Heck reactions using segmented flow conditions

Article abstract of DOI:10.1016/j.tetlet.2009.02.133

Various Heck couplings have been carried out using segmented flow conditions to accelerate the reactions. Aryl iodides and aryl bromides as well as anilines in diazonium-type Heck reactions have been used successfully.

Full text of DOI:10.1016/j.tetlet.2009.02.133

Tetrahedron Letters 50 (2009) 3352–3355
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Heck reactions using segmented flow conditions
b,
Batoul Ahmed-Omer a,b, David A. Barrow a, , Thomas Wirth
*
*
a metaFAB Laboratory for Applied Microsystems, Cardiff School of Engineering, Cardiff University, Cardiff CF23 3AA, UK
b School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Various Heck couplings have been carried out using segmented flow conditions to accelerate the reac-
tions. Aryl iodides and aryl bromides as well as anilines in diazonium-type Heck reactions have been used
successfully.
Received 13 January 2009
Revised 30 January 2009
Accepted 13 February 2009
Available online 24 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The Heck reaction is one of the best-known methods used in
organic synthesis for formation of substituted alkenes by the cou-
pling of two sp2 carbon centres. Since discovered by Heck in the
late 1960s,1 the reaction has occupied a special place among
metal-catalysed transformations along with Suzuki, Stille and
Sonogashira reactions due to its versatility and applicability to a
wide range of substrates. As a result, Heck coupling has become
a popular transformation used in the synthesis of many structur-
ally diverse compounds, such as Taxol,2 morphine3 and other mac-
rocyclic compounds.4 The Heck coupling normally takes place
between an organohalide (aryl or vinyl) and an alkene typically
in the presence of a zerovalent palladium catalyst. It is a very reli-
able reaction and many non-conventional methodologies have
been exploited successfully.5
Currently there is high interest in continuous-flow processes
and organic reactions performed in microfluidic systems.6 This
technology offers advantages over classical approaches by allowing
miniaturisation of structural features up to the micrometre regime.
Enhanced mass- and heat transfer due to a very large surface to
volume ratio as well as regular flow profiles lead to higher yields
with increased selectivities. The mixing of substrates and reagents
can be performed under highly controlled conditions leading to
improved protocols. Liquid–liquid biphasic reactions are routinely
performed but microreactors can offer advantages by intense mix-
ing of immiscible liquids.7 We have already shown that ester
hydrolysis performed under liquid–liquid biphasic reaction condi-
tions can be accelerated in microreactors.8 In such multiphase
flow, mass transfer is accelerated by alternating immiscible fluid
packets benefiting from having both (i) a continually refreshing
interface between adjacent fluid packets, and (ii) a rapid vortex
flow within a fluid packet.9 One early study of the Heck reaction
under biphasic conditions was reported by Arai et al. using tolu-
ene/ethylene glycol as a biphasic solvent system.10 The best choice
of catalyst under these conditions was Pd(OAc)2. Keeping the cata-
lyst separated from the reactants and product phase is a typical
strategy used in biphasic catalysis giving the advantage of prod-
uct/catalyst separation and recycling. Such a strategy has been
adopted by Ryu et al. by dissolving the palladium catalyst in an
ionic liquid. This allowed Heck reactions with an easy continuous
recycling of the catalyst.11
Also, other research groups have investigated Heck reactions in
flow using supported palladium catalysts. Kirschning et al.12 used a
monolith containing nanoparticular palladium while Garcia-Ver-
dugo and Luis et al.13 investigated an imidazolium-functionalised
polystyrene monolith successfully for such cross-coupling reac-
tions. Palladium-containing monoliths were also used by Ley
et al. for Heck reactions carried out in superheated ethanol.14 See-
berger and co-workers used palladium on charcoal as a catalyst for
Heck reactions.15 Jensen and Buchwald demonstrated an accelera-
tion of such reactions when performed at elevated temperatures
and pressures facilitated by microreactors.16 A review on the use
of transition metal-catalysed Heck reactions using microwave
and microreactor technologies has appeared recently.17
Initially, the arylation of methyl acrylate 2a and styrene 2b with
iodobenzene 1a was performed using 10 mol % of a metal catalyst
with 20 mol % triphenylphosphine in dimethylformamide (DMF) in
the presence of triethylamine as a base to yield products 3a and 3b
as shown in Scheme 1.
The first microflow study we conducted on monophasic Heck
coupling was carried out under laminar flow conditions, screening
various metal catalysts in the reaction of iodobenzene and methyl
acrylate. The monophasic reactions were performed using a very
10 mol% metal catalyst
I
R
20 mol% PPh3
R
DMF, Et3N, 70°C
1a
2a: R = CO2Me
3a R = CO2Me
2b
: R = Ph
3b
R = Ph
* Corresponding authors. Fax: +44 29 2087 5921 (D.A.B.); fax: +44 29 2087 6968
(T.W.).
E-mail addresses: barrow@cf.ac.uk (D.A. Barrow), wirth@cf.ac.uk (T. Wirth).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.133

B. Ahmed-Omer et al. / Tetrahedron Letters 50 (2009) 3352–3355
3353
Table 1
Homogeneous Heck reaction: conventional flask versus laminar flow
10 mol% metal catalyst
I
CO 2Me
20 mol% PPh3
CO2Me
DMF, Et3N, 70 °C
1a
Entry
2a
3a
Metal catalyst
Flask reactiona
PTFE microtubingb
yield 3a (%)
yield 3a (%)
1
2
3
4
5
6
7
8
9
Pt(COD)Cl2
CoCl2
RuCl3
Ni(OAc)2
PdCl2
8
21
28
45
34
47
53
19
21
52
62
17
12
20
30
26
—
—
29
—
Pd(OAc)2
c
PdCl2
c
Pd(OAc)2
d
Pd(OAc)2
10
Pd(PPh3)4
a
Figure 1. Laminar and segmented flows.
Reaction conditions: metal catalyst (10 mol %), PPh3 (20 mol %), iodobenzene
(0.2 mmol), methyl acrylate (0.2 mmol), Et3N (0.2 mmol), in DMF, 70 °C (oil bath),
reaction time: 35 min.
b
Reaction conditions: metal catalyst (10 mol %), PPh3 (20 mol %), iodobenzene
Table 2
(1.0 mmol), methyl acrylate (1.0 mmol), Et3N (1.0 mmol), in DMF, 70 °C (oil bath),
Laminar versus segmented flow applied to Heck coupling of iodobenzene 1a with
residence time: 35 min under laminar flow conditions.
methyl acrylate 2a to form methyl cinnamate 3a or with styrene 2b to form stilbene
3b
c
1 mol % catalyst used.
Pd(OAc)2 (5 mol %), Et4NCl (1.0 mmol), iodobenzene (1.0 mmol), methyl acry-
d
Entry
Catalyst Pd(PPh3)4
(mol %)
Laminar flowa
yield (%)
Segmented flowa
yield (%)
late (1.0 mmol), K2CO3 (1.0 mmol), in DMF/ethylene glycol (4:1), 70 °C (oil bath),
residence/reaction time: 50 min.
1b
2b
3c
4c
5
10
5
3a: 36
3a: 53
3b: 38
3b: 43
3a: 65
3a: 76
3b: 57
3b: 59
simple experimental set-up. Two solutions were introduced into
the system via a syringe pump: (i) a solution of iodobenzene,
methyl acrylate and triethylamine in DMF; and (ii) a solution of
metal catalyst and PPh3 in DMF. The two solutions were mixed
in a T-inlet connected to PTFE microtubing (length: 2000 mm,
10
a
Reaction conditions: Pd(PPh3)4 (5 or 10 mol %), iodobenzene (1 mmol), methyl
acrylate or styrene (1 mmol), Et3N (1 mmol), in DMF, 70 °C (oil bath).
b
Residence time: 35 min.
Residence time: 45 min.
c
internal diameter: 500 lm, reactor volume: 393 ll), which was
immersed in an oil bath. The data in Table 1 demonstrate that
the performance of the monophasic coupling reaction using the
microflow system is better than that in a flask, and PdCl2 and
Pd(OAc)2 showed better performance than other catalysts, both
in flask and in microflow.
In addition, in some cases where heating was applied, the inert
phase such as decane homogenised with the reaction phase caus-
ing loss of segmentation resulting in the formation of laminar flow.
Segmentation by an inert gas presented intrinsic problems in the
control of the flow rate requiring different equipment. Perfluori-
nated solvents, such as perfluorodecalin, were found to be immis-
cible with DMF even at high temperatures (120 °C), hence it was
used as the segmentating phase. As shown in Table 2, significant
improvements in reaction yields of methyl cinnamate 1 and stil-
bene 2 were obtained as a result of introducing segmentation,
showing that high conversions were achievable with a relatively
low loading of catalyst. The temperature dependence of potential
partially miscible solvents has not been investigated. Also segment
sizes have not been varied in the experiments described here.
On the basis of these encouraging results obtained in the first
attempts to synthesise 3a and 3b, the study was extended to a vari-
ety of Heck coupling substrates, leading to the successful reaction
of substituted iodobenzenes and bromobenzenes with a variety of
alkenes as shown in Table 3 (entries 1–9). As expected, iodoben-
zene showed generally higher reactivity, whereas bromobenzene
required longer residence times or higher temperatures. Further
optimisation studies on the coupling between iodobenzene and
methyl acrylate showed that by decreasing the concentration of
iodobenzene from 0.2 M to 0.09 M and increasing the temperature
to 85 °C in the presence of 10 mol % of Pd(PPh3)4, the reaction rate
was increased remarkably allowing a shorter residence time of
approximately 1 min to produce methyl cinnamate 3a in 97% yield
(Table 3, entry 10). We then applied the segmented flow method to
another type of Heck coupling of alkenes using arene-diazonium
salts instead of aryl halides as shown in Table 4.19 Once the
However, on many occasions when using Pd catalysts, we
observed formation of a black particulate as a result of catalyst
decomposition. A reduction of metal catalyst loading decreased
the amount of particulate formed inside the microchannel, but at
the same time lowered the reaction yields significantly (Table 1,
entries 7 and 8). The ligand-free methodology employing Jeffery’s
conditions in Heck coupling18 uses a combination of a divalent pal-
ladium with a quaternary ammonium salt in the presence of an inor-
ganic base. The arylation of methyl acrylate was performed in the
microchannelunder Jeffery’s conditions usingtetraethylammonium
chloride in the presence of Pd(OAc)2 and potassium carbonate in a
DMF/ethylene glycol solvent system. A 5 mol % loading of Pd(OAc)2
resulted in slightly improved yields compared to that in the flask
(Table 1, entry 9), while 10 mol % again led to particulate formation.
Almost no particulate was formed when using Pd(PPh3)4 as catalyst
(Table 1, entry 10) which improved the yield to 62%.
A segmented flow technique was then applied to reactions
previously carried out under laminar flow conditions in order to
achieve further optimisation. We transformed the laminar flow
into segmented flow by introducing an immiscible inert liquid into
the laminar flow as shown in Figure 1. We aimed to exploit the
advantages of segmentation, that is, the generation of internal
circulation within segments leading to improved mixing compared
to laminar diffusion. Besides, having to be immiscible with the
reaction phase, the segmented phase must not interfere with, or
dissolve any of the reaction components, and must have a boiling
point compatible with the reaction conditions.

3354
B. Ahmed-Omer et al. / Tetrahedron Letters 50 (2009) 3352–3355
Table 3
Heck coupling of aryl halides to alkenes under segmented flow conditions
R2
Hal
10 mol% Pd(PPh3)4
DMF, Et3N
R2
R1
R1
1
2
3
Entry
R1
R2
Producta
Hal = Brb yield (%)
Hal = Ic yield (%)
1
2
3
4
5
6
7
8
H (1a)
H (1a)
H (1a)
H (1a)
CO2Me (2a)
Ph (2b)
3a20
3b21
3c22
3d23
3e24
3f22
3g22
3h25
3i24
3a
51
25
38
22
21
32
29
19
65
—
68
57
63
60
35
49
47
44
—
4-CF3C6H4 (2c)
4-FC6H4 (2d)
3-NO2C6H4 (2e)
4-CF3C6H4 (2c)
4-MeC6H4 (2f)
3-NO2C6H4 (2e)
Ph (2b)
H (1a)
Me (1b)
Me (1b)
Me (1b)
NO2 (1c)
H (1a)
9
10d
CO2Me (2a)
97
a
Reaction conditions: Pd(PPh3)4 (10 mol %), aryl halide (1 mmol), alkene (1 mmol), Et3N (1 mmol), in DMF, residence time: 40 min.
130 °C (oil bath).
70 °C (oil bath).
85 °C (oil bath), residence time: 1 min.
b
c
d
and uncontrolled explosions, making their use generally hazardous
in conventional flask chemistry especially on large scale. One of the
greatest advantages of microflow systems is the safe generation of
reactive hazardous intermediates in a continuous flow due to the
Table 4
Diazonium Heck coupling of aniline derivatives 4
10 mol% Pd(OAc)2
R2
NH2
4 eq. t-BuONO
R2
handling of only very small volumes within
environment.
a contained
R1
R1
AcOH, DMF
4
2
3
The microflow system set-up for the Heck diazonium reaction
was modified as shown in Figure 2 to allow the in situ diazotisation
prior to the Pd-catalysed coupling. The aniline derivative 4 was
converted into the diazonium intermediate by pumping a mixture
of t-butyl nitrite (t-BuONO) with excess of acetic acid and aniline at
low temperatures (0 °C) through Section 1. A solution of Pd(OAc)2
and the alkene is then introduced and the Heck reaction can take
place in Section 2 at room temperature. A variety of aniline deriv-
atives were reacted with several alkenes using 10 mol % of
Pd(OAc)2 successfully as shown in Table 4. Reasonable conversions
were initially obtained when a diluted solution of t-BuONO and a
standard solution of acetic acid in DMF were used. The reactivity
of the diazonium intermediate, largely influenced by the nature
of the aniline substrate, has a noticeable effect on the reaction
yields. The presence of electron-withdrawing substituents
activates the diazonium intermediate whereas electron-donating
Entry
R1
R2
Producta
Yield (%)
1
2
3
4
5
6
7
8
H (4a)
H (4a)
H (4a)
OMe (4b)
OMe (4b)
OMe (4b)
Cl (4c)
CO2Me (2a)
Ph (2b)
4-FC6H4 (2d)
CO2Me (2a)
Ph (2b)
3-NO2C6H4 (2e)
CO2Me (2a)
CO2Me (2a)
3a
3b
3d
54
66
72
27
33
18
62
90
3j25
3k25
3l26
3m29
3n27
I (4d)
a
Reaction conditions: Pd(OAc)2 (10 mol %), aniline derivative 4 (1 mmol), alkene
2 (1 mmol), t-BuONO (4 mmol), AcOH, DMF, 0–25 °C, residence time: 27 min.28
diazonium salt is formed in situ from an aniline derivative under
acidic conditions, decomposition follows with rapid elimination
of nitrogen gas. As a consequence, diazonium salts may give rapid
NH2
R2
R1
2
4
Segmenter
phase
Pd(OAc)2
R2
Section 2
Section 1
R1
3
Ambient
temperature
Cooling bath
t-BuONO +AcOH
Figure 2. Experimental set-up.

B. Ahmed-Omer et al. / Tetrahedron Letters 50 (2009) 3352–3355
3355
Table 5
7. Ahmed-Omer, B.; Wirth, T. In Microreactors in Organic Synthesis and Catalysis;
Wirth, T., Ed.; Wiley-VCH: Weinheim, 2008; pp 122–139.
Heck coupling of preformed diazonium salt 5 with alkenes 2
8. (a) Ahmed, B.; Barrow, D.; Wirth, T. Adv. Synth. Catal. 2006, 348, 1043–1048; (b)
Ahmed-Omer, B.; Barrow, D.; Wirth, T. Chem. Eng. J. 2008, 135S, S280–S283.
9. Harries, N.; Burns, J. R.; Barrow, D. A.; Ramshaw, C. J. Heat Mass Transfer 2003,
46, 3313–3322.
10. Bhanage, B. M.; Zhao, F.-G.; Shirai, M.; Arai, M. Tetrahedron Lett. 1998, 39, 9509–
9512.
N2+BF4
R
10 mol% Pd(OAc)2
R
AcOH, DMF
O2N
O2N
5
2
3
11. (a) Liu, S.; Fukuyama, T.; Sato, M.; Ryu, I. Synlett 2004, 1814–1816; (b) Liu, S.;
Fukuyama, T.; Ryu, I. Org. Process Res. Dev. 2004, 8, 477–481.
12. Solodenko, W.; Wen, H.; Leue, S.; Stuhlmann, F.; Sourkouni-Argirusi, G.; Jas, G.;
Schönfeld, H.; Kunz, U.; Kirschning, A. Eur. J. Org. Chem. 2004, 3601–3610.
13. Karbass, N.; Sans, V.; Garcia-Verdugo, E.; Burguete, M. I.; Luis, S. V. Chem.
Commun. 2006, 3095–3097.
14. Nikbin, N.; Ladlow, M.; Ley, S. V. Org. Process Res. Dev. 2007, 11, 458–462.
15. Snyder, D. A.; Noti, C.; Seeberger, P. H.; Schael, F.; Bieber, T.; Rimmel, G.;
Ehrfeld, W. Helv. Chim. Acta 2005, 88, 1–9.
Entry
R
Producta
Yield (%)
1
2
3
4
5
CO2Me (2a)
Ph (2b)
4-CF3C6H4 (2c)
3-NO2C6H4 (2e)
4-BrC6H4 (2g)
3o29
3i
64
42
57
49
61
3p30
3q31
3r32
a
Reaction conditions: Pd(OAc)2 (10 mol %), aniline derivative 4 (1 mmol), alkene
2 (1 mmol), t-BuONO (4 mmol), AcOH, DMF, 0–5 °C, residence time: 27 min.
16. Murphy, E. R.; Martinelli, J. R.; Zaborenko, N.; Buchwald, S. L.; Jensen, K. F.
Angew. Chem. Int. Ed. 2007, 46, 1734–1737.
17. Singh, B. K.; Kaval, N.; Tomar, S.; Van der Eycken, E.; Parmar, V. S. Org. Process
Res. Dev. 2008, 12, 468–474.
18. Jeffery, T. Tetrahedron 1996, 52, 10113–10130.
19. Roglans, A.; Pla-Quintana, A.; Moreno-Mañas, M. Chem. Rev. 2006, 106, 4622–
4643.
20. Zhou, P.; Li, Y.; Sun, P.; Zhou, J.; Bao, J. Chem. Commun. 2007, 1418–1420.
21. (a) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733–1738;
(b) Wang, J. X.; Wang, K.; Zhao, L.; Li, H.; Fu, Y.; Hu, Y. Adv. Synth. Catal. 2006,
348, 1262–1270.
22. (a) Mu, B.; Li, T.; Xu, W.; Zeng, G.; Liu, P.; Wu, Y. Tetrahedron 2007, 63, 11475–
11488; (b) Warner, P.; Sutherland, R. J. Org. Chem. 1992, 57, 6294–6300.
23. (a) Pews, R. G.; Ojha, N. D. J. Am. Chem. Soc. 1969, 91, 5769–5773; (b)
Djakovitch, L.; Heise, H.; Kohler, K. J. Organomet. Chem. 1999, 584, 16–26.
24. Cai, M.; Huang, Y.; Zhao, H.; Song, C. J. Organomet. Chem. 2003, 682, 20–25.
25. Grasa, G. A.; Singh, R.; Stevens, E. D.; Nolan, S. P. J. Organomet. Chem. 2003, 687,
269–279.
26. Anstead, G. M.; Katzenellenbogen, J. A. J. Phys. Chem. 1988, 92, 6249–6258.
27. Brunner, H.; de Courcy, N. L. C.; Genêt, J. P. Tetrahedron Lett. 1999, 40, 4815–
4818.
28. Representative experimental procedure: Stock solutions were prepared in
individual Schlenk tubes under inert atmosphere. In a typical experiment,
solutions were prepared as follows: (A) 0.1 m solution of aniline (93 mg, 1
mmol) in DMF (10 mL); (B) 0.005 m solution of Pd(OAc)2 (22.4 mg, 0.1 mmol)
in DMF (20 mL); (C) 0.2 m solution of alkene (1 mmol) in DMF (5 mL); (D) 0.8m
solution of t-BuONO (4 mmol) and AcOH (1.25 mL) in DMF (5 mL); and (E) pure
substituents make them unreactive, as reflected in the very low
yields given by substrates such as p-methoxyaniline 4b, in contrast
to the very good conversions achieved using substrates such as
p-iodoaniline 4d.
For comparison, we also performed a series of reactions using
commercially available p-nitrobenzenediazonium tetrafluorobo-
rate 5 to provide an alternative viable route with relatively high
product yields as shown in Table 5. By the direct use of an isolated
intermediate one could expect cleaner reactions and better yields.
However, only small improvements were seen meaning that the
in situ production of the diazonium compounds in the microchan-
nel worked rather well.
In conclusion, by utilising the large specific interfacial area
provided by the microreactor under segmented flow, the Heck reac-
tion of aryl halides and diazonium intermediates was found to be
more efficient than in parallel flow and under conventional (batch)
conditions in a flask. This demonstrates that even homogeneous
reactions can be enhanced by using the segmented flow technique.
hydrocarbon solvent (hexane, heptane, nonane or decane) used as
a
segmenting phase. Each solution was loaded individually into gas-tight glass
syringes which were then connected onto the microflow system (PTFE)
through a designated inlet using a T-connector. Tubing length 2920 mm
(section 1 150 mm, residence time 3.2 min) + (section 2 - 2770 mm, residence
Acknowledgements
We thank EPSRC for support of this work and the National Mass
Spectrometry Service Centre, Swansea, for mass spectrometric data.
time 23.7 min), internal diameter 500
lm, and system volume 573 ll. The
solutions were then delivered into the microchannel at the required flow rates,
in a continuous segmented flow manner using KD Scientific syringe pumps.
First the diazotisation of aniline was carried out in section 1 at 0 °C by pumping
solution (A) along with solutions (D) and (E), while in section 2 solutions (B)
and (C) were introduced then mixed with the diazotised flow from section 1 at
ambient temperature to carry out the Heck coupling. The reactions were run
for the appropriate total residence time of approximately 27 min. After
collecting the output of the reaction, the crude mixture was first washed with
water followed by 5% aq. sodium bicarbonate solution. After drying the
mixture with sodium sulfate, the solvent was removed under reduced
References and notes
1. (a) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320–2322; (b) Heck, R. F. Org.
React. 1982, 27, 345–390; (c) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000,
100, 3009–3066; (d) Knowles, J. P.; Withing, A. Org. Biomol. Chem. 2007, 5, 31–
44; (e)The Mizoroki-Heck Reaction; Oestreich, M., Ed.; Wiley: Chichester, 2009.
2. Masters, J. J.; Link, J. T.; Snyder, L. B.; Young, W. B.; Danishefsky, S. J. Angew.
Chem. Int. Ed. Engl. 1995, 34, 1723–1726.
3. Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 11028–11029.
4. Ziegler, F. E.; Chakraborty, U. R.; Weisenfeld, R. B. Tetrahedron 1981, 37, 4035–
4040.
5. Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2005, 61, 11771–11835.
6. (a) Microreactors in Organic Synthesis and Catalysis; Wirth, T., Ed.; Wiley-VCH:
Weinheim, 2008; (b) Yoshida, J.; Nagaki, A.; Yamada, T. Chem. Eur. J. 2008, 14,
7450–7459; (c) Watts, P.; Wiles, C. Org. Biomol. Chem. 2007, 5, 727–732; (d)
Ahmed-Omer, B.; Brandt, J. C.; Wirth, T. Org. Biomol. Chem. 2007, 5, 733–740;
(e) Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T.
Chem. Rev. 2007, 107, 2300–2318.
pressure. Finally, the product was isolated by preparative TLC
chromatography on silica gel using an appropriate solvent system.
29. Zhang, Z.; Wang, Z. J. Org. Chem. 2006, 71, 7485–7487.
/ column
30. Hanna, P. E.; Gammans, R. E.; Sehon, R. D.; Lee, M. K. J. Med. Chem. 1980, 23,
1038–1044.
31. Ling, C.; Minato, M.; Lahti, P. M.; Willigen, H. V. J. Am. Chem. Soc. 1992, 114,
9959–9969.
32. Choudary, B. M.; Kantam, M. L.; Reddy, N. M.; Gupta, N. M. Catal. Lett. 2002, 82,
79–83.