Microwave-assisted aza-Cope rearrangement of N-allylanilines

Article abstract of DOI:10.1016/j.tetlet.2008.01.078

The aza-Cope rearrangement of N-allylanilines is described. The use of BF₃·OEt₂ and microwave irradiation allows to run the transformation under mild conditions and in reaction times of minutes.

Full text of DOI:10.1016/j.tetlet.2008.01.078

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2002–2004
Microwave-assisted aza-Cope rearrangement of N-allylanilines
*
´
´
´
Israel Gonzalez, Iria Bellas, Ana Souto, Ramon Rodrıguez, Jacobo Cruces
GalChimia, S.L. R & D Department. Cebreiro s/n 15823 O Pino. A Corun˜a, Spain
Received 27 November 2007; revised 15 January 2008; accepted 16 January 2008
Available online 20 January 2008
Abstract
The aza-Cope rearrangement of N-allylanilines is described. The use of BF3ÁOEt2 and microwave irradiation allows to run the
transformation under mild conditions and in reaction times of minutes.
Ó 2008 Published by Elsevier Ltd.
Keywords: Microwave; N-Allylaniline; Aza-Cope; Rearrangement
Among the most efficient reactions in terms of atom
economy are the [3,3] sigmatropic shifts, that allow the
formation of a C–C bond through the rearrangement of
the molecule. While the Claisen rearrangement of vinyl
and aryl allyl ethers has been extensively explored,1 the
nitrogen analogue of this reaction (aza-Cope rearrange-
ment) has received much less attention due to several limit-
ations. The rearrangement of aromatic N-allylamines is
more difficult than that of the corresponding O-allylethers;
thus the thermal uncatalyzed aza-Cope rearrangement
requires temperatures ranging from 250 °C to 280 °C.
Many of the reported procedures for this transformation
call for the use of harsh reaction conditions, most of them
requiring long reaction times and high temperatures.
Usually, aromatic N-allylamines are not stable under these
conditions, and significant amounts of anilines are formed
by thermal decomposition. Some improvements have
been achieved through the use of Lewis acids (BF3ÁOEt2,
ZnCl2, AlCl3)2 and protic acids (HCl, H2SO4, pTsOH)3
to decrease both temperature and reaction times, neverthe-
less the harsh reaction conditions limit the use of the aza-
Cope rearrangement.
in the last few years.4 But it has not been until very recently
that its application has been claimed to facilitate [3,3] sigma-
tropic rearrangements of nitrogen-containing systems.5
To the best of our knowledge, only one example of micro-
wave-assisted aza-Cope rearrangement of allylanilines has
been reported in the literature. A paper from Yadav
et al.6 called for the use of the microwave irradiation for
the preparation of indolines from allylanilines, with the
aid of montmorillonite as a catalyst. These compounds
were formed by means of a [3,3] sigmatropic rearrange-
ment, followed by in situ cyclization. However, the inter-
mediate ortho-allyl anilines were not isolated, and its
preparation was poorly described in the publication.
That prompted us to undertake a comprehensive study
of the use of microwave-assisted reaction conditions for
the transformation of N-allylanilines into ortho-allyl-
anilines (Scheme 1), as these are quite interesting starting
materials for the preparation of different bicyclic nitro-
gen-containing heterocycles through the cyclization of the
nitrogen onto the double bond.7
The use of microwave energy to directly heat chemical
reactions has become one of the most popular techniques
R
R
NH
N
microwaves
*
Corresponding author. Tel.: +34 981 814 506; fax: +34 981 814 507.
Scheme 1.
E-mail address: jacobo.cruces@galchimia.com (J. Cruces).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.01.078

I. Gonza´lez et al. / Tetrahedron Letters 49 (2008) 2002–2004
2003
Table 1
With these results, we decided to further investigate the
use of Lewis acids to catalyze the transformation (Table 2).
Reactions were carried out using N-benzylated N-allyl ani-
line as the starting material, as it was the most promising
substrate previously tested. The reactions were monitored
by HPLC–MS and the conversion (as percent of product
formed) was used as a comparative parameter.
Microwave-assisted reaction conditions screening
Entry
R
Solvent
Power
(W)
T
Time
(min)
Output
(°C)
1
2
3
4
5
6
7
8
9
Boc DMF
Boc Xylenes 250
H
Ts
Bn DMF
Bn Toluene 250
Bn H2O 100
Bn Xylenes 250
Bn Neat 290
Bn Xylenesa 220
H
200
170
170
170
170
170
125
120
170
160
170
170
170
10
10
10
10
10
10
10
10
10
10
10
10
Deprotection
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction
10%
Xylenes 290
Xylenes 250
Several Lewis Acids were able to promote the reaction.
Among them, BF3ÁOEt2 and Bi(OTf)3 gave by far the best
results. ZnCl2 and SnCl2 also facilitated the reaction,
although with very low conversion. When stronger Lewis
acids were used (AlCl3 and TiCl4), the only product iso-
lated was that arising from the loss of the allyl group.
We focused our efforts on the optimization of the BF3ÁOEt2
catalyzed reaction, as this reagent is easy to handle, cheap
and it was the catalyst that gave cleaner reactions.
Reaction conditions were then finely tuned in terms of
reaction time, temperature and catalyst load (Table 3). The
power seemed to have little influence on the reaction, and
it was lowered from 290 W, used in the former experiments,
to 200 W with no decrease in the reaction time or conversion.
The catalyst load could be lowered down to 0.5 equiv
with no effects on conversion and reaction times (entries
1–3). When it was used in less than 15% mol, a drop in
the conversion was observed. The reaction could be run
even with lower loadings, and taken to completion, but
longer reaction times were needed.
We found that the best temperature to run the reaction
was above 150 °C. Complete conversion was always
achieved at 170 °C, but longer reaction times or catalyst
loadings were needed if reactions had to be run at lower
temperatures.
Finally, we were gratified to find that, maintaining a cata-
lyst load of 1.2 equiv, we could perform the reaction with
complete conversion in as short times as 30 s (entry 10). It
was observed that longer reaction times resulted in lower
yield (entry 7), mainly due to the formation of by-products,
arising from the decomposition of the ortho-allyl aniline.
When a sample of purified product was submitted again
to the same reaction conditions, several products were
formed. Two of these compounds were identified as cycli-
zation products (BF3ÁOEt2 also catalyzes the cyclization
of the nitrogen by activating the allyl group), but some
others were not characterized.
250
10
11
12
a
30%
Mixture
No reaction
Xylenesa 290
Xylenesa 290
Ts
BF3ÁOEt2 was added to the reaction mixture.
Initially, we investigated the aza-Cope reaction of non-
substituted N-allylanilines (Table 1), with different groups
on the nitrogen (H, Boc, Ts and Bn). We found that in
most of the cases no reaction took place when the com-
pounds were submitted to microwave irradiation.8 When
N-Boc protected aniline was used, only deprotection prod-
ucts were isolated, and unreacted material was recovered
when NH and N-tosylated precursors were irradiated for
10 min at 170 °C.
Only when neat N-benzylated N-allylaniline was irradi-
ated, was the desired ortho-allyl aniline obtained in a 10%
yield (entry 9). We then turned our attention to the use
of Lewis acids as catalyst for this transformation. We
found out that when 1 equiv of BF3ÁOEt2 was added to
the microwave vessel, the reaction rate was dramatically
increased, to furnish the product in a 30% yield, with no
starting material remaining unreacted (entry 10). When
the same reaction conditions were applied to the NH ana-
logue, a very complex mixture of products was obtained
(entry 11). Once again, when the N-tosylated precursor
was used no reaction was detected, and unreacted starting
material was recovered (entry 12).
The reactivity of the different N-substituted compounds,
suggests that the coordination of the Lewis acid to the
nitrogen is a major factor of the process. While it is accel-
erating the reaction for the N-benzylated aniline, that is
able to coordinate to the Lewis acid, no effect is observed
for the less coordinating N-tosylated analogue. When the
reaction was attempted over non-protected allylanilines,
complex mixtures were obtained. Coordination of free ani-
lines to the Lewis acid is stronger, and decomposition due
to the generation of HF can occur.
Table 3
Fine-tuning of the BF3ÁOEt2 catalyzed reaction
Entry Catalyst load T (°C) Time
Power (W) Conversion (%)
1
2
3
4
5
6
7
8
9
1.2 equiv
0.75
0.5
170
170
170
170
150
135
170
170
170
170
5 min
5 min
5 min
5 min
5 min
10 min 290
10 min 220
2 min
1 min
30 s
290
290
290
290
290
98
98
98
60
85
30
30
98
98
98
Table 2
Catalyst screening
Entry
Catalyst
Conversion
0.15
1
2
3
4
5
6
SnCl2
ZnCl2
Bi(OTf)3
BF3ÁOEt2
AlCl3
20%
6%
78%
98%
Loss of allyl
Loss of allyl
1.2 equiv
1.2 equiv
1.2 equiv
1.2 equiv
1.2 equiv
1.2 equiv
200
200
200
TiCl4
10

2004
I. Gonza´lez et al. / Tetrahedron Letters 49 (2008) 2002–2004
Bn
Bn
NH
N
NH2
HN
N
R
R
or
Scheme 2.
Me
Me
Me
To further explore the scope of the reaction, substitution
on the aryl ring was investigated for different N-benzylated
N-allyl anilines (Scheme 2, Table 4).9 In general, most of
the microwave-assisted reactions proceeded with good con-
version within 1–2 min at 170 °C.10 Again, excessive irradi-
ation showed significantly diminished product yield with
multiple uncharacterized by-products being formed.
1
2a
2b
Scheme 3.
be carried out in minutes, which represents an improvement
over current practices. Further application of this metho-
dology for the preparation of bicyclic systems is currently
under way in our laboratories.
Alkyl substitution is well tolerated (entries 1–4) even
when the alkyl group is in the ortho position. When non-
symmetrical substrates were irradiated, a non-separable
mixture of both possible regioisomers was obtained in 1:1
ratio (entry 2). Electron rich groups are also well tolerated
(entries 5 and 6), although in this case, when the group is
located in the ortho position, lower yield was obtained
due to the formation of several by-products (allyl loss
was also detected). When the reaction was tried over
halogen-bearing rings (entries 7 and 8), low yields were
obtained due to the by-product formation. Entry 9 shows
that strong electron withdrawing groups can be also pre-
sent in the molecule, even with non-benzylated anilines,
but the product is again obtained in low yield. It seems that
these substrates are too reactive under the reaction condi-
tions, and milder conditions should be developed to opti-
mize the yield by minimizing the by-product formation.
Quite interestingly, the reaction can also be run with N-
bisallylated anilines (Scheme 3). Both allyl groups are trans-
ferred to the benzyl ring under usual reaction conditions to
furnish 2b in a 56% yield after purification. When the reac-
tion is carried out under mild reaction conditions, it can be
stopped when only one of the two allyl groups has migrated.
Therefore, when a load of only 0.4 equiv of BF3ÁOEt2 was
used, and the reaction was allowed to react for only 1 min,
2a was isolated in a 54% yield as the major reaction product.
In summary, a mild method for the [3,3] aza-Cope reac-
tion of N-allyl anilines has been developed. The reaction can
Acknowledgement
The authors are grateful for the financial support from
Xunta de Galicia, PGIDIT06BTF006E.
References and notes
1. Lutz, R. P. Chem. Rev. 1984, 84, 205.
2. Nebbemeyer, U. Top. Curr. Chem. 2005, 244, 149; Anderson, W. K.;
Lai, G. Synthesis 1995, 1287; Nicolau, K. C.; Roecker, A. J.; Hughes,
R.; van Summeren, R.; Pfefferkorn, J. A.; Winssinger, N. Bioorg.
Med. Chem. 2003, 11, 465; Beholz, L. G.; Stille, J. R. J. Org. Chem.
1993, 58, 5095.
3. Cooper, M. A.; Lucas, M. A.; Taylor, J. M.; Ward, A. D.;
Williamson, N. M. Synthesis 2001, 4, 621; Jolidon, S.; Hansen, H.
J. Helv. Chim. Acta 1977, 60, 978.
4. For reviews on microwave-assisted reactions see: (a) Kappe, C. O.
´
Angew. Chem., Int. Ed. 2004, 43, 6250–6284; (b) de la Hoz, A.; Dıaz-
Ortiz, A.; Moreno, A. Chem. Soc. Rev. 2005, 34, 164–178; (c)
Microwave-Assisted Organic Synthesis; Lidstro¨m, P., Tierney, J. P.,
Eds.; Blackwell: Oxford, 2005; (d) Kappe, C. O.; Stadler, A.
Microwaves in Organic and Medicinal Chemistry; Wiley-VCH: Wein-
heim, 2005.
5. Marion, N.; Gealageas, R.; Nolan, S. P. Org. Lett. 2007, 9, 2653;
Johnson, B. F.; Marrero, E. L.; Turley, W. A.; Lindsay, H. A. Synlett
2007, 893.
6. Yadav, J. S.; Reddy, B. V. S.; Rasheed, M. A.; Kumar, H. M. S.
Synlett 2000, 487.
7. For the preparation of dihydroquinolines and indolines see: Hetero-
cycles 2006, 68, 23; Tetrahedron 2003, 59, 8775; Tetrahedron 1998, 54,
9961. For the preparation of dibenz[b,e]azepine derivatives see:
Palma, A.; Barajas, J. J.; Kouznetsov, V. V.; Stashenko, E.; Bahsas,
A.; Amaro-Luis, J. Synlett 2005, 2721.
Table 4
Substrate substitution studies
8. Experiments were carried out in a CEM Explorer microwave reactor,
in a sealed vial applying a maximum power level of 290 W.
9. Substrates were prepared from commercially available anilines: they
were N-benzylated by reductive amination with benzaldehyde, and
then N-allylated by treating with allyl bromide and Cs2CO3 in DMF,
to afford the products as colourless viscous oils.
10. To a solution of starting material (0.149 g, 0.63 mmol) in xylenes
(1 mL) was added BF3ÁEt2O (0.09 g, 0.63 mmol). The mixture was
irradiated in a CEM Explorer microwave reactor for 2 min at 170 °C
and 290 W. The reaction was poured over saturated NH4Cl solution
(5 mL) and extracted twice with CH2Cl2. Organic layers were dried
with anhydrous Na2SO4, filtered and concentrated in vacuo. The
crude residue was purified in a SP1 medium pressure chromatography
equipment (column 25 + M, gradient of AcOEt/hexane from 0% to
15%) to yield 0.105 g (70%) of the product as a colourless oil.
Entry
R
Yield (%)
1
2
3
4
5
6
7
8
9
2-Me
3-Me
4-Me
2,4-Me
2-OMe
4-OMe
2-F
76
50a (1:1)
70
72
30
64
21
38
33b
2-I
2-NO2
Reaction conditions: xylenes, 170 °C, 200 W, 2 min.
a
The reaction afforded a 1:1 mixture of regioisomers, that could not be
separated by flash chromatography.
b
Non-benzylated aniline was used.