Microwave-promoted tandem reactions for the synthesis of bicyclic γ-lactams

Article abstract of DOI:10.1016/j.tetlet.2011.02.089

A microwave-promoted three-step tandem process for the synthesis of bicyclic γ-lactams is developed. In all cases examined this led to significantly faster tandem processes producing the bicyclic γ-lactams more cleanly and reproducibly compared to standard thermal conditions.

Full text of DOI:10.1016/j.tetlet.2011.02.089

Tetrahedron Letters 52 (2011) 2330–2332
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-promoted tandem reactions for the synthesis of bicyclic c-lactams
Fiona I. McGonagle a, Lindsay Brown b, Andrew Cooke b, Andrew Sutherland a,
⇑
a WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, UK
b MSD, Newhouse, Motherwell ML1 5SH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A microwave-promoted three-step tandem process for the synthesis of bicyclic
all cases examined this led to significantly faster tandem processes producing the bicyclic
cleanly and reproducibly compared to standard thermal conditions.
c
-lactams is developed. In
Received 11 January 2011
Revised 8 February 2011
Accepted 18 February 2011
Available online 24 February 2011
c
-lactams more
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Tandem reactions
Overman rearrangement
Ring closing metathesis
Kharasch cyclisation
Microwave synthesis
The use of microwaves to heat chemical reactions has become a
very popular and useful approach in organic synthesis.1 This non-
conventional energy source is based on the ability of some reagents
and solvents to transform electromagnetic energy into heat by
‘microwave dielectric heating’ effects.2 Its use can lead to a specta-
cular acceleration of reactions, resulting in shorter reaction times, a
reduction in side reactions, higher yields, milder reaction condi-
tions and an improvement in reproducibility. More recently, the
combination of microwave technology with the principles of green
chemistry have produced a range of relatively sustainable and
environmentally benign procedures involving solvent-free condi-
tions, supported reagents or reusable catalysts for the synthesis
of biologically-active compounds and fine chemicals.3
yields (60–87% over four steps) for bicyclic
allylic alcohols with an all carbon side chain, more modest yields
(19–36%) were observed for substrates bearing side-chain
heteroatom. The yields for these compounds could be improved
(39–52%) by employing a thermal Overman rearrangement10 dur-
ing the first stage of the tandem process. However, using thermal
conditions rather than a palladium(II)-catalyst resulted in long
reactions times (72 h for X = O, 136 h for X = NTs).
c-lactams derived from
a
As all three steps of this tandem process can be accelerated by
heat, it was proposed that the application of microwave energy
would allow a more rapid and efficient synthesis of the bicyclic
c-lactams. In this Letter, we now report a one-pot tandem process
Our own research into green chemistry has focused on the
development of one-pot tandem processes for the multi-step
synthesis of functionalised carbocyclic amides.4 These processes
involved the use of the Overman rearrangement of allylic trichloro-
acetimidates5 in combination with ring closing metathesis (RCM)
reactions of the resulting trichloroacetamide derived dienes to give
carbocyclic amides of various ring sizes. An asymmetric variant
was also developed and used for the synthesis of the tropane alka-
loid, (+)-physoperuvine.6 More recently, we reported a one-pot
tandem process for the synthesis of bicyclic [3.3.0], [4.3.0] and
X
X
Cl3CCN,
DBU
X
Pd(II)
n
n
n
HN
O
HN
O
OH
CCl3
CCl3
X= CH2, n= 0
X= CH2, n= 1
X= CH2, n= 2
X= O, n= 1
Grubbs I, rt
X
[5.3.0] c
-lactams from allylic alcohols.7 This process involved a pal-
X= NTs, n= 1
Cl
X
4 Å MS,
ladium(II)-catalysed Overman rearrangement followed by a RCM
reaction and a Kharasch cyclisation,8 both mediated by Grubbs
1st generation catalyst (Scheme 1).9 While this process gave high
155 °C
n
Cl
Cl
n
19−87%
HN
O
HN
O
CCl3
⇑
Corresponding author. Tel.: +44 141 330 5936; fax: +44 141 330 4888.
E-mail address: Andrew.Sutherland@glasgow.ac.uk (A. Sutherland).
Scheme 1. Tandem synthesis of bicyclic
c
-lactams.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.089

F. I. McGonagle et al. / Tetrahedron Letters 52 (2011) 2330–2332
2331
Table 1
Development of the microwave-promoted tandem process
1. Cl3CCN, DBU (cat.),
CH2Cl2, rt, 2 h
2. K2CO3, toluene,
MW 180 °C
HN
O
OH
CCl3
1
3. Grubbs I
(10 mol%)
4. 4 Å MS,
MW 180 °C
Cl
O
Cl
Cl
HN
2
Entry
Overman rearrangement
RCM reaction
Kharasch cyclisation
Yielda (%)
1
2
3
4
MeCN (10%), 0.5 h
SiC PHE, 1 h
SiC PHE, 1 h
rt, 3 h
rt, 1 h
MW 60 °C, 0.75 h
MW 60 °C, 0.25 h
0.5 h
0.5 h
0.5 h
0.75 h
24
42
44
64
SiC PHE, 1 h
a
Isolated yield from (2E)-octa-2,7-dien-1-ol (1).
Table 2
Comparison of microwave-promoted and thermal tandem processes
Cl
O
X
X
Cl3CCN, DBU (cat.),
X
2. Grubbs I
CH2Cl2, rt, 2 h
Cl
Cl
n
n
n
1. K2CO3, toluene
HN
O
3. Kharasch
cyclisation
HN
OH
CCl3
Entry
Allylic alcohol
Bicyclic
c
-lactam
Reaction conditions: (1) Overman rearrangement; (2) RCM; (3) Kharasch cyclisation
Yielda (%)
64
(1) MW 180 °C, 1 h; (2) MW 60 °C, 0.25 h; (3) MW 180 °C, 0.75 hb
Cl
Cl
Cl
1
(1)
D
, 140 °C, 18 h; (2) rt, 1 h; (3)
D
, 155 °C, 4 Å MS, 2 hc
61
OH
HN
O
1
2
(1) MW 180 °C, 1 h; (2) MW 60 °C, 0.25 h; (3) MW 180 °C, 1.25 hb
50
48
Cl
Cl
Cl
D, 140 °C, 18 h; (2) rt, 1 h; (3) D
, 155 °C, 4 Å MS, 4 hc
2
3
4
(1)
OH
HN
O
3
4
(1) MW 180 °C, 1.5 h; (2) MW 60 °C, 0.5 h; (3) MW 180 °C, 1 hb
Cl
44
39
TsN
TsN
Cl
Cl
(1)
D, 140 °C, 136 h; (2) rt, 1 h; (3) D
, 155 °C, 4 Å MS, 3 hc
OH
HN
O
5
6
(1) MW 180 °C, 1 h; (2) MW 60 °C, 0.5 h; (3) MW 180 °C, 5 hb,d
Cl
43
45
O
O
Cl
Cl
(1)
D, 140 °C, 72 h; (2) rt, 1.5 h; (3) D
, 155 °C, 4 Å MS, 3 hc,d
OH
HN
O
7
8
a
b
c
Isolated yields from allylic alcohols.
All steps were promoted by microwave heating using a SiC passive heating element.
Overman rearrangement and Kharasch cyclisation were carried out under standard thermal conditions.
RCM and Kharasch steps were accomplished using the Hoveyda–Grubbs 2nd generation catalyst.
d

2332
F. I. McGonagle et al. / Tetrahedron Letters 52 (2011) 2330–2332
for the synthesis of bicyclic
c
-lactams in which all three-steps are
developing the microwave-promoted tandem processes shown in
Table 2, it was found that the short reaction times for the Kharasch
cyclisation meant that the addition of molecular sieves was not
required.
accelerated using microwave heating. For comparison, the synthe-
sis of these compounds under standard thermal conditions is also
described.
The development of a microwave-assisted tandem process was
initially studied using (2E)-octa-2,7-dien-1-ol (1) (Table 1).11 This
was converted into the allylic trichloroacetimidate using trichloro-
acetonitrile and DBU under standard conditions.12 Our previous
In summary, a one-pot tandem process where all three-steps
are promoted by microwave heating has been developed for the
effective synthesis of a series of bicyclic
c-lactams. These new con-
ditions allow the synthesis of the bicyclic
c-lactams more cleanly,
tandem process for the synthesis of bicyclic
c
-lactams used tolu-
more reproducibly and in significantly shorter reaction times com-
pared to standard thermal conditions. In particular, this new ap-
proach circumvents the problems and limitations of using
palladium(II)-catalysed or thermal Overman rearrangements dur-
ing the three-step tandem process for the synthesis of heteroatom
ene as the solvent. However, toluene is an example of a microwave
transparent solvent due to its inability to absorb effectively the
microwave energy (low tan d value).2 Thus, our initial attempt in-
volved using more polar acetonitrile as a co-solvent (entry 1). The
Overman rearrangement was carried out at 180 °C in a microwave
reactor and was complete in 0.5 h. The reaction vessel was cooled
to room temperature and Grubbs 1st generation catalyst
(10 mol %) was added. After 3 h, molecular sieves were added13
and the microwave reactor was again heated to 180 °C. Although
the three steps were complete in only 4 h, (1S⁄,5S⁄,6S⁄)-5,7,7-tri-
chloro-8-oxo-9-azabicyclo[4.3.0]nonane (2) was isolated in only
24% overall yield from allylic alcohol 1.14
derived bicyclic c-lactams.
Acknowledgements
Financial support from the Scottish Funding Council, the
University of Glasgow and MSD is gratefully acknowledged.
References and notes
Other co-solvents that are known to absorb microwave energy
more efficiently such as DMSO, acetic acid and chlorobenzene were
briefly investigated but all interfered with the various steps of the
tandem process resulting in low yields of 2. Kremsner and Kappe
showed that microwave-assisted reactions could be done in non-
polar solvents using silicon carbide bars as passive heating ele-
ments (PHE).15 This chemically inert and strongly microwave
absorbing material can transfer thermal energy to the reaction
mixture via conduction phenomena. Thus, a second attempt at
the microwave-assisted synthesis of bicyclic c-lactam 2 was car-
ried out in toluene using silicon carbide PHE throughout (entry
2). Under these conditions both the Overman rearrangement and
the RCM step were complete in one hour, producing bicyclic c-lac-
tam 2 after the Kharasch cyclisation in a much-improved 42% yield.
The next attempt then investigated the use of microwave heating
(at 60 °C) of the RCM step (entry 3). This gave bicyclic c-lactam 2
in a slightly improved 44% yield. Using NMR spectroscopy to inves-
tigate the progress of the tandem process under these conditions, it
was found that the RCM reaction could be completed more rapidly,
while the Kharasch cyclisation required slightly more time for
complete conversion (entry 4). These optimised conditions allowed
1. For reviews, see: (a) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199–9223; (b)
Hayes, B. L. Aldrichim. Acta 2004, 37, 66–77; (c) de la Hoz, A.; Díaz-Ortiz, Á.;
Moreno, A. Chem. Soc. Rev. 2005, 34, 164–178.
2. Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284.
3. For reviews, see: (a) Roberts, B. A.; Strauss, C. R. Acc. Chem. Res. 2005, 38, 653–
661; (b) Polshettiwar, V.; Varma, R. S. Acc. Chem. Res. 2008, 41, 629–639; (c)
Polshettiwar, V.; Varma, R. S. Chem. Soc. Rev. 2008, 37, 1546–1557; (d)
Polshettiwar, V.; Nadagouda, M. N.; Varma, R. S. Aust. J. Chem. 2009, 62, 16–26.
4. (a) Swift, M. D.; Sutherland, A. Org. Lett. 2007, 9, 5239–5242; (b) Swift, M. D.;
Donaldson, A.; Sutherland, A. Tetrahedron Lett. 2009, 50, 3241–3244.
5. Overman, L. E.; Carpenter, N. E. In Organic Reactions; Overman, L. E., Ed.; Wiley:
Hoboken, NJ, 2005; 66, pp 1–107. and references cited therein.
6. Zaed, A. M.; Swift, M. D.; Sutherland, A. Org. Biomol. Chem. 2009, 7, 2678–2680.
7. McGonagle, F. I.; Brown, L.; Cooke, A.; Sutherland, A. Org. Biomol. Chem. 2010, 8,
3418–3425.
8. (a) Kharasch, M. S.; Jensen, E. V.; Urry, W. H. Science 1945, 102, 128; (b)
Nagashima, H.; Wakamatsu, H.; Ozaki, N.; Ishii, T.; Watanabe, M.; Tajima, T.;
Itoh, K. J. Org. Chem. 1992, 57, 1682–1689.
9. (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2039–2041; (b) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am.
Chem. Soc. 1996, 118, 100–110.
10. (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597–599; (b) Overman, L. E. J. Am.
Chem. Soc. 1976, 98, 2901–2910.
11. All allylic alcohols used in this study were prepared as previously reported. See
Ref. 7 for full details.
12. Anderson, C. E.; Overman, L. E.; Watson, M. P. Org. Synth. 2005, 82, 134–139.
13. During previous studies on the Kharasch cyclisation of cyclic allylic
trichloroacetamides, we found that 4 Å molecular sieves act as an effective
acid scavenger resulting in high yields of products. See Refs. 4b,7 for full
details.
the isolation of bicyclic
yield.
c-lactam 2 after only 2 h in 64% overall
With these optimised conditions in hand, a number of other
allylic alcohols were subjected to the microwave-assisted tandem
process (Table 2).16 For comparison, the three-step tandem process
for each substrate was also performed under standard thermal
14. Although racemic, the bicyclic
c-lactams formed from this tandem process are
isolated as single diastereomers.
15. Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2006, 71, 4651–4658.
16. General procedure: The allylic alcohol (0.4 mmol) was dissolved in CH2Cl2
(10 mL) and cooled to 0 °C. To the solution was added DBU (0.5 equiv) and
trichloroacetonitrile (1.5 equiv). The reaction mixture was allowed to warm to
room temperature before stirring for 2 h. The reaction mixture was filtered
through a short pad of silica gel and the filtrate concentrated in vacuo to give
the allylic trichloroacetimidate which was used without further purification.
The allylic trichloroacetimidate was dissolved in toluene (5 mL) and
conditions. In all cases, the bicyclic c-lactams were isolated much
more cleanly using the microwave-promoted process than under
the standard thermal conditions. However, the most dramatic dif-
ference between the two types of reaction conditions is the time
required for completion of the tandem process. Bicyclic c-lactams
transferred to
a microwave vial containing K2CO3 (0.02 g) and a silicon
carbide (SiC) bar. The vial was then sealed under Ar and the reaction mixture
heated in a microwave reactor (Biotage initiator, 300 W) for the required time
at 180 °C. Grubbs first-generation catalyst (10 mol %) was added and the
mixture was heated at 60 °C until complete. The temperature was then raised
to 180 °C and heating continued until the reaction was complete. Purification
was carried out by flash column chromatography eluting with petroleum
2 and 4 could be prepared in 2 and 2.5 h, respectively, under micro-
wave conditions, while requiring nearly one day under standard
thermal conditions. The heterocyclic analogues 6 and 8 could be
prepared in 3 and 6.5 h, respectively, using the microwave-pro-
moted process while requiring several days under standard ther-
mal conditions. Although the microwave heating of the RCM and
Kharasch steps does, in most cases, lead to significant shortening
of reaction times,17 it is the acceleration of the Overman rearrange-
ment that leads to the dramatic differences observed between the
microwave and thermal tandem processes.18 Furthermore, while
ether/EtOAc to afford the desired bicyclic
c-lactam.
17. The use of Hoveyda–Grubbs 2nd generation catalyst for the RCM and Kharasch
steps gave more consistent yields of bicyclic
generation catalyst.
c-lactam 8 than using Grubbs 1st
18. Gonda, J.; Martinková, M.; Zadrosová, A.; Soteková, M.; Raschmanová, J.; Conka,
P.; Gajdosíková, E.; Kappe, C. O. Tetrahedron Lett. 2007, 48, 6912–6915.