Diazo reagents in copper(I)-catalyzed olefination of aldehydes

Article abstract of DOI:10.1002/adsc.200800381

The olefination of aldehydes to synthesize unsaturated ketones, esters, amides and phosphonates using diazo reagents and triphenylphosphine in the presence of copper(I) iodide as catalyst, is described. Good to excellent E:Z selectivities as well as yields were obtained for a large variety of aliphatic, aromatic and heteroaromatic aldehydes. The reaction showed also an excellent functional group compatibility and aldehydes were selectively reacted in the presence of ketone, nitro, amine, ether, acetal, thioether and halide groups. The use of a cost-effective copper salt as a catalyst is advantageous compared to previously reported expensive transition metal complexes. The method was used in the total synthesis of the scutifoliamide A, a biologically active compound that exhibits antifungal activity.

Full text of DOI:10.1002/adsc.200800381

FULL PAPERS
DOI: 10.1002/adsc.200800381
Diazo Reagents in Copper(I)-Catalyzed Olefination of Aldehydes
HØl›ne Lebela,* and Michal Davia
a
DØpartement de chimie, UniversitØ de MontrØal, 2900 boul. Edouard Montpetit, MontrØal, QuØbec, Canada, H3T 1J4
Fax : (+1)-514-343-2177; phone (+1)-514-343-5826; e-mail: helene.lebel@umontreal.ca
Received: June 16, 2008; Revised: August 27, 2008; Published online: October 7, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800381.
Abstract: The olefination of aldehydes to synthesize thioether and halide groups. The use of a cost-effec-
unsaturated ketones, esters, amides and phospho- tive copper salt as a catalyst is advantageous com-
nates using diazo reagents and triphenylphosphine in pared to previously reported expensive transition
the presence of copper(I) iodide as catalyst, is de- metal complexes. The method was used in the total
scribed. Good to excellent E:Z selectivities as well synthesis of the scutifoliamide A, a biologically
as yields were obtained for a large variety of aliphat- active compound that exhibits antifungal activity.
ic, aromatic and heteroaromatic aldehydes. The reac-
tion showed also an excellent functional group com-
patibility and aldehydes were selectively reacted in Keywords: alkenes; C C bond formation; conjugat-
the presence of ketone, nitro, amine, ether, acetal, ed esters; phosphorus ylides; Wittig reaction
À
Introduction
phosphine in the presence of copper iodide to pro-
duce conjugated esters, ketones, amides and phospho-
Copper complexes are known to catalyze numerous nates in good to excellent yields.
carbon-carbon bond forming reactions.[1] For instance,
copper(I) salts were reported as catalysts for the for-
mation of stabilized antimony, arsenic and tellurium Results and Discussion
ylides from diazo carbonyl reagents to perform olefi-
nation of carbonyl compounds.[2] The low cost and the Copper(I) salts have been shown to catalyze the
wide availability of copper complexes are among the methylenation reaction with trimethylsilyldiazome-
advantages of using such a strategy. Recently, we thane, 2-propanol and triphenylphosphine.[4] A variety
have reported the use of copper catalysts as an inex- of copper(I) and copper(II) complexes were tested in
pensive alternative to rhodium complexes[3] for the the olefination of benzaldehyde with ethyl diazoace-
methylenation of aldehydes and ketones with trime- tate and triphenylphosphine (Table 1). The corre-
thylsilyldiazomethane, triphenylphosphine and 2- sponding conjugated ester 1 was obtained in good to
propanol.[4] A phosphonium ylide intermediate was excellent yields, favoring the E-diastereomer, in the
identified as the reactive olefination species. Overall presence of many copper(I) catalysts (entries 1–4 and
the copper-catalyzed methylenation reaction exhibits 6–8), with the notable exception of copper oxide
a better functional group compatibility, particularly (entry 5).
with nitrogen-containing substrates. A number of
Copper(II) complexes were less active, even though
transition metal complexes derived from Mo,[5] Re,[6] it was still possible in some cases to obtain the desired
Fe,[7] Ru,[8] Co[9] and Ir[10] are known to catalyze the product in good yields (entries 9, 11, 12, 14, 15 and
olefination of carbonyl compounds[11] with diazo car- 17). Better results were observed when hydrate com-
bonyl reagents, in most cases, diazoacetate deriva- plexes were used (entries 16 vs. 17). The best catalyst
tives. Not only the use of a cost-effective catalyst, was the cationic copper tetrafluoroborate hydrate
such as a copper(I) salt, would be beneficial, but also complex (entry 14), although we pursued our study
the use of other diazo reagents would be highly desir- with the cheaper and more readily available copper(I)
able to further expand the scope of these synthetic iode complex (entry 4).
methods. Herein we report the olefination of alde-
The optimization of the reaction conditions re-
hydes with a variety of diazo reagents and triphenyl- vealed that neither an increase nor a decrease of the
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Adv. Synth. Catal. 2008, 350, 2352 – 2358

Diazo Reagents in Copper(I)-Catalyzed Olefination of Aldehydes
FULL PAPERS
Table 1. Various copper complexes as catalysts for the olefi-
nation of benzaldehyde with ethyl diazoacetate.
These reaction conditions were tested with a large
variety of aliphatic aldehydes (Table 3). Not only
were the products from linear aldehydes obtained in
excellent yields (entries 1–5), but also sterically hin-
dered aldehydes were converted to conjugated esters
in good yields under these reaction conditions (en-
tries 6 and 7). Various chiral enantiopure aldehydes
were reacted to produce the desired conjugated esters
with complete retention of the stereochemistry (en-
tries 8–12). Moreover, an excellent functional group
compatibility was observed, as ethers, secondary and
tertiary amines, thioethers and acetals were not affect-
ed under the olefination reaction conditions (en-
tries 8–12). In all cases, the corresponding conjugated
ester was obtained in good yields. Conjugated alde-
hydes led also to the desired product in excellent
yields (entries 13 and 14).
Aromatic and heteroaromatic aldehydes were also
excellent substrates (Table 4). Electron-poor and elec-
tron-rich-substituted benzaldehydes were efficiently
converted to the conjugated esters in good to excel-
lent yields and E:Z selectivities (entries 1–7). Aro-
matic ethers, substituted anilines, nitro compounds,
bromides, esters and aliphatic secondary amines were
tolerated under these reaction conditions (entries 1–
9). Furthermore, thiophene-, furan-, pyridine-, pro-
tected pyrrole- and indole-substituted carboxalde-
hydes were converted to the corresponding conjugat-
ed esters in good to excellent yields (entries 10–15).
Clearly the efficiency of the copper catalyst is not af-
fected by these functional groups.
Entry Catalyst (5 mol%) Time [h] Yield [%][a] E:Z[b]
1
2
3
4
5
6
CuCl
16
16
16
10
16
16
16
16
16
16
7
16
16
5
16
7
87
79
86
95:5
97:3
95:5
95:5
97:3
98:2
98:2
97:3
96:4
n.d.
95:5
96:4
96:4
93:7
96:4
95:5
96:4
CuCl/AgPF6
CuBr·DMS
CuI
Cu2O
CuCN
94
56[c]
78
7[d]
8[d]
9
Cu
A
90
92
A
CuCl2
CuO
76
10
11
12
13
14
15
16
17
12[c]
88
Cu
Cu
U
79
CuF2
33[c]
97
Cu
Cu
ACHTREUNG
A
84
CuSO4 anhydrous
CuSO4·5H2O
37[c]
90
7
[a]
[b]
[c]
[d]
Combined yields of E- and Z-isomers after flash chroma-
tography.
Determined by GC-MS analysis of the crude reaction
mixture.
Determined by 1H NMR with bibenzyle as an internal
standard.
Slow addition of ethyl diazoacetate.
The copper-catalyzed olefination reaction was also
tested with aldehyde substrates containing aliphatic,
aromatic and benzyloxymethyl ketones (Table 5). In
stoichiometry of the reagents, or of the catalyst load- all cases, the reaction proceeded with high chemose-
ing led to an improvement in yield of the alkene lectivity to produce exclusively the monoalkene prod-
(Table 2, entries 1–7). The yield also decreased when uct in good yields and E selectivities. This is in sharp
running a more diluted or more concentrated reaction contrast with results obtained using standard olefina-
(entries 8–10). The reaction can be performed in nu- tion procedures. For instance, a complex mixture of
merous solvents, but none of them gave better results products resulting from unselective reactions was ob-
than THF (entries 12–21). Furthermore, it was not served when attempting to synthesize 30 using the
possible to run the reaction at room temperature phosphorane reagent generated by deprotonation of
while maintaining yields higher than 90% and a time the phosphonium salt with NaHMDS or under the
below 16 h. Overall, the best reaction conditions are mild Roush–Masamune reaction conditions.[13]
the ones described in entry 3 of Table 2. Such reaction
Beside diazoacetates, very few other diazo carbonyl
conditions provided a TON of about 20 and a TOF of reagents have been tested in transition metal-cata-
about 2. These values are within the range obtained lyzed olefination reactions.[7f] To enlarge the scope of
with other commercially available catalysts for such this reaction, other ketones, amides and phosphonate-
an olefination reaction.[7a,c,9a] Only the iron(II) phtha- derived diazo reagents[14] were prepared and tested in
locyanine complex showed a better efficiency.[7h] the olefination of various aldehydes (Table 6). For in-
However, the cost of copper iodide is two to three stance, the less reactive diazoacetophenone produced
orders of magnitude lower than the other commer- unsaturated acetophenone from aliphatic, aromatic
cially available catalysts, and thus it clearly is the and heteroaromatic aldehydes in 58–74% yields and
most cost-effective catalyst to use in such a reaction. in 88:12 to 98:2 diastereoselectivities (entries 1, 4, 8
More importantly, neither the slow addition of ethyl and 14). Unsaturated amides including Weinreb
diazoacetate reagent, nor the use of a drybox or amides[15] were also obtained in 72–87% yields favor-
Schlenk line techniques are necessary.[12]
ing the E-diastereomer (entries 2, 5, 7, 9–11, 13 and
Adv. Synth. Catal. 2008, 350, 2352 – 2358
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HØl›ne Lebel* and Michal Davi[a]
FULL PAPERS
Table 2. Optimization on the reaction conditions of the copper-catalyzed olefination of benzaldehyde with ethyl diazoace-
tate.
Entry PPh3
(equiv.)
EDA
(equiv.)
Catalyst loading [x
mol%]
Solvent C [mol/
L]
Temp.
[8C]
Time
[h]
Yield
[%][a]
E:Z[b]
1
2
3
4
5
6
7
8
1.1
1.4
1.5
2
2.5
2
2
2
2
2
2
2
2
2
2
2
2
2
5
5
5
5
THF, 0.25
THF, 0.25
THF, 0.25
THF, 0.25
THF, 0.25
THF, 0.25
THF, 0.25
THF, 0.10
60
60
60
60
60
60
60
60
60
60
25
25
40
25
80
25
50
25
80
25
80
16
16
10
10
16
16
6
16
5
3
24
16
16
24
16
24
6
24
16
16
16
35[c]
70
94
92
43[c]
70
90
79
75
35[c]
85
81
90
66
83
87
58
69
86
76
85
96:4
95:5
95:5
96:4
96:4
97:3
94:6
94:6
94:6
92:8
94:6
96:4
94:6
97:3
96:4
94:6
96:4
96:4
97:3
96:4
97:3
1.2
1.2
1.2
2
5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.5
10
5
5
5
5
5
5
5
5
5
5
5
5
5
5
9
THF, 0.50
THF, 1.00
THF, 0.25
10
11
12
13
14
15
16
17
18
19
20
21
DCM, 0.25
DCM, 0.25
DCE, 0.25
DCE, 0.25
Dioxane, 0.25
Dioxane, 0.25
Benzene, 0.25
Benzene, 0.25
Toluene, 0.25
Toluene, 0.25
2
2
2
2
[a]
[b]
[c]
Combined yields of E- and Z-isomers after flash chromatography.
Determined by GC-MS analysis of the crude reaction mixture.
1
Determined by H NMR with bibenzyl as an internal standard.
15). Finally, the Seyferth reagent[16] was reacted with Conclusions
aliphatic and aromatic aldehydes to produce unsatu-
rated phosphonates in 54–69% yields and in 89:11 to Copper(I) iodide proved to be a general, cost-effec-
98:2 E:Z ratio (entries 3, 6 and 12). tive catalyst for the olefination of aldehydes using a
The use of more functionalized and diversified variety of diazo reagents and triphenylphosphine
diazo reagents should enable more convergent syn- under non-basic conditions. Unsaturated ketones,
thetic strategies for the preparation of complex mole- esters, amides and phosphonates were produced in
cules, thus limiting the number of required functional good to excellent yields and diastereoselectivities. The
group manipulations. For instance, the total synthesis total synthesis of scutifoliamide A was achieved using
of scutifoliamide A (50), an antifungal amide recently the copper-catalyzed olefination reaction as a key
isolated from Piper scutifolium,[17] was achieved in 4 step.
steps and 40% overall yield starting from commercial-
ly available 1-bromo-3,4-(methylenedioxy)benzene.
The synthetic strategy featured an olefination reaction
with the diazoisobutylamide of the aldehyde derived
Experimental Section
from propargylic alcohol 48. The unsaturated amide
49 was produced in 75% yield and in 92:8, E:Z ratio.
Scutifoliamide A (50) was then obtained after a hy-
General Procedure for the Copper-Catalyzed
Olefination of Aldehydes
To a solution of copper(I) iodide (10 mg, 0.050 mmol) and
triphenylphosphine (315 mg, 1.20 mmol) in THF (4 mL)
under an argon atmosphere, was added the aldehyde
(1.00 mmol). The mixture was heated to 608C and then the
diazo compound (2.00 mmol) was added in a single portion.
The solution was stirred until the reaction was completed by
GC or TLC analysis. The resulting mixture was cooled to
drogenation
(Scheme 1).
reaction
with
Lindlar
catalyst
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Diazo Reagents in Copper(I)-Catalyzed Olefination of Aldehydes
FULL PAPERS
Table 3. copper-catalyzed olefination of aliphatic aldehydes
with ethyl diazoacetate.
Table 4. Copper-catalyzed olefination of aromatic aldehydes
with ethyl diazoacetate.
[a]
[a]
[b]
Combined yields of E- and Z-isomers after flash chroma-
tography.
Determined by GC-MS analysis of the crude reaction
mixture.
Combined yields of E- and Z-isomers after flash chroma-
tography.
Determined by GC-MS analysis of the crude reaction
mixture.
[b]
(1.0 mL), HN
(methylenedioxy)benzene
ACHTREUNG
room temperature and the solvent was removed under re-
duced pressure. The residue was purified by flash chroma-
tography on silica gel.
AHCTREUNG
(120 mL, 1.00 mmol), and propargyl alcohol (116 mL,
2.00 mmol) were added and stirred at room temperature
overnight. The reaction mixture was diluted with EtOAc
(10 mL), filtered through a plug of silica gel. The solvent
was removed under reduced pressure to afford the alcohol
48 as a yellow solid after flash chromatography (25%
EtOAc/hexanes); yield: 134 mg (76%); Rf 0.35 (40%
EtOAc/hexanes); mp 738C (lit. 75.5–768C);[19] 1H NMR
Synthesis ofScutifoliamide A
3-(Benzo[d]
ACHTREUNG
A
(48):[18]
CuI (4.0 mg,
Pd-
0.020 mmol), and [(t-Bu)3PH]BF4 (19 mg, 0.065 mmol) were
placed in a vessel which was backfilled with argon. Dioxane
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HØl›ne Lebel* and Michal Davi[a]
FULL PAPERS
Table 5. Copper-catalyzed chemoselective olefination of ke-
toaldehydes.
Table 6. Copper-catalyzed olefination of aldehydes with vari-
ous diazocarbonyl reagents.
[a]
Combined yields of E- and Z-isomers after flash chroma-
tography.
[b]
Determined by GC-MS analysis of the crude reaction
mixture.
(300 MHz, CDCl3): d=6.96 (dd, J=8, 2 Hz, 1H), 6.87 (d,
J=2 Hz, 1H), 6.74 (d, J=8 Hz, 1H), 5.96 (s, 2H), 4.46 (br s,
2H), 1.85 (br s, 1H); 13C NMR (75 MHz, CDCl3): d=148.0,
147.3, 126.3, 115.6, 111.6, 108.3, 101.2, 85.5, 85.5, 51.6; IR
(neat): n=3270, 2951, 2255, 1717, 1490, 1447, 1172, 907,
731 cmÀ1
C10H8O3Ag [M+Ag]+: 282.9524.
(E)-5-(Benzo[d][1,3]dioxol-6-yl)-N-isobutylpent-2-en-4-
;
HR-MS (ESI): m/z=282.9519, calcd. for
ACHTREUNG
ynamide (49): To a solution of MnO2 (200 mg, 11.3 mmol) in
DCM was added the alcohol (200 mg, 1.13 mmol). The mix-
ture was stirred at room temperature overnight. The reac-
tion mixture was filtered through a plug of Celiteꢁ. The mix-
ture was concentrated to give the desired aldehyde as
yellow solid after flash chromatography (25% EtOAc/hex-
anes); yield: 163 mg (83%); Rf 0.42 (40% EtOAc/hexanes);
1
mp 788C; H NMR (300 MHz, CDCl3): d=9.38 (s, 1H), 7.19
(dd, J=8, 2 Hz, 1H), 7.02 (d, J=2 Hz, 1H), 6.83 (d, J=
8 Hz, 1H), 6.04 (s, 2H); 13C NMR (75 MHz, CDCl3): d=
176.6, 150.6, 147.7, 129.5, 112.7, 112.3, 108.9, 101.9, 96.0,
88.0; IR (neat): n=2902, 2181, 1655, 1489, 907 cmÀ1; HR-
MS (ESI): m/z=175.0392, calcd, for C10H7O3 [M+H]+:
175.0395.
[a]
Combined yields of E- and Z-isomers after flash chroma-
tography.
Determined by GC-MS analysis of the crude reaction
mixture.
[b]
To a solution of copper(I) iodide (5.0 mg, 0.030 mmol)
and triphenylphosphine (181 mg, 0.690 mmol) in toluene
(2 mL) under an argon atmosphere, was added the aldehyde
(100 mg, 0.570 mmol). The mixture was heated to 608C and
then the diazo compound (1.14 mmol) was added in a single
portion. The solution was stirred overnight. The resulting
mixture was cooled to room temperature and the solvent
was removed under reduced pressure. The amide 49 was ob-
tained as a yellow gum after flash chromatography on silica
gel (20% EtOAc/hexanes); yield: 116 mg (75%); Rf 0.15
(20% EtOAc/hexanes); 1H NMR (300 MHz, CDCl3): d=
7.00 (dd, J=8, 2 Hz, 1H), 6.92 (d, J=15 Hz, 1H), 6.90 (d,
J=2 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 6.26 (d, J=15 Hz,
1H), 5.99 (s, 2H), 5.55 (s (br), 1H), 3.18 (t, J=7 Hz, 2H),
1.89–1.75 (m, 1H), 0.93 (d, J=7 Hz, 6H); 13C NMR
(75 MHz, CDCl3): d=164.7, 148.5, 147.4, 131.7, 126.9, 121.6,
115.6, 111.6, 108.5, 101.4, 96.6, 85.4, 47.0, 28.5, 20.1; IR
(neat): n=3296, 2962, 2197, 160, 1610, 1220, 1040 cmÀ1; HR-
MS (ESI): m/z=272.1271, calcd. for C16H18NO3 [M+H]+:
272.1281.
A
ACHTRE[UNG 1,3]dioxol-6-yl)-N-isobutylpenta-2,4-
AHCTREUNG
(20.0 mg, 0.074 mmol), quinoline (87.0 mL, 0.74 mol) and
Lindlar catalyst (5% Pd on CaCO3 poisoned with Pb,
8.0 mg) in ethyl acetate (1.0 mL) was evacuated and flushed
with H2 three times. The reaction mixture was stirred at
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Diazo Reagents in Copper(I)-Catalyzed Olefination of Aldehydes
FULL PAPERS
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Scheme 1.
room temperature under H2 (1 atm) for 1 h and then filtered
through a plug of Celiteꢁ. The plug was rinsed with ethyl
acetate (3”5 mL) and the solution was concentrated under
reduced pressure to afford scutifoliamide A (50) as a yellow
oil after flash chromatography (10% EtOAc/hexanes);
yield: 18 mg (89%); Rf 0.09 (20% EtOAc/hexanes);
1H NMR (400 MHz, CDCl3): d=7.72 (dd, J=15, 12 Hz,
1H), 6.83–6.78 (m, 3H), 6.62 (d, J=12 Hz, 1H), 6.22 (t, J=
12 Hz, 1H), 5.98 (d, J=15 Hz, 1H), 5.96 (s, 2H), 5.60 (s
(br), 1H), 3.18 (t, J=6 Hz, 2H), 1.85–1.75 (m, 1H), 0.92 (d,
J=7 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=165.9, 147.7,
147.4, 136.6, 136.0, 130.6, 126.3, 125.9, 123.4, 109.2, 108.3,
101.1, 46.9, 28.6, 20.1; IR (neat): n=3036, 1663, 1501, 1314,
1118 cmÀ1
;
HR-MS (ESI): m/z=274.1435, calcd. for
C16H20O3 [M+H]+: 274.1437.
Supportin Information
Analytical characterization data for all compounds are avail-
able in the Supporting Information.
Acknowledgements
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This research was supported by NSERC (Canada), the Cana-
dian Foundation for Innovation, the Canada Research Chair
Program and the UniversitØ de MontrØal.
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