Toward a Green Atom Economy: Development of a Sustainable Multicomponent Reaction

Article abstract of DOI:10.1055/s-0034-1380719

The recently discovered photoinduced three-component reaction of diazo ketones, carboxylic acids, and isocyanides can be efficiently performed under continuous-flow conditions with consequential advantages in terms of selectivity and productivity. The inv

Full text of DOI:10.1055/s-0034-1380719

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2385–2390
2385
special topic
S. Garbarino et al.
Special Topic
Synthesis
Toward a Green Atom Economy: Development of a Sustainable
Multicomponent Reaction
Silvia Garbarinoa
Stefano Protti*b
Andrea Basso*a
a Bioorganic Chemistry Group, Department of Chemistry and Industrial
Chemistry, University of Genova, Via Dodecaneso 31, 16146 Genova,
Italy
andrea.basso@unige.it
b PhotoGreen Lab, Department of Chemistry University of Pavia, Viale
Taramelli 12, 27100 Pavia, Italy
prottistefano@gmail.com
Received: 19.03.2015
Accepted after revision: 13.04.2015
Published online: 26.05.2015
NC
R3
O
IV
R3
hν
DOI: 10.1055/s-0034-1380719; Art ID: ss-2015-c0183-st
R1
N
H
+
O
O
solvent
COOH
O
Abstract The recently discovered photoinduced three-component re-
action of diazo ketones, carboxylic acids, and isocyanides can be effi-
ciently performed under continuous-flow conditions with consequen-
tial advantages in terms of selectivity and productivity. The
investigation of the flow process and the determination of its sustain-
ability are discussed in detail. This multicomponent reaction affords
stereodefined captodative olefins, useful as synthons in organic chemis-
try.
R2
N2
I
R1
III
R2
II
III, IV
hν
– N2
O
C
R1
Key words multicomponent reactions, photochemistry, flow chemis-
try, green chemistry, diazo compounds, isocyanides
V
Scheme 1 General scheme for the ketene three-component reaction
(K-3CR)
The search for efficient and sustainable organic synthe-
ses is a highly topical subject. Multicomponent reactions
have been recognized as straightforward processes for
diversity-oriented syntheses1 characterized by high atom
economies, limited numbers of synthetic steps, and simpli-
fied product-isolation procedures.2 However, the activation
of substrates under mild conditions remains a challenge,
particularly when high temperatures are required to over-
come energy barriers; various chemical and physical ap-
proaches to this problem have been reported.3 Although
photochemistry has only recently been applied to multi-
component reactions, the number of articles published in
this interdisciplinary field is increasing rapidly.4 In general,
photoactivated reactions are capable of showing superior
selectivity and sustainability to their thermal counter-
parts.5
The key step is a photoinduced Wolff rearrangement of
the diazo ketone II7 into a reactive ketene V that reacts with
III and IV in a formal Passerini reaction.7c The products are
useful as synthons in various reactions, including cycload-
ditions,8 rearrangements,9 and radical additions.10
When the K-3CR was performed as a batch process in a
Rayonet merry-go-round reactor equipped with 16 Wood’s
lamps (8 W; λmax = 364 nm), olefins I were isolated as mix-
tures of E/Z geometric isomers in variable amounts.6b This
was explained as the consequence of competitive light ab-
sorption by the generated (Z)-captodative olefin and its
subsequent isomerization.11 The use of triplet quenchers
such as penta-1,3-diene (piperylene) or trans-stilbene was
beneficial in suppressing the isomerization. However, the
use of these additives in equimolar amount with respect to
the reactants and the highly dilute conditions required (up
to 0.07 M) resulted in the production of significant
amounts of waste.
We recently discovered a new phototriggered multi-
component reaction that we named the ketene three-
component reaction (K-3CR; Scheme 1). This proceeds un-
der mild conditions upon UV irradiation to give a captoda-
tive olefin of general formula I, starting from a diazo ketone
II, a carboxylic acid III, and an isocyanide IV.6
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2385–2390

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Special Topic
Synthesis
Continuous-flow reactors have recently emerged as a
promising technology in organic synthesis, especially in
photochemistry, where the reduced size of the reaction
channels permits efficient penetration of light to the photo-
lyzed solution. This results in a marked reduction in the
residence time thereby suppressing the generation of by-
products and, consequently, improving the efficiency and
selectivity of the process while permitting an increase in
the concentration of the substrate.12 A preliminary study6b
of the K-3CR in a photochemical flow reactor incorporating
the multilamp reactor used in the batch reactions as a light
source showed that the reaction could be performed with a
short residence time, thereby suppressing E/Z isomeriza-
tion of the captodative olefins, even in the absence of a trip-
let quencher additive. This encouraged us to examine the
continuous-flow approach with the aim of optimizing the
K-3CR process from the environmental point of view. We
assembled a continuous-flow photoreactor consisting of a
12-m-long coil of UV-transparent fluorinated ethylene–
propylene polymer (FEP) tubing with an outer diameter of
1.6 mm and an inner diameter of 0.8 mm, wound around a
conventional water-cooled photochemical reactor. The light
source consisted of a Wood’s lamp (16 W), and the capacity
of the reactor was 6 mL (Figure 1). The solution was circu-
lated by means of an HPLC pump.
concentration of the reactants and the flow speed of the
solution on the yield and selectivity of this reaction. An
equimolar mixture of the three reagents dissolved in tolu-
ene (2 mL) was loaded in the injection loop of the HPLC
pump. The solution was then pumped through the reaction
coil and collected in a flask. The solvent was evaporated un-
der reduced pressure and the crude material was analyzed
by NMR spectroscopy to control the consumption of the di-
azo ketone and to determine the E/Z ratio of the products.
The crude product was finally purified by flash chromatog-
raphy to calculate the isolated yield of the desired product.
The results are summarized in Table 1.
BuNC
O
O
+
N2
Bu
hν
N
H
O
O
toluene
Cl
Cl
Pr
+
PrCO2H
4a
Scheme 2 Model reaction used to optimize the process under flow
conditions
Table 1 Optimization of the K-3CR Route to 4a under Continuous-
Flow Conditions
Entry
Concentrationa (M) Flow rate (mL/h)
Yieldb (%)
Z/E
1:0.04
1
0.1
0.2
0.3
0.1
3.6
1.8
0.6
1.2
36
56
59
–
2
1:0.05
1:0.15
1:0.10
3
4c
a The concentration refers to that of the diazo ketone. (Equimolar amounts
of the diazo ketone, carboxylic acid, and isocyanide were used in argon-
equilibrated anhydrous toluene.)
b Isolated yield of the Z-isomer;
c Isomerization reaction of the (Z)-captodative olefin. Diastereomerically
pure (Z)-4a was pumped into the flow apparatus and collected after irradia-
tion.
The flow speed was adjusted to achieve almost com-
plete consumption of the diazo ketone. More highly con-
centrated solutions gave better conversions, probably be-
cause the reactive ketene intermediate could interact more
easily with the other components; however, because con-
centrated solutions required longer irradiation times and,
consequently, slower flow speeds, they also favored alkene
isomerization. The fact that isomerization of the generated
captodative olefin (Z)-4a occurred under our flow condi-
tions was confirmed by irradiating the a solution of the
product under similar reaction conditions (Table 1, entry
4). Reducing the flow speed from 3.6 to 1.8 mL/h resulted in
only a slight worsening of the isomer ratio (entries 1 and 2),
Figure 1 Photograph of the photochemical reactor
We initially focused on optimization of the conditions
for the photochemical reaction by examining the reaction
shown in Scheme 2, and we investigated the effects of the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2385–2390

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Synthesis
hν
O
R2
R1
R1
N
H
O
NC
N2
R2
COOH
+
+
O
R3
O
4
2
3
R3
1
toluene
O
O
O
n-Bu
t-Bu
t-Bu
N
H
O
Ph
N
Ph
N
H
O
H
O
0.17 M, 3 mL/h
4c, 69% 0.354 mmol/h
O
O
O
Cl
OMe
0.14 M, 3 mL/h
0.3 M, 1.8 mL/h
4a, 56%, 0.202 mmol/h
4b, 59% 0.242 mmol/h
O
O
H
O
O
N
Cl(H2C)3
N
H
O
t-Bu
N
H
N
H
O
O
O
O
O
O
Cl
Ph
0.12 M, 1.8 mL/h
4f, 37% 0.078 mmol/h
0.14 M, 3 mL/h
4d, 50%, 0.207 mmol/h
0.14 M, 3 mL/h
4e, 74% 0.306 mmol/h
Scheme 3 Reactions carried out under flow conditions. For each compound, the yield and productivity are reported. The yield is the isolated yield of
the Z-isomer.
whereas increasing the solution concentration from 0.2 to
0.3 M produced only a modest improvement in the yield
(entries 2 and 3).
The results for the synthesis of enamide 4g (Scheme 4)
confirmed the advantages of the continuous–flow photo-
chemical approach over a batch approach in terms of both
efficiency and sustainability.
The disappearance quantum yield Φ–1 for 1-diazo-3-
phenylacetone has been determined to be 0.26 (a similar
value, Φ–1 = 0.28, was obtained for 2-diazo-1-phenyleth-
anone), and comparable values have been obtained for the
Wolff rearrangements of various α-diazo ketones.13 We
therefore examined the yield, productivity, waste produc-
tion, and energy expenditure of the reaction. The waste
production is well described by the PMI parameter, i.e., the
In light of these preliminary results, we decided to carry
out a set of photoinduced K-3CRs (Scheme 3). Slight chang-
es in flow and concentration conditions, compared were
those shown in Table 1, entry 2 were dictated by the differ-
ent reactivities of the diazo ketones employed. (Z)-Acyloxy-
acrylamides 4a–g were obtained in moderate to satisfacto-
ry yields in amounts of up to 3.1 g/day (product 4c) and
with a Z/E selectivity in excess of 90:10 in all cases.
O
NC
N
H
O
COOH
N2
hν
O
+
+
O
toluene
Φ
-1 = 0.26
4g
Scheme 4 Photochemical synthesis of compound 4g
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2385–2390

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Table 2 Performance of Batch and Continuous-Flow Reactors in the K-3CR Reaction for the Synthesis of 4g
Entry
Conditions
Conc.
(M)a
Flow rate
(mL/min)
Yield
(%)b
Productivity
(mmol/h)
STY
(M/h)
PMI
(kg/kg)
Specific productivity
(mmol/W × 103)
1
2
3
4
5
6
Batchc
0.070
0.034
0.078
0.156
0.173
0.234
–
75
71
58
74
64
78
0.0525
0.362
0.217
0.346
0.199
0.219
0.0105
0.0603
0.0361
0.0577
0.0332
0.0365
39.43
100.7
54.75
23.14
23.30
14.50
0.410
2.83
13.6
21.6
12.4
13.7
Flow Ad
Flow Be
Flow Be
Flow Be
Flow Be
0.25
0.08
0.05
0.03
0.02
a Concentration of the diazo ketone (equimolar amounts of the diazo ketone, carboxylic acid, and isocyanide were used in argon-equilibrated anhydrous tolu-
ene).
b Isolated yield of the Z-isomer.
c The solution (5 mL) was irradiated in a multilamp reactor equipped with 16 × 8 W Wood’s lamps (λ = 350 nm).
d Flow reactor described in ref. 6b.
e Flow reactor described in this work (see above).
total mass of materials required to produce a unit mass of
the desired product.14 The energy expenditure was ana-
lyzed by calculating the specific productivity, the number
of mmol of product produced for a given amount of energy;
in this case, it is the amount of energy consumed by the
light source.15 There are few reports regarding the ecologi-
cal sustainability of photochemical reactions.5,15,16
eral reduction in the waste produced (Table 2; PMI).
However, the story is somewhat different when we consid-
er the energy supplied. In our case, the use of a highly con-
centrated solution required a longer irradiation time with-
out any significant improvement in the yield of the reac-
tion. In consequence, the production of the desired product
under these conditions involved a greater expenditure of
energy, as demonstrated by the specific productivity value
(Table 2, entries 5 and 6). We are currently conducting in-
vestigations with the aim of further lowering the produc-
tion of waste while improving the absorption of light by the
reaction mixture (for example, by changing from a meso-
flow to microflow reactor).12a
In conclusion, captodative olefins of general formula I
have been used as substrates for base-mediated rearrange-
ments to pyrrolones and pyrrolidinediones with antitumor
activity.9 The availability of a straightforward and sustain-
able method for the production of such compounds could
open a route to novel applications that we are currently in-
vestigating and will report in due course.
The use of a batch reactor resulted in a low productivity
because of the dilute conditions and the long irradiation
time (5 h) that were required (Table 2, entry 1). Further-
more, this process gave an unsatisfactory PMI value and a
high energy expenditure. However, changing to continu-
ous-flow conditions did not necessarily improve the pro-
cess. The use of a nonoptimized photochemical flow reac-
tor6b resulted in a highly unsatisfactory PMI (100.7 kg/kg),
despite a general improvement in the other parameters
[space time yield (STY), productivity, and specific produc-
tivity] (entry 2). In this case, a lower concentration of sub-
strate was required to achieve a similar performance to that
achieved under batch conditions. With our new photoreac-
tor, however, we were able to use a concentrated solution
(up to 0.256 M; entries 3–6). This significantly reduced the
amount of waste produced to 14.50 kg/kg (entry 6); it also
reduced the energy consumed in the process. The specific
productivity increased up to 40 times on changing from a
batch reactor to a flow reactor (entries 1 and 4).
As in other photochemical processes discussed in the
literature,15 two issues arise from the assessment of such
reactions, namely the highly dilute conditions and the en-
ergy supply required to operate the lamps. These are criti-
cal points, especially when the reaction has a low quantum
yield, as is the case in the photoinduced Wolff rearrange-
ment of diazo ketones 1 that we investigated.
The use of a photochemical flow reactor, with its opti-
mized light absorption, permitted an increase in the con-
centration of the substrates while maintaining a satisfacto-
ry yield and selectivity. This, predictably, resulted in a gen-
Photoinduced reactions were performed with a Rayonet instrument
equipped with up to 16 Wood’s light lamps (8 W; λmax: 364 nm), or
with the in-house-fabricate flow apparatus described above.
The disappearance quantum yield (Φ–1) was been measured with a
0.070 mM solution of 1-diazo-3-phenylacetone in toluene on an opti-
cal bench equipped with a 150 W high-pressure mercury lamp (λIRR
=
317 nm) with potassium ferrioxalate as actinometer.
Commercially available anhydrous toluene was used as the solvent.
All solvents and reagents used were purchased from commercial sup-
pliers and employed without any further purification, apart from the
diazo ketones, which were prepared from the corresponding acyl
chlorides or mixed anhydrides by the reported procedures. Flash col-
umn chromatography was performed on 220−400 mesh silica. NMR
spectra were recorded at 300 MHz (1H) or 75 MHz (13C) on a Varian
Mercury-300 spectrometer at 295 K, and the chemical shifts are ex-
pressed in ppm relative to TMS as internal standard (0.00 ppm). High-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2385–2390

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S. Garbarino et al.
Special Topic
Synthesis
resolution mass spectra were recorded on a Waters MicroMass LCT
spectrometer, operated in the ESI+ ionization mode, with a TOF ana-
lyzer.
(1Z)-5-Chloro-1-[(cyclohexylamino)carbonyl]pent-1-en-1-yl (2E)-
3-Phenylacrylate (4e)
Colorless oil; yield: 78 mg (74%).
1H NMR (300 MHz, CDCl3): δ = 7.82 (d, J = 16.0 Hz, 1 H), 7.58–7.26 (m,
5 H), 6.53 (d, J = 16.0 Hz, 1 H), 5.89 (br d, J = 7.9 Hz, 1 H), 5.74 (t, J = 8.1
Hz, 1 H), 3.82 (m, 1 H), 3.61 (t, J = 6.9 Hz, 2 H), 2.81 (q, J = 7.2 Hz, 2 H),
2.05–1.08 (m, 12 H).
13C NMR (75 MHz, CDCl3): δ = 164.1, 160.9, 148.0, 141.7, 133.9, 131.2,
129.2, 128.6, 125.4, 115.8, 48.5, 44.3, 33.0, 31.0, 25.6, 24.9, 23.5.
Continuous-Flow Synthesis of Captodative Olefins 4; General Pro-
cedure
Equimolar amounts of the diazo ketone, carboxylic acid, and isocya-
nide were dissolved in anhyd toluene (2 mL) in a test tube, and the
solution was flushed with argon for 10 min. The clear solution was
loaded into the injection loop of the HPLC system and pumped into
the reaction coil (carrier solvent: MeCN) at the preset speed. The
solution exiting the reactor was collected in a flask and, when elution
HRMS: m/z [M
+
H]+ calcd for C21H27ClNO3: 376.1674; found:
376.1669.
1
was complete, concentrated under vacuum and analyzed by H NMR
(1Z)-3-[(tert-Butoxycarbonyl)amino]-1-[(cyclohexylamino)car-
bonyl]but-1-en-1-yl Butyrate (4f)
spectroscopy. The crude material was then purified by flash chroma-
tography (silica gel, PE–EtOAc).
White foam; yield: 34 mg (37%).
1H NMR (300 MHz, DMSO-d6): δ = 7.42 (br d, J = 6.9 Hz, 1 H), 6.63 (br
d, J = 6.9 Hz, 1 H), 6.10 (d, J = 8.7 Hz, 1 H), 4.23 (sextet, J = 6.9 Hz, 1 H),
3.57 (m, 1 H), 2.49 (t, J = 7.5 Hz, 2 H), 1.75–1.07 (m, 24 H), 0.95 (t, J =
7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.0, 161.2, 155.0, 140.6, 127.4, 79.8,
48.5, 43.1, 35.9, 33.1, 32.5, 28.6, 28.5, 25.6, 24.9, 20.7, 18.5, 13.8.
(Z)-1-[(Butylamino)carbonyl]-2-(4-chlorophenyl)vinyl Butyrate
(4a)
Yellow foam; yield: 72 mg (56%).
1H NMR (300 MHz, CDCl3): δ = 7.42 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 8.4
Hz, 2 H), 7.15 (s, 1 H), 6.00 (br s, 1 H), 3.36 (q, J = 7.5 Hz, 2 H), 2.52 (t,
J = 7.5 Hz, 2 H), 1.74 (sextet, J = 7.5 Hz, 2 H), 1.58–1.50 (m, 2 H), 1.42–
1.28 (m, 2 H), 1.00 (t, J = 7.5 Hz, 3 H), 0.94 (t, J = 7.5 Hz, 3 H).
HRMS: m/z [M + H]+ calcd for C20H35N2O5: 383.2540; found: 383.2537.
13C NMR (75 MHz, CDCl3): δ = 170.5, 162.6, 140.5, 135.1, 131.2, 130.8,
129.1, 122.2, 39.8, 36.2, 31.8, 20.2, 18.4, 13.9, 13.8.
(1Z)-1-[(Cyclohexylamino)carbonyl]-3-phenylprop-1-en-1-yl Ben-
zoate (4g)
HRMS: m/z [M
+
H]+ calcd for C17H23ClNO3: 324.1361; found:
324.1365.
White solid; yield: 133 mg (78%); mp 125–126 °C.
1H NMR (300 MHz, CDCl3): δ = 8.17 (dd, J = 8.2, 1.1 Hz, 2 H), 7.67 (tt,
J = 7.4, 1.2 Hz, 1 H), 7.53 (t, J = 7.6 Hz, 2 H), 7.31–7.18 (m, 5 H), 6.68 (t,
J = 7.6 Hz, 1 H), 5.84 (br d, J = 8.0 Hz, 1 H), 3.89–3.77 (m, 1 H), 3.44 (d,
J = 7.6 Hz, 2 H), 1.94–1.05 (m, 10 H).
(Z)-1-[(tert-Butylamino)carbonyl]-2-phenylvinyl Propionate (4b)
White solid; yield: 45 mg (59%); mp 96–97 °C.
1H NMR (300 MHz, CDCl3): δ = 7.47–7.32 (m, 5 H), 7.12 (s, 1 H), 5.83
(s, 1 H), 2.14 (q, J = 7.8, 2 H), 1.43 (s, 9 H), 1.24 (t, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 163.9, 161.0, 141.3, 138.1, 134.3, 130.4,
128.9, 128.7, 128.7, 128.4, 126.7, 125.5, 48.5, 33.0, 32.5, 25.5, 24.8.
HRMS: m/z [M + H]+ calcd for C23H26NO3: 364.1907; found: 364.1909.
13C NMR (75 MHz, CDCl3): δ = 171.4, 162.1, 140.8, 132.8, 129.5, 129.1,
128.8, 122.5, 51.7, 28.8, 27.8, 9.1.
HRMS: m/z [M + H]+ calcd for C16H22NO3: 276.1594; found: 276.1596.
Acknowledgment
(Z)-1-[(tert-Butylamino)carbonyl]-2-phenylvinyl (3-Methoxyphe-
nyl)acetate (4c)
The authors would like to thank Mr. Alessandro Sannino (University
of Genova) for his valuable contribution to the development of the
flow apparatus. We also thank Dr. Davide Ravelli (University of Pavia)
for fruitful discussion.
White solid; yield: 86 mg (69%); mp 104–105 °C.
1H NMR (300 MHz, CDCl3): δ = 7.41–7.26 (m, 6 H), 6.99–6.86 (m, 3 H),
5.49 (s, 1 H), 3.80 (s, 3 H), 3.78 (s, 2 H), 1.22 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 167.8, 161.5, 160.2, 140.1, 134.1, 132.6,
130.3, 129.5, 129.1, 128.8, 123.2, 121.7, 115.0, 113.5, 55.4, 51.4, 41.9,
28.5.
References
HRMS: m/z [M + H]+ calcd for C22H26NO4: 368.1856; found: 368.1864.
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White solid; yield: 49 mg (50%); mp 126–127 °C.
1H NMR (300 MHz, CDCl3): δ = 7.44–7.31 (m, 4 H), 7.13 (s, 1 H), 5.83
(br d, J = 7.9 Hz, 1 H), 3.92–3.79 (m, 1 H), 2.54 (t, J = 7.3 Hz, 2 H), 2.00–
1.11 (m, 11 H), 1.01 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.4, 161.7, 140.6, 134.9, 131.2, 130.7,
129.0, 121.9, 48.7, 36.1, 33.0, 25.5, 24.8, 18.3, 13.7.
HRMS: m/z [M
+
H]+ calcd for C19H25ClNO3: 350.1517; found:
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2385–2390

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