Enantio- and diastereoselective organocatalytic α-alkylation of aldehydes with 3-substituted 2-(bromomethyl)acrylates

Article abstract of DOI:10.1021/jo202073n

The catalytic direct α-alkylation of aldehydes with 2-(bromomethyl)acrylates has been accomplished, giving rise to α-branched and functionalized aldehydes of high diastereo- and enantiopurity. The influence of the nature of the ester group of the acrylates in reaction stereoselectivity and especially in reactivity is investigated. Optimum conditions implicate the use of phenyl acrylates in conjunction with organocatalyst 8. Application of thus obtained adducts in synthesis is illustrated with a concise stereocontrolled preparation of trisubstituted cyclopentenes.

Full text of DOI:10.1021/jo202073n

Note
pubs.acs.org/joc
Enantio- and Diastereoselective Organocatalytic α-Alkylation of
Aldehydes with 3-Substituted 2-(Bromomethyl)acrylates
Jacqueline Jimenez,† Aitor Landa, Aitziber Lizarraga, Miguel Maestro,# Antonia Mielgo, Mikel Oiarbide,
́
Irene Velilla, and Claudio Palomo*
́ ́
Departamento de Química Organica I, Facultad de Química, Universidad del País Vasco, Apdo. 1072, 20080, San Sebastian, Spain
S
* Supporting Information
ABSTRACT: The catalytic direct α-alkylation of aldehydes with 2-
(bromomethyl)acrylates has been accomplished, giving rise to α-branched
and functionalized aldehydes of high diastereo- and enantiopurity. The
influence of the nature of the ester group of the acrylates in reaction
stereoselectivity and especially in reactivity is investigated. Optimum
conditions implicate the use of phenyl acrylates in conjunction with
organocatalyst 8. Application of thus obtained adducts in synthesis is
illustrated with a concise stereocontrolled preparation of trisubstituted
cyclopentenes.
At the outset, we were optimistic that the aldehydes
alkylation protocol according to Scheme 1 would also be
orming new carbon−carbon bonds directly adjacent to a
Fcarbonyl group constitutes one of the most versatile tools
during the construction of molecular complexity; therefore,
direct, catalytic, and asymmetric methodologies for the α-
alkylation of enolate equivalents are of great demand. While
most traditional studies have been focused on the α-alkylation
of carboxylic acid derivatives,1 and also ketones,2 recent works
based on the in situ generation of enamines as nascent enolate
equivalents,3,4 have allowed the realization of the direct α-
alkylation of aldehydes using a variety of electrophilic alkylating
reagents. Namely, ω-iodoaldehydes via an intramolecular SN2
mechanism,5,6 vinyl trifluoroborates, olefins, nitroalkanes,
allylsilanes, Togni’s reagent, and active bromides and iodides
via radical or organophotoredox mechanisms,7 or propargylic
alcohols,8 diarylmethanols,9 3-(1-arylsulfonylalkyl)indoles,10
and benzydryl halides11 via a SN1 pathway,12 have been
reported. In this context, and complementing the above
developments, we have recently reported a mechanistically
distinct enamine mediated asymmetric α-alkylation of alde-
hydes which relies on the use of 2-(bromomethyl)acrylates as
the alkylating reagent and most likely proceeds via a SN2′
pathway.13 Our preliminary study was largely restricted to the
use of 2, a relatively reactive alkylating reagent since the acrylate
β(or 3)-position remains unsubstituted. In contrast, initial
experiments soon evidenced difficulties in extending this
methodology to superior, 3-substituted 2-(bromomethyl)-
acrylates 5, which logically exhibit attenuated reactivity.
Furthermore, for β-substituted acrylates 5 control of the
relative configuration of the resulting products becomes an
additional concern of no obvious solution. Now, we have
developed conditions that satisfactorily address these two
limiting aspects thus expanding the range of alkylating reagents
amenable for this direct and enantioselective aldehydes α-
alkylation methodology.
Scheme 1. SN2′-Type Enamine-Mediated Asymmetric α-
Alkylation of Aldehydes with 2-(Bromomethyl)acrylates
applicable to β-substituted acrylates, thus giving access to a
relatively wide range of α-branched aldehyde products
enantioselectively (Scheme 2). Unfortunately, this was not
the case as, for example, the reaction of butyraldehyde 1A with
β-phenyl substituted acrylate 5a in the presence of DABCO
and a 20 mol % of catalyst 4 resulted unpractical (Table 1, entry
1) under several conditions examined. Reactions carried out in
the presence of DMAP proceed even worse (entry 2). Similar
constrains in reactivity were observed again with the ethyl
acrylate 5b which bears a p-chlorophenyl substituent. In this
instance, however, the measured level of reaction stereo-
selectivity was highly promising regardless of the amine catalyst
used (entries 3−5), an observation that prompted us to
investigate several other reaction parameters. During the study
it was eventually found that the ester group has a critical
Received: October 17, 2011
Published: December 2, 2011
© 2011 American Chemical Society
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The Journal of Organic Chemistry
Note
minor fluctuations in the range from 80:20 to 94:6, with ee’s
being around 95% or higher for the most cases. In general, a 6-
fold excess aldehyde was used for optimum results; when using
a 2-fold excess aldehyde reaction selectivity was maintained, but
at expenses of an elapsed reaction time.
Scheme 2. Organocatalytic α-Alkylation of Aldehydes with β-
Substituted 2-(Bromomethyl)acrylates
Regarding the reaction mechanism, previous work from this
laboratory has provided theoretical as well as experimental
evidence in support of a two step sequence for the alkylation
reactions involving unsubstituted acrylate 2. As outlined in
Scheme 1, the first step would involve formation of the
corresponding ammonium salt from 2 and DABCO or DMAP.
Subsequent SN2′-type displacement effected by in situ
generated enamine species would then render product 3. In
the current examples with β-substituted acrylates 5, formation
of the corresponding ammonium salt A (Figure 1a) as reaction
intermediate was confirmed in all cases by 1H NMR monitoring
of reaction aliquots. Interestingly, ammonium salts B,
regioisomeric to A, were not observed within the limit of
1
detection of H NMR, a fact that further support a SN2′ type
influence. Thus while thioester 5c did not lead to any
significant improvement under these conditions (entries 6−
7), a considerable increase in reaction conversion was observed
when phenyl ester 5f was the alkylating partner employed: less
significant with catalyst 4 (34% yield after 48 h, entry 8), but
notable with catalysts 7 and 8 (60% and 67% yield, respectively,
entries 9−10). Moreover, the latter two reactions proceeded
with good syn/anti selectivity and excellent enantioselectivity
for the major syn isomer, apparently being catalyst 8 slightly
superior. Finally, it was observed that variation of the electronic
nature of the ester aryl group, as in aryl acrylates 5d and 5e, did
not provide any significant improvement and generally led to
deleterious reactivity and/or selectivity (entries 11 and 12).
With the new conditions set, based on the use of O-phenyl
acrylates, catalyst 8, and DABCO as the coadyuvant amine base,
the reaction with several aldehydes and β-substituted acrylates
5f−j was explored (Table 2). It was gratifying to observe that
the reaction proceeded with generally good yields for aldehydes
bearing alkyl or alkenyl side chains (compounds 1A−C),
including those aldehydes with a carbamate, acetal, or ester
functionality (compounds 1D−F). With respect to the β-
substituent of the acrylate, not only aryl, but also the ester
group was tolerated (entries 5 and 9). Importantly, for the
range of aldehydes and β-substituted 2-(bromoethyl) acrylates
screened, the level of reaction diastereoselectivity display only
pathway for the subsequent C−C bond-forming step. On the
other hand, NMR analysis also showed that both the E- and Z-
configured ammonium salts A14 are formed in compositions
ranging from 60:40 to around 80:20 ratio in favor of E-A in all
cases studied and that this ratio remains essentially unchanged
at different reaction conversions for each individual case
(Supporting Information). These observations seem to indicate
that the reactivity of both the E and the Z ammonium salts
during the key SN2′ process, is comparable. Alternatively, a
scenario with differences in reactivity between the E and Z
isomers, but fast E/Z equilibration, cannot be ruled out. On the
other hand, the observed stereochemical outcome of the
reaction may be explained by invoking an open (antiperiplanar)
transition state with the enamine in its most stable, E/s-trans,
configuration. As the stereomodels in Figure 1b show, upon
this assumption the Si−Si approach would be the most
favorable in order to minimize severe gauche interactions,
which would nicely predict the observed sense of stereo-
induction.
In order to illustrate the utility of this catalytic reaction (eq
1), an aldehyde protection−Grubbs cyclization sequence was
applied to adducts 6Cf and 6Ch which rendered trisubstituted
cyclopentenes 9 and 10 as the only isolated diastereomers in
good yield and excellent enantioselectivity. Both the absolute
a
Table 1. Screening of the Catalyst and the Ester Group X of 5 for the Alkylation of 1A
b
c
entry
X
R1
product
cat.
yield (%)
30
syn/anti
ee (%)
1
2
EtO
EtO
Ph
6Aa
4
90:10
ND
98
ND
99
d
<5
e
3
4-ClC6H4
6Ab
4
7
8
4
8
4
7
8
4
4
<10
81:19
88:12
ND
e
4
20
95
e
5
<10
ND
98
e
6
PhS
Ph
6Ac
6Ad
24
70:30
70:30
85:15
87:13
91:9
e
7
20
95
e
8
PhO
4-ClC6H4
34
97
9
60
67
98
10
11
12
95
e
4-MeOC6H4O
4-ClC6H4O
6Ad
6Ae
<10
ND
ND
ND
62
85:15
a
Reactions carried out on a 0.3 mmol scale. General conditions: aldehyde (1.8 mmol), bromide (0.3 mmol), DABCO (0.3 mmol), and catalyst (20
b
c
1
mol %) were stirred in CH2Cl2 at 0 °C for 48 h. Determined by H NMR. ee of major (syn) diastereomer determined by chiral HPLC of crude
product before chromatography. Using DMAP. Incomplete reaction after 48 h.
d
e
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Note
a
Table 2. Scope of the Aldehyde and the β-Substituted 2-(Bromomethyl)acrylate
b
c
entry
aldehyde
acrylate
R1
product
T (°C)
yield (%)
syn/anti
ee (%)
d
1
2
1A
5f
5g
5h
5i
5j
5f
5f
5h
5j
5f
5f
5f
4-ClC6H4
Ph
6Af
6Ag
6Ah
6Ai
6Aj
6Bf
6Cf
6Ch
6Cj
6Df
6Ef
6Ff
0
0
67
91:9
95
98
95
97
98
98
95
96
96
94
90
87
60
83
65
66
50
94:6
3
4-MeC6H4
4-CNC6H4
CO2Me
20
0
89:11
87:13
87:13
92:8
4
5
0
6
1B
1C
4-ClC6H4
4-ClC6H4
4-MeC6H4
CO2Me
0
e
7
0
78
91:9
8
0
62
64
87
69
65
92:8
9
0
82:18
90:10
81:19
80:20
10
11
12
1D
1E
1F
4-ClC6H4
4-ClC6H4
4-ClC6H4
20
20
20
a
Reactions carried out on a 0.3 mmol scale. General conditions: aldehyde (1.8 mmol), 2-(bromomethyl)acrylate (0.3 mmol), DABCO (0.3 mmol),
b
c
and catalyst 8 (20 mol %) were stirred in CH2Cl2 for 48 h at the indicated temperature. Determined by 1H NMR. ee of major (syn) diastereomer
determined by HPLC of crude product before chromatography. Using catalyst 7. Reactions carried out at 1.4 mmol scale.
d
e
Watanabe,17 respectively. Aldehyde 1D was prepared as described
below. Catalyst 7 was obtained from commercial sources and
immediately before use was dissolved in CH2Cl2 and washed with
saturated NaHCO3 aqueous solution. Catalysts 4 and 8 were prepared
following previously reported methods.13,18 1H and 13C NMR spectra
were recorded at 300 and 75 MHz instruments. Chemical shifts are
reported in ppm relative to CDCl3 (δ = 7.26) for 1H NMR and to the
central resonances of CDCl3 (δ = 77.0) for 13C NMR. Analytical high
performance liquid chromatography (HPLC), optical rotations, and
MS spectra were recorded on standard instruments. Purification of
reaction products was carried out by flash column chromatography
using silica gel 60 (0.040−0.063 mm, 230−400 mesh). Visualization
(TLC) was accomplished with a solution of phosphomolybdic acid (1
g) in 100 mL of ethanol (limited lifetime), followed by heating.
Preparation of Aldehyde 1D. The following procedure adapted
from Cushman et al.19 was employed. CH2Cl2 (100 mL) and (COCl)2
(3.9 mL, 46 mmol, 1.5 equiv) were successively placed in an oven-
dried three-necked flask, and the solution was cooled to −60 °C under
dry Ar. DMSO (4.8 mL, 68 mmol) in CH2Cl2 (15 mL) was added at a
rate where a temperature below −60 °C was maintained. The mixture
was then stirred for ca. 5 min followed by dropwise addition of a
solution of the N-Boc aminohexanol (31 mmol) in CH2Cl2 (25 mL)
over a period of ca. 5 min. The mixture was stirred for an additional 25
min, then rapidly quenched with Et3N (22 mL, 0.16 mol). The
obtained white slurry was stirred for ca. 5 min and then allowed to
warm to room temperature. The reaction mixture was washed with
water (300 mL) and the aqueous layer was extracted with Et2O (300
mL). The combined organic layers were washed with brine (2 × 200
mL). The residue was subjected to flash chromatography (eluent: n-
hexane/ethyl acetate 5:1), yielding a colorless oil (yield 90%) with
physical and spectroscopic data coincident with previously reported.19
Preparation of 2-(Bromomethyl)acrylates 5e−i. A three-step
sequence was applied following procedures adapted from liter-
ature.20,21 Acryloylchloride (7.28 g, 80 mmol) in dichloromethane
(10 mL) was added within 0.5 h to a solution of the corresponding
aryl alcohol (80 mmol) and triethylamine (10.1 g, 100 mmol) in
dichloromethane (20 mL). The reaction mixture was stirred at room
temperature for 24 h, then washed with water (2 × 30 mL) and
extracted with dichloromethane (2 × 10 mL). The organic layer was
dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure and the residue was purified by silica gel
chromatography (hexane/EtOAc 95:5) to give the aryl acrylate as a
colorless oil. Ten mmol of this acrylate was added to a solution of
DABCO (360 mg, 3 mmol) and the corresponding aldehyde (5
mmol) in DMF (5 mL), and the reaction mixture was stirred at room
temperature for 60 h. The reaction product was extracted with
dichloromethane (100 mL) and washed with water (3 × 100 mL). The
organic layer was dried over anhydrous MgSO4, the solvent was
removed under reduced pressure and the residue was purified by flash
Figure 1. (a) Two possible regioisomeric ammonium salt
intermediates and (b) proposed transition state models that would
account for the formation of syn and anti products from A.
and the relative configuration of 9 were unequivocally
established by X-ray structure analysis. Thus configurational
assignment of the precursor 6Cf was made by correlation and
for the remaining adducts by analogy assuming a uniform
reaction mechanism.
In conclusion, the present catalytic system introduces an
operationally simple protocol for the α-alkylation of aldehydes
with β-substituted α-(bromomethyl)acrylates. A distinguishing
feature of the method is that the C−C bond forming step
proceeds with concomitant generation of two contiguous
stereocenters with high diastereo- and enantioselectivity. The
method, moreover, provides a quick entry for the stereo-
controlled synthesis of trisubstituted 5-membered carbocycles,
an important class of products for further elaboration.15
EXPERIMENTAL SECTION
■
General and Materials. All solvents were of p.a. quality and were
dried by standard procedures prior to use when necessary. Materials
were obtained from commercial sources and used without purification
unless otherwise specified. Aldehydes were obtained from commercial
sources or prepared through known procedures, purified by distillation
and stored in the refrigerator at −30 °C under argon. Aldehydes 1E
and 1F were prepared according to the procedures of Tanaka16 and
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The Journal of Organic Chemistry
Note
silica gel column chromatography (hexane/EtOAc 8:2) to give the
corresponding Baylis−Hillman adducts. To a solution of thus obtained
adduct (3 mmol) in dichloromethane (10 mL) LiBr (6 mmol) and
DABCO (39 mg, 0.315 mmol), and butanal (0.16 mL, 1.8 mmol),
the crude material was purified by flash column chromatography on
silica gel (eluting with hexane/ethyl acetate 95/5) to give the title
compound as a colorless oil. Yield: 67% (69 mg). Spectroscopic data
of the major diastereomer: 1H NMR (300 MHz, CDCl3) δ 9.61 (d, J =
4.2 Hz, 1H), 7.39−7.21 (m, 7H), 7.01−6.99 (m, 2H), 6.61 (s, 1H),
5.94 (s, 1H), 4.25 (d, J = 11.5 Hz, 1H), 2.98−2.88 (m, 1H), 1.53−1.43
(m, 2H), 0.83 (t, 3H, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ
203.2, 164.8, 150.6, 141.0, 137.9, 130.0, 128.9, 125.9, 121.5, 56.3, 45.4,
22
previously prepared NaHSO4·SiO2 (300 mg) were added. The
mixture was stirred at room temperature and the reaction was
monitored by TLC. On completion the mixture was filtered and the
filtrate was concentrated and subjected to flash column chromatog-
raphy over silica gel (hexane/EtOAc 95:5 to 90:10).
Data of 5e. Starting from 4-chlorophenol (step 1, 10 mmol) and 4-
chlorobenzaldehyde (step 2): overall yield 65%; white solid; mp 70.8
°C; 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.57 (d, J = 8.4 Hz,
2H), 7.47 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.7
Hz, 2H), 4.45 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 164.3, 149.2,
143.1, 139.2, 136.2, 132.3, 131.0, 130.4, 129.3, 128.5, 122.9, 26.0;
HRMS C16H11BrCl2O2 [M + H]+ calcd 386.9380, found 386.9377.
Data of 5f. Starting from phenol (step 1, 30 mmol) and 4-
chlorobenzaldehyde (step 2): overall yield 65%; white solid; mp 77
°C; 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.60 (d, J = 8.4 Hz,
2H), 7.52−7.35 (m, 4H), 7.33−7.21 (m, 3H). 4.49 (s, 2H); 13C NMR
(75 MHz, CDCl3) δ 164.4, 150.7, 142.7, 138.8, 136.0, 132.4, 131.0,
129.4, 129.2, 125.9, 121.5, 26.9; HRMS C16H12BrClO2 [M + H]+ calcd
352.9780, found 352.9766.
Data of 5g. Starting from phenol (step 1, 10 mmol) and
benzaldehyde (step 2); overall yield 58%; white solid; mp 58−60
°C; 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.65 (d, J = 6.8 Hz,
2H), 7.54−7.40 (m, 5H), 7.30−7.20 (m, 3H), 4.51 (s, 2H); 13C NMR
(75 MHz, CDCl3) δ 164.7, 150.8, 144.3, 134.0, 128.9, 125.9, 121.6,
26.6; HRMS C16H13BrO2 [M + H]+ calcd 317.0177, found 317.0180.
Data of 5h. Starting from phenol (step 1, 10 mmol) and 4-
methylbenzaldehyde (step 2): overall yield 63%; white solid; mp 68
°C; 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.58 (d, J = 8.1 Hz,
2H), 7.45 (t, J = 7.83 Hz 2H), 7.36−7.20 (m, 5H), 4.56 (s, 2H), 2.44
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.9, 150.9, 144.5, 140.5,
131.2, 130.0, 129.7, 129.4, 127.4, 125.8, 121.6, 26.9, 21.4; HRMS
C17H15BrO2 [M + H]+ calcd 331.0332, found 331.0334.
1
21.2, 11.0. The diastereomeric ratio (91:9) was determined by H
NMR. The enantiomeric excess was determined by HPLC with
Chiralpack IC column at 254 nm (hexane/iPrOH in the ratio of 90/
10, flow rate = 0.5 mL/min, tR = 15.8 min (minor), tR = 16.6 min
(major)); HRMS C20H20ClO3 [M + H]+ calcd 343.1101, found
343.1089.
(3S,4R)-Phenyl 4-Formyl-2-methylene-3-phenylhexanoate
(6Ag) (Entry 2, Table 2). Starting from (Z)-phenyl 2-(bromometh-
yl)-3-phenylacrylate (95 mg, 0.3 mmol), DABCO (39 mg, 0.315
mmol), and butanal (0.16 mL, 1.8 mmol), the crude material was
purified by flash column chromatography on silica gel (eluting with
hexane/ethyl acetate 95/5) to give the title compound as a colorless
oil. Yield: 60% (55 mg). Spectroscopic data of the major diastereomer:
1H NMR (300 MHz, CDCl3) δ 9.59 (d, J = 4.3 Hz, 1H), 7.35−7.17
(m, 7H), 7.21−7.18 (m, 1H), 6.96 (d, 2H, J = 7.6 Hz), 6.57 (s, 1H),
5.92 (s, 1H), 4.25 (d, 1H, J = 11.5 Hz), 2.95−2.89 (m, 1H), 1.50−1.43
(m, 2H), 0.83 (t, 3H, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3): δ
203.7, 165.0, 150.7, 141.3, 139.3, 129.4, 128.7, 127.2, 125.8, 121.5,
56.7, 46.0, 21.2, 11.1. The diastereomeric ratio (94:6) was determined
by 1H NMR. The enantiomeric excess was determined by HPLC with
Chiralpack AS-H column at 210 nm (hexane/iPrOH in the ratio of
98/2, flow rate = 0.5 mL/min, tR = 19.9 major, tR = 22.0 min); HRMS
C20H20O3 [M + H]+ calcd 309.1491, found 309.1504.
(3S,4R)-Phenyl 4-Formyl-2-methylene-3-p-tolylhexanoate
(6Ah) (Entry 3, Table 2). Starting from (Z)-phenyl 2-(bromometh-
yl)-3-p-tolylacrylate (99 mg, 0.3 mmol), DABCO (39 mg, 0.315
mmol), and butanal (0.16 mL, 1.8 mmol), the crude material was
purified by flash column chromatography on silica gel (eluting with
hexane/ethyl acetate 95/5) to give the title compound as a colorless
oil. Yield: 83% (80 mg). Spectroscopical data of the major
Data of 5i. Starting from phenol (step 1, 10 mmol) and 4-
cyanobenzaldehyde (step 2): overall yield 14%; white solid; mp 106.3
1
°C; H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.75 (dd, J = 8.4,
20.9 Hz, 4H), 7.44 (t, J = 7.8 Hz, 2H), 7.33−7.18 (m, 3H), 4.41 (s,
2H); 13C NMR (75 MHz, CDCl3) δ 164.1, 150.7, 141.5, 138.5, 132.6,
131.3, 129.9, 129.6, 126.2, 121.4, 118.1, 115.3, 113.3, 25.2; HRMS
C17H12BrNO2 [M + H]+ calcd 342.0144, found 342.0130.
1
diastereomer: H NMR (300 MHz, CDCl3) δ 9.59 (d, J = 4.3 Hz,
1H), 7.41−7.30 (m, 2H), 7.28−7.10 (m, 5H), 7.02−6.95 (m, 2H),
6.56 (s, 1H), 5.91 (s, 1H), 4.23 (d, J = 11.5 Hz, 1H), 2.97−2.85 (m,
1H), 2.34 (s, 3H) 1.53−1.41 (m, 2H), 0.84 (t, J = 7.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 203.8, 165.0, 150.8, 141.5, 136.8, 136.2,
129.3, 128.5, 126.9, 125.7, 121.5, 56.6, 45.6, 21.1, 21.0, 11.1. The
diastereomeric ratio (89:11) was determined by 1H NMR. The
enantiomeric excess was determined by HPLC with Chiralpack AS-H
column at 254 nm (hexane/iPrOH in the ratio of 95:5, flow rate = 0.5
mL/min tR = 18.5 min (major), tR = 21.0 min (minor)); HRMS
C21H22O3 [M + H]+ calcd 322.1569, found 322.1584.
Preparation of 5j. (Adapted from the literature.23) A mixture of
dimethyl methylmaleate (1.58 g, 10 mmol), N-bromosuccinimide
(2.67 g, 15 mmol), and a catalytic amount of AIBN (33 mg, 0.20
mmol) in carbon tetrachloride (50 mL) was gently refluxed for 12 h in
a 100 mL round-bottom flask. The mixture was left overnight at room
temperature and then filtered. The residue was washed with CCl4 (4
mL × 2); the combined organic layer was washed with water (15 mL)
and brine (10 mL) and then dried over Na2SO4. The organic layer was
concentrated in vacuo to furnish a thick yellow oil, which was purified
by flash column chromatography on silica gel (hexane/ethyl acetate
90:10). The product’s physical and chemical characterization data were
coincident with the reported data.23
(3S,4R)-Phenyl 3-(4-cyanophenyl)-4-formyl-2-methylene-
hexanoate (6Ai) (Entry 4, Table 2). Starting from (Z)-phenyl 2-
(bromomethyl)-3-(4-cyanophenyl)acrylate (103 mg, 0.3 mmol),
DABCO (39 mg, 0.315 mmol), and butanal (0.16 mL, 1.8 mmol),
the crude material was purified by flash column chromatography on
silica gel (eluting with hexane/ethyl acetate 95/5) to give the title
compound as a colorless oil. Yield: 65% (65 mg). Spectroscopic data
of the major diastereomer: 1H NMR (300 MHz, CDCl3) δ 9.60 (d, J =
3.9 Hz, 1H), 7.63 (dd, J = 1.7, 6.6 Hz, 2H), 7.47−7.17 (m, 5H), 6.97
(dd, J = 1.1, 7.5 Hz, 2H), 6.64 (s, 1H), 5.97 (s, 1H), 4.31 (d, J = 11.6
Hz, 1H), 3.03−2.92 (m, 1H), 1.55−1.36 (m, 2H), 0.85 (t, J = 7.5 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 202.5, 164.5, 150.4, 145.0, 140.2,
135.5, 132.4, 129.5, 128.0, 126.0, 121.3, 118.5, 111.2, 55.8, 46.0, 21.1,
General Procedure for the Catalytic α-Alkylation of
Aldehydes with 5. A solution of the corresponding 2-(bromometh-
yl)-3-(aryl)acrylate 5 (0.3 mmol) and DABCO (39 mg, 0.315 mmol)
in CH2Cl2 (1 mL) was stirred at room temperature for 30 min and
then was cooled to the specified temperature (Table 2). To this cooled
solution were successively added freshly distilled aldehyde 1 (6 equiv)
and catalyst 8 (0.06 mmol, 20 mol %). The mixture was stirred at
specified temperature and time (see below), then diluted with
dichloromethane (10 mL), washed with H2O (10 mL), HCl 1 N
(10 mL) and brine (10 mL), and dried with anhydrous MgSO4. The
solvent was evaporated under vacuum and the crude material was
purified by flash chromatography (eluent EtOAc/Hex from 2:98 to
10:90).
1
10.9. The diastereomeric ratio (87:13) was determined by H NMR.
The enantiomeric excess was determined by HPLC with Chiralpack
AD-H column at 254 nm (hexane/iPrOH in the ratio of 90:10, flow
rate = 0.5 mL/min, tR = 40.2 min (major), tR = 45.4 min (minor));
HRMS C21H19NO3 [M + H]+ calcd 334.1443, found 334.1436.
(3R,4R)-Methyl 3-(Methoxycarbonyl)-4-formyl-2-methylene-
hexanoate (6Aj) (Entry 5, Table 2). Starting from dimethyl
(3S,4R)-Phenyl 3-(4-chlorophenyl)-4-formyl-2-methylene-
hexanoate (6Af) (Entry 1, Table 2). Starting from (Z)-phenyl 2-
(bromomethyl)-3-(4-chlorophenyl)acrylate (106 mg, 0.3 mmol),
750
dx.doi.org/10.1021/jo202073n | J. Org. Chem. 2012, 77, 747−753

The Journal of Organic Chemistry
Note
bromomethylfumarate (72 mg, 0.3 mmol), DABCO (39 mg, 0.315
mmol), and butanal (0.16 mL, 1.8 mmol), the crude material was
purified by flash column chromatography on silica gel (eluting with
hexane/ethyl acetate 90/10) to give the title compound as a colorless
oil. Yield: 66% (45 mg). Spectroscopic data of the major diastereomer:
1H NMR (300 MHz, CDCl3) δ 9.59 (d, J = 2.6 Hz, 1H), 6.43 (s, 1H),
5.82 (s, 1H), 4.00 (d, J = 8.7 Hz, 1H), 3.78 (s, 3H), 3.71 (s, 3H),
97/3, flow rate = 0.5 mL/min, tR = 15.5 min, tR = 19.2 major); HRMS
C22H22O3 [M + H]+ calcd 335.1647, found 335.1663.
(3R,4R)-Methyl 4-Formyl-3-methoxycarbonyl-2-methylene-
hept-6-enoate (6Cj) (entry 9, Table2). Starting from dimethyl
bromomethylfumarate (72 mg, 0.3 mmol), DABCO (39 mg, 0.315
mmol), and 4-pentenal (0.18 mL, 1.8 mmol), the crude material was
purified by flash column chromatography on silica gel (eluting with
hexane/ethyl acetate 98/2) to give the title compound as a colorless
oil. Yield: 64% (46 mg). Spectroscopic data of the major diastereomer:
1H NMR (300 MHz, CDCl3) δ 9.65 (d, J = 1.8 Hz, 1H), 6.43 (s, 1H),
2.90−2.80 (m, 1H), 1.81−1.69 (m, 2H), 0.93 (t, J = 3.6 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) δ 202.0, 171.9, 166.3, 136.1, 128.7, 54.7, 52.3,
45.8, 20.5, 11.5. The diastereomeric ratio (87:13) was determined by
1H NMR. The enantiomeric excess was determined by HPLC with
5.81 (s, 1H), 5.78−5.65 (m, 1H), 5.07 (dd, J = 1.5, 5.3 Hz, 2H), 4.00
(d, J = 8.0 Hz, 1H), 3.77 (s, 3H), 3.71 (s, 3H), 3.10−3.02 (m, 1H),
2.57−2.50 (m, 1H), 2.37−2.31 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 201.6, 171.8, 166.1, 135.8, 134.2, 129.1, 127.4, 118.1, 52.4, 45.9, 31.3.
Chiralpack IC column at 209.8 nm (hexane/iPrOH in the ratio of 90/
10, flow rate = 0.5 mL/min, tR = 48.8 min (mayor), tR = 53.3 min
(minor)); HRMS C11H16O5 [M + H]+ calcd 229.1076, found
229.1075.
1
The diastereomeric ratio (82:18) was determined by H NMR. The
enantiomeric excess was determined by HPLC with Chiralpack IC
column at 209.8 nm (hexane/iPrOH in the ratio of 90/10, flow rate =
0.5 mL/min, tR = 37.5 min (minor), tR = 44.7 min (major)); HRMS
C12H17O5 [M + H]+ calcd 241.1076, found 241.1083.
(3S,4R)-Phenyl 3-(4-Chlorophenyl)-4-formyl-2-methyleneoc-
tanoate (6Bf) (Entry 6, Table 2). Starting from (Z)-phenyl 2-
(bromomethyl)-3-(4-chlorophenyl)acrylate (106 mg, 0.3 mmol),
DABCO (39 mg, 0.315 mmol), and hexanal (0.22 mL, 1.8 mmol),
the crude material was purified by flash column chromatography on
silica gel (eluting with hexane/ethyl acetate 98/2) to give the title
compound as a yellow oil. Yield: 50% (57 mg). Spectroscopic data of
(3S,4R)-Phenyl 8-(tert-Butoxycarbonylamino)-3-(4-chloro-
phenyl)-4-formyl-2-methyleneoctanoate (6Df) (Entry 10,
Table 2). Starting from (Z)-phenyl 2-(bromomethyl)-3-(4-
chlorophenyl)acrylate (106 mg, 0.3 mmol), DABCO (39 mg, 0.315
mmol) and 6-(N-Boc-amino)hexanal (387 mg, 1.8 mmol). The crude
material was purified by flash column chromatography on silica gel
(eluting with hexane/ethyl acetate 90/10) to give the title compound
as a yellow oil. Yield: 87% (127 mg). Spectroscopic data of the major
1
the major diastereomer: H NMR (300 MHz, CDCl3) δ 9.56 (d, J =
4.7 Hz, 1H), 7.36−7.18 (m, 7H), 6.99 (d, J = 8.4 Hz, 2H), 6.58 (s,
1H), 5.91 (d, J = 0.9 Hz, 1H), 4.20 (d, J = 11.5 Hz, 1H), 3.01−2.91
(m, 1H), 1.38−1.06 (m, 6H), 0.92−0.86 (m, 3H); 13C NMR (75
MHz, CDCl3) δ 203.3, 150.6, 141.0, 138.0, 133.1, 130.1, 126.0, 121.5,
54.9, 45.8, 28.7, 22.5, 13.7. The diastereomeric ratio (92:8) was
1
diastereomer: H NMR (300 MHz, CDCl3): δ 9.60 (d, J = 4.2 Hz,
1H), 7.38−7.23 (m, 7H), 7.00 (d, J = 7.4 Hz, 2H), 6.61 (s, 1H), 5.95
(s, 1H), 4.23 (d, J = 11.5 Hz), 3.18−3.09(m, 1H), 3.07−2.96 (m, 2H),
1.51−1.48 (m, 2H), 1.47 (s, 3H), 1.46 (s, 6H), 1.41−1.31 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 202.0, 164.7, 155.9, 150.6, 140.9, 137.8,
133.2, 129.4, 129.0, 127.6, 126.0, 121.4, 70.8, 54.8, 45.8, 40.1, 30.0,
28.4, 27.7, 23.8. The diastereomeric ratio (90:10) was determined by
1H NMR. The enantiomeric excess was determined by HPLC with
1
determined by H NMR.The enantiomeric excess was determined by
HPLC with Chiralpack IB column at 210 nm (hexane/iPrOH in the
ratio of 99/1, flow rate = 0.5 mL/min, tR = 15.9 min, tR = 18.2 major);
HRMS C22H24ClO3 [M + H − C6H5O]+ calcd 277.0995, found
277.1002.
(3S,4R)-Phenyl 3-(4-Chlorophenyl)-4-formyl-2-methylene-
hept-6-enoate (6Cf) (Entry 7, Table 2). Starting from (Z)-phenyl
2-(bromomethyl)-3-(4-chlorophenyl)acrylate (106 mg, 0.3 mmol),
DABCO (39 mg, 0.315 mmol), and 4-pentenal (0.18 mL, 1.8 mmol),
the crude material was purified by flash column chromatography on
silica gel (eluting with hexane/ethyl acetate 95/5) to give the title
compound as a yellow oil. Yield: 78% (84 mg). Spectroscopic data of
Chiralpack IC column at 254 nm (hexane/iPrOH in the ratio of 80/
20, flow rate =0.5 mL/min, tR = 42.5 min (major), tR = 46.2 min
(minor); HRMS C27H33ClNO5 [M + H − C5H10O2]+ calcd 368.1417,
found 368.1416.
(3S,4R)-Phenyl 3-(4-Chlorophenyl)-4-formyl-6,6-dimethoxy-
2-methylenehexanoate (6Ef) (Entry 11, Table 2). Starting from
4,4-dimethoxybutanal (3 mmol, 3 equiv), (Z)-phenyl 2-(bromometh-
yl)-3-(4-chlorophenyl)acrylate (176 mg, 0.5 mmol), and DABCO
(56.1 mg, 0.51 mmol) at room temperature for 60 h according to the
general procedure: yield 69% (140 mg) (diastereomeric ratio 5:1); 1H
NMR (major diastereoisomer) (300 MHz, CDCl3) δ 9.67 (d, J = 3.3
Hz, 1H), 7.40−7.18 (m, 7H), 7.00−6.96 (m, 2H), 6.59 (s, 1H), 5.97
(d, 1H, J = 0.9 Hz), 4.26−4.20 (m, 2H), 3.24 (s, 3H), 3.22 (s, 3H),
1.90−1.80 (m, 2H), 1.63−1.53 (m, 1H); 13C NMR (major
diastereoisomer) (75 MHz, CDCl3) δ 202.5, 164.6, 150.6, 140.6,
137.8, 133.2, 130.0, 129.9, 129.4, 128.9, 127.5, 125.9, 121.4, 103.0,
54.2, 53.3, 50.2, 46.1, 32.5. The diastereomeric ratio (81:19) was
determined by 1H NMR. The enantiomeric excess was determined by
HPLC with Chiralpack IA column at 254 nm (hexane/iPrOH in the
ratio of 98/2, flow rate = 0.5 mL/min, tR = 31.9 min (major), tR = 46.7
min (minor)).
1
the major diastereomer: H NMR (300 MHz, CDCl3) δ 9.63 (d, J =
3.6 Hz, 1H), 7.39−7.29 (m, 4H), 7.25−7.18 (m, 3H), 7.00−6.96 (m,
2H), 6.58 (s, 1H), 5.91 (d, J = 1.0 Hz, 1H), 5.63 (dt, J = 8.5, 8.5, 17.1
Hz, 1H), 5.08−4.92 (m, 2H), 4.28 (d, J = 11.4 Hz, 1H), 3.14 (dd, J =
3.6, 11.4 Hz, 1H), 2.19 (t, J = 6.5 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 202.8, 164.7, 150.6, 140.8, 137.6, 135.6, 133.3, 130.0, 129.4,
128.9, 127.3, 125.9, 121.4, 118.1, 54.1, 45.3, 32.5. The diastereomeric
1
ratio (91:9) was determined by H NMR. The enantiomeric excess
was determined by HPLC with Chiralpack IC column at 254 nm
(hexane/iPrOH in the ratio of 95/5, flow rate =0.5 mL/min, tR = 22.0
min, tR = 25.1 major); HRMS C21H20ClO3 [M + H − C6H5O]+ calcd
261.0682, found 261.0682.
(3S,4R)-Phenyl 4-Formyl-2-methylene-3-p-tolylhept-6-
enoate (6Ch) (Entry 8, Table 2). Starting from (Z)-phenyl 2-
(bromomethyl)-3-p-tolylacrylate (99 mg, 0.3 mmol), DABCO (39 mg,
0.315 mmol), and 4-pentenal (0.18 mL, 1.8 mmol), the crude material
was purified by flash column chromatography on silica gel (eluting
with hexane/ethyl acetate 95/5) to give the title compound as a
colorless oil. Yield: 62% (62 mg). Spectroscopic data of the major
diastereomer: 1H NMR (300 MHz, CDCl3) δ 9.63 (d, J = 3.8 Hz, 1H),
7.34 (t, J = 7.7 Hz 2H), 7.22−7.11 (m, 4H), 7.00−6.96 (m, 2H), 6.83
(d, J = 7.6 Hz, 1H), 6.55 (s, 1H), 5.90 (d, J = 1.0 Hz, 1H), 5.65 (dt, J =
8.6, 17.2 Hz, 1H), 4.98 (dd, J = 6.1, 26.2 Hz, 2H), 4.25 (d, J = 11.4 Hz,
1H), 3.13 (dd, J = 3.9, 11.3 Hz, 1H), 2.34 (s, 3H), 2.38−2.30 (m, 1H),
2.21 (t, J = 6.8, Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 203.5, 165.0,
150.7, 141.4, 133.9, 129.5, 125.8, 121.5, 120.8, 117.8, 115.3, 54.6, 45.6,
(3S,4R)-7-Methyl 1-Phenyl 3-(4-chlorophenyl)-4-formyl-2-
methyleneheptanedioate (6Ff) (Entry 12, Table 2). Starting
from methyl 5-oxopentanoate (3 mmol, 3 equiv), (Z)-phenyl 2-
(bromomethyl)-3-(4-chlorophenyl)acrylate (176 mg, 0.5 mmol), and
DABCO (56.1 mg, 0.51 mmol) at room temperature for 60 h
according to the general procedure: yield 65% (132 mg)
1
(diastereomeric ratio 4:1); H NMR (major diastereoisomer) (300
MHz, CDCl3) 9.59 (d, J = 4.0 Hz, 1H), 7.37−7.30 (m, 3H), 7.27−7.21
(m, 4H), 6.99 (dd, J = 8.4, 9.7 Hz, 2H), 6.60 (s, 1H), 5.94 (s, 1H),
4.24−4.21(m, 1H), 4.08 (t, J = 6.1 Hz, 2H), 3.68 (s, 3H) 2.44−2.38
(m, 2H), 1.74−1.70 (m, 2H); 13C NMR (major diastereoisomer) (75
MHz, CDCl3) δ 202.4, 172.8, 164.6, 150.5, 140.6, 137.3, 133.3, 129.0,
121.4, 63.9, 53.8, 51.6, 51.5, 46.0, 30.8, 28.0, 22.9, 21.4, 20.1. The
diastereomeric ratio (80:20) was determined by 1H NMR. The
1
32.7, 21.0. The diastereomeric ratio (92:8) was determined by H
NMR. The enantiomeric excess was determined by HPLC with
Chiralpack AD-H column at 254 nm (hexane/iPrOH in the ratio of
751
dx.doi.org/10.1021/jo202073n | J. Org. Chem. 2012, 77, 747−753

The Journal of Organic Chemistry
Note
enantiomeric excess was determined by HPLC with Chiralpack AS-H
column at 210 nm (hexane/iPrOH in the ratio of 95/5, flow rate = 0.5
mL/min, tR = 53.3 min (major), tR = 60.0 min (minor)); HRMS
C22H21ClO5 [M + H − C6H5O]+ calcd 308.0815, found 308.0794.
Ring-Closing Metathesis. Synthesis of Cyclopentenes 9 and
10. Triethyl orthoformate (429 μL, 2.58 mmol) and pTsOH·H2O
(32.7 mg, 0.17 mmol, 20 mol %) were added to a solution of the
corresponding adduct 6C (0.86 mmol) in EtOH (6 mL). The mixture
was stirred for 3 h at room temperature. After dilution with
dichloromethane (10 mL), the mixture was washed with 1% aqueous
NaOH (10 mL) and brine (10 mL), and the aqueous layer was
extracted with dichloromethane (3 × 10 mL). The combined organic
layers were dried (MgSO4), and evaporation of the solvent under
reduced pressure gave a brown oil of protected adduct, which was used
as such in the next step. To a solution of this diethyl acetal protected
aldehyde (0.8 mmol) in dry dichloromethane (6 mL) and under argon
atmosphere was added Grubbs' second-generation catalyst (35 mg, 5
mol %). The reaction mixture was refluxed for 12 h (50 °C), diluted
with dichloromethane (10 mL), and filtered through a small pad of
silica gel (with dichloromethane rinsing). Evaporation of the solvent
under reduced pressure gave an oil that was purified through column
chromatography (eluent EtOAc/hexane 1:9).
ACKNOWLEDGMENTS
■
This work was financially supported by the University of the
Basque Country (UPV/EHU) and Ministerio de Educacion
Ciencia (Grant CTQ2007-68095-C02). J.J. thanks CONACYT
(Mexico) and A.L. and I.V. thank UPV/EHU for fellowships.
A.L. thanks MEC and the European Social Foundation for a
Ramon y Cajal contract.
́
y
́
́
REFERENCES
■
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cyclopent-1-enecarboxylate (9): overall yield from 6Cf (0.86
1
mmol) 322 mg, 71%; H NMR (CDCl3, 500 MHz) δ 7.33−7.11 (m,
8H), 6.94−6.90 (m, 1H), 4.26 (dd, J = 9.0, 1.8 Hz, 1H), 3.90 (d, 1H, J
= 9.0 Hz), 3.55−3.42 (m, 3H), 3.12−3.00 (m, 1H), 2.96−2.86 (m,
1H), 2.71−2.54 (m, 2H), 1.15 (t, 3H, J = 6.9 Hz), 1.11 (t, 3H, J = 6.9
Hz); 13C NMR (75 MHz, CDCl3) δ 162.2, 150.5, 145.6, 139.3, 137.5,
132.4, 130.0, 129.1, 128.1, 125.5, 121.3, 103.2, 62.1, 60.4, 50.5, 46.5,
34.3, 15.4, 15.0. The enantiomeric excess was determined by HPLC
with Chiralpack AY-H column at 254 nm (hexane/iPrOH in the ratio
of 95/5, flow rate = 0.5 mL/min, tR = 16.3 min (major), tR = 26.2 min
(minor)); HRMS C23H25ClO4 [M − C2H5O]+ calcd 355.1101, found
355.1098.
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1
mg, 77%; mp 81−83 °C; H NMR (CDCl3, 300 MHz) δ: 7.31−7.22
(m, 2H), 7.17−7.03 (m, 5H), 6.95−6.90 (m, 2H), 4.24 (d, 1H, J = 8.9
Hz), 3.91 (d, 1H, J = 9.1 Hz), 3.56−3.40 (m, 3H), 3.09−2.97 (m, 1H),
2.90 (dq, 1H, J = 7.1, 14.1 Hz), 2.64−2.59 (m, 2H), 2.31 (s, 3H),
1.16−1.08 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 162.4, 150.6,
145.1, 139.8, 135.5, 128.7, 125.4, 121.5, 103.5, 62.1, 60.3, 50.7, 46.7,
34.4, 21.0, 15.5, 15.1. The enantiomeric excess was determined by
HPLC with Chiralpack IC column at 254 nm (hexane/iPrOH in the
ratio of 95/5, flow rate = 0.5 mL/min, tR = 15.5 min (major), tR = 19.2
min (min)); HRMS C24H28O4 [M−C2H5O]+ calcd 335.1647, found
335.1631.
Sunden
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, H.; Dziedzic, P.; Cor
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dova, A. Chem.Eur. J. 2008, 14, 7867−
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ASSOCIATED CONTENT
■
S
* Supporting Information
Selected NMR spectra, HPLC chromatograms, and X-ray data
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
D.; Brase, S. J. Am. Chem. Soc. 2009, 131, 2086−2087. Also see:
̈
(f) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133,
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Cozzi, P. G. Chem. Commun. 2009, 5919−5921. (h) Neumann, M.;
Fuldner, S.; Konig, B.; Zeitler, K. Angew. Chem., Int. Ed. 2011, 50,
̈
̈
AUTHOR INFORMATION
951−954. (i) Zhang, B.; Xiang, S.-K.; Zhang, L.-H.; Cui, Y.; Jiao, N.
■
Org. Lett. 2011, 13, 5212−5215.
Corresponding Author
(8) (a) Ikeda, M.; Miyake, Y.; Nishibayashi, Y. Angew. Chem., Int. Ed.
2010, 49, 7289−7293. (b) Sinisi, R.; Vita, M. V.; Gualandi, A.; Emer,
E.; Cozzi, P. G. Chem.Eur. J. 2011, 17, 7404−7408. (c) Yoshida, A.;
Ikeda, M.; Hattori, G.; Miyake, Y.; Nishibayashi, Y. Org. Lett. 2011, 13,
592−595.
*E-mail: claudio.palomo@ehu.es.
Present Addresses
†Centro de Investigacion
́
, Facultad de Ciencias Quımicas,
́
́ ́
Benemerita Universidad Autonoma de Puebla, Mexico.
(9) (a) Cozzi, P. G.; Benffati, F.; Zoli, L. Angew. Chem., Int. Ed. 2009,
48, 1313−1316. (b) Zhang, L.; Cui, L.; Li, X.; Li, J.; Luo, S.; Cheng, J.-
P. Chem.Eur. J. 2010, 16, 2045−2049. (c) Xiang, S.-K.; Zhang, B.;
Zhang, L. H.; Cui, Y.; Jiao, N. Chem. Commun. 2011, 47, 5007−5009.
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(X-ray analysis) Departamento de Quımica Fundamental,
Facultad de Ciencias, Universidade da Coruna, Campus
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Zapateira s/n, 15071, A Coruna, Spain.
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The Journal of Organic Chemistry
Note
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