Microwave versus Conventional Light Activation of O-Radical Scission Processes

Article abstract of DOI:10.1002/ejoc.201601034

Domino or sequential processes initiated by cleavage of O radicals has led to the conversion of low-cost, readily available substrates into high-profit products. The optimization of these processes by using different activation sources (irradiation with v

Full text of DOI:10.1002/ejoc.201601034

A Journal of
Accepted Article
Title: Microwave versus Conventional Light Activation of O-Radical Scission Proces-
ses
Authors: Alicia Boto; Ivan Romero-Estudillo; Carmen Carro
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European Journal of Organic Chemistry
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Microwave versus conventional Light Activation of O-Radical
Scission Processes
Carmen Carro,[a,b] Iván Romero,[a,c] and Alicia Boto*[a]
Abstract: Domino or sequential processes initiated by cleavage of
O-radicals allow the conversion of low-cost, readily available
substrates into high-profit products. The optimization of these
processes by using different activation sources (irradiation with
visible light, microwaves and conventional heating) is described
herein, as well as the application to the conversion of carbohydrates,
amino acids, peptides, and terpenes into valuable derivatives.
Introduction
In the last years, our group has reported different domino or
sequential processes which allow the direct conversion of readily
Scheme 1. One-pot oxidative radical scission processes.
available amino acids, hydroxy amines and carbohydrates into a
diversity of products, such as amino acid or nucleoside
analogues and alkaloid precursors.1 The initial step is the
transformation of an alcohol, acetal or carboxylic acid (R-OH)
into a hypoiodite 1 (R-OI, Scheme 1).1,2 Then, the homolytic
cleavage of the O-I bond generates an O-radical 2 which can
undergo -scission, to afford the final products 3.1-3
Results and Discussion
The first studies were dedicated to the scission of O-radicals
derived from terpenes. Inexpensive (-)-menthol 4 (Scheme 2)
was used as substrate, since its fragmentation would likely
afford the valuable aldehyde (R)-(+)-citronellal 5.7
The conversion of the R-OH substrate into the hypoiodite R-OI is
carried out by treatment with (diacetoxyiodo)benzene (DIB) and
iodine.1-3 The scission energy of the O-I bond is about 44
kcal/mol, which can be achieved by irradiation with visible light
(3570 kcal/mol) from sunlight or lamps.4 Although the
procedure works well in the laboratory, the use of light in larger
reactors could pose problems, complicating the scale-up of the
processes.
In this reaction, three activation sources were compared: visible
light at 26oC, conventional heating and microwave heating at
80oC. In the three cases, a complex product mixture was
formed initially (conversion 4→8). The mixture presumably
consisted mainly of diastereomeric scission products 8, but
could also contain products from side-reactions such as
hydrogen abstraction or oxidation.2,3 In order to clarify this point,
the reaction mixture was treated with base, and a main product
5 was isolated, resulting from elimination of the scission
products 8. Interestingly, the three activation sources afforded
similar yields (47-55%, Table 1); the variations probably resulted
from the high product volatility.8 However, the reaction time was
drastically reduced with microwaves or conventional heating.
A suitable alternative could be the use of heating, either by
conventional ways or by microwave irradiation.5 In recent years,
the utility of microwaves to activate many chemical processes,
from spn-spn couplings to aldol condensations, has been
highlighted.5,6 Although in most organic reactions their effect is
purely thermal,5a microwaves present advantages over
traditional heating such as reaching the desired temperature in a
very short time, easy control of the reaction conditions, and short
reaction times. We wondered whether microwave irradiation
could offer advantages over traditional heating or light in these
radical scission processes, from an operational standpoint. This
communication reports the comparison of these activation
sources, as well as their application to the conversion of low-
cost, readily available substrates (carbohydrates, amino acids,
peptides, and terpenes) into high-profit products.
[a] Instituto de Productos Naturales y Agrobiología CSIC; Avda.
Astrofísico Fco. Sánchez, 3. 38206-La Laguna, Tenerife (Spain). Fax:
+34 922 260135; E-mail: alicia@ipna.csic.es
[b] Current work: BIOSIGMA SL, c/ A. Dominguez Afonso 16, 38003-S/C
Tenerife, Spain
[c] Current work: Centro de Investigaciones Químicas–IICBA, Universidad
Autónoma del Estado de Morelos , Cuernavaca, Mexico
Supporting information for this article is given via a link at the end of
the document.
Scheme 2. Radical scission processes with terpenes (menthol).
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Using similar solvent (DCE) and reagent amounts (entries 1, 2,
and 5), and carrying out the reaction until disappearance of
substrate 9, the three activation sources gave similar yields (74-
78%). However, with microwaves (entry 2) the reaction was
completed in 15 min, and with conventional heating (entry 5) in
30 min, in contrast with visible light activation (150 min, entry 1).
Using microwave irradiation, the effect of solvent and reagent
amount was studied. When the apolar solvent DCE was
replaced by polar MeCN (entries 2 and 3), the results were
similar. However, when the amount of iodine was reduced from
0.5 to 0.3 equiv. (entries 2 and 4), the yields decreased
considerably.
Table 1. Radical scission processes with (-)-menthol 4
Activation conditionsa
Entry
t (min)
Product 5 (%)
h (visible), 26 oC
MW (100 W), 80 oC
80 oC
1
2
3
47
48
55
150 min
15 min
15 min
[a] Substrate 4 (0.2 mmol), PhI(OAc)2 [DIB] (1.5 eq), I2 (0.5 eq), DCE, during
time t; then work-up; the residue was treated with DBU, CH2Cl2, 3h. Yields for
products purified by chromatography
The process was then applied to the scission of O-radicals
derived from carbohydrates, as shown by the stereoselective
conversion of commercial mannose derivative 9 (Scheme 3) into
the acetal 10.9 The scission afforded a C-radical 11 stabilized by
the -oxygen function, precursor of the unstable intermediate 12
whose halogenated group X was readily extruded, giving the
oxycarbenium ion 13. Finally, this ion reacted with acetate ions
from DIB to give the acetal 10. The direct conversion 9→10 was
carried out under different conditions (Table 2).
The sequential process was then studied with 2-aminosugars
and -hydroxyamines (conversions 14→17 and 18→21, Scheme
4). In these cases the scission generated a C-radical stabilized
by a nitrogen function (such as intermediates 15 and 19), which
underwent oxidation to an acyliminium ion (i.e. 16 and 20). The
mechanism is similar to the formation of oxycarbenium ions in
carbohydrates.1b-c,10
Scheme 3. One-pot oxidative radical scission with carbohydrate substrate 9.
Table 2. One-pot oxidative radical scission of substrate 9 to give product 10
DIB / I2 (equiv.)
Energy
source
Yield 10
entry
solvent
t (min)
(%)a
h, 26 oC
1
2
1.5 /0.5
1.5 /0.5
DCE
DCE
150
15
74
77
MW 100
W, 80 oC
MW 100
W, 70 oC
3
79
1.5 /0.5
MeCN
15
MW 100
W, 80 oC
4
5
53
78
1.5 /0.3
1.5 /0.5
DCE
DCE
15
30
80 oC
[a] Yields for products purified by chromatography
Scheme 4. One-pot oxidative radical scission with -hydroxyamines.
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European Journal of Organic Chemistry
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Once formed, the acyliminium ion reacted with acetate ions to
afford N,O-acetals such as compounds 17 and 21. The
formation of N,O-acetals is particularly interesting, since their
reduction can afford N-alkyl compounds; thus, the reduction of
compound 19 gives a valuable N-methyl homoserine lactone.1b
units in peptides can be challenging, since side-reactions such
as hydrogen abstraction or oxidation could take place.
Nevertheless, the scission of the dipeptide 2512 via the glycyl
cation 26 proceeded to give mainly the desired scission product
27 as a diastereomer mixture.
The transformations 14→17 and 18→21 was studied under
different conditions (Table 3). In the case of the 2-aminosugar
14, the optimized reagent and solvent conditions were used with
visible light (entry 1), microwaves (entries 3 and 4) and
conventional heating (entry 6). The reaction was carried out until
disappearance of the starting material. Microwaves and
conventional heating gave similar yields (91 / 86%), which were
superior to that obtained with visible light (69%). In addition, the
reaction proceeded in only 30 min with the alternative sources
(the reaction time with visible light was 150 min). In the case of
microwaves, the yields at different times were compared (entries
3 and 4); the optimum yield was obtained at 30 min (91%) but at
15 min a good result was still obtained (79%).
In an attempt to increase the yields with visible light, the reagent
amounts were increased (entries 1 and 2) but the results were
similar. However, when the amounts of reagents (iodine) were
reduced with respect to the standard conditions (entries 4 and 5
with MW) the yields dropped significantly.
In the case of L-hydroxyproline substrate 18, good yields were
obtained with the three activation sources (77-81%, entries 7-9),
but again, microwaves or conventional heating allowed a
significant reduction in reaction times (entries 8 and 9). L-
hydroxyproline was recently introduced as
a
versatile
“customizable unit” in the site-selective modification of
peptides,1b,c,f and thus, these results are particularly interesting.
Table 3. One-pot oxidative radical scission with -hydroxyamines
Scheme 5. One-pot oxidative radical scission with serine derivatives 20/23.
Table 4. One-pot oxidative radical scission with serine derivatives
DIB / I2
Energy
source
t
equiv.a
Products (%) b
entry
substrate
(min)
1.5 /
0.5
17 (69, dr 1:1)
h (visible)
1
2
3
14
14
14
150
150
15
t
26 oC
entry
substrate
Energy source a
Products (%) b
(min)
h, 26 oC
2.0 /1.0
1.5 /0.5
17 (72)
17 (79)
1
2
3
4
5
6
22
22
22
25
25
25
h (visible) 26 oC
100 W, 80 oC
80 oC
180
15
15
60
15
15
24 (89)
24 (87)
MW 100 W,
80 oC
24 (84)
MW 100 W,
80 oC
4
5
14
14
1.5 /0.5
1.5 /0.3
30
30
17 (91)
17 (52)
h (visible) 26 oC
100 W, 80 oC
80 oC
27 (38)
MW 100 W,
80 oC
27 (53) / [78],c 25 (34)
27 (50) / [71],c 25 (31)
80 oC
30
17 (86)
21 (81)
6
7
14
18
1.5 /0.5
1.5 /0.5
h, 26 oC
[a] Reactions in 1,2-dichloroethane, with an 1.0:1.5:0.5 relationship for
substrate: DIB: iodine. [b] Yields for products purified by chromatography.
[c] Yields for products with respect to transformed starting material.
120
MW 100 W,
80 oC
8
9
18
18
1.5 /0.5
1.5 /0.5
15
15
21 (77)
21 (79)
80 oC
Again, the activation with visible light was compared with the
activation with microwaves and conventional heating (Table 4).
In the case of the conversion 22→24, the optimized reagent and
solvent conditions under irradiation with visible light for 3 h (entry
1), afforded the (acetoxy)glycine derivative 24 in very good yield.
The microwave irradiation (entry 2) gave a similar yield in a
shorter time (15 min). When conventional heating (80 oC) was
used (entry 3), the results were similar to the reaction with
microwave irradiation.
[a] Reactions in 1,2-dichloroethane. [b] Yields for products purified by
chromatography.
Other “customizable unit” in peptide chemistry is serine,1g,2d
since its hydroxymethyl group can be cleaved and replaced by
other chains. Scheme 5 displays the fragmentation of serine
derivative 22, which generated a glycyl cation intermediate 23
which was trapped by acetate ions from the reagent to give the
final product 24.1g,11 The scission of the serine customizable
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European Journal of Organic Chemistry
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In the case of the conversion 25→27, the best results were
obtained with MW (entry 5) and conventional heating (entry 6).
The reaction was not allowed to proceed until completion, in
order to minimize side-products; good yields with respect to the
transformed starting material (71-78%) were obtained.
residues in peptides can afford interesting derivatives; for
instance, the allyl group in compound 34 can be used to link two
peptide chains using olefin metathesis.16
As shown in Table 5, the best results for the one-pot
decarboxylation-allylation process were obtained using
microwave irradiation (entry 5, 71%) and heating (entry 6, 78%)
during the scission step. The reaction times for scission were
also reduced with the new activation sources (15 min).
The cleavage of amino acids by oxidative radical
decarboxylation using different activation sources was studied
next. The decarboxylation of the simple proline derivative 28
(Scheme 6) afforded an iminium intermediate 29, which
presumably gave an unstable 2-acetoxypyrrolidine which was
transformed into the 2-hydroxypyrrolidine 30 during the aqueous
work-up.13 A minor iodinated product 31 was also obtained,
resulting from isomerization of the iminium intermediate 29 to an
encarbamate and -iodination.14
Table 5. One-pot oxidative radical decarboxylation with proline derivatives
substrate
Energy sourcea
t (min)
Products (%) c
entry
h 26 oC
100 W, 80 oC
80 oC
1
2
3
4
5
6
28
28
28
32
32
32
90
10
10
90
15
15
30 (56), 31 (14)
30 (76), 31 (7)
30 (82), 31 (3)
34 (66) d
The iodination process was previously observed in the
decarboxylation of proline carbamates,14 and was favored in
polar aprotic solvents and with excess iodine. As shown in Table
5 (entries 1-3), despite a non-polar solvent (DCE) and a sub-
stoichiometric amount of iodine were used, the iodinated product
31 was obtained in all the cases. Longer reaction times favor
iodination, which can explain the higher yields of iodopyrrolidine
31 and the smaller yields of non-halogenated product 30 with
visible light irradiation (Table 5, entry 1) with respect to
microwave or heating activation (entries 2 and 3). Again, the
reaction times were considerably reduced with the new
activation sources (10 min, entries 2-3).
h26 oC b
100 W, 80 oC b
80 oC b
34 (71) d
34 (78) d
[a] Reactions in DCE, with an 1.0:1.5:0.5 relationship for substrate: DIB:
iodine. [b] After the scission step, the reaction was cooled to 0oC and
allylTMS (3 equiv) and BF3OEt2 (2 equiv) were added, and the mixture was
stirred for 3 h. [c] Yields for products purified by chromatography. [d] Yields
after the addition of the C-nucleophile.
The scale-up of the reaction was studied with carbohydrate and
amino acid derivatives, namely the N-acetyl glucosamine 14,
and the serine ester 22. The reaction proceeded in good yields
giving compounds 17 or 24 (71% and 84%, respectively), and
allowing the readily preparation of 300-600 mg of these
compounds. Moreover, since the microwave-activated reaction
is fast, it is possible to prepare several batches in a short time,
and then carry out a joint purification. The use of continuous-flow
microwave equipment could further enhance the applications of
this methodology.17
Conclusions
Low-cost substrates such as terpenes, carbohydrate and amino
acid derivatives were converted into high-profit products, using
metal-free sequential processes initiated by O-radical scissions.
The classical activation source, visible light irradiation (at room
temperature), was successfully replaced by microwaves or
conventional heating, which provided similar or superior yields
and shorter reaction times. The similar results obtained with MW
and conventional heating suggest that microwaves do not have
specific effects but a thermic effect. The scale-up of the reaction
with glucosamine and serine derivatives proceeded in good
yields. Therefore, although comparisons between light and other
activation sources should be taken with caution, the current
results suggest that from a production/operational standpoint,
MW and conventional heating could be excellent alternatives to
visible light irradiation, facilitating the scale-up of the process
using conventional reactors.
Scheme 6. One-pot oxidative radical decarboxylation with proline derivatives.
As shown in the next example, proline amides are less prone to
iodination. Interestingly, in the scission of the dipeptide model
32,15 the cationic intermediate 33 was trapped by C-nucleophiles,
to give the 2-(allyl)pyrrolidine derivative 34. This example
highlights that the selective modification of the C-terminal
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previous procedure. After workup and product purification, R-citronellal 5
(17 mg, 55%) was obtained.7
Experimental Section
General methods: Microwave experiments were carried out in a CEM
Discover System (100 W at T= 80 oC). Visible light irradiation was
performed with a 80W tungsten-filament lamp, at 26 oC. All reactions
involving air- or moisture-sensitive materials were carried out under a
nitrogen atmosphere. Merck silica gel 60 PF254 and 60 (0.063–0.2 mm)
were used for preparative thin layer chromatography and column
chromatography, respectively. For product characterization, the optical
rotations were measured at the sodium line at ambient temperature (26
oC) in CHCl3 solutions. The melting points were determined with a hot-
stage apparatus and are uncorrected. NMR spectra were determined at
500 MHz for 1H and 125.7 MHz for 13C in the presence of TMS as
(1S)-1-((R)-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)(formyloxy)methyl)-
2,2-dimethyl-1,3-dioxolan-4-yl acetate (10). Table 2, entry 1.
A
solution of 2,3:5,6-di-O-isopropyliden--D-mannofuranose 9 (50 mg, 0.2
mmol) in dichloroethane (3 mL) was treated according to Method A
during 150 min. After usual workup, the residue was purified by rotatory
chromatography on silica gel (hexanes:EtOAc, 80:20) giving the scission
product 10 (47 mg, 74%). Table 2, entry 2. A solution of substrate 9 (50
mg, 0.2 mmol) in dichloroethane (3 mL) was treated according to Method
B during 15 min. After usual workup, the residue was purified according
to the previous procedure, affording the scission product 10 (49 mg,
77%). Table 2, entry 3. A solution of substrate 9 (50 mg, 0.2 mmol) in
dry MeCN (3 mL) was treated according to Method B during 15 min. After
usual workup, the residue was purified according to the previous
procedure, affording the scission product 10 (50 mg, 79%). Table 2,
entry 4. A solution of substrate 9 (50 mg, 0.2 mmol) in dry MeCN (3 mL)
was treated with (diacetoxyiodo)benzene (97 mg, 0.3 mmol) and iodine
(15 mg, 0.06 mmol) and was irradiated according to Method B during 15
min. After usual workup, the residue was purified according to the
previous procedure, affording the scission product 10 (34 mg, 53%).
internal standard, unless otherwise stated.
determined at 70 eV.
Mass spectra were
Method A (irradiation with visible light). A solution of the substrate
(0.2 mmol) in dry solvent (3 mL) was treated with
(diacetoxyiodo)benzene (97 mg, 0.3 mmol) and iodine (25 mg, 0.10
mmol) under irradiation with visible light (80W tungsten-filament lamp) at
o
26 C during the time given in the Table. The reaction mixture was then
poured into 10% aqueous Na2S2O3, and extracted with CH2Cl2. The
organic layer was dried over anhydrous sodium sulfate, filtered and then
the solvent was evaporated under vacuum. The residue was purified by
column or rotatory chromatography on silica gel (hexanes-EtOAc) giving
the scission products.
Table 2, entry 5.
A solution of 2,3:5,6-di-O-isopropyliden--D-
mannofuranose 9 (50 mg, 0.2 mmol) in dichloroethane (3 mL) was
treated according to Method C during 30 min. After usual workup, the
residue was purified according to the previous procedure, affording the
scission product 10 (49.6 mg, 78%) as a colorless oil; []D = 40.1 (c
Method B (microwave irradiation). A solution of the substrate (0.2
mmol) in dry solvent (3 mL) was treated with (diacetoxyiodo)benzene (97
mg, 0.3 mmol) and iodine (25 mg, 0.10 mmol) in a sealed microwave
tube under darkness. The reaction mixture was heated at 80 oC and
irradiated with microwaves (100 W) during the time given in the Table.
After usual workup, the residue was purified as commented in Method A
giving the scission products.
0.007, CHCl3); IR (CHCl3): nu(tilde) = 3026, 2989, 2939, 1733 cm–1
;
1H
o
NMR (500 MHz, CDCl3, 26 C): δ = 1.36 (s, 3H, Me), 1.41 (s, 3H, Me),
1.50 (s, 6H, 2  Me), 2.09 (s, 3H, Me), 3.87 (dd, J = 6.0, 8.8 Hz, 1H, 5-
Ha), 4.06 (dd, J = 6.3, 8.8 Hz, 1H, 5-Hb), 4.27 (ddd, J = 6.0, 6.0, 6.2 Hz,
1H, 4-H), 4.48 (dd, J = 2.5, 3.2 Hz, 1H, 2-H), 5.28 (dd, J = 3.3, 6.2 Hz, 1H,
3-H), 6.12 (d, J = 2.2 Hz, 1H, 1-H), 8.16 (s, 1H, CHO) ppm; 13C NMR
o
(125.7 MHz, CDCl3, 26 C): δ = 21.0 (CH3), 25.2 (CH3), 26.4 (CH3), 26.7
Method C (conventional heating). A solution of the substrate (0.2
mmol) in dry solvent (3 mL) was treated with (diacetoxyiodo)benzene (97
mg, 0.3 mmol) in a heated flask attached to a condenser, and was
heated to 80 oC before iodine (25 mg, 0.10 mmol) was added. The
(CH3), 27.0 (CH3), 66.2 (CH2), 71.1 (CH), 74.1 (CH), 81.3 (CH), 96.7
(CH), 109.7 (C), 113.6 (C), 159.9 (CH), 170.0 (C, Ac) ppm; MS (EI, 70
eV): m/z (%) = 303 (26) [M+  CH3], 201 (12) [M+ OCHOC4H8O], 101
(100) [C5H9O2]+; HRMS: calc. for C13H19O8 303.1080, found 303.1074;
calc. for C5H9O2 101.0603, found 101.0605. C14H22O8 (318.32): C 52.82,
H 6.97; found C 52.67, H 7.00.
o
reaction mixture was stirred at 80 C during the time given in the Table.
After usual workup, the residue was purified as commented in Method A
giving the scission products.
(2S,3R,4R)-1-Acetamido-1,2,3,5-tetraacetoxy-4-(formyloxy)pentane
(17). Table 3, entry 1. A solution of 2-acetamido-2-desoxy-3,4,6-tri-O-
acetyl-D-glucopiranose (14) (69 mg, 0.2 mmol) in dichloroethane (3 mL)
was treated according to Method A during 150 min. After usual workup,
the residue was purified by rotatory chromatography on silica gel
(hexanes:EtOAc, 30:70) giving the diastereomeric acetates 17a (30 mg,
37%) and 17b (26 mg, 32%) (69% global yield). Table 3, entry 2. A
solution of substrate 14 (69 mg, 0.2 mmol) in dichloroethane (3 mL) was
treated as in Entry 1 but using different amounts of DIB (130 mg, 0.4
mmol) and iodine (50 mg, 0.2 mmol). Usual workup and purification
afforded the diastereomeric acetates 17a (32 mg, 39%) and 17b (31 mg,
33%) (72% global yield). Table 3, entry 3. A solution of substrate 14 (69
mg, 0.2 mmol) in dichloroethane (3 mL) was treated according to Method
B during 15 min. After usual workup, the residue was purified as before
giving the diastereomeric acetates 17a (33 mg, 41%) and 17b (31 mg,
38%) (79% global yield). Table 3, entry 4. The reaction was performed
as in entry 3 but using a longer reaction time (30 min). After usual workup,
the residue was purified as before giving the diastereomeric acetates 17a
(37 mg, 46%) and 17b (36 mg, 45%) (91% global yield). Table 3, entry 5.
(R)-Citronellal (5).7 Table 1, entry 1. A solution of (-)-menthol 4 (32 mg,
0.2 mmol) in dry dichloromethane (3 mL) was treated according to
Method A during 150 min. After usual workup, the residue was dissolved
in dry CH2Cl2 (2 mL) and DBU (0.02 mL) was added. The solution was
stirred at 26 oC for 3 h, and then was poured into 5% aqueous HCl and
extracted with CH2Cl2. After usual drying and evaporation of the organic
layer, the residue was purified by rotatory chromatography on silica gel
(hexanes:EtOAc, 95:5) giving the scission product 5 (14 mg, 47%).
Table 1, entry 2. A solution of (-)-menthol 4 (32 mg, 0.2 mmol) in dry
dichloromethane (3 mL) was treated according to Method B during 15
min. After usual workup, the residue was dissolved in dry CH2Cl2 (2 mL)
and treated with DBU (0.02 mL) according to the previous procedure.
After workup and product purification, the scission product 5 (15 mg,
48%) was obtained. Table 1, entry 3. A solution of (-)-menthol 4 (32 mg,
0.2 mmol) in dry dichloromethane (3 mL) was treated according to
Method C during 15 min. After usual workup, the residue was dissolved
in dry CH2Cl2 (2 mL) and treated with DBU (0.02 mL) according to the
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European Journal of Organic Chemistry
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The reaction was performed as in entry 4 but using less iodine (15 mg,
0.06 mmol). After stirring for 30 min, usual workup and purification
afforded the diastereomeric acetates 17a (20 mg, 25%) and 17b (21 mg,
27%) (52% global yield). Table 3, entry 6. A solution of substrate 14 (69
mg, 0.2 mmol) was treated according to Method C during 30 min. Usual
workup and purification afforded the diastereomeric acetates 17a (36 mg,
44%) and 17b (34 mg, 42%) (86% global yield).
B during 15 min. After usual workup, the residue was purified as before
giving the acetate 21 (52 mg, 77%). Table 3, entry 9. A solution of
MeO2C-Hyp-OBn 18 (56 mg, 0.2 mmol) in dichloroethane (3 mL) was
treated according to Method C during 15 min. After usual workup, the
residue was purified as before giving the acetate 21 (53 mg, 79%) as an
oil; IR (CHCl3): nu(tilde) = 3024, 1727, 1480, 1447, 1203 cm–1 1H NMR
;
(500 MHz, CDCl3, 26 oC, 1:1 rotamer mixture): δ = 1.88/1.92 (s/s, 3H,
Me), 2.97/3.18 ( [dd, J = 8.6, 23 Hz/ dd, J = 10.1, 23 Hz], 1H, 3-Ha),
3.39/3.40 ( [dd, J = 5.7, 23 Hz/ m], 1H, 3-Hb), 3.54/3.75 (s, 3H, OMe),
4.90/4.97 (m/m, 1H, 2-H), 5.13 (d, J = 15.9 Hz, 1H, OCHaPh), 5.17 (d, J =
15.8 Hz, 1H, OCHbPh), 5.38/5.49 ( [d, J = 14.3 Hz/ d, J = 14 Hz], 1H,
OCHaN), 5.43/5.51 ( [d, J = 15.5 Hz/ d, J = 15 Hz], 1H, OCHbN), 7.28-
7.52 (m, 5H, Ar), 9.77 (s, 1H, CHO) ppm; 13C NMR (125.7 MHz, CDCl3,
26 oC): δ = 20.6 (CH3), 44.5/45.2 (CH2), 53.2/53.4 (CH3), 55.6/56.2 (CH),
67.6 (CH2), 72.4/73.0 (CH2), 128.1 (2 × CH), 128.4 (CH), 128.6 (2 × CH),
135.3 (C), 155.6 (C), 169.6/170.8 (C), 198.0/198.6 (C) ppm; MS (EI, 70
eV): m/z (%) = 278 (1) [M+ +H  OCOMe], 250 (1) [M+ + H OCOMe
CO], 249 (5) [M+ OCOMe CO], 142 (78) [CH2=N(CO2Me)-CH=CH-
CHO]+, 91 (100) [PhCH2]+ ppm; HRMS: calc. for C14H16NO5 278.1028,
found 278.1029; calc. for C13H16NO4 250.1079, found 250.1088; calc.
for C13H15NO4 249.1005, found 249.1011; calc. for C6H8NO3 142.0504,
found 142.0500; calc. for C7H9 91.0548, found 91.0552. C16H19NO7
(337): C 56.97, H 5.68, N 4.15; found C 56.60, H 5.67, N 4.35.
Compound 17a: colorless oil, [α]D = 21.1 (c 0.007, CHCl3); IR (CHCl3):
nu(tilde) = 3672, 3431, 3368, 3026, 1738, 1699 cm–1; 1H NMR (500 MHz,
CDCl3, 26 oC): δ = 1.98 (s, 3H, Ac), 2.00 (s, 3H, Ac), 2.06 (s, 3H, Ac),
2.10 (s, 3H, Ac), 2.14 (s, 3H, Ac), 4.08 (dd, J = 6.3, 12.6 Hz, 1H, 5-Ha),
4.29 (dd, J = 2.8, 12.6 Hz, 1H, 5-Hb), 5.30 (m, 1H, 4-H), 5.46 (dd, J = 2.8,
7.9 Hz, 1H, 3-H), 5.60 (dd, J = 2.8, 8.2 Hz, 1H, 2-H), 6.36 (dd, J = 8.4,
10.2 Hz, 1H, 1-H), 7.01 (d, J = 10.4 Hz, 1H, NH), 8.01 (s, 1H, CHO) ppm;
o
13C NMR (125.7 MHz, CDCl3, 26 C): δ = 20.5 (CH3), 20.5 (CH3), 20.5
(CH3), 20.8 (CH3), 23.0 (CH3), 61.7 (CH2), 67.8 (CH), 68.0 (CH), 69.4
(CH), 73.8 (CH), 159.6 (CH), 169.7 (C), 169.8 (C), 169.9 (C), 170.0 (C),
170.4 (C) ppm; MS (EI, 70 eV): m/z (%) = 243 (9) [M+  H  2  OAc
OCHO], 183 (29) [M+  3  OAc OCHO], 156 (100) [M+ C5H7O4 2

OAc], 143 (69) [M+ C8H11O6 OAc], 114 (84) [M+ H OAc
CHOC8H12NO5] ppm; HRMS: calc. for C11H17NO5 243.1107, found
243.1107; calc. for C7H10NO3 156.0661, found 156.0659. C16H23NO11
(405.36): C 47.41, H 5.72, N 3.46; found C 47.75, H 5.79, N 3.28.
Compound 17b: colorless oil, [α]D = 36.8 (c 0.007, CHCl3); IR (CHCl3):
nu(tilde) = 3617, 3431, 3018, 2973, 2895, 1740, 1701 cm–1; 1H NMR (500
Methyl 2-Acetoxy-2-(benzamido)acetate (24).11a Table 4, entry 1. A
solution of N-benzoylserine methyl ester 22 (45 mg, 0.2 mmol) in
dichloroethane (3 mL) was treated according to Method A during 180 min.
After usual workup, the residue was purified by rotatory chromatography
on silica gel (hexanes:EtOAc, 80:20), yielding compound 2411a (45 mg,
89%) as a white solid. Table 4, entry 2. A solution of substrate 22 (45
mg, 0.2 mmol) in DCE (3 mL) was treated according to Method B during
15 min. Workup and purification as before afforded compound 24 (44 mg,
87%). Table 4, entry 3. A solution of substrate 22 (45 mg, 0.2 mmol) in
DCE (3 mL) was treated according to Method C during 15 min. Workup
and purification as before afforded compound 24 (42 mg, 84%).
o
MHz, CDCl3, 26 C): δ = 2.00 (s, 3H, Ac), 2.02 (s, 3H, Ac), 2.07 (s, 3H,
Ac), 2.11 (s, 3H, Ac), 2.14 (s, 3H, Ac), 4.15 (dd, J = 5.8, 12.4 Hz, 1H, 5-
Ha), 4.27 (dd, J = 3.0, 12.4 Hz, 1H, 5-Hb), 5.31 (m, 1H, 4-H), 5.38 (dd, J =
3.4, 6.6 Hz, 1H, 2-H), 5.42 (dd, J = 3.2, 7.9 Hz, 1H, 3-H), 6.41 (br d, J =
10.1 Hz, 1H, NH), 6.55 (dd, J = 6.6, 10.1 Hz, 1H, 1-H), 8.00 (s, 1H, CHO)
ppm; 13C NMR (125.7 MHz, CDCl3, 26 oC): δ = 20.5 (CH3), 20.6 (CH3),
20.6 (CH3), 20.7 (CH3), 23.2 (CH3), 61.5 (CH2), 67.5 (CH), 67.8 (CH),
69.4 (CH), 72.1 (CH), 159.3 (CH), 168.9 (C), 169.4 (C), 169.9 (C), 170.3
(C), 170.4 (C) ppm; MS (EI, 70 eV): m/z (%) = 243 (14) [M+  OAc 
NHAc OCHO], 183 (43) [M+  3  OAc OCHO], 156 (100) [M+
C5H7O4 2  OAc), 143 (81) [M+ C8H11O6 OAc], 114 (95) [M+ H
OAc CHOC8H12NO5], 101 (99) [M+ H CHOC11H16NO7];
HRMS: calc. for C11H15O6 243.0869, found 243.0869; calc. for C7H10NO3
156.0661, found 156.0653. C16H23NO11 (405.36): C 47.41, H 5.72, N
3.46; found C 47.25, H 5.95, N 3.76.
Scale-up of the reaction. Condition
1 (MW): A solution of N-
benzoylserine methyl ester 22 (225 mg, 1.0 mmol) in dichloroethane (7
mL) was treated with (diacetoxyiodo)benzene (485 mg, 1.5 mmol) and
iodine (127 mg, 0.5 mmol) according to Method B (MW) at 80 ºC for 15
min, then was allowed to reach room temperature, poured into sodium
thiosulfate and extracted with dichloromethane. A second batch was
prepared in the same way (15 min) and after the usual work-up, the two
organic layers were joined and concentrated under vacuum. The residue
was purified by column chromatography on silica gel (hexanes:EtOAc,
80:20) giving compound 24 (421 mg, 84%). Condition B (conventional
heating): A solution of N-benzoylserine methyl ester 22 (500 mg, 2.2
mmol) in dichloroethane (15 mL) was placed in a flask attached to a
condenser and treated with (diacetoxyiodo)benzene (1.08 g, 3.4 mmol).
The reaction mixture was heated to 80ºC in the dark and then iodine (285
Scale-up of the reaction (MW): A solution of glucosamine derivative 14
(346 mg, 1.0 mmol) in dichloroethane (7 mL) was treated with
(diacetoxyiodo)benzene (485 mg, 1.5 mmol) and iodine (127 mg, 0.5
mmol) according to Method B (MW) at 80 ºC for 15 min, then was
allowed to reach room temperature, poured into sodium thiosulfate and
extracted with dichloromethane. A second batch was prepared in the
same way (15 min) and after the usual work-up, the two organic layers
were joined and concentrated under vacuum. The residue was purified
by column chromatography on silica gel (hexanes:EtOAc, 30:70) giving
the diastereomeric acetates 17a (299 mg, 37%) and 17b (274 mg, 34%)
(573 mg, 71% global yield).
o
mg, 1.1 mmol) was added. After stirring at 80 C for 15 min, the mixture
was cooled to room temperature, poured into sodium thiosulfate, and
extracted and purified as before, yielding compound 24 (386 mg, 69%),
whose physical and NMR data matched those reported in the
literature:11a white solid; m.p. 87-89 ºC (EtOAc/n-hexane); 1H NMR (400
MHz, CDCl3, 26 oC): δ = 2.11 (s, 3H, Ac), 3.83 (s, 3H, OMe), 6.60 (d, J =
8.8 Hz, 1H, CHN), 7.45 (dd, J = 7.8, 7.9 Hz, 2H, Ar), 7.54 (1H, dd, J = 7.9,
7.9 Hz), 7.56 (d, J = 8.5 Hz, 1H, NH), 7.82 (d, J = 7.9 Hz, 2H, Ar) ppm;
13C NMR (100.6 MHz, CDCl3, 26 oC): δ = 20.6 (CH3), 53.3 (CH3), 72.7
Benzyl
N-(Acetoxymethyl)-N-(methoxycarbonyl)-4-oxo-L-homo-
alanine (21). Table 3, entry 7. A solution of MeO2C-Hyp-OBn 18 (56 mg,
0.2 mmol) in dichloroethane (3 mL) was treated according to Method A
during 120 min. After usual workup, the residue was purified by rotatory
chromatography on silica gel (hexanes:EtOAc, 85:15) giving the acetate
21 (55 mg, 81%). Table 3, entry 8. A solution of MeO2C-Hyp-OBn 18 (56
mg, 0.2 mmol) in dichloroethane (3 mL) was treated according to Method
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601034
FULL PAPER
(CH), 127.4 (2 × CH), 128.6 (2 × CH), 132.5 (CH), 166.7 (C), 167.3 (C),
170.4 (C) ppm.
at 70 oC ): δ = 2.16 (m, 1H, 4-Ha), 2.57 (m, 1H, 4-Hb), 3.63 (m, 1H, 5-Ha),
3.68 (m, 1H, 5-Hb), 4.22 (d, J = 4.4 Hz, 1H, 3-H), 5.20 (br s, 2H,
OCH2Ph), 5.77 (br s, 1H, 2-H), 7.37-7.29 (m, 5H, Ar) ppm; 13C NMR
(125.7 MHz, CDCl3, 26 oC): δ = major rotamer 26.5 (CH), 34.0 (CH2),
44.8 (CH2), 67.3 (CH2), 89.8 (CH), 127.8 (2 × CH), 128. 1 (CH), 128.5 (2
× CH), 136.1 (C), 155.6 (C) ppm; minor rotamer 27.4 (CH), 33.0 (CH2),
45.1 (CH2), 67.3 (CH2), 89.2 (CH), 127.8 (2 × CH), 128. 2 (CH), 128.6 (2
× CH), 136.1 (C), 154.3 (C) ppm; MS (EI, 70 eV): m/z (%) = 329 (6) [M+
 H2O], 91 (100) [PhCH2]+
Methyl N-(N-(Benzyloxycarbonyl)-L-alanyl)-2-(acetoxy)glycine (27).
Table 4, entry 4. A solution of dipeptide Cbz-Ala-Ser-OMe 25 (65 mg,
0.20 mmol) in dry dichloroethane (3 mL) was treated according to
Method A during 60 min. After usual workup, the residue was purified by
rotatory chromatography on silica gel (hexanes:EtOAc, 30:70), yielding
compound 27 (27 mg, 38%) as a white solid. Table 4, entry 5. A
solution of substrate 25 (65 mg, 0.2 mmol) in DCE (3 mL) was treated
according to Method B during 15 min. Usual workup and purification
yielded starting material (22 mg, 34%) and compound 27 (37 mg, 53%;
yield with respect to transformed starting material 78%). Table 4, entry 6.
A solution of substrate 25 (65 mg, 0.2 mmol) in DCE (3 mL) was treated
according to Method C during 15 min. Usual workup and purification
yielded starting material (20 mg, 31%) and compound 27 (35 mg, 50%;
yield with respect to transformed starting material 71%) as a white solid;
m.p. 103104 °C (n-hexane/EtOAc); IR (CHCl3): nu(tilde) = 3427, 3319,
N-Benzyloxycarbonyl-phenylalanyl-2S/R-allylpyrrolidine (34). Table
5, entry 4. A solution of Cbz-Phe-Pro-OH 32 (79 mg, 0.2 mmol) in
dichloroethane (3 mL) was treated according to Method A during 90 min.
Then the irradiation stopped and the reaction mixture was cooled to 0 oC
and treated with allyltrimethylsilane (0.10 mL, 0.6 mmol) and BF3OEt2
(0.05 mL, 0.4 mmol), and the reaction mixture was stirred for 3 h. Then it
was poured into aqueous saturated NaHCO3 with 5% sodium thiosulfate,
and extracted with dichloromethane. The organic layer was dried over
Na2SO4, filtered and evaporated as before. The residue was purified by
rotatory chromatography on silica gel (hexanes:EtOAc, 70:30) giving the
allylated product 34 (52 mg, 66%). Table 3, entry 5. A solution of Cbz-
Phe-Pro-OH 32 (79 mg, 0.2 mmol) in dichloroethane (3 mL) was treated
according to Method B during 15 min. Then the irradiation stopped and
the reaction mixture was cooled to 0 oC and treated with the allylTMS and
BF3OEt2 as described in entry 4. Usual workup and purification afforded
product 34 (56 mg, 71%). Table 3, entry 6. A solution of Cbz-Phe-Pro-
OH 32 (79 mg, 0.2 mmol) in dichloroethane (3 mL) was treated according
to Method C during 15 min. Then the reaction mixture was cooled to 0 oC
and treated with the allylTMS and BF3OEt2 as described in entry 4. After
usual workup and purification, product 34 (61 mg, 78%) was isolated as
;
3022, 2955, 1753, 1705 cm–1 1H NMR (500 MHz, CDCl3, 70 oC, 1:1
diastereomer mixture): δ = RMN 1H (500 MHz, CDCl3, 26 oC): δH
1.39/1.40 ( [d, J = 6.9 Hz/ d, J = 6.9 Hz], 1H, 2’-Me), 2.07/2.09 (s/s, 3H,
Ac), 3.78/3.80 (s/s, 3H, OMe), 4.34 (m, 1H, 2’-H), 5.11 (d, J = 13 Hz, 1H,
OCHaPh), 5.13 (d, J = 13.5 Hz, 1H, OCHbPh), 5.37 (br b, 1H, NH), 6.39
(d, J = 6.1 Hz, 1H, OCHaN), 6.40 (d, J = 6.3 Hz, 1H, OCHbN), 7.267.38
(m, 5H, Ar), 7.56/7.60 (br b., 1H, NH) ppm; 13C NMR (100.6 MHz, CDCl3)
diastereomer mixture: δC = 18.1/18.3 (CH3), 20.5 (CH3), 50.4 (CH), 53.3
(CH3), 67.2 (CH2), 72.1 (CH), 128.1 (2 × CH), 128.2 (CH), 128.5 (2 × CH),
136.0 (C), 156.0 (C), 166.9 (C), 170.1 (C), 172.4 (C) ppm; MS (EI, 70
eV): m/z (%) = 234 (2) [M+ + H COPh], 233 (13) [M+ COPh], 217 (20)
[M+ H NHCOPh], 213 (26) [M+ COOBn], 189 (71) [M+ COOBn],
105 (48) [PhCO], 91 (100) [C7H7]; HRMS: calc. for C13H17N2O2, 233.1290,
found 233.1287; calc. for C12H15N2O 203.1184, found 203.1186.
C19H20N2O3 (324): C 54.54, H 5.72, N 7.95; found C 54.67, H 5.87, N
7.76.
an oil; IR (CHCl3): nu(tilde) = 3428, 1715, 1636, 1504, 1452 cm–1
;
1H
o
NMR (500 MHz, CDCl3, 70 C, 4:1 diastereomer mixture): Major isomer:
δ = 1.50 (m, 1H, 3-Ha), 1.65-1.70 (m, 2H, 4-H2), 1.80 (m, 1H, 3-Hb), 2.15
(m, 1H, 1‘-Ha), 2.59 (m, 1H, 1‘-Hb), 2.76 (ddd, J = 7.8, 7.9, 8.5 Hz, 1H, 5-
Ha), 3.02 (d, J = 13.6 Hz, 1H, 3‘‘-Ha), 3.06 (d, J = 13.5 Hz, 1H, 3‘‘-Hb),
3.40 (m, 1H, 5-Hb), 4.07 (m, 1H, 2-H), 4.68 (m, 1H, 2‘‘-H), 5.06 (d, J = 9.3
Hz, 1H, 3‘-Ha), 5.08 (d, J = 9.2 Hz, 1H, 3‘-Hb), 5.12 (d, J = 12.5 Hz, 1H,
OCHa), 5.16 (d, J = 12.3 Hz, 1H, OCHb), 5.58 (br b, 1H, NH), 5.76 (dddd,
J = 7.2, 7.2, 7.3, 7.4 Hz, 1H, 2‘-H), 7.217.42 (m, 10H, 2 x Ar); Minor
isomer: δ = 1.50-2.00 (m, 6H, 3-H2 + 4-H2 + 1‘-H2), 3.04 (m, 1H, 3‘‘-Ha),
3.22 (m, 1H, 3‘‘-Hb), 3.38 (m, 1H, 5-Ha), 3.67 (m, 1H, 5-Hb), 4.29 (m, 1H,
2-H), 4.73 (m, 1H, 2‘-H), 5.005.18 (m, 4H, OCH2 + 3‘-H2), 5.37 (br b, 1H,
NH), 5.63 (m, 1H, 2‘-H), 7.217.42 (m, 10H, 2 x Ar) ppm; 13C NMR
(125.7 MHz, CDCl3, 70 oC): Two diastereomers, most signals
overlapped: δ = 23.4 (CH2), 28.5 (CH2), 37.1 (CH2), 39.9 (CH2), 46.6
(CH2), 54.3/54.4 (CH), 57.0 (CH), 66.8 (CH2), 117.1 (CH2), 126.9 (CH),
127.9 (CH), 128.0 (CH), 128.4 (CH x 4), 129.5 (3 x CH), 134.7 (CH),
136.6/136.7 (C x 2), 155.6 (C), 169.6 (C) ppm; MS (EI, 70 eV): m/z (%) =
392 (1) [M+], 351 (1) [M+ CH2CH=CH2], 243 (27) [M+ CbzNH], 91 (72)
[PhCH2]+, 70 (100) [dihydropyrrole +H]+ ppm; HRMS: calc. for
C24H28N2O3 392.2100, found 392.2094; calc. for C21H23N2O3 351.1709,
found 351.1713; calc. for C16H21NO 243.1623, found 243.1620; calc. for
C7H7 91.0548, found 91.0545; calc. for C4H8N 70.0657, found 70.0659.
C24H28N2O3 (392): C 73.44, H 7.19, N 7.14; found C 73.46, H 7.14, N
7.39.
Benzyl 2-hydroxypyrrolidin-1-carboxylate (30)13 and Benzyl 2,3-trans
2-hydroxy-3-iodopyrrolidin-1-carboxylate (31).14 Table 5, Entry 1. A
solution of commercial 1-(benzyloxycarbonyl)proline 2813 (50 mg, 0.2
mmol) in DCE (3 mL) was treated according to Method A for 90 min.
After usual workup and purification by rotatory chromatography
(hexanes:EtOAc 90:10), known products 3013 (25 mg, 56%) and 3114 (10
mg, 14%) were isolated. Table 5, Entry 2. A solution of substrate 28 (50
mg, 0.2 mmol) in DCE (3 mL) was treated according to Method B for 10
min. After usual workup and purification, products 30 (34 mg, 76%) and
31 (5 mg, 7%) were isolated. Table 5, Entry 3. A solution of substrate 28
(50 mg, 0.2 mmol) in DCE (3 mL) was treated according to Method C for
10 min. After usual workup and purification, products 30 (36 mg, 82%)13
and 31 (2 mg, 3%)14 were isolated as oils. Their spectroscopic data
matched those reported in the literature.
Compound 30: IR (CHCl3): nu(tilde) = 3448, 3015, 1698 cm–1
;
1H NMR
o
(500 MHz, CDCl3, 26 C, 2:1 rotamer mixture): δ = 1.75-1.82 (m, 1H, 4-
Ha), 1.80-1.95 (m, 2H, 3-H2), 1.99-2.14 (m, 1H, 4-Hb), 3.32 (m, 1H, CHaN),
3.56 (m, 1H, CHbN), 5.13/5.17 (2H, s/s, OCH2Ph), 5.47/5.52 (1H, [d, J =
5.1 Hz/ br s], 2-H), 7.27-7.40 (5H, m, Ar) ppm; 13C NMR (125.7 MHz,
o
CDCl3, 26 C): δ = 21.0 (CH3), 25.2 (CH3), 26.4 (CH3), 26.7 (CH3), 27.0
(CH3), 66.2 (CH2), 71.1 (CH), 74.1 (CH), 81.3 (CH), 96.7 (CH), 109.7 (C),
113.6 (C), 159.9 (CH), 170.0 (C) ppm; MS (EI, 70 eV): m/z (%) = 203
(18) [M+  H2O], 108 (12) [PhCH2OH]+, 91 (100) [PhCH2]+
Compound 31: IR (CHCl3): nu(tilde) = 3585, 3408, 1700, 1416 cm–1
;
1H
NMR (500 MHz, CDCl3, 70 oC, 2:1 rotamer mixture at 26oC, one rotamer
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601034
FULL PAPER
[8]
[9]
High vacuum should be avoided during the work-up and purification.
Due to product volatility, small variations in the yields can be observed.
Each reaction was repeated several times and the optimized yield is
given in Table 1.
Acknowledgements
This work was supported by the Research Program SAF-2013-
48399-R, Plan Estatal de I+D, Ministerio de Economía y
Competitividad (MINECO), Spain, and European Social Funds
(FSE). IRE thanks CSIC (Spanish Research Council) for his JAE
predoctoral contract and CC thanks MINECO for her Doctorado
Industrial contract. CC is currently a student of the PhD Program
Doctorado en Química e Ingeniería Química of the University of
La Laguna (ULL). Finally, we particularly thank our colleagues
Dr. Fernando García-Tellado and Dr. David Tejedor (IPNA-
CSIC) for access to and support with the MW equipment.
P. de Armas, C. G. Francisco, E. Suarez, Angew. Chem.,-Int. Ed. 1992,
31, 772-774; Angew. Chem., 1992 , 104, 746 – 748.
[10] A. Boto, J. A. Gallardo, E. Alvarez, Eur. J. Org. Chem. 2012, 391-397.
[11] a) A. Boto, J. A. Gallardo, D. Hernández, R. Herández, J. Org. Chem.
2007, 72, 7260–7269. b) A. Boto, J. A. Gallardo, R. Hernández, F.
Ledo, A. Muñoz, J. R. Murguía, M. Menacho-Márquez, A. Orjales, C. J.
Saavedra, Bioorg. Med. Chem. Lett. 2006, 16, 6073–6077.
[12] a) Dipeptide substrate: A. K. Saha, P. Schultz, H. Rapoport, J. Am.
Chem. Soc. 1989, 111, 4856 – 4859; b) E. Altmann, K. H. Altmann, M.
Mutter, Angew. Chem. 1988, 100, 855 – 856.
[13] A. Boto, R. Hernández, E. Suárez, J. Org. Chem. 2000, 65, 4930-4937.
[14] a) A. Boto, R. Hernández, Y. de León, E. Suárez, J. Org. Chem. 2001,
66, 7796-7803. b) See also: A. Boto, D. Hernández, R. Hernández, Eur.
J. Org. Chem. 2010, 6633−6642.
Keywords: Sequential Processes • Radical Reactions •
Microwaves
[15] a) P. Wipf, P. C. Fritch, J. Am. Chem. Soc. 1996, 118, 12358–12367; b)
J-C. Monbaliu, F. K. Hansen, L. K. Beagle, M. J. Panzner, P. J. Steel,
E. Todadze, C. V. Stevens, A. R. Katritzky, Chem. – A Eur. J. 2012, 18,
2632–2638; c) A. R. Katritzky, E. Todadze, P. Angrish, B. Draghici, J.
Org. Chem. 2007, 72, 5794 – 5801.
[1]
a) For a review on azanucleosides, see: D. Hernández, A. Boto, Eur. J.
Org. Chem. 2014, 2201-2220. b) For other work, see: I. Romero-
Estudillo, A. Boto, J. Org. Chem. 2015, 80, 9379−9391. c) I. Romero-
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European Journal of Organic Chemistry
10.1002/ejoc.201601034
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Microwaves in Organic Synthesis
Carmen Carro,[a] Iván Romero,[a] and
Alicia Boto*[a]
Page No. – Page No.
Microwave versus Conventional Light
Activation of O-Radical Scission
Processes
Low-cost substrates (terpenes, carbohydrate and amino acid derivatives) were
converted into high-profit products using metal-free sequential processes initiated
by O-radical scissions. The classical activation source, visible light irradiation, was
replaced by microwaves and conventional heating, which provided similar or
superior yields and shorter reaction times, thus facilitating process scale-up.
This article is protected by copyright. All rights reserved