl)carbamate
((S,R)-4). Following the general procedure for cyclic ketones with
nPentMgBr: colorless oil; [α]D −5.5 (c 1.0, CHCl3, 60% ee); 1H NMR
(600 MHz, CDCl3, δ) 7.42−7.28 (m, 5H), 5.19−5.00 (m, 3H), 3.38
(ddd, J = 14.1, 10.0, 4.4 Hz, 1H), 3.30−3.23 (m, 1H), 2.77−2.68
(m, 1H), 2.41−2.32 (m, 1H), 2.32−2.17 (m, 2H), 1.93−1.70 (m, 4H),
1.36−0.97 (m, 8H), 0.87 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3, δ) 213.2 (CO), 156.4 (qC), 136.6 (qC), 128.5 (CH), 128.06
(CH), 128.03 (CH), 66.6 (CH2), 55.4 (CH), 41.5 (CH2), 40.3 (CH),
39.1 (CH2), 31.7 (CH2), 27.6 (CH2), 27.2 (CH2), 26.6 (CH2), 22.54
(CH2), 22.51 (CH2), 14.0 (CH3); HRMS (m/z) [M + H]+ calcd for
C20H30NO3 332.2220, found 332.2262; HPLC (OD-H, hexane/
i-PrOH = 95:5, 0.7 mL min−1) tR(major) 20.4 min, tR(minor) 23.2 min;
IR (ATR) νmax (cm−1) 3387, 3328 (s, N−H), 1715, 1690 (s, CO).
(S,S)-Benzyl 6-(3-Methylbutyl)-2-oxocyclohexyl)methyl)-
carbamate ((S,S)-5). Following the general procedure for cyclic
ketones with i-PentMgBr: colorless oil; [α]D −6.7 (c 1.0, CHCl3, 60% ee);
1H NMR (600 MHz, CDCl3, δ) 7.39−7.27 (m, 5H), 5.17−5.03
(m, 3H), 3.39 (ddd, J = 14.2, 10.0, 4.5 Hz, 1H), 3.31−3.23 (m, 1H),
2.76−2.69 (m, 1H), 2.41−2.34 (m, 1H), 2.31−2.22 (m, 1H), 2.22−
2.14 (m, 1H), 1.91−1.71 (m, 4H), 1.52−1.40 (m, 1H), 1.27−1.09
(m, 2H), 1.09−0.96 (m, 2H), 0.86 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 6.6 Hz,
3H, CH3); 13C NMR (75 MHz, CDCl3, δ) 213.2 (CO), 156.4 (qC),
136.5 (qC), 128.5 (CH), 128.04 (CH), 128.01 (CH), 66.6 (CH2),
55.4 (CH), 41.5 (CH2), 40.6 (CH), 39.1 (CH2), 36.2 (CH2), 28.0
(CH), 27.6 (CH2), 24.9 (CH2), 22.9 (CH3), 22.4 (CH2), 22.2 (CH3);
HRMS (m/z) [M + H]+ calcd for C20H30NO3 332.2220,
found 332.2212; HPLC (OJ-H, hexane/i-PrOH = 92:8, 0.7 mL .min−1)
tR(minor) 12.6 min, tR(major) 14.9 min; IR (ATR) νmax (cm−1) 3345
(m, N−H), 1704 (s, CO).
(R,R)-Benzyl ((6-Hexyl-2-oxocyclohexyl)methyl)carbamate ((R,R)-7).
Following the general procedure for cyclic ketones with HexMgBr:
colorless oil; [α]D −8.4 (c 1.0, CHCl3, 92% ee); 1H NMR (300 MHz,
CDCl3, δ) 7.42−7.27 (m, 5H), 5.43−5.30 (m, 1H), 5.15−5.01
(m, 2H), 3.57 (ddd, J = 13.8, 6.9, 2.8 Hz, 1H), 3.27 (ddd, J = 13.9,
7.7, 6.2 Hz, 1H), 2.44−2.20 (m, 3H), 2.13−2.01 (m, 1H), 2.01−1.88
(m, 1H), 1.75−1.10 (m, 13H), 0.88 (t, J = 6.2 Hz, 3H); 13C NMR
(150 MHz, CDCl3, δ) 213.9 (CO), 156.4 (qC), 136.7 (qC), 128.5
(CH), 128.01 (CH), 127.98 (CH), 66.5 (CH2), 55.8 (CH), 42.0
(CH2), 41.4 (CH), 38.0 (CH2), 33.5 (CH2), 31.8 (CH2), 30.3 (CH2),
29.5 (CH2), 26.04 (CH2), 26.01 (CH2), 22.65 (CH2), 14.1 (CH3);
HRMS (m/z) [M + H]+ calcd for C21H32NO3 346.2377, found
346.2390; HPLC (OD-H, hexane/i-PrOH = 85:15, 0.6 mL min−1)
tR(major) 11.0 min, tR(minor) 15.6 min; IR (ATR) νmax (cm−1) 3455,
3379 (m, N−H), 1703 (s, CO).
(S,R)-Benzyl ((6-Hhexyl-2-oxocyclohexyl)methyl)carbamate
((S,R)-7). Following the general procedure for cyclic ketones with
1
HexMgBr: colorless oil; [α]D −9.3 (c 1.2, CHCl3, 92% ee); H NMR
(300 MHz, CDCl3, δ) 7.42−7.27 (m, 5H), 5.20−5.00 (m, 3H), 3.32
(dddd, J = 21.9, 13.6, 9.0, 4.3 Hz, 2H), 2.79−2.65 (m, 1H), 2.45−2.15
(m, 3H), 1.97−1.65 (m, 4H), 1.40−0.96 (m, 10H), 0.87 (t, J = 6.7 Hz,
3H); 13C NMR (150 MHz, CDCl3, δ) 213.2 (CO), 156.4 (qC), 136.6
(qC), 128.5 (CH), 128.06 (CH), 128.03 (CH), 66.6 (CH2), 55.4
(CH), 41.5 (CH2), 40.3 (CH), 39.1 (CH2), 31.8 (CH2), 29.2 (CH2),
27.7 (CH2), 27.2 (CH2), 26.9 (CH2), 22.6 (CH2), 22.5 (CH2), 14.1
(CH3); HRMS (m/z) [M + H]+ calcd for C21H32NO3 346.2377, found
346.2394; HPLC (OD-H, hexane/i-PrOH = 85:15, 0.6 mL min−1)
tR(major) 20.8 min, tR(minor) 23.4 min; IR (ATR) νmax (cm−1) 3347
(m, N−H), 1704 (s, CO).
(R,S)-Benzyl 6-(3-Methylbutyl)-2-oxocyclohexyl)methyl)-
carbamate ((R,S)-5). Following the general procedure for cyclic
ketones with i-PentMgBr: colorless oil; [α]D −6.7 (c 1.0, CHCl3, 92% ee);
1H NMR (600 MHz, CDCl3, δ) 7.38−7.32 (m, 4H), 7.32−7.27
(m, 1H), 5.40−5.33 (m, 1H, NH), 5.14−5.01 (m, 2H, CH2O), 3.57
(ddd, J = 13.7, 6.8, 2.7 Hz, 1H), 3.28 (ddd, J = 13.8, 7.6, 6.3 Hz, 1H),
2.41−2.35 (m, 1H), 2.34−2.24 (m, 2H), 2.10−2.02 (m, 1H), 1.98−
1.90 (m, 1H), 1.70−1.63 (m, 1H), 1.63−1.48 (m, 3H), 1.48−1.39
(m, 1H), 1.39−1.30 (m, 1H), 1.30−1.21 (m, 1H), 1.18−1.09 (m, 1H),
0.94−0.84 (m, 6H); 13C NMR (75 MHz, CDCl3, δ) 213.8 (CO),
156.4 (qC), 136.7 (qC), 128.5 (CH), 128.00 (CH), 127.97 (CH),
66.5 (CH2), 55.7 (CH), 42.0 (CH2), 41.5 (CH), 38.0 (CH2), 35.1
(CH2), 31.1 (CH2), 30.3 (CH2), 28.2 (CH), 26.0 (CH2), 23.0 (CH3),
22.3 (CH3); HRMS (m/z) [M + H]+ calcd for C20H30NO3 332.2220,
found 332.2220; HPLC (OD-H, hexane/i-PrOH = 85:15, 0.6 mL min−1)
tR(major) 11.2 min, tR(minor) 16.6 min; IR (ATR) νmax (cm−1) 3455,
3390 (m, N−H), 1703 (s, CO).
(S,S)-Benzyl ((2-Methyl-3,3-dimethyl-6-oxocyclohexyl)methyl)-
carbamate ((S,S)-8). Following the general procedure for cyclic
ketones with MeMgBr: colorless crystalline solid; mp 73−78 °C
(heptane); 1H NMR (600 MHz, CDCl3, δ) 7.39−7.32 (m, 4H), 7.32−
7.28 (m, 1H), 5.18 (br, 1H), 5.10 (d, J = 12.2 Hz, 1H), 5.05 (d, J =
12.2 Hz, 1H), 3.33 (ddd, J = 13.3, 9.4, 3.8 Hz, 1H), 3.25−3.17
(m, 1H), 2.99−2.93 (m, 1H), 2.41 (dt, J = 14.1, 7.0 Hz, 1H), 2.21
(ddd, J = 14.5, 5.0, 1.7 Hz, 1H), 1.93−1.85 (m, 1H), 1.81 (dt, J = 13.7,
5.0 Hz, 1H), 1.55 (tdd, J = 13.6, 7.0, 1.7 Hz, 1H), 1.38 (s, 3H), 0.98
(s, 3H), 0.74 (d, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3, δ)
213.4 (qC−CO), 156.3 (qC), 136.6 (qC), 128.5 (CH-Ph), 128.04
(CH-Ph), 128.03 (CH-Ph), 66.6 (CH2), 51.0 (CH), 45.5 (CH), 39.7
(CH2), 38.3 (CH2), 34.5 (CH2), 33.7 (qC), 28.3 (CH3), 26.8 (CH3),
10.8 (CH3); HRMS (m/z) [M + H]+ calcd for C18H26NO3, 304.1907;
found 304.1915. HPLC (OD-H, hexane/i-PrOH = 90:10, 0.6 mL.min−1)
tR(major) 29.3 min, tR(minor) 33.5 min; IR (ATR) νmax (cm−1) 3372,
3329 (m, N−H), 1715, 1697 (s, CO).
(S,S)-Benzyl ((6-Cyclopentyl-2-oxocyclohexyl)methyl)carbamate
((S,S)-6). Following the general procedure for cyclic ketones with
1
CpMgBr: colorless crystalline solid; H NMR (300 MHz, CDCl3, δ)
7.40−7.27 (m, 5H), 5.06 (s, 2H), 4.84 (brs, 1H), 3.67−3.48 (m, 1H),
3.40 (td, J = 13.4, 5.1 Hz, 1H), 2.75−2.61 (m, 1H), 2.61−2.45
(m, 1H), 2.35−2.19 (m, 1H), 2.10−1.91 (m, 1H), 1.91−1.40 (m, 11H),
1.15−0.96 (m, 2H); 13C NMR (75 MHz, CDCl3, δ) 213.7 (CO),
156.3 (qC), 136.4 (qC), 128.5 (CH), 128.1 (CH), 128.0 (CH), 66.8
(CH2), 55.4 (CH), 47.3 (CH), 41.6 (CH), 39.2 (CH2), 38.8 (CH2),
32.1 (CH2), 30.9 (CH2), 27.1 (CH2), 25.03 (CH2), 24.98 (CH2), 24.7
(CH2); HPLC (OD-H, hexane/i-PrOH = 95:5, 0.6 mL min−1)
(R,S)-Benzyl ((2-Methyl-3,3-dimethyl-6-oxocyclohexyl)methyl)-
carbamate ((R,S)-8). Following the general procedure for cyclic
ketones with MeMgBr: colorless oil; [α]D −5.0 (c = 1.0, CHCl3, 62% ee);
1H NMR (600 MHz, CDCl3, δ) 7.38−7.33 (m, 4H), 7.33−7.28 (m,
1H), 5.39 (br, 1H), 5.08 (s, 2H), 3.57 (ddd, J = 13.8, 6.5, 2.6 Hz, 1H),
763
dx.doi.org/10.1021/jo202146f | J. Org. Chem. 2012, 77, 760−765

The Journal of Organic Chemistry
Note
3.29 (td, J = 13.7, 6.8 Hz, 1H), 2.48 (dt, J = 14.2, 6.0 Hz, 1H), 2.33−
2.26 (m, 1H), 2.26 (ddd, J = 13.9, 4.3, 2.8 Hz, 1H), 1.74 (ddd,
J = 13.5, 5.9, 2.6 Hz, 1H), 1.59 (dt, J = 14.1, 4.3 Hz, 1H), 1.49 (qd, J =
13.2, 6.7 Hz, 1H), 1.07−1.02 (m, 6H), 0.98 (s, 3H); 13C NMR (150
MHz, CDCl3, δ) 213.7 (qC−CO), 156.5 (qC), 136.7 (qC), 128.5
(CH-Ph), 128.02 (CH-Ph), 128.00 (CH-Ph), 66.5 (CH2), 52.9 (CH),
44.1 (CH), 41.5 (CH2), 38.8 (CH2), 38.2 (CH2), 33.5 (qC), 29.4
(CH3), 19.0 (CH3), 14.2 (CH3); HRMS (m/z) [M + H]+ calcd for
C18H26NO3 304.1907, found 304.1921; HPLC (OD-H, hexane/
i-PrOH = 90:10, 0.6 mL min−1) tR(minor) 14.1 min, tR(major) 19.5 min;
IR (ATR) νmax (cm−1) 3455, 3390 (m, N−H), 1704 (s, CO).
(S*,S*)-Benzyl ((2-Ethyl-3,3-dimethyl-6-oxocyclohexyl)methyl)-
carbamate ((S*,S*)-9). Colorless crystalline solid: mp 85−87 °C
Anal. Calcd for C23H35NO3: C, 73.96; H, 9.44; N, 3.75. Found: C,
74.19; H, 9.45; N, 3.61.
Benzyl ((2-Ethyl-7-oxocycloheptyl)methyl)carbamate (11). Fol-
lowing the general procedure for cyclic ketones with MeMgBr:
1
colorless oil, diastereomeric mixture; H NMR (600 MHz, CDCl3, δ)
signals for minor diastereomer are in italics: 7.39−7.27 (m, 5H), 5.19;
5.18 (br, 1H), 5.11−5.02 (m, 2H), 3.45 (ddd, J = 13.6, 6.8, 3.4 Hz,
1H), 3.39−3.34 (m, 1H), 3.34−3.27 (m, 1H), 3.12−3.04 (m, 1H),
2.68−2.59 (m, 1H), 2.55−2.48 (m, 1H), 2.48−2.32 (m, 2H), 2.31−
2.22 (m, 1H), 2.00−1.93 (m, 1H), 1.86−1.20 (m, 8H), 1.06−0.97
(m, 1H), 0.94 (t, J = 7.4 Hz, 3H), 0.85 (t, J = 7.3 Hz, 3H); 13C NMR
(150 MHz, CDCl3, δ) signals for minor diastereomer are in italics:
215.3; 214.9 (qC−CO), 156.42; 156.41 (qC), 136.59; 136.56 (qC),
128.5 (CH-Ph), 128.05; 128.03 (CH-Ph), 128.00 (CH-Ph), 66.59;
66.58 (CH2), 56.8; 56.1 (CH), 43.9; 42.5 (CH2), 41.1; 40.8 (CH2),
39.3; 38.8 (CH), 32.4; 29.74 (CH2), 26.4 (CH2), 24.8; 24.3 (CH2),
23.73; 23.66 (CH2), 21.0 (CH2), 12.4; 11.4 (CH3); HRMS (m/z)
[M + H]+ calcd for C18H26NO3 304.1907, found 304.1881; HPLC
(OJ-H, hexane/i-PrOH = 92:8, 0.7 mL min−1) tR(major-trans) 16.7 min,
tR(minor-trans) 18.0 min, tR(cis − both enantiomers) 19.3 min; IR (ATR)
νmax (cm−1) 3442 (m, N−H), 1694 (s, CO).
1
(EtOAc/hexane); H NMR (300 MHz, CDCl3, δ) 7.44−7.27 (m, 5H),
5.21 (br, 1H), 5.08 (m, 2H), 3.43−3.23 (m, 2H), 3.00−2.90 (m, 1H),
2.41 (dt, J = 14.0, 6.9 Hz, 1H), 2.22 (ddd, J = 14.6, 5.3, 2.3 Hz, 1H),
1.79 (dt, J = 13.5, 5.3 Hz, 1H), 1.62−1.47 (m, 2H), 1.40−1.17 (m,
1H), 1.28 (s, 3H), 1.10−0.92 (m, 1H), 1.01 (s, 3H), 0.90 (t, J = 7.3
Hz, 3H); 13C NMR (75 MHz, CDCl3, δ) 213.6 (qC−CO), 156.4
(qC), 136.6 (qC), 128.5 (CH-Ph), 128.06 (CH-Ph), 128.05 (CH-Ph),
66.6 (CH2), 53.2 (CH), 51.6 (CH), 39.7 (CH2), 38.3 (CH2), 35.7
(CH2), 34.5 (qC), 27.5 (CH3), 27.4 (CH3), 19.5 (CH2), 15.9 (CH3);
HPLC (OD-H, hexane/i-PrOH = 95:5, 0.7 mL min−1) tR 24.8 min, tR
27.2 min; IR (ATR) νmax (cm−1) 3357 (m, N−H), 1706 (s, CO).
Anal. Calcd for C19H27NO3: C, 71.89; H, 8.57; N, 4.41. Found: C,
72.17; H, 8.64; N, 4.44.
General Procedure for One-Pot Reaction on Linear
Ketones. (R,R)-Josiphos (19.2 mg, 0.03 mmol) and CuBr·SMe2
(5.2 mg, 0.025 mmol) were dissolved in t-BuOMe, and the solution
was stirred for 30 min at room temperature. The solution was then
cooled to −75 °C, and ketone 12 (0.5 mmol) was added. After an
additional 5 min of stirring, Grignard reagent (0.5 mmol) was added
during 30 min and the resulting mixture was stirred for 1.5 h at −75 °C.
A mixture of CbzNHCH2O-i-Pr (89.3 mg, 0.4 mmol) and TiCl4 (55 μL,
0.48 mmol) in CH2Cl2 (3 mL), which was stirred in another Schlenck
tube for 2 h at −60 °C was added. The reaction temperature was then
allowed to reach room temperature overnight. The reaction was then
quenched with a few drops of satd solution of NH4Cl and extracted
with CH2Cl2. Combined organic extracts were concentrated. Column
chromatography (SiO2, Hex/AcOEt 4:1−6:1) of the residue afforded
pure product (mixture of diastereoms) as colorless oil. Enantiomeric
and diastereomeric ratio was determined by HPLC with chiral sta-
tionary phase and detected by UV at 211 nm.
Benzyl 2-Acetyl-3-methylheptylcarbamate (13). Following the
general procedure for linear ketones with MeMgBr: colorless oil, dia-
stereomeric mixture; 1H NMR (300 MHz, CDCl3, δ) 7.28−7.39
(m, 5H), 4.95−5.15 (m, 3H), 3.36−3.49 (m, 1H), 3.20−3.35 (m, 1H),
2.68−2.79 (m, 1H), 2.15 (s, 3H), 1.11−1.51 (m, 7H), 0.99, 0.81(d, J =
6.9 Hz, 3H), 0.84−0.96 (m, 3H); 13C NMR (75 MHz, CDCl3, δ):
211.8, 211.7 (CO); 156.3 (CONH); 136.5 (qC); 128.5; 128.1; 128.1
(CH); 66.6 (OCH2); 58.2, 57.2 (CH); 38.8, 37.4 (NCH2); 34.7,32.9
(CH2); 33.3; 33.1 (CH); 30.7, 29.7 (CH3); 29.6, 29.4 (CH2); 22.70,
22.67 (CH2); 17.6, 15.7 (CH3); 14.04, 14.00 (CH3); IR (CHCl3) νmax
(cm−1) 3454 (w, N−H), 1705 (s, CO), 1513 (m, σ N−H), 1241
(m, C−O); HRMS (m/z) [M + H]+ calcd for C18H28NO3 306.2064,
found 306.2074.
(R*,S*)-Benzyl ((2-Ethyl-3,3-dimethyl-6-oxocyclohexyl)methyl)-
carbamate ((R*,S*)-9). Colorless crystalline solid: mp 73−75 °C
1
(EtOAc/hexane); H NMR (300 MHz, CDCl3, δ) 7.40−7.27 (m, 5H),
5.48 (br, 1H), 5.07 (m, 2H), 3.62 (ddd, J = 13.5, 8.2, 2.7 Hz, 1H), 3.16
(ddd, J = 13.6, 8.8, 4.8 Hz, 1H), 2.56−2.33 (m, 2H), 2.26 (ddd, J =
14.0, 4.5, 2.8 Hz, 1H), 1.71 (ddd, J = 13.5, 6.1, 2.8 Hz, 1H), 1.66−1.33
(m, 3H), 1.18−1.06 (m, 1H), 1.07 (s, 3H), 0.99 (s, 3H), 0.97 (t, J =
7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3, δ) 214.1 (qC−CO), 156.4
(qC), 136.6 (qC), 128.5 (CH-Ph), 128.02 (CH-Ph), 128.01 (CH-Ph),
66.5 (CH2), 53.0 (CH), 51.8 (CH), 41.5 (CH2), 39.1 (CH2), 38.6
(CH2), 34.4 (qC), 29.2 (CH3), 22.8 (CH2), 20.1 (CH3), 15.0 (CH3);
HPLC (OD-H, hexane/i-PrOH = 85:15, 0.6 mL min−1) tR 12.5 min, tR
17.3 min; IR (ATR) νmax (cm−1) 3433 (m, N−H), 1716, 1702 (s, CO).
Anal. Calcd for C19H27NO3: C, 71.89; H, 8.57; N, 4.41. Found: C,
72.03; H, 8.63; N, 4.37.
(S*,S*)-Benzyl ((2-Hexyl-3,3-dimethyl-6-oxocyclohexyl)methyl)-
carbamate ((S*,S*)-10). Colorless oil: 1H NMR (600 MHz,
CDCl3, δ) 7.38−7.32 (m, 4H), 7.32−7.27 (m, 1H), 5.23 (br, 1H),
5.10 (d, J = 12.3 Hz, 1H), 5.04 (d, J = 12.3 Hz, 1H), 3.30 (dd, J = 13.4,
4.1 Hz, 2H), 2.95 (td, J = 8.5, 4.2 Hz, 1H), 2.40 (dt, J = 13.8, 6.9 Hz,
1H), 2.25−2.17 (m, 1H), 1.79 (dt, J = 13.4, 5.2 Hz, 1H), 1.60−1.49
(m, 2H), 1.28 (s, 3H), 1.32−1.16 (m, 10H), 1.00 (s, 3H), 0.86 (t, J =
7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3, δ) 213.7 (CO), 156.3
(qC), 136.6 (qC), 128.5 (CH), 128.03 (CH), 66.6 (CH2), 51.5 (CH),
51.3 (CH), 39.7 (CH2), 38.4 (CH2), 35.6 (CH2), 34.5 (qC), 31.58
(CH2), 31.55 (CH2), 29.6 (CH2), 27.6 (CH3), 27.2 (CH3), 26.8
(CH2), 26.2 (CH2), 14.0 (CH3); HRMS (m/z) [M + H]+ calcd for
C23H36NO3 374.2695, found 374.2708; HPLC (OJ-H, hexane/i-PrOH =
90:10, 0.7 mL min−1) tR 9.1 min, tR 12.0 min; IR (ATR) νmax (cm−1)
3454, 3348 (m, N−H), 1704 (s, CO).
Benzyl 2-Acetyl-3-ethylheptylcarbamate (14). Following the
general procedure for linear ketones with EtMgBr: colorless oil;
1
diastereomeric mixture. H NMR (300 MHz, CDCl3, δ) 7.28−7.39
(m, 5H), 4.99−5.11 (m, 2H), 4.85 (br s, 1H), 3.34−3.47 (m, 1H),
3.16−3.29 (m, 1H), 2.72−2.89 (m, 1H), 2.15 (s, 3H), 1.65−1.79
(m, 1H), 1.09−1.51 (m, 8H), 1.01 (t, J = 7.3 Hz, 3H) 0.86 (t, J = 7.1 Hz,
3H); 13C NMR (75 MHz, CDCl3, δ): 212.2, 212.1 (CO);
156.3(CONH); 136.5 (Cq); 128.5(CHPh); 128.1(CH); 128.0 (CH);
66.6 (OCH2); 55.4, 55.2 (CH); 40.1; 40.0 (CH); 37.6, 37.3; 30.8,
30.0; 29.72, 29.67 (CH2); 29.53, 29.50 (CH3); 24.6, 24.4; 22.8, 22.7
(CH2); 14.1, 14.0 (CH3); 12.0, 11.9 (CH3); HRMS (m/z) [M + H]+
calcd for C19H30NO3 320.2220, found 320.2240; IR (CHCl3) νmax
(cm−1) 1455 (w, N−H), 1705 (s, CO), 1513 (m, σN−H), 1255
(w, C−O).
(R*,S*)-Benzyl ((2-Hexyl-3,3-dimethyl-6-oxocyclohexyl)methyl)-
1
carbamate ((R*,S*)-10). Colorless crystalline solid: H NMR (300
MHz, CDCl3, δ) 7.43−7.27 (m, 5H), 5.47 (br, 1H), 5.20−4.95 (m, 2H),
3.70−3.48 (m, 1H), 3.13 (ddd, J = 13.6, 9.1, 4.6 Hz, 1H), 2.56−2.32
(m, 2H), 2.25 (ddd, J = 14.0, 4.3, 2.8 Hz, 1H), 1.72 (ddd, J = 13.4, 6.0,
2.5 Hz, 1H), 1.65−1.42 (m, 2H), 1.42−1.09 (m, 10H), 1.06 (s, 3H),
0.98 (s, 3H), 0.88 (t, J = 6.2 Hz, 3H); 13C NMR (150 MHz, CDCl3, δ)
214.0 (CO), 156.3 (qC), 136.7 (qC), 128.5 (CH), 128.00 (CH),
127.97 (CH), 66.5 (CH2), 53.5 (CH), 50.6 (CH), 41.5 (CH2), 39.2
(CH2), 38.6 (CH2), 34.3 (qC), 31.7 (CH2), 31.1 (CH2), 30.4 (CH2),
29.7 (CH2), 29.2 (CH3), 22.7 (CH2), 19.8 (CH3), 14.1 (CH3); HPLC
(OD-H, hexane/i-PrOH = 85:15, 0.6 mL min−1) tR 9.6 min, tR 14.6
min; IR (ATR) νmax (cm−1) 3458, 3327 (m, N−H), 1702 (s, CO).
Benzyl 2-Acetyl-3-butylnonylcarbamate (15). Following the
general procedure for linear ketones with HexMgBr: colorless oil,
1
diastereomeric mixture; H NMR (300 MHz, CDCl3, δ) 7.29−7.40
(m, 5H), 4.99−5.16 (m, 3H), 3.34−3.46 (m, 1H), 3.16−3.29 (m, 1H),
2.76−2.86 (m, 1H), 2.15 (s, 3H), 1.78 (m, 1H); 1.02−1.55 (m, 16H),
764
dx.doi.org/10.1021/jo202146f | J. Org. Chem. 2012, 77, 760−765

The Journal of Organic Chemistry
Note
0.92 (t, J = 7.3 Hz, 3H) 0.78−0.98 (m, 3H); 13C NMR (75 MHz,
CDCl3, δ): 212.0 (CO); 156.3 (CONH); 136.5 (qC); 128.5; 128.1;
128.0 (CH); 66.6 (OCH2); 55.6 (CH); 38.4 (CH); 31.8, 31.7; 31.6,
31.3; 30.6, 30.3; 29.7, 29.6; 29.58, 29.55 (CH3); 29.5, 29.4; 27.5, 27.4;
24.6, 24.3; 22.9, 22.7; 22.7, 22.6; 14.10, 14.07 (CH3); 14.0, 13.8
(CH3); HRMS (m/z) [M + H]+ calcd for C23H38NO3 376.2846,
found 376.2834; IR (CHCl3) νmax (cm−1) 3455 (w, N−H), 1705
(s, CO), 1513 (m, σN−H), 1254 (w, C−O).
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ASSOCIATED CONTENT
■
(26) Suar
Biomol. Chem. 2005, 3, 729.
́
ez, R. M.; Pena, D.; Minnaard, A. J.; Feringa, B. L. Org.
̃
S
* Supporting Information
1H and 13C NMR spectra and HPLC chromatograms for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org/.
́
(27) den Hartog, T.; Rudolph, A.; Macia, B.; Minnaard, A. J.; Feringa,
B. L. J. Am. Chem. Soc. 2010, 132, 14349.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: radovan.sebesta@fns.uniba.sk.
ACKNOWLEDGMENTS
■
(33) Gonzal
2008, 49, 2343.
́ ́
ez-Gomez, J. C.; Foubelo, F.; Yus, M. Tetrahedron Lett.
Financial support from the Slovak Grant Agency VEGA, Grant
Nos. VEGA 1/0265/09 and VEGA 1/0546/10, and the Slovak
Research and Development Agency, Grant No. VVCE 0070/07,
are gratefully acknowledged. This publication is the result of
the project implementation 26240120025 supported by the
Research & Development Operational Programme funded by
the Research & Development Operational Programme funded
by the European Regional Development Fund. NMR measure-
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