Microwave-accelerated cross-metathesis reactions of N-allyl amino acid substrates

Article abstract of DOI:10.1016/j.tetlet.2005.08.126

Microwave heating has been utilised for the cross-metathesis reaction of N-allyl amino acid substrates to generate olefin homodimers. Remarkable acceleration of the cross-metathesis reaction (minutes compared to hours) over conventional reflux heating was

Full text of DOI:10.1016/j.tetlet.2005.08.126

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7389–7392
Microwave-accelerated cross-metathesis reactions of
N-allyl amino acid substrates
Sally-Ann Poulsen* and Laurent F. Bornaghi
Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan campus, Brisbane 4111, Australia
Received 7 June 2005; revised 18 August 2005; accepted 23 August 2005
Available online 9 September 2005
Abstract—Microwave heating has been utilised for the cross-metathesis reaction of N-allyl amino acid substrates to generate olefin
homodimers. Remarkable acceleration of the cross-metathesis reaction (minutes compared to hours) over conventional reflux heat-
ing was observed. In addition, improved reaction yields and similar E/Z ratios for the cross-metathesis products were achieved.
Ó 2005 Published by Elsevier Ltd.
Olefin metathesis using the carbene ruthenium catalysts
developed by Grubbs is well studied in conventional
organic chemistry, where reactions are most likely direc-
ted towards high yields and selective products (Fig. 1).1
The cross-metathesis (CM) variant of the olefin meta-
thesis reaction in general exhibits unpredictability in
both these respects and consequently has much less rep-
resentation in the organic synthesis literature when com-
pared to the ring-opening metathesis polymerisation
(ROMP) and ring-closing metathesis (RCM) variants.
A general model of the selectivity of the CM reaction
has recently been described by Grubbs and co-workers.2
The model was derived from the propensity of olefin
homodimers, rather than the terminal olefins them-
selves, to undergo CM, with the underlying premise to
circumvent many of the complexities of a system in
which both primary (from the terminal olefin counter-
part) and secondary (from the olefin dimer) metathesis
pathways participate and compete.
As part of our ongoing investigation into the develop-
ment of newly modified amino acid building blocks for
application of the metathesis reaction to dynamic com-
binatorial chemistry (DCC), we needed to synthesise
amino acid building blocks containing a terminal olefin.
N-Allyl amino acid precursors were chosen and synthesi-
sed; however, to simplify the complexity of the DCC
system, it was decided to prepare the corresponding
olefin homodimers for building blocks by CM, Scheme 1.
We investigated both the Grubbs first- and second-
generation catalysts. This manuscript reports the results
with a number of our building blocks.
P(Cy)3
P(Cy)3
Ru
The synthesis of the N-allyl substituted amino acid pre-
cursors 2a–c from commercially available amino acid
methyl esters is outlined in Scheme 2.3 The synthesis uti-
lises the 2-nitrobenzene sulfonamide (oNBS) group for
the concomitant protection and activation of the amino
acid nitrogen. The electron withdrawing nature of the
oNBS group increases the acidity of the amino acid
NH proton improving the susceptibility for substitution
Ph
Ph
Cl
Cl
Cl
Cl
Ru
P(Cy)3
N
N
(a)
(b)
Figure 1. Grubbs first-generation catalyst (a) and Grubbs second-
generation catalyst (b).
R'
cross
metathesis
2
+
Keywords: Olefin; Cross-metathesis; Microwave; Amino acids; N-Allyla-
tion.
R'
R'
*
Corresponding author. Tel.: +61 7 3735 7825; fax: +61 7 3735
7656; e-mail: s.poulsen@griffith.edu.au
Scheme 1. CM reaction for the preparation of olefin homodimers.
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.08.126

7390
S.-A. Poulsen, L. F. Bornaghi / Tetrahedron Letters 46 (2005) 7389–7392
O
O
Cl-H3N+
CO2Me
(i)
H
N
(ii)
S
CO2Me
S
N
CO2Me
O
R
O
R
R
NO2
NO2
(iv)
(iii)
Ph
N
CO2Me
HN
CO2Me
1a R = Ch2Ph (from Phe)
1b R =iButyl (from Leu)
1c R = iPropyl (from Val)
2a
2b
2c
O
R
R
Scheme 2. General synthesis of N-allyl substituted amino acid precursors 2a–c: (i) oNBSCl, Et3N, CH2Cl2, rt, 16 h, 80–97%; (ii) K2CO3, DMF, allyl
bromide, rt, 16 h, 83–85%; (iii) PhSꢀNa+, K2CO3 or LiOH, mercaptoacetic acid; DMF, rt, 2–3 h, 57–94%; (iv) BzCl, Et3N, CH2Cl2, rt, 2 h, 65–72%.
with allyl bromide. Following allylation, the oNBS
group is removed by either phenyl thiolate or mercapto-
acetic acid. Finally, amide formation with benzoyl chlo-
ride generates the olefin precursors 2a–c.4
tate the thermal reaction, albeit with moderate yields
(Table 1, entries 3, 4, 7 and 10).
In an attempt to increase the CM yield and shorten the
reaction time, microwave (MW) irradiation, in place of
conventional heating, was investigated. Thermally
driven organic transformations can take place by con-
ventional heating or MW-accelerated heating. MW irra-
diation, using either a domestic microwave oven or
mono-mode reactors, has become a powerful tool for
the preparation of organic compounds.8 The premise
for this investigation was the reported success of MW
irradiation in the promotion of the RCM variant of
the olefin metathesis reaction.9 In RCM applications,
MW irradiation has demonstrated improved yields, sub-
stantially reduced reaction times, and reduced thermal
degradation of the ruthenium catalyst. It is believed that
these improvements arise from the more effective and
efficient heating compared to conventional thermal reac-
tions. We could find only one reported example where
MW irradiation has been applied to promote the CM
variant of the metathesis reaction (in a RCM–CM
domino reaction).10 CM is, therefore, unexplored with
respect to the application of MW irradiation and so pre-
sented itself as an ideal candidate reaction for the inves-
tigation of the effects of MW irradiation on reaction
time and product yield. Herein, we report a systematic
analysis of the effect of MW heating on the CM reaction
on olefin substrates 2a–c.ꢀ
With the three precursors 2a–c in hand, the CM reaction
for the preparation of the corresponding olefin homodi-
mer building blocks 3a–c was investigated, Scheme 3.5
Initial studies with Grubbs first-generation catalyst
failed to generate any CM product, even with varying
reaction times either at room temperature or at elevated
temperatures: refluxing CH2Cl2 (40 °C) or refluxing 1,2-
dichloroethane (1,2-DCE) (80 °C). Analogues of a-allyl
amino acid methyl esters (allylglycines) have undergone
CM at room temperature with Grubbs first-generation
catalyst,6 so our results demonstrate the severely re-
duced efficiency of participation of N-allyl amino acid
substrates in the CM reaction.
Grubbs second-generation catalyst is reported to have
higher activity in the CM reaction7 and an investigation
with substrates 2a–c was undertaken (Table 1). The
second-generation catalyst was also not sufficient for
CM of our substrates at room temperature (Table 1
entries 1, 2, 6 and 9). The use of refluxing 1,2-DCE for
an extended period (18–72 h) was required to facili-
R
O
MeO2C
N
Ph
ꢀ In the CEM Discover microwave system used in this study, a circular
single-mode cavity directs the microwave energy into a defined area,
resulting in a homogenous field pattern surrounding the sample and
an instantaneous coupling to all polar and ionic components in the
sample, leading to a rapid rise in temperature. This microwave can
accommodate a single 10 mL 25 bar pressure rated sealed reaction
vial. The system incorporates both temperature and pressure
feedback systems for control of the reaction conditions. The
temperature feedback system uses an infrared temperature sensor
positioned below the reaction vessel to permit reproducible temper-
ature control. The reactions were quenched following heating by
forced gas cooling with nitrogen gas.
cross
Ph
N
CO2Me metathesis
2
O
R
2a-c
Ph
N
CO2Me
O
R
3a-c
Scheme 3. Synthesis of olefin homodimers 3a–c from precursors 2a–c
by CM.

S.-A. Poulsen, L. F. Bornaghi / Tetrahedron Letters 46 (2005) 7389–7392
Table 1. CM of N-allyl amino acids 2a–c with Grubbs second-generation catalyst
7391
Entry
CM Substrate
Heating conditions
Temperature (°C)
Catalyst (mol %)
Time
Yielda (%)
E/Z Ratiob
1
2
3
4
5
2a
None
None
Reflux
Reflux
MW
24
24
80
80
100
7.5
7.5
7.5
7.5
5
18 h
72 h
18 h
72 h
0
0
29
34
48
2.3/1
2.3/1
2.7/1
10 min
6
7
8
2b
2c
None
Reflux
MW
24
80
100
15
15
20
18 h
72 h
10 min
0
32
54
3.0/1
2.1/1
9
10
11
None
Reflux
MW
24
80
100
15
15
20
18 h
72 h
10 min
0
27
40
4.3/1
4.8/1
a Yield calculated following reaction workup and purification by chromatography.
b 1H NMR spectroscopy was used to determine E/Z ratio.
We first investigated the effect of MW heating in the
application of CM to the synthesis of the olefin homodi-
References and notes
1. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413;
(b) Grubbs, R. H. Tetrahedron 2004, 60, 7117.
2. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R.
H. J. Am. Chem. Soc. 2003, 125, 11360.
3. (a) Bowman, W. R.; Coghlan, D. R. Tetrahedron 1997, 53,
15787; (b) Reichwein, J. F.; Liskamp, R. M. J. Tetra-
hedron Lett. 1998, 39, 1243; (c) Reichwein, J. F.; Liskamp,
R. M. J. Eur. J. Org. Chem. 2000, 2335; (d) Bornaghi, L.
F.; Poulsen, S.-A.; Healy, P. C. Acta Crystallogr. 2004,
E60, o383; (e) Poulsen, S.-A.; Noack, C. L.; Healy, P. C.
Acta Crystallogr. 2003, E59, o967.
mer building block 3a in the presence of Grubbs first-
generation catalyst. Our procedure used 1,2-DCE as sol-
vent with MW irradiation at 100 °C for 10 min.11 No
CM product was produced. We then turned our atten-
tion to Grubbs second-generation catalyst. The yields
obtained with 10 min of MW irradiation at 100 °C are
given in Table 1, entries 5, 8 and 11. An improvement
in yield of the CM homodimer products compared to
conventional reflux (Table 1, entries 3, 4, 7 and 10)
was observed for each substrate, this improvement was
in the order of 40–60%. Higher MW reaction tempera-
tures (120 and 150 °C) were also studied, but gave no
further improvement in yield.
4. General synthesis of N-allyl substituted amino acid precur-
sors 2a–c: Typical procedures for the synthesis of N-
allylamino acid methyl esters to generate H–(Nall)aa–
OMe 1a–c can be found in Ref. 3. Compound 1a (250 mg,
1.1 mmol), benzoyl chloride (0.26 mL, 2.2 mmol) and
triethylamine (0.32 mL, 2.2 mmol) were stirred in anhy-
drous CH2Cl2 (5 mL) at room temperature for 2 h. The
reaction mixture was diluted with CH2Cl2 (5 mL) and
washed with citric acid (50% solution in water, 10 mL) and
brine (10 mL). The organic fraction was dried over
anhydrous MgSO4, filtered and the volatiles were
removed. The remaining residue was purified by solid
phase extraction on normal phase silica sorbent, eluted
with hexane/EtOAc (3:1, v/v) to generate 2a in 71% yield.
1H NMR (400 MHz, toluene-d8, 90 °C, ppm): d 2.86 (d,
2H, J = 6.6 Hz, bCH2), 3.38 (s, 3H, OCH3), 3.89–4.06 (m,
2H, AllCH2), 4.45–4.48 (t, 1H, J = 6.4 Hz, aCH), 4.91–
5.06 (m, 2H, @CH2), 5.79–5.88 (m, 1H, @CH), 6.97–6.99
(m, 4H, ArH), 7.04–7.07 (m, 5H, ArH), 7.34–7.37 (m, 1H,
ArH); 13C NMR (100 MHz, CDCl3, ppm): d 37.2 (bCH2),
48.4 (AllCH2), 51.6 (aCH), 59.8 (OCH3), 118.6 (@CH2),
123.9, 128.6, 129.8, 132.4, 134.2 and 136.4 (ArCH, @CH),
172.3 (CO); ESI MS: m/z 324.5 [M+H]+, 346.6 [M+Na]+;
HRMS (ESI) 324.1595. Calcd for C20H21N1O3ÆH+:
324.1594. Synthesis of 2b and 2c proceeded similarly.
This is the first report of MW irradiation applied solely
to the CM variant of the metathesis reaction. Specifi-
cally, we have demonstrated the application of MW
irradiation to CM of N-allyl amino acid substrates to
generate olefin homodimers. The CM reaction with
these allylic amine substrates was not viable with either
the Grubbs first- or second-generation catalysts at room
temperature and only moderately viable with Grubbs
second-generation catalyst after lengthy reaction times
at elevated temperatures. With MW irradiation, an
impressive acceleration of reaction time (10 min com-
pared to 72 h) and increase in overall yield were ob-
served when compared to conventional reflux. The
synthesis is both practical and efficient for each sub-
strate. This preliminary study demonstrates that MW
irradiation has potential as one of the easiest and most
efficient routes for the preparation of olefin homodimers
using CM. A larger investigation of the CM reactions
using microwave irradiation is underway.
1
Compound 2b: Yield 65%; H NMR (400 MHz, toluene-
d8, 90 °C, ppm): d 0.89 (d, 6H, J = 6.1 Hz, dCH3, d0CH3),
1.60–1.74 (m, 2H, bCH2), 1.89–1.96 (m, 1H, cCH), 3.39 (s,
3H, OCH3), 3.81–3.97 (m, 2H, AllCH2), 4.63 (t, 1H,
J = 7.0 Hz, aCH), 4.89–4.92 (dd, 1H, @CH2), 4.93–4.98
(d, 1H, @CH2), 5.80–5.87 (d, 1H, @CH), 6.67–6.99 (m,
2H, ArH), 7.04–7.07 (m, 2H, ArH), 7.35–7.37 (m, 1H,
ArH); 13C NMR (50 MHz, CDCl3, ppm): d 20.2 and 21.9
(dCH3, d0CH3), 24.7 (cCH), 40.6 (bCH2), 49.0 (AllCH2),
52.6 (aCH), 57.4 (OCH3), 115.8 (@CH2), 126.9, 128.6,
129.3, 129.7 and 134.5 (ArCH, @CH), 172.6 (CO); ESI
Acknowledgements
We thank Professor I. Jenkins for helpful discussion and
for the opportunity to use a microwave oven. We grate-
fully acknowledge the funding provided by the Austra-
lian Research Council. We thank Mr. Alan White and
Dr. Sue Boyd, for assistance with mass spectrometry
and NMR instrumentation, respectively.

7392
S.-A. Poulsen, L. F. Bornaghi / Tetrahedron Letters 46 (2005) 7389–7392
MS: m/z 290.3 [M+H]+, 312.5 [M+Na]+; HRMS (ESI)
OCH3), 4.18–4.22 (m, 4H, AllCH2), 4.29–4.33 (t, 2H,
J = 7.0 Hz, aCH), 5.83–6.01 (m, 2H, @CH), 6.90–7.02 (m,
18H, ArH), 7.14–7.16 (m, 2H, ArH); 13C NMR (100 MHz,
CDCl3, ppm): d 36.4 (bCH2), 48.8 (AllCH2), 52.3 (aCH),
59.9 (OCH3), 124.2, 127.9, 128.3, 131.4, 133.7 and 135.9
(ArCH and @CH), 171.8 (CO); ESI MS: m/z 619.7
[M+H]+, 641.5 [M+Na]+; HRMS (ESI) 619.2802. Calcd
for C30H38N2O6ÆH+: 619.2809. Compound 3b: Yield 32%;
290.1779. Calcd for C17H23N1O3ÆH+: 290.1750. Com-
pound 2c: Yield 72%; 1H NMR (400 MHz, toluene-d8,
90 °C, ppm): d 0.86 (d, 3H, J = 6.6 Hz, cCH3), 0.88 (d,
3H, J = 6.8 Hz, c0CH3), 2.32–2.42 (m, 1H, bCH), 3.41 (s,
3H, OCH3), 3.81–3.88 (m, 1H, AllCH2), 4.08–4.16 (m, 1H,
AllCH2), 4.30–4.34 (d, 1H, J = 7.0 Hz, aCH), 4.94–5.02
(m, 2H, @CH2), 5.81–5.92 (m, 1H, @CH), 7.08–7.12
(m, 3H, ArH), 7.38–7.42 (m, 2H, ArH); 13C NMR
(50 MHz, CDCl3, ppm): d 19.3, 20.2 (cCH3, c0CH3),
28.2 (bCH), 51.7 (AllCH2), 52.6 (aCH), 57.4 (OCH3),
115.9 (@CH2), 127.3, 128.6, 129.1, 129.8, 130.8 and 136.5
(ArCH and @CH), 172.6 (CO); ESI MS: m/z 276.3
[M+H]+, 298.5 [M+Na]+; HRMS (ESI) 276.1602. Calcd
for C16H21N1O3ÆH+: 276.1594.
1
the E/Z ratio was determined by integration of H NMR
peaks at 3.35 and 3.43 ppm; 1H NMR (400 MHz, toluene-
d8, 90 °C, ppm): d 0.93 (d, 12H, J = 6.4 Hz, dCH3, d0CH3),
1.58–1.76 (m, 4H, bCH2), 1.92–1.97 (m, 2H, cCH), 3.43 (s,
6H, OCH3), 3.82–3.99 (m, 4H, AllCH2), 4.65 (t, 2H,
J = 7.2 Hz, aCH), 5.69–5.72 (d, 2H, @CH), 6.85–6.90 (m,
4H, ArH), 7.01–7.06 (m, 4H, ArH), 7.38–7.41 (m, 2H,
ArH); 13C NMR (50 MHz, CDCl3, ppm): d 22.4, 22.9
(dCH3, d0CH3), 25.6 (cCH), 39.6 (bCH2), 51.7 (AllCH2),
51.9 (aCH), 58.1 (OCH3), 127.1, 127.5, 127.7, 128.9 and
132.7 (ArCH and @CH), 171.9 (CO); ESI MS: m/z 551.5
[M+H]+, 573.3 [M+Na]+; HRMS (ESI) 551.3109. Calcd
for C32H42N2O6ÆH+: 551.3115.
5. General experimental procedure for CM using conventional
reflux heating: To a stirred solution of 2c (58 mg,
0.21 mmol) in 1,2-DCE (0.8 mL) was added Grubbs
second-generation catalyst (26 mg, 15 mol %). The reac-
tion mixture was refluxed at 80 °C for 72 h. Removal of
the solvent afforded a black oil. This crude material was
purified by solid phase extraction on normal phase silica
sorbent, eluted with hexane/EtOAc (3:1, v/v) to generate
3c as a yellow syrup in 27% yield. The E/Z ratio was
6. Biagini, S. C. G.; Gibson, S. E.; Keen, S. P. J. Chem. Soc.,
Perkin Trans. 1 1998, 2485.
7. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
1
determined by integration of H NMR peaks at 5.46 and
5.59 ppm. 1H NMR (400 MHz, toluene-d8, 90 °C, ppm): d
0.77 (d, 12H, J = 6.8 Hz, cCH3, c0CH3), 2.22–2.27 (m, 2H,
bCH), 3.45 (s, 6H, OCH3), 3.73–3.78 (m, 2H, AllCH2),
3.92–4.02 (m, 2H, AllCH2), 4.16–4.18 (d, 2H, J = 9.2 Hz,
aCH), 5.59 (br s, 2H, @CH), 6.90–6.92 (m, 4H, ArH),
6.99–7.03 (m, 4H, ArH), 7.35–7.37 (m, 2H, ArH); 13C
NMR (50 MHz, CDCl3, ppm): d 19.1, 19.9 (cCH3,
c0CH3), 27.8 (bCH), 52.6 (AllCH2), 52.9 (aCH), 57.2
(OCH3), 128.2, 129.0, 130.0, 130.7 and 135.5 (ArCH
and @CH), 173.9 (CO); ESI MS: m/z 523.7 [M+H]+,
545.6 [M+Na]+; HRMS (ESI) 545.2623. Calcd for
C30H38N2O6Na+: 545.2622. Synthesis of 3a and 3b pro-
ceeded similarly. Compound 3a: Yield 34%; the E/Z ratio
8. (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250;
(b) Hayes, B. L. Aldrichim. Acta 2004, 37, 66.
9. Aitken, S. G.; Abell, A. D. Aust. J. Chem. 2005, 58, 3.
10. Salim, S. S.; Bellingham, R. K.; Brown, R. C. D. Eur. J.
Org. Chem. 2004, 800.
11. General experimental procedure for microwave accelerated
CM: All reactions were carried out in a pressure tube,
sealed with a Teflon septum. Reactions contained the
N-allyl amino acid substrate 2a–c (0.1–0.2 mmol) and
Grubbs second-generation catalyst (5–20%) in 1,2-DCE
(0.8 mL). The pressure tube was introduced to the centre
of a CEM Discover microwave oven and then heated to
100 °C for 10 min. On completion of the heating cycle, the
reaction mixture was purified and characterised in a
manner identical to that described in Ref. 5. Yields: 3a
48%, 3b 54%, 3c 40%.
1
was determined by integration of H NMR peaks at 5.76
and 5.92 ppm; 1H NMR (400 MHz, toluene-d8, 90 °C,
ppm): d 2.93 (d, 4H, J = 6.6 Hz, bCH2), 3.42 (s, 6H,