Solarylations via 4-aminophenyl cations

Article abstract of DOI:10.1021/jo902669j

(Chemical Equation Presented) The application of the photo-S_N1 reaction on some 4-chloroanilines was explored under solar irradiation in view of obtaining a convenient metal-free arylation method. Several reactions previously carried out by UV irradiation, as well as some new ones, where either a new trap (α-methylstyrene) or a new halide (N,N-dimethyl-4- fluoroaniline) were adopted, were studied under these conditions and found to occur conveniently. Furthermore, at least in some cases the halide starting concentration could be raised up to 0.2 M, the excess trapping agent reduced from 20:1 to 2.5:1, and the solvent replaced by more environmentally friendly (co)solvents including water. Under these improved conditions, the photoarylation was carried out in a gram scale by merely exposing the solution to solar irradiation. This process has a low impact on the environment and can be considered a serious competitor of metal-catalyzed arylations. 2010 American Chemical Society.

Full text of DOI:10.1021/jo902669j

pubs.acs.org/joc
Solarylations via 4-Aminophenyl Cations
Valentina Dichiarante, Maurizio Fagnoni,* and Angelo Albini
Department of Organic Chemistry, University of Pavia, Viale Taramelli 10, 27100 Pavia, Italy
fagnoni@unipv.it
Received December 16, 2009
The application of the photo-SN1 reaction on some 4-chloroanilines was explored under solar
irradiation in view of obtaining a convenient metal-free arylation method. Several reactions
previously carried out by UV irradiation, as well as some new ones, where either a new trap
(R-methylstyrene) or a new halide (N,N-dimethyl-4-fluoroaniline) were adopted, were studied under
these conditions and found to occur conveniently. Furthermore, at least in some cases the halide
starting concentration could be raised up to 0.2 M, the excess trapping agent reduced from 20:1 to
2.5:1, and the solvent replaced by more environmentally friendly (co)solvents including water. Under
these improved conditions, the photoarylation was carried out in a gram scale by merely exposing the
solution to solar irradiation. This process has a low impact on the environment and can be considered
a serious competitor of metal-catalyzed arylations.
Introduction
photoreactions have been generally carried out by using
artificial light. As a matter of fact, a photochemical reaction
does not ‘‘automatically’’ classify as green despite the pecu-
liar advantages, primarily because of the considerable
amount of energy from nonrenewable sources that has to
be supplied for the lamp.7 An obvious opportunity of mini-
mizing energy consumption in photochemical reactions is to
leave artificial lamps and return to sunlight, a clean, renew-
able, and free energy source.5,8 An important advancement
has been the application of solar mediated processes to a few
reactions on a large scale,9 (products in the kilogram scale)
and the use of light-concentrators for making solar irradia-
tion available in a more concentrated form than the natural
flux (although of course one still needs a large surface for
collecting enough light).9 Furthermore, a number of examples
of viable syntheses have been reported in the last years (and
have been recently reviewed)9a in which the reaction occurs
by simply exposing the reaction vessel to sunlight (e.g., on a
window ledge). However, these processes remain a tiny
The close relation between photochemistry and what is
now called green chemistry was suggested for the first time by
the Italian chemist Giacomo Ciamician, at the beginning of
the 20th century.1,2 In a talk addressed to the French
Chemical Society,3 he underlined that light is able to pro-
mote under mild conditions reactions not observed ther-
mally.4 The later development of photochemistry has
demonstrated that the photon can be considered as the ideal
clean reagent for organic synthesis,5 in contrast to toxic/
dangerous chemical activators. Furthermore, it leaves
no residue that has to be eliminated after the reaction.
Ciamician and contemporary scientists6 used solar light
for promoting a variety of reactions, but in later times
(1) Albini, A.; Fagnoni, M. Green Chem. 2004, 6, 1–6.
(2) (a) Ciamician, G. Science 1912, 36, 385–394. (b) Ciamician, G.; Silber,
P. Ber. Dtsch. Chem. Ges. 1900, 33, 2911–2913.
(3) Ciamician, G. Bull. Soc. Chim. Fr. 1908, 3 (4), i–xxxvi.
(4) Albini, A.; Dichiarante, V. Photochem. Photobiol. Sci. 2009, 8, 248–
254.
(5) Protti, S.; Manzini, S.; Fagnoni, M.; Albini, A. The contribution of
photochemistry to green chemistry. In Eco-Friendly Synthesis of Fine Che-
micals; Ballini, R., Ed.; RSC Green Chemistry Series; Royal Society of
Chemistry: Cambridge, UK, 2009; pp 80-111.
(7) Cian, C.-L.; Bochet, C. G. Chimia 2007, 61, 650–654.
(8) Albini, A.; Fagnoni, M. The greenest reagent in organic synthesis:
light. In Green Chemical Reactions; Tundo, P., Esposito, V., Eds.; Springer
Science þ Business Media B.V.: London, UK, 2008; pp 173-189.
(9) (a) Protti, S.; Fagnoni, M. Photochem. Photobiol. Sci. 2009, 8, 1499–
(6) See, for example: (a) Stobbe, H. Liebigs Ann. Chem. 1908, 359, 1–48.
ꢀ
€
(b) Stobbe, H. Z. Elektrochem. 1908, 33, 473–483. (c) Paterno, E.; Chieffi, G.;
1516. (b) Oelgemoller, M.; Jung, C.; Mattay, J. Pure Appl. Chem. 2007, 79,
ꢀ
Perret, G. Gazz. Chim. Ital. 1914, 44, 151–164. (d) Paterno, E.; Chieffi, G.
Gazz. Chim. Ital. 1909, 39, 341–361.
1939–1947. (c) Esser, P.; Pohlmann, B.; Scharf, H.-D. Angew. Chem., Int. Ed.
1994, 33, 2009–2023.
DOI: 10.1021/jo902669j
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Published on Web 01/28/2010
J. Org. Chem. 2010, 75, 1271–1276 1271
2010 American Chemical Society

Dichiarante et al.
JOCArticle
SCHEME 1. Photogeneration and Reactivity of Aryl Cations
fraction of those carried out by artificial light and it appears
appropriate to extend the scope of solar-induced syntheses
by adding new classes of photochemical reactions.
A field where photochemistry has recently acquired a role
is that of arylations,10 an important class of reactions in
modern organic synthesis, in particular when leading to the
formation of a carbon-carbon bond. It has been found that
the photochemical method may be a valid alternative to
metal-catalysis for the activation of an Ar-Y bond.10,11 The
use of solar light for such a reaction is not common, however.
For example, Rajan et al. reported an efficient phenylation
of dimsyl anion by a solar-stimulated ArSRN1 reaction in
DMSO in the presence of iodo- or bromobenzene.12 The
sunlight-induced nucleophilic substitution of an alkoxy
group by n-butylamine has been likewise successfully applied
to the synthesis of a nitrobenzacrown aminoether.13
FIGURE 1. The reactions were carried out on 100 mL solution
corresponding to a layer of about 1 cm thick with a surface area of
about 1 dm2 in the cylindrical Pyrex vessel used.
mediate,16 and of a base as a buffering agent. These issues are
confronted for some known reactions and for some new ones
in the present work.
Results and Discussion
Before actually exploring the effect of solar light, the
process was optimized by carrying out comparative experi-
ments by using a solar simulator (SolarBox) as a nonvariable
light source. Screw-capped cylindrical Pyrex vessels were
used (100 mL solution, see Figure 1).20 Small scale experi-
ments were carried out in vessels containing 5 mL.
On the other hand, a new metal-free photochemical
arylation procedure based on the intermediacy of aryl cat-
ions has recently emerged (an ArSN1 process)10,14 and allows
the formation of Ar-C bonds. Irradiation of electron-rich
aryl chlorides, fluorides, and esters15 (such as phosphates
and sulfonates), in polar solvents, generates phenyl cations
through a heterolytic cleavage of the Ar-X bond as illu-
strated in Scheme 1.
The cation is trapped by nucleophiles (e.g., alkenes,
alkynes, and arenes) and yields a variety of arylation pro-
ducts under mild conditions through a simple experimental
protocol. However, labeling the process as eco-sustainable
requires confronting the negative aspects, viz. the consump-
tion of nonrenewable energy for powering the lamp, as well
as the use of expensive and harmful solvents such as 2,2,2-
trifluoroethanol (TFE) to make heterolysis efficient, of a
large excess of the nucleophile (10 to 20 times with respect to
Ar-X) in order to suppress side-processes, in particular
hydrogen abstraction from the solvent by the cation inter-
Under these conditions, 4-chloroanisole and 4-chlorophe-
nol showed very little reaction after 24 h. With the latter
compound, a partial conversion was obtained only when
using a TFE solution in a quartz tube. The inefficiency is due
to the poor absorption of these compounds above 300 nm
and to the fact that the tiny fraction of low-wavelength
radiation present in this source is filtered by the Pyrex walls.
On the contrary, 4-chloro-N,N-dimethylaniline (1a) re-
acted due to the absorption tailing in the UV-A region and
was thus chosen for optimizing the reaction with representa-
tive nucleophiles in the SolarBox. A convenient reaction was
performed by using mesitylene (2a) as the π-trap, with which
the photogenerated 4-N,N-dimethylaminophenyl cation af-
forded the corresponding polymethyl-substituted biaryl 3
(Scheme 2, path a).
Experiments with a solar simulator were compared
with the same reaction performed in acetonitrile but using
UV lamps (six phosphor-coated lamps, emission centered at
310 nm, Table 1, entry 1).18 Irradiations were continued until
the total consumption of the starting aniline.
With the SolarBox apparatus the yield of biphenyl 3
was similar (ca. 60%) to that obtained under artificial light
and that of reduced 3 dropped from 12% to less than 3%
(entry 2). In this and in all of the other reactions considered,
(10) Dichiarante, V.; Fagnoni, M.; Albini, A. Photochemical arylation
reactions. In Modern Arylation Methods; Ackermann, L., Ed.; Wiley-VCH:
Weinheim, Germany, 2009; pp 513-535.
(11) Protti, S.; Dondi, D.; Fagnoni, M.; Albini, A. Photochemistry for
mild metal-free arylation reactions. In Experiments in green and sustainable
chemistry; Roesky, H. W., Kennepohl, D. K., Eds.; Wiley-VCH Verlag
GmbH & Co.: Weinheim, Germany, 2009; pp 260-265.
(12) Rajan, S.; Muralimohan, K. Tetrahedron Lett. 1978, 5, 483–486.
(13) Samoshin, A. V.; Samoshin, V. V. J. Undergrad. Chem. Res. 2006, 2,
13–16.
(14) (a) Dichiarante, V.; Fagnoni, M. Synlett 2008, 787–800. (b) Penenory,
A. B.; Arg€uello, J. E. Aromatic and heteroaromatic substitution by SRN1 ans SN1
reactions. In Handbook of Synthetic Photochemistry; Albini, A., Fagnoni, M.,
Eds.; Wiley-VCH: Weinheim, Germany, 2010; pp 319-352.
(15) De Carolis, M.; Protti, S.; Fagnoni, M.; Albini, A. Angew. Chem.,
Int. Ed. 2005, 44, 1232–1236.
(16) The irradiation of electron-rich aromatic chlorides in hydrogen
donating media (e.g., 2-propanol) or in the presence of a reducing agent (e.
g., H3PO2) causes a quite efficient hydrodehalogenation reaction via photo-
generated phenyl cations (see ref 17). In a less H donating solvent such as
MeCN this reduction occurs to some extent, depending on the concentration
and type of nucleophile present in solution. Reduction of phenyl cations by
hydrogen or electron transfer has been demonstrated by laser flash photo-
lysis experiments (see refs 18 and 19).
(17) Dichiarante, V.; Fagnoni, M.; Albini, A. Green Chem. 2009, 11, 942–
945.
(18) Guizzardi, B.; Mella, M.; Fagnoni, M.; Freccero, M.; Albini, A.
J. Org. Chem. 2001, 66, 6353–6363.
(19) Manet, I.; Monti, S.; Grabner, G.; Protti, S.; Dondi, D.; Dichiarante,
V.; Fagnoni, M.; Albini, A. Chem.;Eur. J. 2008, 14, 1029–1039.
(20) Similar vessels were recently used in solar photocatalyzed reactions.
See: Protti, S.; Ravelli, D.; Fagnoni, M.; Albini, A. Chem. Commun. 2009,
7351–7353.
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SCHEME 2. Arylation Products from the Solar-Induced Gen-
eration of 4-N,N-Dimethylaminophenyl Cation
lysis. The negative side was that extraction with methylene
chloride was required in this case.
Increasing the concentration of aniline 1a is another
possibility for diminishing the proportion of solvent. When
increasing the amount of the starting aniline up to 0.1-0.2 M
(entries 5 and 6) a longer irradiation time (up to 40 h) was
required, but a complete consumption of 1a was obtained
and biphenyl 3 was formed in a yield (48%) that could be
considered decent when taking into account that only 2.5 mol
excess mesitylene was used.
The substitution of acetonitrile with the less toxic and less
expensive acetone was next tested. The above experiments
were thus repeated in a 1:5 water-acetone mixture (entries
7-9). The result was that in acetone the arylation yield was
acceptable as long as the concentration of 1a did not exceed
0.1 M (entry 8).
Finally, compound 3 was isolated in 45% yield after 40 h
SolarBox irradiation of a solution of 1a (0.2 M, the highest
concentration as yet used for a preparative photo-ArSN1
reaction) and 2a (0.5 M) in 5:1 MeCN/water (Table 2). A
similar yield of 3 was obtained when the same mixture
was placed on a window ledge of the Department and
exposed to sunlight for 6 consecutive days (from 9 a.m. to
5 p.m., see the Supporting Information). To summarize, the
above data show that (i) the arylation reaction is effective
also under solar light irradiation, (ii) aqueous acetonitrile
and acetone could be likewise used as reaction media, (iii) the
concentration of the starting chloride can be increased up to
0.2 M, and (iv) the molar excess of the nucleophile can be
lowered.
The reaction of chloroaniline 1a was then extended to
other nucleophiles, likewise comparing the solar simulator
and solar light. Preparative experiments were carried out on
100 mL solution samples, and thus on a gram scale. In
Table 2 the results under optimized reaction conditions are
reported, showing that there is no significant difference in the
products yield ((5%) with the two sets of experiments.
Thus, irradiation of 1a was carried out in neat i-PrOH, a
good hydrogen-donor medium that induced hydrodehalo-
genation as recently demonstrated (Scheme 2, path b).17 N,
N-Dimethylaniline 4 was obtained in 65% yield after 40 h
SolarBox irradiation even with [1a] raised to 0.2 M. Six days
of solar exposure of the reaction mixture gave similar results.
The reaction with alkenes was next tested, namely, with R-
methylstyrene (2b), allyltrimethylsilane (2c), 1-methoxy-1-
[(trimethylsilyl)oxy]propene (2d), 4-pentenoic acid (2e), and
ethyl vinyl ether (2f). Addition of phenyl cations to alkenes
has been observed in a large number of cases14 and was
followed by the loss of an electrofugal group, either a proton
or a trimethylsilyl cation. A new reaction following the first
path was that with R-methylstyrene that gave the allylation
product 5 in 63% yield (see Scheme 3).
no other volatile byproducts except aniline 4 was detected.
Thus, this reaction was well suited for confronting the
environmental limitations. In previous reports, arylations
via phenyl cation10,14 have been reported by using a 0.05 M
solution of ArX in the presence of a large excess of the
nucleophile (0.5-1 M). Clearly, a 20:1 molar ratio between
the reagents is far from being desirable from the point of view
of atom economy. However, the yield of biphenyl 3 de-
creased to 40% upon halving the mesitylene concentration
(to 0.5 M) and a significant amount of aniline 4 (14%) was
formed (entry 3). At any rate, the concentration of the
reagent is too low for an environmentally sound process
and indeed using such a large amount of solvent has been
shown to be the main adverse factor on the eco-sustainability
of the photo-ArSN1 arylations.21,22
The explorative study was carried out by maintaining the
0.5 M concentration of the trap and varying the other
parameters. A move was the use of water as a (co)solvent.
This was possible because the intermediate triplet 4-N,N-
dimethylaminophenyl cation was known not to react with
water or alcohols.24 Adding water reduced the amount of
organic solvents and it was hoped that it may give further
advantages, that is that highly polar water both favored the
photoheterolytic step14a,25 and buffered the acidity produced
in the reaction, allowing a base to be omitted. All of this was
verified in the experiment, and when a 1:5 water-acetonitrile
mixture was used (entry 4), a satisfactory 55% yield of 3 was
obtained with no significant concurrent reduction or solvo-
(21) Protti, S.; Dondi, D.; Fagnoni, M.; Albini, A. Green Chem. 2009, 11,
239–249.
Elimination of Me3Siþ took place from the adduct cation
with both allyltrimethylsilane (2c) and ketene silyl acetal (2d)
leading respectively to the corresponding allyl derivative 6
(51%, Scheme 2 path d)14 and the R-aryl propionic ester 7
(58%, path e).14
With alkenes containing a tethered nucleophilic moiety, as
in the case of 4-pentenoic acid (2e), intermolecular trapping
of the aryl cation was followed by intramolecular cyclization
to give benzyl γ-lactone 8 (45%, path f).14 In the preparation
of 5, 6, and 8 a satisfactory isolated yield was obtained even
(22) In a recent paper,21 the environmental impact and the cost (euros per
gram of product) of photo-SN1 arylations have been assessed by means of the
EATOS software.23 From the economical point of view, photochemical
reactions via phenyl cations were more expensive, if compared with the
corresponding metal-catalyzed reactions, and the main negative influence
was due to the solvent (usually 2,2,2-trifluoroethanol).
(23) Eissen, M.; Metzger, J. O. EATOS, Environmental Assessment Tool
for Organic Syntheses, http://www.chemie.uni-oldenburg.de/oc/metzger/ea-
tos/.
(24) Lazzaroni, S.; Dondi, D.; Fagnoni, M.; Albini, A. J. Org. Chem.
2010, 75, 315–323.
(25) Manet, I.; Monti, S.; Bortolus, P.; Fagnoni, M.; Albini, A. Chem.;
Eur. J. 2005, 11, 4274–4282.
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TABLE 1. Arylation of Mesitylene by Irradiating 4-Chloro-N,N-Dimethylaniline by Means of a Solar Simulator (SolarBox)
entry
[1a], M
solvent
[2a], M
light source
time,a h
3,b %
4,b,c
%
1d
2
3
4
5
6
7
8
9
0.05
0.05
0.05
0.05
0.1
0.2
0.05
0.1
MeCNe
1
1
UV lampsf
SolarBoxi
SolarBoxi
SolarBoxi
SolarBoxi
SolarBoxi
SolarBoxi
SolarBoxi
SolarBoxi
3
6
6
65d,g
60
40
55
46
48
42
50
12d,g,h
2.4
14
4
1.5
0
3
MeCNe
MeCNe
0.5
0.5
0.5
0.5
0.5
0.5
0.5
H2O/MeCN (1:5)
H2O/MeCN (1:5)
H2O/MeCN (1:5)
H2O/Me2CO (1:5)
H2O/Me2CO (1:5)
H2O/Me2CO (1:5)
6
22
40
6
20
40
8
3
0.2
25
aMinimum time required for the total consumption of 1a. bThe yields in entries 2-9 were determined by GC analysis by comparative peak areas with
the reaction in entry 1. cN,N-Dimethylaniline. dSee ref 18. e0.05 M NEt3 added. fIrradiated in a multilamp apparatus by using six phosphor-coated lamps
(emission centered at 310 nm). gIsolated yields. hTraces of 5-chloro-2,40-bis(dimethylamino)biphenyl were also detected. iIrradiated in a solar simulator
(SolarBox, Xe lamp, see the Supporting Information).
TABLE 2. Metal-Free Arylation by Solar Exposure of 4-Chloro(fluoro)-N,N-dimethylaniline
ArX
[ArX] (M)
solvent
Nu, concn
time (h,a db)
product and yield (%)c-e
ArCl, 1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
ArF, 1b
1b
0.2
0.2
0.1
0.1
0.1
0.05
0.1
H2O/MeCN (1:5)
i-PrOH
MeCN
H2O/MeCN (1:5)
H2O/Me2CO (1:5)
MeCN þ NEt3 0.05M
H2O/MeCN (1:5)
H2O/Me2CO (1:5)
MeOH þ Cs2CO3 0.03M
MeOH/Me2CO (1:3) Cs2CO3 0.03M
H2O/MeCN (1:5)
2a, 0.5 M
40, 6
40, 6
23, 3
24, 3
24, 3
6, 1
24, 3
24, 3
8, 1
3 (48, 45)
4 (71, 65)
5 (72, 63)
6 (68, 51)
6 (64)
2b, 0.5 M
2c, 0.5 M
2c, 0.5 M
2d, 0.7 M
2e, 0.5 M
2e, 0.5M
2f, 0.5M
2f, 0.5M
2c, 0.5 M
2f, 0.5M
7 (58)
8 (52, 45)
8 (77, 71)
9 (81, 60)
9 (40)
6 (52)
9 (88)
0.1
0.05
0.05
0.1
6, 1
22, 3
16, 2
0.05
MeOH þ Cs2CO3 0.03M
aHours of irradiation in SolarBox. bUnderlined, days of exposition to sunlight (each day for 8 h, from 9 a.m. to 5 p.m.). cGC yields, in italics isolated
yields. dAniline 4 was also formed in variable amounts (see the Supporting Information and text). eThe arylation yields obtained by exposing the Pyrex
vessel directly to sunlight differed by (5% of that obtained in the SolarBox.
SCHEME 3. Sunlight-Induced Arylation of R-Methylstyrene
SCHEME 4. Arylation Reactions via Sunlight Activation of the
Ar-F Bond
with both enol ethers 2d and 2f was only reached with the
concentration of 1a e 0.05 M, although [2d] could be lowered
to 0.7 M.
The exploration was extended to the activation of the
Ar-F bond and new arylations were found in the solar light-
induced reactions of 4-fluoro-N,N-dimethyl aniline (1b,
Scheme 4). As it appears in Table 2, anilines 6 and 9 were
obtained in a yield comparable to that obtained in the case of
the chloroaniline 1a.
Further structural variations in the starting material were
then tested with the same optimized solar protocol, with
consistently good results. As an example, 4-chloro-3-methyl-
N,N-dimethylaniline (1c, 0.1 M) was photoreduced to 10 in
a high yield (89%, isolated yield) by irradiation in neat
2-propanol (Scheme 5).
Using 4-chloroaniline (1d) with the free NH2 group re-
quired some care. In fact, exposure of 0.1-0.2 M solutions of
1d to sunlight led to incomplete consumption of the starting
aniline and to a rapid darkening of the reaction mixtures.
However, under more dilute conditions (0.05 M) in the
presence of a base (cesium carbonate) satisfactory arylation
yields were obtained, as shown in Scheme 6 for the synthesis
of acetal 11.
starting from a 0.1 M solution of 1a and with a 5-fold excess
nucleophile. Moreover, in the preparation of allylaniline 6
and lactone 8, acetonitrile could be replaced by cheaper
acetone, maintaining or even increasing (from 45% to 71%
in the case of 8) the arylation yield.
Another synthetic application of phenyl cations is the
reaction with vinyl ethers (e.g., ethyl vinyl ether, 2f) where
the stabilized cation, resulting from the attack onto the
alkene, adds a nucleophilic solvent such as methanol.26 3-
Aryl acetal 9 was thus prepared by this three-component
reaction (60%, path g) along with 13% of reduced 4. Using
methanol only as cosolvent decreased the yield of com-
pound 9 to 40% in 1:3 methanol/acetone (see Table 2).
Notice also that a total consumption of 1a in the reaction
(26) Lazzaroni, S.; Protti, S.; Fagnoni, M.; Albini, A. Org. Lett. 2009, 11,
349–352.
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SCHEME 5. Sunlight-Induced Hydrodehalogenation of 1c
when working with larger amounts. The impact can be
minimized, at least for chloro (and fluoro!) anilines, simply
by replacing UV lamps with sunlight, by increasing the
concentration of substrates, and by optimizing the atom
economy of the process. In conclusion, the above data
strengthen the idea that photo-ArSN1 arylations (and photo-
chemistry, in general) represent a simple, yet extremely
versatile tool for organic synthesis and, in particular in the
solar version, easily comply with the green chemistry postu-
lates. Therefore, this may be advantageously used in syn-
thetic laboratories, in conjunction with solar concentrator
when a faster transformation is desired.
SCHEME 6. β-Arylacetals via Sunlight-Induced Photoreaction
of 4-Chloroaniline
Experimental Section
A. General. NMR spectra were recorded on a 300 MHz
1
spectrometer. The attributions were made on the basis of H
and 13C NMR, as well as DEPT experiments; chemical shifts are
reported in ppm downfield from TMS. Compounds 1a-c were
obtained by methylation of the corresponding anilines following
the procedure of Giumanini et al.28 Commercial 4-chloroaniline
(1d) was crystallized from ethanol before use. Mesitylene,
R-methylstyrene, allyltrimethylsilane, 4-pentenoic acid, and
ethyl vinyl ether were all commercially available and were
freshly distilled before use. Compound 2d (as an E þ Z mixture)
was synthesized starting from methyl propionate.29 All the
solvents were of HPLC purity grade and were used as received.
All the photochemical products were isolated from preparative
irradiations and characterized. The photochemical reactions
were performed by using nitrogen-purged solutions in Pyrex
glass reactors, in Pavia (Italy, latitude 45°110 N, 9°090 E, 77 m
above sea level) in the June-July 2009 period. Detailed infor-
mation for the sunlight flux and solar simulator used can be
found in the Supporting Information.
B. General Procedure for Preparative Sunlight-Induced Aryla-
tions. A solution (100 mL) of the starting aniline (1a-d,
0.05-0.2 M) and the nucleophile (2, 0.5-0.7 M) in the chosen
solvent was poured into a Pyrex vessel (see Figure 1) and purged
for 10 min with nitrogen, then screw-capped and exposed to
sunlight on a window ledge or irradiated in a solar simulator.
After the completion of the reaction (detected by GC analysis),
the solvent was removed in vacuo. When water was used as
cosolvent, the irradiated mixture was extracted with dichloro-
methane and then concentrated. The end arylation products
were purified from the residue by using flash silica gel, using
cyclohexane/ethyl acetate mixtures as eluant containing 0.2%
triethylamine. Compounds 4 and 10 were isolated by bulb-to-
bulb distillation.
Conclusion
The present work demonstrates that the performance of
the photo-ArSN1 method for arylation reactions can be
improved in terms of higher concentration of the starting
material, lower proportion of the trap, and use of solvents in
a lower amount and chosen among the more environment-
friendly ones, including water. Furthermore, UV lamps
could be replaced by solar irradiation with no adverse effect
on the yields and requiring essentially the same time (6 h UV
irradiation ꢀ 8 h, 1 d, exposure to the sun). Under the
conditions of Table 2, arylations can be carried out in gram
scale by simply exposing 100 mL of a solution with a really
simple setup (see Figure 1).
The introduction of such conditions drastically improves
the environmental performance and makes the photochemi-
cal method a better competitor of thermal catalytic aryla-
tions in terms of atom economy. Limitations remain, such as
the difficult extension to non-N-alkylated anilines, and the
impossibility of lowering the concentration of the trap below
0.5 M (in some cases above that) and of eliminating the side
paths completely. These are due to the fact that in the present
method an aggressive electrophile, the phenyl cation, is the
intermediate, whereas a more stable complex is formed in
catalysis.27 Therefore, competing processes (e.g., reduction
by reaction with the solvent, attack to the nucleophilic
starting material) become significant unless trapping is
quite effective. On the other hand, this is also the strength
of the photochemical method and gives to it an unparalleled
versatility, since the intermediate is generated by (solar)
irradiation, a step that is limitedly affected by the conditions.
Thus one can freely choose the conditions best suited to
direct the reactions of the cation, giving less attention to
those favoring its generation. On the contrary, the activation
of the starting material is the key issue in thermal catalytic
methods and is often much less tolerating in terms of experi-
mental conditions. Furthermore, the environmental impact
of our arylation protocol is modest. The use of energy and
manipulations are kept to a minimum. The nonstirred solu-
tion is exposed to solar light, then the solvent is evaporated
and the products, in the most favorable cases, simply dis-
tilled. Under this condition, yields are decent and the fact
that GC yields are higher suggests that they may be improved
4-(N,N-Dimethylamino)-20,40,60-trimethylbiphenyl (3). 1a (3.1
g, 20 mmol, 0.2 M) and 2a (6.8 mL, 50 mmol, 0.5 M) were
dissolved in a 1:5 water/acetonitrile mixture (100 mL) and
irradiated for 40 h in the SolarBox or 6 days on a window ledge.
Purification afforded 1.9 g of biaryl 3 (45% yield, colorless solid,
mp 105-108 °C, lit.30 mp 111-112 °C). N,N-Dimethylaniline 4
was also detected (4%, GC yield). Spectroscopic data of com-
pound 3 were in accordance with the literature.18 IR (neat) ν
(cm-1) 2917, 1608, 1521, 1349, 810. Anal. Calcd for C18H23N: C,
85.30; H, 8.84; N, 5.85. Found: C, 85.3; H, 8.8; N, 5.8.
N,N-Dimethylaniline (4). Aniline 1a (3.1 g, 20 mmol, 0.2 M)
was dissolved in 2-propanol (100 mL) and irradiated for 40 h in
the SolarBox or 6 days on a window ledge. Bulb-to-bulb
(28) Giumanini, A. G.; Chiavari, G.; Musiani, M. M.; Rossi, P. Synthesis
1980, 743–746.
(29) Mikami, K.; Matsumoto, S.; Ishida, A.; Takamuku, S.; Suenobu, T.;
Fukuzumi, S. J. Am. Chem. Soc. 1995, 117, 11134–11141.
€
(30) Hafelinger, G.; Hack, F.; Westermayer, G. Chem. Ber. 1978, 111,
(27) Fagnoni, M; Albini, A. Acc. Chem. Res. 2005, 38, 713–721.
1323–1329.
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Dichiarante et al.
JOCArticle
distillation at reduced pressure gave 1.6 g of 4 (colorless oil, 65%
yield), which was identified by comparison with a commercial
sample. Anal. Calcd for C8H11N: C, 79.29; H, 9.15; N, 11.56.
Found: C, 79.3; H, 9.2; N, 11.6.
4-(2-Ethoxy-2-methoxyethyl)-N,N-dimethylaniline (9). Ani-
line 1a (780 mg, 5 mmol, 0.05 M), cesium carbonate (814 mg,
2.5 mmol, 0.025 M), and ethyl vinyl ether (4.8 mL, 50 mmol,
0.5 M) were dissolved in methanol (100 mL) and irradiated for
8 h in the SolarBox or 1 day on a window ledge. Flash
chromatography afforded acetal 9 (colorless oil, 670 mg, 60%
yield) and N,N-dimethylaniline 4 (colorless oil, 77 mg, 13%
yield). Data for 9: Spectroscopic data were in accordance with
the literature.26 IR (neat) ν (cm-1) 2927, 1618, 1523, 1120, 1061,
809. Anal. Calcd for C13H21NO2: C, 69.92; H, 9.48; N, 6.27.
Found: C, 69.9; H, 9.6; N, 6.2.
3-Methyl-N,N-dimethylaniline (10). Aniline 1c (1.7 g, 10
mmol, 0.1 M) was dissolved in 2-propanol (100 mL) and
irradiated for 30 h in the SolarBox or 4 days on a window ledge.
Bulb-to-bulb distillation at reduced pressure afforded 1.2 g of 10
(oil, 89% yield), which was identified by comparison with a
commercial sample. Anal. Calcd for C9H13N: C, 79.95; H, 9.69;
N, 10.36. Found: C, 79.9; H, 9.6; N, 10.3.
4-(2-Ethoxy-2-methoxyethyl)aniline (11). A mixture of 1d
(640 mg, 5 mmol, 0.05 M), cesium carbonate (815 mg, 2.5 mmol,
0.025 M), and ethyl vinyl ether (4.8 mL, 50 mmol, 0.5 M) in
methanol (100 mL) was irradiated in the SolarBox for 12 h or 1.5
days on a window ledge. Acetal 11 was isolated in 63% yield (533
mg, oil). Traces of aniline 10 were also detected by GC analysis.
Data for 11: 1H NMR (CDCl3) δ 7.05 and 6.60 (AA0XX0, 4 H),
4.55 (t, 1 H, J = 5.6 Hz), 3.75-3.60 (m, 1 H), 3.55-3.40 (m, 1
H), 3.35 (s, 3 H), 2.85 (d, 2 H, J = 5.6 Hz), 1.20 (t, 3 H, J = 7 Hz);
13C NMR (CDCl3), δ: 144.7, 130.2 (CH), 126.9, 115.0 (CH),
104.9 (CH), 61.9 (CH2), 53.2 (CH3), 39.3 (CH2), 15.2 (CH3); IR
(neat) ν (cm-1) 3364, 2927, 1626, 1519, 1122, 1061. Anal. Calcd
for C11H17NO2: C, 67.66; H, 8.78; N, 7.17. Found: C, 67.5; H,
8.9; N, 7.1.
C. Irradiations of 4-Fluoro- N,N-dimethylaniline (1b). With
allyltrimethylsilane. A solution (5 mL) of the starting aniline (1b,
70 mg, 0.5 mmol, 0.1 M) and allyltrimethylsilane (0.4 mL,
2.5 mL, 0.5 M) in a 1:5 water/acetonitrile mixture was poured
into a Pyrex vessel and purged for 5 min with nitrogen, then capped
and exposed to sunlight on a window ledge (3 days) or irradiated in
a solar simulator (22 h). After the completion of the reaction, GC
analysis showed the formation of product 6 in 52% yield.
With Ethyl Vinyl Ether. Aniline 1b (35 mg, 0.25 mmol, 0.05
M), ethyl vinyl ether (0.24 mL, 2.5 mmol, 0.5 M), and cesium
carbonate (40 mg, 0.125 mmol, 0.025 M) were dissolved in
methanol (5 mL). After irradiation (16 h in the Solarbox or 2 days
on the window ledge), the resulting mixture was analyzed by GC
and product 9 was detected in 88% yield along with 4 (8% yield).
N,N-Dimethyl-4-(2-phenylallyl)aniline (5). A solution of 1a
(1.5 g, 10 mmol, 0.1 M) and R-methylstyrene (6.7 mL, 50 mmol,
0.5 M) in acetonitrile (100 mL) was irradiated for 23 h in the
SolarBox or 3 days on a window ledge. Allylaniline 5 was
isolated in 63% yield (1.5 g, solid, mp 55-58 °C). GC analysis
also detected N,N-dimethylaniline 4 (5% yield). Data for 5: 1H
NMR (CDCl3) δ 7.50-7.20 (m, 5 H), 7.10 and 6.70 (AA0XX0, 4
H), 5.50 (s, 1 H), 5.05 (s, 1 H), 3.75 (s, 2 H), 2.90 (s, 6 H); 13C
NMR (CDCl3) δ 149.0, 147.6, 141.1, 129.4 (CH), 128.7, 128.0
(CH), 127.2 (CH), 126.0 (CH), 113.9 (CH), 112.8 (CH2), 40.7
(CH3), 40.5 (CH2); IR (neat) ν (cm-1) 2892, 1613, 1519, 1346,
1189, 808. Anal. Calcd for C17H19N: C, 86.03; H, 8.07; N, 5.90.
Found: C, 86.2; H, 8.1; N, 5.8.
4-Allyl-N,N-dimethylaniline (6). Compound 1a (1.5 g, 10 mmol,
0.1 M) and allyltrimethylsilane (8 mL, 50 mmol, 0.5 M) were
dissolved in a 1:5 water/acetonitrile mixture (100 mL) and irra-
diated for 24 h in the SolarBox or 3 days on a window ledge.
Allylaniline 6 was obtained as the exclusive product in 51% yield
(815 mg, colorless oil). Spectroscopic data were in accordance with
the literature.31 IR (neat) ν (cm-1) 2925, 1641, 1343, 837. Anal.
Calcd for C11H15N: C, 81.94; H, 9.38; N, 8.69. Found: C, 82.1; H,
9.2; N, 8.7.
2-(4-N,N-Dimethylaminophenyl)propionic Acid Methyl Ester
(7). A mixture of 1a (780 mg, 5 mmol, 0.05 M), triethylamine
(700 μL, 5 mmol, 0.05 M), and 1-methoxy-1-[(trimethylsilyl)-
oxy]propene (11.3 g, 70 mmol, 0.7 M) in acetonitrile (100 mL)
was irradiated in the SolarBox for 6 h or 1 day on a window
ledge. Ester 7 was obtained in 58% yield (oil, 600 mg). GC
analysis showed traces of N,N-dimethylaniline 4, not isolated.
Data for 7: NMR data were in accordance with the literature.32
IR (neat) ν (cm-1) 1740, 1621, 1519, 1170. Anal. Calcd for
C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.7, H, 8.1;
N, 6.8.
5-(N,N-Dimethyl-4-aminobenzyl)-2,3,4,5-tetrahydro-2-fura-
none (8). A solution of 1a (1.5 g, 10 mmol, 0.1 M) and 4-
pentenoic acid (5.1 mL, 50 mmol, 0.5 M) in a 1:5 water/
acetonitrile mixture (100 mL) was irradiated in the Solarbox
for 24 h or 3 days on a window ledge. Purification of the mixture
gave lactone 8 (940 mg, 45% yield, colorless solid, mp 54-57 °C)
and N,N-dimethylaniline 4 (77 mg, 6% yield). The same reaction
was repeated by using a 1:5 water/acetone mixture as the solvent.
Lactone 8 (1.5 g) was formed in 71% yield along with 90 mg of 4
(7% yield). Data for 8: Spectroscopic characterization was in
accordance with the literature.33 IR (neat) ν (cm-1) 2956, 1616,
1524, 1061, 975, 803. Anal. Calcd for C13H17NO2: C, 71.21; H,
7.81; N, 6.39. Found: C, 71.1; H, 7.9; N, 6.4.
Acknowledgment. Partial support of this work by Murst,
Rome is gratefully acknowledged. V.D. thanks INCA
(Interuniversity National Consortium “Chemistry for the
Environment”) for a fellowship.
(31) Milanesi, S.; Fagnoni, M.; Albini, A. J. Org. Chem. 2005, 70, 603–
610.
(32) Fraboni, A.; Fagnoni, M.; Albini, A. J. Org. Chem. 2003, 68, 4886–
4893.
(33) Mella, M.; Coppo, P.; Guizzardi, B.; Fagnoni, M.; Freccero, M.;
Albini, A. J. Org. Chem. 2001, 66, 6344–6352.
Supporting Information Available: Experimental details and
1H spectra for products 3-11. This material is available free of
charge via the Internet at http://pubs.acs.org.
1276 J. Org. Chem. Vol. 75, No. 4, 2010