Copper mediated atom transfer radical cyclisations with AIBN

Article abstract of DOI:10.1016/j.tetlet.2008.06.016

We have shown that it is possible to mediate a range of 5-exo trig and 5-exo dig atom transfer radical cyclisations of bromoacetamides using 0.1-1 mol % CuBr or CuBr₂ in conjunction with 0.1-1 mol % tri(pyridin-2-ylmethyl)amine and 10 mol % AIBN. This equates to a 30-300-fold reduction in the amount of catalyst previously reported for these reactions and allows cyclisation to be carried out with the more oxidatively stable CuBr₂ without the requirement of an inert atmosphere.

Full text of DOI:10.1016/j.tetlet.2008.06.016

Tetrahedron Letters 49 (2008) 4848–4850
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper mediated atom transfer radical cyclisations with AIBN
*
Andrew J. Clark , Paul Wilson
Department of Chemistry, University of Warwick, Coventry, West Midlands, CV4 7AL, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
We have shown that it is possible to mediate a range of 5-exo trig and 5-exo dig atom transfer radical cyc-
lisations of bromoacetamides using 0.1–1 mol % CuBr or CuBr2 in conjunction with 0.1–1 mol % tri(pyri-
din-2-ylmethyl)amine and 10 mol % AIBN. This equates to a 30–300-fold reduction in the amount of
catalyst previously reported for these reactions and allows cyclisation to be carried out with the more
oxidatively stable CuBr2 without the requirement of an inert atmosphere.
Received 17 April 2008
Revised 23 May 2008
Accepted 3 June 2008
Available online 7 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Catalysis
Copper
ATRC
Radical
AIBN
Lactams
Copper(I) halide catalysed atom transfer radical cyclisation
(ATRC) reactions have been extensively studied.1 The majority of
the published reactions utilise CuCl in combination with bipyri-
dine2 or TMEDA3 to generate precursor radicals from reactive tri-
chloro derivatives. We have shown that alternative ligands such
as Me6-tren4 1 or tripyridylamine (TPA)5 2 facilitate the cyclisation
of less activated substrates (e.g., monobromide precursor 3,
Scheme 1). However, relatively high levels of CuBr are required
(e.g., 30 mol %).1 Some particularly ‘difficult’ reactions (e.g., cyclisa-
tions onto alkynes) often require stoichiometric amounts of Cu
mediators at elevated temperature although the reason for this is
unclear.5b,d For industrial applications, any reaction utilising a
large catalyst loading will be unattractive and is likely to require
the separation and recycling of the CuBr. As a consequence, a range
of polymeric supported Cu reagents have been reported that medi-
ate ATRC reactions.6 However, in all cases moving the reaction
from a homogeneous to a heterogeneous manifold decreases the
rate of the reactions leading to higher temperatures and/or even
larger ‘catalyst’ loadings for successful reactions. Although it has
been shown that polymeric supported reagents can be re-used,
their activities drop after subsequent reaction runs. This may be
due to either leaching of the CuBr from the polymeric support or
by competing oxidation of the CuBr active species and build up
of CuBr2 complexes under the reaction conditions or via adventi-
tious oxygen.6
modifying the reaction to include an additive that would reduce
any built-up CuBr2 complex to the active CuBr. A number of poten-
tial additives have been used to reduce CuBr2 complexes in the
related atom transfer radical polymerisation (ATRP) reactions
In order to lower catalyst loadings and to potentially allow reac-
tions to be carried out under aerobic conditions we investigated
* Corresponding author. Tel.: +44 (0)2476 523242; fax: +44 (0)2476 524112.
E-mail address: a.j.clark@warwick.ac.uk (A. J. Clark).
Scheme 1. Atom transfer radical cyclisation of 3.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.016

A. J. Clark, P. Wilson / Tetrahedron Letters 49 (2008) 4848–4850
4849
including phenols, hydrazine7 and glucose.8 We chose to investi-
Table 2
Effect of ligand on reaction conversion 3 to 4
gate the role of AIBN as a reducing agent, as the by-products should
be volatile and facilitate work-up. This approach has shown prom-
ise in intermolecular atom transfer radical additions (ATRA).9 Ini-
tial studies focussed on the 5-exo cyclisation of the monobromide
3 with CuBr and TPA 2, Table 1. Utilising conventional conditions
(30 mol % Cu(2)Br, CH2Cl2, rt) the expected atom transfer product
was produced in 98% yield after 2 h (entry 1). Lowering the catalyst
loading to 1 mol % Cu(2)Br decreased the conversion to only 5%
over a 24 h period at room temperature (entry 2) or 14% at 50 °C
(entry 3). On the other hand, if 10 mol % AIBN was added (entry
4) the reaction proceeded to completion to give an 84% yield of
4. The reaction also proceeded in toluene at reflux (entry 8). In or-
der to check that the AIBN was not mediating the reaction on its
own we repeated the process using 10 mol % AIBN without added
Cu(2)Br (entry 5). We were pleased to observe that the reaction
did not proceed at all. Attempts at lowering the loading of AIBN
(5 mol %, entry 6) and Cu(2)Br (0.1 mol %, entry 7) met with mixed
success. Finally, we investigated the effect of changing the oxida-
tion state of the copper salt from CuBr to CuBr2, (entry 9). This
change furnished the product in the greatest yield (97%) and is
noteworthy in that it shows that either CuBr or CuBr2 can be uti-
lised under these reaction conditions.10
It is known that different ligand complexes can mediate the
same cyclisation with different efficiencies.1 The rate of cyclisation
of the related monobromide 7a proceeds with 30 mol % CuBr and
ligands in the order of TPA 2 > Me6-Tren 1 > pentamethyldiethyl-
enetriamine (PMDETA)11 9 > bipyridine 10.4,12 These reactivity or-
ders were observed when using our AIBN modification and
substrate 3, Table 2. Heating substrate 3 under the standard condi-
tions chosen from Table 1 (entry 4) indicated that ligands 2 and 1
were more reactive than pentamethyldiethylenetriamine (PMDE-
TA) 9 which in turn was more reactive than bipyridine 10, Table
2 (entries 1–4). Shortening the reaction time to just 2 h allowed
us to determine that the ligand 2 was superior to 1 thus confirming
the order of reactivity. In conclusion we managed to lower the cat-
alyst loading from (30 mol %, rt, 2 h) by a factor of 30 (1 mol %,
50 °C, 6 h) without compromising the yield (Scheme 2).
Entrya
Ligand
Time (h)
Convb (%)
1
2
3
4
5
6
7
8
1
2
9
10
1
2
24
24
24
24
6
6
2
2
100
100
85
5
100
100
15
2
1
5
a
Reactions were carried out using 1 mol % CuBr and 1 mol % ligand in CH2Cl2 at
50 °C with substrate 3 (0.17 M).
b
Determined by 300 MHz 1H NMR. Only starting material and product detected.
Me2N
NMe2
N
N
Me
N
10
9
over in less than 1 h and furnished the atom transfer products
8a–c in excellent yields (95–100%). It has been reported that the
nature of the N-protecting group can control the efficiency of 5-
exo cyclisations of acetamides.1,2b Of the two possible amide con-
formers of acetamides, only the anti conformer has the correct
geometry for cyclisation. Large or electron withdrawing N-substit-
uents favour the anti conformer and so facilitate cyclisation.
Changing the N-Ts group 7d to an N-Bn group 7e would be ex-
pected to retard the rate of cyclisation. This was observed and even
after 24 h the reactions had only proceeded with 14% conversion.
This low conversion was observed irrespective of whether CuBr
or CuBr2 was utilised in the reaction. Increasing the temperature
and performing the reaction in toluene at reflux allowed the reac-
tion to proceed at an acceptable rate (standard conditions entry 8,
Table 1). However, cyclisation of 7e now produced the two alkene
regioisomers 11 and 12 in a 1:2 ratio, respectively. Presumably this
is formed by elimination of HBr from the unobserved 3° bromide
atom transfer product 8e under the reaction conditions. Once again
there was little change in yield or reaction efficiency when either
CuBr or CuBr2 was utilised. As already highlighted, cyclisations of
the N-Ts compounds 7a–c were more rapid than the N-Bn com-
pounds 3 and 7e. Thus it was possible to mediate these reactions
at even lower catalyst loadings. Hence, reaction of 7b with
0.1 mol % Cu(2)Br and 10 mol % AIBN furnished the expected prod-
uct 8b in 99% yield after 24 h with the same diastereoselectivity
(Fig. 1, Table 3).
We next investigated the scope and limitation of the reaction by
investigating a range of relatively facile 5-exo trig cyclisations 7a–e
as well as cyclisations known to be much harder to facilitate such
as 5-exo dig cyclisations onto alkynes5d 13a–b and 5-exo trig cycli-
sations of secondary bromide 16. The cyclisations of 7a–e pro-
ceeded as expected. Thus, cyclisation of compounds 7a–c was
Table 3
Table 1
5-Exo trig cyclisation of compounds 7a–e
Effect of Cu(2)Br and AIBN loadings on conversion
Compound
Temp (°C)
Solvent
CH2Cl2
R1
Ts
R2
H
R3
H
Cu Source
CuBr
Yielda (%)
95
Entry
Solvent
Temp
(°C)
AIBN
(mol %)
Cu(2)Br
(mol %)
Conva
(%)
Mass balance
(%)
7a
50
7b
7c
7d
7e
7e
7e
7e
50
50
50
50
110
50
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
Toluene
Ts
Ts
Ts
Bn
Bn
Bn
Bn
Me
Ph
H
H
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr2
CuBr2
100b
99c
99
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
rt
rt
—
—
—
10.0
10.0
5.0
10.0
10.0
10.0
30.0
1.0
1.0
1.0
—
1.0
0.1
1.0
1.0c
100
5
14
100
0
95
40
100
100
98
98
99
84
98
99
89
87
97
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
3
50
50
50
50
50
110
50
14d
80e
13d
88e
4b
5
6
110
7
8b
9b
a
All reactions of 7a–c were complete within 1 h, 7e required 24 h.
3.5:1.0 mixture of diastereomers.
6.0:1.0 mixture of diastereomers.
Remaining mass balance is recovered starting material.
1.0:2.0 mixture 11:12.
b
c
Determined by 300 MHz 1H NMR. Reaction time for entry 1, 2 h.
Italicized rows indicate the conditions chosen for further experiments.
1.0 mol % of CuBr2 was used.
a
d
e
b
c

4850
A. J. Clark, P. Wilson / Tetrahedron Letters 49 (2008) 4848–4850
ceeded with an order of magnitude less catalyst (0.1 mol %). It is
likely that for the even more reactive trichloroacetyl derivatives,
even lower catalyst loadings will be possible. By applying the AIBN
protocol in conjunction with solid supported atom transfer cata-
lysts,6 it now should be possible to make efficient heterogeneous
catalysts that can be recycled efficiently and re-used (Scheme 2).
Figure 1. Alkene regioisomers produced in ATRC of 7e.
We next turned our attention to the previously reported 5-exo
dig cyclisation of the alkyne 13a.5d This has been reported to be
approximately 100 times slower than for the correponding 5-exo
trig cyclisation of 7a. Indeed, cyclisation under the conditions high-
lighted in grey in Table 1 (24 h) proceeded to only give a 33% and
9% combined yield of the expected products 14a and 15a with CuBr
or CuBr2, respectively. Switching to toluene at reflux allowed the
reactions to proceed at a reasonable rate (Table 4, entries 3 and
4). The same pattern of reactivity was observed with the N-benzyl
analogue 13b. The ratio of the atom transfer products 14 to re-
duced products 15 has been reported to be solvent and ligand
dependent and so the variation in the ratio between CH2Cl2 and
toluene was expected.4c Vinyl bromides 14a–b were produced as
a 9:1 mixture of E:Z isomers in all cases. The ratio was determined
by comparison to authentic samples.4c
Finally, we investigated the cyclisation of the secondary bro-
mide 16. Cyclisation rates of secondary bromides are known to
be slower than the corresponding tertiary bromide derivatives,
presumably due to the Thorpe–Ingold effect.4c Heating 16 in tolu-
ene at reflux under the standard conditions determined for sub-
strate 3 (Table 1, entry 8) produced a 90% yield of the expected
atom transfer product as a 4:1 mixture of diastereomers (de
60%). The major diastereomer was identified as 17a based upon
comparison of spectral details with authentic samples.4c The dia-
stereoselectivity was slightly eroded compared to that reported
(de 76%) for the cyclisation of 16 with 30 mol % Cu(1)Br at rt.4c
In conclusion, we have shown that it is possible to mediate a
range of relatively slow 5-exo trig and 5-exo dig atom transfer
radical cyclisations of tertiary and secondary bromoacetamides
using 1 mol % Cu(2)Br in conjunction with 10 mol % AIBN as an
additive. This allows for a 30-fold reduction in the amount of metal
catalyst previously required to mediate these reactions efficiently.
This coupled with the fact that the reactions can be mediated with
either CuBr or the more oxidatively stable CuBr2 without the need
for an inert atmosphere should make the atom transfer radical cyc-
lisation approach more attractive for use in industrial applications.
Cyclisation of the more reactive N-Ts compounds (e.g., 7b) pro-
Scheme 2. Cyclisation of secondary bromide 16.
Acknowledgement
We thank the EPSRC for a DTA studentship (PW).
References and notes
1. Clark, A. J. Chem. Soc. Rev. 2002, 31, 1.
2. (a) Nagashima, H.; Ozaki, N.; Ishii, M.; Seki, K.; Washiyama, M.; Itoh, K. J. Org.
Chem. 1993, 58, 464; (b) Iwamatsu, S.; Matsubara, K.; Nagashima, H. J. Org.
Chem. 1999, 64, 9625; (c) Nagashima, H.; Isono, Y.; Iwamatsu, S. J. Org. Chem.
2001, 66, 315; (d) Udding, J. H.; Tuijp, C. J. M.; van Zanden, M. N. A.; Hiemstra,
H.; W.N.Speckamp J. Org. Chem. 1994, 59, 1993; (e) Bryans, J. S.; Chessum, N. E.
A.; Huther, N.; Parsons, A. F.; Ghelfi, F. Tetrahedron 2003, 59, 6221; (f) Felluga,
F.; Forzato, C.; Ghelfi, F.; Nitti, P.; Pitacco, G.; Pagnoni, U. M.; Roncaglia, F.
Tetrahedron: Asymmetry 2007, 18, 527.
3. (a) Benedetti, M.; Forti, L.; Ghelfi, F.; Pagnoni, U. M.; Ronzoni, R. Tetrahedron
1997, 41, 14031; (b) Ghelfi, F.; Bellesia, F.; Forti, L.; Ghirardini, G.; Grandi, R.;
Libertini, E.; Montemaggi, M. C.; Pagnoni, U. M.; Pinetti, A.; De Buyck, L.;
Parsons, A. F. Tetrahedron 1999, 55, 5839; (c) Ghelfi, F.; Parsons, A. F. J. Org.
Chem. 2000, 65, 6249; (d) De Buyck, L.; Cagnoli, R.; Ghelfi, F.; Merighi, G.;
Mucci, A.; Pagnoni, U. M.; Parsons, A. F. Synthesis 2004, 10, 1680; (e) Bellesia, F.;
Daniel, C.; De Buyck, L.; Galeazzi, R.; Ghelfi, F.; Mucci, A.; Orean, M.; Pagnoni, U.
M.; Parsons, A. F.; Roncaglia, F. Tetrahedron 2006, 62, 746.
4. (a) Clark, A. J.; Dell, C. P.; Ellard, J. M.; Hunt, N. A.; McDonagh, J. P. Tetrahedron
Lett 1999, 40, 8619; (b) Clark, A. J.; Filik, R. P.; Thomas, G. H. Tetrahedron Lett.
1999, 40, 4885; (c) Clark, A. J.; De Campo, F.; Deeth, R. J.; Filik, R. P.; Gatard, S.;
Hunt, N. A.; Lastécouères, D.; Thomas, G. H.; Verlac, J.-B.; Wongtap, H. J. Chem.
Soc., Perkin Trans. 1 2000, 671.
5. (a) De Campo, F.; Lastécouères, D.; Verlac, J.-B. Chem. Commun. 1998, 2117; (b)
Clark, A. J.; Dell, C. P.; McDonagh, J. P. C.R. Acad. Sci. Ser IIC: Chim. 2001, 4, 575;
(c) Clark, A. J.; Battle, G. M.; Bridge, A. Tetrahedron Lett. 2001, 42, 4409; (d)
Clark, A. J.; Battle, G. M.; Bridge, A. Tetrahedron Lett. 2001, 42, 1999; (e) Clark, A.
J.; Geden, J. V.; Thom, S.; Wilson, P. J. Org. Chem. 2007, 72, 5923.
6. (a) Clark, A. J.; Filik, R. P.; Haddleton, D. M.; Radique, A.; Saunders, C. J.; Smith,
M. E.; Thomas, G. S. J. Org. Chem. 1999, 64, 8954; (b) Clark, A. J.; Gedev, J. V.;
Thom, S. J. Org. Chem. 2006, 71, 1471.
7. Matyjasewski, K.; Jakubowski, W.; Min, K.; Tang, W.; Huang, J.; Braunecker, W.
A.; Tsarevsky, N. V. Proc. Natl. Acad. Sci. U.S.A. 2006, 45, 4482.
8. Jakubowski, W.; Matyjasewski, K. Macromolecules 2006, 39, 39.
9. (a) Eckenhoff, W. T.; Pintauer, T. Inorg. Chem. 2007, 46, 5844; (b) Eckenhoff, W.
T.; Garrity, S. T.; Pintauer, T. Eur. J. Inorg. Chem. 2008, 563.
Table 4
5-Exo dig cyclisation of compounds 13a–b
10.
A
typical procedure is illustrated for entry 4, Table 1. N-Allyl-N-
(phenylmethyl)-N-2-bromo-2-methylpropanamide was dissolved in dry
3
CH2Cl2 at room temperature (123 mg, 0.42 mmol in 2 ml, 0.21 M). AIBN
(7 mg, 0.042 mmol) was added followed by a 0.01 M solution of CuBr/TPA in
dry CH2Cl2 (0.42 ml, 0.0042 mmol, final concentration of 3 0.17 M) solution
and the mixture was heated at reflux for 6 h. The mixture was allowed to cool
then passed through a silica plug and washed with CH2Cl2 (2 Â 50 ml). The
solvent was removed in vacuo to yield the crude product which was purified by
flash chromatography, 9:1 pet ether/EtOAc, to yield 3,3-dimethyl-4-
bromomethyl-1-(phenylmethyl)-pyrrolidin-2-one
4
(103 mg, 0.35 mmol,
Entry
1
Comp
Temp (°C)
Solvent
CH2Cl2
Cu Source
CuBr
Ratio 14a:15
Yieldb (%)
33
84%). Data for 4: Rf (3:1 petrol/EtOAc) 0.30; mmax 2964, 2929, 1684, 1427,
1269, 699 cmÀ1; dH (300 MHz, CDCl3) 7.29 (5H, m), 4.52 (1H, d, 14.6 Hz), 4.35
(1H, d, 14.6 Hz), 3.46 (1H, dd, 10.0, 4.8 Hz), 3.35 (1H, dd, 10.0, 7.5 Hz), 3.22 (1H,
app t, 10.0 Hz), 2.88 (1H, app t, 10.0 Hz), 2.40 (1H, m), 1.24 (3H, s), 0.99 (3H, s);
dC (75.5 MHz, CDCl3) 178.5, 136.3, 128.8 (Â2), 128.1 (Â2), 127.7, 48.9, 46.7,
46.1, 44.0, 31.5, 24.3, 19.6; ESI [Na+] found 318.0464, Na+C14H18NO79Br
requires 318.0469.
13a
50
1:2
2
3
4
5
6
13a
13a
13a
13b
13b
50
CH2Cl2
CuBr2
CuBr
CuBr2
CuBr
CuBr
2:3
1:1
1:1
3:2
1:1
9
110
110
50
Toluene
Toluene
CH2Cl2
67
80
30
51
11. De Buyck, L.; Forzato, C.; Ghelfi, F.; Mucci, A.; Nitti, P.; Pagnoni, U. M.; Parsons,
A. F.; Pitacco, G.; Roncaglia, F. Tetrahedron Lett. 2006, 62, 746.
12. Clark, A. J.; Battle, G. M.; Heming, A. M.; Haddleton, D. M.; Bridge, A.
Tetrahedron Lett. 2001, 41, 2003.
110
Toluene
a
9:1 mixture of E:Z isomers.
Remaining mass balance is recovered starting material.
b