Scale-up of microwave-promoted reactions to the multigram level using a sealed-vessel microwave apparatus

Article abstract of DOI:10.1021/op8001239

A range of synthetic transformations have been scaled up successfully using a sealed-vessel multimode microwave unit. These include metal-catalyzed couplings, synthesis of heterocycles, reactions under an atmosphere of reactive gas and two-step one-pot procedures. Also, observations have been made along the way that are of use to chemists addressing scale-up of microwave-promoted reactions.

Full text of DOI:10.1021/op8001239

Organic Process Research & Development 2008, 12, 1078–1088
Scale-Up of Microwave-Promoted Reactions to the Multigram Level Using a
Sealed-Vessel Microwave Apparatus
Matthew D. Bowman,† Jason R. Schmink,† Cynthia M. McGowan,‡ Chad M. Kormos,† and Nicholas E. Leadbeater*,†
Department of Chemistry, UniVersity of Connecticut, Unit 3060, 55 North EagleVille Road, Storrs, Connecticut 06269-3060, U.S.A.,
and Department of Chemistry, Merrimack College, 315 Turnpike Street, North AndoVer, Massachusetts 01845, U.S.A.
Abstract:
centimetres into a reaction mixture, thus limiting the size of
the vessel that can be used. However, it is possible to use batch
processing to move into the multigram scale using one large
vessel or parallel batch reactors.8,9 Focusing on single-vessel
operation, reactions can be performed open to the atmosphere
or else in a sealed pot. Using an open reaction vessel has the
advantage of operating at atmospheric pressure.10 This means
that it is possible to work in vessels up to 5 L in capacity without
needing special safety precautions. However, many reactions
benefit from the elevated temperatures and pressures possible
in a sealed vessel. Also, much of the small-scale microwave-
promoted chemistry reported in the literature has been per-
formed using sealed vessels. Chemists often would like to be
able to take conditions optimized on the small scale to a larger
scale without the need for reoptimization. In a study recently
undertaken in our laboratory we have probed the scalability of
reactions performed in sealed vessels as well as developing
scale-up approaches to key organic transformations. We have
found that in many cases reactions performed on a small scale
can be directly scaled without the need for reoptimization of
reaction conditions. However, there are some instances where
we, like others,11 have found that modifications need to be made.
In addition, sealed-vessel processing opens up avenues for
A range of synthetic transformations have been scaled up suc-
cessfully using a sealed-vessel multimode microwave unit. These
include metal-catalyzed couplings, synthesis of heterocycles, reac-
tions under an atmosphere of reactive gas and two-step one-pot
procedures. Also, observations have been made along the way that
are of use to chemists addressing scale-up of microwave-promoted
reactions.
Introduction
Microwave heating is proving a valuable tool for synthetic
chemists. It is often possible to perform reactions faster and
yields can be higher.1 To this end within industrial settings, for
small-scale synthesis microwave heating is often the method
of choice. It is possible to prepare a few grams of material using
sealed glass tubes up to a working volume of approximately
50 mL or open round-bottom flasks to a volume of up to 125
mL. However, it is going to be necessary to address issues of
scale if the technique is going to continue to gain acceptance
and become practical at the process level. Possible approaches
to scale-up include both batch and continuous-flow processing.2
Recent work in our laboratory and others has been focused at
exploring both possibilities.3-5 While continuous-flow has
advantages in terms of throughput and automation, issues arise
when processing heterogeneous reaction mixtures.6,7 When
using a batch approach, issues of microwave penetration into
the sample become important. Microwaves penetrate only a few
(7) For examples of continuous-flow processing see: (a) Moseley, J. D.;
Lawton, S. J. Chem. Today 2007, 25, 16–19. (b) Khadilkar, B. M.;
Madyar, V. R. Org. Process Res. DeV. 2001, 5, 452–455. (c) Kazba,
K.; Chapados, B. R.; Gestwicki, J. E.; McGrath, J. L. J. Org. Chem.
2000, 65, 1210–1214. (d) Esveld, E.; Chemat, F. van Haveren.
J. Chem. Eng. Technol. 2000, 23, 429–435. (e) Marquie´, J.; Salmoria,
G.; Poux, M.; Laporterie, A.; Dubac, J.; Roques, N. Ind. Eng. Chem.
Res. 2001, 40, 4485–4490.
* Corresponding author. E-mail: nicholas.leadbeater@uconn.edu.
† University of Connecticut.
‡ Merrimack College.
(8) For examples of batch processing using one vessel see: (a) Raner,
K. D.; Strauss, C. R.; Trainor, R. W.; Thorn, J. S. J. Org. Chem. 1995,
60, 2456–2460. (b) Shackelford, S. A.; Anderson, M. B.; Christie,
L. C.; Goetzen, T.; Guzman, M. C.; Hananel, M. A.; Kornreich, W. D.;
Li, H.; Pathak, V. P.; Rabinovich, A. K.; Rajapakse, R. J.; Truesdale,
L. K.; Tsank, S. M.; Vazir, H. N. J. Org. Chem. 2003, 68, 267–275.
(c) Khadilkar, B. M.; Rebeiro, G. L. Org. Process Res. DeV. 2002, 6,
826–828. (d) Fraga-Dubreuil, J.; Famelart, M. H.; Bazureau, J. P. Org.
Process Res. DeV. 2002, 6, 374–378. (e) Cleophax, J.; Liagre, M.;
Loupy, A.; Petit, A. Org. Process Res. DeV. 2000, 4, 498–504. (f)
Perio, B.; Dozias, M.-J.; Hamelin, J. Org. Process Res. DeV. 1998, 2,
428–430.
(1) A number of books on microwave-promoted synthesis have been
published recently. For examples see: (a) Loupy, A. Ed. MicrowaVes
in Organic Synthesis, 2nd ed.; Wiley-VCH: Weinheim, 2006. (b)
Kappe, C. O.; Stadler, A. MicrowaVes in Organic and Medicinal
Chemistry; Wiley-VCH: Weinheim, 2005. (c) Lidstro¨m, P., Tierney,
J. P., Eds.; MicrowaVe-Assisted Organic Synthesis; Blackwell: Oxford,
2005.
(2) For reviews see: (a) Lehmann, H. In New AVenues to Efficient Chemical
Synthesis; Seeberger, P. H., Blume, T.,. Eds.; Springer-Verlag: Berlin,
2007. (b) Roberts, B. A.; Strauss, C. R. Acc. Chem. Res. 2005, 38,
653–661.
(3) For a recent report from our laboratories see: Bowman, M. D.;
Holcomb, J. L.; Kormos, C. M.; Leadbeater, N. E.; Williams, V. A.
Org. Process. Res. DeV. 2008, 12, 41–57.
(9) For examples of batch processing using multiple vessels see: (a)
Stadler, A.; Yousefi, B. H.; Dallinger, D.; Walla, P.; Van der Eycken,
E.; Kaval, N.; Kappe, C. O. Org. Process Res. DeV. 2003, 7, 707–
716. (b) Stadler, A.; Pichler, S.; Horeis, G.; Kappe, C. O. Tetrahedron
2002, 58, 3177–3183. (c) Alca´zar, J.; Diels, G.; Schoentjes, B. QSAR
Comb. Sci 2004, 23, 906–932.
(4) For a recent comparison of apparatus for scale-up, see: Moseley, J. D.;
Lenden, P.;.; Lockwood, M.; Ruda, K.; Sherlock, J.-P.;.; Thomson,
A. D.; Gilday, J. P. Org. Process Res. DeV. 2008, 12, 30–40.
(5) For an evaluation of microwave reactors for use in a kilolab see:
Lehmann, H.; LaVecchia, L. J. Assoc. Lab. Autom. 2005, 10, 412–
417.
(10) For a recent example see: Barnard, T. M.; Vanier, G.; Collins, M. J.
Org. Process Res. DeV. 2006, 10, 1233–1237.
(11) For an example see: Pawluczyk, J. M.; McClain, R. T.; Denicola, C.,
Jr.; Rudd, D. J.; Lindsley, C. W. Tetrahedron Lett. 2007, 48, 1497–
1501.
(6) For a recent review see: Kappe, C. O.; Glasnov, T. N. Macromol.
Rapid Commun. 2007, 28, 395–410.
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10.1021/op8001239 CCC: $40.75
2008 American Chemical Society
Published on Web 09/19/2008

Figure 1. Biotage Advancer.
performing reactions under an atmosphere of reactive gas. We
present our results from a representative range of reactions in
this article.
bromides can be effectively coupled with phenylboronic acid,
reactions taking approximately 20 min to reach completion.14
Aryl chloride substrates are unreactive in the open-vessel
approach but can be coupled using small sealed vessels using
Pd/C as the catalyst, water as the solvent, and tetrabutylam-
monium bromide (TBAB) as a phase-transfer catalyst.15 The
reaction requires the use of simultaneous cooling in conjunction
with microwave heating to prolong the lifetime of the aryl
chloride substrate in the hot basic aqueous medium. To initiate
our current scale-up study using the 350-mL capacity sealed
vessel in the Advancer we chose to focus on the coupling of
4-bromoanisole with phenylboronic acid (Scheme 1). We
decided first to reoptimize the reaction on the 5 mmol scale
with the objective of finding the minimum palladium loading
that could be used. Using sodium hydroxide as base and water/
ethanol as solvent we were able to obtain a 78% conversion to
the desired product in 10 min at 150 °C at a homogeneous
palladium catalyst concentration of 100 ppb (0.0004 mol % Pd).
Workup of the reaction mixture led to a 77% isolated yield of
the biaryl, thus showing that, in the Suzuki reaction, conversions
and yields are almost identical. We then performed the coupling
of 4-bromoanisole with phenylboronic acid on the 50 mmol
scale in the Advancer. We programmed the unit to follow
exactly the same heating profile as recorded for our 5 mmol
studies in order to see if the conditions were directly scalable.
We obtained a 90% yield of the product, the higher recovery
being attributed to the larger scale of the reaction and certainly
showing that the reaction was directly scalable. We then turned
attention to the coupling of 4-chloroanisole with phenylboronic
acid, again on the 50 mmol scale and using Pd/C as the catalyst
(Scheme 1). Using the Advancer, we did not have the capability
to perform the reaction using simultaneous cooling but found
that this was not necessary when working on scale. We used
exactly the same conditions as for our previously reported
protocol (with the exception of not using cooling), thus requiring
heating the reaction mixture to 120 °C and holding at this
Results and Discussion
Microwave Apparatus Used. For optimization of reactions
on a small scale we used a monomode microwave unit (Biotage
Initator). For our scale-up studies we used the Biotage Advancer
(Figure 1).4,12 Reactions are performed in a 350-mL capacity
Teflon vessel, temperature being monitored using a fiber-optic
probe inserted directly into the mixture by means of a glass
thermowell. The unit can operate at temperatures up to 250 °C
and pressures up to 20 bar. The contents of the vessel can be
stirred by means of a mechanical paddle stirrer. The lid of the
reactor also comprises an inlet for gas and three extra available
entry/exit ports. Product mixtures can be cooled at the end of
a run by using a flash cooling option, the contents of the Teflon
reaction vessel being ejected into a stainless steel holding tank.
Using this, the temperature of the mixture can be reduced
rapidly to the boiling point of the solvent used. This is
advantageous since it obviates the long cooling time inherent
in other microwave units.
Suzuki-Miyaura Coupling Reaction. A reaction we have
focused some considerable attention on previously is the
Suzuki-Miyaura coupling.13 We find that it is possible to
perform the reaction using ppm levels of palladium salts in a
water/ethanol solvent mixture. Reactions are complete within
5 min heating at 150 °C. We have scaled up the reaction using
an open-vessel batch approach and found that a range of aryl
(12) For previous reports using this unit see: (a) Lehmann, F.; Pilotti, Å.;
Luthman, K. Mol. DiVersity 2003, 7, 145–152. (b) Ekstro¨m, J.;
Wettergren, J.; Adolfsson, H. AdV. Synth. Catal. 2007, 349, 1609–
1613. (c) Carlsson, A.-C.; Jam, F.; Tullberg, M.; Pilotti, Å.; Toannidis,
P.; Luthman, K.; Grøtli, M. Tetrahedron Lett. 2006, 47, 5199–5201.
(d) Hoogenboom, R.; Paulus, R. M.; Pilotti, Å.; Schubert, U.
Macromol. Rapid Commun. 2006, 27, 1556–1560. (e) Andappan,
M. M. S.; Nilsson, P.; von Schenck, H.; Larhed, M. J. Org. Chem.
2004, 69, 5212–5218.
(13) For a review of the Suzuki-Miyaura reaction using water as a solvent
in conjunction with microwave heating see: Leadbeater, N. E. Chem.
Commun. 2005, 2881–2902.
(14) Leadbeater, N. E.; Williams, V. A.; Barnard, T. M.; Collins, M. J.
Org. Process Res. DeV. 2006, 10, 833–837.
(15) Arvela, R. K.; Leadbeater, N. E. Org. Lett. 2005, 7, 2101–2104.
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Scheme 1. Microwave-promoted Suzuki-Miyaura couplings on the 50 mmol scale
Scheme 2. Heck coupling of 4-bromoanisole with methyl acrylate
temperature for 10 min. We obtained an 87% yield of
4-methoxybiphenyl and also recovered a small quantity (8%)
of unreacted 4-chloroanisole showing that the competitive side
reactions of the aryl chloride starting material were not as
prevalent on the larger scale.
We completed our focus on the Suzuki-Miyaura reaction
by attempting the coupling of 2-bromobenzonitrile and p-
tolylboronic acid (Scheme 1) since this is more challenging,
and also the product formed is the central motif of the
hypertension drugs Atacand (Astra-Zeneca), Cozaar (Merck),
and Diovan (Novartis).16 Working on the 50 mmol scale, we
performed the reaction in triplicate using sodium carbonate as
the base, water/ethanol as the solvent, and a homogeneous
palladium catalyst loading of 0.01 mol % and obtained an
average yield of 96.6% with a standard deviation of 1.8%
showing the reproducibility of the protocol.
catalyst. On the 1 mmol scale, it is possible to perform the
reaction in 5-20 min at 170 °C using 1-10 ppm Pd catalyst
loadings; the exact conditions being dependent on the substrates
used.17 However, unlike our analogous Suzuki-Miyaura cou-
pling procedure, the low-catalyst loading Heck coupling is not
amenable to scale-up using open-vessel conditions, the elevated
temperature obtained under sealed-vessel conditions being
required. We have used an automated stop-flow approach to
address scale-up of the reaction18 and have also used the
Advancer unit previously for scaling this to the 100 mmol level.3
On the basis of our smaller-scale protocol, we used 1:2
stoichiometric ratio of aryl bromide (0.1 mol) to methyl acrylate
(0.2 mmol), 1 equiv of tetrabutylammonium bromide as phase-
transfer agent, 3.7 equiv of potassium carbonate as base, a
palladium loading of 0.002 mol % and water as the solvent.
We obtained a quantitative conversion to 4′-methoxycinnamic
acid and an isolated yield of 93% after 15 min at 170 °C. In
our current study we wanted to revisit this reaction, looking
particularly at the effects of decreasing the palladium loading
since we knew that the Heck coupling was particularly sensitive
to changes in catalyst concentration (Scheme 2). Working on
the 5 mmol scale in a sealed glass tube using the monomode
microwave unit we observed no decrease in product yield when
reducing the catalyst loading from 0.002 mol % to 0.001 mol
%, an 82% isolated yield being obtained in each case. However,
Heck coupling. Having scaled the Suzuki-Miyaura reaction
successfully, we turned our attention to the Heck coupling of
4-bromoanisole and methyl acrylate. Again we had previously
developed conditions for performing the reaction using water
as a solvent and low concentrations of ligandless palladium
(16) As an example, for synthetic approaches to Cozaar see: (a) Larsen,
R. D.; King, A. O.; Chen, C. Y.; Corley, E. G.; Foster, B. S.; Roberts,
F. E.; Yang, C.; Lieberman, D. R.; Reamer, R. A.; Tschaen, D. M.;
Verhoeven, T. R.; Reider, P. J.; Young, S. L.; Rossano, L. T.; Brookes,
A. S.; Meloni, D.; Moore, J. R.; Amett, J. F. J. Org. Chem. 1994, 59,
6391–6394. (b) Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.;
Johnson, A. L.; Pierce, M. E.; Price, W. A.; Santella, J. B., III; Wells,
G. J.; Wexler, R. R.; Wong, P. C.; Yoo, S.-E.; Timmermanns,
P. B. M. W. M. J. Med. Chem. 1991, 34, 2525–2547.
(17) Arvela, R. K.; Leadbeater, N. E. J. Org. Chem. 2005, 70, 1786–1790.
(18) Arvela, R. K.; Leadbeater, N. E.; Collins, M. J. Tetrahedron 2005,
61, 9349–9355.
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Scheme 3. Synthesis of an N-aryl functionalized ꢀ-amino ester by an aza-Michael addition reaction
Scheme 4. Synthesis of 3-acetylcoumarin
when we repeated the reaction in the Advancer at the 50 mmol
scale, we observed only a 12% product conversion. We repeated
the reaction a number of times to confirm that indeed it was
not directly scalable. During the course of these reactions we
began to notice a slight grey coloration on the walls of the
previously white Teflon reaction vessel. This led us to believe
that a reason for the poor conversions we obtained were due to
the fact that the Teflon is slightly permeable to the reaction
of phenols with R-keto esters), Perkin reaction (aldol condensa-
mixture and adsorbs small quantities of the palladium in
solution. Although this is not critical when performing the
reaction at higher palladium concentrations, when we were
running the reaction at the lower limit of catalyst concentrations,
this adsorption of small quantities of metal had the result of
impeding the coupling, thus resulting in poor yields. We believe
it is necessary to pay some considerable attention to catalyst
loading when moving from a sealed glass vessel in a momo-
mode microwave unit to a vessel made from Teflon or other
such material such as HDPE or PEEK when the reaction is
highly dependent on catalyst concentration.
Synthesis of an N-Aryl Functionalized ꢀ-Amino Ester.
We have recently reported the rapid, simple, microwave-
promoted synthesis of N-aryl functionalized ꢀ-amino esters
using a Michael addition protocol.19 Reactions are performed
using anilines and methyl acrylate as substrates and are
catalyzed by acetic acid. They are run solvent-free at 200 °C
for 20 min. Significant pressure is generated during the course
of the reaction due to the volatility of the methyl acrylate. The
chemistry is also highly temperature dependent. Insufficient
heating leads to very poor yields, and too much heating leads
to side-product formation and decomposition. We believed that
the flash cooling possible with the Advancer would be beneficial
when scaling up the reaction since the product mixture can be
brought from 200 °C down to ambient temperature rapidly, thus
preventing over-reaction and formation of byproducts. The fact
that we were able to monitor pressure accurately during the
course of the reaction would also be beneficial. Using aniline
and methyl acrylate as reagents and performing the reaction
on the 1.5 mol scale, we obtained a 76% conversion to the
desired N-aryl functionalized ꢀ-amino ester product (Scheme
3). This is comparable with that obtained both on the small
scale and also in our previous scale-up approach using multiple
sealed vessels.3
tion of aromatic aldehydes and acid anhydrides), and Knoev-
enagel condensation (base-catalyzed reaction of an aldehyde
or ketone with a dicarbonyl compound).20 Microwave heating
has been used as a tool for the synthesis of coumarins.21 As
our model reaction, we chose the reaction of salicylaldehyde
with ethylacetoacetate to yield 3-acetylcoumarin since we had
studied it previously using in situ reaction monitoring. By
interfacing a Raman spectrometer with one of our monomode
microwave units it is possible to monitor reactions in real
time.22-24 This makes reaction optimization of reaction param-
eters possible on the small scale. We wanted to see if we could
take a reaction, optimize the reaction conditions on the 1 mmol
scale, and then directly scale it. This would make for rapid
workflow. Using a 1 M ethyl acetate solution of salicylaldehyde
and ethyl acetoacetate and 8 mol % piperidine as a catalyst
and performing the reaction at 130 °C, our qualitative in situ
monitoring studies of this reaction showed that it took ap-
proximately 8 min to reach completion.25 Using these reaction
parameters we performed the reaction on the 0.3 mol scale in
the Advancer. A 71% isolated yield of 3-acetylcoumarin was
obtained, this being comparable with the small-scale runs.
Synthesis of Allyl Phenyl Ether. To investigate the effects
of heterogeneity on product yields we turned attention to the
synthesis of allyl phenyl ether using a Williamson etherification
(20) For an overview see: Hepworth, J. D.; Gabbut, C. D.; Heron, B. M.
In ComprehensiVe Heterocyclic Chemistry II Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., McKillop, A., Eds.; Pergamon: Oxford, 1996;
Vol. 5, Chapter 8.
(21) (a) Rong, L. C.; Li, X. Y.; Shi, D. Q.; Tu, S. J.; Zhuang, Q. Y. Synth.
Commun. 2007, 37, 183–189. (b) Rajitha, B.; Kumar, V. N.;
Someshwar, P.; Madhav, J. V.; Reddy, P. N.; Reddy, Y. T. ARKIVOC
2006, 23–27. (c) Al-Zaydi, K. M. Molecules 2003, 8, 541–555. (d)
Frere, S.; Thiery, V.; Besson, T. Tetrahedron Lett. 2001, 42, 2791–
2794. (e) de la Hoz, A.; Moreno, A.; Vazquez, E. Synlett 1999, 608–
610. (f) Bogdal, D. J. Chem. Res. 1998, 468–469.
Synthesis of 3-Acetylcoumarin and the Use of in Situ
Raman Spectroscopy To Model and Then Scale-Up a
Reaction. Coumarins can be prepared using a number of
synthetic routes including the Pechmann condensation (reaction
(22) Leadbeater, N. E.; Smith, R. J. Org. Lett. 2006, 8, 4588–4591.
(23) Leadbeater, N. E.; Smith, R. J.; Barnard, T. M. Org. Biomol. Chem.
2007, 5, 822–825.
(24) Leadbeater, N. E.; Smith, R. J. Org. Biomol. Chem. 2007, 5, 2770–
2774.
(19) Amore, K. M.; Leadbeater, N. E.; Miller, T. A.; Schmink, J. R.
Tetrahedron Lett. 2006, 47, 8583–8586.
(25) Leadbeater, N. E.; Schmink, J. R. Nat. Protoc. 2008, 3, 1–7.
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Scheme 5. Synthesis of allyl phenyl ether
Scheme 7. Claisen rearrangement of allyl phenyl ether
Scheme 6. Diels-Alder reaction between isoprene and
maleic anhydride
desired temperature of 155 °C. After 5 min at 155 °C and then
cooling to room temperature, the product crystallized out of
solution, and we obtained a 96% yield. We then moved to the
Advancer, and performing the reaction on the 0.1 mol level
using conditions identical to those of our smaller-scale experi-
ment, we obtained a 92% yield of the desired product.
Claisen Rearrangement. To test further the heating capa-
bility of the Advancer as well as working at the temperature
limit of the unit we decided to study the Claisen rearrangement
of the allyl phenyl ether prepared previously (Scheme 7). There
is literature precedent for the use of microwave heating in
Claisen rearrangements. Reactions are generally performed
using a polar solvent or else on a solid support and require
heating to temperatures in the range of 190-250 °C.30 We
wanted to perform the reaction solvent-free. The motivation
behind this was that we knew allyl vinyl ether was not
particularly microwave absorbent and would require substantial
energy input to reach the elevated temperatures required to effect
the rearrangement. This would therefore give us an insight into
the heating capability of the unit. We initially performed the
reaction using an analogous substrate (allyl p-tolyl ether) in a
monomode microwave unit. Since the temperature ceiling of
the unit used was 250 °C, we set the reaction to heat to 247
°C. The target temperature was reached, and after holding at
this temperature for 15 min, product was obtained. Moving to
the Advancer, we attempted to heat allyl phenyl ether to 245
°C, but the maximum temperature reached was 145 °C. Looking
for a reason behind the difference in heating between the small
microwave unit and the Advancer, our attention focused on the
heating cross section as well as the reaction vessels used. With
the monomode microwave unit, the power density is signifi-
cantly higher than in the multimode Advancer. This certainly
plays a role in the difference in heating characteristics. The
small-scale experiment was performed in a sealed glass tube,
whereas the larger run was performed using a Teflon vessel.
Borosilicate glass tubes contain small quantities of salt impuri-
ties which can lead to indirect heating of nonpolar reaction
mixtures. Teflon, on the other hand, does not contain such
impurities. Thus, the vessel material may also have had an effect
on the heating profile of the reaction mixture. In order to reach
the temperature required for the Claisen rearrangement we
repeated the reaction but doped the reaction mixture with
tetrabutylammonium bromide (TBAB), this being a highly
microwave-absorbent material. We28 and others31 have used a
similar procedure before for heating nonpolar reaction mixtures
using microwave irradiation. We performed the reaction using
reaction (Scheme 5).26 We used allyl bromide and phenol as
substrates, potassium carbonate as base, and acetone as the
solvent. This was a case of a reaction involving a solid
component (K2CO3), and thus effective stirring was going to
be important.27 Working on the 2 mmol scale we had already
screened a series of reaction conditions for similar etherification
reactions and found that using 2 equiv of potassium carbonate,
heating the mixture to 120 °C, and holding at this temperature
for 20 min was optimal.28 Moving to the Advancer, we
performed the etherification of phenol with allyl bromide on
the 0.2 mol level and used the same reaction conditions.
Efficient agitation was possible using the paddle stirrer. At the
end of the reaction we tried using the flash cooling method,
but due to the quantity of solid material in the mixture, it did
not prove efficient due to clogging of the exit line. A similar
problem was encountered previously by Pawluczyk and co-
workers11 in their preparation of supported reagents. We did
however obtain a 72% isolated yield of the ether product. We
repeated the reaction, reducing the quantity of potassium
carbonate to 1.1 equiv and also using passive cooling which,
although taking longer (10 min), allowed us to recover all of
the product easily. An 89% yield of the desired product was
obtained.
Diels-Alder Reaction. To test the heating capability of the
Advancer and also in preparation for a later experiment we
studied the Diels-Alder reaction between isoprene and maleic
anhydride in toluene (Scheme 6). Microwave heating has been
used in Diels-Alder reactions before.29 In our case neither the
reagents nor the solvent is particularly microwave absorbent.
In addition isoprene is highly volatile (bp 34 °C). We first
performed the reaction on a 5 mmol scale in the monomode
microwave unit. It was possible to heat the mixture to the
(26) For other reports on microwave-promoted ether formation, see: (a)
Yadav, G. D.; Desai, N. M. Catal. Commun. 2006, 7, 325–330. (b)
Park, K. K.; Jeong, J. S. Tetrahedron 2005, 61, 545–553. (c) Lloung,
M.; Loupy, A.; Marque, S.; Petit, A. Heterocycles 2004, 63, 297–
308.
(27) For a report on the importance of agitation in microwave-promoted
reactions see: Moseley, J. D.; Lenden, P.; Thomson, A. D.; Gilday,
J. P. Tetrahedron Lett. 2007, 48, 6084–6087.
(28) Leadbeater, N. E.; Schmink, J. Tetrahedron 2007, 63, 6764–6773.
(29) (a) Majetich, G.; Hicks, R. Radiat. Phys. Chem. 1995, 45, 567–579.
(b) An, J. Y.; Bagnell, L.; Cablewski, T.; Strauss, C. R.; Trainor, R. W.
J. Org. Chem. 1997, 62, 2505–2511. (c) Schobert, R.; Gordon, G. J.;
Mullen, G.; Stehle, R. Tetrahedron Lett. 2004, 45, 1121–1124. (d)
Davis, C. J.; Hurst, T. E.; Jacob, A. M.; Moody, C. J. J. Org. Chem.
2005, 70, 4414–4422.
(30) Kotha, S.; Mandal, K.; Deb, A. C.; Banerjee, S. Tetrahedron Lett.
2004, 45, 9603–9605.
(31) (a) Ley, S. V.; Leach, A. G.; Storer, R. I. J. Chem. Soc., Perkin Trans.
1 2001, 358–361. (b) Van der Eycken, E.; Appukkuttan, P.; De
Borggraeve, W.; Dehaen, W.; Dallinger, D.; Kappe, C. O. J. Org.
Chem. 2002, 67, 7904–7907. (c) Kremsner, J. M.; Kappe, C. O. J.
Org. Chem. 2006, 71, 4651–4658.
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Scheme 8. Grandberg synthesis of 2-methyltryptamine
different quantities of TBAB and found that 11 mol % was
required in order to be able to heat the reaction mixture to the
target temperature of 245 °C. Holding at this temperature for
30 min allowed us to obtain an 83% conversion to the desired
rearranged product. This was accompanied with a 17% decom-
position of the allyl phenyl ether to phenol.
performing the synthesis as part of our current study. We wanted
to determine whether the yield could be improved by using
microwave heating while at the same time take advantage of
the impressive safety features of the Advancer unit in the case
of an uncontrollable exothermic incident.
We first performed the reaction on a small scale (5 mmol),
using a 1:1.4 stoichiometric ratio of phenylhydrazine to chlo-
roketone and ethanol as solvent.34 The chloroketone was added
slowly to a tube containing phenylhydrazine in ethanol as
solvent. The resultant mixture was then sealed and placed into
the microwave cavity and the apparatus programmed to heat it
to 150 °C. However, once a temperature of 75 °C was reached,
the onset of an exotherm was observed, and the heating was
stopped. Reports have appeared in the literature suggesting that
microwave heating can be used for initiating exothermic
reactions and then the power turned off, the temperature rising
over the period of a few minutes and the reaction reaching
completion without the need for significant energy input.35 In
our mind, this method is highly undesirable when performing
a reaction on scale. It is far better to use a slow, controlled
heating protocol where the reaction is in complete control during
its entirety. However, we went back and attempted the 2-me-
thyltryptamine synthesis using just the first heating stage (i.e.,
heating to 75 °C then stopping). No product was obtained,
showing that either elevated temperature or extended reaction
time was going to be necessary. We performed the reaction a
third time, heating to 75 °C and holding at this temperature for
10 min before continuing to ramp to 150 °C (using a maximum
microwave power of 50 W) and holding for 15 min. Using this
two-step protocol it was possible to heat the reaction mixture
controllably, and upon workup we obtained an 81% isolated
product yield.
The 5-chloropentan-2-one purchased for use in our studies
was of technical grade (85-90%). Purification of this proved
to be a lengthy process so we wanted to determine whether the
material could be used as-purchased without compromising the
reaction (taking into account the impurity level in stoichiometry
calculations). We found this was indeed the case, and so we
used the crude material in all further experiments. A similar
observation was made by the Novartis team in their conven-
tional synthetic approach.
We next scaled to the limit possible using the monomode
microwave unit which was 15 mmol. The reaction was
performed at a phenylhydrazine concentration of 1.25 M in
ethanol. Using the same two-stage heating program we obtained
Synthesis of 2-Methyltryptamine. LBH589, a histone
deacetylase (HDAC) inhibitor developed by Novartis, is cur-
rently being investigated in phase II clinical trials in cutaneous
T-cell lymphoma, chronic myeloid leukemia, and multiple
myeloma. HDAC inhibitors have been shown to have multiple
effects in tumor cell lines: decreased oncoprotein expression,
decreased angiogenesis, induction of apoptosis, induction of cell-
cycle arrest, and decreased tumor cell motility and invasion.32
Of importance to the synthesis of LBH589 is the availability
of the key starting material, 2-methyltryptamine. Issues with
the initial medicinal chemistry routes to 2-methyltryptamine
include poor product purity or the need for expensive starting
materials or reagents such as nitromethane or LiAlH4 which,
on a larger scale, become serious concerns. Recently a team
from Novartis have reported the optimization and scale-up of
the Grandberg synthesis of 2-methyltryptamine, which in
essence is a modified Fisher indole synthesis (Scheme 8).33 The
chemistry starts with the formation of the hydrazone between
the phenylhydrazine and the 5-chloropentan-2-one. After a
proton shift and ring formation, a series of rearrangements takes
place to afford a tricyclic intermediate which, after loss of a
proton, yields 2-methyltryptamine. Prior to the scale-up of the
reaction, the team performed a series of experiments in order
to optimize the stoichiometry of the phenylhydrazine and
ketone. Yields varied from 28-58% and purities from 17 to
>99.9%. The stoichiometry chosen for scaling was 1:1, and
working at the 20 kg level, a 47% yield was obtained and the
purity was in excess of 99%. The addition of the 5-chloropentan-
2-one to phenylhydrazine was highly exothermic, and during
the course of the reaction (performed in refluxing ethanol) an
additional exothermic response was observed. On the basis of
observations from the smaller-scale runs, we saw that these
exotherms, if not controlled, led to the formation of impurities
that were difficult to remove. The fact that the product yield
was only moderate together with the observation of exotherms
during the course of the reaction attracted our interest in
(32) (a) Marks, P. A.; Dokmanovic, M. Expert Opin. InVest. Drugs 2005,
14, 1497–1511. (b) Monneret, C. Anticancer Drugs 2007, 18, 363–
370. (c) Richon, V. M.; Sandhoff, T. W.; Rifkind, R. A.; Marks, P. A.
Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 10014–10019. (d) Brehm, A.;
Miska, E. A.; McCance, D. J.; Reid, J. L.; Bannister, A. J.; Kouzarides,
T. Nature 1998, 391, 597–601. (e) Matsumura, T.; Suzuki, T.; Aizawa,
K.; Munemasa, Y.; Muto, S.; Horikoshi, M.; Nagai, R. J. Biol. Chem.
2005, 280, 12123–12129.
(34) We deviated from the 1:1 stoichiometric ratio used by Slade and co-
workers in their scale-up of the reaction since the 1:1.4 ratio was
reported by them to give a higher product yield. They chose to use
the 1:1 ratio for ease of product isolation in the plant.
(35) See for example: Manhas, M. S.; Ganguly, S. N.; Mukherjee, S.; Jain,
A. K.; Bose, A. K. Tetrahedron Lett. 2006, 47, 2423–2425.
(33) Slade, J.; Parker, D.; Girgis, M.; Wu, R.; Joseph, S.; Repic, O. Org.
Process Res. DeV. 2007, 11, 721–725.
Vol. 12, No. 6, 2008 / Organic Process Research & Development
•
1083

Scheme 9. Alkoxycarbonylation of iodobenzene
an 85% isolated product yield upon workup. With these results
in hand we moved to the Advancer with the objective of
performing the reaction on the 0.2 mol scale at the same
phenylhydrazine concentration (1.25 M) and the same heating
program as used for the small-scale experiments. In our first
attempt, while the initial heating stage to 75 °C was smooth,
upon initiating the second stage, we found that the heating rate
was too fast, and at approximately 120 °C, we observed the
onset of an exotherm. The unit is designed to sense such
occurrences and released the contents of the reaction vessel into
the cooling collection pot, thus quenching the reaction. We
performed the reaction a second time, ramping to 75 °C as
before and then very gradually increased the reaction temper-
ature to 150 °C over the period of 15 min where it was held
for a further 10 min. Using this heating protocol it was possible
to heat the mixture controllably. After flash cooling and workup
an 80% isolated yield of 2-methyltryptamine was obtained. This
shows a rapid approach to the synthesis of this important
compound. It should be noted however that we ran into some
of the same issues with product purification found by the
Novartis team.33 Our product, while pure by 1H NMR and TLC,
was a brown oil. This is indicative of colored impurities from
the ketone starting material that were carried through the
synthesis and purification procedure, or else polymerization
byproducts formed during the course of the reaction.
chromatography. The Advancer has the capability for loading
the reaction vessel with gas and has been used for performing
an oxidative Heck reaction under a pressure of compressed air.41
For the purposes of our current study we wanted to use the
ethoxycarbonylation as a test for the gas-loading feature of the
Advancer unit (Scheme 9). We started by performing the
reaction on the 50 mmol scale using the optimized conditions
from our small-scale protocol. This required using palladium
acetate as catalyst and DBU (diaza(1,3)bicyclo[5.4.0]undecene)
as base, heating the reaction mixture to 125 °C, and holding at
this temperature for 30 min. Under these conditions and using
a catalyst loading of 1 mol % and a CO loading of 200 psi
(13.8 bar) we obtained a quantitative conversion of iodobenzene
to ethyl benzoate. The same was true when we increased the
scale to 75 mmol and at the same time decreased the palladium
loading to 0.5 mol %. We next wanted to take advantage of
the discovery that, on a small scale, the reaction can be run
using near-stoichiometric quantities of carbon monoxide.42
Deciding to perform the reaction on the 100 mmol scale, we
calculated that an initial loading of 250 psi (17 bar) of CO would
equate to 1.1 equiv. Running the reaction on this scale using a
catalyst loading of 0.1 mol % resulted in >95% conversion to
product and, after column chromatography, an 86% isolated
yield. We could not increase the scale of the reaction any further
since at the 0.1 mol level we were approaching the pressure
limits of the apparatus.
Preparation of Ethylbenzoate. We have reported the use
of microwave heating in small-scale carbonylation reactions
using gaseous CO as a reagent.36-38 When transferring this
chemistry from conventional to microwave heating a number
of approaches have been developed to circumvent the problem
of working with gaseous carbon monoxide.39 Larhed and co-
workers have used Mo(CO)6 as a source of carbon monoxide
in conjunction with microwave heating.40 Advantages of using
Mo(CO)6 as a replacement for gaseous CO include the fact that
it is a solid and is easily used on a small scale with commercially
available monomode microwave apparatus with no modification
required. However, Mo(CO)6 is costly and toxic, and its use
results in metal waste, these factors being particular problems
if the reaction is to be scaled up. In a recent approach we have
scaled up our alkoxycarbonylation protocol using a multimode
microwave reactor equipped with eight heavy-walled quartz
reaction vessels.3 This gave us the capability to load up to
eight reaction vessels and run them simultaneously by means
of a reaction carousel. Using the ethoxycarbonylation of
iodobenzene as a test reaction and starting with 0.1 mol of
iodobenzene across the eight reaction vessels, we obtained an
overall conversion of 91% and an isolated yield of 81% after
Two-Step One-Pot Approaches to Synthesis. Taking
advantage of the reagent addition port of the Advancer unit,
we wanted to see if it was possible to perform a series of two
reactions in one-pot (Scheme 10). Our objective was to perform
the first reaction and then, while still at temperature, add further
reagents and effect a second transformation. Building on our
earlier work, we chose as our first case study the Diels-Alder
reaction of isoprene and maleic anhydride followed by conver-
sion of the anhydride product to an imide using benzylamine.
Working on the 0.1 mol scale, the first step of the sequence
(36) Kormos, C. M.; Leadbeater, N. E. Org. Biomol. Chem. 2007, 65–68.
(37) Kormos, C. M.; Leadbeater, N. E. Synlett 2006, 1663–1666.
(38) For general reviews of palladium-mediated carbonylation chemistry
see: (a) Zapf, A.; Beller, M. Chem. Commun. 2005, 431–440. (b)
Skoda-Fo¨ldes, R.; Kolla´r, L. Curr. Org. Chem. 2002, 6, 1097–1119.
(39) For a general review of alternatives to CO gas, see: Morimoto, T.;
Kakiuchi, K. Angew. Chem., Int Ed. 2004, 43, 5580.
(40) For examples see: (a) Lagerlund, O.; Larhed, M. J. Comb. Chem. 2006,
8, 4–6. (b) Wu, X.; Larhed, M. Org. Lett. 2005, 7, 3327–3329. (c)
Wu, X. Y.; Nilsson, P.; Larhed, M. J. J. Org. Chem. 2005, 70, 346–
349. (d) Wannberg, J.; Larhed, M. J. Org. Chem. 2003, 68, 5750–
5753.
(41) Lindh, J.; Enquist, P.-A.; Pilotti, A.; Nilsson, P.; Larhed, M. J. Org.
Chem. 2007, 72, 7957–7962.
(42) Kormos, C. M.; Leadbeater, N. E. Synlett 2007, 2006–2010.
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Scheme 10. Two-step one-pot syntheses
(Diels-Alder reaction) we knew could be performed in 5 min
at 155 °C, and so our main challenge was the introduction of
benzylamine into the reaction vessel after this was complete.
To achieve this, we used a gear pump which we linked to a
back-pressure valve using narrow gauge Teflon tubing. This in
turn was interfaced with the reagent addition port on the
Advancer unit. This then allowed us to introduce the benzyl-
amine (in acetic acid) into the reaction vessel over the period
of 3 min while the microwave was still turned on. This was
followed by passing nitrogen (75 psi) through the lines to flush
any remaining solution into the reaction vessel. The second
reagent was added slowly to avoid rapid changes in temperature
and pressure inside the reaction vessel. After holding the reaction
mixture at 155 °C for a further 5 min, we used flash cooling to
return the mixture to room temperature. After workup the
desired imide product was obtained in overall 76% yield. This
showed us that it was indeed possible to perform two-step one-
pot reactions using the apparatus. We decided to perform
another two-step one-pot sequence and chose the synthesis of
4-methoxy-ꢀ-bromostyrene via a Heck coupling between 4-bro-
moanisole and methyl acrylate followed by a decarboxylative
bromination. Again this builds on our previous work in the
study. We knew that the optimum conditions for the Heck
coupling involved using water as the solvent and heating the
reaction mixture to 170 °C and holding for 15 min. The
decarboxylative bromination of cinnamic acid has been the
subject of previous research.43 N-Bromosuccinimide (NBS) is
used as the brominating agent, and the most common solvent
mixture used in this reaction is acetonitrile-water, 97:3. This
seemed amenable with our conditions for the Heck coupling
step. We performed a series of small-scale reactions and found
that the optimum temperature for the reaction was 100 °C. With
this in mind, we attempted the complete reaction sequence.
Working on the 50 mmol scale, the reaction vessel was loaded
with the reagents, catalyst, and solvent for the Heck reaction
and then sealed. After heating to 170 °C and holding at this
temperature for 15 min, we allowed the mixture to cool
passively to 100 °C before introducing NBS in acetonitrile over
the period of 4 min using the gear pump. After holding at 100
C for a further 5 min, we used the flash cooling to bring the
reaction mixture down to room temperature. After workup an
isolated product yield of 70% was obtained.
Summary
In this article we have shown that a range of synthetic
transformations can be scaled up successfully using the sealed-
vessel multimode microwave unit and have made observations
along the way that are of use to chemists addressing scale-up
of microwave-promoted reactions. In most cases, reactions can
be directly scaled from a small 10-mL capacity sealed glass
tube to the larger 350-mL capacity Teflon reaction vessel
without need for modification of reaction conditions. In the case
of reactions performed using low levels of metal catalysts, a
factor that needs to be taken into consideration is that Teflon is
slightly permeable to reaction mixtures and adsorbs small
quantities of the palladium in solution. Although not critical
when performing the reaction at higher catalyst concentrations,
when we were running the reaction at the lower limit, this
(43) Bazin, M.-A.; El Kihel, L.; Lancelot, J.-C.; Rault, S. Tetrahedron Lett.
2007, 48, 4347–4351.
Vol. 12, No. 6, 2008 / Organic Process Research & Development
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1085

adsorption of small quantities of metal could have the effect of
impeding the desired transformation. While microwave heating
can be used for scaling up many reactions, if the reaction
mixture is highly nonpolar, then an additive may be required
in order to heat the reaction mixture to the desired temperature
efficiently. Such effects are magnified when moving from small
to larger scales. In addition, borosilicate glass tubes contain
small quantities of salt impurities which can lead to indirect
heating of nonpolar reaction mixtures. Teflon, on the other hand,
does not contain such impurities. Thus, the vessel material may
also have had an effect on the heating profile of nonpolar
reaction mixtures. In cases where the reaction is exothermic,
careful microwave heating to the desired temperature is essential
when working on larger scales. It is advisable to use multistage
heating protocols to ensure smooth and controllable heating of
the reaction mixture. It is possible to perform two-step one-pot
reactions using the apparatus, this being achieved by addition
of the second set of reagents into the reaction vessel while still
at elevated temperature and pressure.
was extracted with a further portion (400 mL) of diethyl ether.
The organics were combined, dried over magnesium sulfate,
filtered, and concentrated under reduced pressure to afford
1
4-methoxybiphenyl as a white solid (8.30 g, 90% yield). H
NMR (300 MHz, CDCl3): δ 7.54 (m, 2H), 7.52, 6.97 (AA′XX′
peak, Jaa′ ) Jxx′ ) 1.9, Jax ) 7.8, Jax′ ) 0.6 Hz, 4H), 7.40 (m,
2H), 7.28 (m, 1H), 3.84 (s, 3H).
Suzuki-Miyaura Coupling Reaction between 4-Chloroani-
sole and Phenylboronic Acid. In a 350-mL Teflon vessel were
combined 4-chloroanisole (6.12 mL, 50 mmol), phenylboronic
acid (7.93 g, 65 mmol), sodium carbonate (19.61 g, 185 mmol),
tetrabutylammonium bromide (16.1 g, 50.0 mmol), Pd on
carbon (10% Pd/C, 50% water by wt, 1.0 g, 1.0 mol %), and
water (100 mL). The vessel was placed into the microwave
and the reaction mixture heated to 120 °C using an initial
microwave power of 1200 W. The contents of the vessel were
then held at this temperature for 10 min, agitating using the
mechanical stirrer. After cooling, the contents of the collection
vessel were added into diethyl ether (400 mL) and water (400
mL) and an aqueous-organic extraction performed. The
aqueous phase was extracted with a further portion (400 mL)
of diethyl ether. The organics were combined, dried over
magnesium sulfate, filtered, and concentrated under reduced
pressure to afford a white solid. The solid was purified by silica
gel chromatography (hexane, then ether) to recover 4-chloro-
anisole (600 mg, 4.2 mmol, 8% recovery) and 4-methoxybi-
phenyl (7.70 g, 84% yield).
Experimental Section
(a) General Experimental. All reagents were obtained from
commercial suppliers and used without further purification. 1H
NMR spectra were recorded at 293 K on a 300 or 400 MHz
spectrometer. For reactions involving the use of low concentra-
tions of palladium, an ICP standard was used (Aldrich) and
diluted accordingly.
(b) Equipment Used. Small-scale reactions were performed
in a Biotage Initiator monomode microwave unit. Larger-scale
reactions were performed in a Biotage Advancer multimode
microwave unit. The instrument, shown in Figure 1, consists
of a continuous microwave power delivery system with power
output from 0 to 1200 W. Reactions were performed in a 350-
mL capacity Teflon vessel. The temperature of the contents of
the vessel was monitored using a fiber-optic probe inserted
directly into the reaction mixture by means of a glass ther-
mowell. The contents of the vessel were stirred by means of a
mechanical paddle stirrer. The lid of the reactor also comprises
an inlet for nitrogen/air and three extra available entry ports.
Pressure is monitored using a load cell. Product mixtures were
cooled at the end of a run by using the flash cooling capability,
the contents of the Teflon reaction vessel being ejected into a
stainless steel holding tank. By using this, the temperature of
the mixture is rapidly reduced to the boiling point of the solvent
used.
(c) Experimental Procedures for the Reactions Per-
formed in This Study. Suzuki-Miyaura Coupling Reaction
between 4-Bromoanisole and Phenylboronic Acid. In a 350-
mL Teflon vessel were combined 4-bromoanisole (6.26 mL,
50 mmol), phenylboronic acid (7.93 g, 65 mmol), 1.0 M sodium
hydroxide (100 mL, 100 mmol), 1000 ppm Pd stock solution
(20 µL, 188 µmol, 0.0004 mol %), ethanol (100 mL), and water
(100 mL). The vessel was placed into the microwave and the
reaction mixture heated to 150 °C using an initial microwave
power of 1200 W. The contents of the vessel were then held at
this temperature for 10 min, agitating using the mechanical
stirrer. After cooling, the contents of the collection vessel were
added into diethyl ether (400 mL) and water (400 mL), and an
aqueous-organic extraction was performed. The aqueous phase
Suzuki-Miyaura Coupling Reaction between 2-Bromoben-
zonitrile and p-Tolylboronic Acid. In a 350-mL Teflon vessel
were combined 2-bromobenzonitrile (9.10 g, 50 mmol), p-
tolylboronic acid (7.14 g, 52.5 mmol), sodium carbonate (15.90
g, 150 mmol), 1000 ppm Pd stock solution (500 µL, 0.01 mol
%), ethanol (100 mL), and water (100 mL). The vessel was
placed into the microwave and the reaction mixture heated to
140 °C using an initial microwave power of 1200 W. The
contents of the vessel were then held at this temperature for 10
min, agitating with the mechanical stirrer. After cooling, the
product was purified and isolated, in an identical manner to
that used in the coupling of 4-bromoanisole and phenylboronic
acid, to give 4′-methyl-2-biphenylcarbonitrile as a white solid
(9.484 g, 98% yield).
Preparation of 4′-Methoxycinnamic Acid. A 2 ppm Pd
standard stock solution was prepared by diluting a commercially
available 1000 ppm Pd solution (1.0 mL) to 500 mL with
deionized water. 4-Bromoanisole (12.5 mL, 100 mmol), methyl
acrylate (18 mL, 200 mmol), potassium carbonate (51.2 g, 370
mmol), tetrabutylammonium bromide (32.2 g, 100 mmol), 2
ppm Pd stock solution (100 mL, 1.88 µmol, 0.002 mol %),
and water (100 mL) were combined in a 350-mL Teflon vessel.
The vessel was placed into the microwave and the reaction
mixture heated to 170 °C using a 0.5 °C/sec ramp (this taking
5 min), agitating using the mechanical stirrer. The contents of
the vessel were then held at this temperature for 15 min. After
cooling, the contents of the collection vessel were added into
dilute hydrochloric acid (600 mL of a 2 M solution), whereupon
a white precipitate formed. The mixture was extracted twice
with ethyl acetate (500 mL); the organic fractions were
combined, dried over magnesium sulfate, filtered, and concen-
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trated under reduced pressure. The white solid obtained was
recrystallized from ethanol (70 mL) to yield 4′-methoxycin-
namic acid (16.6 g, 93% yield) as colorless needles. 1H NMR
(300 MHz, DMSO-d6): δ 12.0 (bs, 1H), 7.64, 6.97 (AA′XX′
peak, Jaa′ ) Jxx′ ) 2.5, Jax ) 8.5, Jax′ ) 0.2 Hz, 4H), 7.55 (d,
J ) 15.9 Hz, 1H), 6.38 (d, J ) 15.9 Hz, 1H), 3.80 (s, 3H).
Preparation of Methyl N-Phenyl-3-aminopropanoate. In a
350-mL Teflon vessel were combined aniline (137 mL, 1.50
mol), methyl acrylate (135 mL, 1.50 mol),and acetic acid (8.6
mL, 0.15 mol, 10 mol %). The vessel was placed into the
microwave and the reaction mixture heated to 200 °C using an
initial microwave power of 1200 W. The contents of the vessel
were then held at this temperature for 20 min, agitating using
the mechanical stirrer. After cooling, the product was obtained
and the reaction mixture heated to 155 °C using an initial
microwave power of 1200 W. The contents of the vessel were
then held at this temperature for 5 min, agitating using the
mechanical stirrer. After cooling, the solution was concentrated
under reduced pressure. Hexane (50 mL) was added to initiate
crystallization. The white crystals were filtered and washed with
hexane (50 mL) to afford the Diels-Alder adduct 3a,4,7,7a-
tetrahydro-5-methylisobenzofuran-1,3-dione (15.3 g, 92% yield).
1H NMR (600 MHz, CDCl3): δ 5.62 (m, 1H), 3.39 (ddd, J )
10.0, 7.2, 3.1 Hz, 1H), 3.32 (ddd, J ) 9.8, 7.2, 2.3 Hz, 1H),
2.57 (ddd, J ) 15.8, 6.1, 2.3 Hz, 1H), 2.49 (dd, J ) 15.8, 2.6
Hz, 1H), 2.26 (m, 2H), 1.8 (bs, 3H).
Claisen Rearrangement. In a 350-mL Teflon vessel were
combined allyl phenyl ether (60 mL, 0.437 mol) and tetrabu-
tylammonium bromide (16.12 g, 50 mmol, 11.4 mol %). The
vessel was placed into the microwave and the reaction mixture
heated to 245 °C using an initial microwave power of 1200
W. The contents of the vessel were then held at this temperature
for 30 min, agitating using the mechanical stirrer. After cooling,
NMR spectroscopy showed an 83% conversion to 3-(2-
hydroxyphenyl)-1-propene. 1H NMR (300 MHz, CDCl3): δ 7.1
(m, 2H), 6.9 (m, 2H), 6.0 (m, 1H), 5.2 (dd, 1H), 5.1 (d, 1H),
3.5 (d, 2H).
1
in 76% conversion as determined by NMR spectroscopy. H
NMR (300 MHz, CDCl3): δ 7.18 (t, J ) 7.5 Hz, 2H), 6.70 (t,
J ) 7.3 Hz, 1H), 6.62 (d, J ) 7.7 Hz, 2H), 4.00 (bs, 1H), 3.70
(s, 3H), 3.46 (t, J ) 6.4 Hz, 2H), 2.63 (t, J ) 6.4 Hz, 2H).
Preparation of 3-Acetylcoumarin. In a 350-mL Teflon vessel
were combined salicylaldehyde (32.0 mL, 0.30 mol), ethyl
acetoacetate (38.5 mL, 0.31 mol), and piperidine (2.36 mL, 8
mol %). Ethyl acetate was added to make a total volume of
300 mL. The vessel was placed into the microwave and the
reaction mixture heated to 130 °C using an initial microwave
power of 1200 W. The contents of the vessel were then held at
this temperature for 8 min, agitating using the mechanical stirrer.
After cooling, the product was collected by vacuum filtration
and recrystallized from ethanol to give 3-acetylcoumarin in 71%
yield (40.10 g). 1H NMR (300 MHz, CDCl3): δ 8.51 (s, 1H),
7.67 (m, 2H), 7.40 (m, 2H), 2.73 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 195.4, 159.2, 155.3, 147.4, 134.4, 130.2, 125.0, 124.5,
118.2, 116.7, 30.5.
Synthesis of 2-Methyltryptamine. In a 350-mL Teflon vessel
were combined ethanol (150 mL) and phenylhydrazine (19.78
g, 0.183 mol, 18 mL). To this, 5-chloro-2-pentanone (39.63 g,
37.5 mL of the 85% pure reagent, 0.280 mol) was slowly added
with continuous agitation. The vessel was placed into the
microwave and the reaction mixture heated to 75 °C over a
period of 2 min. The temperature was then slowly raised
manually to 150 °C over the period of 15 min where it was
held for a further 10 min, agitating using the mechanical stirrer.
After cooling, the product mixture was transferred to a round-
bottom flask and concentrated to half the volume. This
concentrate was placed into a separatory funnel, and water (400
mL) added. The solution was washed three times with ethyl
acetate (150 mL) to remove any unreacted chloroketone.
Saturated sodium carbonate (50 mL) was added to the aqueous
solution. This was again washed three times with ethyl acetate
(150 mL). This removed any unreacted phenylhydrazine.
Sodium hydroxide (2 M, 200 mL) was then added to the
aqueous and the solution extracted three times with ethyl acetate
(150 mL). The organic layer was washed with water (150 mL)
and brine solution (150 mL). The organic layers were combined
and dried over MgSO4, and the diethyl ether was removed under
reduced pressure to give 2-methyltryptamine (brown oil, 23.9 g)
Synthesis of Allyl Phenyl Ether. In a 350-mL Teflon vessel
were combined allyl bromide (24.20 g, 200.0 mmol), phenol
(24.40 g, 260.0 mmol, 1.3 equiv), and K2CO3 (30.4 g, 220
mmol, 1.1 equiv). Reagent grade acetone (99%) was added to
make a total volume of 250 mL. The vessel was placed into
the microwave and the reaction mixture heated to 120 °C using
an initial microwave power of 1200 W, agitating using the
mechanical stirrer. The contents of the vessel were then held at
this temperature for 20 min. After this time, the mixture was
allowed to cool passively to 60 °C, at which point the reaction
chamber was opened. The contents were poured into a sepa-
ratory funnel containing cold water. The aqueous phase was
extracted three times with diethyl ether (100 mL). The organic
extracts were combined, washed sequentially with 2.0 M NaOH
(25 mL), H2O (50 mL), and saturated NaCl (50 mL). The
organics were dried over MgSO4, and the diethyl ether was
removed under reduced pressure until a constant weight was
observed to afford allyl phenyl ether (23.86 g, 89%) as an
1
in 76% yield. H NMR (300 MHz, CDCl3) δ 7.96 (bs, 1H),
1.1 (bs, 2H), 7.40 (d, 1H), 7.21 (d, 1H), 7.04 (m, 2H), 2.93 (m,
2H), 2.30 (s, 3H), 1.1 (s, 2H).
Ethoxycarbonylation of Iodobenzene. Palladium acetate (22.2
mg, 0.10 mmol) and ethanol (100 mL) were combined in a
350-mL Teflon vessel and stirred. DBU (15.23 g, 100.0 mmol),
iodobenzene (20.41 g, 100.0 mmol), and ethanol (80 mL) were
combined and then added to the vessel. The vessel was closed
and sealed. The toggle valve was opened, the vessel charged
with 250 psi carbon monoxide (110 mmol), and then the toggle
valve was closed. The mixture was prestirred for 60 s using
the mechanical stirrer and then was heated on a slow ramp of
1
amber-colored oil. H NMR (300 MHz, CDCl3): δ 7.32 (m,
2H, J ) 7.5 Hz), δ 6.95 (m, 3H, J ) 7.0 Hz), δ 6.12 (m, 1H,
J ) 5.7 Hz), δ 5.45 (d, 1H, J ) 15.8 Hz), δ 5.31 (d, 1H, J )
10.5 Hz), δ 4.59 (2H, d, 5.6 Hz).
Diels-Alder Reaction between Isoprene and Maleic Anhy-
dride. In a 350-mL Teflon vessel were combined isoprene (20.0
mL, 200 mmol), maleic anhydride (9.8 g, 100 mmol), and
toluene (100 mL). The vessel was placed into the microwave
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0.5 °C/s to 125 °C and held at this temperature for 30 min.
After cooling, water (150 mL) was added and the mixture
extracted with diethyl ether/petroleum ether (1:1, 3 × 150 mL).
The combined organics were washed with 2 M HCl (2 × 50
mL) and dried over magnesium sulfate, and the solvent was
removed under reduced pressure until a constant weight was
observed. Silica gel (100 g) chromatography using petroleum
ether to elute the remaining iodobenzene followed by ethyl
acetate/petroleum ether (90:10) yielded ethyl benzoate (12.88
g, 86% yield) as a clear colorless oil.
Two-Step One-Pot Synthesis of N-Benzyl 3a,4,7,7a-Tetrahy-
dro-5-methylisobenzopyrrole-1,3-dione. In a 350-mL Teflon
vessel were combined isoprene (20.0 mL, 200 mmol), maleic
anhydride (9.8 g, 100 mmol), and toluene (100 mL). The vessel
was placed into the microwave and the reaction mixture heated
to 155 °C using an initial microwave power of 1200 W. The
contents of the vessel were then held at this temperature for 5
min, agitating using the mechanical stirrer. Upon completion
of this heating stage, benzyl amine (20 mL, 183 mL) dissolved
in glacial acetic acid (80 mL) was added to the reaction vessel
over the period of 3 min using a gear pump while maintaining
the temperature at 155 °C. Nitrogen gas (75 psi) was then used
to flush any remaining reagent solution from the lines into the
reaction flask. The temperature of the reaction mixture was
maintained at 155 °C for an additional 5 min before cooling.
The solution was washed with 0.2 M HCl (200 mL) and then
twice with sat. sodium bicarbonate (200 mL). The organic phase
was dried over MgSO4, filtered, and concentrated under reduced
pressure to afford the product as a white solid (19.5 g, 76%
yield). 1H NMR (600 MHz, CDCl3): δ 7.62 (m, 5H), 5.48 (bs,
1H), 4.62, 4.61 (AB peak, J ) 14.5 Hz, 2H), 3.08 (td, J ) 8.0,
2.4 Hz, 1H), 3.04 (td, J ) 8.0, 2.3 Hz, 1H), 2.55 (ddd, J )
15.4, 7.0, 2.2 Hz, 1H), 2.46 (dd, J ) 15.4, 2.2 Hz, 1H), 2.19
(m, 2H), 1.64 (bs, 3H).
mL) to 500 mL with deionized water. 4-Bromoanisole (12.5
mL, 100 mmol), methyl acrylate (18 mL, 200 mmol), potassium
carbonate (51.2 g, 370 mmol), tetrabutylammonium bromide
(32.2 g, 100 mmol), 2 ppm Pd stock solution (100 mL, 1.88
µmol, 0.002 mol %), and water (100 mL) were combined in a
350-mL Teflon vessel. The vessel was placed into the micro-
wave and the reaction mixture heated to 170 °C using a 0.5
°C/s ramp (this taking 5 min), agitating using the mechanical
stirrer. The contents of the vessel were then held at this
temperature for 15 min. The reaction mixture was allowed to
cool to 100 °C passively, this taking 8 min. A solution of
N-bromosuccinimide (10.7 g, 60 mmol) in acetonitrile (150 mL)
was added to the vessel over 4 min, using a gear pump while
maintaining the mixture at 100 °C. Nitrogen gas (55 psi) was
used to flush the remaining solution from the lines into the
reaction flask. The temperature of the reaction mixture was
maintained at 100 °C for an additional 5 min before cooling.
The contents of the collection vessel were added into dilute
hydrochloric acid (600 mL of a 2 M solution), whereupon a
white precipitate formed. The mixture was extracted twice with
ethyl acetate (500 mL), the organic fractions were combined,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The white solid obtained was recrystallized from
ethanol (70 mL) to yield 4′-methoxy-ꢀ-bromostyrene (16.6 g,
93% yield) as colorless needles. 1H NMR (300 MHz, DMSO-
d6): δ 12.0 (bs, 1H), 7.64, 6.97 (AA′XX′ peak, Jaa′ ) Jxx′
)
2.5, Jax ) 8.5, Jax′ ) 0.2 Hz, 4H), 7.55 (d, J ) 15.9 Hz, 1H),
6.38 (d, J ) 15.9 Hz, 1H), 3.80 (s, 3H).
Acknowledgment
We thank the University of Connecticut Research Founda-
tion and the American Chemical Society Petroleum Research
Foundation (45433-AC1) for funding and Biotage for the loan
of Initiator and Advancer microwave units.
Two-Step One-Pot Synthesis of trans-4′-Methoxy-ꢀ-bro-
mostyrene. A 2 ppm Pd standard stock solution was prepared
by diluting a commercially available 1000 ppm Pd solution (1.0
Received for review May 23, 2008.
OP8001239
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