Photocatalytic Reaction of Diazo Compounds with Aldehydes

Article abstract of DOI:10.1002/adsc.201600084

Photocatalytic reactions of diazoacetates with aldehydes led to α-alkylated carbonyl compounds instead of the expected cyclopropane derivatives. The reaction requires a dual catalytic system – photocatalysis merged with enamine-iminium catalysis. NMR, EPR, UV/Vis, and ESI-MS analyses provided sufficient data to corroborate the proposed radical mechanism – enamine catalysis merged with photocatalysis. (Figure presented.).

Full text of DOI:10.1002/adsc.201600084

FULL PAPERS
DOI: 10.1002/adsc.201600084
Photocatalytic Reaction of Diazo Compounds with Aldehydes
a
a,b
a,
K. Rybicka-Jasi n´ ska, Ł. W. Ciszewski, and D. Gryko *
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
E-mail: dorota.gryko@icho.edu.pl
Department of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
b
Received: January 20, 2016; Revised: March 2, 2016; Published online: April 27, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600084.
Abstract: Photocatalytic reactions of diazoacetates vided sufficient data to corroborate the proposed
with aldehydes led to a-alkylated carbonyl com- radical mechanism – enamine catalysis merged with
pounds instead of the expected cyclopropane deriva- photocatalysis.
tives. The reaction requires a dual catalytic system –
photocatalysis merged with enamine-iminium cataly- Keywords: aldehydes; diazo compounds; organoca-
sis. NMR, EPR, UV/Vis, and ESI-MS analyses pro- talysis; photocatalysis; radicals
Introduction
methyl diazomalonate in acetaldehyde, in the pres-
ence of benzophenone as a photosensitizer, led pri-
The chemistry of diazo compounds has been exten- marily to hydrogen abstraction giving dimethyl malo-
[
24d]
sively investigated over the past decades and a variety nate in 83% yield.
of practical reactions such as CÀH and heteroatomÀH was conducted in acetone (1), product 3 predominat-
insertion, cyclopropanation, addition,
merization, nucleophilic olefination,
But, when the same experiment
[
1,2]
7]
10–15]
[3,4]
[5,6]
poly- ed and the apparent CÀH insertion also occurred
[
[8,9]
etc. has been giving alkylated malonate 4 in 15% yield (Scheme 1).
[
developed.
However, little is known about their Formation of compound 3 resulted from the ylide that
reactivity under light irradiation. Light is a very pow- demands the singlet carbene as a primary reacting
erful source of energy, a fact nature has exploited species.
[
16]
since the beginning. But organic chemists have only
We wondered whether the reactivity of diazo com-
recently started to realize the potential of light-in- pounds could be shifted towards functionalization of
duced transformations with effective photocycloaddi- aldehydes at the a-position under visible light irradia-
tions, rearrangements, cyclization, alkylation, photo- tion. MacMillan and co-workers have shown that
oxidation, and photooxygenation reactions being al- under light irradiation, in the presence Ru(bpy) Cl
3
2
[
17–23]
ready developed.
aldehydes, in fact enamines, reacted with bromomalo-
In this regard, it has been already reported that the nate furnishing alkylated derivatives. This approach
reaction of a diazo compound with a carbonyl starting was subsequently used for iridium-catalyzed benzyla-
[25]
[
26]
[27]
[28]
material, depending on the conditions used, follows tion and trifluoromethylation. Zeitler and Mel-
[
24a–c]
[29,30]
different pathways.
In the presence of light diazo chiorre
have advanced this methodology by show-
compounds furnish carbenes in a singlet ground state ing that organic dyes were also efficient photoredox
via direct photolysis while less reactive triplet car- catalysts for this reaction and, what was more, in cer-
benes are formed in the presence of triplet-sensitizers. tain cases no photoredox catalyst was required. On
In this respect, Jones showed that irradiation of di- the other hand, it has been also shown that aryldi-
azoacetates reacted with enamines in the presence of
copper and rhodium complexes giving keto esters in
[31,32]
moderate yields (Scheme 2a).
But the reported
transformation was limited to acetophenones and re-
quired preformed enamines. We have found that
under visible light irradiation diazo compounds react
with aldehydes giving a-alkylated carbonyl compounds
Scheme 1. Photoinduced reaction of dimethyl diazomalonate instead of the expected cyclopropanes (Scheme 2b).
with acetone.
Adv. Synth. Catal. 2016, 358, 1671 – 1678
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1671

K. Rybicka-Jasi n´ ska et al.
FULL PAPERS
Table 1. Choice of an organocatalyst for the model reaction
of 3-phenylpropanal (8) with EDA (9) catalyzed by
[
a]
Ru(bpy) Cl .
3
2
[
36]
En-
try
Amine
pKb
Time
[h]
Yield
[b]
[%]
1
2
3
4
5
6
7
8
9
pyrrolidine
piperidine
piperazine
piperazine
N-methylpiperazine
N-methylpiperazine
morpholine
morpholine
1-phenypropan-1-amine
dicyclohexylamine
2.89
2.73
4.19
4.19
4.87
4.87
5.6
5.6
–
–
3
3
3
5
3
5
3
5
3
4
18
31
65
62
42
62
55
61
0
Scheme 2. a-Alkylation of carbonyl compounds with diazo
reagents.
1
0
4
[
a]
Reaction conditions: aldehyde 8 (1 equiv.), morpholine
0.4 equiv.), Ru(bpy) Cl (2 mol%), EDA (9, 1 equiv.),
(
3
2
Results and Discussion
CH CN, 4 ꢁhouseholdꢂ LEDs, 398C.
Yields were determined by GC.
3
[
b]
Model Studies
In our initial experiment, 3-phenylpropanal (8) was lyzed reaction furnished product 10 in a very low
reacted with ethyl diazoacetate (EDA, 9) in the pres- yield, opposite to most enamine-iminium catalyzed
[34]
ence of morpholine and the common, in diazo reactions (entry 1). However, less basic secondary,
compounds chemistry, catalysts Cu(CH CN)BF or cyclic amines were quite effective (entries 3–8). The
3
4
[
32]
Rh(CF CH CH CO ) . Contrary to the reported re- superiority of six-membered, secondary amines over
3
2
2
2 2
actions with keto enamines, no product formed. In pyrrolidine suggests that nucleophilicity of the nitro-
the benzophenone-photocatalyzed reaction under gen could play a role, as the highest yields were ob-
light irradiation no extrusion of nitrogen was ob- tained for amines with extra heteroatoms (oxygen or
[35]
served and GC analysis confirmed the recovery of nitrogen). These heteroatoms through an inductive
starting material 8. Hence, we speculated that benzo- effect, withdraw electron density from the nitrogen,
phenone was not a suitable photocatalyst for this making it less nucleophilic. Primary amines failed in
transformation. Other organic dyes: eosin Y, Rose catalyzing our model reaction (entry 9).
Bengal, fluorescein, PDI, and methylene blue, and
The yield also depended on the light intensity and
Ir(ppy) , upon irradiation with white light from LEDs the reaction time. Irradiation with 4 ꢁhouseholdꢂ
3
as well as TiO upon irradiation with UV failed to LEDs, for 5 h proved the most effective and the use
2
promote the reaction in CH CN. However, among Ru of a CFL bulb did not alter the reaction outcome sig-
3
complexes tested, in the presence of Ru(bpy) Cl the nificantly (for details see the Supporting Informa-
3
2
model reaction gave the desired product 10 in 55% tion).
[
33]
yield. Control experiments revealed that the exclu-
It has been reported that the base-catalyzed addi-
sion of any of the reaction components: morpholine, tion of EDA (9) to enamines affording cyclopropanes
light, or the photocatalyst stopped the reaction com- was very slow in CH CN. Hence, to avoid the unde-
3
pletely. This suggested a dual mode of activation, or- sired side reaction (cyclopropanation), we thought it
ganocatalysis merged with photoredox or photocataly- to be a suitable solvent for our model reaction but
sis.
We
assumed
that
aldehyde
8
other media, commonly used in organocatalyzed reac-
transformed into a more reactive enamine while tions, were also tested (Table 2). An increase in yield
Ru(bpy) Cl in the presence of light facilitated carbe- was observed when the reaction was performed in
3
2
noid or carbene formation. As it is known that this re- DMSO (entry 6). The use of dry solvents was not ben-
active species may be also generated from diazo com- eficial for the reaction outcome (entries 2 and 5); pre-
pounds using heat, aldehyde 8 was reacted with EDA sumably traces of water were crucial for the enamine
(
9) at elevated temperature with no photocatalyst hydrolysis, hence for the recovery of morpholine in
added and shielded from light. Surprisingly, the reac- the catalytic cycle. The alkylation could be also per-
tion failed to afford functionalized aldehyde 10 sug- formed in a mixture of CH CN/buffer (entry 9).
3
gesting that another mechanism operates.
Furthermore, in enamine-iminium catalysis, the use
Next, we performed a series of experiments in an of an acidic co-catalyst usually influences hydrolysis
effort to optimize the reaction conditions. Firstly, vari- of an iminium salt, facilitating the recovery of a cata-
[38,39]
ous amines were tested (Table 1). Pyrrolidine-cata- lyst in a catalytic cycle.
A series of acids was
1
672
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 1671 – 1678

FULL PAPERS
Photocatalytic Reaction of Diazo Compounds with Aldehydes
Table 2. Solvent screening for the a-alkylation of aldehyde
Table 4. Effect of the pH of a buffer on the a-alkylation of
aldehydes.
[a]
[a]
(
9).
En-
try
Solvent
Dielectric
constant [er]
Yield
[%]
En- Solvent
try
Yield
[%]
En- Buffer in
try DMSO [%] [%]
Yield
[b]
[37]
[b]
[
a]
1
2
3
4
5
6
7
8
9
CH CN
37.5
37.5
36.7
37.8
46.7
46.7
46.7
8.9
61
62
25
25
48
75
57
0
1
2
3
4
5
6
7
8
9
CH CN/H O
55
10
11
12
13
14
15
16
17
19
2
4
6
8
10
12
50
10
10
10
70
71
71
69[
83
75
0
3
3
2
CH CN
DMSO/buf. pH 3.0 67
DMSO/buf. pH 3.5 67
DMSO/buf. pH 4.0 83
DMSO/buf. pH 4.5 74
DMSO/buf. pH 5.0 70
DMSO/buf. pH 6.0 70
DMSO/buf. pH 7.0 67
DMSO/buf. pH 8.0 36
3
dry
DMF
DMA
DMSOdry
c]
DMSO
DMSO
[
c]
[
d]
[e]
f]
CH Cl2
59
23
2
[
d]
CH CN/H O
–
55
3
2
[
[c]
2
0
88
[a]
Reaction conditions: aldehyde 8 (1 equiv.), morpholine
0.4 equiv.), Ru(bpy) Cl2 (2 mol%), EDA (9, 1 equiv.),
[
a]
(
Reaction conditions: aldehyde (8, 0.5 mmol), morpholine
(0.4 equiv.), Ru(bpy) Cl (2 mol%), EDA (9, 1 equiv.),
additive (0.4 equiv.), 5 h, DMSO, 4 ꢁhouseholdꢂ LEDs;
entries 1–9 solvent/buffer (5 mL, 9:1 mixture), for en-
tries 10–19 DMSO/buffer mixtures (5 mL, buffer pH 4,
c=0.1M).
3
solvent (5 mL), 5 h, 4 ꢁhouseholdꢂ LEDs.
Yields were determined by GC.
Ru(bpy) Cl (2.5 mol%).
3
2
[
[
[
b]
c]
d]
3
2
9
:1 mixture.
[
[
[
[
[
b]
c]
d]
e]
f]
Yields were determined by GC.
therefore tested as additives with the goal of finding
a probable relationship between pK of the acid and
the outcome of the a-alkylation of aldehydes. Careful
analysis of the data included in Table 3 led to interest-
ing observations and generalizations. With an increase
Isolated yield.
Reaction was performed in CH CN/buffer
Ru(bpm) Cl (2 mol%) was used.
LiBF (20 mol%) was added.
3
a
3
2
4
in pK of an acid added the yield increased reaching
Reactions carried out in wet DMSO turned out to
a
8
3% for AcOH with a dissociation constant of 4.73 be pH dependent and the highest yield was obtained
(
entry 12). The addition of strong acids halted the re- in a 9:1 mixture with the buffer of pH 4 containing
action almost completely (entries 1 and 2), while LiBF as an additive (Table 4, entries 4 and 20). Our
4
other acids did have an influence albeit less pro- data suggest that at pH~4 EDA (9) is stable, and at
nounced.
the same time the organocatalytic cycle, requiring
acidic conditions, is effective.
In the last step, the organocatalyst loading was opti-
mized. A decrease in the amount of morpholine led
to a decrease in yield although the use of 20 mol%
was still sufficient for the activation of the aldehyde
[a]
Table 3. Co-catalyst influence.
pKa[40]
[b]
Entry
Additive
Yield [%]
1
2
3
4
5
6
7
8
9
TsOH
TFA
F CHCO H
2,4-dinitrobenzoic acid
2-bromobenzoic acid
ICH CO H
2,4-dihydroxybenzoic acid
HCO H
À1.34
0.26
1.24
1.43
2.85
3.12
3.29
3.75
4.20
4.37
4.54
4.76
–
0
6
37
0
51
3
44
58
61
79
70
83
83
63
16
59
56
(
73%).
2
2
Scope and Limitation Studies
2
2
Under optimal conditions: aldehyde (1 mmol.), mor-
pholine (0.4 equiv.), Ru(bpy) Cl (2 mol%), LiBF4
2
3
2
PhCO H
2
(
20 mol%), EDA (9, 1 equiv.), a mixture of DMSO/
buffer (9:1, 10 mL, buffer pH 4, c=0.1M), 5 h, 4
householdꢂ LEDs, the scope and limitation of the a-
1
1
1
0
1
2
4-methylbenzoic acid
4-hydroxybenzoic acid
AcOH
ꢁ
functionalization of aldehydes with diazo esters were
explored (Table 5).
1
1
1
1
1
3
4
5
6
7
AcOH/LiBF4
phenol
K PO4
H O
2,6-lutidine
9.99
–
–
The CÀH alkylation was applicable to various alde-
3
2
hydes giving the desired products 10, 22–32 in decent
yields, although the generation of quaternary centers
proved difficult under the developed conditions. The
results indicate that various functional groups are well
tolerated: OMe and even Cl (compounds 22 and 25).
The list of aldehydes is not exhaustive but it is defi-
nitely representative. Furthermore, it is noteworthy
–
[a]
Reaction conditions: aldehyde 8 (0.5 mmol), morpholine
0.4 equiv.), Ru(bpy) Cl2 (2 mol%), EDA (9, 1 equiv.),
(
3
additive (0.4 equiv.), 5 h, DMSO (5 mL), 4 ꢁhouseholdꢂ
LEDs.
[b]
Yields were determined by GC.
Adv. Synth. Catal. 2016, 358, 1671 – 1678
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1673

K. Rybicka-Jasi n´ ska et al.
FULL PAPERS
Table 5. Scope and limitations of the a-functionalization of opening may also operate. We proved that each com-
aldehydes.
ponent of the reaction: amine, photocatalyst, and
light is required for the reaction to take place and to
validate the proposed mechanism, several experi-
ments were conducted.
Firstly, the reaction proceeds via enamine-iminium
catalysis as in the presence of NEt and DABCO in-
3
stead of secondary amines recovery of the starting
material only was observed. The generated enamine
1
B was detected by ESI-MS and H NMR analyses. In
1
2
3
+
Alde- Diazo R , R , R
Prod- Yield MS the corresponding peak at 204.14 Da [M] was
hyde
ester
uct
[%]
observed not only when aldehyde 8 was treated with
morpholine but also in the reaction mixture. More-
over, the H NMR spectrum clearly shows characteris-
tic proton resonances for enamine B at 5.95 and
4.56 ppm (Figure 1).
8
9
9
9
9
9
9
9
9
CH Ph, H, Et
10
22
23
24
25
26
27
28
29
30
88
80
76
44
71
63
0
2
1
1
1
1
1
1
1
1
8
8
8
8
1
2
3
4
5
6
7
CH -4-CH OC H , H, Et
2
3
6
4
CH (CH) CH , H, Et
2
6
3
Ph, H, Et
CH -3-ClC H , H, Et
Secondly, the composition of the reaction mixture
2
6
4
1
CH(CH ) , H, Et
was monitored using LR ESI-MS, GC, and H NMR
3
2
Ph, CH , Et
3
techniques after 0, 30, 90, 150, 210 min under light ir-
radiation (for details see the Supporting Information).
CH CH , CH , Et
0
2
3
3
18
CH Ph, H, t-Bu
67
78
80
71
1
2
One of the main features of the H NMR spectra was
[
[
[
a]
a]
a]
19
20
21
CH Ph, H, CH Ph
2
2
the progressive disappearance of the aldehyde proton
resonance at 9.74 ppm (triplet) and concurrent occur-
rence of the signals corresponding to product 10
CH Ph, H, CH CH CH Ph 31
2
2
2
2
CH Ph, H, N-Boc-Pro
32
2
[a]
[41]
Prepared according to the literature procedure.
(
CHO protons at 9.72 ppm, doublet, Figure 2).
GC and NMR analyses also clearly denoted the
presence of aldehyde 8, EDA (9), and the respective
that sterically hindered diazo esters 18 and 21 reacted enamine of type B (Figure 1), while LR ESI-MS anal-
equally well. The reaction with diazoacetate 21 con- ysis showed a more complex picture presumably due
sisting of an l-proline moiety afforded the desired to additional reactions taking place in the gas phase.
compound in 71% yield as a mixture of diastereoiso- Nevertheless, peaks at m/z=204.14, 407.27, 579.36 Da
mers (3:2).
corresponding, respectively, to the iminium (formed
from aldehyde 8 and morpholine) [M] , [2M+H]
and product 10 in the form of enamine [2M+H]
+
+
+
Mechanistic Consideration
were present in all spectra corroborating the enamine
mechanism.
The proposed mechanism for the functionalization of
Thirdly, it was not clear whether an Ru-carbenoid
aldehydes is shown in Scheme 3. We assumed that the is involved in the CÀC bond formation step. Hogsten
reaction proceeds mainly via a radical pathway but and Angrish found that the Ru complex has the abili-
the formation of cyclopropane with subsequent ring- ty to dimerize EDA. In our case, ESI MS analyses,
neither of the reaction mixture nor of the mixture of
[42]
Ru complex with EDA, showed the peak correspond-
ing to the EDA dimer. Moreover, the control analysis
of Ru(bpy) Cl in CH CN showed the base peak at
3
2
3
2+
2
85.05 corresponding to [Ru(bpy) Cl ] . As the spec-
3 2
tra of Ru complex and the mixture of Ru complex+
EDA, and Ru complex+EDA+morpholine were
almost identical, we could rule out the possible for-
mation of an Ru carbenoid.
Fourthly, the addition of TEMPO, a radical scav-
enger, to the reaction mixture, rendered it inactive
suggesting a radical mechanism. Hence, the model re-
action was studied using EPR spectroscopy. The con-
centration of free radicals in the reaction mixture was
too low to be detected directly, therefore phenyl-N-
[43,44]
Scheme 3. Plausible mechanism for photocatalytic reaction tert-butylnitrone (PBN) was added as a spin trap.
of aldehydes with EDA (9).
The EPR spectrum of the reaction mixture was mea-
1
674
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 1671 – 1678

FULL PAPERS
Photocatalytic Reaction of Diazo Compounds with Aldehydes
1
Figure 1. H NMR spectrum of the reaction measured just after dissolution (* 3-phenylpropanal (8),
line, and ~ enamine).
&
EDA (9), ^ morpho-
Stern–Volmer analyses for each of the reaction
components clearly showed that for enamine of type
B very strong, in comparision to EDA and morpho-
3+
line, quenching of [Ru*(bpy) Cl ]
occurred thus
3
2
confirming the proposed radical C being a reactive in-
termediate (Figure 4). In accord with the proposed
mechanism the aldehyde resulted in minute Stern–
Volmer quenching.
As an alternative pathway, cyclopropanation of en-
amine followed by ring-opening was considered.
Kuehne and King reported that treatment of the pre-
formed enamines with diazomethane in the presence
of CuCl led to cyclopropylamines which after thermal
hydrolysis gave alkylated carbonyl compounds as
1
Figure 2. H NMR spectra of the reaction mixture after 0,
0, 90, 150, 210 min under light irradiation.
3
[45]
a mixture of regioisomeric products. It was report-
sured after 10 min of irradiation (Figure 3). The for- ed that in the presence of Rh(II) complex the reac-
mation of ꢁspin adductsꢂ was ascertained thus support- tion of a-diazo ketones with vinyl ethers afforded cy-
ing the radical mechanism. On the basis of these find- clopropane derivatives which underwent ring-opening
[46]
ings, we concluded that the CÀH insertion at the a- leading to 1,4-diketones. Such cyclopropanes bear-
position involves radicals.
ing both electron-donating and electron-withdrawing
Figure 3. EPR of the reaction mixture: aldehyde
8
(
(
(
1 equiv., 0.5 mmol), EDA (9, 1 equiv.), morpholine
0.4 equiv., 0.2 mmol), Ru(bpy) Cl2 (2 mol%), CH CN
5 mL), spin trap PBN after 10 min of irradiation with LED.
Figure 4. Stern–Volmer analyses for each of the reaction
components.
3
3
Adv. Synth. Catal. 2016, 358, 1671 – 1678
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1675

K. Rybicka-Jasi n´ ska et al.
FULL PAPERS
[
45–49]
groups were found to be easily cleaved.
We have Experimental Section
prepared a cyclopropylamine derivative using a report-
ed methodology and subjected it to the developed re- General Procedure for a-Functionalization of
[
24a]
action conditions (Scheme 4).
Aldehydes
Photocatalyst (2 mol%) was placed in a reaction tube and
dissolved in DMSO and buffer pH 4 (mixture 9:1, 10 mL).
Then aldehyde (1 mmol), morpholine (0.4 equiv., 0.4 mmol),
EDA (1 equiv., 1 mmol) and LiBF (20 mol%) were added
4
to the solution. The reaction mixture was stirred at 398C
under irradiation (4”LED, 1200 lumens) for 5 h. The light
was turned off and the reaction mixture was diluted with
AcOEt, and extracted with 1N HCl. The aqueous phase was
separated and then extracted with AcOEt three times. Com-
bined organic phases were washed with NaHCO , brine and
3
dried over Na SO , filtered and concentrated. The crude
2
4
product was purified by flash chromatography using silica
gel (hexanes/AcOEt) to afford the corresponding product.
Ethyl 3-benzyl-4-oxobutanoate (10): yield: 194 mg (88%);
Scheme 4. Ring-opening of cyclopropylamine.
1
H NMR (CDCl , 500 MHz): d=9.79 (s, 1H, CHO), 7.31–
3
7
3
.17 (m, 5H, Ph), 4.11 (q, J=7.1 Hz, 2H, COCH CH ),
2 3
.14–3.08 (m, 2H, CH ), 2.77–2.71 (m, 1H, CH), 2.65 (dd,
2
Under light irradiation ring cleavage occurred and J=7.6 Hz, 1H, CH), 1.40 (dd, J=4.8 Hz, 1H, CH), 1.23 (t,
1
3
subsequent hydrolysis of the iminium moiety yielded J=7.0 Hz, 3H, COCH CH ); C NMR (CDCl , 125 MHz):
2
3
3
the a-functionalized product. GC-MS analysis (see d=202.2, 171.6, 137.7, 129.0, 128.6, 126.7, 60.7, 49.2, 34.6,
3
1
(
2
7
2.7, 14.1; IR: n=3029, 2982, 2934, 2725, 1733 (CO), 1496,
the Supporting Information) revealed the presence of
two regioisomeric derivatives 34 and 35 (ratio 1: 4.5),
hence the photocatalytic ring opening was not regio-
selective. As only one product formed in our model
reaction, we postulate that the described a-alkylation
proceeds mainly via the radical pathway but to some
extent cyclopropanation followed by ring opening
may also operate. In addition, chain propagation reac-
À1
454 (CHO), 1375, 1199, 1161, 1031, 750, 702 cm ; HR-MS
ESI): m/z=243.0993, calcd. for C H O [M+Na] :
43.0997; elemental analysis; calcd. (%) for C H O : C
0.89, H, 7.32; found: C 70.74, H, 7.40.
Ethyl 3-formyl-4-(4-methoxyphenyl)butanoate (22): yield:
00 mg (80%); H NMR (CDCl , 500 MHz): d=9.78 (s, 1H,
CHO), 7.09–7.07 (m, 2H, Ph), 6.84–6.83 (m, 2H, Ph), 4.10
+
1
3
16
3
13 16 3
1
2
3
(
q, J=7.0 Hz, 2H, COCH CH ), 3.78 (s, 3H, OCH ), 3.08–
2
3
3
[
50]
tions may likely also be involved.
3
.01 (m, 2H, CH ), 2.71–2.60 (m, 2H, CH ), 2.40 dd, J=
2 2
5
.5 Hz, (1H, CH), 1.23 (t, J=7.0 Hz, 3H, COCH CH );
2
3
1
3
C NMR (CDCl , 125 MHz): d=202.5, 171.7, 158.3, 129.9,
3
Conclusions
129.5, 114.0, 60.7, 55.2, 49.4, 33.7, 32.6, 14.1; IR: n=2982,
2
958, 2935, 2837, 1731 (CO), 1612, 1514 (CHO), 1249
À1
(OCH ), 1179, 1034, 838 cm ; HR-MS (ESI): m/z=
We have found that a dual mode of activation – en-
amine converged with photocatalysis – changed the
reaction pathway from the usual condensation of an
aldehyde with EDA to the CÀH insertion at the a-po-
3
+
273.1102, calcd. for C H O [M+Na] : 273.11032; elemen-
14 18 4
tal analysis calcd. (%) for C H O : C 67.18, H 7.25; found:
1
4
18
4
C 67.24, H 7.10.
Ethyl 3-formylundecanoate (23): yield: 184 mg (76%);
sition. Specifically, the reaction of aldehydes with
diazo reagents in the presence of morpholine as an or-
1
H NMR (CDCl , 400 MHz): d=9.71 (s, 1H, CHO), 4.15 (q,
3
J=4 Hz, 2H, COCH CH ), 2.83–2.79 (m, 1H, CH), 2.70–
2
3
ganocatalyst and Ru(bpy) Cl as a photoredox cata-
3
2
2.64 (m, 1H, CH), 3.39 (dd, J=4 Hz, 1H, CH), 1.72–1.68
lyst under visible light irradiation furnished exclusive- (m, 1H, CH), 1.49–1.43 (m, 1H, CH), 1.35- 1.23 (m, 15H,
1
3
ly a-alkylated aldehydes. The reported reaction pro- CH ), 0.87 (t, J=4 Hz, 3H, CH ); C NMR (CDCl3,
2
3
ceeds via the carbene transfer pathway but the forma- 100 MHz): d=202.9, 171.9, 60.7, 47.7, 33.1, 31.8, 29.5, 29.3,
tion of the cyclopropane cannot be excluded definite- 29.1, 28.6, 26.7, 22.6, 14.1, 14.0; IR: n=2927, 2856, 1737
À1
(
(
2
6
CO), 1466 (CHO), 1374, 1185, 1032, 723 cm ; HR-MS
ly, a detailed mechanistic overview is needed for
further exploration.
Our findings proved that the reactivity of diazo
compounds can be altered under visible light irradia-
tion thus opening new opportunities in the chemistry
of diazo reagents.
+
ESI): m/z=265.1779, calcd. for C H O [M+Na] :
1
4
26
3
65.1780; elemental analysis calcd. (%) for C H O : C
14 26 3
9.38, H 10.81; found: C 69.30, H 10.85.
[
51]
Ethyl 4-oxo-3-phenylbutanoate (24):
yield: 103 mg
1
(
7
3
44%); H NMR (CDCl , 400 MHz): d=9.70 (s, 1H, CHO),
.40–7.32 (m, 3H, Ph), 7.21–7.19 (m, 2H, Ph), 4.17–4.10 (m,
H, COCH CH , CH), 3.14 (dd, J=8.0 Hz, 1H, CH), 2.61
3
2
3
(
dd, J=8 Hz, 1H, CH), 1.22 (t, J=8 Hz, 3H, COCH CH );
2 3
1
3
C NMR (CDCl , 100 MHz): d=198.5, 171.5, 134.8, 129.2,
3
128.8, 128.0, 60.7, 54.6, 34.6, 14.0.
1
676
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 1671 – 1678

FULL PAPERS
Photocatalytic Reaction of Diazo Compounds with Aldehydes
1
Ethyl 3-(3-chlorobenzyl)-4-oxobutanoate (25): yield:
H NMR (CDCl , 600 MHz): d=9.78 (s, 1H, CHO), 7.33–
3
1
1
80 mg (71%); H NMR (CDCl , 400 MHz): d=9.78 (s, 1H,
7.30 (m, 2H, Ph), 7.27 (m, 1H, Ph), 7.19–7.17 (m, 2H, Ph),
4.17–3.99 (m, 3H, CH , CH), 3.34–3.32 (m, 2H, CH ), 3.16–
3
CHO), 7.26–7.18 (m, 3H, Ph), 7.07–7.06 (m, 1H, Ph), 4.12
2
2
(
q, J=7.2 Hz, 2H, COCH CH ), 3.12–3.07 (m, 2H, CH ),
3.09 (m, 2H, CH
), 2.79–2.72 (m, 1H, CH), 2.69–2.61 (m,
2
2
3
2
2
.74–2.69 (m, 1H, CH), 2.65 (dd, J=7.1 Hz, 1H, CH), 2.40
1H, CH), 2.40 (dd, J=6 Hz, 1H, CH), 2.01–1.70 (m, 4H,
2CH ), 1.46 (s, 9H, t-Bu); C NMR (CDCl , 150 MHz): d=
2 3
202.1, 171.5, 154.4, 137.5, 129.9, 128.7, 126.7, 79.7, 79.3, 64.9,
1
3
(dd, J=5.1 Hz, 1H, CH), 1.24 (t, J=7.1 Hz, 3H,
13
COCH CH ); C NMR (CDCl , 100 MHz): d=201.7, 171.4,
2
3
3
1
1
39.9, 134.5, 129.9, 129.1, 127.2, 127.0, 60.9, 49.0, 34.1, 32.7,
4.1; IR: n=2982, 2934, 1730 (CO), 1598, 1574, 1476, 1374
55.4, 49.1, 46.4, 34.5, 32.5, 28.7, 28.4, 27.8, 23.7, 22.9;
1
H NMR [(CD ) SO, 808C, 500 MHz]: d=9.70 (s, 1H,
3 2
À1
(CHO), 1198, 1157, 1027, 878, 783, 703, 684, 443 cm ; HR-
CHO), 7.31–7.27 (m, 2H, Ph), 7.23–7.18 (m, 3H, Ph), 4.11–
4.06 (m, 1H, CH), 4.05–3.99 (m, 1H, CH), 3.92–3.86 (m,
MS (ESI): m/z=309.0867, calcd. for C H ClO [M+
CH OH+Na] : 309.0870; elemental analysis calcd. (%) for
C H ClO : C 61.30, H, 5.94, Cl 13.92; found: C 61.27, H
13
15
3
+
1H, CH), 3.33–3.27 (m, 1H, CH), 3.10–3.02 (m, 3H, CH
CH), 2.80–2.73 (m, 1H, CH), 2.63–2.57 (dd, J=6 Hz, 1H,
CH), 2.49–2.41 (m, 1H, CH), 1.97–168 (m, 4H, 2CH ), 1.41
+
3
2
1
3
15
3
5.91, Cl 13.86.
2
1
3
[52]
(
s, 9H, t-Bu); C NMR [(CD ) SO, 808C, 125 MHz]: d=
Ethyl 2-formyl-3-methylbutanoate (26); (yield: 117 mg
3 2
1
2
6
3
2
7
03.1, 171.4, 171.4, 154.0, 138.7, 129.3, 128.7, 126.7, 79.0,
4.9, 55.7, 55.7, 49.1, 46.7, 40.8, 40.7, 40.5, 40.3, 40.2, 40.0,
9.8, 34.2, 32.8, 28.6, 28.5, 28.3, 23.3. IR: n=2975, 2932,
(63%); H NMR (CDCl , 400 MHz): d=9.74 (s, 1H, CHO),
3
4.12 (q, J=8.0 Hz, 2H, COCH CH ), 2.81–2.64 (m, 2H,
2 3
CH), 2.42–2.28 (ddd, J=4.0 Hz, 1H, CH), 2.19–2.01 (m, 1H,
CH), 1.25–1.21 (td, J=8.0 Hz, J=4 Hz, 3H, COCH CH ),
880, 1736 (CO), 1693 (CO), 1394 (CHO), 1366, 1167, 1109,
2
3
À1
13
02 cm ; HR-MS (ESI): m/z=430,2208, calcd. for C H O
1
2
1
.01–0.92 (m, 6H, 2CH ); C NMR (CDCl , 100 MHz): d=
03.3, 179.8, 172.2, 60.7, 60.6, 53.5, 47.2, 32.6, 29.8, 27.7, 20.1,
9.9, 19.3, 19.1, 14.0, 14.0; residual peaks from AcOEt,
20 22
3
3
3
+
[M+CH OH+Na] : 430.2206; elemental analysis calcd.
3
(
%) for C H NO : C 67.18, H 7.79, N 3.73; found: C 67.22,
21 29 5
H 7.72, N 3.69.
hexane and CH Cl – product is very volatile and difficult to
2
2
dry.
tert-Butyl 3-benzyl-4-oxobutanoate (29): yield: 166 mg
1
(
67%); H NMR (CDCl , 500 MHz): d=9.78 (s, 1H, CHO),
3
Acknowledgements
7
.30–7.16 (m, 5H, Ph), 3.10–3.04 (m, 2H, CH ), 2.74–2.2.72
2
(m, 1H, CH), 2.56 (dd, J=7.6 Hz, 1H, CH), 2.35 (dd, J=
13
This work was supported by the Ministry of Science and
Higher Education, grant number N NT204 187139.
5
1
4
1
.1 Hz, 1H, CH), 1.42 (s, 9H, t-Bu); C NMR (CDCl3,
25 MHz): d=202.5, 170.8, 137.9, 129.0, 128.6, 126.6, 81.1,
9.4, 34.5, 34.1, 28.0; IR: n=2979, 2931, 1728 (CO), 1455,
À1
368 (CHO), 1255, 1150, 751, 701 cm ; HR-MS (ESI):
+
m/z=303.1562, calcd. for C H O [M+CH OH+Na] :
15
20
3
3
References
3
7
03.1572; elemental analysis calcd. (%) for C H O : C
2.55; H 8.12; found: C 72.31, H 8.29.
Benzyl 3-benzyl-4-oxobutanoate (30): yield: 219 mg
15 20 3
[1] F. Hu, Y. Xia, C. Ma, Y. Zhang, J. Wang, Chem.
Commun. 2015, 51, 7986–7995.
1
(78%); H NMR (CDCl , 500 MHz): d=9.79 (s, 1H, CHO),
3
[2] H. M. L. Davies, D. Morton, Chem. Soc. Rev. 2011, 40,
857–1869.
7
2
2
.36–7.28 (m, 6H, Ph), 7.27–7.22 (m, 2H, Ph), 7.15–7.13 (m,
H, Ph), 5.08 (s, 2H, CH Ph), 3.14–3.07 (m, 2H, CH ), 2.76–
.67 (m, 2H, CH ), 2.42 (dd, J=4.0 Hz, 1H, CH); C NMR
1
2
2
3
[3] W. I. Dzik, X. Xu, X. P. Zhang, J. N. H. Reek, B. de
Bruin, J. Am. Chem. Soc. 2010, 132, 10891–10902.
[4] X. Cui, X. Xu, H. Lu, S. Zhu, L. Wojtas, X. P. Zhang, J.
Am. Chem. Soc. 2011, 133, 3304–3307.
1
2
(CDCl , 125 MHz): d=202.1, 171.5, 137.5, 135.5, 129.0,
3
1
3
1
28.7, 128.5, 128.3, 128.2, 126.7, 66.6, 49.2, 34.5, 32.6; IR: n=
087, 3063, 3030, 2925, 2828, 2724, 1732 (CO), 1496, 1455,
383 (CHO), 1352, 1189, 1160, 748, 700, 491 cm ; HR-MS
[5] T. Hashimoto, K. Maruoka, Bull. Chem. Soc. Jpn. 2013,
À1
86, 1217–1230.
nd
(
ESI): m/z=337.1413, calcd. for C H O [M+CH OH+
18 18 3 3
+
[6] R. Bates, Organic Synthesis Using Transition Metals, 2
edn., Wiley, 2012, chap. 8, pp 312–320.
Na] : 337.1416; elemental analysis calcd. (%) for C H O :
1
8
18
3
C 76.57, H 6.43; found: C 76.48, H 6.24.
-Phenylpropyl 3-benzyl-4-oxobutanoate (31): yield:
[7] E. Jellema, A. L. Jongerius, J. N. H. Reek, B. de Bruin,
3
Chem. Soc. Rev. 2010, 39, 1706–1723.
[8] O. Fujimura, T. Honma, Tetrahedron Lett. 1998, 39,
625–626.
1
248 mg (80%); H NMR (CDCl , 500 MHz): d=9.79 (s, 1H,
3
CHO), 7.31–7.25 (m, 5H, Ph), 7.19–7.16 (m, 5H, Ph), 4.06
td, J=4.0 Hz, 2H, CH ), 3.12–3.10 (m, 2H, CH ), 2.75 (d,
(
[9] G. A. Mirafzal, G. Cheng, L. K. Woo, J. Am. Chem.
2
2
J=4.0 Hz, 1H, CH), 2.68–2.62 (m, 3H, CH +CH), 2.39 (dd,
J=4.0 Hz, 1H, CH), 1.95–1.91 (m, 2H, CH ); C NMR
Soc. 2002, 124, 176–177.
2
13
2
[10] Y. Xi, Y. Su, Z. Yu, B. Dong, E. J. McClain, Y. Lan, X.
Shi, Angew. Chem. 2014, 126, 9975–9979; Angew.
Chem. Int. Ed. 2014, 53, 9817–9821.
[11] a) H. M. L. Davies, S. J. Hedley, Chem. Soc. Rev. 2007,
36, 1109–1119; b) A. Ford, H. Miel, A. ring, C. N. Slat-
tery, A. R. Maguire, M. A. McKervey, Chem. Rev.
2015, 115, 9981–10080.
[12] Z. Zhang, J. Wang, Tetrahedron 2008, 64, 6577–6605.
[13] A. C. B. Burtoloso, R. M. P. Dias, B. Bernardim, Acc.
Chem. Res. 2015, 48, 921–934.
(CDCl , 125 MHz): d=202.2, 171.7, 141.0, 137.6, 129.0,
3
1
3
1
4
28.7, 128.4, 128.3, 126.7, 126.0, 64.2, 49.2, 34.6, 32.6, 32.1,
0.1; IR: n=3085, 3061, 3027, 2952, 2925, 2858, 1731 (CO),
603, 1496, 1453 (CHO), 1192, 1163, 1030, 748, 701,
À1
92 cm ; HR-MS (ESI): m/z=333.1461, calcd. for C H O
2
0
22
3
+
[M+Na] : 333.1467; elemental analysis calcd. (%) for
C H O : C 77.39, H 7.14; found: C 77.36, H 7.01.
2
0
22
3
(2S)-tert-Butyl-2-{[(3-benzyl-4-oxobutanoyl)oxy]methyl}-
pyrrolidine-1-carboxylate (32): yield: 266 mg (71%);
Adv. Synth. Catal. 2016, 358, 1671 – 1678
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1677

K. Rybicka-Jasi n´ ska et al.
FULL PAPERS
[
[
[
[
14] T. Ye, M. A. McKervey, Chem. Rev. 1994, 94, 1091–
160.
15] M. P. Doyle, R. Duffy, M. Ratnikov, L. Zhou, Chem.
Rev. 2010, 110, 704–724.
16] M. Fontecave, Angew. Chem. 2015, 127, 7050-7051;
Angew. Chem. Int. Ed. 2015, 54, 6946–6947.
[29] E. Arceo, I. D. Jurberg, A. lvarez-Fernµndez, P. Mel-
chiorre, Nat. Chem. 2013, 5, 750–756.
[30] M. Silvi, E. Arceo, I. D. Jurberg, C. Cassni, P. Mel-
chiorre, J. Am. Chem. Soc. 2015, 137, 6120–6123.
[31] C. R. Holmquist, E. J. Roskamp, J. Org. Chem. 1989,
54, 3258–3260.
1
17] a) D. A. Nicewicz, T. M. Nguyen, ACS Catal. 2014, 4,
[
[
[
32] W.-J. Zhao, M. Yan, D. Huang, S.-J. Ji, Tetrahedron
005, 61, 5585–5593.
33] We have not studied eosin Y under the optimized con-
355–360; b) J. M. R. Narayanam, C. R. J. Stephenson,
2
Chem. Soc. Rev. 2011, 40, 102–113; c) D. Ravelli, S.
Protti, P. Neri, M. Fagnoni, A. Albini, Green Chem.
ditions.
2
011, 13, 1876–1884; d) Sanofi-Aventis, WO Patent
34] D. Gryko, D. Walaszek, Stereoselective Organocatalysis,
WO 2011/026865A1C, 2011; e) S. Liu, M. Tong, Y. Yu,
st
(
Ed.: R. R. Torres), 1 edn., Wiley, 2013, chap 2,
H. Xie, H. Li, W. Wang, Chem. Commun. 2015, 51,
pp 81–126.
11221–11224; f) D. M. Hodgson, A. Charlton, Tetrahe-
[
[
35] P. W. Hickmott, Tetrahedron 1982, 38, 1975–2050.
36] S. Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem.
Rev. 2007, 107, 5471–5569.
dron 2014, 70, 2207–2236; g) K. Fidaly, C. Ceballos, A.
Falgui›res, M. Sylla-Iyarreta, A. Guy, C. Ferroud,
Green Chem. 2012, 14, 1293–1297; h) E. R. Welin,
A. A. Warkentin, J. C. Conrad, D. W. C. MacMillan,
Angew. Chem. 2015, 127, 9804–9808; Angew. Chem.
Int. Ed. 2015, 54, 9668–9672; i) P. Riente, A. M. Adams,
J. Albero, E. Palomares, M. A. Pericàs, Angew. Chem.
[
37] Y. Cui, L. Zeng, Y. Fang, J. Zhu, C. H. Devillers, D.
Lucas, N. Desbois, C. P. Gros, K. M. Kadish, ChemElec-
troChem 2016, 3, 110–121.
[
[
[
[
[
[
[
38] A. Erkkilä, I. Majander, P. M. Pihko, Chem. Rev. 2007,
1
07, 5416–5470.
39] A. G. Cook, M. L. Absi, V. K. Bowden, J. Org. Chem.
995, 60, 3169–3171.
40] F. Ramirez, J. F. Marecek, Pure Appl. Chem. 1980, 52,
021–1045.
41] T. Toma, J. Shimokawa, T. Fukuyama, Org. Lett. 2007,
, 3195–3197.
42] D. M. Hodgson, D. Angrish, Chem. Commun. 2005, 39,
902–4904.
43] J. Zhao, W. Wu, J. Sun, S. Guo, Chem. Soc. Rev. 2013,
2, 5323–5351.
2
014, 126, 9767–9770; Angew. Chem. Int. Ed. 2014, 53,
9
613–9616; j) Ł. Wo z´ niak, J. J. Murphy, P. Melchiorre, J.
1
Am. Chem. Soc. 2015, 137, 5678–6581; k) L. Caruana,
F. Kniep, T. K. Johansen, P. H. Poulsen, K. A. Jçrgen-
sen, J. Am. Chem. Soc. 2014, 136, 15929–15932.
1
[
18] a) D. Ravelli, M. Fagnoni, A. Albini, Chem. Soc. Rev.
9
2
013, 42, 97–113; b) D. Ravelli, M. Fagnoni, Chem-
CatChem 2012, 4, 169–171.
4
[
[
19] A. Nijland, S. R. Harutyunyan, Catal. Sci. Technol.
2013, 3, 1180–1189.
4
20] J. W. Tucker, J. D. Nguyen, J. M. R. Narayanam, S. W.
44] a) H. Tomioka, E. Iwamoto, H. Itakura, K. Hirai,
Nature 2001, 412, 626–628; b) Tomioka, M. Itoh, S. Ya-
makawa, Y. Izawa, J. Chem. Soc. Perkin Trans. 2 1980,
603–609.
Krabbe, C. R. Stephenson, Chem. Commun. 2010, 46,
4985–4987.
[
[
21] D. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem.
Rev. 2013, 113, 5322–5363.
22] R. Brimioulle, D. Lenhart, M. M. Maturi, T. Bach,
Angew. Chem. 2015, 127, 3944–3963; Angew. Chem.
Int. Ed. 2015, 54, 3872–3890.
23] a) C. Müller, T. Bach, Aust. J. Chem. 2008, 61, 557–564;
b) C. Müller, Ch. Bauer, T. Bach, Angew. Chem. 2009,
[45] M. E. Kuehne, J. C. King, J. Org. Chem. 1973, 38, 304–
311.
[46] K. Saigo, H. Kurihara, H. Miura, A. Hongu, N. Kubota,
H. Nohira, M. Hasegawa, Synth. Commun. 1984, 14,
787–796.
[47] E. Wenkert. C. A. McPherson, E. L. Sanchez, R. L.
Webb, Synth. Commun. 1973, 3, 255–258.
[48] E. Kunkel, I. Reichelt, H. U. Reibig, Liebigs Ann.
Chem. 1984, 802–819.
[
[
121, 6767–6769; Angew. Chem. Int. Ed. 2009, 48, 6640–
6642.
24] a) A. C. Lottes, J. A. Landgrebe, K. Larsen, Tetrahe-
dron Lett. 1989, 30, 4093–4096; b) P. Yates, B. L. Sha-
piro, J. Am. Chem. Soc. 1963, 85, 1171–1176; c) E.
Wenkert, C. A. McPherson, J. Am. Chem. Soc. 1972,
[
[
[
49] E. Wenkert, T. S. Arrhenius, B. Bookser, M. Guo, P,
Mancini, J. Org. Chem. 1990, 55, 1185–1193.
50] M. A. Cismesia, T. P. Yoon, Chem. Sci. 2015, 6, 5426–
94, 8084–8090; d) R. P. L’⁄sperance, T. M. Ford, M.
Jones, J. Am. Chem. Soc. 1988, 110, 209–213.
5434.
[
[
[
[
25] D. A. Nicewicz, D. W. C. MacMillan, Science 2008, 322,
51] P. Deslongchamps, A. BØlanger, D. J. F. Berney, H.-J.
Borschberg, R. Brousseau, A. Doutheau, R. Durand,
H. Katayama, R. Lapalme, D. M. Leturc, C.-C. Liao,
F. N. MacLachlan, J.-P. Maffrand, F. Marazza, R. Marti-
no, C. Moreau, L. Ruest, L. Saint-Laurent, R. Sain-
tonge, P. Soucy, Can. J. Chem. 1990, 68, 127–152.
77–80.
26] H.-W. Shih, M. N. Vander Wal, R. L. Grange, D. W. C.
MacMillan, J. Am. Chem. Soc. 2010, 132, 13600–13603.
27] D. A. Nagib, M. E. Scott, D. W. C. MacMillan, J. Am.
Chem. Soc. 2009, 131, 10875–10877.
28] M. Neumann, S. Füldner, B. Kçnig, K. Zeitler, Angew.
[52] L. Carman, L. D. Kwart, T. Hulicky, Synth. Commun.
Chem. 2011, 123, 981–985; Angew. Chem. Int. Ed. 2011,
1986, 16, 169–182.
50, 951–954.
1
678
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 1671 – 1678